Pharmaceutical compositions, dosage forms, and methods of making and using same

Abstract

Pharmaceutical compositions of Compound (I) including solid dispersions of Compound (I) and nanocrystalline powder forms of Compound (I). Related unit dosage forms, and methods of making and using the same are also provided.

Description

PHARMACEUTICAL COMPOSITIONS, DOSAGE FORMS, AND METHODS OF MAKING AND USING SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 666,013 filed on June 28, 2024, the entire content of which is incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The disclosure relates generally to pharmaceutical compositions of Compound (I) as described herein. More particularly, the disclosure relates to solid dispersions of Compound (I) and nanocrystalline powder forms of Compound (I). Related dosage forms and methods of making and using the same are also provided.BACKGROUND

[0003] Hypoxia inducible factors (HIFs) are a family of transcription factors that modulate the cellular response to hypoxia. HIF is a heterodimer consisting of an oxygen-regulated alpha subunit (of which there are 3 isoforms: HIF-la, HIF-2a, and HIF-3a) that can heterodimerize with a constitutively expressed beta subunit. Under normal tissue oxygen saturation, HIF-2a protein is continuously degraded. In hypoxic tissue oxygen status, or in the case of VHL mutation or epigenetic silencing (pseudohypoxia), HIF-2a is stabilized and undergoes nuclear translocation. Upon dimerization with HIF-ip, HIF -2a mediates transcription of pro- tumorigenic genes associated with proliferation and angiogenesis. International (PCT) patent publication WO 2021 / 188769A1 describes tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2a. There remains a need to provide pharmaceutical compositions for the administration of Compound (I).SUMMARY

[0004] One aspect of the disclosure provides a solid dispersion (SD) comprising Compound (I) and one or more pharmaceutically acceptable polymers, wherein Compound (I) has the structure:

[0005] In one embodiment, the solid dispersion (SD) is a spray-dried dispersion (SDD).

[0006] Another aspect of the disclosure provides a nanocrystalline powder form of Compound (I), wherein the nanocrystalline powder form has a Z-average hydrodynamic diameter (dZ) measured by dynamic light scattering (DLS) of 500 nm or less, or 400 nm or less, or 300 nm or less, and the nanocrystalline powder form can further include one or more aggregation inhibitors. In one embodiment, the nanocrystalline powder form is spray-dried to give a spray-dried nanocrystalline (SDNC) form.

[0007] Another aspect of the disclosure is a plurality of granules wherein the granules comprise a solid dispersion (e.g., a spray-dried solid dispersion) as described herein and one or more excipients.

[0008] Another aspect of the disclosure is a unit dosage form, e.g., a tablet, comprising a) the plurality of granules according to this disclosure; and b) an extragranular composition comprising one or more excipients.

[0009] Another aspect provides a tablet comprising Compound (I) and one or more excipients.

[0010] Another aspect of the disclosure is a pharmaceutical composition comprising Compound (I):and a means for improving the dissolution of Compound (I) and / or the bioavailability of Compound (I).

[0011] Another aspect of the disclosure provides a tablet comprising: a) about 56.5 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I):about 75 wt.% HPMCAS-M; b) about 24.5 wt.% MCC;c) about 13.0 wt.% mannitol; d) about 5.0 wt.% croscarmellose sodium; and e) about 1.0 wt.% magnesium stearate.

[0012] Another aspect of the disclosure provides a tablet comprising: a) about 54.3 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I):about 75 wt.% HPMCAS-M; b) about 23.5 wt.% MCC; c) about 12.5 wt.% mannitol; d) about 4.8 wt.% croscarmellose sodium; e) about 1.0 wt.% magnesium stearate; and f) about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof.

[0013] Another aspect of the disclosure is a method of preparing a SD, nanocrystalline powder form, SDD, SDNC comprising Compound (I). Further contemplated herein are methods for preparing the SD, nanocrystalline powder form, the SDD, and SDNC as a pharmaceutical composition or a pharmaceutical unit dosage form.

[0014] Another aspect of the disclosure is a method of treating a disease, disorder, or condition mediated at least in part by HIF-2a, said method comprising administering the solid dispersion, the nanocrystalline powder form, the SDD, the SDNC, the pharmaceutical composition, or the pharmaceutical unit dosage form to a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Fig. 1 depicts the powder X-ray diffractogram of Compound (I), abbreviated as CPD 1 here and throughout the figures.

[0016] Fig. 2 depicts the polymer sustainment of supersaturated concentrations of Compound (I) in the presence of HPMCAS-L, HPMCAS-M, HPMCAS-H, and PVP-VA64.

[0017] Fig. 3 depicts the SEM images for select Compound (I) SDDs. Left corresponds to 25 / 75 Compound (I) / PVP-VA64; right corresponds to 25 / 75 Compound (I) / HPMCAS-L; Fig.3 (Continued) corresponds to 25 / 75 Compound (I) / HPMCAS-M.

[0018] Fig. 4 depicts the SEM images for selected Compound (I) SDDs. Left corresponds to 25 / 75 Compound (I) / HPMCAS-H; right corresponds to 40 / 60 Compound (I) / HPMCAS-H.

[0019] Fig. 5 depicts the SEM image for crystalline Compound (I).

[0020] Fig. 6 depicts the PXRD diffractograms of the Compound (I) SDDs compared to crystalline Compound (I). Top pattern is 25 / 75 CPD 1 / PVP-VA; second pattern from the top is 25 / 75 CPD 1 / HPMCAS-M; third pattern from the top is 25 / 75 CPD 1 / HPMCAS-L; fourth pattern from the top is 25 / 75 CPD 1 / HPMCAS-H; fifth pattern from the top is 40 / 60 CPD 1 / HPMCAS-H; and bottom pattern is CPD 1.

[0021] Fig. 7 depicts the dissolution results for Compound (I) SDD compositions with Compound (I) for comparison. Data were measured by HPLC after ultracentrifuge for the 90- and 1200-min time points. All other measurements were collected by HPLC after centrifuge.

[0022] Fig. 8 depicts the dissolution results for Compound (I) SDNC compositions with Compound (I) and a selected SDD composition for comparison. Data were measured by HPLC after ultracentrifuge for the 90- and 1200-min time points. All other measurements were collected by HPLC after centrifuge.

[0023] Fig. 9 depicts a zoom in of the dissolution results for Compound (I) SDNC compositions with Compound (I) for comparison. Data were measured by HPLC after ultracentrifuge for the 90- and 1200-min time points. All other measurements were collected by HPLC after centrifuge.

[0024] Fig. 10 depicts the PXRD diffractograms of the Compound (I) SDNCs, and Compound (I) (API) for comparison.

[0025] Fig. 11 depicts the dissolution results for Compound (I) SDNC capsule compositions and SDNC powders for comparison. Data were measured by HPLC after ultracentrifuge for the 90 min time point. All other measurements were collected by HPLC after centrifuge.

[0026] Fig. 12 depicts the dissolution results for Compound (I) SDD capsule compositions and SDD powders for comparison. Data were measured by HPLC after ultracentrifuge for the 90 min time point. All other measurements were collected by HPLC after centrifuge.DETAILED DESCRIPTIONDefinitions

[0027] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those ofskill in the art to which this disclosure pertains. It is understood that aspects of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects. The terms “comprising”, “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. The term “consisting essentially of’ means that specific further components can be present, namely those not materially affecting the essential characteristics of the compound or composition.

[0028] Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a particle” includes reference to one or more particles, and equivalents thereof known to those skilled in the art.

[0029] The term “about” as used herein has its original meaning of approximately and is to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In general, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values.

[0030] The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof — for example, “A, B, and / or C” would mean “A, or B, or C”, “A and B”, “A and C”, “B and C”, or the combination of “A, B, and C.”

[0031] The terms “wt.%” and “% (w / w)” are used interchangeably and refer to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w / w in a 100 mg composition, component A is present in an amount of 50 mg.

[0032] A “Dv50” value refers to the size of 50% of the total volume of material in a sample. A “Dv90” value refers to the size of 90% of the total volume of material in a sample.

[0033] A Z-average hydrodynamic diameter (dZ) is the intensity weighted mean hydrodynamic size of a collection of particles measured by dynamic light scattering.

[0034] The term “amorphous” refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patternsand, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition).

[0035] The term “polymer matrix” as used herein is defined to mean compositions comprising one or more polymers in which Compound (I) is dispersed or included within the matrix.

[0036] The term “excipient” as used herein refers to pharmaceutically acceptable additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms (e.g., capsules, tablets, and the like) which are suitable for administration to patients. Suitable excipients include, for example, fillers, binders, disintegrants, surfactants, lubricants, and glidants.

[0037] The term “disintegrant” refers to a substance which, upon addition to a solid preparation (e.g., a pharmaceutical composition, tablet, etc.), facilitates its break-up or disintegration after administration and permits the release of an active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution. Non-limiting examples of disintegrants include maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid. In some embodiments, the disintegrant comprises one or more in the group of crospovidone, croscarmellose calcium, croscarmellose sodium, and sodium starch glycolate, for example croscarmellose sodium.

[0038] The term “filler” (also known as a diluent) refers to a substance that is used to dilute the compound of interest in a pharmaceutical preparation. Fillers can also serve to stabilize one or more components of a pharmaceutical preparation. Non-limiting examples of diluents include starch, saccharides, di saccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, silicified microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate. In some embodiments, the filler comprises one or more in the group of a pharmaceutically acceptable polymer, a mineral, a metal salt, a sugar, and a starch, optionally one or more in the group of lactose, MCC, silicified microcrystalline cellulose, starch, a natural starch, a modified starch, calcium phosphate, calcium carbonate, sucrose, maltodextrin, mannitol, sorbitol, and sodiumchloride, optionally one or more in the group of MCC, mannitol, and lactose, optionally selected from one or both of MCC and mannitol.

[0039] The term “glidanf ’ as used herein is intended to mean a substance used in tablet and capsule compositions to improve flow-properties, for example, during tablet compression or, for example, to produce an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite. In some embodiments, the glidant comprises one or more in the group of fumed silica, magnesium carbonate, magnesium stearate, silicon dioxide, and talc, for example silicon dioxide.

[0040] The term “lubricant” refers to a substance which is added to a powder blend, for example, to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It may aid in the ejection of the tablet from the dies, and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, or talc; and solubilizers such as fatty acids including lauric acid, oleic acid, and Cs / Cio fatty acid. In some embodiments, the lubricant comprises one or more in the group of calcium stearate, magnesium stearate, talc, and liquid paraffin, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl dibehenate, for example magnesium stearate.

[0041] The term “coating” or “film coating” refers to a thin, uniform, film on the surface of an intermediate substrate such as a tablet or granule. Film coatings may be useful for protecting a composition or individual components of a composition from photolytic degradation. A film coating can contain an opacifying agent. A film coating can also be used to protect a composition or individual components of a composition from moisture. Coatings may also be used to provide color to a tablet, e.g., different colors may be used to indicate different dosages. Non-limiting examples of film coatings include acrylic acid copolymers, ammonio methacrylates, ammonio methacrylate copolymers, polyvinylalcohol, carboxymethylcellulose, ethycellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methacrylic acid copolymers, amino diethyl-methacrylate copolymers, amino dimethyl-methacrylate copolymers, methyl methacrylate and diethylamino-ethyl ethacrylate copolymer dispersion, sodium carboxymethylcellulose, polyethylene glycol 4000, polyvinyl alcohol-polyethylene glycol (PVA-PEG copolymer), Poly (ethyl acrylate-co-methyl methacrylate) 2: 1, coatings comprising polyvinyl alcohol or a copolymer thereof (e g., OPADRY®, OPADRY® AMB, OPADRY® AMB II), cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, sodium alginate, and shellac film coatings.

[0042] The terms “treat”, “treating”, treatment” and the like refer to a course of action that eliminates, reduces, suppresses, mitigates, ameliorates, or prevents the worsening of, either temporarily or permanently, a disease, disorder or condition to which the term applies, or at least one of the symptoms associated therewith. Treatment includes alleviation of symptoms, diminishment of extent of disease, inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease, delaying or slowing of disease progression, improving the quality of life, and / or prolonging survival of a subject as compared to expected survival if not receiving treatment or as compared to a published standard of care therapy for a particular disease.

[0043] The term “in need of treatment” as used herein refers to a judgment made by a physician or similar professional that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s expertise, which may include a positive diagnosis of a disease, disorder or condition.

[0044] The terms “prevent,” “preventing,” “prevention,” “prophylaxis,” and the like refer to a course of action initiated in a manner (e.g., prior to the onset of a disease, disorder, condition, or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition, or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder, or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder, or condition or inhibiting progression thereof to a harmful or otherwise undesired state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or a symptom associated therewith in order to prevent relapse of that disease, disorder, condition, or symptom.

