Dosage forms of n-(1-(2-chloro-3-fluorophenyl)-1-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide and methods of their preparation and use

Abstract

The present disclosure provides solid forms of N-(1-(2-chloro-3-fluorophenyl)-1-hydroxypentan- 2-yl)-7-fluoro-2-oxoindoline-4-carboxamide, pharmaceutical compositions and dosage forms thereof, and methods for their use. Solid forms of N-(1-(2-chloro-3-fluorophenyl)-1- hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide may be useful in the treatment of alpha- 1 -antitrypsin mediated diseases.

Description

DOSAGE FORMS OF N-(l-(2-CHLORO-3-FLUOROPHENYL)-l- HYDROXYPENTAN-2-YL)-7-FLUORO-2-OXOINDOLINE-4-CARBOXAMIDE AND METHODS OF THEIR PREPARATION AND USE1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 535,864 and 63 / 535,854, each filed August 31, 2023; 63 / 593,495 filed October 26, 2023; and 63 / 560,597 and 63 / 560,598, each filed March 1, 2024, the disclosure of each of which is incorporated by reference herein in its entirety.2. FIELD

[0002] The present disclosure relates generally to dosage forms of N-(l-(2-chl oro-3 - fluorophenyl)-! -hydroxypentan-2 -yl)-7-fluoro-2-oxoindoline-4-carboxamide (Compound 1), pharmaceutical compositions and dosage forms thereof, and therapeutic methods of using such compounds and pharmaceutical compositions. Such compounds may be useful in treating diseases, disorders, and conditions associated with alpha- 1 -antitrypsin.3. BACKGROUND

[0003] Alpha- 1 -antitrypsin or ai-antitrypsin (Al AT, sometimes referred to as AAT) is a protease inhibitor belonging to the serpin superfamily. It is a protein made in hepatocytes (as well as in other cells) and secreted into the blood where it functions to limit enzymatic activity of key proteases, in particular, neutrophil elastase. In its absence, the activity of key proteases including neutrophil elastase is unchecked resulting in excessive breakdown of elastin and connective tissues.

[0004] Alpha- 1 -antitrypsin or al -antitrypsin deficiency (A1ATD, also referred to as AATD or AATLD) is an autosomal co-dominant genetic disorder usually caused by mutations in the SERPINA1 gene. Most severe cases of Al ATD are caused by homozygosity for the mutant Z allele (protease inhibitor [Pi]ZZ), in which a single amino acid substitution (E342K) produces a thermodynamically unstable protein. This unstable protein readily forms an unstable intermediate which in turn accepts the reactive center loop (RCL) of other Al AT proteins, forming large intracellular polymers. As a result, the mutated Z form of the A1AT protein(Z-A1AT) is poorly secreted and a substantial reduction in the median plasma concentration of Al AT is observed. The organ most commonly affected by accumulation of Z-A1AT is the liver,where polymer accumulation can lead to liver fibrosis and other forms of liver damage. Liver fibrosis is commonly measured in stages, e.g., as stage 0, 1, 2, 3, or 4. On this scale, stage 0 indicates a healthy liver (i.e., a liver essentially free of fibrosis) whereas stage 4 is the most severe stage and indicates cirrhosis. Stages 1-3 indicate progressively more severe intermediate stages of fibrosis that are not yet cirrhosis. Polymers of Z-Al AT are also found in other tissues including blood, lungs, and skin. Polymers have been shown to be pro-inflammatory and may contribute to pathology in tissues where they are found, particularly the lung and the skin.

[0005] Heterozygous carriage of the Z mutation (PiMZ genotype) acts as a disease modifier in individuals with co-existing liver disease caused by another etiology such as alcohol, viral hepatitis, or MASH (metabolic dysfunction-associated steatohepatitis). PiMZ individuals with MASH have a higher risk of cirrhosis, comparable or greater than risks associated with well- established risk variants in MASH such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene.

[0006] Liver fibrosis, which is one of the hallmark pathophysiologies in the progression of Al AT-associated liver disease, is a variable process. In a 3-year longitudinal study of 98 adults with Al AT-associated liver disease, 37.2% of patients had fibrosis progression of at least one stage, 47.1% of patients had no change in fibrosis stage and 15.1% had an improvement in fibrosis by one stage (biopsy sampling variability may be an alternative explanation for the cases of regression, progression, and stability of fibrosis) (see e.g., Clark et al., Hepatology. 2021 ; 74(S1):25). Findings from other liver conditions have shown that the risk for progression to liver-related events is minimal amongst patients with mild fibrosis at presentation. However, the risk and the speed of progression increase with greater fibrotic burden (see e.g., Bruden et al., Hepatology, 2017;66(l):37-45; Hagstrbm et al., J Hepatol. 2017; 67(6): 1265-73; and Sanyal et al., N Engl J Med. 2021; 385(17): 1559-69). While this may imply that only those with moderate-to-severe fibrosis represent the population of concern, as in other liver diseases, a residual risk for de novo hepatocellular carcinoma may exist even at lower fibrosis stages or in treated disease (e.g., having achieved removal of a primary etiological factor for hepatocellular carcinoma), suggesting that early intervention may be beneficial (see e.g., de Franchis et al., J Hepatol. 2022; 76(4):959-74 and Semmler et al., J Hepatol. 2022;76(4):812-21).

[0007] Further, currently, there are no approved pharmacologic therapies for Al AT- associated liver disease for individuals with either PiZZ or PiMZ genotypes, and diseasemanagement focuses on supportive measures or transplant in the setting of end-stage disease. At present, liver transplantation is the only approved treatment option for patients with advanced chronic liver disease due to Al AT-associated liver disease (typically who have cirrhosis with decompensation events, and / or hepatocellular carcinoma). Like many other rare diseases, Al AT- associated liver disease faces numerous challenges with drug development. There is a lack of precedent for drug development, the natural history of the disease is poorly understood and there is considerable phenotypic diversity. Small populations restrict study design and replication and sensitive, specific, well defined and validated surrogate endpoints and biomarkers are lacking. Indeed, Vertex has initiated and subsequently terminated four different clinical trials of drugs (VX-668, VX-634, VX-864, and VX-81) targeting AATD due to issues relating to suboptimal pharmacokinetics and adverse effects. Centessa likewise initiated a clinical trial with ZF874and subsequently terminated due to liver toxicities.

[0008] Although N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2- oxoindoline-4-carboxamide (herein “Compound 1”) has been identified as potentially therapeutic in treating Al AT-associated liver disease (see, e.g., US20220340525A1), which is incorporated herein by reference in its entirety, pharmaceutical compositions of Compound 1 having satisfactory stability, bioavailability, workability, etc. are not available. Further no studies have been done to determine if Compound 1 has any therapeutic effect in humans. Therefore, a need exists for a process to not only prepare Compound 1 as a pharmaceutically-acceptable composition suitable for human use and manufacturable, particularly on a commercial scale, that is, safe, efficient, economically viable, has long term stability, and has bioavailability upon administration, especially oral administration but also to provide a pharmaceutical composition that can most effectively be utilized to treat and / or prevent the progression of AlAT-associated liver disease in a patient population having little to no treatment options currently available.4. SUMMARY

[0009] In one aspect, the present disclosure provides a pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising: an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1 - B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form, and at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form; optionally wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 10% after one month at 25 °C and 60% relative humidity.

[0010] In one embodiment, the pharmaceutical composition comprises an admixture of Compound 1-A and at least one polymer selected from the group consisting of polyethylene oxide, a polymethacrylate-based copolymer, ethylene-vinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene, ethylene-methyl acrylate (EMA), ethylene n-butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In one embodiment, the polymer is selected from the group consisting of one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or moreesters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In one embodiment, the admixture is a solid dispersion. In one embodiment, Compound 1-A is in a solid, amorphous form. In one embodiment, the active pharmaceutical ingredient comprises one or more of compounds 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable solvate thereof.

[0011] In one embodiment, the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1- D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 5% after three months at 25 °C and 60% relative humidity. In one embodiment, the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1- D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 10% after one month, and preferably after three months, at 40 °C and 75% relative humidity. In one embodiment, the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 2.5% after one month, and preferably after three months, at 25 °C and 60% relative humidity. In one embodiment, the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 5% after one month, and preferably after three months, at 40 °C and 75% relative humidity.

[0012] In one embodiment, the at least one polymer is not a surfactant. In one embodiment, the active pharmaceutical ingredient consists of one or more of Compounds 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form. In one embodiment, the at least one polymer comprises an acidic polymer. In one embodiment, the at least one polymer comprises polyethylene oxide, a polymethacrylate-based copolymer, ethylenevinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene, ethyl ene-methyl acrylate (EMA), ethylene n-butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, acopolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In one embodiment, the at least one polymer comprises one or more esters of HPMC. In one embodiment, the one or more esters of HPMC comprise one or more of acetate ester and succinate ester. In one embodiment, the at least one polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In one embodiment, the ratio of the active pharmaceutical ingredient to the at least one polymer is about 1 : 10 to about 9: 10 (w / w), preferably about 1 :4 to about 3:4 (w / w). In one embodiment, the solid dispersion comprises no more than about 90%, no more than about 80%, no more than about 75%, no more than about 60%, no more than about 50%, no more than about 40%, no more than about 30%, or no more than about 25% by weight of the active pharmaceutical ingredient. In one embodiment, the solid dispersion comprises no less than about 5%, no less than about 10%, no less than about 25%, no less than about 30%, no less than about 40%, no less than about 50%, no less than about 60%, or no less than about 70% by weight of the active pharmaceutical ingredient. In one embodiment, the solid dispersion comprises the active pharmaceutical ingredient, the at least one polymer, and no more than a trace amount of a liquid solvent. In one embodiment, the pharmaceutical composition has no more than a trace amount of a liquid solvent. In one embodiment, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A, based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A, based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form).

[0013] In one embodiment, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), furtherpreferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, the ambient conditions are 25 °C (+ / - 2 °C) and 60% (+ / - 5%) relative humidity.

[0014] In one embodiment, the solid dispersion consists essentially of the at least one active pharmaceutical ingredient and the at least one polymer. In one embodiment, the active pharmaceutical ingredient consists of Compound 1-A. In one embodiment, the active pharmaceutical ingredient consists essentially of Compound 1-A. In one embodiment, the active pharmaceutical ingredient contains no more than 1.5% (e.g., 0% to 1.5%, no more than 0.5%, no more than 0.75%, no more than 1%, or no more than 1.25%) of Compounds 1-B, 1-C, and 1-Dbased on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D). In one embodiment, the at least one polymer consists of one and only one polymer. In one embodiment, the at least one polymer comprises two or more polymers. In one embodiment, the solid dispersion comprises no more than a trace amount of citric acid. In one embodiment, the pharmaceutical composition contains no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-B by weight based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion. In one embodiment, the pharmaceutical composition comprises no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-D by weight based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion. In one embodiment, the pharmaceutical composition comprises no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-C by weight based on the total weight of all of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion. In one embodiment, the pharmaceutical composition comprises no less than 98%, preferably no less than 98.5%, more preferably no less than 99%, even more preferably no less than 99.25%, still more preferably no less than 99.5%, yet more preferably no less than 99.75%, yet more preferably no less than 99.8%, and most preferably no less than 99.9% by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion. In one embodiment, the solid dispersion is in the form of a powder.

[0015] In one embodiment, the solid dispersion is monolithic.

[0016] In one embodiment, the solid dispersion is prepared by a method comprising: contacting the at least one active pharmaceutical ingredient and the at least one polymer with a liquid to form a liquid solution or a dispersion; and lyophilizing or spraying the liquid solution or dispersion to form the solid dispersion.

[0017] In one embodiment, the liquid is a solvent for the at least one active pharmaceutical ingredient, the at least one polymer, or both the at least one active pharmaceutical ingredient and the at least one polymer. In one embodiment, the at least one active pharmaceutical ingredient iscontacted with the at least one polymer with a liquid to form a solution. In one embodiment, the liquid comprises one or more of acetone, ethanol, methanol, and propanol, preferably methanol or acetone, and most preferably acetone. In one embodiment, the method further comprises a step of drying the solid dispersion to remove some of the liquid, preferably all except a trace amount of liquid, and most preferably all of the liquid from the pharmaceutical composition. In one embodiment, the lyophilizing or spraying of the liquid solution or dispersion comprises lyophilizing the liquid solution or dispersion. In one embodiment, the lyophilizing or spraying of the liquid solution or dispersion comprises spray drying the dispersion.

[0018] In one embodiment, the solid dispersion is prepared by a method comprising: contacting the active pharmaceutical ingredient in a molten state together with the at least one polymer in a molten state to form a melt; mixing the melt; and cooling the melt to form a solid dispersion.

[0019] In one embodiment, the mixing of the melt comprises extruding the melt. In one embodiment, the melt is extruded through a single screw extruder. In one embodiment, the melt is extruded through a twin-screw extruder.

[0020] In one embodiment, the pharmaceutical composition further comprises an active pharmaceutical ingredient that is not Compound 1-A, 1-B, 1-C, or 1-D, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition does not include an active pharmaceutical ingredient other than Compound 1-A, 1-B, 1-C, or 1-D in a solid, amorphous form.

[0021] In another aspect, the present disclosure provides a plurality of granules, wherein each granule comprises a pharmaceutical composition according to any embodiment disclosed herein, e.g., in Section 6.3.

[0022] In one embodiment, each granule further comprises one or more intragranular excipients. In one embodiment, the one or more intragranular excipients is selected from the group consisting of one or more filler, one or more disintegrant, one or more glidant, and one or more lubricant. In one embodiment, the one or more intragranular excipients comprises at least one filler, the at least one filler optionally selected from the group consisting of a starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, xylitol, dextrose, crystallinemaltose, a maltodextrin, and any combination thereof, preferably a sugar or sugar alcohol, and more preferably mannitol. In one embodiment, the one or more intragranular excipients comprises at least one filler optionally comprising a cellulose-based polymer, and preferably comprising microcrystalline cellulose, and more preferably comprising silicified microcrystalline cellulose. In one embodiment, the one or more intragranular excipients comprises a disintegrant, preferably croscarmellose, and more preferably croscarmellose sodium. In one embodiment, the one or more intragranular excipients comprises a glidant, preferably talc, silicon dioxide, or aluminum dioxide, and most preferably silicon dioxide. In one embodiment, the one or more intragranular excipients comprises a lubricant, preferably stearic acid or a salt thereof or stearyl fumarate or a salt thereof, more preferably stearyl fumarate or a salt thereof, and even more preferably sodium stearyl fumarate. In one embodiment, each of the granules comprises no less than 20% (w / w), no less than 25% (w / w), no less than 30% (w / w), no less than 40% (w / w), no less than 50% (w / w), no less than 60% (w / w), no less than 70% (w / w), or no less than 75% (w / w) of a pharmaceutical composition as disclosed herein, e.g., in Section 6.3.

[0023] In one embodiment, each of the granules comprises no less than 20% (w / w), no less than 25% (w / w), no less than 30% (w / w), no less than 40% (w / w), no less than 50% (w / w), no less than 60% (w / w), no less than 70% (w / w), or no less than 75% (w / w) of a solid dispersion of: an active pharmaceutical ingredient comprising at least one drug molecule that comprises amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof, and at least one polymer that sustains Compound 1-A or pharmaceutically acceptable salt or solvate thereof in the amorphous form; wherein the mass of Compound 1-A in the solid dispersion does not decrease by more than 5% after four weeks at 40 °C and 75% relative humidity.

[0024] In one embodiment, each of the granules comprises no more than about 75% (w / w), no more than about 70% (w / w), no more than about 60% (w / w), no more than about 50% (w / w), no more than about 40% (w / w), no more than about 30% (w / w), no more than about 25% (w / w), or no more than about 20% (w / w) of a pharmaceutical composition as disclosed herein, e.g., in Section 6.3.

[0025] In one embodiment, each of the granules comprises no more than about 75% (w / w), no more than about 70% (w / w), no more than about 60% (w / w), no more than about 50% (w / w),no more than about 40% (w / w), no more than about 30% (w / w), no more than about 25% (w / w), or no more than about 20% (w / w) of a solid dispersion of: an active pharmaceutical ingredient comprising at least one drug molecule that comprises amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof, and at least one polymer that sustains Compound 1-A or pharmaceutically acceptable salt or solvate thereof in amorphous form; wherein the mass of Compound 1-A in the solid dispersion does not decrease by more than 5% after four weeks at 40 °C and 75% relative humidity.

[0026] In one embodiment, each of the granules comprises about 30% (w / w) to about 70% (w / w) of the solid dispersion, preferably about 40% (w / w) to about 60% (w / w) of the solid dispersion. In one embodiment, the pharmaceutical dosage form comprises Compound 1-A, a composition as disclosed herein, e.g., in Section 6.2, a pharmaceutical composition as disclosed herein, e.g., in Section 6.3 or a plurality of granules as disclosed herein, e.g., in Section 6.3.2. In one embodiment, the pharmaceutical dosage form further comprises a second plurality of granules, wherein the second plurality of granules do not comprise Compound 1-A, 1-B, 1-C, and 1-D.

[0027] In one embodiment, the pharmaceutical dosage form is a capsule, a tablet, or a sachet, preferably a capsule or a tablet, and most preferably a tablet. In one embodiment, the tablet comprises a plurality of granules as disclosed herein, e.g., in Section 6.3.2, and one or more extra-granular excipients.

[0028] In one embodiment, the one or more extra-granular excipients comprises at least one compression excipient, disintegrant, glidant, lubricant, or fdler. In one embodiment, the one or more extra-granular excipients comprises at least one compression excipient. In one embodiment, the one or more extra-granular excipients comprises a sugar or sugar alcohol, preferably mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, or a mixture of one or more of the foregoing, preferably one or more of mannitol or silicified microcrystalline cellulose, and more preferably mannitol and silicified microcrystalline cellulose. In one embodiment, the one or more extra-granular excipients comprise one or more glidant, one or more lubricant, one or more disintegrant, or any combination thereof. In one embodiment, the one or more extra-granular excipients comprises a disintegrant, preferably croscarmellose sodium. In one embodiment, the one or more extra-granular excipients comprises a glidant,preferably talc, silicon dioxide, or aluminum dioxide. In one embodiment, the one or more extra- granular excipients comprises a lubricant, preferably one or more of stearic acid or a salt thereof and sodium stearyl fumarate, and more preferably sodium stearyl fumarate. In one embodiment, the pharmaceutical dosage form is in the form of a tablet. In one embodiment, the tablet comprises a coating. In one embodiment, the coating comprises a pigment.

[0029] In one embodiment, the dosage form comprises no less than about 5 mg, no less than about 10 mg, no less than about 20 mg, no less than about 25 mg, no less than about 30 mg, no less than about 40 mg, or no less than about 50 mg of Compound 1-A. In one embodiment, the dosage form comprises no more than about 250 mg, no more than about 200 mg, no more than about 175 mg, no more than about 150 mg, no more than about 125 mg, no more than about 100 mg, no more than about 75 mg, no more than about 60 mg, or no more than about 50 mg of Compound 1-A. In one embodiment, the dosage form comprises about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A. In one embodiment, the dosage form comprises about 23 mg to about 27 mg, preferably about 25 mg of Compound 1-A. In one embodiment, the dosage form comprises about 25 mg of Compound 1-A. In one embodiment, the dosage form comprises about 123 mg to about 127 mg, preferably about 125 mg of Compound 1-A. In one embodiment, the dosage form comprises about 125 mg of Compound 1-A.

[0030] In one embodiment, the plurality of granules comprises a solid dispersion that is about 40% (w / w) to about 60% (w / w), preferably about 48% (w / w) to about 52% (w / w), more preferably about 50% (w / w) Compound 1-A, and 40-60% (w / w), preferably 48-52% (w / w), more preferably 50% (w / w) hydroxypropyl methylcellulose acetate succinate.

[0031] In one embodiment, the pharmaceutical dosage form comprises: a plurality of granules, the plurality of granules consisting essentially of: 50 mg of a solid dispersion, the solid dispersion comprising: 23-27 mg, preferably 25 mg, of Compound 1-A; and 23-27 mg, preferably 25 mg, of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising:I-4 mg croscarmellose sodium; and 0.8-1.75 mg sodium stearyl fumarate.

[0032] In one embodiment, the pharmaceutical dosage form comprises: a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:123-127 mg, preferably 125 mg, of Compound 1-A; and123-127 mg, preferably 125 mg, of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising:I I-15 mg croscarmellose sodium; and 5-8 mg sodium stearyl fumarate.

[0033] In one embodiment, the pharmaceutical dosage form comprises about 25 mg of Compound 1-A. In one embodiment, the pharmaceutical dosage form comprises about 125 mg of Compound 1-A.

[0034] In one embodiment, the pharmaceutical dosage form comprises: a plurality of granules, the plurality of granules consisting essentially of: about 50 mg of a solid dispersion, the solid dispersion comprising: about 25 mg of Compound 1-A; and about 25 mg of hydroxypropyl methylcellulose acetate succinate;about 47.5 mg silicified microcrystalline cellulose; about 24 mg mannitol; about 5.5 mg croscarmellose sodium; about 1.5 mg silicon dioxide; and about 1.5 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising: about 2.5 mg croscarmellose sodium; and about 1.5 mg sodium stearyl fumarate.

[0035] In one embodiment, the pharmaceutical dosage form comprises: a plurality of granules, the plurality of granules consisting essentially of: 250 mg of a solid dispersion, the solid dispersion comprising: about 125 mg of Compound 1-A; and about 125 mg of hydroxypropyl methylcellulose acetate succinate; about 238 mg silicified microcrystalline cellulose; about 119 mg mannitol; about 26.5 mg croscarmellose sodium; about 6.5 mg silicon dioxide; and about 6.5 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising: about 13.5 mg croscarmellose sodium; and about 6.5 mg sodium stearyl fumarate.

[0036] In one embodiment, Compound 1-A is present as an amorphous solid.

[0037] In one embodiment, the pharmaceutical dosage form comprises no more than about10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A, based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the pharmaceutical dosage form (the remainder of Compound 1-A being in amorphous form).

[0038] In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty -four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form).

[0039] In one embodiment, the pharmaceutical dosage form exhibits a release profile, when measured under sink conditions, as follows: (i) at least about 50% of Compound 1-A is released from the pharmaceutical dosage form by about 5 minutes; (ii) at least about 80% of Compound 1-A is released from the pharmaceutical dosage form by about 15 minutes; (iii) at least about 95% of Compound 1-A is released from the pharmaceutical dosage form by about 20 minutes; and (iv) at least about 98% of Compound 1-A is released from the pharmaceutical dosage form by about 30 minutes. In one embodiment, the release profile is measured at a temperature of about 37.0 °C at a stirring speed of about 75 rpm. In one embodiment, the release profile is measured in a medium comprising 10 mM sodium phosphate buffer at a pH of about 6.80.

[0040] In one embodiment, a solution resulting from dissolution of the pharmaceutical dosage form comprises no less than 98%, preferably no less than 98.5%, more preferably no less than 99%, even more preferably no less than 99.25%, still more preferably no less than 99.5%, yet more preferably no less than 99.75%, even more preferably no less than 99.8%, and most preferably no less than 99.9% by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solution.

[0041] In another aspect, the present disclosure provides an admixture comprising: solid amorphous Compound 1-A or a pharmaceutically acceptable salt or solvate thereof, preferably amorphous Compound 1-A or a solvate thereof, and more preferably amorphous Compound 1-A, and a means for sustaining the amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof in an amorphous form.

[0042] In one embodiment, the means comprises a solid dispersion of amorphous Compound 1- A or a pharmaceutically acceptable salt or solvate thereof, preferably amorphous Compound 1-Aor a solvate thereof, and more preferably amorphous Compound 1-A and an excipient that sustains the amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof in an amorphous form. In one embodiment, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.05% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1- A, based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no morethan about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compound 1-A in the solid dispersion (the remainder of Compound 1-A being in amorphous form). In one embodiment, the ambient conditions are 25 °C (+ / - 2 °C) and 60% (+ / - 5%) relative humidity.

[0043] In one embodiment, the excipient comprises a polymer. In one embodiment, the means comprises a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3.