[0045] In certain embodiments, Compound (I) is contained in a “unit dosage form”. The phrase “unit dosage form” refers to physically discrete units, each unit containing a predetermined amount of Compound (I), either alone or in combination with one or more additional agents, sufficient to produce the desired effect.Compound (I)

[0046] Compound (I) can be prepared as described in WO 2021 / 188769 Al. Crystalline Compound (I) can be obtained by triturating amorphous Compound (I) with dichloromethane, filtering the resulting suspension, and washing with a minimum amount of cold dichloromethane and hexanes. PXRD and SEM characterization of crystalline Compound (I),prepared in this fashion, is shown in Figs 1 and 5, respectively. Amorphous and crystalline Compound (I) was found to have low aqueous solubility across the physiological pH range. Physicochemical properties of Compound (I) in an amorphous or crystalline form (without polymer) are provided in Table 1 below.Table 1SIF (simulated intestinal fluid) refers to FaSSIF / FeSSIF / FaSGF V.l powder from Biorelevant comprising an equimolar ratio of sodium taurocholate (NaTC) and egg lecithin. This preparation has three properties: the phosphate buffer concentration is 68 mM, osmolarity is 290 mOsm, and the bile salt concentration is 0.5 wt%.0.5% SIF corresponds to 6.7 mM sodium taurocholate (NaTC) and 6.7 m egg lecithinSolid dispersion

[0047] One aspect of the disclosure is a solid dispersion of Compound (I). The solid dispersion comprises one or more pharmaceutically acceptable polymers. In some embodiments, the solid dispersion of Compound (I) is amorphous or substantially amorphous. In some embodiments, the distribution of Compound (I) within the solid dispersion ishomogenous. In some embodiments, the solid dispersion of Compound (I) is characterized by a single Tg. In some embodiments, the solid dispersion of Compound (I) is characterized by having a single phase. In some embodiments, Compound (I) is amorphous and the solid dispersion of Compound (I) has a single amorphous phase. The terms “solid dispersion” and “solid dispersion of Compound (I)” are used interchangeably throughout this disclosure.

[0048] The solid dispersion can be formed by a variety of methods including employing a solvent to facilitate mixing of the components of the solid dispersion. The components of the solid dispersion along with the solvent for facilitating mixing can be considered an intermediate solution. The solvent used to facilitate mixing is removed (either completely or substantially) from the mixture to result in the solid dispersion. Solvents can be removed by a variety of methods, commonly by evaporation. Such techniques include, but are not limited to, evaporation under reduced pressure or evaporation by spray drying, electrospray, or other methods which may or may not include reduction of pressure.

[0049] In some embodiments, the solid dispersion is made by spray drying. Spray drying may be used to form a dry powder (e.g., a spray-dried dispersion) from a liquid, emulsion, suspension, low viscosity paste, or slurry by rapidly removing solvent using hot gas.

[0050] Other methods may be used to form solid dispersions according to the disclosure, including, e.g., melt dispersion, melt extrusion, solvent-anti solvent precipitation, spray granulation, wet granulation, bead layering, solvent evaporation, etc. Accordingly, in some embodiments, the solid dispersion is an extrudate, a spray-dried dispersion, or a co-precipitate.

[0051] In some embodiments, the one or more pharmaceutically acceptable polymers are selected from one or more of: a) cellulose-based polymers, including cellulose esters and cellulose ethers (e.g., cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC)); b) polymethacrylates; c) pyrrolidones (e.g., polyvinyl pyrrolidine (PVP) or polyvinyl pyrrolidine and vinyl acetate (PVP / VA) copolymer); and d) polyethylene glycols (PEG).

[0052] Other examples of acceptable polymers include, but are not limited to, starch derivates (cyclodextrins), methacrylate pharmaceutically acceptable polymers and co- pharmaceutically acceptable polymers (e.g., poly(methylacrylic acid-co-m ethyl metacrylate), methacrylic acid ethyl acrylate co-pharmaceutically acceptable polymer (MAEA)), polyethylene glycols, povidones (e.g., polyvinylpyrrolidone (PVP), e.g., with molecular weight30kto 100k), and polyvinylpyrrolidone-vinylacetate (PVP-VA), e.g., 60 / 40 VP / Vac, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-pharmaceutically acceptable polymers, polyvinyl alcohol, and poly (vinyl acetal) diethyl amino acetate.

[0053] Additional examples of acceptable polymers include, but are not limited to, cellulose- based pharmaceutically acceptable polymers (e.g., cellulose esters, cellulose ethers, or combinations thereof). Exemplary combinations of cellulose ethers and cellulose esters include, but are not limited to, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate (CAP), carboxy methyl ethyl cellulose (CMEC), ethyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC, e.g., E3 grade having a viscosity of about 2 to 4 cP or 2.4-3.6 cP measured as 2% aqueous solution at 20 °C), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC)).

[0054] In some embodiments, the one or more pharmaceutically acceptable polymer comprises HPMCAS.

[0055] HPMCAS is available in several grades varying in extent of substitution of acetyl and succinoyl groups. HPMCAS includes four types of substituents semi-randomly substituted on the hydroxyls: methoxy, 2-hydroxypropoxy, acetyl, and succinoyl. AquaSolve™ HPMCAS is available in grades of HPMCAS-L (5-9% acetyl, 14-18% succinoyl, 20-24% methoxyl, and 5-9% hydroxypropoxy), HPMCAS-M (7-11% acetyl, 10-14% succinoyl, 21- 25% methoxyl, and 5-9% hydroxypropoxy), and HPMCAS-H (10-14% acetyl, 4-8% succinoyl, 22-26% methoxyl, and 6-10% hydroxypropoxy). The solid dispersion can include or consist of both HPMCAS-M and HPMCAS-H grades. The solid dispersion can include or consist of HPMCAS-M.

[0056] In one embodiment, the one or more pharmaceutically acceptable polymers are selected from hydrophilic polymers. In some embodiments the one or more pharmaceutically acceptable polymers are selected from amphiphilic polymers.

[0057] In one embodiment, the one or more pharmaceutically acceptable polymers for use in the solid dispersion according to this disclosure are characterized by a glass transition temperature (Tg) greater than 112°C or at least 115°C, or at least 120°C, or at least 125°C, or in a range of 120°C to 200°C, or in a range of 120°C to 155°C. For the avoidance of doubt, the recited Tg values correspond to polymers that have not absorbed solvent (e.g., water). For polymers that have absorbed solvent (e.g., water), the Tg may be lower (e.g., greater than 95°C,greater than 100°C, or greater than 105°C). Tg may be determined by modulated differential scanning calorimetry (mDSC).

[0058] The pharmaceutically acceptable polymer or pharmaceutically acceptable polymers selected may modulate the properties of the solid dispersion. In one embodiment, the one or more pharmaceutically acceptable polymers may operate to stabilize an amorphous form of Compound (I) within the solid dispersion, for example, from agglomerating or becoming crystalline.

[0059] As demonstrated by the examples, amorphous solid dispersions comprising amorphous Compound (I) allow for Compound (I) to achieve a supersaturated state upon dissolution. This may lead to enhanced properties for administration, for example improved bioavailability. Further, the use of solid dispersions in unit dosage forms may allow for larger drug loading as compared to a unit dosage form formulated without use of a solid dispersion. Unit dosage forms with higher drug loading may be useful in reducing pill burden during administration. Additionally, the use of the solid dispersion described herein may enhance stability of the unit dosage form, allowing for a longer shelf-life.

[0060] In some embodiments, the solid dispersion can further comprise one or more excipients.

[0061] In some embodiments, the one or more excipients is a surfactant. Surfactants include, but are not limited to, glyceryl dibehenate, lauroyl polyoxyl-32 glycerides, medium and long chain carbamoylated inulins (e.g., inulin lauryl carbamate), polysorbate 80, and poloxamers (e.g., poloxamer 407). In some embodiments, the surfactant is present in a range of 0.01 wt.% to 40 wt.%, or 0.1 wt.% to 35 wt.%, or 0.5 wt.% to 30 wt.% or 10 wt.% to 25 wt.%, or 10 wt.% to 20 wt.%, based on the total weight the solid dispersion (excluding solvents removed as described above). A surfactant can be used in any type of solid dispersion, e.g., one made through any desired method, e.g., such as spray drying.

[0062] Further, in some embodiments, a solid dispersion of the present disclosure may consist essentially of (i) Compound (I) and (ii) one or more pharmaceutically acceptable polymers, and optionally (iii) an excipient such as a surfactant. In other embodiments, a solid dispersion of the present disclosure may consist essentially of (i) Compound (I) and (ii) one or more pharmaceutically acceptable polymers.

[0063] The solid dispersion can have an amount of Compound (I) in a range of 1 wt.% to 90 wt.%, based on the total amount of Compound (I) and one or more pharmaceutically acceptable polymer(s) that form the solid dispersion. Other ranges contemplated include, but are notlimited to, 5 wt.% to 70 wt.%, 20 wt.% to 60 wt.%, 20 wt.% to 50 wt.%, 20 wt.% to 40 wt.%,20 wt.% to 30 wt.%, 25 wt.% to 50 wt.%, and 35 wt.% to 50 wt.%.

[0064] In some embodiments, the solid dispersion comprises about 20 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 22.5 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 25 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 27 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 27.5 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 30 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 31.5 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 33 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 32.5 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 35 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 36 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 37.5 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 38.5 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 40 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 42.5 wt.% of Compound (I), In some embodiments, the solid dispersion comprises about 44 wt.% of Compound (I). In some embodiments, the solid dispersion comprises about 45 wt.% of Compound (I).

[0065] In some embodiments, the solid dispersion comprises a pharmaceutically acceptable polymer in a range of 10 wt.% to 99 wt.%, or in a range of 10 wt. % to 90 wt.%, or in a range of 25 wt.% to 85 wt.%, or in a range of 50 wt.% to 80 wt.%, or in a range of 60 wt.% to 75 wt.%.

[0066] In some embodiments, the solid dispersion comprises about 20 wt.% to about 45 wt.% of Compound (I) and about 55 wt.% to about 80 wt.% of the pharmaceutically acceptable polymer; or about 25 wt.% to about 40 wt.% of Compound (I) and about 60 wt.% to about 75 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 20 wt.% to about 35 wt.% of Compound (I) and about 65 wt.% to about 80 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 20 wt.% to about 30 wt.% of Compound (I) and about 70 wt.% to about 80 wt.% of the pharmaceutically acceptable polymer.

[0067] In some embodiments, the solid dispersion comprises about 20 wt.% of Compound (I) and 80 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the soliddispersion comprises about 25 wt.% of Compound (I) and about 75 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 30 wt.% of Compound (I) and about 70 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 35 wt.% of Compound (I) and about 65 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 40 wt.% of Compound (I) and about 60 wt.% of the pharmaceutically acceptable polymer. In some embodiments, the solid dispersion comprises about 45 wt.% of Compound (I) and about 55 wt.% of the pharmaceutically acceptable polymer.

[0068] The solid dispersion can have a range of particle sizes and the sizes can be controlled by the methods described herein. In one embodiment, the solid dispersion, e.g., a spray-dried solid dispersion, has a D50 particle size of less than 100 pm, or in a range of 1 pm to 100 pm, or 5 pm to 50 pm, for example. Particle size can be measured by using, e.g., scanning electron microscopy (SEM), as further detailed in the examples.

[0069] The solid dispersion can have a single glass transition temperature (Tg) that is lower than the individual pharmaceutically acceptable polymer(s) and Compound (I) Tg and Tm values, respectively. The solid dispersion can have a Tg of greater than 75 °C, or at least 80 °C, or at least 90 °C or at least 100 °C, or in a range of 100°C to 130°C, for example. Tg can be measured using, e.g., modulated differential scanning calorimetry (mDSC). Solid dispersions characterized by higher Tgs may provide stability over time or under stressed storage conditions.

[0070] The degree of crystallinity of Compound (I) in the solid dispersion can be determined, for example, by x-ray powder diffraction (XRPD). In some embodiments, the solid dispersion is characterized by a degree of crystallinity of Compound (I) that is no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or an amount that is below the limit of quantitation (LOQ), or the limit of detection (LOD) as determined by XRPD The degree of crystallinity refers to the amount of crystalline Compound (I) to total Compound (I) in the solid dispersion (e.g., a spray-dried dispersion). The degree of crystallinity can be assessed at different timepoints, for example, initially, after 1 month, after 2 months, after 3 months, after 6 months, after 12 months, etc.

[0071] In one embodiment, the solid dispersion of Compound (I) and the pharmaceutically acceptable polymer is characterized by a diffraction pattern as determined by x-ray powder diffraction (XRPD) that is absent of discrete signals.

[0072] In some embodiments, the solid dispersion provides a supersaturated concentration of Compound (I) when dissolved under non-sink conditions in a gastric medium of 0.0 IN HC1, optionally a concentration of at least 100 pg / ml, or at least 200 pg / ml, or at least 300 pg / ml, or in a range of 100 pg / ml to 1000 pg / ml or 100 to 500 pg / ml or 100 to 400 pg / ml. In some embodiments, the solid dispersion is a spray-dried dispersion, and provides a supersaturated concentration of Compound (I) when dissolved under non-sink conditions in a gastric medium of 0.0 IN HC1, optionally a concentration of at least 100 pg / ml, or at least 200 pg / ml, or at least 300 pg / ml, or in a range of 100 pg / ml to 1000 pg / ml or 100 to 500 pg / ml or 100 to 400 pg / ml. In some embodiments, the solid dispersion provides a supersaturated concentration of Compound (I) for at least 90 minutes. In some embodiments, the solid dispersion provides a supersaturated concentration of Compound (I) for at least 1200 minutes.

[0073] In some embodiments, the solid dispersion (e.g., spray-dried dispersion) provides a supersaturated concentration of Compound (I) for at least 90 minutes when dissolved under non-sink conditions in an intestinal buffer solution consisting of 0.5% SIF in lx PBS, optionally a concentration of at least 50 pg / ml, or at least 100 pg / ml, or at least 200 pg / ml, or in a range of 50 pg / ml to 400 pg / ml, or in a range of 75 pg / ml to 350 pg / ml, or in a range of 100 pg / ml to 300 pg / ml. Such a concentration can also be provided after the dispersion is exposed to a gastric medium of 0.01N HC1 for 15 to 30 minutes.

[0074] The solid dispersion can have an amount of residual solvents meeting ICH guideline Q3C (R8). The solid dispersion can have an amount of acetone of less than 5000 ppm on a weight basis.Nanocrystalline powder form

[0075] Another aspect of the disclosure herein is a nanocrystalline powder form of Compound (I) (also, described herein as “nanocrystalline powder form”), compositions comprising, consisting essentially of, or consisting of said nanocrystalline powder form, as well as spray-dried dispersions comprising said compositions. The nanocrystalline powder form can have a Z-average hydrodynamic diameter (dZ) measured by dynamic light scattering (DLS) of 500 nm or less, or 400 nm or less, or 350 nm or less. In some embodiments, the nanocrystalline powder form can include one or more aggregation inhibitors (described in more detail below).

[0076] Nanocrystalline material can be obtained as described in the examples herein.

[0077] In some embodiments, Compound (I) is combined with one or more aggregation inhibitors and the dispersion medium and then milled in an acoustic mixer at 60 G with 0.5 mmzirconium oxide milling beads to produce a nanocrystalline powder form. In some embodiments the amount of Compound (I) present during milling is in a range of 1 wt.% to 30 wt.%, for example 5 wt.% to 15 wt.%, with a relatively small amount of aggregation inhibitor (e.g., 0.01 wt.% to 10 wt.%, or 0.1 wt.% to 5 wt.%), the balance being water or another solvent in the dispersion medium.

[0078] Particle size can be evaluated via techniques in the art. For example, by light scattering, e.g., using a Malvern ZetaSizer or equivalent instrument.

[0079] Alternatives to milling for size reduction are known, and include processing via microfluidizer, such as in U.S. PatentNo. 5,510,118. Other methods of making nanoparticulate compositions include grinding, co-microprecipitation, microprecipitation, and the like.

[0080] In some embodiments, the nanocrystalline powder form of Compound (I) according to this disclosure comprise one or more aggregation inhibitors. In some embodiments, the one or more aggregation inhibitors comprise a pharmaceutically acceptable polymer, a surfactant, or a combination thereof.

[0081] In some embodiments, the aggregation inhibitor comprises a pharmaceutically acceptable polymer (a pharmaceutically acceptable polymer aggregation inhibitor). In some embodiments, the pharmaceutically acceptable polymer aggregation inhibitor is chosen from HPC, PVP, HPMC, and polyethylene glycol (PEGs). In some embodiments, the pharmaceutically acceptable polymer aggregation inhibitor is non-ionic. In some embodiments, the pharmaceutically acceptable polymer aggregation inhibitor is free of acidic groups.

[0082] In some embodiments the pharmaceutically acceptable polymer aggregation inhibitor is HPC. In some embodiments, the HPC is characterized by a viscosity, measured as 2% aqueous solution at 20°C, of less than 6 cPs, optionally less than 4 cPs, for example in a range of 2-3 cPs. For clarity, these characterizations refer to the pharmaceutically acceptable polymer aggregation inhibitor alone.

[0083] Alternatively or in addition to the pharmaceutically acceptable polymer aggregation inhibitor, the nanocrystalline powder form comprises a surfactant (a surfactant aggregation inhibitor). Exemplary surfactant aggregation inhibitors include, but are not limited to, polysorbate 80 (e.g., Tween 80®), polyoxamers (e.g., poloxamer 188), sodium lauryl sulfate (SLS), block co-pharmaceutically acceptable polymers of ethylene oxide and propylene oxide (e.g., Pluronic® F68 and Fl 08), tetrafunctional block copolymers derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine (e.g., Tetronic® 908),dextran, lecithin, dioctyl esters of sodium sulfosuccinic acid, and alkyl aryl polyether sulfonates (e.g., Triton® X-200). In some embodiments, the surfactant aggregation inhibitor is one or more chosen from polysorbate 80, polyoxamers (e.g., poloxamer 188), and sodium lauryl sulfate (SLS).

[0084] In some embodiments, the one or more aggregation inhibitors (e.g., the pharmaceutically acceptable polymer aggregation inhibitor, surfactant aggregation inhibitor, or combination thereof) are present in the nanocrystalline powder form of Compound (I) an amount in a range of 0.01 wt.% to 40 wt.%, or 0.1 wt.% to 35 wt.%, or 0.5 wt.% to 30 wt.%, or 10 wt.% to 25 wt.%, or 10 wt.% to 20 wt.%, based on the total weight of the nanocrystalline powder of Compound (I) (i.e., total weight of Compound (I) and the one or more aggregation inhibitors). Similarly, in some embodiments, Compound (I) is present in the nanocrystalline powder form in an amount in a range of 60 wt.% to 99.99 wt.%, or 65 wt.%. to 99.9 wt.%, or 70 wt.% to 99.5 wt.%, or 75 wt.%. to 90 wt.%, or 80 wt.% to 90 wt.%, based on the total weight of the nanocrystalline powder of Compound (I) (i.e., total weight of Compound (I) and the one or more aggregation inhibitors).

[0085] In some embodiments, the nanocrystalline powder form of Compound (I) described herein has a Z-average hydrodynamic diameter (dZ) measured by dynamic light scattering (DLS) of 500 nm or less, or 400 nm or less, or 300 nm or less.

[0086] One or more additional excipients as described herein can be added to the nanocrystalline powder form of Compound (I), e.g., to produce a free-flowing powder. In some embodiments, the one or more additional excipients comprise a surfactant, pharmaceutically acceptable polymer, or combinations of surfactants and pharmaceutically acceptable polymers. The one or more additional excipients can be added in a further processing step such as, for example, a spray-drying process. Accordingly, in one aspect, this disclosure provides a spray- dried dispersion comprising a nanocrystalline powder form of Compound (I) as described herein. In some embodiments, the spray-dried nanocrystalline powder form of Compound (I) and the one or more additional excipients can have an amount of Compound (I) in a range of about 20 wt.% to about 60 wt.% of the total composition.

[0087] The nanocrystalline powder form of Compound (I) or a composition comprising the nanocrystalline powder form of Compound (I) (for example, the SDNC described herein) can provide a supersaturated concentration of Compound (I) for at least 90 minutes under non-sink conditions in an intestinal buffer solution consisting of 0.5% SIF in lx PBS.Pharmaceutical Compositions

[0088] The compositions as described above can be further incorporated into a pharmaceutical composition for administration, which is described further herein. In the description below, the SDD and SDNC are referred to as an intermediates in the preparation of a pharmaceutical composition comprising the SDD, and / or SDNC.

[0089] In one embodiment, the intermediate (e.g., the SDD described herein) is combined with one or more excipients to prepare a granulate composition, i.e., a plurality of granules. Granules can be formed by various processes as known in the art, for example by dry granulation, wet granulation, fluid bed rotogranulation, or extrusion. Wet extrudates can be broken into particles and spheronized into pellets. Intermediate steps can include delumping and compaction, e.g., roller compaction. The intermediate as described above can be layered with a coating to form a particle. Granules can provide various advantages, such as ease of processing on automated equipment by providing a free-flowing composition, and suitable bulk and characteristics for compression into dosage forms such as tablets. Granules can also be directly filled into sachets or capsule shells, e.g., hard gelatin shells, or vegetable-based shells.

[0090] In some embodiments, the intermediate (e.g., SDD or SDNC) according to this disclosure is combined with one or more excipients to form a plurality of granules (i.e., a plurality of granules wherein the granules comprise a solid dispersion (e.g., SDD or SDNC) according to this disclosure and one or more excipients). In some embodiments, the plurality of granules is further combined with an extragranular composition comprising one or more excipients to form a unit dosage form (e.g., a tablet). In some embodiments, the unit dosage form further comprises an extragranular component (e.g., a coating).

[0091] In another approach, the intermediate (e.g., SDD or SDNC) is combined with one or more excipients to prepare a composition suitable for manipulation into a unit dosage form (e.g., suitable for direct tableting, filling into a capsule, etc.). In another embodiment, the intermediate is directly manipulated into a unit dosage form (e.g., filled into a capsule).

[0092] Suitable excipients for use with the intermediate (e.g., to form a plurality of granules) include, but are not limited to binders, fillers, disintegrants, lubricants, and glidants. In some embodiments, the granules comprise, consist essentially of, or consist of the intermediate (e.g., SDD) and one or more fillers, a disintegrant, and a lubricant.

[0093] The one or more binders can include a dry binder or a wet binder, optionally one or more in the group of starch, pregelatinized starch, sodium alginate, gelatin, polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), hydroxypropylmethylcellulose (HPMC), a polymethacrylate, sodium carboxymethylcellulose, polyethylene glycol (PEG).

[0094] The one or more fillers can include, but are not limited to, one or more in the group of a pharmaceutically acceptable polymer, a mineral, a metal salt, a sugar, and a starch, optionally one or more in the group of lactose, MCC, silicified microcrystalline cellulose, starch, a natural starch, a modified starch, calcium phosphate, calcium carbonate, sucrose, maltodextrin, mannitol, sorbitol, and sodium chloride, optionally one or more in the group of MCC, mannitol, and lactose, optionally selected from one or both of MCC and mannitol.

[0095] The one or more disintegrants can include, but are not limited to, one or more in the group of crospovidone, croscarmellose calcium, croscarmellose sodium, and sodium starch glycolate, for example croscarmellose sodium.

[0096] The one or more lubricants can include, but are not limited to, one or more in the group of calcium stearate, magnesium stearate, talc, and liquid paraffin, for example magnesium stearate.

[0097] The one or more glidants can include, but are not limited to, one or more in the group of fumed silica, magnesium carbonate, magnesium stearate, silicon dioxide, and talc, for example silicon dioxide.

[0098] The plurality of granules can be sorted to desired size ranges by sieving according to known methods.

[0099] In some embodiments the plurality of granules have sizes (diameters) in a range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm. In some embodiments, the particle size is up to 2.5 mm with no more than 10 percent variation over this size, to a maximum size of 2.8 mm.

[0100] The plurality of granules can further be combined with additional excipients (i.e., extragranular excipients), and / or components (i.e., extragranular components such as a capsule shell or coating) for further processing into dosage forms. In such embodiments, the plurality of granules maintain their integrity and can be considered as distinct from the extragranular excipients and components. Extragranular excipients can include one or more fillers, binders, disintegrants, lubricants, and / or glidants as described above. In some embodiments, the one or more extragranular excipients comprise, consist essentially of, or consist of a filler and a lubricant. In some embodiments the amount of extragranular excipients are present in a rangeof 1 wt.% to 20 wt.% based on the weight of a dosage form, for example 2 wt.% to 10 wt.%, 5 wt.% to 15 wt.%, or 8 wt.% to 18 wt.%. In some embodiments, the extragranular component(s) are present in a range of 1 wt.% to 20 wt.% based on the weight of a dosage form, for example 2 wt.% to 10 wt.%, 5 wt.% to 15 wt.%, or 8 wt.% to 18 wt.%. In some embodiments, the extragranular component is a coating.Unit Dosage Forms

[0101] In some embodiments, this disclosure is directed to a unit dosage form (e.g., a tablet), containing a composition as described herein (e.g., a SDD) comprising a specified quantity of Compound (I), and one or more excipients. The one or more excipients may comprise one or more binders, one or more fillers, one or more lubricants, and / or one or more glidants.

[0102] Accordingly, in another aspect, provided herein is a tablet comprising, consisting essentially of, or consisting of Compound (I) and one or more excipients. In some embodiments, Compound (I) is present as a spray-dried dispersion comprising, consisting essentially of, or consisting of Compound (I) and a pharmaceutically acceptable polymer. In some embodiments, the one or more excipients comprise, consist essentially of, or consist of one or more fillers, a disintegrant, one or more lubricants, and optionally a coating. In some embodiments, (a) the one or more fillers is MCC and / or mannitol; (b) the disintegrant is croscarmellose sodium; (c) the lubricant is magnesium stearate; and (d) the optional coating comprises, consists essentially of, or consists of polyvinyl alcohol or a copolymer thereof. In some embodiments, the tablet comprises, consists essentially of, or consists of about 56.5 wt.% of the spray-dried dispersion, about 24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate. In some embodiments, the tablet comprises, consists essentially of, or consists of about 54.3 wt.% of the spray-dried dispersion, about 23.5 wt.% MCC, about 12.5 wt.% mannitol, about 4.8 wt.% croscarmellose sodium, about 1.0 wt.% magnesium stearate, and about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M. In some embodiments, the spray-dried dispersion comprises, consists essentially of, or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M.

[0103] In another aspect, provided herein is a tablet comprising: a) about 56.5 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I); and about 75 wt.% HPMCAS-M;b) about 24.5 wt.% MCC; c) about 13.0 wt.% mannitol; d) about 5.0 wt.% croscarmellose sodium; and e) about 1.0 wt.% magnesium stearate.

[0104] In another aspect, provided herein is a tablet comprising: a) about 54.3 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I); and about 75 wt.% HPMCAS-M; b) about 23.5 wt.% MCC; c) about 12.5 wt.% mannitol; d) about 4.8 wt.% croscarmellose sodium; e) about 1.0 wt.% magnesium stearate; and f) about 3.8 wt.% of a coating comprising, consisting essentially of, or consisting of polyvinyl alcohol or a copolymer thereof.