[0044] In another aspect, the present disclosure provides a tablet or capsule comprising an admixture according to any embodiment herein, e.g., in Section 6.3.1.

[0045] In another aspect, the present disclosure provides a method of treating a subject for a disorder related to A1AT, the method comprising administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, an admixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject. In one embodiment, the disorder relates to the accumulation of A1AT in the liver. In one embodiment, the disorder relates to the polymerization of Al AT. In one embodiment, the disorder is a liver disorder. In one embodiment, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject is a dog, rat, or mouse. In one embodiment, the subject is human. In one embodiment, themethod comprises administering a tablet to the subject. In one embodiment, the method comprises administering the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, or tablet once per day or twice per day. In one embodiment, the method comprises administering a tablet. In one embodiment, the method comprises administering the compound, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule to provide a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg, and preferably about 25 mg or about 125 mg, of Compound 1-A to the subject. In one embodiment, the method comprises administering the compound, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule to provide a dose of about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A to the subject.

[0046] In another aspect, the present disclosure provides a method of making a solid dispersion, the method comprising: contacting an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form in a molten state and at least one polymer in a molten state to form a melt;mixing the melt; and cooling the melt to form a solid dispersion, wherein the polymer comprises at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

[0047] In one embodiment, the mixing of the melt comprises extruding the melt. In one embodiment, the melt is extruded through a single screw extruder. In one embodiment, the melt is extruded through a twin-screw extruder.

[0048] In another aspect, the present disclosure provides a method of making a solid dispersion, the method comprising: contacting an active pharmaceutical ingredient comprising one or more ofCompound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form and at least one polymer with a liquid to form a liquid solution or dispersion; and lyophilizing or spraying the liquid solution or dispersion to form the solid dispersion, wherein the polymer comprises at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

[0049] In one embodiment, the liquid is a solvent for the at least one active pharmaceutical ingredient, the at least one polymer, or both the at least one active pharmaceutical ingredient and the at least one polymer. In one embodiment, the at least one active pharmaceutical ingredient is contacted with the at least one polymer with a liquid to form a solution. In one embodiment, the liquid comprises one or more of acetone, ethanol, methanol, and propanol, preferably methanol or acetone, and most preferably acetone. In one embodiment, the method further comprises a step of drying the solid dispersion to remove at least some, preferably all but a trace amount, of the liquid. In one embodiment, the lyophilizing or spraying of the liquid solution or dispersion comprises lyophilizing the liquid solution or dispersion. In one embodiment, the lyophilizing or spraying of the liquid solution or dispersion comprises spray drying the dispersion. In one embodiment, the at least one polymer is not a surfactant. In one embodiment, the at least one polymer comprises one or more of HPMC, a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC; more preferably one or more esters of HPMC; still more preferably wherein the esters of HPMC comprise one or more of acetate ester and succinate ester; and most preferably HPMCAS. In one embodiment, the at least one polymer comprises an acidic polymer.

[0050] In another aspect the present disclosure provides a method of increasing the level of A1AT in the plasma of a subject, the method comprising administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, an admixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject, wherein the level of Al AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering. In one embodiment, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject is a human. In one embodiment, the level of Al AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma isincreased to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A. In one embodiment, the concentration of polymerized Al AT in the liver of the subject is decreased after the administering. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to the subject at least once per day. In one embodiment, the increased level of Al AT in the plasma is reached after 28 or fewer days of administering. In one embodiment, the increased level of Al AT in the plasma is reached after 14 or fewer days of administering. In one embodiment, the increased level of Al AT in the plasma is reached after 7 or fewer days of administering. In one embodiment, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule contains about 5 mg to about 400 mg, preferably about 10 mg to about 250 mg, and more preferably about 20 mg to about 150 mg of Compound 1-A. In one embodiment, the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 mg to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 25 mg of Compound 1-A per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 100 mg ofCompound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day. In one embodiment, Compound 1-A orpharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0051] In another aspect, the present disclosure provides a method of increasing the level of A1AT in the plasma of a subject comprising administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, an admixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject, wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering. In one embodiment, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has metabolic dysfunction-associated steatohepatitis (MASH). In one embodiment, the subject is a human. In one embodiment, the level of A1AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 110 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 120 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased by about 60 mg / dL or more. In one embodiment, the level of A1AT in the plasma is increased by about 65 mg / dL or more. In one embodiment, the concentration of polymerized A1AT in the liver of the subject is decreased after the administering. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to the subject at least once per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to the subject at least twice per day. In one embodiment, the increased level of A1AT in the plasma is reached after 28 or fewer days ofadministering. In one embodiment, the increased level of A1AT in the plasma is reached after 14 or fewer days of administering. In one embodiment, the increased level of Al AT in the plasma is reached after 7 or fewer days of administering. In one embodiment, about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 mg to about 250 mg of Compound 1-A is administered to the subject per day, and even more preferably about 25 mg to about 125 mg is administered to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 50 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 75 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 100 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 125 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 150 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 250 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 500 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 625 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality ofgranules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 750 mg of Compound 1-A to the subject per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day.

[0052] In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1 -A e.g, not a salt or solvate).

[0053] In another aspect, the present disclosure provides a means of increasing the level of A1AT in the plasma of a subject to about 40 mg / dL or greater comprising a step of administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, an admixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 60 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 70 mg / dL or greater. In one embodiment, the means is a means of increasing the level ofAl AT in the plasma to about 80 mg / dL or greater. In one embodiment, the means is a means of increasing the level of A1AT in the plasma to about 90 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 100 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 110 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 120 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by about 60 mg / dL or more. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by about 65 mg / dL or more. In one embodiment, the step comprises administering the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule once per day to the subject. In one embodiment, the step comprises administrating the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule twice per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 25 mg to about 500 mg of Compound 1-A to the subject per day.

[0054] In another aspect, the present disclosure provides a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, an admixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject to cause improvement in the fibrosis. In one embodiment, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has metabolic dysfunction-associated steatohepatitis (MASH). In one embodiment, the subject has stage 1, stage 2, stage 3, or stage 4 fibrosis prior to the administration. In one embodiment, the improvement in the fibrosis is a decrease in the stage of fibrosis by at least one stage. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 104 weeks or less. In one embodiment, the improvement in thefibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 92 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 70 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 64 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 52 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 40 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 26 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 25 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 100 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition,pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0055] In another aspect, the present disclosure provides a means of treating fibrosis in a subject suffering from Al AT-associated liver disease, comprising a step of administering Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment herein, e.g., in Section 6.3, a plurality of granules according to any embodiment herein, e.g., in Section 6.3.2, a pharmaceutical dosage form according to any embodiment herein, e.g., in Section 6.3.3, anadmixture according to any embodiment herein, e.g., in Section 6.3.1, or a tablet or capsule according to any embodiment herein, e.g., in Section 6.3.3, to the subject. In one embodiment, the subject has a PiZ* genotype. In one embodiment, the subject has PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has metabolic dysfunction-associated steatohepatitis (MASH). In one embodiment, the means is a means of decreasing the stage of the fibrosis in the subject by at least one stage. In one embodiment, the step comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule once per day to the subject. In one embodiment, the step comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule twice per day to the subject.5. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG. 1 provides a schematic of the membrane flux text described in the Examples.

[0057] FIG. 2 provides dissolution profile of 33 / 67 Compound 1-A / HPMCAS-M SDD samples after 3 months storage.

[0058] FIG. 3 provides dissolution profiles of 50 / 50 Compound 1-A / HPMCAS-M samples after 3 months storage.

[0059] FIG. 4 provides dissolution profiles of 33 / 67 Compound 1-A / HPMC E3 SDD samples after 3 months storage.

[0060] FIG. 5 provides data related to change in total plasma human A1AT in transgenic female mice hemizygous for expression of human mutant Z-A1AT (Tg(SERPINAl*E342K)#Slcw mice, also known as PiZ mice, treated with Compound 1-A for 30 days.

[0061] FIG. 6 provides data related to change in plasma A1AT polymers in PiZ mice treated with Compound 1-A for 30 days.

[0062] FIG. 7 provides data related to percent change in liver A1AT polymers in PiZ mice treated with Compound 1-A for 30 days.

[0063] FIG. 8 provides data related to plasma Al AT levels in beagle dogs treated with Compound 1-A.

[0064] FIG. 9 provides data related to calreticulin levels in PiZ mice after treatment with Compound 1-A.

[0065] FIG. 10 provides data related to prolyl 4-hydroxylase beta polypeptide levels in PiZ mice after treatment with Compound 1-A.

[0066] FIG. 11 provides data related to heat shock protein 5 levels in PiZ mice after treatment with Compound 1-A.

[0067] FIG. 12 provides data related to Factor VII coagulation factor levels in PiZ mice after treatment with Compound 1-A.

[0068] FIG. 13 provides data related to C5 complement levels in PiZ mice after treatment with Compound 1-A.

[0069] FIG. 14 provides data related to thyroxine-binding globulin levels in PiZ mice after treatment with Compound 1-A.

[0070] FIG. 15 provides mean plasma concentration of total Compound 1-A in healthy volunteers after orally administering 25, 50, 125, 250, and 500 mg Compound 1-A in the fasted state and 25 mg in the fed state.

[0071] FIG. 16 provides mean plasma concentration of non-AlAT-bound Compound 1-A in healthy volunteers after orally administering 25, 50, 125, 250, and 500 mg Compound 1-A in the fasted state and 25 mg in the fed state.6. DETAILED DESCRIPTION6.1 Definitions

[0072] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0073] In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

[0074] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.

[0075] The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant,child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, rats, mice, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys. In certain embodiments, the subject is a human. As used herein and unless otherwise specified, the terms “treatment” and “treating” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, disorder, or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In one embodiment, “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). In some particular embodiments, “treatment” can mean reducing rate at which Al AT polymers accumulate in the liver, or preferably halting the accumulation of A1AT polymers in the liver, or more preferably reducing the amount of A1AT polymers in the liver (“amount” in this context is usually measured as a concentration but might also refer to weight.) In some particular embodiments, “treatment” can mean increasing the secretion of A1AT from the liver, usually as measured by an increase in the concentration of unpolymerized A1AT outside of the liver, particularly in the plasma.

[0076] In some particular embodiments, “treatment” can mean slowing the progression, halting progression (e.g., stabilization), or reversing liver fibrosis.

[0077] An “effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect. In some particular embodiments, “effective amount” can mean an amount effective for reducing rate at which A1AT polymers accumulate in the liver, or preferably effective for halting the accumulation of Al AT polymers in the liver, or more preferably effective for reducing the amount of Al AT polymers in the liver (“amount” in this context is usually measured as a concentration but might also refer to weight.) In some particular embodiments, “effective amount” can mean an amounteffective for increasing the secretion of Al AT from the liver, usually as measured by an increase in the concentration of Al AT outside of the liver, particularly in the plasma.

[0078] As used herein, the terms “sufficient amount” and “effective amount” are used interchangeably.

[0079] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0080] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0081] As used herein and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyljmorpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, dicyclohexylammonium, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, Na, Ca, K, Mg, Zn, or othermetal salts. Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate. Pharmaceutically acceptable salts, such as those described herein, can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0082] As used herein, “trace amount” means an amount of a component, for example, a liquid solvent or citric acid, that either has no meaningful effect on the pharmaceutically relevant properties of the dispersion (e.g., flux, solubility, bioavailability) or that, in the face of sound scientific or medical judgement, would be considered an acceptable level of impurity for the material described, such as a liquid solvent or citric acid, or both.

[0083] As used herein, “admixture” means more than one component mixed together to form a combination. For purposes of the present invention, “admixture” means the mixture of two or more compounds at any time prior or subsequent to, or concomitant with, administration. In particular embodiments, admixtures are homogeneous mixtures of their components; however, this is not required unless otherwise specified because heterogeneous mixtures may also provide beneficial results in some cases.

[0084] As used herein, unless otherwise specified “fibrosis” refers to liver fibrosis (and not to other forms of fibrosis, such as myocardial fibrosis), and is measured by an art-recognized scale, e.g., the METAVIR scoring system, Knodell score / Histological Activity Index (HAI), or the Batts and Ludwig system. In a typical scoring system, fibrosis severity is indicated by a stage, usually stage 0 to stage 4, wherein stage 0 indicates a healthy liver (z.e., a liver essentially free of fibrosis), stage 4 indicates cirrhosis of the liver (the most severe form of fibrosis), and stages 1-3 indicate progressively more severe intermediate forms of fibrosis that have not progressed to cirrhosis (see, e.g., Chowdhury, A.B., Mehta, K.J., “Liver biopsy for assessment of chronic liver diseases: a synopsis,” Clin Exp Med 23, 273-285 (2023).

[0085] As used herein, “sink conditions” refer to conditions used in pharmaceutical dissolution testing to describe a process that ensures the dissolution rate of a drug is not affected by the amount of drug already dissolved in the media. Sink conditions are typically achieved by using a volume of solvent that is 3-10 times greater than the volume of a saturated solution of the drug being tested.

[0086] As used herein, a PiZ* genotype refers to a genotype, wherein the individual has at least one PiZ allele. Examples of genotypes within the PiZ* genotype are the PiZZ genotype, wherein the subject has two PiZ alleles, and the PiMZ genotype, wherein the individual has one PiZ allele and one normal PiM allele.

[0087] As used herein, AlAT-associated liver disease (or AlATD-associated liver disease) refers to a disease or condition (e. , in a stage not yet severe enough to receive a disease diagnosis) that is caused by or characterized by a deficiency in alpha- 1 antitrypsin. Such disease or condition may be characterized by the presence of liver fibrosis which can, over time, lead to inflammation and cell injury of the liver. Non-limiting examples of AlAT-associated liver diseases include hepatitis, hepatic fibrosis, hepatic cirrhosis, cholestasis, metabolic dysfunction- associated steatohepatitis, liver cancer, or liver disease caused in part by or exacerbated by alcohol use.

[0088] The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.6.2 Compositions

[0089] Provided herein are compositions comprising N-(l-(2-chloro-3-fluorophenyl)-l- hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, shown as Compound (1) below:

[0090] In one embodiment, the N-[(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7-fluoro- 2,3-dihydro-2-oxo-lH-indole-4-caboxamide (Compound 1) is in a solid, amorphous form.

[0091] As used herein, reference to “N-[(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-caboxamide” or “Compound 1”) refers to any stereoisomer or mix of stereoisomers of N-[(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-caboxamide or any mix of stereoisomers of N-[(2-chloro- 3-fluorophenyl)hydroxymethyl]butyl]-7-fluoror-2,3-dihydro-2-oxo-lH-indole-4-caboxamide, which includes:Compound 1-A: N-[(lR)-l-[(S)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide;Compound 1-B: N-[(lR)-l-[(R)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide;Compound 1-C: N-[(lS)-l-[(S)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide; andCompound 1-D: N-[(lS)-l-[(R)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide. Each aforementioned stereoisomer is shown below:

[0092] Thus, references to Compound 1 or N-(l-(2-chloro-3-fluorophenyl)-l- hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide that do not specify any particular stereoisomer or stereoisomers (either by use of a name or of a compound number such as Compound 1-A, 1-B, etc.) can be a single stereoisomer or a mixture of two or more stereoisomers. For example, such a mixture can be a racemic mixture of two enantiomers, a mixture that is stereochemically enriched in one or more of Compounds 1-A, 1-B, 1-C, or 1-D, or even a single stereoisomer.

[0093] In some embodiments, the compositions disclosed herein comprise one or more of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0094] In a certain embodiment, the composition comprises Compound 1-A:(1-A)

[0095] In one embodiment, the composition comprises no more than about 2% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weightof Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition comprises no more than about 1.5% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition comprises no more than about 1% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1- A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition comprises no more than about 0.5% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition comprises no more than about 0.25% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition comprises no more than about 0.1% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In one embodiment, the composition consists of Compound 1-A.

[0096] In one embodiment, the active pharmaceutical ingredient consists essentially of Compound 1 -A. In one embodiment, the active pharmaceutical ingredient contains 1.5% (e.g, 0% to 1.5%, no more than 0.5%, no more than 0.75%, no more than 1%, or no more than 1.25%) of Compounds 1-B, 1-C, and 1-D based on the total weight of Compounds 1-A, 1-B, 1-C, and 1- D).

[0097] In another embodiment, the composition comprises no less than about 98% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 98.5% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 99% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 99.25% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 99.5% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 99.75% by weight of Compound 1-A based on the combined weight of Compound 1- A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition. In another embodiment, the composition comprises no less than about 99.9% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition.6.3 Pharmaceutical Compositions

[0098] Provided herein are pharmaceutical compositions comprising, as an active pharmaceutical ingredient, N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2- oxoindoline-4-carboxamide (Compound 1) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0099] Such pharmaceutical compositions may be prepared from or comprise any composition disclosed herein, such as disclosed in Section 6.2.

[0100] In one embodiment, the N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7- fluoro-2-oxoindoline-4-carboxamide (Compound 1) is in a solid, amorphous form.

[0101] In some embodiments, the pharmaceutical compositions disclosed herein comprise, as an active pharmaceutical ingredient, one or more of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0102] In one embodiment, the pharmaceutical composition comprises Compound 1 (z.t?., one or more of Compounds 1-A, 1-B, 1-C, and 1-D) as the only active pharmaceutical ingredient in the pharmaceutical composition. In yet other embodiments, the pharmaceutical composition further comprises an active pharmaceutical ingredient that is not a stereoisomer of Compound 1 (e. ., second therapeutic agent).

[0103] In one embodiment, the pharmaceutical composition comprises no more than about 2% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises nomore than about 1.5% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises no more than about 1% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1- B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises no more than about 0.5% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises no more than about 0.25% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises no more than about 0.1% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In one embodiment, Compound 1-A is the only active pharmaceutical ingredient in the pharmaceutical composition.

[0104] In another embodiment, the pharmaceutical composition comprises no less than about 98% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises no less than about 98.5% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises no less than about 99% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises no less than about 99.25% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises no less than about 99.5% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceuticalcomposition. In another embodiment, the pharmaceutical composition comprises no less than about 99.75% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises no less than about 99.9% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the pharmaceutical composition.

[0105] In one embodiment, a pharmaceutical composition comprises Compound 1-A in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg. In one embodiment, a pharmaceutical composition comprises about 25 mg or about 125 mg of Compound 1-A. In one embodiment, a pharmaceutical composition comprises about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A.

[0106] In one embodiment, a pharmaceutical composition comprises Compound 1-A in an amount of about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1 -A.

[0107] In one embodiment, a pharmaceutical composition comprises a plurality of granules, wherein each granule comprises Compound 1 or a pharmaceutically acceptable salt or solvate thereof, particularly Compound 1 or a pharmaceutically acceptable solvate thereof and more particularly Compound 1, dispersed in at least one polymer (“solid dispersion”). In some embodiments, each granule in the plurality of granules further comprises one or more intragranular excipients. In some embodiments, a pharmaceutical composition comprises (a) a plurality of granules, wherein each granule comprises Compound 1 dispersed with a polymer in a solid dispersion; and (b) one or more extra-granular excipients. Further characteristics of the solid dispersion according to any of the foregoing embodiments is discussed in further detail in Section 6.3.1. Further characteristics of the granules according to any of the foregoing embodiments, including intragranular excipients, is discussed in further detail in Section 6.3.2. More specific description of the pharmaceutical composition according to any of the foregoingembodiments, including extra-granular excipients and exemplary formulations, is discussed in further detail in Section 6.3.3.6.3.1 Solid Dispersions

[0108] As described herein, Compound 1, and particularly Compound 1-A is highly bioavailable when dissolved in liquid vehicles made up of propylene glycol, caprylocaproyl macrogol-8 glycerides (available under the trade designation LABRASOL®), and the like. While such vehicles may be acceptable for experimental administration to animals, they are not necessarily acceptable for clinical administration to humans at the volumes necessary to provide adequate doses to humans. Thus, a problem is how to make a solid dosage form containing Compound 1, particularly Compound 1-A, which provides good bioavailability of Compound 1, and particularly of Compound 1-A.

[0109] As further described herein, it has been found as a solid, Compound 1, and more particularly Compound 1-A, tends to be highly crystalline, for example, 80, 85, 90, 95, or 100% crystalline, as measured according to a technique known to one of ordinary skill in the art. As disclosed herein, it has been found that solid crystalline Compound 1-A has a poor dissolution profde in relevant biological liquids, such as water at biological pH and simulated intestinal fluid (SIF). Similarly, Compound 1, and more particularly Compound 1-A, has poor flux through gastric epithelium, such as the gastric epithelium of a mammal and particularly human gastric epithelium. That is to say, it has been found that Compound 1, and more particularly Compound 1-A, is poorly dissolved and has poor flux (e.g., through the gastric epithelium). Among other variables, one of ordinary skill in the art will understand that poor flux makes it difficult to achieve bioavailability of a therapeutically effective amount of Compound 1, and more particularly Compound 1-A, in a subject following administration of a solid dosage form, particularly a solid oral dosage form, such as a sachet, tablet, or capsule.

[0110] Thus, one problem that arises in developing pharmaceutical formulations of Compound 1-A that have sufficient bioavailability is how to improve the dissolution and bioavailability of solid Compound 1 and particularly Compound 1-A. Another problem to be solved is how to improve the flux (e.g., through the gastric epithelium) of Compound 1 and particularly Compound 1-A, particularly when present in a solid dosage form. Yet another problem is how to improve the flux (e.g, through the gastric epithelium) of Compound 1 and particularly Compound 1-A when present in a solid dosage form. Still another problem can bearticulated as how to make a solid dosage form, and more particularly a solid oral dosage form, containing Compound 1, and particularly Compound 1-A, wherein Compound 1, and more particularly Compound 1-A, have sufficient bioavailability that the solid dosage form or solid oral dosage form can provide a therapeutically effective amount of Compound 1, more particularly Compound 1-A, when administered to a subject.

[0111] Successful solutions to this problem are surprising. As described in detail herein, and particularly with reference to the Examples section, Compound 1, and more particularly Compound 1-A, were tested for compatibility with common pharmaceutical surfactant and solubilizer excipients. However, those surfactants and solubilizer excipients were not compatible with Compound 1, and more particularly Compound 1-A, because they caused an unacceptable degree of degradation. Although Compound 1 was not incompatible with sodium docusate, sodium docusate is an active pharmaceutical compound that is used for treating constipation, and it is not considered to be an appropriate excipient to achieve the required solubility.

[0112] As further described herein, and with particular reference to the Examples section, nanomilling of Compound 1, and more particularly Compound 1-A, in the presence of a polymeric excipient (e.g., as the milling matrix) provides smaller particles of the compound. Smaller particles are typically more readily dissolved, and the solubility of some such nanomilled material was improved. However, nanomilling did not improve the flux.

[0113] As additionally described herein, Compound 1, and particularly Compound 1-A, was prepared as an amorphous solid. While the amorphous solid was more readily dissolved than the crystalline form, and also showed improved flux, it reverted to the low-solubility crystalline form relatively quickly. A solution to the problem, as more fully described herein, is the use of pharmaceutical compositions specially designed to provide a means for sustaining the amorphous Compound 1, and particularly Compound 1-A, or a pharmaceutically salt or solvate thereof, in the amorphous form. In one embodiment, the means for sustaining the amorphous nature of Compound 1, and particularly Compound 1-A, or a pharmaceutically acceptable salt of solvate thereof, is by forming a solid dispersion of Compound 1, and particularly Compound 1- A, or a pharmaceutically acceptable salt or solvate thereof, with at least one polymer. More particularly, provided herein is a pharmaceutical composition that comprises a solid dispersion of an active pharmaceutical ingredient comprising one or more stereoisomers of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form and at least onepolymer that sustains the one or more stereoisomers of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in amorphous form.

[0114] In one embodiment, a pharmaceutical composition comprises an admixture of Compound 1-A and at least one polymer. In one embodiment, the at least one polymer comprises polyethylene oxide, a polymethacrylate-based copolymer, ethylene-vinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene, ethylene-methyl acrylate (EMA), ethylene n-butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In one embodiment, the at least one polymer comprises one or more of hydroxypropyl methylcellulose HPMC, a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone. In one embodiment, the at least one polymer comprises HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In yet another embodiment, the at least one polymer comprises one or more esters of HPMC. In yet a further embodiment, the at least one polymer comprises one or more esters of HPMC wherein the esters of HPMC comprise one or more of acetate ester and succinate ester. In one embodiment, the esters of HPMC comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS). In one embodiment, the admixture is a solid dispersion.

[0115] In one embodiment, Compound 1-A is in a solid, amorphous form.

[0116] As such, in one embodiment, a pharmaceutical composition comprises a solid dispersion, the solid dispersion comprising: an active pharmaceutical ingredient comprising one or more stereoisomers of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form; and at least one polymer.

[0117] In one embodiment, the at least one polymer is a polymer or combination of polymers that sustains the one or more stereoisomers of Compound 1 or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

[0118] In one embodiment, the active pharmaceutical ingredient in the solid dispersion comprises Compound 1-A or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form.

[0119] In one embodiment, the active pharmaceutical ingredient in the solid dispersion consists of one or more of Compound 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

[0120] In one embodiment, the active pharmaceutical ingredient consists essentially of Compound 1-A. In one embodiment, the active pharmaceutical ingredient contains 1.5% (e.g, 0% to 1.5%, no more than 0.5%, no more than 0.75%, no more than 1%, or no more than 1.25%) of Compounds 1-B, 1-C, and 1-D based on the total weight of Compounds 1-A, 1-B, 1-C, and 1- D).

[0121] In one embodiment, the active pharmaceutical ingredient consists of Compound 1-A or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form.

[0122] In one embodiment, the solid dispersion consists of one or more stereoisomers of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form and at least one polymer that sustains the one or more stereoisomers of Compound 1 or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form. In one embodiment, the stereoisomer of Compound 1 is Compound 1-A.

[0123] In one embodiment, the at least one polymer consists of only one polymer. In one embodiment, the at least one polymer comprises two or more different polymers.

[0124] In one embodiment, the at least one polymer comprises an acidic polymer.

[0125] In one embodiment, the at least one polymer comprises polyethylene oxide, a polymethacrylate-based copolymer, ethylene-vinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene, ethylene-methyl acrylate (EMA), ethylene n- butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC.

[0126] In one embodiment, the at least one polymer comprises one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone. In one embodiment, the at least one polymer comprises HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In yet another embodiment, the at least one polymer comprises one or more esters of HPMC. In yet a further embodiment, the at least one polymer comprises one or more esters of HPMC wherein the esters of HPMC comprise one or more of acetate ester and succinate ester. In one embodiment, the esters of HPMC comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0127] In one embodiment, the polymer that sustains amorphous form of Compound 1 (or salt or solvate thereof) is not a surfactant.

[0128] In one embodiment, the solid dispersion comprises the active pharmaceutical ingredient, the at least one polymer, and no more than a trace amount of a liquid solvent, in particular no more than 5,000 ppm of liquid solvent. In one embodiment, the solid dispersion comprises no more than a trace amount of citric acid, in particular, no more than 1,000 ppm of citric acid. In this context, “comprises no more than a trace amount” of a particular amount of a substance, such as a liquid solvent or citric acid, includes those cases where the substance is present in a minute or barely detectable amount or where there is no detectable amount of that substance.

[0129] In one embodiment, the solid dispersion comprises no more than about 90%, no more than about 80%, no more than about 75%, no more than about 60%, no more than about 50%, no more than about 40%, no more than about 30%, or no more than about 25% by weight of theactive pharmaceutical ingredient. In one embodiment, the solid dispersion comprises no less than about 5%, no less than about 10%, no less than about 25%, no less than about 30%, no less than about 40%, no less than about 50%, no less than about 60%, or no less than about 70% by weight of the active pharmaceutical ingredient. Said differently, the solid dispersion comprises the active pharmaceutical ingredient in a range of 5% to 90% by weight of the active pharmaceutical ingredient, such as 5% to 90%, 5% to 80%, 5% to 75%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 25%, 10% to 90%, 10% to 80%, 10% to 75%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 25%, 25% to 90%, 25% to 80%, 25% to 75%, 25% to 60%, 25% to50%, 25% to 40%, 25% to 30%, 30% to 90%, 30% to 80%, 30% to 75%, 30% to 60%, 30% to50%, 30% to 40%, 40% to 90%, 40% to 80%, 40% to 75%, 40% to 60%, 40% to 50%, 50% to90%, 50% to 80%, 50% to 75%, 50% to 60%, 60% to 90%, 60% to 80%, 60% to 75%, 70% to90%, 70% to 80%, or 70% to 75% by weight of the active pharmaceutical ingredient.

[0130] In one embodiment, the solid dispersion comprises the active pharmaceutical ingredient in a range of about 40% to about 60%, about 45% to about 55%, or about 48% to about 52% of the active pharmaceutical ingredient, e.g., Compound 1-A. In one embodiment, the solid dispersion comprises about 50% by weight of the active pharmaceutical ingredient, e.g., Compound 1-A.

[0131] In one embodiment, the solid dispersion comprises the active pharmaceutical ingredient (API, e.g., Compound 1 -A) and the at least one polymer at a ratio (APfpolymer) of about 1 : 10 to about 9: 10 (w / w). In one embodiment, the solid dispersion comprises the active pharmaceutical ingredient and the at least one polymer at a ratio of about 1 :4 to about 3 :4 (w / w).

[0132] In one embodiment, the solid dispersion is a powder. In another embodiment, the solid dispersion is monolithic.

[0133] Advantageously, by dispersing Compound 1 (or any stereoisomer thereof) together with a polymer disclosed herein, a stable pharmaceutical composition having an acceptable dissolution profde and an acceptable flux may be produced. One of skill in the art will readily recognize various methods that can be used to assess and measure the dissolution profde of a pharmaceutical composition or dosage form. For example, the Paddle Method (Apparatus II) can be used to dissolve the dosage form or pharmaceutical composition containing the drug, e.g., Compound 1 (or 1-A, 1-B, 1-C, or 1-D) and any suitable analysis method, such as UV-Vis or titration can be used to quantify the amount of drug concentration in the dissolution medium.Any suitable dissolution media may be used, e.g., phosphate buffer solution (pH 6.8), hydrochloric acid solution (pH 1.2), acetate buffer solution (pH 4.5), buffered water, simulated gastric fluid, or simulated intestinal fluid. In one embodiment, a phosphate buffer solution at pH 6.8 is used. Typical paddle rotation speeds are about 50 rpm to about 100 rpm and dissolution profiles are typically measured at about 37 °C (e.g., 37 ± 0.5 °C).

[0134] As one of ordinary skill in the art would understand, dissolution testing will provide insight into, and in certain embodiments, may be considered a proxy for, drug release of an active drug from a pharmaceutical dosage form.

[0135] In one embodiment, Compound 1 remains in amorphous form and does not substantially convert to crystalline form during storage.

[0136] In one embodiment, the solid dispersion comprises no more than about 10% (w / w) of Compound 1 in crystalline form, more particularly no more than about 10% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1 in the solid dispersion.

[0137] In one embodiment, the solid dispersion comprises no more than about 5% (w / w) of Compound 1 in crystalline form, more particularly no more than about 5% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1 in the solid dispersion.

[0138] In one embodiment, the solid dispersion comprises no more than about 2.5% (w / w) of Compound 1 in crystalline form, more particularly no more than about 2.5% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1 in the solid dispersion.

[0139] In one embodiment, the solid dispersion comprises no more than about 1% (w / w) of Compound 1 in crystalline form, more particularly no more than about 1% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1 in the solid dispersion.

[0140] In one embodiment, the solid dispersion comprises no more than about 0.25% (w / w) of Compound 1 in crystalline form, more particularly no more than about 0.25% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1 in the solid dispersion.

[0141] Methods of measuring the amount of crystalline solid in a composition may be measured by any suitable method, such as XRPD (x-ray powder diffraction) or modulated dynamic scanning calorimetry, or indirectly by looking at changes in dissolution.

[0142] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptablesolvate thereof in such a solid dispersion does not decrease by more than 10% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions (Ze., 25 °C (+ / - 2 °C) and 60% (+ / - 5%) relative humidity).

[0143] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 10% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0144] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 10% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0145] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 10% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0146] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 5% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0147] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 5% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0148] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 5% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0149] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 5% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0150] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 2.5% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0151] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 2.5% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0152] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 2.5% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0153] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 2.5% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0154] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 1% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0155] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 1% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0156] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 1% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0157] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptablesolvate thereof in such a solid dispersion does not decrease by more than 1% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0158] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.5% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0159] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.5% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0160] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.5% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0161] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.5% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0162] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.25% after four weeks storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0163] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.25% after two months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0164] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.25% after four months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0165] In one embodiment, the mass of solid, amorphous Compound 1 (more particularly Compound 1-A), pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof in such a solid dispersion does not decrease by more than 0.25% after twelve months storage at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity or at ambient conditions.

[0166] In principle, a solid dispersion as discussed herein can be made by any suitable method, such as methods known in the art.

[0167] One exemplary method is co-melting. In one embodiment that demonstrates an exemplary use of co-melting, a method of preparing a solid dispersion comprises: contacting an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a molten state with at least one polymer in a molten state to form a melt; mixing the melt; and cooling the melt to form a solid dispersion.

[0168] In one embodiment, co-melting comprises admixing the components of the solid dispersion, such as Compound 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof, and more particularly Compound 1-A or, a pharmaceutically acceptable solvate thereof, and the polymer, wherein at least one, and, in some embodiments, all, of the components are in a molten state. In one embodiment, both components are co-melted and mixed as a comelt. In one embodiment, for example, when one of the components has a higher melting pointthan the other, the lower-melting point component may be melted first and then the lower melting-point component may be added as a solid and the solid dispersion is formed mixing. In one embodiment, the mixing step is performed with an extruder, such as a single-screw extruder or a twin-screw extruder, though other mixing methods can be used. The mixture may be cooled, e.g., after extrusion, to provide the solid dispersion. When this method is employed, Compound 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof, need not be in amorphous form before it is melted. Prior to melting, Compound 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof, can be crystalline, either in a single crystal form or a mixture of crystal forms, amorphous, or a mixture of one or more crystal forms with amorphous material. Without wishing to be bound by theory, this is possible because melting a crystalline form into a liquid will cause it to lose its long-range order and, after the co-melting is complete, it can cool to form an amorphous solid in a solid dispersion with the polymer, and, if employed, the other components of the solid dispersion. Similarly, in most cases, either a solvate or anhydrous form of Compound 1-A, 1-B, 1-C, and 1-D may be used because a solvent typically evaporates during the melting process.[00169J Other exemplary methods of making a solid dispersion include solvent-based methods, but are not limited to, such as lyophilizing and spray-drying. In one embodiment, a method of preparing a solid dispersion comprises: contacting an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1-B, 1-C, and 1-D:1-B 1-Dor a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form and at least one polymer with a liquid to form a solution or liquid dispersion; and lyophilizing or spray drying the solution to form a solid dispersion.

[0170] In one embodiment, the lyophilizing or spray drying to form a solid dispersion comprises spray drying to form a solid dispersion. Optionally, the method further comprises a step of drying the solid dispersion.

[0171] In the solvent-based methods, such as a lyophilizing or a spray drying method, and particularly a spray drying method, as discussed above, the active pharmaceutical ingredient and the polymer, along with other components, if employed, are contacted with a liquid to dissolve, or disperse the active pharmaceutical ingredients and, optionally, other component(s) therein.

[0172] In one embodiment, the liquid is a solvent (z.e., is capable of dissolving at least in part) the active pharmaceutical ingredient, the at least one polymer, or both. Therefore, in one embodiment, the active pharmaceutical ingredient and the at least one polymer may be contacted with a liquid to form a solution or a suspension.

[0173] The liquid is selected to disperse or, preferably, to dissolve the active pharmaceutical ingredient, the polymer, or both, and optionally other components (if any) of the solid dispersion. The liquid can also be selected to provide a high concentration of the components of the solid dispersion. In some embodiments, high concentrations can be advantageous because using less liquid can reduce the cost of materials as well as the energy needed to spray dry or lyophilize.

[0174] Exemplary liquids include, but are not limited to, volatile organic solvents. In one embodiment, the liquid comprises one or more of acetone, dichloromethane, tetrahydrofuran, ethanol, methanol, and propanol. In one embodiment, the liquid comprises methanol or acetone. In a further embodiment, the liquid comprises or consists of acetone.

[0175] The identity and amounts of components used to prepare a solid dispersion are the same as those components (including amounts) as described with respect to characteristic the solid dispersion herein. In most cases, the ratio of components inputted into any of the aforementioned processes will be the same as the ratio of components in the final solid dispersion.

[0176] For example, in one embodiment, the composition comprising the active pharmaceutical ingredient comprises no more than about 2%, no more than 1.5%, no more than 1%, no more than 0.5%, no more than 0.25%, or no more than 0.1% of any one of Compound 1-B, Compound 1-C, and Compound 1-D by weight based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D, if present, in the composition.

[0177] In one embodiment, the composition comprising the active pharmaceutical ingredient consists essentially of Compound 1-A. In one embodiment, the active pharmaceutical ingredient contains 1.5% (e.g., 0% to 1.5%, no more than 0.5%, no more than 0.75%, no more than 1%, or no more than 1.25%) of Compounds 1-A, 1-B, 1-C, and 1-D).

[0178] In another example, the composition comprising the active pharmaceutical ingredient comprises no less than about 98%, no less than 98.5%, no less than 99%, no less than 99.25%, no less than 99.5%, or no less than 99.75% by weight of Compound 1-A based on the combined weight of Compound 1-A, Compound 1-B, Compound 1-C, and Compound 1-D in the composition.

[0179] In any aforementioned embodiment, the active pharmaceutical ingredient may be contacted with the polymer in an amount according to any embodiment disclosed herein. For example, in one embodiment, the active pharmaceutical ingredient comprises Compound 1-A. In one embodiment, the active pharmaceutical ingredient consists of Compound 1-A.

[0180] In any aforementioned embodiment, the at least one polymer may be any polymer disclosed herein, such as in Section 6.3.1. In one embodiment, the at least one polymer is not a surfactant. In one embodiment, the at least one polymer is an acidic polymer. In one embodiment, the at least one polymer comprises one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone. In one embodiment, the at least one polymer comprises HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC. In yet another embodiment, the at least one polymer comprises one or more esters of HPMC. In yet a further embodiment, the at least one polymer comprises one or more esters of HPMC wherein the esters of HPMC comprise one or more of acetate ester and succinate ester. In one embodiment, the esters of HPMC comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0181] The choice of method to be employed will depend on the properties of the polymer and any other components of the solid dispersion, as well as factors of convenience. For example, if the polymer or other component of the solid dispersion is not stable at its meltingtemperature or the melting temperature of the form of the active pharmaceutical ingredient that is employed, then the co-melting method may be inappropriate and a solvent-based method, such as lyophilization or spray drying, may be preferred. On the other hand, if a very large amount of solvent is required to dissolve the active pharmaceutical ingredient and the polymer and other components of the solid dispersion, then the co-melting method may be preferred.6.3.2 Granules

[0182] In one embodiment, the pharmaceutical compositions disclosed herein comprise a solid dispersion according to any embodiment described in section 6.3.1 in the form of a powder or a monolith. In one embodiment, the solid dispersion, particularly when the solid dispersion is in the form of a powder, may be combined with one or more intragranular excipients to form a plurality of granules.

[0183] The nature and amount of the intragranular excipients will depend on the nature and desired properties of the final composition, for example, the pharmaceutical dosage form for administration. For example, in one embodiment, the final composition is a compressed tablet, and the intragranular excipients include excipients suitable for compression. In another embodiment, the final composition is a powder-in-capsule and the excipients may include even those not suitable for compression. In another embodiment, the final composition is a powder sachet to be sprinkled on food or drink and consumed, and the excipients include sweeteners or taste-masking excipients. Excipients may be selected from those listed in the US Pharmacopeia; however, this is not required in all cases because other excipients may also be suitable.

[0184] In one embodiment, the one or more intragranular excipients selected from the group consisting of one or more filler, one or more disintegrant, one or more glidant, one or more lubricant, one or more binder, or any combination thereof. Encompassed herein is any combination of the specific intragranular excipients mentioned below.

[0185] In one embodiment, the one or more intragranular excipients comprises a filler. Examples of suitable fillers include, but are not limited to, starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, xylitol, dextrose, crystalline maltose, and maltodextrins. In one embodiment, the filler is mannitol.

[0186] In one embodiment, the one or more intragranular excipients comprises a disintegrant. Examples of suitable disintegrants include, but are not limited to, crosslinkedpolyvinylpyrrolidone (PVP), crosslinked croscarmellose, croscarmellose sodium, sodium starch glycolate, and microcrystalline cellulose. In one embodiment, the disintegrant is croscarmellose sodium.

[0187] In one embodiment, the one or more intragranular excipients comprises a glidant. Examples of suitable glidants include, but are not limited to, silicon dioxide, talc, starch, calcium silicate, magnesium silicate, and magnesium aluminometasilicate. In one embodiment, the glidant is silicon dioxide.

[0188] In one embodiment, the one or more intragranular excipients comprises a lubricant. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl behenate, glyceryl palmitostearate, waxes (e.g., bees wax, carnauba wax, stearyl alcohol, and polyglycolized esters of fatty acids with registered names: GELUCIRE®, COMPRITOL® 888, PRECIROL® ATO5, palmitic acid, myristic acid, polyethylene glycol (e.g, CARBOWAX™), sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and sodium benzoate. In one embodiment, the lubricant is stearyl fumarate or a salt thereof, particularly sodium stearyl fumarate.

[0189] Examples of suitable binders include, but are not limited to, gums (e.g., guar gum, xanthan gum, acacia, tragacanth), pregelatinized starches or cross-linked starches, and celluloses (e.g, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium).

[0190] In principle, the minimum amount, or percent of, the solid dispersion in the granules is limited only by the total mass of granules needed to provide an effective dose of the active pharmaceutical ingredient (e.g., Compound 1 and particularly Compound 1-A, plus any other active agent if employed). A lower amount or percent of solid dispersion will require a higher mass of granules to achieve a particular dose as opposed to a higher amount or percent, which could be a limiting factor in some cases, for example, a tablet which needs to be a suitable size for oral administration. Conversely, the maximum amount or percent of the solid dispersion in the granules is limited in principle by either the need to have the function of the intragranular excipients (e.g., a need to have sufficient disintegrant to ensure disintegration), or a need to increase the total mass of the granules in the pharmaceutical composition (e.g, to have a sufficient mass to compress into a tablet or reproducibly fill into a capsule).

[0191] In one embodiment, the granules in the plurality of granules comprise, on average, about 20% to about 75% (w / w) of the solid dispersion according to any embodiment described in section 6.3.1. In one embodiment, each of the granules in the plurality of granules comprises, on average, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 20% to about 25%, about 30% to about 75%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 75%, about 40% to about 60%, about 40% to about 50%, about 50% to about 75%, about 50% to about 60%, or about 60% to about 75% (w / w) of the solid dispersion according to any embodiment described in section 6.3.1. In one embodiment, the granules in the plurality of granules comprise, on average, about 30% to about 70% (w / w) of the solid dispersion according to any embodiment described in section 6.3.1. In one embodiment, the granules in the plurality of granules comprise, on average, about 40% to about 60% (w / w) of the solid dispersion according to any embodiment described in section 6.3.1. In one embodiment, the solid dispersion comprises solid amorphous Compound 1 or a pharmaceutically acceptable salt or solvate thereof and at least one polymer as described in section 6.3.1. In one embodiment, the mass of Compound 1-A in the granules does not decrease by more than 5% after four weeks at 40 °C and 75% relative humidity.

[0192] The granules as described herein can be made by any suitable method. Exemplary methods include fluid bed granulation, high-sheer mixing, liquid granulation, and dry granulation. The method employed will depend on a variety of factors known to the person of skill in the art, such as the nature of the intragranular excipients, the ultimate form of the pharmaceutical composition to be produced, and the like.6.3.3 Extra-granular Excipients and Exemplary Dosage Forms

[0193] The nature and amount of the extra-granular excipients will depend in large part on the nature and desired properties of the final composition, for example, the pharmaceutical dosage form for administration. For example, in one embodiment, the final composition is a compressed tablet, and the extra-granular excipients include excipients suitable for compression. In another embodiment, the final composition is a powder-in-capsule and the extra-granular excipients may include even those not suitable for compression. In another embodiment, the final composition is a powder sachet to be sprinkled on food or drink and consumed, and the extra- granular excipients include sweeteners or taste-masking excipients. Excipients may be selectedfrom those listed in the US Pharmacopeia; however, this is not required in all cases because other suitable extra-granular excipients may also be suitable.

[0194] In one embodiment, the plurality of granules comprising a solid dispersion may be combined with one or more extra-granular excipients to generate a pharmaceutical composition suitable for administration to a subject. In one embodiment, the one or more extra-granular excipients are selected from the group consisting of one or more compression excipients, one or more disintegrants, one or more glidants, one or more lubricants, one or more binders, one or more fillers, and any combination thereof. Encompassed herein is any combination of the specific extra-granular excipients mentioned below.

[0195] In one embodiment, the one or more extra-granular excipients comprises one or more compression excipients.

[0196] In one embodiment, the one or more extra-granular excipients comprises one or more disintegrants. Examples of suitable disintegrants include, but are not limited to, crosslinked polyvinylpyrrolidone (PVP), crosslinked croscarmellose, croscarmellose sodium, sodium starch glycolate, and microcrystalline cellulose. In one embodiment, the disintegrant is croscarmellose sodium.

[0197] In one embodiment, the one or more extra-granular excipients comprises one or more glidants. Examples of suitable glidants include, but are not limited to, silicon dioxide, talc, starch, calcium silicate, magnesium silicate, and magnesium aluminometasilicate.

[0198] In one embodiment, the one or more extra-granular excipients comprises one or more sugars or sugar alcohols. In one embodiment, the one or more extra-granular excipients comprises mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, or a mixture of one or more of the foregoing. In one embodiment, the one or more extra-granular excipients comprises one or both of mannitol and silicified microcrystalline cellulose.

[0199] In one embodiment, the one or more extra-granular excipients comprises a lubricant. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl behenate, glyceryl palmitostearate, waxes (e.g, bees wax, carnauba wax, stearyl alcohol, and polyglycolized esters of fatty acids with registered names: GELUCIRE®, COMPRITOL® 888, PRECIROL® ATO5), palmitic acid, myristic acid, polyethylene glycol (e.g, CARBOWAX™), sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and sodium benzoate.In one embodiment, the lubricant is stearyl fumarate or a salt thereof, particularly sodium stearyl fumarate.

[0200] Examples of suitable binders include, but are not limited to, gums (e.g., guar gum, xanthan gum, acacia, tragacanth), pregelatinized starches or cross-linked starches, and celluloses (e. , hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium).

[0201] In one embodiment, the pharmaceutical composition is manufactured into and provided in a dosage form as a capsule, a tablet, or a sachet. In one embodiment, the pharmaceutical composition is manufactured into and provided as a capsule or a tablet. In one embodiment, the pharmaceutical composition is manufactured into and provided in the form of a tablet. In one embodiment, the pharmaceutical composition is manufactured into and provided in the form of a tablet comprising a coating. In one embodiment, the coating comprises a pigment.

[0202] In one embodiment, the dosage form (c.g, tablet, capsule, etc.) comprises no less than about 5 mg, no less than about 10 mg, no less than about 20 mg, no less than about 25 mg, no less than about 30 mg, no less than about 40 mg, or no less than about 50 mg of Compound 1-A. In one embodiment, the dosage form comprises no more than about 250 mg, no more than about 200 mg, no more than about 175 mg, no more than about 150 mg, no more than about 125 mg, no more than about 100 mg, no more than about 75 mg, no more than about 60 mg, or no more than about 50 mg of Compound 1-A. In one embodiment, the dosage form (e.g, tablet, capsule, etc.) comprises about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 175 mg, about 10 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 20 mg to about 250 mg, about 20 mg to about 200 mg, about 20 mg to about 175 mg, about 20 mg to about 150 mg, about 20 mg to about 125 mg, about 20 mg to about 100 mg, about 20 mg to about 75 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, 25 mg to about 250 mg, about 25 mg to about 200 mg, about 25 mg to about 175 mg, about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 60 mg, about 25 mg to about 50 mg, 30 mg to about 250 mg, about 30 mg to about 200 mg, about 30 mg to about 175 mg, about 30 mg to about 150 mg, about 30 mg to about 125 mg, about 30 mg to about 100 mg, about 30 mg to about 75 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, 40 mg to about 250 mg, about 40 mg toabout 200 mg, about 40 mg to about 175 mg, about 40 mg to about 150 mg, about 40 mg to about 125 mg, about 40 mg to about 100 mg, about 40 mg to about 75 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, or about 50 mg to about 60 mg of Compound 1-A.