[0105] In some embodiments, the unit dosage form comprises a) a plurality of granules as described herein; and b) an extragranular composition. The granules comprise, consist essentially of, or consist of a spray-dried dispersion comprising Compound (I) as described herein and one or more excipients. The one or more excipients may comprise, consist essentially of, or consist of one or more fillers, a disintegrant, and a lubricant. The extragranular composition comprises one or more excipients that comprise, consist essentially of, or consist of a filler and a lubricant. In some embodiments, the unit dosage form further comprises an extragranular component (e.g., a coating or a capsule shell). The amount of extragranular component in the unit dosage form is in a range of 1 wt.% to 20 wt.% based on the weight of the dosage form, for example 2 wt.% to 10 wt.%, 5 wt.% to 15 wt.%, or 8 wt.% to 18 wt.%.

[0106] In other embodiments, the unit dosage form comprises a solid dispersion comprising Compound (I) and one or more excipients. The one or more excipients may comprise, consist essentially of, or consist of one or more fillers, one or more lubricants, and a disintegrant. In some embodiments, the unit dosage form further comprises a coating.

[0107] A unit dosage form (e.g., a tablet) can have an amount of Compound (I) in a range of 1 mg to 500 mg, or 1 mg to 200 mg, or 1 mg to 150 mg, or 1 mg to 100 mg, or 20 mg to 200 mg, or 25 mg to 100 mg, for example 25 mg, or 50 mg, 75 mg, 100 mg, or 125 mg. The unit dosage form can be a monolithic dosage form in which the total quantity of Compound (I) is contained, such as a tablet, or it can be a collection of smaller forms which collectively havethe total quantity of Compound (I) desired in the unit, such as a sachet or capsule filled with granules or mini-tablets.

[0108] In some embodiments, the unit dosage form has an amount of Compound (I) in a range of about 1 wt.% to about 50 wt.%, or in a range of about 2 wt.% to about 40 wt.%., or in a range of about 5 wt.% to about 25 wt.%, for example in a range of about 10 wt.% to about 20 wt.%.

[0109] In some embodiments, the unit dosage form has an amount of Compound (I) in a range of 1 wt.% to 50 wt.%, or in a range of 2 wt.% to 40 wt.%., or in a range of 5 wt.% to 25 wt.%, for example in a range of 10 wt.% to 20 wt.%.

[0110] The dosage form is contemplated to include one or more of the excipients described above, e.g., one or more of a binder, a filler, a disintegrant, a lubricant, and a glidant, and of the types described above.

[0111] Some embodiments provide for a unit dosage form comprising a solid dispersion as described herein and one or more fillers, one or more disintegrants, one or more lubricants, and optionally one or more binders, and one or more glidants. In some embodiments, the unit dosage form comprises a solid dispersion as described herein and one or more fillers, one or more disintegrants, and one or more lubricants.

[0112] In some embodiments, the amount of solid dispersion in the unit dosage form is in a range of 10 wt.% to 90 wt.%, or in a range of 20 wt.% to 80 wt.%., or in a range of 30 wt.% to 70 wt.%, or in a range of 40 wt.% to 70 wt.%, or in a range of 45 wt.% to 65 wt.%, or in a range of 40 wt.% to 60 wt.%, or in a range of 50 wt.% to 65 wt.%, or in a range of 55 wt.% to 60 wt.%, or in a range of 53 wt.% to 63 wt.%, for example in a range of 35 wt.% to 65 wt.%.

[0113] In some embodiments, the unit dosage form comprises about 40 wt.% to about 70 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 45 wt.% to about 65 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 50 wt.% to about 65 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 53 wt.% to about 63 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 53 wt.% to about 60 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 55 wt.% to about 60 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 54.3 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises about 56.5 wt.% of the solid dispersion.

[0114] In some embodiments, the unit dosage form comprises 40 wt.% to 70 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 45 wt.% to 65 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 50 wt.% to 65 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 53 wt.% to 63 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 53 wt.% to 60 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 55 wt.% to 60 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 54.3 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises 56.5 wt.% of the solid dispersion.

[0115] In some embodiments, the unit dosage form comprises at least 40 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises at least 45 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises at least 50 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises at least 53 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises at least 55 wt.% of the solid dispersion.

[0116] In some embodiments, the unit dosage form comprises less than 70 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises less than 65 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises less than 63 wt.% of the solid dispersion. In some embodiments, the unit dosage form comprises less than 60 wt.% of the solid dispersion.

[0117] In some embodiments, the unit dosage form comprises about 30 wt.% to about 60 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises about 30 wt.% to about 50 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises about 35 wt.% to about 45 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises about 36 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises about 37.5 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises about 42.5 wt.% of the one or more fillers.

[0118] In some embodiments, the unit dosage form comprises 30 wt.% to 60 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises 30 wt.% to 50 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises 35 wt.% to 45 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises 36 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises 37.5wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises 42.5 wt.% of the one or more fillers.

[0119] In some embodiments, the unit dosage form comprises at least 30 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises at least 35 wt.% of the one or more fillers.

[0120] In some embodiments, the unit dosage form comprises less than 60 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises less than 50 wt.% of the one or more fillers. In some embodiments, the unit dosage form comprises less than 45 wt.% of the one or more fillers.

[0121] In some embodiments, the unit dosage form comprises about 1 wt.% to about 10 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises about 1 wt.% to about 8 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises about 1 wt.% to about 6 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises about 4 wt.% to about 6 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises about 5 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises about 4.8 wt.% of the one or more disintegrants.

[0122] In some embodiments, the unit dosage form comprises 1 wt.% to 10 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises 1 wt.% to 8 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises 1 wt.% to 6 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises 4 wt.% to 6 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises 5 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises 4.8 wt.% of the one or more disintegrants.

[0123] In some embodiments, the unit dosage form comprises at least 1 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises at least 4 wt.% of the one or more disintegrants.

[0124] In some embodiments, the unit dosage form comprises less than 10 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises less than 8 wt.% of the one or more disintegrants. In some embodiments, the unit dosage form comprises less than 6 wt.% of the one or more disintegrants.

[0125] In some embodiments, the unit dosage form comprises about 0.5 wt.% to about 3.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprisesabout 0.5 wt.% to about 2.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises about 0.5 wt.% to about 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises about 1.0 wt.% of the one or more lubricants.

[0126] In some embodiments, the unit dosage form comprises 0.5 wt.% to 3.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises 0.5 wt.% to 2.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises 0.5 wt.% to 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises 1.0 wt.% of the one or more lubricants.

[0127] In some embodiments, the unit dosage form comprises at least 0.5 wt.% of the one or more lubricants.

[0128] In some embodiments, the unit dosage form comprises less than 3 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises less than 2 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises less than 1.5 wt.% of the one or more lubricants.

[0129] In some embodiments, the unit dosage form comprises about 40 wt.% to about 70 wt.% of the solid dispersion, about 30 wt.% to about 60 wt.% of the one or more fillers, about 1 wt.% to about 10 wt.% of the one or more disintegrants, and about 0.5 wt.% to about 3.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of about 40 wt.% to about 70 wt.% of the solid dispersion, about 30 wt.% to about 60 wt.% of the one or more fillers, about 1 wt.% to about 10 wt.% of the one or more disintegrants, and about 0.5 wt.% to about 3.0 wt.% of the one or more lubricants.

[0130] In some embodiments, the unit dosage form comprises 40 wt.% to 70 wt.% of the solid dispersion, 30 wt.% to 60 wt.% of the one or more fillers, 1 wt.% to 10 wt.% of the one or more disintegrants, and 0.5 wt.% to 3.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of 40 wt.% to 70 wt.% of the solid dispersion, 30 wt.% to 60 wt.% of the one or more fillers, 1 wt.% to 10 wt.% of the one or more disintegrants, and 0.5 wt.% to 3.0 wt.% of the one or more lubricants.

[0131] In some embodiments, the unit dosage form comprises at least 40 wt.% of the solid dispersion, at least 30 wt.% of the one or more fillers, at least 1 wt.% of the one or more disintegrants, and at least 0.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of at least 40 wt.% of the solid dispersion,at least 30 wt.% of the one or more fillers, at least 1 wt.% of the one or more disintegrants, and at least 0.5 wt.% of the one or more lubricants.

[0132] In some embodiments, the unit dosage form comprises about 1 wt.% to about 20 wt.%, about 2 wt.% to about 10 wt.%, about 5 wt.% to about 15 wt.%, or about 8 wt.% to about 18 wt.% of the extragranular component. In some embodiments, the unit dosage form comprises about 3.8 wt.% of the extragranular component. In some embodiments, the extragranular component is a coating comprising polyvinyl alcohol or a copolymer thereof.

[0133] In some embodiments, the unit dosage form comprises less than 70% wt.% of the solid dispersion, less than 60% wt.% of the one or more fillers, less than 10% wt.% of the one or more disintegrants, and less than 3.0% wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of less than 70% wt.% (w / w) of the solid dispersion, less than 60% wt.% (w / w) of the one or more fillers, less than 10% wt.% (w / w) of the one or more disintegrants, and less than 3.0% wt.% (w / w) of the one or more lubricants.

[0134] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of about 53 wt.% to about 60 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and about 0.5 wt.% to about 1.5 wt.% of the one or more lubricants.

[0135] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of 53 wt.% to 60 wt.% of the solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and 0.5 wt.% to 1.5 wt.% of the one or more lubricants.

[0136] In some embodiments, the unit dosage form comprises about 55 wt.% to about 60 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and about 0.5 wt.% to about 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of about 55 wt.% to about 60 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and about 0.5 wt.% to about 1.5 wt.% of the one or more lubricants.

[0137] In some embodiments, the unit dosage form comprises 55 wt.% to 60 wt.% of the solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and 0.5 wt.% to 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of 55 wt.% to 60 wt.% ofthe solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and 0.5 wt.% to 1.5 wt.% of the one or more lubricants.

[0138] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of at least 53 wt.% of the solid dispersion, at least 35 wt.% of the one or more fillers, at least 4 wt.% of the one or more disintegrants, and at least 0.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises at least 55 wt.% of the solid dispersion, at least 35 wt.% of the one or more fillers, at least 4 wt.% of the one or more disintegrants, and at least 0.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of at least 55 wt.% of the solid dispersion, at least 35 wt.% of the one or more fillers, at least 4 wt.% of the one or more disintegrants, and at least 0.5 wt.% of the one or more lubricants.

[0139] In some embodiments, the unit dosage form comprises less than 60 wt.% of the solid dispersion, less than 45 wt.% of the one or more fillers, less than 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of less than 60 wt.% of the solid dispersion, less than 45 wt.% of the one or more fillers, less than 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants.

[0140] In some embodiments, the unit dosage form comprises about 53 wt.% to about 63 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of about 53 wt.% to about 63 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form comprises, consists essentially of, or consists of about 53 wt.% to about 60 wt.% of the solid dispersion, about 35 wt.% to about 45 wt.% of the one or more fillers, about 4 wt.% to about 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants.

[0141] In some embodiments, the unit dosage form comprises 53 wt.% to 63 wt.% of the solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of 53 wt.% to 63 wt.% of the solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants. In some embodiments, theunit dosage form comprises, consists essentially of, or consists of 53 wt.% to 60 wt.% of the solid dispersion, 35 wt.% to 45 wt.% of the one or more fillers, 4 wt.% to 6 wt.% of the one or more disintegrants, and less than 1.5 wt.% of the one or more lubricants.

[0142] In some embodiments, the unit dosage form comprises about 56.5 wt.% of the solid dispersion, about 37.5 wt.% of the one or more fillers, about 5.0 wt.% of the one or more disintegrants, and about 1.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of about 56.5 wt.% of the solid dispersion, about 37.5 wt.% of the one or more fillers, about 5.0 wt.% of the one or more disintegrants, and about 1.0 wt.% of the one or more lubricants.

[0143] In some embodiments, the unit dosage form comprises 56.5 wt.% of the solid dispersion, 37.5 wt.% of the one or more fillers, 5.0 wt.% of the one or more disintegrants, and 1.0 wt.% of the one or more lubricants. In some embodiments, the unit dosage form consists essentially of or consists of 56.5 wt.% of the solid dispersion, 37.5 wt.% of the one or more fillers, 5.0 wt.% of the one or more disintegrants, and 1.0 wt.% of the one or more lubricants.

[0144] In some embodiments, the unit dosage form comprises about 56.5 wt.% of the solid dispersion, about 24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate. In some embodiments, the unit dosage form consists essentially of or consists of about 56.5 wt.% of the solid dispersion, about 24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate. In some embodiments, the solid dispersion comprises Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form comprises about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion consists essentially of or consists of Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form consists essentially of or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion is a spray-dried dispersion.

[0145] In some embodiments, the unit dosage form comprises about 56.5 wt.% of the spray-dried dispersion, about 24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate. In some embodiments, the unit dosage form consists essentially of or consists of about 56.5 wt.% of the spray-dried dispersion, about 24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate. In some embodiments, the spray-dried dispersion comprises Compound (I) and HPMCAS-M. In some embodiments, the spray-drieddispersion of the unit dosage form comprises about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M. In some embodiments, the spray-dried dispersion consists essentially of or consists of Compound (I) and HPMCAS-M. In some embodiments, the spray-dried dispersion of the unit dosage form consists essentially of or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M.

[0146] In some embodiments, the unit dosage form comprises 56.5 wt.% of the solid dispersion, 24.5 wt.% MCC, 13.0 wt.% mannitol, 5.0 wt.% croscarmellose sodium, and 1.0 wt.% magnesium stearate. In some embodiments, the unit dosage form consists essentially of or consists of 56.5 wt.% of the solid dispersion, 24.5 wt.% MCC, 13.0 wt.% mannitol, 5.0 wt.% croscarmellose sodium, and 1.0 wt.% magnesium stearate. In some embodiments, the solid dispersion comprises Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form comprises 25.0 wt.% Compound (I), and 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion consists essentially of or consists of Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form consists essentially of or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion is a spray-dried dispersion.

[0147] In some embodiments, the unit dosage form comprises 56.5 wt.% of the spray-dried dispersion, 24.5 wt.% MCC, 13.0 wt.% mannitol, 5.0 wt.% croscarmellose sodium, and 1.0 wt.% magnesium stearate. In some embodiments, the unit dosage form consists essentially of or consists of 56.5 wt.% of the spray-dried dispersion, 24.5 wt.% MCC, 13.0 wt.% mannitol, 5.0 wt.% croscarmellose sodium, and 1.0 wt.% magnesium stearate. In some embodiments, the spray-dried dispersion comprises Compound (I) and HPMCAS-M. In some embodiments, the spray-dried dispersion of the unit dosage form comprises 25.0 wt.% Compound (I), and 75.0 wt.% HPMCAS-M. In some embodiments, the spray-dried dispersion consists essentially of or consists of Compound (I) and HPMCAS-M. In some embodiments, the spray-dried dispersion of the unit dosage form consists essentially of or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M.

[0148] In some embodiments, the unit dosage form is a tablet.

[0149] In some embodiments, this disclosure is directed to a tablet comprising a composition as described herein. In one embodiment, the tablet is prepared from granules as described above, and optionally with extragranular excipients and / or components as described above.

[0150] For example, an intermediate (e.g., solid dispersion) can be blended with one or more excipients in a suitable blender. Such excipients can include, but are not limited to, one or more fillers (e.g., MCC, mannitol, lactose), one or more disintegrants (e.g., croscarmellose sodium) and one or more lubricants (e.g., magnesium stearate). The blend can be de-lumped using a suitable mill, followed by further blending with intragranular components to ensure uniform mixing. The lubricant (e.g., magnesium stearate) optionally can be added after the filler(s) and disintegrant(s). The blend with lubricant can be roller compacted into ribbons followed by milling the ribbons into granules using a roller compactor with an oscillating mill equipped with a suitable screen. Extragranular excipients can be added into the above blend mix, if desired, and tumble blended. The blend with extragranular excipients, for example, includes one or more fillers. A lubricant can be added to the blend with extragranular excipients. The final blend can be compressed into tablets at the target mass using a tablet press. A coating can further be applied to the compressed tablet cores to form a film coated tablet. Alternatively, the coating material may be added earlier in the process, for example, as an extragranular component to form a coated extragranular composition. The extragranular composition can be further processed into a tablet. Optionally, a design can be introduced to the surface of the tablet by, for example, embossing or debossing.

[0151] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of about 54.3 wt.% of the solid dispersion, about 36.0 wt.% of the one or more fillers, about 4.8 wt.% of the one or more disintegrants, about 1.0 wt.% of the one or more lubricants, and about 3.8 wt.% of an extragranular component (e.g., a coating mixture).

[0152] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of 54.3 wt.% of the solid dispersion, 36.0 wt.% of the one or more fillers, 4.8 wt.% of the one or more disintegrants, 1.0 wt.% of the one or more lubricants, and 3.8 wt.% of an extragranular component (e.g., a coating mixture).

[0153] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of about 54.3 wt.% of the solid dispersion, about 23.5 wt.% MCC, about 12.5 wt.% mannitol, about 4.8 wt.% croscarmellose sodium, about 1.0 wt.% magnesium stearate, and about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof. In some embodiments, the solid dispersion comprises, consists essentially of, or consists of Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form comprises, consists essentially of, or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion is a spray-dried dispersion.

[0154] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of about 54.3 wt.% of the spray-dried dispersion, about 23.5 wt.% MCC, about 12.5 wt.% mannitol, about 4.8 wt.% croscarmellose sodium, about 1.0 wt.% magnesium stearate, and about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof. In some embodiments, the spray-dried dispersion comprises, consists essentially of, or consists of Compound (I) and HPMCAS-M. In some embodiments, the spray-dried dispersion of the unit dosage form comprises, consists essentially of, or consists of about 25.0 wt.% Compound (I), and about 75.0 wt.% HPMCAS-M.

[0155] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of 54.3 wt.% of the solid dispersion, 23.5 wt.% MCC, 12.5 wt.% mannitol, 4.8 wt.% croscarmellose sodium, 1.0 wt.% magnesium stearate, and 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof. In some embodiments, the solid dispersion comprises, consists essentially of, or consists of Compound (I) and HPMCAS-M. In some embodiments, the solid dispersion of the unit dosage form comprises, consists essentially of, or consists of 25.0 wt.% Compound (I), and 75.0 wt.% HPMCAS-M. In some embodiments, the solid dispersion is a spray-dried dispersion.

[0156] In some embodiments, the unit dosage form comprises, consists essentially of, or consists of 54.3 wt.% of the spray-dried dispersion, 23.5 wt.% MCC, 12.5 wt.% mannitol, 4.8 wt.% croscarmellose sodium, 1.0 wt.% magnesium stearate, and 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof. In some embodiments, the spray-dried dispersion comprises, consists essentially of, or consists of Compound (I) and HPMCAS-M. In some embodiments, the spray-dried dispersion of the unit dosage form comprises, consists essentially of, or consists of 25.0 wt.% Compound (I), and 75.0 wt.% HPMCAS-M.

[0157] In some embodiments, this disclosure is directed to a pharmaceutical composition comprising Compound (I) and a means for improving dissolution of Compound (I) and / or the bioavailability of Compound (I). Dissolution can be measured using methods described herein, e.g., non-sink dissolution testing. Bioavailability can be measured using methods described herein, e.g., measuring plasma concentration from a subject who has been administered a composition comprising Compound (I). Without wishing to be bound by theory, compositions that enhance the surface area of Compound (I), e.g., solid dispersions, provide a means for improving dissolution and / or bioavailability. Compositions suitable for improving dissolution will demonstrate greater solubility (e.g., achieve supersaturation sustainment) and greater dissolution as compared to amorphous or crystalline Compound (I).

[0158] The compositions described herein can provide increased bioavailability of Compound (I) as compared to an alternative composition containing the identical amount of Compound (I), for example, as demonstrated by the examples below.

[0159] The unit dosage form or tablet provides a serum / plasma exposure of Compound (I), measured as AUC (96hr) of at least 50,000 (ng-h / ml), when dosed to fasted male beagle dogs at a dose of 25 mg, or at least 200,000 (ng-h / ml), when dosed to male beagle dogs at a dose of 100 mg.

[0160] In some embodiments, the unit dosage form or tablet provides a plasma exposure of Compound (I), measured as AUCo-inf of at least about 20,000 ng-h / mL, or at least about 21,000 ng-h / mL, or at least about 21,500 ng-h / mL, or at least about 22,000 ng-h / mL, or at least about 22,500 ng-h / mL, or at least about 23,000 ng-h / mL, or at least about 23,500 ng-h / mL when administered to a human subject at a dose of 100 mg.

[0161] In some embodiments, the pharmaceutical compositions described herein have a total impurity amount of less than 2% (% area), measured by HPLC. Analysis of impurity by HPLC may be carried out as described herein. In some embodiments pharmaceutical compositions have a total impurity amount of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% (% area), measured by HPLC. In some embodiments, the pharmaceutical compositions have a total impurity amount of less than 1% (% area), measured by HPLC. In some embodiments, pharmaceutical compositions have a total impurity amount of less than 0.5% (% area), measured by HPLC.

[0162] The pharmaceutical compositions described herein are physically stable, chemically stable, and / or have stable in vitro dissolution properties upon storage at 25 °C ± 2 °C and 60% ± 5% relative humidity (long term stability testing) or 40 °C ± 2 °C and 75% ± 5% relative humidity (accelerated stability testing) in a closed or open packaging for 3 months or more (e.g., 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months). Stability may be evaluated by a variety of analytical methods including XRPD, mDSC, assay of Compound (I) and impurities by HPLC, and non-sink dissolution testing.

[0163] In some embodiments, upon storage at 25 °C ± 2 °C and 60% ± 5% relative humidity and / or at 40 °C ± 2 °C and 75% ± 5% relative humidity, in a closed or open packaging for 3 months or more, the spray-dried dispersion is characterized by (i) a single glass transition measured by MSDC, (ii) no other melt or crystallization events measured by MSDC, (iii) adiffraction pattern by XRPD that is absent of discrete signals, (iv) a degree of crystallinity of no more than 5%, or no more than 1%, or below a LOQ or LOD by XRPD, or (v) any combination of (i) to (iv).

[0164] In some embodiments, upon storage at 25 °C ± 2 °C and 60% ± 5% relative humidity and / or at 40 °C ± 2 °C and 75% ± 5% relative humidity, in a closed or open packaging for 3 months or more, the amount (e.g., concentration and / or area under the curve) of Compound (I) measured by non-sink dissolution testing differs by no more than 25%, or no more than 15%, or no more than 12%, or no more than 10%, or no more than 5% of the same value measured at 0 months at the same time point and under the same conditions. The non-sink dissolution testing can be according to the method described in Example 2 or 3 or 4 below.

[0165] In some embodiments, upon storage at 25 °C and 60% relative humidity and / or at 40 °C ± 2 °C and 75% ± 5% relative humidity, in a closed or open packaging for 3 months or more, the amount (e.g., concentration and / or area under the curve) of Compound (I) measured by non-sink dissolution testing differs by no more than about 25% or no more than about 15%, or no more than 12%, or no more than about 10%, or no more than about 5% of the same value measured at 0 months at the same time point and under the same conditions. The non-sink dissolution testing can be selected from the method of Example 2, or Example 3, or Example 4 below, for example.

[0166] In some embodiments, upon storage at 25 °C ± 2 °C and 60% ± 5% relative humidity in a closed packaging for 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months:(i) the amount of Compound (I) in the solid dispersion is about 90% to about 110% of the value measured at 0 months;(ii) the solid dispersion has a total impurity amount of less than or equal to 2%, or less than or equal to 1% (% area), measured by high-performance liquid chromatography (HPLC);(iii) the solid dispersion is characterized by a single Tg, and optionally a single melting temperature (Tm), by modulated differential scanning calorimetry (mDSC);(iv) the solid dispersion is characterized by a diffraction pattern by XRPD that is absent of discrete signals;(v) the amount of Compound (I) released from the solid dispersion measured by non- sink dissolution testing differs by no more than 15% of the value measured at 0 months; or(vi) any combination of (i) to (v).Dosage amounts

[0167] In general, the disclosed methods comprise administering the solid dispersions, nanocrystalline powder forms, pharmaceutical compositions, and unit dosages as described herein of Compound (I) in an effective amount to a subject in need thereof. An “effective amount” with reference to Compound (I), and solid dispersions, nanocrystalline powder forms, pharmaceutical compositions, and unit dosage forms comprising that compound, means an amount of Compound (I) that is sufficient to engage the target (by inhibiting the target) at a level that is indicative of the potency of the compound. For HIF-2a, target engagement can be determined by one or more biochemical or cellular assays resulting in an IC50, or similar value which can be used as one assessment of the potency of the compound. Assays for determining target engagement include, but are not limited to, those described in WO2021188769. The effective amount may be administered as a single quantity or as multiple, smaller quantities (e.g., as one tablet with “x” amount, as two tablets each with “x / 2” amount, etc.).

[0168] In some embodiments, the disclosed methods comprise administering a therapeutically effective amount of Compound (I), or a pharmaceutical composition or unit dosage form described herein, to a subject in need thereof. As used herein, the phrase “therapeutically effective amount” means a dose regimen (i.e., amount and interval) of the compound, or pharmaceutical composition or unit dosage form comprising the compound, that provides the specific pharmacological effect for which the compound is administered to a subject in need of such treatment. For prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, including biochemical, histological and / or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with a disease, delay disease progression, prolong survival, decrease the dose of other medication(s) required to treat the disease, or a combination thereof. With respect to cancer specifically, a therapeutically effective amount may, for example, result in the killing of cancer cells, reduce cancer cell counts, reduce tumor burden, eliminate tumors or metastasis, or reduce metastatic spread. A therapeutically effective amount need not always be effective in treating every individual subject to be deemed to be a therapeutically effective amount by those of skill in the art. A therapeutically effective amount may vary based on, for example, one or more of the following: the age and weight of the subject, the subject’s overall health, the stage of the subject’s disease, the route of administration, and prior or concomitant treatments.

[0169] Administration may comprise one or more (e.g., one, two, or three or more) dosing cycles.

[0170] In certain embodiments, Compound (I), or the pharmaceutical compositions or unit dosage forms contemplated by the present disclosure may be administered (e.g., orally, parenterally, etc.) to deliver about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of Compound (I) per kilogram of a subject’s body weight per day, one or more times a day, to obtain the desired effect. In some embodiments, a suitable weight-based dose of Compound (I) contemplated by the present disclosure is used to determine a dose that is administered independent of a subject’s body weight. In certain embodiments, the solid dispersions, nanocrystalline powder forms, pharmaceutical compositions, and unit dosages as described herein of Compound (I) contemplated by the present disclosure are administered (e.g., orally, parenterally, etc.) to deliver a fixed dosage level of about 1 mg to about 1000 mg, particularly 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, or 300 mg of Compound (I), one or more times a day, to obtain the desired effect. In some embodiments, the solid dispersions, nanocrystalline powder forms, pharmaceutical compositions, and unit dosages as described herein of Compound (I) contemplated by the present disclosure may be administered (e.g., orally) at dosage levels of Compound (I) of about 50 mg to about 250 mg, one or more times a day, to obtain the desired therapeutic effect.