[0203] In one embodiment, the dosage form (e.g., tablet, capsule, etc.) comprises about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A. In one embodiment, the dosage form (e.g., tablet, capsule, etc.) comprises about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A.[00204J In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises about 23 mg to about 27 mg of Compound 1-A. In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises about 25 mg of Compound 1-A. In certain other embodiments, the dosage form comprises about 123 mg to about 127 mg of Compound 1-A. In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises about 125 mg of Compound 1-A.

[0205] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 40% to about 60% (w / w) of Compound 1-A; and about 40% to about 60% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0206] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 48% to about 52% (w / w) of Compound 1-A; and about 40% to about 60% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0207] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 50% (w / w) of Compound 1-A; and about 40% to about 60% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0208] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 40% to about 60% (w / w) of Compound 1-A; and about 48% to about 52% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0209] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 48% to about 52% (w / w) of Compound 1-A; and about 48% to about 52% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0210] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 50% (w / w) of Compound 1-A; and about 48% to about 52% (w / w) of hydroxypropyl methyl cellulose acetate succinate.

[0211] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 40% to about 60% (w / w) of Compound 1-A; and about 50% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0212] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 48% to about 52% (w / w) of Compound 1-A; and about 50% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0213] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises a plurality of granules comprising a solid dispersion comprising: about 50% (w / w) of Compound 1-A; andabout 50% (w / w) of hydroxypropyl methylcellulose acetate succinate.

[0214] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:50 mg of a solid dispersion, the solid dispersion comprising:23-27 mg of Compound 1-A; and23-27 mg of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:1-4 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.[00215J In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:50 mg of a solid dispersion, the solid dispersion comprising:25 mg of Compound 1 -A; and23-27 mg of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:1-4 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.

[0216] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:50 mg of a solid dispersion, the solid dispersion comprising:23-27 mg of Compound 1-A; and25 mg of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:1-4 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.

[0217] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:50 mg of a solid dispersion, the solid dispersion comprising:25 mg of Compound 1-A; and25 mg of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:1-4 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.

[0218] In certain embodiments, the dosage form (e.g, tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:123-127 mg of Compound 1-A; and123-127 mg of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:11-15 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.

[0219] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:125 mg of Compound 1-A; and123-127 mg of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:11-15 mg croscarmellose sodium; and5-8 mg sodium stearyl fumarate.

[0220] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:123-127 mg of Compound 1-A; and125 mg of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:11-15 mg croscarmellose sodium; and5-8 mg sodium stearyl fumarate.

[0221] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:125 mg of Compound 1-A; and125 mg of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising:1 1-15 mg croscarmellose sodium; and5-8 mg sodium stearyl fumarate.

[0222] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of: about 50 mg of a solid dispersion, the solid dispersion comprising: about 25 mg of Compound 1-A; and about 25 mg of hydroxypropyl methylcellulose acetate succinate; about 47.5 mg silicified microcrystalline cellulose; about 24 mg mannitol; about 5.5 mg croscarmellose sodium; about 1.5 mg silicon dioxide; and about 1.5 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising: about 2.5 mg croscarmellose sodium; and about 1.5 mg sodium stearyl fumarate.

[0223] In certain embodiments, the dosage form (e.g., tablet, capsule, etc.) comprises:(a) a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising: about 125 mg of Compound 1-A; and about 125 mg of hydroxypropyl methylcellulose acetate succinate; about 238 mg silicified microcrystalline cellulose; about 119 mg mannitol; about 26.5 mg croscarmellose sodium; about 6.5 mg silicon dioxide; and about 6.5 mg sodium stearyl fumarate;(b) extra-granular excipients that are not contained in the plurality of granules, the extra-granular excipients comprising: about 13.5 mg croscarmellose sodium; and about 6.5 mg sodium stearyl fumarate.

[0224] In certain embodiments, Compound 1-A is present in any of the aforementioned dosage forms as an amorphous solid.

[0225] In one embodiment, the dosage form of any of the aforementioned embodiments comprises no more than about 10% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion. In one embodiment, the dosage form of any of the aforementioned embodiments comprises no more than about 5% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion. In one embodiment, the dosage form of any of the aforementioned embodiments comprises no more than about 2.5% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion. In one embodiment, the dosage form of any of the aforementioned embodiments comprises no more than about 1% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion. In one embodiment, the dosage form of any of the aforementioned embodiments comprises no morethan about 0.25% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion.

[0226] In one embodiment, the dosage form of any of the aforementioned embodiments comprises no more than about 0.5% (w / w) of Compound 1-A in crystalline form, based on the total amount of Compound 1-A in the solid dispersion. In one embodiment, the dosage form of any of the aforementioned embodiments comprises no crystalline form of Compound 1-A, based on the total amount of Compound 1-A in the solid dispersion.

[0227] In one embodiment, a pharmaceutical dosage form exhibits a dissolution profile when measured under sink conditions as follows: (i) at least about 50% of the pharmaceutical dosage form is dissolved by about 5 minutes; (ii) at least about 80% of the pharmaceutical dosage form is dissolved by about 15 minutes; (iii) at least about 95% of the pharmaceutical dosage form is dissolved by about 20 minutes; or (iv) at least about 98% of the pharmaceutical dosage form is dissolved by about 30 minutes. In certain embodiments, the dissolution profile is measured at a temperature of about 37.0 °C and a stirring speed of about 75 rpm. In certain embodiments, the dissolution profile is measured in a medium comprising 10 mM sodium phosphate buffer at a pH of about 6.80.

[0228] In one embodiment, dissolution testing is a proxy for drug release of Compound 1 (or Compound 1-A, 1-B, 1-C, or 1-D) from a pharmaceutical dosage form.

[0229] Accordingly, in one embodiment, a pharmaceutical dosage form exhibits a release profile, when measured under sink conditions, as follows: (i) at least about 50% of Compound 1- A is released from the pharmaceutical dosage form by about 5 minutes; (ii) at least about 80% of Compound 1-A is released from the pharmaceutical dosage form by about 15 minutes; (iii) at least about 95% of Compound 1-A is released from the pharmaceutical dosage form by about 20 minutes; and (iv) at least about 98% of Compound 1-A is released from the pharmaceutical dosage form by about 30 minutes. In certain embodiments, the release profile is measured at a temperature of about 37.0 °C at a stirring speed of about 75 rpm. In certain embodiments, the release profile is measured in a medium comprising 10 mM sodium phosphate buffer at a pH of about 6.80.

[0230] In one embodiment, a solution resulting from dissolution of a pharmaceutical dosage form manufactured to comprise Compound 1-A as the only active pharmaceutical ingredient, e. ., as occurs during dissolution testing, comprises no less than 98%, preferably no less than98.5%, more preferably no less than 99%, even more preferably no less than 99.25%, still more preferably no less than 99.5%, yet more preferably no less than 99.75%, even more preferably no less than 99.8%, and most preferably no less than 99.9% by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solution. In certain embodiments, the percent by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solution is measured by chiral HPLC, such as is described in the Examples.6.4 Therapeutic Methods and Dosing Regimens

[0231] In another aspect, the present disclosure provides a method of treating a disease, disorder, or condition related to Al AT in a subject comprising administering to the subject Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment in Section 6.3, including, such embodiments as, e.g., a solid dispersion or admixture according to any embodiment in Section 6.3.1, a plurality of granules according to any embodiment in Section 6.3.2, or a dosage form, such as a tablet, according to any embodiment in Section 6.3.3. Similarly, Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment in Section 6.3, including, such embodiments as, e.g., a solid dispersion or admixture according to any embodiment in Section 6.3.1, a plurality of granules according to any embodiment n Section 6.3.2, or a dosage form, such as a tablet, according to any embodiment in Section 6.3.3 may be used in the treatment of a disease, disorder, or condition related to Al AT in a subject. In another embodiment, provided herein is use of Compound 1-A, a composition comprising Compound 1-A according to any embodiment herein, e.g., in Section 6.2, a pharmaceutical composition according to any embodiment in Section 6.3, including, such embodiments as, e.g., a solid dispersion or admixture according to any embodiment in Section 6.3.1, a plurality of granules according to any embodiment in Section 6.3.2, or a dosage form, such as a tablet, according to any embodiment in Section 6.3.3, for manufacturing a medicament for treating a disease, disorder, or condition related to Al AT in a subject. The subject may have been diagnosed with or is suffering from said disease, disorder, or condition related to Al AT.

[0232] In certain embodiments, the present disclosure provides a method of treating a disease, disorder, or condition related to A1AT in a subject comprising administering to the subject a pharmaceutical composition according to any embodiment in Section 6.3. Similarly, apharmaceutical composition according to any embodiment in Section 6.3 may be used in the treatment of a disease, disorder, or condition related to A1AT in a subject. In another embodiment, provided herein is use of a pharmaceutical composition according to any embodiment in Section 6.3 herein, for manufacturing a medicament for treating a disease, disorder, or condition related to Al AT in a subject. The subject may have been diagnosed with or is suffering from said disease, disorder, or condition related to Al AT. In one embodiment, the disease, disorder, or condition is a liver disorder. In one embodiment, the disease, disorder, or condition relates to accumulation of A1AT in the liver of the subject. In one embodiment, the disease, disorder, or condition relates to polymerization of A1AT. In any aforementioned embodiment, the subject is human. In one embodiment, the disease, disorder, or condition relates to accumulation of polymerized Al AT in the liver of the subject. In any aforementioned embodiment, the subject may be homozygous for alpha 1 -antitrypsin deficiency. In one embodiment, the subject is of the genotype PiZZ. In any aforementioned embodiment, the composition administered to the subject to treat the disease, disorder, or condition may be in any form, such as any form listed in Section 6.3. In any aforementioned method, the composition may be administered to the subject once per day, twice per day, or more frequently. In one embodiment, the composition is administered once per day. In another embodiment, the composition is administered twice per day.

[0233] In one embodiment, the disease, disorder, or condition is a liver disorder. In one embodiment, the disease, disorder, or condition relates to accumulation of A1AT in the liver of the subject. In one embodiment, the disease, disorder, or condition relates to polymerization of A1AT. In any aforementioned embodiment, the subject is human. In one embodiment, the disease, disorder, or condition relates to accumulation of polymerized A1AT in the liver of the subject. In one embodiment, the disease, disorder, or condition relates to fibrosis of the liver, particularly in subjects that have accumulation of polymerized Al AT in the liver. In any aforementioned embodiment, the subject may be homozygous for alpha 1-antitrypsin deficiency. In any aforementioned embodiments, the subject may be heterozygous for alpha 1-antitrypsin deficiency. In one embodiment, the subject is of the genotype PiZ*. In one embodiment, the subject is of the genotype PiZZ. In one embodiment, the subject is of the genotype PiMZ. In any aforementioned embodiment, the composition administered to the subject to treat the disease, disorder, or condition may be in any form, such as any form listed in Section 6.3. In anyaforementioned method, the composition may be administered to the subject once per day, twice per day, or more frequently. In one embodiment, the composition is administered once per day. In another embodiment, the composition is administered twice per day. In any aforementioned method, the composition may be administered to the subject orally.

[0234] In any aforementioned embodiment, the subject may be homozygous for alpha 1- antitrypsin deficiency. In one embodiment, the subject is of the genotype PiZZ. In any aforementioned embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to the subject to treat the disease, disorder, or condition may be in any form, such as any form listed in Section 6.2 or 6.3. In any aforementioned method, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule may be administered to the subject once per day, twice per day, or more frequently. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered once per day. In another embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered twice per day.

[0235] In one embodiment, the subject has been diagnosed with or otherwise has a medical condition associated with liver disease caused by alcohol use, viral infection (e.g., hepatitis), or MASH. In one embodiment, the subject is heterozygous for alpha 1-antitrypsin deficiency (e.g., has a PiMZ genotype) and further has been diagnosed with or otherwise has a medical condition associated with liver disease caused in part or exacerbated by alcohol use, viral infection (e.g., hepatitis), or MASH. In one embodiment, the subject has a PiMZ genotype and also has MASH.

[0236] In any aforementioned method of treating a disease, disorder, or condition in a subject by administering to the subject a composition as disclosed herein, the composition may be administered to deliver to the subject a therapeutically effective amount of the active pharmaceutical ingredient (e.g., Compound 1-A or a pharmaceutically acceptable salt or solvate thereof). In any aforementioned embodiment, Compound 1-A is administered to the subject in an amount of about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg. In one embodiment, about 25 mg dose or about 125 mg of Compound 1-A is administered to the subject.

[0237] In any aforementioned embodiment, Compound 1-A is administered in a composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule, as described according to any embodiment disclosed herein, to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg of Compound 1-A to the subject. In one embodiment, about 25 mg dose or about 125 mg of Compound 1-A is administered to the subject. For example, in any forementioned embodiment, Compound 1-A is administered to the subject in an amount of about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A.

[0238] In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g. not a salt or solvate). In one embodiment, the pharmaceutical composition is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 mg to about 250 mg of Compound 1-A per day, and even still more preferably about 25 mg to about 125 mg of Compound 1-A per day. In one particular embodiment, the pharmaceutical composition is administered to provide about 25 mg per day of Compound 1 -A. In one particular embodiment, the pharmaceutical composition is administered to provide about 50 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 75 mg per day of Compound 1- A. In one particular embodiment, the pharmaceutical composition is administered to provide about 100 mg per day of Compound 1-A or a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the pharmaceutical composition is administered to provide about 125 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 150 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 250 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 500 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 625 mg per day. In one particular embodiment, the pharmaceutical composition is administered to provide about 750 mgper day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1000 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1250 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1500 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A as described immediately above. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A as described immediately above.

[0239] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0240] In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is provided as a single daily administration of about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, and still more preferably about 25 mg to about 250 mg of Compound 1-A, and still more preferably about 25 mg to about 125 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is provided as a single daily administration of about 25 mg of Compound 1-A. In one particular embodiment,the single daily administration is of about 50 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 75 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 100 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 125 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 150 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 250 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 500 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 625 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 1000 mg or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 1250 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the single daily administration is of about 1500 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is provided as a twice daily administration of about 5 mg to about 750 mg, preferably about 5 mg to about 500 mg, more preferably about 12.5 mg to about 500 mg, even more preferably about 25 mg to about 250 mg, and still more preferably about 25 mg to about 125 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0241] In one particular embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is provided as a twice daily administration of about 25 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one particular embodiment, the twice daily administration is of 50 mg of Compound 1-A or an equivalentamount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 75 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 100 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 125 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 150 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 250 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 500 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 625 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration. In one particular embodiment, the twice daily administration is of about 750 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof per administration.

[0242] In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is administered to a subject once daily by oral administration of about 25 mg to about 125 mg of Compound 1-A or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is provided in a tablet or capsule formulation, such as described in Section 6.3.3.

[0243] In any embodiment, the pharmaceutical compositions disclosed herein may be administered with other therapeutic agents useful in treating the diseases, disorders, or conditions.

[0244] In another embodiment, the compounds disclosed herein, e.g., Compound 1-A, may be used or be incorporated into a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g.,such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3), as described herein, comprising Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof for use in a method of increasing the level of A1AT in the plasma of a subject, the method comprising administering a sufficient amount of the pharmaceutical composition to the subject, and wherein the level of Al AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject is a human. In one embodiment, the level of Al AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A (e.g., not a salt or solvate). In one embodiment, the concentration of polymerized Al AT in the liver of the subject is decreased after the administering.

[0245] For example, the compounds disclosed herein may be incorporated into a pharmaceutical composition comprising Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient for use in a method of increasing the level of A1AT in the plasma of a subject, the method comprising administering a sufficient amount of the pharmaceutical composition to the subject, and wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject is a human. In one embodiment, the level of Al AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A (e.g., not a salt or solvate). In one embodiment, the concentration of polymerized A1AT in the liver of the subject is decreased after the administering.

[0246] In one embodiment, the subject is a human. In one embodiment, the level of A1AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 110 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 120 mg / dL or greater. In one embodiment, Compound 1-A orpharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A. In one embodiment, the concentration of polymerized Al AT in the liver of the subject is decreased after the administering.

[0247] In one embodiment, the level of A1AT in the plasma is increased by at least about 50 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about60 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about65 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about70 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about80 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about90 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about100 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased by at least about 65 mg / dL to about 90 mg / dL or greater. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A (e.g., not a salt or solvate). In one embodiment, the concentration of polymerized A1AT in the liver of the subject is decreased after the administering.

[0248] In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is administered to the subject at least once per day.

[0249] In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate). In one embodiment, the pharmaceutical composition is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, and still more preferably about 25 mg to about 250 mg of Compound 1-A per day, and still even more preferably about 25 mg to about 125 mg of Compound 1-A per day. In one particular embodiment, the pharmaceutical composition is administered to provide about 25 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 50 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 75 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administeredto provide about 100 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 125 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 150 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 250 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 500 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 625 mg per day. In one particular embodiment, the pharmaceutical composition is administered to provide about 750 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1000 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1250 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered to provide about 1500 mg per day of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A as described immediately above. In one particular embodiment, the pharmaceutical composition is administered as single dose twice per day to provide the daily amount of Compound 1-A as described immediately above.

[0250] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, thepharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0251] In one embodiment, the increased level of Al AT in the plasma is reached after 28 or fewer days of administration. In one embodiment, the increased level of Al AT in the plasma is reached after 14 or fewer days of administration. In one embodiment, the increased level of Al AT in the plasma is reached after 7 or fewer days of administration. In one embodiment, the pharmaceutical composition contains about 5 mg to about 400 mg, preferably about 10 mg to about 250 mg, and more preferably about 20 mg to about 150 mg of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 5 mg to about 800 mg, preferably about 10 mg to about 600 mg, more preferably about 25 mg to about 500 mg, and even more preferably about 30 mg to about 300 mg of Compound 1-A per day.

[0252] In another embodiment, the compounds disclosed herein may be used in a method of increasing the level of A1AT in the plasma of a subject comprising administering Compound 1- A:or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject, wherein the level of A1AT in the plasma of the subject is increased to about 90 mg / dL or greater after the administering. In certain embodiments, Compound 1-A or a pharmaceutically acceptable salt or solvent thereof is administered. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject is a human. In one embodiment, the level of Al AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 60mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 100 mg / dL or greater.

[0253] For example, the compounds disclosed herein may be used in a method of increasing the level of A1AT in the plasma of a subject comprising administering a sufficient amount of a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof to the subject, or a pharmaceutical composition comprising the compound, salt, or solvate thereof, and a pharmaceutically acceptable excipient, wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering. In certain embodiments, Compound 1-A or a pharmaceutically acceptable salt or solvent thereof is administered. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject is a human. In one embodiment, the level of A1AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 100 mg / dL or greater.

[0254] In one embodiment, the level of A1AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dLor greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 110 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 120 mg / dL or greater.

[0255] In one embodiment, the level of A1AT in the plasma is increased by at least about 50 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about60 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about65 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about70 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about80 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about90 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about100 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased by at least about 65 mg / dL to about 90 mg / dL or greater.

[0256] In one embodiment, the compound, salt, or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, the compound, salt, or solvate thereof is Compound 1-A (e.g., not a salt or solvate). In one embodiment, the concentration of polymerized A1AT in the liver of the subject is decreased after the administering. In one embodiment, the compound, salt, or solvate thereof, or pharmaceutical composition, is administered to the subject at least once per day. In one embodiment, the compound, salt, or solvate thereof, or pharmaceutical composition, is administered to the subject at least twice per day. In one embodiment, the increased level of Al AT in the plasma is reached after 28 or fewer days of administration. In one embodiment, the increased level of A1AT in the plasma is reached after 14 or fewer days of administration. In one embodiment, the increased level of Al AT in the plasma is reached after 7 or fewer days of administration.

[0257] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0258] In another embodiment, the compounds disclosed herein may be used in a means of increasing the level of A1AT in the plasma of a subject to about 90 mg / dL or greater comprising a step of administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject. In one embodiment, the means is a means of increasing the level of A1AT in the plasma to about 50 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 60 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 70 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 80 mg / dL or greater. In one embodiment, the means is a means ofincreasing the level of A1AT in the plasma to about 90 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 100 mg / dL or greater. In one embodiment, the sufficient amount is about 25 mg to about 500 mg of Compound 1-A per day.

[0259] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0260] For example, the compounds disclosed herein may be used in a means of increasing the level of A1AT in the plasma of a subject to about 40 mg / dL or greater comprising a step of administering a sufficient amount of Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof to the subject. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 50 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 60 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al ATin the plasma to about 70 mg / dL or greater. In one embodiment, the means is a means of increasing the level of A1AT in the plasma to about 80 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 90 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma to about 100 mg / dL or greater. In one embodiment, the sufficient amount is about 25 mg to about 500 mg of Compound 1-A per day.

[0261] In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 40 mg / dL. In one embodiment, the means is a means of increasing the level of A1AT in the plasma by at least about 50 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 60 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 65 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 70 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 80 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 90 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 100 mg / dL. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 60 mg / dL to about 70 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 65 mg / dL to about 70 mg / dL or greater. In one embodiment, the means is a means of increasing the level of Al AT in the plasma by at least about 65 mg / dL to about 90 mg / dL or greater.

[0262] In one embodiment, the sufficient amount is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the sufficient amount is administered in a pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule containing about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A.

[0263] In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0264] In one embodiment, the step comprises administering a dose of Compound 1-A or a pharmaceutically acceptable salt or solvate thereof once per day to the subject. In one embodiment, the step comprises administering a dose of Compound 1-A or a pharmaceutically acceptable salt or solvate thereof twice per day to the subject.

[0265] In another example, the compound, pharmaceutical composition, the solid dispersion, the pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein are used in a method of treating a subject for a disorder related to A1AT, the method comprising administering the compound, pharmaceutical composition, plurality of granules, admixture, pharmaceutical dosage form, or tablet or capsule to a subject in need thereof. In one example, the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein are used in a method of increasing the level of A1AT in the plasma of a subject, the method comprising administering the compound, pharmaceutical composition, plurality of granules, admixture, pharmaceutical dosage form, or tablet or capsule to a subject in need thereof.

[0266] In another example, provided herein is the use of the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein for the manufacture of a medicament for treating a subject for a disorder related to A1AT. In one example, provided herein is the use of the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein for the manufacture of a medicament for increasing the level of A1AT in the plasma of a subject.

[0267] In one embodiment, the compounds disclosed herein may be used in a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject to cause improvement in the fibrosis. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered. In one embodiment, the subject has stage 1, stage 2, stage 3, or stage 4 fibrosis prior to the administering. In one embodiment, the improvement in the fibrosis is a decrease in the stage of fibrosis by at least one stage.

[0268] For example, the compounds disclosed herein may be used in a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering a sufficient amount of Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject to cause improvement in the fibrosis. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipientis administered. In one embodiment, the subject has stage 1, stage 2, stage 3, or stage 4 fibrosis prior to the administering. In one embodiment, the improvement in the fibrosis is a decrease in the stage of fibrosis by at least one stage.

[0269] In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 104 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 92 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 70 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 64 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 52 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 40 weeks or less. In one embodiment, the improvement in the fibrosis occurs after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, for 26 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 25 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 50 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 75 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 100 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 125 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 150 mg of Compound 1-A per day. In one embodiment, thecompound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, thereof is administered to provide about 250 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 500 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 625 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 750 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 1000 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 1250 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 1500 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered twice per day. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0270] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A.

[0271] In some embodiments, the AlAT-associated liver disease is hepatitis, hepatic fibrosis, hepatic cirrhosis, cholestasis, metabolic dysfunction-associated steatohepatitis, liver cancer, or is caused in part by or exacerbated by alcohol use.

[0272] In another embodiment, the compounds disclosed herein may be used in a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject to stabilize the fibrosis. In certain embodiments, a dosage form comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and at least one pharmaceutically acceptable excipient is administered. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, solid dispersion, admixture, or tablet or capsule is administered to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 250 mg, about 500 mg, about 625 mg, or about 750 mg of Compound 1-A per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, solid dispersion, admixture, or tablet or capsule is administered once per day. In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, solid dispersion, admixture, or tablet or capsule is administered twice per day. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate). In oneembodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0273] In another example, the compounds disclosed herein may be used in a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering a sufficient amount of Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject to stabilize the fibrosis. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 250 mg, about 500 mg, about 625 mg, orabout 750 mg of Compound 1-A per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered once per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered twice per day. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0274] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A.

[0275] In one embodiment, the compounds disclosed herein may be used in a method of treating fibrosis in a subject having a PiZZ genotype, the method comprising administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersionor admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A. In one embodiment, the subject has a fibrosis score of 2 or greater (compensated). In one embodiment, the subject is orally administered 25 mg to 250 mg e.g., 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg, e.g., in a tablet, daily. In one embodiment, the administration is effective to decrease the stage of the liver fibrosis by at least one stage, e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months. In one embodiment, the administration is effective to stabilize the fibrosis (e.g., the fibrosis does not worsen), e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months. In one embodiment, the administration is effective to reduce the PAS-D Globule Burden Score of the subject, e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months.

[0276] In certain embodiments, the subject has a PiZZ genotype with a fibrosis score of 2 to 4.

[0277] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 1 15 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0278] In another example, the compounds disclosed herein may be used in a means of treating fibrosis in a subject suffering from Al AT-associated liver disease, comprising a step of administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject. In certain embodiments, a tablet comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered. In one embodiment, the means is a means of decreasing the stage of the fibrosis in the subject by at least one stage. In one embodiment, the step comprises administering a dose of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, once per day to the subject. In one embodiment, the step comprises administering a dose of the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, twice per day to the subject.

[0279] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, thepharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0280] In some embodiments, the AlAT-associated liver disease is hepatitis, hepatic fibrosis, hepatic cirrhosis, cholestasis, metabolic dysfunction-associated steatohepatitis, liver cancer, or is caused in part by or exacerbated by alcohol use.

[0281] In yet another aspect, the present disclosure provides a composition comprising a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt of solvate thereof (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3), for use in a method of treating fibrosis in a subject, wherein the subject has an Al AT deficiency. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the stage of fibrosis of the subject is any one of stages 1 through 4. In one embodiment, the stage of fibrosis in the subject is stage 1 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 2 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 3 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 4 prior to administration of the pharmaceutical composition. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 104 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 afteradministration of the pharmaceutical composition for 92 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 70 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 64 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 52 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 40 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 26 weeks or less. In one embodiment, the pharmaceutical composition is administered at least once per day to the subject. In one embodiment, the pharmaceutical composition is administered once per day to the subject. In one embodiment, the pharmaceutical composition is administered at least twice per day to the subject. In one embodiment, the pharmaceutical composition is administered twice per day to the subject. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0282] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A.

[0283] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating fibrosis in a subject, wherein the subject has an A1AT deficiency. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the stage of fibrosis of the subject is any one of stages 1 through 4. In one embodiment, the stage of fibrosis in the subject is stage 1 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 2 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 3 prior to administration of the pharmaceutical composition. In one embodiment the stage of fibrosis in the subject is stage 4 prior to administration of the pharmaceutical composition. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 104 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 92 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 70 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 64 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 52 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the pharmaceutical composition for 40 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of thepharmaceutical composition for 26 weeks or less. In one embodiment, the pharmaceutical composition is administered at least once per day to the subject. In one embodiment, the pharmaceutical composition is administered once per day to the subject. In one embodiment, the pharmaceutical composition is administered at least twice per day to the subject. In one embodiment, the pharmaceutical composition is administered twice per day to the subject. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0284] In one embodiment, pharmaceutical composition is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day.

[0285] In another embodiment, the compounds disclosed herein may be used in a means of treating fibrosis in a subject comprising administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersionor admixture (e.g., such as in Section 6.2.1), or tablet or capsule e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject. In certain embodiments, a pharmaceutical dosage form, e.g., a tablet, comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered.

[0286] In another example, the compounds disclosed herein may be used in a means of treating fibrosis in a subject comprising administering a sufficient amount of a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered.

[0287] In one embodiment, the subject has an Al AT deficiency. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the stage of fibrosis of the subject is any one of stages 1 through 4, prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 1 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 2 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition.In one embodiment, the stage of fibrosis of the subject is stage 3 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 4 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis of the subject by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 104 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 92 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 70 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 64 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 52 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 40 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for 26 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered at least once per day to the subject. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered once per day to the subject. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered at least twice per day to the subject. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered twice per day to the subject. In one embodiment, thecompound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is Compound 1-A (e.g., not a salt or solvate).

[0288] In one embodiment, the sufficient amount is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the sufficient amount is administered as a pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule containing about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0289] In another example, the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein are used in a method of treating fibrosis in a subject, the method comprising administering the pharmaceutical composition, plurality of granules, admixture, pharmaceutical dosage form, or tablet or capsule to a subject in need thereof. In one embodiment, the fibrosis in the subject is suffering from AlAT-associated liver disease.

[0290] In another example, provided herein is the use of the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein for the manufacture of a medicament for treating fibrosis in a subject. In one embodiment, the fibrosis in the subject is suffering from AlAT-associated liver disease.

[0291] In another example, the compounds disclosed herein may be used in a means of decreasing the stage of fibrosis in a subject by at least 1, comprising a step of administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject. In certain embodiments, a pharmaceutical dosage form, e.g., a tablet, comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered.

[0292] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0293] In another example, the compounds disclosed herein may be used in a means of decreasing the stage of fibrosis in a subject by at least 1, comprising a step of administering a sufficient amount of a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject. In certain embodiments, the pharmaceutical composition comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered.

[0294] In one embodiment, the subject has an A1AT deficiency. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has a mutant Z allele in the SERPINA1 gene, that is, the subject has a PiZ* genotype. In one embodiment, the subject has a PiZZ genotype. In one embodiment, the subject has a PiMZ genotype. In one embodiment, the subject has a fibrosis score of 1-4 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 1 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 2 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 3 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the stage of fibrosis of the subject is stage 4 prior to administration of the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 104 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 92 weeks orless. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 70 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 64 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 52 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 40 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered for 26 weeks or less. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered at least once per day to the subject. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered once per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered at least twice per day to the subject. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition is administered twice per day. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0295] In one embodiment, the sufficient amount is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the sufficient amount is administered as a pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule containing about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, thepharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0296] In another example, the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein are used in a method of decreasing the stage of fibrosis in a subject, the method comprising administering the compound, pharmaceutical composition, plurality of granules, admixture, pharmaceutical dosage form, or tablet or capsule to a subject in need thereof. In one embodiment, the fibrosis in the subject is suffering from Al AT-associated liver disease.

[0297] In another example, provided herein is the use of the compound, pharmaceutical composition, the admixture, the solid dispersion, the plurality of granules, the pharmaceutical dosage form, or the tablet or capsule disclosed herein for the manufacture of a medicament for decreasing the stage of fibrosis in a subject. In one embodiment, the fibrosis in the subject is suffering from Al AT-associated liver disease.

[0298] In another example, the compounds disclosed herein may be used in a method of increasing the level of Al AT in the plasma of a subject or in a method of treating fibrosis in a subject, wherein the subject has a PiMZ genotype and MASH, wherein the method comprises administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture (e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A, to the subject. In certain embodiments, a pharmaceutical dosageform, e.g., tablet, comprising Compound 1-A or a pharmaceutically acceptable salt or solvent thereof and a pharmaceutically acceptable excipient is administered.

[0299] In one embodiment, the level of A1AT in the plasma is increased to about 40 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 50 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 60 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 80 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased to about 90 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased to about 100 mg / dL or greater. In one embodiment, treating of fibrosis comprises decreasing the stage of fibrosis in the subject by at least 1 or stabilizing the fibrosis in the subject. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 250 mg, about 500 mg, about 625 mg, or about 750 mg of Compound 1-A per day. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 125 mg of Compound 1-A per day. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered once per day. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, is administered twice per day. In one embodiment, Compound 1-A or salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0300] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0301] In one embodiment, Compound 1-A may be administered to the subject having a PiMZ genotype and MASH in combination with an additional therapeutic agent. In one embodiment, the additional therapeutic agent is a therapeutic agent that treats MASH. As used herein, “in combination with” can include administering Compound 1-A and the additional therapeutic to the subject at the same time, either in a dosage form comprising both Compound 1-A and the additional therapeutic agent or in separate dosage forms. “In combination with” can also include administering Compound 1-A and the additional therapeutic to the subject at different times, e.g., on different dosing regimens. Administration of Compound 1-A and the additional therapeutic to the subject may be separate in time by 30 minutes, 1 hour, 12 hours, 24 hours, 48 hours, 72 hours, or longer. Non-limiting examples of therapeutic agents that treat MASH include incretin-based molecules, such as glucagon-like peptide- 1 receptor agonists, glucose-dependent insulinotropic polypeptide (GIP), glucagon receptor agonists, and thyroid hormone receptor beta agonists, such as resmetirom. In one embodiment, the subject having a PiMZ genotype and MASH may be administered the sufficient amount of Compound 1-A in combination with resmetirom to increase the level of A1AT in the plasma of a subject or to treating fibrosis in the subject.

[0302] In one embodiment, the compounds disclosed herein may be used in a method of treating fibrosis in a subject with metabolic dysfunction-associated steatohepatitis (MASH) and a PiMZ genotype, the method comprising administering Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a composition (e.g., such as in Section 6.2), pharmaceutical composition (e.g., such as in Section 6.3), plurality of granules (e.g., such as in Section 6.3.2), pharmaceutical dosage form (e.g., such as in Section 6.3.3), a solid dispersion or admixture e.g., such as in Section 6.2.1), or tablet or capsule (e.g., such as in Section 6.3.3) comprising Compound 1-A. In one embodiment, the subject has a fibrosis score of 3 or greater (compensated). In one embodiment, the subject is orally administered 25 mg to 250 mg (e.g, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg, e.g., in a tablet, daily. In one embodiment, the administration is effective to decrease the stage of the liver fibrosis by at least one stage, e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months. In one embodiment, the administration is effective to stabilize the fibrosis (e.g., the fibrosis does not worsen), e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months. In one embodiment, the administration is effective to improve an ELF score, FIB4 score, PROC3 score, MRE scan, and / or FibroScan, e.g., after administering for 3 months, 6 months, 9 months, 12 months, 24 months, 36 months, 48 months, or 60 months.

[0303] In one embodiment, the compound, composition, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose once per day to provide the daily amount of Compound 1-A. In one particular embodiment, the pharmaceutical composition is administered as a single dose twice per day to provide the daily amount of Compound 1-A.

[0304] In certain embodiments, the subject has MASH, a PiMZ genotype, and a fibrosis score of 3 or 4.

[0305] In certain embodiments, “treating fibrosis” may, in addition to alleviating symptoms or reducing or stabilizing the stage of liver fibrosis, include normalizing (e.g., reducing) levels of biomarkers that are indicative of hepatocyte endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR), such as calreticulin, heat shock protein 5, and prolyl 4- hydroxylase beta polypeptide. In certain embodiments, “treating fibrosis” may additionally or alternatively include normalizing biomarkers related to the biosynthetic function of the liver, such as normalizing (e.g., increasing) levels of thyroxine-binding globulin, factor VII coagulation factor, and C5 complement. In certain embodiment, “treating fibrosis” may include reducing a PAS-D (Periodic Acid Schiff positive and diastase resistant) Globule Burden Score in the subject by at least about 50% after administering Compound 1-A for a period of time, such as 6 months, a year, two years, three years, four years, or up to 5 years. In certain embodiment, “treating fibrosis” may include reducing a PAS-D Globule Burden Score in the subject by at least about 70% after administering Compound 1-A for a period of time, such as 6 months or a year. In certain embodiment, “treating fibrosis” may include improving a subject’s Enhanced Liver Fibrosis (ELF) score, Fibrosis-4 (FIB4) score, and / or PROC3 score. In certain embodiment, “treating fibrosis” may include improving a subject’s magnetic resonance elastography (MRE) scan and / or FibroScan (also known as “transient elastography”). In certain embodiment, “treating fibrosis” may include decreasing a Child-Turcotte-Pugh Score (CTP) score of a subject or decreasing the Model for End-Stage Liver Disease (MELD) score in a subject.

[0306] In another example, the compounds disclosed herein may be used to reduce or prevent polymerization of A1AT in a subject having a PiZ* genotype (e.g., PiZZ or PiMZ genotype). As such, the compounds disclosed herein may be used to prevent or slow the progression of liver fibrosis in a subject having a PiZ* genotype (e.g., PiZZ or PiMZ genotype).Similarly, the compounds disclosed herein may be used to prevent or delay the onset of A1AT- associated liver disease in a subject having a PiZ* genotype (e. , PiZZ or PiMZ genotype). In one embodiment, the subject has MASH. In one embodiment, the pharmaceutical composition is administered to such a subject to provide about 25 mg to about 250 mg of Compound 1-A per day, preferably about 25 mg to about 125 mg of Compound 1-A per day. In one embodiment, the pharmaceutical composition is administered to provide about 25 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 50 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 75 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 100 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 125 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 150 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is administered to provide about 250 mg per day of Compound 1-A. In one embodiment, the pharmaceutical composition is as described, e.g., in Section 6.3. In one embodiment, the pharmaceutical composition is administered orally, e.g., in the form of a tablet.6.5 Pharmacokinetics and Pharmacodynamics

[0307] Another problem addressed by the pharmaceutical compositions disclosed herein is how to increase the A1AT levels in the plasma of a subject suffering from AlAT-associated liver disease. In one embodiment, increasing the A1AT levels in the plasma of a subject suffering from AlAT-associated liver disease is effective to treat the AlAT-associated liver disease. In such patients, A1AT polymerizes in the liver. Polymerized Al AT is not readily secreted from the liver, and therefore accumulates in the liver causing liver disease, which typically manifests as fibrosis of the liver.[00308J Provided herein is a solution to this aforementioned problem, comprising administering Compound 1, and particularly Compound 1-A or a pharmaceutically acceptable solvate thereof to a subject in an amount sufficient to increase the Al AT level in the plasma of the subject. In one embodiment, the pharmaceutical composition disclosed herein, such as a solid oral composition such as those described herein, for example, a composition comprising a solid dispersion, plurality of granules, capsule, tablet, or sachet, as described herein, can be used to administer Compound 1, and particularly Compound 1-A or a pharmaceutically acceptablesolvate thereof to the subject. In certain embodiments, other formulations can be used. Compound 1, and particularly Compound 1-A or a pharmaceutically acceptable solvate thereof, shows good bioavailability in liquid form, for example, when it is dissolved. Thus, a variety of pharmaceutical compositions, such as liquid compositions, can be employed in certain embodiments. Exemplary liquid compositions comprising dissolved Compound 1, and particularly Compound 1-A or a pharmaceutically acceptable solvate thereof, include those containing vehicles with glycerol, caprylocaproyl macrogol-8 glycerides, water, ethanol, and the like.

[0309] In certain embodiments, a method of treating AlAT-associated liver disease in a subject comprises administering an amount of Compound 1, particularly Compound 1-A, or a pharmaceutically acceptable solvate thereof, to a subject that is sufficient to cause an increase of A1AT levels in the plasma of the subject. In one embodiment, plasma A1AT levels are increased to about 60 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 70 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 80 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 90 mg / dL or greater after the administering. In one embodiment, plasma A1AT levels are increased to about 100 mg / dL or greater after the administering.

[0310] In certain embodiments, a method of treating AlAT-associated liver disease in a subject comprises administering an amount of Compound 1, particularly Compound 1-A, or a pharmaceutically acceptable solvate thereof, to a subject that is sufficient to cause an increase of A1AT levels in the plasma of the subject. In one embodiment, plasma Al AT levels are increased to about 60 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 70 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 80 mg / dL or greater after the administering. In one embodiment, plasma A1AT levels are increased to about 90 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 100 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased to about 110 mg / dL or greater after the administering. In one embodiment, plasma A1AT levels are increased to about 120 mg / dL or greater after the administering.

[0311] In one embodiment, the level of A1AT in the plasma is increased by at least about 50 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 70 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 80 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 90 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 100 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL to about 90 mg / dL or greater.

[0312] In certain embodiments, a method of treating AlAT-associated liver disease in a subject comprises administering an amount of Compound 1, particularly Compound 1-A, or a pharmaceutically acceptable solvate thereof, to a subject that is sufficient to cause an increase of A1AT levels in the plasma of the subject. In one embodiment, plasma A1AT levels are increased by about 60 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased by about 65 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased by about 70 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased by about 80 mg / dL or greater after the administering. In one embodiment, plasma A1AT levels are increased by about 90 mg / dL or greater after the administering. In one embodiment, plasma Al AT levels are increased by about 100 mg / dL or greater after the administering. In one embodiment, plasma Al AT are increased by about 60 mg / dL to about 70 mg / dL after the administering. In one embodiment, plasma Al AT are increased by about 65 mg / dL to about 70 mg / dL after the administering. In one embodiment, plasma Al AT are increased by about 65 mg / dL to about 75 mg / dL after the administering.

[0313] In one embodiment, the level of A1AT in the plasma is increased by at least about 50 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 70 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 80 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about90 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 100 mg / dL. In one embodiment, the level of Al AT in the plasma is increased by at least about 60 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of Al AT in the plasma is increased by at least about 65 mg / dL to about 70 mg / dL or greater. In one embodiment, the level of A1AT in the plasma is increased by at least about 65 mg / dL to about 90 mg / dL or greater.

[0314] In certain embodiments, administering a Compound 1, particularly Compound 1-A, or a pharmaceutically acceptable solvate thereof as disclosed herein to a subject causes a decrease in concentration of Al AT in the liver of the subject.

[0315] Another problem addressed by the compounds and pharmaceutical compositions disclosed herein is how to treat fibrosis in a subject suffering from AlAT-associated liver disease and particularly a subject having stage 1 or greater fibrosis. In some embodiments, administering a Compound 1, particularly Compound 1-A, or a pharmaceutically acceptable solvate thereof as disclosed herein to a subject treats fibrosis in the subject. In one embodiment, the subject has a fibrosis score of 1-4 prior to administration of 1-A or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the subject has a fibrosis stage of 1 prior to administration of 1-A or a pharmaceutically acceptable salt or solvate thereof. In one embodiment the subject has a fibrosis stage of 2 prior to administration of 1-A or a pharmaceutically acceptable salt or solvate thereof. In one embodiment the subject has a fibrosis stage of 3 prior to administration of 1-A or a pharmaceutically acceptable salt or solvate thereof. In one embodiment the subject has a fibrosis stage of 4 prior to administration of 1-A or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 104 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 92 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 70 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 64 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 52 weeks or less. In one embodiment, the treatment offibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 40 weeks or less. In one embodiment, the treatment of fibrosis comprises decreasing the stage of fibrosis by at least 1 after administration of the pharmaceutical composition for 26 weeks or less. In one embodiment, Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof. In one embodiment, Compound 1-A or a pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

[0316] In any aforementioned embodiment, the subject may be a human, optionally being homozygous for alpha 1-antitrypsin deficiency, optionally being of the genotype PiZZ. In any aforementioned embodiment, the composition that is administered to the subject comprises Compound 1 as an active pharmaceutical ingredient. In any aforementioned embodiment, the composition that is administered to the subject comprises only Compound 1 as the active pharmaceutical ingredient. In any aforementioned embodiment, the composition that is administered to the subject comprises Compound 1-A as an active pharmaceutical ingredient. In any aforementioned embodiment, the composition that is administered to the subject comprises Compound 1-A as the only active pharmaceutical ingredient.

[0317] In any aforementioned embodiment, the composition may be administered to the subject at least once per day. In such embodiments, the increased plasma A1AT levels in the subject (e.g., an increase to at least 40 mg / dL, 50 mg / dL, 60 mg / dL, 70 mg / dL, 80 mg / dL, 90 mg / dL, 100 mg / dL, 110 mg / dL, or 120 mg / dL; or an increase by at least 40 mg / dL, or 50 mg / dL, or 60 mg / dL, or 70 mg / dL, or 80 mg / dL, or 90 mg / dL, or 100 mg / dL; or an increase by at least about 60 mg / dL to about 70 mg / dL or greater, or. by at least about 65 mg / dL to about 70 mg / dL or greater, or by at least about 65 mg / dL to about 90 mg / dL or greater) may be reached after daily administration for 28 or fewer days. In some embodiments, the aforementioned increased plasma A1AT levels in the subject may be reached after daily administration for 14 or fewer days. In yet further embodiments, the aforementioned increased plasma A1AT levels in the subject may be reached after daily administration for 7 or fewer days.

[0318] In any aforementioned embodiment, the composition may be administered to the subject at least once per day. In such embodiments, the increased plasma A1AT levels in the subject (e.g., an increase to at least 40 mg / dL, 50 mg / dL, 60 mg / dL, 70 mg / dL, 80 mg / dL, 90 mg / dL, 100 mg / dL, 110 mg / dL, or 120 mg / dL; or an increase by at least 40 mg / dL, or50 mg / dL, or 60 mg / dL, or 70 mg / dL, or 80 mg / dL, or 90 mg / dL, or 100 mg / dL; or an increase by at least about 60 mg / dL to about 70 mg / dL or greater, or. by at least about 65 mg / dL to about 70 mg / dL or greater, or by at least about 65 mg / dL to about 90 mg / dL or greater) may be reached after daily administration for 28 or fewer days. In some embodiments, the aforementioned increased plasma Al AT levels in the subject may be reached after daily administration for 14 or fewer days. In yet further embodiments, the aforementioned increased plasma A1AT levels in the subject may be reached after daily administration for 7 or fewer days.

[0319] In embodiments where fibrosis is treated, the decrease of fibrosis by at least one stage may be accomplished after daily administration for 104 weeks or less. In some embodiments, the aforementioned decrease of fibrosis by at least one stage may be accomplished after daily administration for 92 weeks or less. In further embodiments, decrease of fibrosis by at least one stage may be accomplished after daily administration for 70 weeks or less. In yet further embodiments, decrease of fibrosis by at least one stage may be accomplished after daily administration for 64 weeks or less. In still further embodiments, decrease of fibrosis by at least one stage may be accomplished after daily administration for 52 weeks or less. In yet still further embodiments, decrease of fibrosis by at least one stage may be accomplished after daily administration for 40 weeks or less. In additional embodiments, decrease of fibrosis by at least one stage may be accomplished after daily administration for 26 weeks or less.