[0171] As used herein, “a total daily dosage” or “total daily dose” refers to the total amount of active pharmaceutical ingredient (e.g., Compound (I)) to be administered within a 24-hour period. The total daily dosage may be administered by any method (e.g., orally) or frequency. For example, a total daily dosage of 100 mg of an active pharmaceutical ingredient may be administered as 50 mg twice daily or 100 mg once daily.

[0172] In some embodiments, the solid dispersions, nanocrystalline powder forms, pharmaceutical compositions, and unit dosages of Compound (I) contemplated by the present disclosure may be orally administered to a subj ect in need thereof to provide a total daily dosage of about 50 mg Compound (I) to about 250 mg Compound (I), or about 50 mg Compound (I) to about 150 mg Compound (I). In some embodiments, the subject is administered a total daily dosage of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg. In some embodiments, the unit dosage of Compound (I) contemplated by the present disclosure is administered as four 25 mg tablets to achieve a total daily dose of 100 mg.

[0173] For administration of an oral agent, the pharmaceutical compositions and / or unit dosages can be provided in the form of tablets, capsules and the like containing from about 1 to about 200 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 10 mg to 100 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 10 mg to 75 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 10 mg to 50 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 25 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 50 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 75 mg of Compound (I). In some embodiments, the tablet or capsule described herein comprises 100 mg of Compound (I). In some embodiments, the tablets or capsules described herein are administered once daily to obtain the desired therapeutic effect. In some embodiments, the tablets or capsules described herein are administered twice daily to obtain the desired therapeutic effect.

[0174] In some embodiments, a tablet as described herein comprises 10 mg of Compound (I). In some embodiments, a tablet as described herein comprises 25 mg of Compound (I). In some embodiments, a tablet as described herein comprises 50 mg of Compound (I). In some embodiments, a tablet as described herein comprises 75 mg of Compound (I). In some embodiments, a tablet as described herein comprises 100 mg of Compound (I). In some embodiments, a tablet as described herein comprises 150 mg of Compound (I).Treatment Methods

[0175] The present disclosure provides methods for inhibiting HIF-2a using a pharmaceutical composition or unit dosage form described herein and methods for using a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in the preparation of a medicament for inhibiting HIF-2a. As used herein, the terms “inhibit”, “inhibition” and the like refer to the ability of an antagonist to decrease the function or activity of a particular target, e.g., HIF-2a. Suitable measures of decreased HIF-2a function and activity may include, but are not limited to, decreased expression of genes regulated by HIF-2a (e.g., Pdgfb, Serpine 7, Adm, etc. in macrophages; Akapl2, DII4, Adm, Glutl, Glut 3, etc. in endothelial cells, and the like) and / or decreased amounts of EPO or EPO expression. In some embodiments, the solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure is administered to a subject at a daily dose effective to reduce EPO expression by at least 90% in the subject, e.g., by at least 90%, by at least 91%, by at least 92%, by at least 93%, by at least 94%, by at least 95%, by at least 96%, by at least 97%, by at least 98%, by at least 99% or by at least 100%.

[0176] The present disclosure also encompasses methods for the treatment or prevention of diseases, disorders, and / or conditions that would benefit from HIF-2a inhibition (e.g., a disease, disorder, or condition mediated at least in part by HIF-2a) and the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in the preparation of a medicament for the treatment or prevention of diseases, disorders, and / or conditions that would benefit from HIF-2a inhibition. Under normoxic conditions, the a-subunit of HIF-2a is hydroxylated at conserved proline residues by prolyl-4-hydroxylases, and subsequently targeted for degradation by the von Hippel-Lindau ubiquitin E3 ligase complex. Accordingly, diseases, disorders, and / or conditions that would benefit from HIF-2a inhibition may include those disease, disorders and / or conditions associated with HIF-2a- stabilizing defects, HIF-2a overexpression and / or other forms if dysregulation, as well as those diseases, disorders, and / or conditions in which local or systemic hypoxia or pseudohypoxia is prevalent. HIF-2a-stabilizing defects, caused by gene deletion(s), mutation(s), epigenetic silencing, posttranslational modifications, and the like, result in increased stabilization of HIF- 2a and abnormally activate the expression of genes that regulate metabolism, angiogenesis, cell proliferation and survival, immune evasion, and inflammatory response. HIF-stabilizing mutations have been detected in the von Hippel-Lindau gene (VHL as well as in other genes, such as succinate dehydrogenase (SDHB, SDHC, SDHD fumarate hydratase (FH), Egl nine homolog 1 (EGLN1), and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF-2a itself: EPAS1.

[0177] In some embodiments, diseases, disorders, and / or conditions that would benefit from HIF-2a inhibition may be characterized by (i) increased HIF-2a expression in one or more suitable samples as compared to a similar sample from a healthy control or another disease, disorder and / or condition not responsive to HIF-2a inhibition, (ii) increased HIF-2a expression as compared to HIF-la expression in one or more suitable samples as compared to a similar sample from a healthy control or another disease, disorder and / or condition not responsive to HIF-2a inhibition, (iii) increased expression of genes regulated by HIF-2a in one or more suitable samples as compared to a similar sample from a healthy control or another disease, disorder and / or condition not responsive to HIF-2a inhibition, (iv) mutations in a gene that result HIF-2a-stabilizing defects, or (v) any combination thereof. A suitable sample may be a tissue, blood, or lymph sample comprising tumor cells, immune cells, etc., or an enriched or purified sample of cells obtained from tissue, blood, or lymph; etc. In various embodiments, the disease, disorder, and / or condition may be Von Hippel-Lindau (VHL) disease (including VHL disease associated with renal cell carcinoma (RCC), central nervous system (CNS)hemangioblastomas, pancreatic neuroendocrine tumors (pNET), or solid tumors); cancer; an immune-related disease, disorder or condition; an inflammatory-related disease, disorder or condition; cardiovascular disease; kidney disease; or a metabolic disease.

[0178] Accordingly, in some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are administered to a subject in need thereof in an amount effective to inhibit HIF-2a function and activity. HIF-2a function and activity may be assessed using a peripheral blood sample or a tissue sample (e.g., a tumor sample) obtained from the subject. Inhibition may be determined, for example, by comparison to a previous sample obtained from the subject (i.e., prior to administration of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet) or by comparison to a reference value for a control group (e.g., a group of subjects with the same disease that were untreated or that received standard of care, a placebo, etc.).

[0179] Alternatively or in addition, in some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are administered to a subject in need thereof to treat and / or prevent cancer or a cancer-related disease, disorder or condition. In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are administered to a subject in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are set forth elsewhere herein.

[0180] Alternatively or in addition, in some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are administered to a subject with von Hippel -Lindau (VHL) disease to treat and / or prevent a VHL-associated disease, disorder or condition. In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are administered to a subject with von Hippel -Lindau (VHL) disease to treat and / or prevent associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, optionally wherein immediate surgery is not required.Oncology and Oncology-related Disorders

[0181] In one or more embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are useful in the treatment and / or prophylaxis of cancer (e.g., carcinomas, sarcomas, leukemias, lymphomas, myelomas, etc.). In certain embodiments, the cancer may be locally advanced and / or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or nolonger responding to a treatment, such as a standard of care treatment known to one of skill in the art. In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein are useful in the treatment of cancer that has been previously treated (e.g., in the same setting or an earlier setting) with an immune checkpoint inhibitor (e.g., a PD-(L)1 antagonist) and / or a VEGF or VEGFR inhibitor. Exemplary types of cancer contemplated by this disclosure include cancer of the genitourinary tract (e.g., bladder, kidney, renal cell, penile, prostate, testicular, etc.), uterus, cervix, ovary, breast, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), bone, bone marrow, skin (e.g., melanoma), head and neck, liver, gall bladder, bile ducts, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS), peripheral nervous system (PNS), the hematopoietic system (i.e., hematological malignancies), and the immune system (e.g., spleen or thymus). In some embodiments, the cancer is a solid tumor, optionally wherein the solid tumor is associated with von Hippel- Lindau (VHL) disease. In some embodiments, the cancer is kidney cancer, liver cancer, prostate cancer, bladder cancer, breast cancer, gynecological cancer, gastrointestinal (GI) cancer, or is a neuroendocrine tumor. In some embodiments, the cancer is renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma, pancreatic neuroendocrine tumors (pNETs), esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), optionally wherein the cancer is associated with von Hippel-Lindau (VHL) disease.

[0182] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment and / or prophylaxis of hematological malignancies. Exemplary types of cancer affecting the hematopoietic system include, but are not limited to, leukemias, lymphomas and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin’s and Non-Hodgkin’s lymphoma, Diffuse large B Cell lymphoma, and multiple myeloma.

[0183] In another embodiment, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment and / or prophylaxis of solid tumors. The solid tumor may be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), head-and-neck tumors, mesothelioma, melanoma, sarcomas, central nervous system (CNS)hemangioblastomas, and brain tumors (e.g., gliomas, such as astrocytoma, oligodendroglioma and glioblastomas).

[0184] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment and / or prophylaxis of gastrointestinal cancer, genitourinary cancer, gynecological cancer, lung cancer, or a combination thereof.

[0185] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of gastrointestinal (GI) cancer. In some embodiments, the GI cancer is colorectal cancer, pancreatic cancer, or liver cancer. In some embodiments, the GI cancer is an upper GI cancer, such as esophageal or gastric cancer. In further embodiments, the upper GI cancer is an adenocarcinoma, a squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as “gastric cancer”) or any combination thereof.

[0186] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of pancreatic cancer. In further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma.

[0187] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment and / or prophylaxis of liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma. In other embodiments, the liver cancer is liver metastases.

[0188] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of genitourinary cancer. In some embodiments, the genitourinary cancer is bladder cancer, kidney cancer or prostate cancer.

[0189] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal carcinoma.

[0190] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatmentof gynecological cancer. In some embodiments, the gynecological cancer is breast cancer, endometrial cancer, or ovarian cancer. In some embodiments, the gynecological cancer is hormone receptor positive (e.g., ERa-positive cancer, PR-positive cancer, ERa-positive and PR-positive cancer), HER2 positive cancer, HER2 over-expressing cancer, or any combination thereof. In still further embodiments, the cancer is triple negative cancer (e.g., ER, PR and HER2 negative).

[0191] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In still further embodiments, the lung cancer is NSCLC, optionally lung squamous cell carcinoma or lung adenocarcinoma.

[0192] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is pancreatic neuroendocrine tumor, pheochromocytoma, paraganglioma, or a tumor of the adrenal gland (e.g., neuroblastoma).

[0193] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment of brain cancer. In further embodiments, the brain cancer is a glioma. In still further embodiments, the glioma is an astrocytoma, an oligodendroglioma, or a glioblastoma.

[0194] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are useful in the treatment and / or prophylaxis of renal cell carcinoma or hepatocellular carcinoma.

[0195] In the aforementioned embodiments, the methods of the present disclosure may be practiced in an adjuvant setting or neoadjuvant setting. Alternatively or in addition, the methods described herein may be indicated as a first line treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the methods described herein may be indicated as a second line, third line, or greater line of treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the methods of the present disclosure are indicated as a second or greater line of therapy in subjects who have been heavily pre-treated. When indicated as a second line or greater treatment, in some embodiments an earlier line of therapy may have included a checkpoint inhibitor and / or a kinase inhibitor (e.g., a tyrosine kinase inhibitor (TKI)). In someembodiments, the earlier line of therapy may have included a PD-(L)1 antagonist, a CTLA-4 antagonist, an inhibitor of VEGF or VEGFR (e.g., a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, an anti-VEGFR antibody), and / or an inhibitor of mTOR.

[0196] The present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer and non-cancerous proliferative disease, and includes, e.g., angiogenesis, precancerous conditions such as dysplasia, and non-cancerous proliferative diseases disorders or conditions, such as benign proliferative breast disease and papillomas. For clarity, the term(s) cancer-related disease, disorder and condition do not include cancer per se.

[0197] In general, the disclosed methods for treating or preventing cancer, or a cancer- related disease, disorder or condition, in a subject in need thereof comprise administering to the subject a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet disclosed here. In some embodiments, the present disclosure provides methods for treating or preventing cancer, or a cancer-related disease, disorder or condition with a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet disclosed herein and at least one additional therapy, examples of which are set forth elsewhere herein.Von-Hippel-Lindau Disease

[0198] In one or more embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form or tablet described herein are useful in the treatment and / or prophylaxis of von Hippel-Lindau (VHL) disease or VHL disease associated tumors. In some embodiments, the disease, disorder, and / or condition is VHL disease associated with renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors (pNET), or solid tumors).Metabolic and Inflammatory-related Disorders

[0199] In one or more embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form or tablet described herein are useful in the treatment and / or prophylaxis of metabolic or inflammatory-related diseases, disorders and conditions. A nonlimiting list of metabolic diseases, disorders and conditions which may be treated or prevented with the compounds and compositions of the present disclosure include insulin resistance, diabetes, obesity, and the like. A non-limiting list of inflammatory-related diseases, disordersand conditions which may be treated or prevented with the compounds and compositions of the present disclosure include allergic diseases, disorders, and conditions; cardiovascular disease, disorders and conditions (aortic valve stenosis, asthma, arteriosclerosis, atherosclerosis, cardiac ischemia, cardiac fibrosis, chronic obstructive pulmonary disease (COPD), congestive heart failure, pulmonary fibrosis, pulmonary hypertension, stroke, etc.); chronic kidney disease or kidney failure; colitis; inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); anemia; inflammatory neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, etc.); musculoskeletal diseases (e.g., arthritis, rheumatoid arthritis, systemic sclerosis, asthma; fibrosis; fibromyalgia; lupus; pancreatitis; psoriasis; surgical complications (e.g., where inflammatory cytokines prevent healing); infections; allergic contact dermatitis and other eczemas, transplantation and osteoporosis.Selection of patients

[0200] In various embodiments, the methods according to this disclosure may be used in selected patients.