[0320] In one embodiment, the therapeutic effect of Compound 1 -A is not substantially influenced by whether Compound 1-A is administered to a subject in a fed or fasted state. In certain embodiments, the total exposure (z.e., AUCo-«>) to Compound 1-A after administration of a pharmaceutical dosage form containing Compound 1-A is substantially food independent.7. EXAMPLES

[0321] In these examples, N-[(lR)-l-[(S)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide is sometimes abbreviated “API”.Analytical Methods

[0322] HPLC

[0323] In the following examples, unless otherwise specified, HPLC analyses are performed with a Waters Acquity H-CLASS system with UV Detection equipped with an Acquity UPLC CSH-C18 (1.7 pm, 2.1 x 100 mm) column (Waters Corporation, Milford, MA, USA). Thecolumn temperature was 45 + / - 2 °C and the auto sampler temperature was 5 + / - 3 °C. Samples were injected as 0.1 mg / mL solutions in 50 / 50 acetonitrile / water with a 1 pL injection volume. The flow rate was 0.4 mL / min and run time was 11.0 min. The UV detector was set at 220 nm. Gradient elution was performed, using a mixture of 0.1% trifluoracetic acid in water (Mobile Phase A or “MPA”) and 0.1% trifluoracetic acid in acetonitrile (Mobile Phase B or “MPB”). The elution gradient is shown below in Table 1.Table 1: Gradient Elution Program

[0324] Thermogravimetric Analysis

[0325] Approximately 5 mg of API was heated in a thermogravimetric analyzer, in which the sample mass was monitored while the sample was heated. This test was performed as single sample with no replicates. The API was heated at a rate of 2.5 °C / min up to 300 °C. The heating rate was chosen to match a typical heating rate used in differential scanning calorimetry experiments. The conservative onset of degradation was taken to be the temperature at which the weight began to deviate from the tangent line.Example A: Synthesis of Compound 1

[0326] The synthesis of Compound 1 has been previously described in US Patent Publication 20220340525A1, which is incorporated herein by reference with respect to its disclosure of the synthesis of Compound 1. Compound 1 may be synthesized by the following methods:

[0327] In a round bottom flask, sodium carbonate (68.0 g, 0.64 mol) was added to a suspension of 2-aminopentanoic acid (75.0 g, 0.64 mol) in water (250 mL) at room temperature. A solution of di- / c / 7-butyl dicarbonate (139.9 g, 0.64 mol) in tetrahydrofuran (400mL) was added dropwise over one hour. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure (approx. 400 mL). A saturated solution of citric acid (300 mL) was added until pH reached the value of about 3. The aqueous layer was washed with ethyl acetate (4><500 mL). The organic portions were collected, dried over magnesium sulfate, and evaporated under reduced pressure to obtain 2-((tert- butoxycarbonyl)amino)pentanoic acid.

[0328] 4-Methylbenzene-l -thiol (53.5 g, 0.43 mol) and 1 -hydroxybenzotriazole (50.0 g, 0.59 mol) were added to a solution of 2-((tert-butoxycarbonyl)amino)pentanoic acid (85.0 g, 0.39 mol) in ethyl acetate (800 mL) in a round bottom flask. The mixture was cooled to 0 °C and N,N'-dicyclohexylcarbodiimide (80.5 g, 0.39 mol) was added. The reaction mixture was stirred at room temperature for 16 h. The white solid formed was then removed by suction filtration. The filtrate was washed with a saturated solution of NaHCO.3 (700 mL), water (700 mL) and brine (700 mL). The organic portion was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude material as a white solid. The crude material was purified by flash chromatography to afford (S-p-tolyl 2-((tert- butoxycarbonyl)amino)pentanethioate.

[0329] Triethyl phosphite (10.6 g, 64.0 mmol) was added to a round bottom flask containing a mixture of (3-fluoro-2-methylphenyl)boronic acid (50 g, 0.32 mol), S-p-tolyl 2-((tert- butoxycarbonyl)amino)pentanethioate (53.2 g, 0.16 mol), tris(dibenzylideneacetone)dipalladium(0) (7.3 g, 8.0 mmol) and copper(I) thiophene-2- carboxylate (61.0 g, 0.32 mol) in 1,4-dioxane (500 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h and then was filtered over a celite pad. The solvent was evaporated under reduced pressure and the crude was dissolved in ethyl acetate (500 mL). The solution was washed with water (500 mL) and brine (2><500 mL). The organic portion was dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude material (100 g) as black oil. A 65 g batch of the crude material was purified by flash chromatography to afford tert-butyl (1 -(3 -fluoro-2-m ethylphenyl)- l-oxopentan-2-yl)carbamate.

[0330] Tert-butyl (l-(3-fluoro-2-methylphenyl)-l-oxopentan-2-yl)carbamate (18.7 g, 60.4 mmol) was dissolved in toluene (150 mL) in a round bottom flask. Isopropanol (100 mL) and aluminum isopropoxide (49.4 g, 241.8 mmol) were added at room temperature. The solution was stirred at 50 °C for 16 h and then it was poured into a NH4CI saturated solution and extracted with ethyl acetate (4x300 mL). The organic portions were collected, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain crude material. This crudematerial was purified by flash chromatography to afford tert-butyl- 1 -(3 -fluoro-2-methylphenyl)- 1 -hydroxypentan-2-yl)carbamate.

[0331] In a round bottom flask, tert-butyl- 1 -(3 -fluoro-2-methylphenyl)- 1 -hydroxypentan-2- yl)carbamate (15.8 g, 50.74 mmol) was dissolved in HC1 in dioxane (4 M, 100 mL) at 0 °C. The mixture was stirred for 2 h at the same temperature and the solvent was evaporated. The residue was suspended in 300 mL of diethyl ether and stirred for 1 h. The suspension was filtered to obtain (lS,2R)-2-amino-l-(3-fluoro-2-methylphenyl)pentan-l-ol hydrochloride.100332] In a round bottom flask, HATU (19.8 g, 51.9 mmol) was added to a solution of -2- amino-l-(3-fluoro-2-methylphenyl)pentan-l-ol hydrochloride (12.9 g, 51.9 mmol), 2- oxoindoline-4-carboxylic acid (9.2 g, 51.9 mmol) and triethylamine (10.5 g, 103.9 mmol) in dimethylformamide (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then diluted with ethyl acetate (200 mL). The solution was washed with a saturated solution of NaHCCh (100 mL) and brine (2><100 mL). The organic portion was dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude material, which was purified by flash chromatography to afford N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro- 2-oxoindoline-4-carboxamide (Compound 1).Example B: Synthesis of Compound 1-A (N-[(lR)-l-[(S)-(2-chloro-3- fluorophenyl)hydroxymethyl]butyl]-7-fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide) Step 1: Preparation of tert-butyl (R)-(l-(methoxy(methyl)amino)-l-oxopentan-2- yl)carbamate (Compound 2-A)Part A

[0333] (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid dicyclohexylamine (1 eq), was added to a reactor followed by 2-MeTHF (10 vol) and agitated. The slurry was cooled to -10 °C to -5 °C after which 10% aqueous sulfuric acid (5 vol) was added slowly over a period of 15 minutes maintaining the temperature at or below 20 °C. The mixture was then warmed to room temperature and stirred for at least 30 minutes. The mixture was allowed to settle, and the aqueous (bottom) layer was discharged. The remaining organic layer was washed with 10% aqueous sulfuric acid, a mixture of water and brine, and brine. Azeotropic distillation followed by filtration provided a solution of (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid in 2- MeTHF.Part B

[0334] In a separate reactor, DMF (2 vol), 7V,O-dimethylhydroxylamine hydrochloride (1.2 eq), and 2-MeTHF (4 vol) were combined and agitated. Triethylamine (1.2 eq) was slowly added over a period of 30 minutes at a temperature of 30 °C or less. The reaction mixture was stirred at room temperature for at least one hour then cooled to -2 °C to 2 °C.Part C

[0335] In a separate reactor CDI (1.1 eq) was combined with 2-MeTHF (4 vol) and agitated under nitrogen atmosphere. The slurry was cooled to -2 to 2 °C after which the (R)-2-((tert- butoxycarbonyl)amino)pentanoic acid solution in 2-MeTHF was added slowly while maintaining a temperature of no more than 2 °C, and the reaction mixture was stirred for at least 1 hour.

[0336] The reaction mixture was then slowly added to the Part B reactor while maintaining the temperature of the reaction mixture at or below 2 °C. The reaction mixture was then warmed to room temperature and stirred for at least 3 hours. The reaction mixture was then slowly quenched with HC1 (IN) at a temperature of 25 °C or less, followed by washing with HC1 (1 N), with potassium phosphate dibasic (5% aqueous), with water, and with brine. The product was azeotropically distilled, cooled to room temperature, and filtered to yield a solution of tert-butyl (R)-(l -(methoxy (methyl)amino)-! -oxopentan-2 -yl)carbamate (Compound 2-A) in 2-MeTHF.Step 2: Preparation of tert-butyl (R)-(l-(2-chloro-3-fluorophenyl)-l-oxopentan-2- yl)carbamate (Compound 4-A)Part A

[0337] A solution of isopropylmagnesium chloride (2 M in THF, 1.87 eq) was added to 1- bromo-2-chloro-3 -fluorobenzene (1.7 eq) in 2-MeTHF (3.8 vol) maintaining the temperature of the reaction mixture at or below 5 °C. The reaction mixture was stirred for at least 2.5 hours.Part B

[0338] In a second reactor, 2-MeTHF (7 vol) was added to tert-butyl (R)-(l - (methoxy(methyl)amino)-l -oxopentan-2-yl)carbamate (Compound 2-A) and the reaction mixture was cooled to -10 to -5 °C. A solution of isopropylmagnesium chloride (2 M in THF, 1.0 eq) was then added over a period of 1 hour, maintaining the temperature at or below 5 °C.Part C

[0339] The product of Part A was slowly added to the reactor from Part B while maintaining a temperature at or below 15 °C. The reaction mixture was then warmed to 46 °C to 48 °C over a period of 2 hours then stirred at that temperature for 7 hours. The reaction mixture was then slowly quenched with acetic acid (6 eq) at room temperature, followed by washing with acetic acid, with water and brine, with aqueous potassium phosphate dibasic (15%), with water and brine, and with brine. The reaction mixture was then distilled to change solvents to 2- propanol. Following cooling to -5 °C to 0 °C over 2 hours, water (8 vol) was charged to crystallize the product, which was then isolated by filtration and dried to yield tert-butyl (R)-( 1 - (2-chloro-3-fluorophenyl)-l-oxopentan-2-yl)carbamate (Compound 4-A).Step 1-3: Preparation of Compound 6-A

[0340] Toluene (6 vol) and isopropyl alcohol (11 eq) were added to tert-butyl (R)-(l-(2- chloro-3 -fluorophenyl)-! -oxopentan-2 -yl)carbamate (Compound 4-A, 1 eq) and aluminum isopropoxide (0.2 eq) at room temperature. The reaction mixture was heated to 50 °C over 2 hours and agitated at the same temperature for at least 10 hours. The reaction mixture was then cooled to room temperature and quenched with HC1 (IN), followed by washing with HC1 (1 N), with potassium phosphate dibasic (5% aqueous), with water, and with brine.

[0341] The reaction mixture was then distilled to switch solvents to toluene, filtered, and cyclopentyl methyl ether (CMPE, 4 vol) was added. HC1 (3 M) in CPME (7 eq) was then added slowly over a period of 1 hour while maintaining the temperature below 30 °C. The mixture was then stirred at room temperature for at least 24 hours. (lS,2R)-2-amino-l-(2-chloro-3- fluorophenyl)pentan-l-ol hydrochloride (Compound 6-A) was isolated by filtration, and dried.

[0342] The foregoing synthetic conditions, i.e., as specified in Step 1-3 above, provided a high yield of the 1-A enantiomer of Compound 1. If instead a mixture of 1-A and 1-D enantiomers is desired, a non-stereoselective reducing agent, such as sodium borohydride, may be used under the same conditions.Step 1-4: Preparation of Compound 1-A6-A 1-A

[0343] 7 -Fluoro-2-oxoindoline-4-carboxylic acid (Compound 7, 1.2 eq), DMAP (2.5 eq) andEDC (1.5 eq) were charged to a pre-cooled reactor at 0 °C under nitrogen. DMF (5.5 vol) was added followed by (lS,2R)-2-amino-l-(2-chloro-3-fluorophenyl)pentan-l-ol hydrochloride (Compound 6-A). The reaction mixture was warmed to room temperature and stirred for at least 4 hours. Ethyl acetate (8 vol) was added, and the reaction mixture cooled to 13 - 17 °C. I N HC1 (5 vol) was then charged to the reactor and the reaction mixture was agitated. The reaction mixture was then filtered, and the filtrate allowed to settle, after which the lower aqueous phase was removed from the upper organic phase. The organic phase was then washed with 1 N HC1 and brine, potassium phosphate dibasic (5%) and brine, and then with water and brine, followed by brine. The reaction mixture was then distilled with ethyl acetate. The temperature was adjusted to 50-55 °C, and SilaMet S thiol resin (10 wt. %) was added and the resulting mixture stirred at the same temperature for at least 3 hours. The reaction mixture was then filtered, and the solvent was switched to ethanol. The reaction mixture was cooled to 15-20 °C over at least 1.5 h and stirred. Heptane (27 vol) was then added to obtain a slurry. Compound 1-A was isolated by filtration, washed with 4: 1 heptane / ethanol, dried, and analyzed by chiral HPLC, which revealed no detectable amount of Compound 1-B, 1-C, or 1-D. Due to instrument error of ± 0.2%, the stereochemical purity of the obtained compound was determined to be 99.8% or greater.

[0344] Step l-4a: First Exemplary Synthesis of Compound 7: 4-bromo-7-fluoroindoline- 2,3-diketone (50 g, 205 mmol) and hydrazine hydrate (15.4 g (250 mmol, 80%) was added to ethylene glycol (250 mL) in a 500 mL three-necked flask and the reaction mixture was stirred for 30 minutes maintaining the temperature at 55-65 °C. The reaction was allowed to occur for 2-6 hours. The temperature was lowered to room temperature, and filtration was carried out to obtain 60 g of a crude product. In a separate three-neck flask, ethylene glycol (500 mL) and sodium acetate (1.7 g, 20.5 mmol) were added to the crude product (60 g) and the reaction temperature was raised to 145 °C after which the contents of the flask were concentrated under reduced pressure to a third of the original volume, cooled to 0-10 °C, filtered, leached with 100 mL of water, and dried in vacuum to obtain 40 g of 4-bromo-7-fluoroindolin-2-one. Methanol (300 mL), 4-bromo-7-fluoroindolin-2-one (30 g), triethylamine (27 mL), and (dppfjPdCh (21.55 g) were charged to a 500 mL pressure reactor, which was purged with CO three times, maintaining the pressure of CO in the reaction kettle at 0.5 mPa and the temperature at 115-125 °C. Thereaction was carried out for 10 h after which the reaction mixture was cooled to room temperature and concentrated. DMF and DCM were added, and the mixture was stirred for 30 minutes then filtered to obtain 23 g of 4-(but-l-en-2-yl)-7-fluoroindolin-2-one. Methanol (100 mb) and 4-(but-l-en-2-yl)-7-fluoroindolin-2-one (20 g, 95.7 mmol) were charged to a 250 mb three-neck flask and sodium hydroxide (7.7 g, 191 mmol) and water (100 mb) were added. The reaction mixture was stirred for 30 minutes at a temperature of 40 to 60 °C for 5 hours. The reaction mixture was then concentrated, and the pH adjusted to 1-2 with 1 M hydrochloric acid. The mixture was filtering to obtain 17.7 g of Compound 7.

[0345] Step l-4b: Second Exemplary Synthesis of Compound 7:

[0346] A solution of 4-bromo-7-fluoro-indolin-2-one (1.0 eq) in THF (7.0 vols) was charged to a mixture of sodium hydride in mineral oil (60% w / w, 2.76 eq) and THF (3.0 vols) at 5 ± 5 °C in a first vessel. The mixture was stirred for 10 mins at 5 ± 5 °C and a solution of tertbutyldimethylsilyl chloride (TBDMS-C1, 2.56 eq) in THF (2.5 vols) was charged at 5 ± 5 °C. The mixture was warmed to 20 to 25 °C and stirred for 2 hours until reaction completion. The reaction mixture was cooled to -10 °C. A biphasic mixture of 1 M potassium phosphate buffer (10.0 vols) and n-heptane (12.0 vols) was cooled to 15 ± 5 °C in a second vessel. The contents of the first vessel were added to the second vessel over approximately 1 hour, during which time off-gassing was controlled by the rate of addition and a temperature of 15 ± 5 °C was maintained. The residue in the first vessel was rinsed into the second vessel with THF (1 .0 vols). The biphasic mixture was warmed to 25 ± 5 °C and the two phases were separated. The organic layer was washed with water (10.0 vols) at 25 ± 5 °C and distilled in vacuo to 8 volumes at approximately 50 °C. n-Heptane (3.0 vols) was added, and the mixture was distilled in vacuo to 8 volumes at approximately 50 °C. The mixture was cooled to 25 ± 5 °C and analyzed for THF content by GC-HS. Basic aluminum oxide (0.1% w / w) was added, followed by rinsing with n- heptane (1.0 vols) and the mixture was stirred at 25 ± 5 °C for about 1 hour. The slurry was filtered into a third vessel, followed by a line rinse with n-heptane (2.0 vols). The followingprocedure was repeated three times: isopropanol (9.0 vols) was added, and the solution was distilled to 7 to 8 volumes at NMT 60 °C. The mixture was heated at 75 to 80 °C until dissolution was confirmed. The solution was cooled to 17 ± 3 °C at 0.2 °C / min and held at this temperature for approximately 22 hours. The solid was fdtered off, washed with isopropanol (4.0 vols) at 17 ± 3 °C, and dried in vacuo at 50 ± 5 °C. This resulted in 4-bromo-l-(tert- butyldimethylsilyl)-2-((tert-butyldimethylsilyl)oxy)-7-fluoro-lH-indole as Compound 8:

[0347] A solution of the bis-silyl-bromo-oxindole intermediate (Compound 8, 1.00 eq) in THF (6.8 vols) was cooled to 4°C in a vessel. Isopropyl magnesium chloride in THF (2 M, 0.47 eq) was added to the vessel over 8 minutes, followed by the addition of n-butyl lithium in hexanes (2.5 M, 0.93 eq) over 10 minutes at 0-5 °C. The mixture was stirred for 15 minutes. Gaseous carbon dioxide (1.5 eq) was added by sparging, with the gas addition rate adjusted as needed to maintain the reaction temperature <10 °C, after which time the mixture was stirred at 0 °C for 70 minutes. The mixture was diluted with methanol (1.4 vol) then 85% w / w H3PO4 (2.5 eq) was added. The mixture was warmed to 25°C over 3 hours and stirred for at least 16 hours. Water (6 vols) was added and the mixture was agitated for 30 minutes. The pH of the mixture was adjusted to pH < 2 by addition of 85% w / w aqueous H3PO4 and stirred for another 30 minutes. The solids were isolated by fdtration, washed with water (2 x 1 .4 vols) THF:MeOH (85:15 v / v, 1.4 vol), then MeOH (1.4 vol) and dried at 50 °C under vacuum to give Compound 7.Example C: Preparation of Crystalline API

[0348] The compound from Example B (5 g) was taken in 100 mL of methanol (MeOH) and heated at 40 °C for 30 minutes. Then 100 mL of heptane was added. The resultant solution was then kept at room temperature overnight. Then the solution was further cooled to -20 °C for 2 hours. Solid were filtered and dried under vacuum for 2 hours at room temperature. The obtained solid was further dried at 50 °C for 2-4 hours.Comparative Examples 1-5: Crystalline Solubility of API

[0349] Crystalline API was characterized for its aqueous solubility by starting with an aqueous media as specified in Table 2, below, saturated with crystalline N-(l-(2-chloro-3- fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide at 0.5-2 mg / mL at 37 °C. Samples were centrifuged at 15,800 g for 1 minute. An aliquot of the sample was removed and centrifuged at 300,000 g for 8 minutes. Fractions of each supernatant were diluted for HPLC analysis. All samples were measured in duplicate. Results are reported in Table 2.Table 2: Crystalline Solubility of APIComparative Examples 6-11 and Reference Examples 1-2: Solubility of API in Surfactants

[0350] To attempt to improve solubility of crystalline API, the use of surfactants was investigated. 20 mg of each surfactant listed in Table 3 below was filled in glass tubes (HPLC vials, 1.5 mL; 32 x 11.6 mm). A 50 pL aliquot of 2 mg / mL solution of 2 mg / mL N-(l-(2-chloro- 3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide in methanol was added. Control samples were prepared by the same procedure without adding the N-(l-(2-chloro- 3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide. All surfactants were stable under the test conditions (detailed results not shown). Reference samples of N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide were prepared by the same procedure without adding surfactants.

[0351] After 15 minutes at room temperature, the solvent was evaporated using a centrifugal vacuum evaporator (DD-4 Genevac Technology, Suffolk, UK) at 45 °C for 30 min.

[0352] Samples were stored at 40 °C / 75% relative humidity in open vials or -20 °C / ambient humidity in closed vials, as specified. After 4 weeks storage under applicable conditions, the N- ( 1 -(2-chl oro-3 -fluorophenyl)- 1 -hy droxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide was extracted by adding 1,000 pL methanol to each tube, vortexing for 2-5 minutes, and incubating for 30 minutes at room temperature. 250 pL aliquots of the obtained suspensions were centrifuged and filtered through 0.2 pm modified nylon low protein filters in centrifugal Eppendorf tubes (part no. 516-0233, VWR, Randor, PA, USA) at 1850 x g speed for 1 minute and analyzed by HPLC to determine percent degradation. Samples were considered stable if the percent degradation was less than 10% in both stability conditions. Percent degradation was determined by comparing the area under the curve of the sample peaks to the area under the curve of a reference peak.

[0353] Results are shown in Table 3. Under the test conditions, the API is not chemically stable in the presence of the surfactants in Table 3.Table 3: API Stability in SurfactantsJSOLUPLUS® is a polymeric solubilizer with an amphiphilic chemical structure available from BASF North America (Florham Park, NJ, US).2TWEEN® is also known as polysorbate 80.3KOLLIPHOR® RH 40 is nonionic solubilizer and emulsifying agent obtained by reacting 40 moles of ethylene oxide with 1 mole of hydrogenated castor oil and is available from BASF.4CE denotes comparative example.5RE denotes reference example.NAI-1541065753vl129Comparative Examples 12-20: Nanomilling

[0354] To attempt to improve solubility of crystalline API, API was subjected to nanomilling. Mixtures of materials as shown in Table 4 were nanomilled for the indicated duration. Milling was performed using a LabRAM II Acoustic Mixer (Resodyn, Montana, USA), adapted with a 9-vial jacketed vessel fixture. The milling containers were 2 mb propylene cryo- vials. The milling containers were loaded with 0.75 mb of 0.5 mm zirconia high wear resistant grinding spheres, and then adding the 1.5 g suspension of the materials as specified in Table 4. The excipients were added first, followed by the active pharmaceutical ingredient. Milling was performed at 60 G for the specified time. The milled media suspension was passed through a #20 (850 pm) sieve to remove the zirconia spheres. Before analysis, an aliquot of the resulting suspension was then spray dried using a 2-fluid nozzle at 5 g / min. Polydispersity indexes (PDI) and z-average particle size were measured by laser diffraction using a Zetasizer Ultra Red ZSU3305 (Malvern Panalytical Ltd, Malvern, UK) apparatus, and remeasured by the same method two days and one week after storage in aqueous solvent under ambient conditions.

[0355] Trials that produced product having sufficiently small particle size (except for CE8, which was not further studied because N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7- fluoro-2-oxoindoline-4-carboxamide is chemically unstable in the presence of poloxamer - see CE4) were stored under ambient conditions for 2 days or 1 week, after which time the z-average particle size and poly dispersity index were measured again.Table 4: Nano-milled Compositions and StabilityExamples 1-6 and Comparative Examples 21-22: Amorphous Solubility and Sustainment

[0356] To understand solubility of the API in biologically relevant environments, the solubility of amorphous API was tested in simulated intestinal fluid.

[0357] A stock solution of API in 95 / 5 THF / water at 225 mg / mL was prepared. The solution was loaded into 1 mb syringes and dosed into 10 mL of the indicated liquid (note: PBS stands for phosphate buffered saline at pH 6.5, SIF stands for simulated intestinal fluid) using a syringe pump at 25 pL / min. UV-Vis spectral data was recorded using fiber optic probes across the 200 - 720 nm range. Scattering was monitored at 400 nm. The maximum concentration achieved refers to the maximum concentration of API and was determined by monitoring the second derivative of the absorbance at 305 - 320 nm. Sustainment time is the time at which the maximum achievedconcentration begins to decrease, presumably due to crystallization and precipitation of the N-(l- (2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide.

[0358] The results from the amorphous solubility and polymer sustainment tests are summarized in Table 5. Where present, polymers are at a concentration of 500 pg / mL.Table 5: Amorphous Solubility and Polymer Sustainment^BS = phosphate buffered saline, pH 6.52SIF = 0.5% simulated intestinal fluid*polymer solution was hazy, measured concentration is artificially inflated above the actual dose of APIExamples 7-11: Preparation of Solid Dispersions

[0359] Solubility of the crystalline API was next attempted in spray solutions. Solid dispersions were manufactured using a Bend Lab Dryer (BLD-35) with 35 kg / hr drying gas capability. The desired spray solutions were prepared by dissolving the API and the dispersion polymer in acetone at a 2-3 wt.% solids loading, except for HPMC E3 where the solvent was methanol, and the solids loading was 1.5 wt.%. The atomization pressure was 120 PSIG, the dryer inlet temperature was 106 + / - 1 °C (except for HPMC E3, where the inlet temperature was 134 °C) and the outlet temperature was 40 °C (except for HPMC E3, where the outlet temperature was 40 °C). Residual solvent was removed by drying overnight under vacuum at 40 °C. Table 6 shows each spray-dried dispersion.Table 6: Spray-Dried DispersionsAPI loading refers to the wt. % API in the final solid dispersion. The remainder of each dispersion is the dispersion polymer.Examples 12-13 and Comparative Examples 23-24[00360J Two lead SDD formulations (33 / 67 API / HPMCAS-M and 33 / 67 API / HPMC E3) were selected and compared with the SDNC and bulk API in the membrane flux dissolution test.

[0361] Membrane flux tests were performed as shown in FIG. 1, by placing the sample in a donor vessel and adding 5 mb of 0.5% SIF in lx PBS (pH 6.5). A receiver vessel having a glass tube and a lipid-filled polypropylene membrane (PION GIT-0 Lipid Solution, available from Pion Inc (UK) Ltd. East Sussex, UK, which was used to saturate an Accurel PP IE membrane, available from 3M Company, St. Paul, MN, USA) is placed in contact with the donor vessel so that the membrane separates the two vessels. The receiving vessel is fdled with 10 mL of 2% SLS in lx PBS (pH 6.5). Samples were maintained at 37 °C for the duration of the test with a custom heating block mounted on a Pion pDiss Profiler. Results are reported in Table 7.Table 7: Membrane Flux Dissolution TestExamples 14-32 and Reference Examples 3-4

[0362] Samples of Examples 7, 8, and 10 were stored at 25 °C / 60% relative humidity or40 °C / 75% relative humidity for three months. An aliquot was removed at one and three months for dissolution testing, which was performed following the centrifugation method that was used for Comparative Examples 6-11. The one- and three-month aliquots were also examined by XRPD. All XRPD tests showed no distinct or sharp peaks, thus no evidence of crystallinity was observed. Dispersion formulations still show fast dissolution even upon aging, as shown in FIGS. 2-4 and in Tables 8-10.Table 8: Dissolution of Example 7 After AgingTable 9: Dissolution of Example 8 After AgingTable 10: Dissolution of Example 10 After...

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising: an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form, and at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form; optionally wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form in the solid dispersion does not decrease by more than 10% after one month at 25 °C and 60% relative humidity.

2. A pharmaceutical composition comprising an admixture of Compound 1-A or a pharmaceutically acceptable salt or solvate thereof and at least one polymer selected from the group consisting of polyethylene oxide, a polymethacrylate-based copolymer, ethylene-vinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene,ethylene-methyl acrylate (EMA), ethylene n-butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC.

3. The pharmaceutical composition of claim 1 or claim 2, wherein the polymer is selected from the group consisting of one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC.

4. The pharmaceutical composition of claim 2 or claim 3, wherein the admixture is a solid dispersion.

5. The pharmaceutical composition of any one of claims 2-4, wherein Compound 1-A is in a solid, amorphous form.

6. The pharmaceutical composition of claim 1 or any one of claims 3-5, wherein the active pharmaceutical ingredient comprises one or more of compounds 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable solvate thereof.

7. The pharmaceutical composition of claims 1-6, wherein Compound 1-A or a pharmaceutically acceptable salt or solvate thereof is a pharmaceutically acceptable solvate of Compound 1-A, preferably wherein Compound 1-A or a pharmaceutically acceptable salt or solvate thereof is Compound 1-A (i.e., not a salt or solvate).

8. The pharmaceutical composition of claim 1 or any one of claims 5-7, wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form does not decrease by more than 5% after three months at 25 °C and 60% relative humidity.

9. The pharmaceutical composition of claim 1 or any one of claims 5-8, wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form does not decrease by more than 10% after one month, and preferably after three months, at 40 °C and 75% relative humidity.

10. The pharmaceutical composition of claim 1 or any one of claims 5-9, wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form does not decrease by more than 2.5% after one month, and preferably after three months, at 25 °C and 60% relative humidity.

11. The pharmaceutical composition of claim 1 or any one of claims 5-10, wherein the mass of the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form does not decrease by more than 5% after one month, and preferably after three months, at 40 °C and 75% relative humidity.

12. The pharmaceutical composition of any one of claims 1-11, wherein the at least one polymer is not a surfactant.

13. The pharmaceutical composition of any one of claims 1 and 6-11, wherein the active pharmaceutical ingredient consists of one or more of Compounds 1-A, 1-B, 1-C, and 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form.

14. The pharmaceutical composition of any one of claims 1-13, wherein the at least one polymer comprises an acidic polymer.

15. The pharmaceutical composition of any one of claims 1 and 6-14, wherein the at least one polymer comprises polyethylene oxide, a polymethacrylate-based copolymer, ethylene-vinyl acetate (EVA), a polyolefin, a polyamide, a polyester, a styrene block copolymer, polyethylene, ethylene-methyl acrylate (EMA), ethylene n-butyl acrylate (EnBA), one or more of hydroxypropyl methylcellulose (HPMC), a copolymer comprising HPMC, one or more esters of 1TPMC, a copolymer comprising one or more esters of HPMC, an enteric polymer or copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, acopolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC.

16. The pharmaceutical composition of any one of claims 1-15, wherein the at least one polymer comprises one or more esters of HPMC.

17. The pharmaceutical composition of claim 16, wherein the one or more esters of HPMC comprise one or more of acetate ester and succinate ester.

18. The pharmaceutical composition of any one of claims 1-17, wherein the at least one polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).

19. The pharmaceutical composition of any one of claims 1-18, wherein the ratio of the active pharmaceutical ingredient to the at least one polymer is about 1 : 10 to about 9:10 (w / w), preferably about 1 :4 to about 3:4 (w / w).

20. The pharmaceutical composition of any one of claims 1 and 4-19, wherein the solid dispersion comprises no more than about 90%, no more than about 80%, no more than about 75%, no more than about 60%, no more than about 50%, no more than about 40%, no more than about 30%, or no more than about 25% by weight of the active pharmaceutical ingredient.

21. The pharmaceutical composition of any one of claims 1 and 4-20, wherein the solid dispersion comprises no less than about 5%, no less than about 10%, no less than about 25%, no less than about 30%, no less than about 40%, no less than about 50%, no less than about 60%, or no less than about 70% by weight of the active pharmaceutical ingredient.

22. The pharmaceutical composition of any one of claims 1 and 4-21, wherein the solid dispersion comprises the active pharmaceutical ingredient, the at least one polymer, and no more than a trace amount of a liquid solvent.

23. The pharmaceutical composition of any one of claims 1-21, which has no more than a trace amount of a liquid solvent.

24. The pharmaceutical composition of any of any one of claims 1-23, wherein the solid dispersion or pharmaceutical composition comprises no more than about 10% (w / w), preferablyno more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A, based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the pharmaceutical composition (the remainder of Compound 1-A being in amorphous form).

25. The pharmaceutical composition of any one of claims 1-24, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion or pharmaceutical composition comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the pharmaceutical composition (the remainder of Compound 1-A being in amorphous form).

26. The pharmaceutical composition of any one of claims 1-25, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion or pharmaceutical composition comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the pharmaceutical composition (the remainder of Compound 1-A being in amorphous form).

27. The pharmaceutical composition of any one of claims 23-26, wherein the ambient conditions are 25 °C (+ / - 2 °C) and 60% (+ / - 5%) relative humidity.

28. The pharmaceutical composition of any one of claims 1-27, wherein the solid dispersion or admixture consists essentially of the at least one active pharmaceutical ingredient and the at least one polymer.

29. The pharmaceutical composition of any one of claims 1-28, wherein the active pharmaceutical ingredient consists of or consists essentially of Compound 1-A.

30. The pharmaceutical composition of any one of claims 1-29, wherein the at least one polymer consists of one and only one polymer.

31. The pharmaceutical composition of any one of claims 1-30, wherein the at least one polymer comprises two or more polymers.

32. The pharmaceutical composition of any one of claims 1-31, wherein the solid dispersion or admixture contains no more than a trace amount of citric acid.

33. The pharmaceutical composition of any one of claims 1-32, wherein the pharmaceutical composition comprises no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-B by weight based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D.

34. The pharmaceutical composition of any one of claims 1-33, wherein the pharmaceutical composition comprises no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-D by weight based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D.

35. The pharmaceutical composition of any one of claims 1-34, wherein the pharmaceutical composition comprises no more than 2%, preferably no more than 1.5%, more preferably no more than 1%, yet more preferably no more than 0.5%, still more preferably no more than 0.25%, and most preferably no more than 0.1% of Compound 1-C by weight based on the total weight of all of Compounds 1-A, 1-B, 1-C, and 1-D.

36. The pharmaceutical composition of any one of claims 1-35, wherein the pharmaceutical composition comprises no less than 98%, preferably no less than 98.5%, more preferably no less than 99%, even more preferably no less than 99.25%, still more preferably no less than 99.5%, yet more preferably no less than 99.75%, yet more preferably no less than 99.8%, and mostpreferably no less than 99.9% by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D.

37. The pharmaceutical composition of any one of claims 1-36, wherein the solid dispersion or admixture is in the form of a powder.

38. The pharmaceutical composition of any one of claims 1-36, wherein the solid dispersion or admixture is monolithic.

39. The pharmaceutical composition of any one of claims 1 and 6-38, wherein the solid dispersion is prepared by a method comprising: contacting the at least one active pharmaceutical ingredient and the at least one polymer with a liquid to form a liquid solution or a dispersion; and lyophilizing or spraying the liquid solution or dispersion to form the solid dispersion.

40. The pharmaceutical composition of claim 39, wherein the liquid is a solvent for the at least one active pharmaceutical ingredient, the at least one polymer, or both of the at least one active pharmaceutical ingredient and the at least one polymer.

41. The pharmaceutical composition of claim 39 or claim 40, wherein the at least one active pharmaceutical ingredient and the at least one polymer is contacted with the liquid to form a solution.

42. The pharmaceutical composition of any one of claims 39-41, wherein the liquid comprises one or more of acetone, ethanol, methanol, and propanol, preferably methanol or acetone, and most preferably acetone.

43. The pharmaceutical composition of any one of claims 39-42, further comprising a step of drying the solid dispersion to remove some of the liquid, preferably all of the liquid except a trace amount, and most preferably all of the liquid, from the pharmaceutical composition.

44. The pharmaceutical composition of any one of claims 39-43, wherein the lyophilizing or spraying of the liquid solution or dispersion comprises lyophilizing the liquid solution or dispersion.

45. The pharmaceutical composition of any one of claims 39-44, wherein the lyophilizing or spraying of the liquid solution or dispersion comprises spray drying the dispersion.

46. The pharmaceutical composition of any one of claims 1-45, wherein the solid dispersion is prepared by a method comprising: contacting the active pharmaceutical ingredient in a molten state together with the at least one polymer in a molten state to form a melt; mixing the melt; and cooling the melt to form a solid dispersion.

47. The pharmaceutical composition of claim 46, wherein the mixing of the melt comprises extruding the melt.

48. The pharmaceutical composition of claim 46 or claim 47, wherein the melt is extruded through a single screw extruder.

49. The pharmaceutical composition of any one of claims 46-48, wherein the melt is extruded through a twin-screw extruder.

50. The pharmaceutical composition of any one of claims 1-49, wherein the pharmaceutical composition further comprises an active pharmaceutical ingredient that is not Compound 1-A, 1- B, 1-C, or 1-D, or a pharmaceutically acceptable salt or solvate thereof.

51. The pharmaceutical composition of any one of claims 1-49, wherein the pharmaceutical composition does not include an active pharmaceutical ingredient other than Compound 1-A, 1- B, 1-C, or 1-D in a solid, amorphous form.

52. A plurality of granules, wherein each granule comprises the pharmaceutical composition of any one of claims 1-51.

53. The plurality of granules of claim 52, wherein each granule further comprises one or more intragranular excipients.

54. The plurality of granules of claim 52 or claim 53, wherein the one or more intragranular excipients is selected from the group consisting of one or more filler, one or more disintegrant, one or more glidant, and one or more lubricant.

55. The plurality of granules of any one of claims 52-54, wherein the one or more intragranular excipients comprises at least one filler, the at least one filler optionally selected from the group consisting of a starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, xylitol, dextrose, crystalline maltose, a maltodextrin, and any combination thereof, preferably a sugar or sugar alcohol, and more preferably mannitol.

56. The plurality of granules of any one of claims 52-55, wherein the one or more intragranular excipients comprises at least one filler optionally comprising a cellulose-based polymer, and preferably comprising microcrystalline cellulose, and more preferably comprising silicified microcrystalline cellulose.

57. The plurality of granules of any one of claims 52-56, wherein the one or more intragranular excipients comprises a disintegrant, preferably croscarmellose, and more preferably croscarmellose sodium.

58. The plurality of granules of any one of claims 52-57, wherein the one or more intragranular excipients comprises a glidant, preferably talc, silicon dioxide, or aluminum dioxide, and most preferably silicon dioxide.

59. The plurality of granules of any one of claims 52-58, wherein the one or more intragranular excipients comprises a lubricant, preferably stearic acid or a salt thereof or stearyl fumarate or a salt thereof, more preferably stearyl fumarate or a salt thereof, and even more preferably sodium stearyl fumarate.

60. The plurality of granules of any one of claims 52-59, wherein each of the granules comprises no less than 20% (w / w), no less than 25% (w / w), no less than 30% (w / w), no less than40% (w / w), no less than 50% (w / w), no less than 60% (w / w), no less than 70% (w / w), or no less than 75% (w / w) of the pharmaceutical composition of any one of claims 1-51.

61. The plurality of granules of any one of claims 52-60, wherein each of the granules comprises no less than 20% (w / w), no less than 25% (w / w), no less than 30% (w / w), no less than 40% (w / w), no less than 50% (w / w), no less than 60% (w / w), no less than 70% (w / w), or no less than 75% (w / w) of a solid dispersion of: an active pharmaceutical ingredient comprising at least one drug molecule that comprises amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof, and at least one polymer that sustains Compound 1-A or pharmaceutically acceptable salt or solvate thereof in the amorphous form; wherein the mass of Compound 1-A in the solid dispersion does not decrease by more than 5% after four weeks at 40 °C and 75% relative humidity.

62. The plurality of granules of any one of claims 52-61, wherein each of the granules comprises no more than about 75% (w / w), no more than about 70% (w / w), no more than about 60% (w / w), no more than about 50% (w / w), no more than about 40% (w / w), no more than about 30% (w / w), no more than about 25% (w / w), or no more than about 20% (w / w) of the pharmaceutical composition of any one of claims 1 -51.

63. The plurality of granules of any one of claims 52-62, wherein each of the granules comprises no more than about 75% (w / w), no more than about 70% (w / w), no more than about 60% (w / w), no more than about 50% (w / w), no more than about 40% (w / w), no more than about 30% (w / w), no more than about 25% (w / w), or no more than about 20% (w / w) of a solid dispersion of: an active pharmaceutical ingredient comprising at least one drug molecule that comprises amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof, and at least one polymer that sustains Compound 1-A or pharmaceutically acceptable salt or solvate thereof in amorphous form; wherein the mass of Compound 1-A in the solid dispersion does not decrease by more than 5% after four weeks at 40 °C and 75% relative humidity.

64. The plurality of granules of any one of claims 52-63, wherein each of the granules comprises about 30% (w / w) to about 70% (w / w) of the solid dispersion, preferably about 40% (w / w) to about 60% (w / w) of the solid dispersion.

65. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of claims 1-51 or the plurality of granules of any one of claims 52-64.

66. The pharmaceutical dosage form of claim 65, further comprising a second plurality of granules, wherein the second plurality of granules do not comprise Compound 1-A, 1-B, 1-C, and 1-D.

67. The pharmaceutical dosage form of claim 64 or claim 66, wherein the pharmaceutical dosage form is a capsule, a tablet, or a sachet, preferably a capsule or a tablet, and most preferably a tablet.

68. The pharmaceutical dosage form of any one of claims 65-67, which is in the form of a tablet comprising the plurality of granules of any one of claims 52-64 and one or more extra- granular excipients.

69. The pharmaceutical dosage form of any one of claims 65-68, wherein the one or more extra-granular excipients comprises at least one compression excipient, disintegrant, glidant, lubricant, or fdler.

70. The pharmaceutical dosage form of any one of claims 65-69, wherein the one or more extra-granular excipients comprises at least one compression excipient.

71. The pharmaceutical dosage form of any one of claims 65-70, wherein the one or more extra-granular excipients comprises a sugar or sugar alcohol, preferably mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, or a mixture of one or more of the foregoing, preferably one or more of mannitol or silicified microcrystalline cellulose, and more preferably mannitol and silicified microcrystalline cellulose.

72. The pharmaceutical dosage form of any one of claims 65-71, wherein the one or more extra-granular excipients comprise one or more glidant, one or more lubricant, one or more disintegrant, or any combination thereof.

73. The pharmaceutical dosage form of any one of claims 65-72, wherein the one or more extra-granular excipients comprises a disintegrant, preferably croscarmellose sodium.

74. The pharmaceutical dosage form of any one of claims 65-73, wherein the one or more extra-granular excipients comprises a glidant, preferably talc, silicon dioxide, or aluminum dioxide.

75. The pharmaceutical dosage form of any one of claims 65-74, wherein the one or more extra-granular excipients comprises a lubricant, preferably one or more of stearic acid or a salt thereof and sodium stearyl fumarate, and more preferably sodium stearyl fumarate.

76. The pharmaceutical dosage form of any one of claims 65-75, which is in the form of a tablet.

77. The pharmaceutical dosage form of claim 76, wherein the tablet comprises a coating.

78. The pharmaceutical dosage form of claim 76 or 77, wherein the coating comprises a pigment.

79. The pharmaceutical dosage form of any one of claims 65-78, wherein the dosage form comprises no less than about 5 mg, no less than about 10 mg, no less than about 20 mg, no less than about 25 mg, no less than about 30 mg, no less than about 40 mg, or no less than about 50 mg of Compound 1-A.

80. The pharmaceutical dosage form of any one of claims 65-79, wherein the dosage form comprises no more than about 250 mg, no more than about 200 mg, no more than about 175 mg, no more than about 150 mg, no more than about 125 mg, no more than about 100 mg, no more than about 75 mg, no more than about 60 mg, or no more than about 50 mg of Compound 1-A.

81. The pharmaceutical dosage form of any one of claims 65-80, wherein the dosage form comprises about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A.

82. The pharmaceutical dosage form of any one of claims 65-81, wherein the dosage form comprises about 23 mg to about 27 mg, preferably about 25 mg of Compound 1-A.

83. The pharmaceutical dosage form of claim 82, wherein the dosage form comprises about 25 mg of Compound 1-A.

84. The pharmaceutical dosage form of any one of claims 65-81, wherein the dosage form comprises about 123 mg to about 127 mg, preferably about 125 mg of Compound 1-A.

85. The pharmaceutical dosage form of claim 84, wherein the dosage form comprises about 125 mg of Compound 1-A.

86. The pharmaceutical dosage form of any one of claims 65-85, wherein the plurality of granules comprises a solid dispersion that is about 40% (w / w) to about 60% (w / w), preferably about 48% (w / w) to about 52% (w / w), more preferably about 50% (w / w) Compound 1-A, and 40-60% (w / w), preferably 48-52% (w / w), more preferably 50% (w / w) hydroxypropyl methylcellulose acetate succinate.

87. The pharmaceutical dosage form of any one of claims 65-83 and 86, comprising: a plurality of granules, the plurality of granules consisting essentially of:50 mg of a solid dispersion, the solid dispersion comprising: 23-27 mg, preferably 25 mg, of Compound 1-A; and 23-27 mg, preferably 25 mg, of hydroxypropyl methylcellulose acetate succinate;45-49 mg silicified microcrystalline cellulose;21-26 mg mannitol;3.5-7 mg croscarmellose sodium;0.8-1.75 mg silicon dioxide; and0.8-1.75 mg sodium stearyl fumarate;extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising:I-4 mg croscarmellose sodium; and0.8-1.75 mg sodium stearyl fumarate.

88. The pharmaceutical dosage form of any one of claims 65-80, 84, and 86, comprising: a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising:123-127 mg, preferably 125 mg, of Compound 1-A; and123-127 mg, preferably 125 mg, of hydroxypropyl methylcellulose acetate succinate;235-241 mg silicified microcrystalline cellulose;117-121 mg mannitol;25-28 mg croscarmellose sodium;5-8 mg silicon dioxide; and5-8 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising:I I-15 mg croscarmellose sodium; and5-8 mg sodium stearyl fumarate.

89. The pharmaceutical dosage form of claim 87, comprising about 25 mg of Compound 1- A.

90. The pharmaceutical dosage form of claim 88, comprising about 125 mg of Compound 1- A.

91. The pharmaceutical dosage form of claim 87, comprising: a plurality of granules, the plurality of granules consisting essentially of: about 50 mg of a solid dispersion, the solid dispersion comprising: about 25 mg of Compound 1-A; and about 25 mg of hydroxypropyl methylcellulose acetate succinate; about 47.5 mg silicified microcrystalline cellulose;about 24 mg mannitol; about 5.5 mg croscarmellose sodium; about 1.5 mg silicon dioxide; and about 1.5 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising: about 2.5 mg croscarmellose sodium; and about 1.5 mg sodium stearyl fumarate.

92. The pharmaceutical dosage form of claim 88, comprising: a plurality of granules, the plurality of granules consisting essentially of:250 mg of a solid dispersion, the solid dispersion comprising: about 125 mg of Compound 1-A; and about 125 mg of hydroxypropyl methyl cellulose acetate succinate; about 238 mg silicified microcrystalline cellulose; about 119 mg mannitol; about 26.5 mg croscarmellose sodium; about 6.5 mg silicon dioxide; and about 6.5 mg sodium stearyl fumarate; extra-granular excipients that are not contained in the plurality of granules, the extra- granular excipients comprising: about 13.5 mg croscarmellose sodium; and about 6.5 mg sodium stearyl fumarate.

93. The pharmaceutical dosage form of any one of claims 65-92, wherein Compound 1-A is present as an amorphous solid.

94. The pharmaceutical dosage form of any one of claims 65-93, comprising no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A,based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the pharmaceutical dosage form (the remainder of Compound 1-A being in amorphous form).

95. The pharmaceutical dosage form of any one of claims 65-94, wherein the pharmaceutical dosage form exhibits a release profde, when measured under sink conditions, as follows: (i) at least about 50% of Compound 1-A is released from the pharmaceutical dosage form by about 5 minutes; (ii) at least about 80% of Compound 1-A is released from the pharmaceutical dosage form by about 15 minutes; (iii) at least about 95% of Compound 1-A is released from the pharmaceutical dosage form by about 20 minutes; and (iv) at least about 98% of Compound 1-A is released from the pharmaceutical dosage form by about 30 minutes.

96. The pharmaceutical dosage form of claim 95, wherein the release profile is measured at a temperature of about 37.0 °C at a stirring speed of about 75 rpm.

97. The pharmaceutical dosage form of claim 95 or claim 96, wherein the release profile is measured in a medium comprising 10 mM sodium phosphate buffer at a pH of about 6.80.

98. The pharmaceutical dosage form of any one of claims 65-97, wherein a solution resulting from dissolution of the pharmaceutical dosage form comprises no less than 98%, preferably no less than 98.5%, more preferably no less than 99%, even more preferably no less than 99.25%, still more preferably no less than 99.5%, yet more preferably no less than 99.75%, even more preferably no less than 99.8%, and most preferably no less than 99.9% by weight of Compound 1-A based on the total weight of Compounds 1-A, 1-B, 1-C, and 1-D in the solution.