[0201] The methods according to this disclosure may be used in patients with renal impairment, for example, mild or moderate renal impairment. In some embodiments, methods according to this disclosure may be used in patients with creatine clearance (CLCR) > 40 ml / minute as determined by Cockcroft-Gault equation. In some embodiments, methods according to this disclosure may be used in patients with a glomerular filtration rate > 30 ml / min / 1.73 m2, > 45 ml / min / 1.73 m2, or > 60 ml / min / 1.73 m2.

[0202] Alternatively or in addition, in some embodiments, the methods according to this disclosure may be used in patients identified or previously identified as having a biomarker of hypoxia or pseudohypoxia, microsatellite instability, or high tumor mutational burden as measured in a relevant tissue or sample.Combination Therapy

[0203] The present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet as described herein alone or in combination with one or more additional therapy. Each additional therapy can be a therapeutic agent or another treatment modality. In embodiments comprising one or more additional therapeutic agents, each agent may target a different, but complementary, mechanism of action. The additional therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA or fragments of such macromolecules; or cellular or gene therapies. Non-limiting examples of additional treatment modalities includesurgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. The use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet as described herein in combination with one or more additional therapies may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition. In addition or alternatively, the combination therapy may allow for a dose reduction of one or more of the therapies, thereby ameliorating, reducing or eliminating adverse effects associated with one or more of the agents.

[0204] In embodiments comprising one or more additional treatment modality, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet as described herein can be administered before, after or during treatment with the additional treatment modality. In embodiments comprising one or more additional therapeutic agent, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and / or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.Cancer Therapies

[0205] The present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more additional therapies useful in the treatment of cancer.

[0206] In some embodiments, one or more of the additional therapies is an additional treatment modality. Exemplary treatment modalities include, but are not limited to, surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy.

[0207] In some embodiments, one or more of the additional therapies is a therapeutic agent. Exemplary therapeutic agents include, but are not limited to, chemotherapeutic agents, radiopharmaceuticals, hormone therapies, epigenetic modulators, ATP-adenosine axistargeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, AXL inhibitors, PAK4 inhibitors,immunotherapeutic agents, cellular therapies, gene therapies, immune checkpoint inhibitors, and agonists of stimulatory or co-stimulatory immune checkpoints.

[0208] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes (i.e., “platinum-containing chemotherapeutic agent”) such as cisplatin, carboplatin andoxaliplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracy clines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises chemotherapy (e.g., a chemotherapy regimen) that includes one or more chemotherapeutic agents. In one embodiment, combination therapy comprises chemotherapy comprising one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), FOLFIRINOX (e.g., fluorouracil, leucovorin, irinotecan, and oxaliplatin), CAPOX (capecitabine and oxaliplatin), a taxoid (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), a fluoropyrimidine-containing chemotherapeutic agent (e.g., fluorouracil, capecitabine, floxuridine), a platinum-containing chemotherapeutic agent, and / or gemcitabine.

[0209] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a source of radiation (i.e., one or more radionuclide) is put inside a subject’s body. The radiation source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide 1-131, radium -223 di chloride, lobenguane iodine-131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides comprise a radionuclide associated (e.g., by covalent or ionic interactions) with a molecule (“a targeting agent”) that specifically binds to a target on a cell, typically a cancer cell or an immune cell. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural pharmaceutically acceptable polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor- associated antigen (i.e., an antigen enriched but not specific to a cancer cell), a tumor-specific antigen (i.e., an antigen with minimal to no expression in normal tissue), or a neo-antigen (i.e., an antigen specific to the genome of a cancer cell generated by non-synonymous mutations inthe tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides attached to: somatostatin or peptide analogs thereof (e.g., 177Lu-Dotatate, etc.); prostate specific membrane antigen or peptide analogs thereof (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a receptor’s cognate ligand, peptide derived from the ligand, or variants thereof (e.g., 188Re-labeled VEGF125-136 or variants thereof with higher affinity to VEGF receptor, etc.); antibodies targeting tumor antigens (e.g., 1311-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), 1131-omburtamab, etc.).

[0210] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormone therapies act to regulate or inhibit hormonal action on tumors. Examples of hormone therapies include, but are not limited to: selective estrogen receptor degraders such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene; aromatase inhibitors such as anastrozole, exemestane, letrozole and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists such as degarelix, antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide; 5a-reductase inhibitors such as finasteride, dutasteride; and the like. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. In one embodiment, combination therapy comprises administration of enzalutamide.

[0211] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. An epigenetic modulator alters an epigenetic mechanism controlling gene expression, and may be, for example, an inhibitor or activator of an epigenetic enzyme. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HD AC) inhibitors. In one or more embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include, but are not limited to, decitabine, zebularine and azacitadine. In one or more embodiments, combinations of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure with a histone deacetylase (HD AC) inhibitor is also contemplated. Exemplary HD AC inhibitors include, but are not limited to, vorinostat, givinostat, abexinostat, panobinostat, belinostat and trichostatin A.

[0212] In some embodiments, one or more of the additional therapeutic agents is an ATP- adenosine axis-targeting agent. ATP-adenosine axis-targeting agents alter signaling mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example by modulating the level of adenosine or targeting adenosine receptors. Adenosine and ATP, acting at different classes of receptors, often have opposite effects on inflammation, cell proliferation and cell death. For instance, ATP and other adenine nucleotides have antitumor effects via activation of the PS2Y1 receptor subtype, while accumulation of adenosine in the tumor microenvironment has been shown to inhibit the antitumor function of various immune cells and to augment the immunosuppressive activity of myeloid and regulatory T cells by binding to cell surface adenosine receptors. In certain embodiments, an ATP-adenosine axis-targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of adenosine receptor. Ectonucleotidases involved in the conversion of ATP to adenosine include the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, also known as CD39 or Cluster of Differentiation 39) and the ecto- 5 '-nucleotidase (NT5E or 5NT, also known as CD73 or Cluster of Differentiation 73). Exemplary small molecule CD73 inhibitors include, but are not limited to, CB-708, ORIC-533, LY3475070 and quemliclustat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include, but are not limited to, ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates combination of the solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with a CD39 inhibitor such as those described in WO 2023165561. In further embodiments the CD39 inhibitor is AB598. In one embodiment, the present disclosure contemplates combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with a CD73 inhibitor such as those described in WO 2017 / 120508, WO 2018 / 067424, WO 2018 / 094148, and WO 2020 / 046813. In further embodiments, the CD73 inhibitor is quemliclustat. Adenosine can bind to and activate four different G-protein coupled receptors: AiR, A2AR, A2BR, and A3R. A2R antagonists include Compound (I), inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS- 21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with an A2AR antagonist, an A2BR antagonist, or an antagonist of A2AR and A2BR. In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet describedherein with the adenosine receptor antagonists described in WO 2018 / 136700, WO 2018 / 204661, WO 2018 / 213377 or WO 2020 / 023846. In one embodiment, the adenosine receptor antagonist is Compound (I).

[0213] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, a targeted therapy may comprise a targeting agent and a drug. The drug may be a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug attached to a targeting agent. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural pharmaceutically acceptable polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen, a tumor-specific antigen, or a neo-antigen. In some embodiments, the targeted therapy is an antibody-drug conjugate comprising an antibody and a drug, wherein the antibody specifically binds to HER2, HER3, nectin-4, or Trop-2. Specific examples of a targeted therapy comprising an antibody and a drug include, but are not limited to, patritumab deruxtecan, sacituzumab govitecan-hziy, telisotuzumab vedotin, and trastuzumab deruxtecan. In other aspects, a targeted therapy may inhibit or interfere with a specific protein that helps a tumor grow and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axistargeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, PD-1 antagonists, PD-L1 antagonists, CTLA-4 antagonists, a VEGF or VEGFR inhibitor. ATP-adenosine axis-targeting agents are described above, while other agents are described in further detail below.

[0214] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. Signal transduction inhibitors are agents that selectively inhibit one or more steps in a signaling pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, andosimertinib), and anti-EGFR antibodies; (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, e.g., HER-2 / neu receptor inhibitors (e.g., trastuzumab) and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor (VEGF) inhibitors or VEGFR receptor (VEGFR) inhibitors including small molecule inhibitors (e.g., axitinib, regorafenib, sunitinib and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, vorolanib, etc.) anti-VEGF antibodies (e.g., bevacizumab), and anti-VEGFR antibodies (e.g., ramucirumab); (v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin); (vi) inhibitors of mTOR, such as, for example, everolimus, sirolimus, temsirolimus; (vii) inhibitors of serine / threonine-protein kinase B-Raf (BRAF), such as, for example, vemurafenib, dabrafenib and encorafenib; (viii) inhibitors of rearranged during transfection (RET), including, for example, selpercatinib and pralsetinib; (ix) tyrosine-protein kinase Met (MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib and crizotinib); (x) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (xi) inhibitors of the RAS signaling pathway (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK) as described elsewhere herein; (xii) FLT-3 inhibitors (e.g., gilteritinib); (xiii) inhibitors of Trop-2; (xiv) inhibitors of the JAK / STAT pathway, e.g., JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin; (xv) inhibitors of NF-kB; (xvi) cell cycle kinase inhibitors (e.g., flavopiridol); (xvii) phosphatidyl inositol kinase (PI3K) inhibitors; (xviii) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xix) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); and (xx) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). In one or more embodiments, the additional therapeutic agent comprises an inhibitor of EGFR, VEGFR, HER- 2, HER-3, BRAF, RET, MET, ALK, RAS (e g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF- kB, PI3K, AKT, or any combinations thereof.

[0215] In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with an mTOR inhibitor. In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with everolimus, sirolimus, or temsirolimus.

[0216] In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with a VEGF inhibitor or a VEGFR inhibitor. In some embodiment, theVEGF or VEGFR inhibitor is a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody. In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, ramucirumab, regorafenib, sunitinib, sorafenib, or tivozanib. In some embodiments, the present disclosure contemplates the combination of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein with axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sunitinib, sorafenib, or tivozanib.

[0217] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in the RAS family of genes, e.g., HRAS, KRAS, and NRAS, are associated with a variety of cancers. For example, mutations of G12C, G12D, G12V, G12A, G13D, Q61H, G13C and G12S, among others, in the KRAS family of genes have been observed in multiple tumor types. Direct and indirect inhibition strategies have been investigated for the inhibition of mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, and include, but are not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g, S0S1), mTORCl, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC- 5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963. Direct inhibitors of RAS mutants have also been explored, and generally target the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), adagrasib (MRTX849), mRNA-5671 and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, S0S1 inhibitors, mTORCl inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0218] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), through physical degradation, at the protein / protein level, at the protein / DNA level, or by binding in an activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunit of the MLL complex (e g., HDAC, DOT1L, BRD4, Menin, LEDGF, WDR5, KDM4C (JMJD2C) and PRMT1), and the like.

[0219] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis and is believed to mediate resistance to a variety of cancer therapies. There are a variety of AXL inhibitors under development that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases including MET, FLT3, RON and AURORA, among others. Exemplary multikinase inhibitors include, but are not limited to, sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX-106. AXL specific inhibitors have also been developed, e.g., small molecule inhibitors including DS-1205, SGL7079, SLC-391, TP-0903 (i.e., dubermatinib), BGB324 (i.e., bemcentinib), AB801, and DP3975; anti-AXL antibodies such as ADCT-601; and antibody drug conjugates (ADCs) such as BA3011. Another strategy to inhibit AXL signaling involves targeting AXL’s ligand, GAS6. For example, batiraxcept (AVB-500) is under development as a Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure is combined with one or more AXL inhibitors described in WO 2022246177, WO 2022246179, or WO 2024006726. In some embodiments, the AXL inhibitor is AB801.

[0220] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly (ADP -ribose) pharmaceutically acceptable polymerase (e.g., olaparib, niraparib and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47- SIRPa pathway (e.g., the anti-CD47 antibody, magrolimab, etc.); (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.).

[0221] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat a disease by stimulating or suppressing the immune system. Immunotherapeutic agents useful in the treatment of cancers typically elicit or amplify an immune response to cancer cells. Non-limiting examples of suitable immunotherapeutic agents include: immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis-targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis-targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are described further below.

[0222] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cytokine or chemokine, such as, IL-1, IL-2, IL- 12, IL-18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, TNF, IL-15, MDC, IFNa / p, M-CSF, IL- 3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharides (LPS); an organic or inorganic adjuvant that activates antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex molecules agonists including, but not limited to Toll-like receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2,3 -dioxygenase 1 (IDO1) inhibitors and immune-stimulatory oligonucleotides, as well as other T cell adjuvants.

[0223] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cellular therapy. Cellular therapies are a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents is a cellular immunotherapy that activates or suppresses the immune system. Cellular immunotherapies useful in the treatment of cancers typically elicit or amplify an immune response. The cells can be autologous or allogenic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subject. Alternatively, the cells can be “(re)programmed” allogenic immune cells produced from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be an expanded subset of cells with distinct effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), Ml macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to a specific antigen and / or enhance the cells’ anti-tumor effects (e.g., engineered T cell receptor (TCR) cellular therapies, chimeric antigen receptor (CAR) cellular therapies, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to express of have increased expression of a tumor-associated antigen, or may be any combination thereof. Non-limiting types of cellular therapies include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include, but are not limited to, sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.Z.