99. An admixture comprising: solid amorphous Compound 1-A or a pharmaceutically acceptable salt or solvate thereof, preferably amorphous Compound 1-A or a solvate thereof, and more preferably amorphous Compound 1-A, and a means for sustaining the amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof in an amorphous form.

100. The admixture of claim 99, wherein the means comprises a solid dispersion of amorphous Compound 1-A or a pharmaceutically acceptable salt or solvate thereof, preferably amorphousCompound 1-A or a solvate thereof, and more preferably amorphous Compound 1-A and an excipient that sustains the amorphous Compound 1-A or pharmaceutically acceptable salt or solvate thereof in an amorphous form.

101. The admixture of claims 99 or 100, wherein the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than 0.05% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1- A, based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form).

102. The admixture of any one of claims 99-101, wherein after being held at 40 °C (+ / - 2 °C) and 75% (+ / - 5%) relative humidity for two months, preferably four months, and most preferably six months, the solid dispersion comprises no more than 10% (w / w), preferably no more than 5% (w / w), more preferably no more than 2.5% (w / w), still more preferably no more than 1% (w / w), further preferably no more than 0.5% (w / w), and most preferably no more than 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion (the remainder of Compound 1-A being in amorphous form).

103. The admixture of any one of claims 99-102, wherein after being held at ambient conditions for about six months, preferably about twelve months, more preferably about eighteen months, and most preferably about twenty-four months, the solid dispersion comprises no more than about 10% (w / w), preferably no more than about 5% (w / w), more preferably no more than about 2.5% (w / w), still more preferably no more than about 1% (w / w), further preferably no more than about 0.5% (w / w), and most preferably no more than about 0.25% (w / w) of crystalline Compound 1-A based on the total amount of Compounds 1-A, 1-B, 1-C, and 1-D in the solid dispersion, (the remainder of Compound 1-A being in amorphous form).

104. The admixture of claim 103, wherein the ambient conditions are 25 °C (+ / - 2 °C) and 60% (+ / - 5%) relative humidity.

105. The admixture of any one of claims 99-104, wherein the excipient comprises a polymer.

106. The admixture of any one of claims 99-105, wherein the means comprises a pharmaceutical composition of any one of claims 1-51.

107. A tablet or capsule comprising the admixture of any one of claims 99-106.

108. A method of treating a subject for a disorder related to A1AT, the method comprising administering Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject.

109. The method of claim 108, wherein the disorder relates to the accumulation of Al AT in the liver.

110. The method of claim 108 or claim 109, wherein the disorder relates to the polymerization of A1AT.

111. The method of any one of claims 108-110, wherein the disorder is a liver disorder.

112. The method of any one of claims 108-111, wherein the subject has a PiZ* genotype.

113. The method of claim 112, wherein the subject has a PiZZ genotype.

114. The method of claim 112, wherein the subject has a PiMZ genotype.

115. The method of any one of claims 108-114, wherein the subject is a dog, rat, or mouse.

116. The method of any one of claims 108-115, wherein the subject is human.

117. The method of any one of claims 108-116, wherein the method comprises administering a tablet to the subject.

118. The method of any one of claims 108-117, wherein the method comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule once per day or twice per day.

119. The method of any one of claims 108-118, wherein the method comprises administering a tablet.

120. The method of any one of claims 108-119, wherein the method comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule to provide a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg, and preferably about 25 mg or about 125 mg, of Compound 1-A to the subject.

121. The method of any one of claims 108-119, wherein the method comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule to provide a dose of about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A.

122. A method of making a solid dispersion, the method comprising: contacting an active pharmaceutical ingredient comprising one or more of Compound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form in a molten state and at least one polymer in a molten state to form a melt; mixing the melt; and cooling the melt to form a solid dispersion, wherein the polymer comprises at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

123. The method of claim 122, wherein the mixing of the melt comprises extruding the melt.

124. The method of claim 122 or claim 123, wherein the melt is extruded through a single screw extruder.

125. The method of claim 122 or claim 123, wherein the melt is extruded through a twin- screw extruder.

126. A method of making a solid dispersion, the method comprising: contacting an active pharmaceutical ingredient comprising one or more ofCompound 1-A, 1-B, 1-C, and 1-D:1-B 1-D or a pharmaceutically acceptable salt or solvate thereof in a solid, amorphous form and at least one polymer with a liquid to form a liquid solution or dispersion; and lyophilizing or spraying the liquid solution or dispersion to form the solid dispersion, wherein the polymer comprises at least one polymer that sustains the one or more of Compounds 1-A, 1-B, 1-C, and 1-D or pharmaceutically acceptable salt or solvate thereof in the solid, amorphous form.

127. The method of claim 126, wherein the liquid is a solvent for the at least one active pharmaceutical ingredient, the at least one polymer, or both of the at least one active pharmaceutical ingredient and the at least one polymer.

128. The method of claim 126 or claim 127, wherein the at least one active pharmaceutical ingredient is contacted with the at least one polymer with a liquid to form a solution.

129. The method of any one of claims 126-128, wherein the liquid comprises one or more of acetone, ethanol, methanol, and propanol, preferably methanol or acetone, and most preferably acetone.

130. The method of any one of claims 126-129, further comprising a step of drying the solid dispersion to remove at least some, preferably all but a trace amount, of the liquid.

131. The method of any one of claims 126-130, wherein the lyophilizing or spraying of the liquid solution or dispersion comprises lyophilizing the liquid solution or dispersion.

132. The method of any one of claims 126-131, wherein the lyophilizing or spraying of the liquid solution or dispersion comprises spray drying the dispersion.

133. The method of any one of claims 126-132, wherein the at least one polymer is not a surfactant.

134. The method of any one of claims 126-133, wherein the at least one polymer comprises one or more of HPMC, a copolymer comprising HPMC, one or more esters of HPMC, a copolymer comprising one or more esters of HPMC, an enteric copolymer, polyvinylpyrrolidone, or a copolymer comprising polyvinylpyrrolidone; preferably a HPMC, a copolymer comprising HPMC, ester or esters of HPMC, or a copolymer comprising ester or esters of HPMC; more preferably one or more esters of HPMC; still more preferably wherein the esters of HPMC comprise one or more of acetate ester and succinate ester; and most preferably HPMCAS.

135. The method of any one of claims 126-134, wherein the at least one polymer comprises an acidic polymer.

136. A method of increasing the level of Al AT in the plasma of a subject, the method comprising administering a Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, a pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject, wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering.

137. The method of claim 136, wherein the subject has a PiZ* genotype.

138. The method of claim 137, wherein the subject has a PiZZ genotype.

139. The method of claim 137, wherein the subject has a PiMZ genotype.

140. The method of any one of claims 136-139, wherein the subject is a human.

141. The method of any one of claims 136-140, wherein the level of Al AT in the plasma is increased to about 60 mg / dL or greater.

142. The method of any one of claims 136-141, wherein the level of A1AT in the plasma is increased to about 70 mg / dL or greater.

143. The method of any one of claims 136-142, wherein the level of A1AT in the plasma is increased to about 80 mg / dL or greater.

144. The method of any one of claims 136-143, wherein the level of A1AT in the plasma is increased to about 90 mg / dL or greater.

145. The method of any one of claims 136-144, wherein the level of Al AT in the plasma is increased to about 100 mg / dL or greater.

146. The method of any one of claims 136-145, wherein Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A.

147. The method use of any one of claims 136-146, wherein the concentration of polymerized A1AT in the liver of the subject is decreased after the administering.

148. The method of any one of claims 136-147, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to the subject at least once per day.

149. The method of claim 148, wherein the increased level of Al AT in the plasma is reached after 28 or fewer days of administering.

150. The method of any one of claims 136-149, wherein the increased level of Al AT in the plasma is reached after 14 or fewer days of administering.

151. The method of any one of claims 136-150, wherein the increased level of Al AT in the plasma is reached after 7 or fewer days of administering.

152. The method of any one of claims 136-151, wherein the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule contains about 5 mg to about 400 mg, preferably about 10 mg to about 250 mg, and more preferably about 20 mg to about 150 mg of Compound 1-A.

153. The method of any one of claims 136-152, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 mg to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day to the subject.

154. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg of Compound 1-A per day to the subject.

155. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject.

156. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject.

157. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 100 mg of Compound 1-A per day to the subject.

158. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject.

159. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject.

160. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject.

161. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject.

162. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject.

163. The method of any one of claims 136-153, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject.

164. The method of any one of claims 136-163, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day.

165. The method of any one of claims 136-163, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day.

166. The method of any one of claims 136-165, wherein Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof.

167. The method of any one of claims 136-166, wherein Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A.

168. A method of increasing the level of Al AT in the plasma of a subject comprising administering Compound 1-A:or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1- 1, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject, wherein the level of Al AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering.

169. The method of claim 168, wherein the subject has a PiZ* genotype.

170. The method of claim 169, wherein the subject has a PiZZ genotype.

171. The method of claim 169, wherein the subject has a PiMZ genotype.

172. The method of any one of claims 171, wherein the subject has metabolic dysfunction- associated steatohepatitis (MASH).

173. The method of any one of claims 168-172, wherein the subject is a human.

174. The method of any one of claims 168-173, wherein the level of A1AT in the plasma is increased to about 60 mg / dL or greater.

175. The method of any one of claims 168-174, wherein the level of A1AT in the plasma is increased to about 70 mg / dL or greater.

176. The method of any one of claims 168-175, wherein the level of A1AT in the plasma is increased to about 80 mg / dL or greater.

177. The method of any one of claims 168-176, wherein the level of A1AT in the plasma is increased to about 90 mg / dL or greater.

178. The method of any one of claims 168-177, wherein the level of A1AT in the plasma is increased to about 100 mg / dL or greater.

179. The method of any one of claims 168-178, wherein the level of A1AT in the plasma is increased to about 110 mg / dL or greater.

180. The method of any one of claims 168-179, wherein the level of A1AT in the plasma is increased to about 120 mg / dL or greater.

181. The method of any one of claims 168-180, wherein the level of Al AT in the plasma is increased by about 60 mg / dL or more.

182. The method of any one of claims 168-181, wherein the level of Al AT in the plasma is increased by about 65 mg / dL or more.

183. The method of any one of claims 168-182, wherein the concentration of polymerized A1AT in the liver of the subject is decreased after the administering.

184. The method of any one of claims 168-183, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to the subject at least once per day.

185. The method of any one of claims 168-184, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to the subject at least twice per day.

186. The method of any one of claims 168-185, wherein the increased level of Al AT in the plasma is reached after 28 or fewer days of administering.

187. The method of any one of claims 168-186, wherein the increased level of Al AT in the plasma is reached after 14 or fewer days of administering.

188. The method of any one of claims 168-187, wherein the increased level of Al AT in the plasma is reached after 7 or fewer days of administering.

189. The method of any one of claims 168-188, wherein about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 mg to about 250 mg of Compound 1-A is administered to the subject per day, and even more preferably about 25 mg to about 125 mg is administered to the subject per day.

190. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 25 mg of Compound 1-A to the subject per day.

191. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 50 mg of Compound 1-A to the subject per day.

192. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 75 mg of Compound 1-A to the subject per day.

193. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 100 mg of Compound 1-A to the subject per day.

194. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 125 mg of Compound 1-A to the subject per day.

195. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 150 mg of Compound 1-A to the subject per day.

196. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 250 mg of Compound 1-A to the subject per day.

197. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 500 mg of Compound 1-A to the subject per day.

198. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 625 mg of Compound 1-A to the subject per day.

199. The method of any one of claims 168-189, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 750 mg of Compound 1-A to the subject per day.

200. The method of any one of claims 168-199, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day.

201. The method of any one of claims 168-199, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day.

202. The method of any one of claims 168-201, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof.

203. The method of claim 202, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A.

204. A means of increasing the level of Al AT in the plasma of a subject to about 40 mg / dL or greater comprising a step of administering Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject.

205. The means of claim 204, wherein the means is a means of increasing the level of Al AT in the plasma to about 60 mg / dL or greater.

206. The means of claim 205, wherein the means is a means of increasing the level of Al AT in the plasma to about 70 mg / dL or greater.

207. The means of claim 206, wherein the means is a means of increasing the level of Al AT in the plasma to about 80 mg / dL or greater.

208. The means of claim 207, wherein the means is a means of increasing the level of Al AT in the plasma to about 90 mg / dL or greater.

209. The means of claim 208, wherein the means is a means of increasing the level of Al AT in the plasma to about 100 mg / dL or greater.

210. The means of claim 209, wherein the means is a means of increasing the level of Al AT in the plasma to about 110 mg / dL or greater.

211. The means of claim 210, wherein the means is a means of increasing the level of Al AT in the plasma to about 120 mg / dL or greater.

212. The means of any one of claims 204-211, wherein the means is a means of increasing the level of A1AT in the plasma by about 60 mg / dL or more.

213. The means of any one of claims 204-212, wherein the means is a means of increasing the level of Al AT in the plasma by about 65 mg / dL or more.

214. The means of any one of claims 204-213, wherein the step comprises administering the pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule once per day to the subject.

215. The means of any one of claims 204-214, wherein the step comprises administrating the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule twice per day to the subject.

216. The means of any one of claims 204-215, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 25 mg to about 500 mg of Compound 1-A to the subject per day.

217. A method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject to cause improvement in the fibrosis.

218. The method of claim 217, wherein the subject has a PiZ* genotype.

219. The method of claim 218, wherein the subject has a PiZZ genotype.

220. The method of claim 218, wherein the subject has a PiMZ genotype.

221. The method of any one of claims 220, wherein the subject has metabolic dysfunction- associated steatohepatitis (MASH).

222. The method of any one of claims 217-221, wherein the subject has stage 1, stage 2, stage 3, or stage 4 fibrosis prior to the administration.

223. The method of any one of claims 217-222, wherein the improvement in the fibrosis is a decrease in the stage of fibrosis by at least one stage.

224. The method of any one of claims 217-223, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 104 weeks or less.

225. The method of any one of claims 217-224, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 92 weeks or less.

226. The method of any one of claims 217-225, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 70 weeks or less.

227. The method of any one of claims 217-226, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 64 weeks or less.

228. The method of any one of claims 217-227, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 52 weeks or less.

229. The method of any one of claims 217-228, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 40 weeks or less.

230. The method of any one of claims 217-229, wherein the improvement in the fibrosis occurs after administration of the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule for 26 weeks or less.

231. The method of any one of claims 217-230, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 25 mg of Compound 1-A per day.

232. The method of any one of claims 217-231, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject.

233. The method of any one of claims 217-232, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject.

234. The method of any one of claims 217-233, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 100 mg of Compound 1-A per day to the subject.

235. The method of any one of claims 217-234, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject.

236. The method of any one of claims 217-235, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject.

237. The method of any one of claims 217-236, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject.

238. The method of any one of claims 217-237, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject.

239. The method of any one of claims 217-238, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject.

240. The method of any one of claims 217-239, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject.

241. The method of any one of claims 217-240, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered once per day.

242. The method of any one of claims 217-241, wherein the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule is administered twice per day.

243. The method of any one of claims 217-242, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof.

244. The method of claim 243, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A.

245. A means of treating fibrosis in a subject suffering from AlAT-associated liver disease, comprising a step of administering Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 to the subject.

246. The means of claim 245, wherein the subject has a PiZ* genotype.

247. The means of claim 246, wherein the subject has PiZZ genotype.

248. The means of claim 246, wherein the subject has a PiMZ genotype.

249. The means of any one of claims 245-248, wherein the subject has metabolic dysfunction- associated steatohepatitis (MASH).

250. The means of any one of claims 245-249, wherein the means is a means of decreasing the stage of the fibrosis in the subject by at least one stage.

251. The means of any one of claims 245-250, wherein the step comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule once per day to the subject.

252. The means of any one of claims 245-251, wherein the step comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, tablet, or capsule twice per day to the subject.

253. A compound, wherein the compound is Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 for use in a method of treating a subject for a disorder related to A1AT, the method comprising administering the compound, pharmaceutical composition, plurality of granules, admixture, pharmaceutical dosage form, or tablet or capsule to a subject in need thereof.

254. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 253, wherein the disorder relates to the accumulation of A1AT in the liver.

255. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 253 or claim 254, wherein the disorder relates to the polymerization of A1AT.

256. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 253-255, wherein the disorder is a liver disorder.

257. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 253-256, wherein the subject has a PiZ* genotype.

258. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 257, wherein the subject has a PiZZ genotype.

259. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 258, wherein the subject has a PiMZ genotype.

260. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 253-259, wherein the subject is a dog, rat, or mouse.

261. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 252-259, wherein the subject is human.

262. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 252-261, wherein the method comprises administering the compound, pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule to the subject.

263. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims252-262, wherein the method comprises administering the compound, pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule once per day or twice per day.

264. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims253-263, wherein the method comprises administering the compound, pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule.

265. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 253-264, wherein the method comprises administering the compound, pharmaceuticalcomposition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule to provide a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 200 mg, or about 250 mg, and preferably about 25 mg or about 125 mg, of Compound 1-A to the subject.

266. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 253-265, wherein the method comprises administering the compound, pharmaceutical composition, plurality of granules, pharmaceutical dosage form, admixture, or tablet or capsule to provide a dose of about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg of Compound 1-A to the subject.

267. A compound, wherein the compound is Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof, the pharmaceutical composition of any one of claims 1-51, the plurality of granules of any one of claims 52-64, the pharmaceutical dosage form of any one of claims 65-98, the admixture of any one of claims 99-106, or the tablet or capsule of claim 107 for use in a method of increasing the level of Al AT in the plasma of a subject, the method comprising administering a sufficient amount of the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule, wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering.

268. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 267, wherein the subject has a PiZ* genotype.

269. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 267, wherein the subject has a PiZZ genotype.

270. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 267, wherein the subject has a PiMZ genotype.

271. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-270, wherein the subject is a human.

272. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-271, wherein the level of Al AT in the plasma is increased to about 60 mg / dL or greater.

273. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-272, wherein the level of A1AT in the plasma is increased to about 70 mg / dL or greater.

274. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-273, wherein the level of Al AT in the plasma is increased to about 80 mg / dL or greater.

275. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-274, wherein the level of A1AT in the plasma is increased to about 90 mg / dL or greater.

276. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-275, wherein the level of Al AT in the plasma is increased to about 100 mg / dL or greater.

277. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-276, wherein Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof, and preferably Compound 1-A.

278. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-277, wherein the concentration of polymerized A1AT in the liver of the subject is decreased after the administering.

279. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-278, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to the subject at least once per day.

280. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any claim 279, wherein the increased level of Al AT in the plasma is reached after 28 or fewer days of administering.

281. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-280, wherein the increased level of A1AT in the plasma is reached after 14 or fewer days of administering.

282. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims267-281, wherein the increased level of A1AT in the plasma is reached after 7 or fewer days of administering.

283. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-282, wherein the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule contains about 5 mg to about 400 mg, preferably about 10 mg to about 250 mg, and more preferably about 20 mg to about 150 mg of Compound 1-A.

284. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-283, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day to the subject.

285. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 25 mg of Compound 1-A per day to the subject.

286. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject.

287. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject.

288. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 100 mg of Compound 1-A per day to the subject.

289. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject.

290. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject.

291. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject.

292. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject.

293. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject.

294. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-284, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject.

295. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-294, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered once per day.

296. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-295, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered twice per day.

297. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-296, wherein Compound 1-A or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof.

298. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 267-297, wherein Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A.

299. A compound, wherein the compound is Compound 1-A:(1-A) or a pharmaceutically acceptable salt of solvate thereof for use or the pharmaceutical composition of any one of claims 1-50, the plurality of granules of any one of claims 51-63, the pharmaceutical dosage form of any one of claims 64-97, the admixture of any one of claims 98- 105, or the tablet or capsule of claim 106 for use in a method of treating fibrosis in a subject suffering from AlAT-associated liver disease, the method comprising administering a sufficient amount of the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule to the subject to cause improvement in the fibrosis.

300. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 299, wherein the subject has a PiZ* genotype.

301. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 299, wherein the subject has a PiZZ genotype.

302. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 299, wherein the subject has a PiMZ genotype.

303. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 299, wherein the subject has metabolic dysfunction-associated steatohepatitis.

304. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims298-303, wherein the subject has stage 1, stage 2, stage 3, or stage 4 fibrosis prior to the administration.

305. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-304, wherein the improvement in the fibrosis is a decrease in the stage of fibrosis by at least one stage.

306. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-305, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 104 weeks or less.

307. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-306, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 92 weeks or less.

308. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-307, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 70 weeks or less.

309. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 217298-226, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 64 weeks or less.

310. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-309, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 52 weeks or less.

311. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-310, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 40 weeks or less.

312. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-311, wherein the improvement in the fibrosis occurs after administration of the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for 26 weeks or less.

313. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 25 mg of Compound 1-A per day to the subject.

314. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 50 mg of Compound 1-A per day to the subject.

315. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, thepharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 75 mg of Compound 1-A per day to the subject.

316. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 100 mg of Compound 1-A per day to the subject.

317. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 125 mg of Compound 1-A per day to the subject.

318. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 150 mg of Compound 1-A per day to the subject.

319. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 250 mg of Compound 1-A per day to the subject.

320. The compound, pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 500 mg of Compound 1-A per day to the subject.

321. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 299-312, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 625 mg of Compound 1-A per day to the subject.

322. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-312, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered to provide about 750 mg of Compound 1-A per day to the subject.

323. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-322, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered once per day.

324. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-323, wherein the compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule is administered twice per day.

325. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of any one of claims 298-324, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A or a pharmaceutically acceptable solvate thereof.

326. The compound, the pharmaceutical composition, the plurality of granules, the pharmaceutical dosage form, the admixture, or the tablet or capsule for use of claim 325, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

327. A pharmaceutical composition comprising Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof for use in increasing the level of A1AT in the plasma of a subject, the use comprising administering a sufficient amount of the pharmaceutical composition to the subject, and wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering.

328. The pharmaceutical composition for use of claim 327, wherein the subject has a PiZZ genotype.

329. The pharmaceutical composition for use of claim 327 or claim 328, wherein the level of Al AT in the plasma is increased to about 90 mg / dL or greater.

330. The pharmaceutical composition for use of any one of claims 327-329, wherein the pharmaceutical composition is administered to provide about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day.

331. The pharmaceutical composition for use of any one of the claims 327-330, wherein the pharmaceutical composition is administered once per day.

332. The pharmaceutical composition for use of any one of the claims 327-331, wherein the Compound 1-A or a pharmaceutically acceptable solvate thereof is Compound 1-A (e.g., not a salt or solvate).

333. A method of increasing the level of A1AT in the plasma of a subject comprising administering a sufficient amount of a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject, wherein the level of A1AT in the plasma of the subject is increased to about 40 mg / dL or greater after the administering.

334. The method of claim 333, wherein the subject has a PiZZ genotype.

335. The method of claim 333 or claim 334, wherein the level of A1AT in the plasma is increased to about 90 mg / dL or greater.

336. The method of any one of claims 333-335, wherein the sufficient amount is about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day.

337. The method of any one of claims 333-336, wherein the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, is administered once per day.

338. The method of any one of claims 333-337, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

339. A means of increasing the level of Al AT in the plasma of a subject to about 40 mg / dL or greater comprising a step of administering a sufficient amount of a compound, wherein the compound is Compound 1-A:1-A or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, to the subject.

340. The means of claim 339, wherein the subject has a PiZZ genotype.

341. The means of claim 339 or claim 340, wherein the means is a means of increasing the level of Al AT in the plasma to about 90 mg / dL or greater.

342. The means of any one of claims 339-341, wherein the sufficient amount is about 5 mg to about 1500 mg, preferably about 10 mg to about 1000 mg, more preferably about 25 mg to about 1000 mg, even more preferably about 25 mg to about 500 mg, still more preferably about 25 to about 250 mg of Compound 1-A per day, and even more preferably about 25 mg to about 125 mg per day.

343. The method of any one of claims 339-342, wherein the compound or pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, is administered once per day.

344. The method of any one of claims 339-343, wherein the compound or pharmaceutically acceptable salt or solvate thereof is Compound 1-A (e.g., not a salt or solvate).

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