[0224] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a gene therapy. Gene therapies comprise recombinant nucleic acids administered to a subject or to a subject’s cells ex vivo in order to modify the expression of an endogenous gene or to result in heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, micro RNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not comprise a nucleic acid component (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, and the like. Non-limiting examples of gene therapies that may be useful in cancer treatment include (rAd- p53), rAD5-H101), talimogene laherparepvec, Mx-dnGl, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0225] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically an agent that modulates an immune checkpoint. Immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints engage when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with agonists of stimulatory or co-stimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or co-stimulatory pathways and antagonists of inhibitory pathways may have utility as agents to overcome distinct immune suppressive pathways within the tumor microenvironment, inhibit T regulatory cells, rever se / prevent T cell anergy or exhaustion, trigger innate immune activation and / or inflammation at tumor sites, or combinations thereof.

[0226] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term “immune checkpoint inhibitor” refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms “immune checkpoint inhibitor”, “checkpoint inhibitor” and “CPI” may be used herein interchangeably. Immune checkpoint inhibitors may antagonize an inhibitory or co-inhibitory immune checkpoint by interfering with receptor -ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells, that can be antagonized include, but are not limited to, PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (T cellimmunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, Galectin 9, CEACAM-1, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and Killer Inhibitory Receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Also contemplated are other less well-defined immune checkpoints that have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (also known as CD276) and B7- H4 (also known as B7-S1, B7x and VCTN1)).

[0227] In some embodiments, an immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, as well as bispecific antibodies such as MEDI5752 and KN046.

[0228] In some embodiments, an immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody, small molecule or peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDL0680 (AMP-514; WO2012 / 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab; as well as bi-specific antibodies such as LY3434172. In still further embodiments, the PD-1 antagonist can be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl (AMP-224). In certain embodiments, an immune checkpoint inhibitor is zimberelimab.

[0229] In some embodiments, a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet according to this disclosure are combined zimberelimab. In some embodiments, zimberelimab is administered at a dose of about 100 mg to about 600 mg or about 200 mg to about 600 mg, about 600 mg to about 800 mg. In some embodiments, zimberelimab is administered at a dose of about 100 mg, 150 mg, 200 mg, 220 mg, 240 mg, 260 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, or 460 mg. Doses of zimberelimab may be administered once a week, or less frequently (e.g., once every two, three, four, five, six weeks, or more). In some embodiments, a dosing cyclecomprises administering domvanalimab at a dose of about 360 mg once every three weeks or at a dose of about 480 mg once every four weeks.

[0230] In some embodiments, an immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab as well as bi-specific antibodies such as LY3434172 and KN046.

[0231] In some embodiments, an immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include, but are not limited to, monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, belrestotug, etigilimab, IBI-929, JS006, dargistotug, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; as well as bi-specific antibodies such as AGEN1777 and AZD2936. In certain embodiments, an immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, an immune checkpoint inhibitor is domvanalimab or AB308.

[0232] In some embodiments, an immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, fianlimab, BMS-986016 (WO 10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (W008 / 132601, WO09 / 44273).

[0233] In certain embodiments, an immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab (MGA271; WO11 / 109400), omburtumab, DS-7300a, ABBV-155, and SHR-A1811.

[0234] In some embodiments, an immune checkpoint inhibitor is a TIM-3 antagonist. In further embodiments, the TIM-3 antagonist can be an antagonistic TIM-3 antibody. Suitable antagonistic TIM-3 antibodies include, for example, dostarlimab, sabatolimab, BMS-986258, and RG7769 / RO7121661.

[0235] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or co-stimulatory immune checkpoint. Examples of stimulatory or co-stimulatory immune checkpoints (ligands and receptors) include, but are not limited to, B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

[0236] In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab (PF-05082566; WO12 / 32433). In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (W006 / 105021, W009 / 009116) and MK-4166 (WO11 / 028683). In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is an 0X40 agonist. In further embodiments, the 0X40 agonist can be an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, an agent that activates a stimulatory or co- stimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0237] In some embodiments, one or more of the additional therapies is an immunotherapeutic agent, more specifically an intracellular signaling molecules that influences immune cell function. For example, one or more of the additional therapies may be an inhibitor of hematopoietic progenitor kinase 1 (HPK1). HPK1 is serine / threonine kinase that functions as a negative regulator of activation signals generated by the T cell antigen receptor. As another example, one or more of the additional therapies may be an inhibitor of Cbl-b, an E3 ubiquitin ligase involved in the regulation of TCR signaling. As another example, one or more of the additional therapies may be an inhibitor of diacylglycerol kinase (DGK). In some embodiments, the inhibitor is a small molecule. Non-limiting examples of small molecule HPK1 inhibitors in clinical development include CFI-402411 and BGB-15025; nonlimiting examples of Cbl-b inhibitors in clinical development include HST-1011, and NX- 1607. Non-limiting examples of small molecule DAG inhibitors include those described in W02020006016A1 and WO2021130638.

[0238] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immune-suppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes the agent may be CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553,WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13 169264), or CSF-1R antagonists disclosed in WO14 / 036357. In another example, to inhibit or deplete regulatory T cells (Tregs) the agent may be an anti-CD25 antibody or immunotoxin targeting CD25.

[0239] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more chemotherapeutic agent and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more chemotherapeutic agent and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy.

[0240] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more chemotherapeutic agent and one or more tyrosine kinase inhibitor, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy.

[0241] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more chemotherapeutic agent and one or more inhibitor independently selected from (i) BCR-ABL kinase inhibitor; (ii) an EGFR inhibitor (e.g., EGFR TKI or anti-EGFR antibody); (iii) HER-2 / neu receptor inhibitor; (iv) a VEGF inhibitor or a VEGFR inhibitor (e.g., a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody); (v) AKT inhibitor; (vi) BRAF inhibitor; (vii) RET inhibitor; (viii) MET inhibitor; (ix) ALK inhibitor, and (x) an inhibitor of CDK-4 and / or CDK-6 (e.g., abemaciclib, palbociclib, ribociclib, etc.), and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy.

[0242] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more immunotherapeutic agent and optionally one or more additional therapeutic agent, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, a chemotherapeutic agent, a cellular therapy, or a gene therapy.

[0243] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more immunotherapeutic agent and one or more tyrosine kinase inhibitor, and optionally one or more additional therapeutic agent, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, a chemotherapeutic agent, a cellular therapy, or a gene therapy. In some embodiments, the combination comprises one or more immunotherapeutic agent and a multitargeted tyrosine kinase inhibitor, optionally wherein the multi -targeted tyrosine kinase inhibitor inhibits VEGFR.

[0244] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more immunotherapeutic agent and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cellular therapy.

[0245] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more immune checkpoint inhibitor and / or one or more ATP- adenosine axis-targeting agent, and optionally one or more additional therapeutic agent, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cellular therapy.

[0246] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more ATP-adenosine axis-targeting agent and one or more tyrosine kinase inhibitor, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cellular therapy. In some embodiments, the combination comprises one or more ATP-adenosine axis-targeting agent and a multi -targeted tyrosinekinase inhibitor, optionally wherein the multi-targeted tyrosine kinase inhibitor inhibits VEGFR.

[0247] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more ATP-adenosine axis-targeting agent, one or more immunotherapeutic agent, and one or more tyrosine kinase inhibitor, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cellular therapy. In some embodiments, the combination comprises one or more ATP-adenosine axis-targeting agent, one or more immunotherapeutic agent, and a multi-targeted tyrosine kinase inhibitor, optionally wherein the multi -targeted tyrosine kinase inhibitor inhibits VEGFR.

[0248] In another embodiment, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more immune checkpoint inhibitor and / or one or more ATP- adenosine axis-targeting agent, and one or more inhibitor independently selected from (i) a BCR-ABL kinase inhibitor; (ii) an EGFR inhibitor (e.g., EGFR TKI or anti-EGFR antibody); (iii) a HER-2 / neu receptor inhibitor; (iv) a VEGF inhibitor or a VEGFR inhibitor (e.g., a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody); (v) an AKT inhibitor; (vi) a BRAF inhibitor; (vii) a RET inhibitor; (viii) a MET inhibitor; (ix) an ALK inhibitor, and (x) an inhibitor of CDK-4 and / or CDK-6.

[0249] Selection of the additional therapeutic agent(s) may be informed by current standard of care for a particular cancer and / or mutational status of a subject’s cancer and / or stage of disease. Detailed standard of care guidelines are published, for example, by National Comprehensive Cancer Network (NCCN). See, for instance, NCCN Colon Cancer v3.2024, NCCN Rectal Cancer v2.2024, NCCN Hepatobiliary Cancers vl.2023, NCCN Hepatocellular Carcinoma vl.2024, NCCN Kidney Cancer, v4.2024, NCCN NSCLC v5.2024, NCCN Pancreatic Adenocarcinoma v2.2024.

[0250] In some embodiments, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein for treating kidney cancer, optionally clear cell renal cell carcinoma, in combination with: (a) an mTOR inhibitor; or (b) a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody; or (c) an mTOR inhibitorand an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody; (d) a checkpoint inhibitor; or (e) a checkpoint inhibitor and an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody. The checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, or a PD-1 antagonist. In some embodiments, the kidney cancer is a von-Hippel- Lindau (VHL) disease-associated cancer.

[0251] In some embodiments, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein for treating liver cancer, optionally hepatocellular carcinoma, in combination with: (a) a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody; or (b) a checkpoint inhibitor; or (d) a checkpoint inhibitor and an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody. The checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, or a PD-1 antagonist. In some embodiments, the kidney cancer is a von-Hippel-Lindau (VHL) disease-associated cancer. In some embodiments, the liver cancer is inoperable, has extensive liver tumor burden, locally advanced or metastatic.

[0252] In another aspect, the present disclosure contemplates the use of a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein in combination with one or more additional therapeutic agents useful in the treatment of metabolic and / or inflammatory-related diseases, disorders or conditions.

[0253] In some embodiments, one or more additional therapeutic agents is a non-steroidal anti-inflammatory drug (NS AID), a cyclooxygenase-2 (COX-2) inhibitor, or a steroid.

[0254] In some embodiments, one or more additional therapeutic agents is a JAK inhibitor.

[0255] In some embodiments, one or more additional therapeutic agents is an immune checkpoint inhibitor. Suitable immune checkpoint inhibitors are described above.

[0256] In some embodiments, one or more additional therapeutic agents is cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to, or antagonists of, other human cytokines or growth factors, for example, TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL- 16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0257] Particular combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade, and include, but are not limited to, TNFantagonists such as chimeric, humanized or human TNF antibodies, infliximab, adalimumab, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, derivatives thereof, p75TNFRIgG (entanercept) or p55TNFRlgG (lenercept), soluble IL-13 receptor (sIL-13), and also TNFa-converting enzyme (TACE) inhibitors; similarly, IL-1 inhibitors (e.g., Interleukin- 1 -converting enzyme inhibitors) may be effective. Other combinations include Interleukin 11, anti-P7s and p-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with a solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet as described herein include, but are not limited to, interferon P-la; interferon-P-lb, glatiramer acetate; hyperbaric oxygen; intravenous immunoglobulin; clabribine; and antibodies to, or antagonists of, other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0258] In some embodiments, each of the one or more additional therapy is independently selected from a kinase inhibitor, an immune checkpoint inhibitor, an ATP-adenosine axistargeting agent, a chemotherapeutic agent, and radiation therapy. In some embodiments, the one or more additional therapy comprises: one or more kinase inhibitors that inhibit one or more kinases selected from the group consisting of mTOR, VEGF, VEGFR, EGFR, HER-2, HER-3, BRAF, RET, MET, MER, TYRO3, ALK, MEK, ERK, FLT-3, JAK, PI3K, AKT, FGFR, KIT, and AXL; one or more immune checkpoint inhibitors selected from a CTLA-4 antagonist, a PD-(L)1 antagonist, a PD-1 antagonist, a TIGIT antagonist, a TIM-3 antagonist, a LAG-3 antagonist, and a BTLA antagonist; one or more ATP-adenosine axis-targeting agents selected from an adenosine receptor (e.g., A2A and / or A2B receptor) antagonist, a CD73 inhibitor, and a CD39 inhibitor; and / or one or more chemotherapeutic agents selected from a platinum-based, taxoid-based, or anthracycline-based chemotherapeutic agent. In some embodiments, the kinase inhibitor inhibits one or more kinases selected from the group consisting of mTOR, VEGF, VEGFR, MET, RET, TYRO3, AXL, and MER. In some embodiments, the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1. In some embodiments, the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiplimab, envafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab. In some embodiments, the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is zimberelimab. In some embodiments, the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activityof TIGIT. In some embodiments, the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, domvanalimab, etigilimab, ociperlimab, tiragolumab, or vibostolimab. In some embodiments, the immune checkpoint inhibitor is domvanalimab or AB308. In some embodiments, the one or more ATP-adenosine axis-targeting agents are selected from the group consisting of AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaradenant, ciforadenant, and quemliclustat. In some embodiments, the one or more ATP-adenosine axis-targeting agents are AB598, etrumadenant, and / or quemliclustat. In some embodiments, the chemotherapeutic agent comprises one or more of gemcitabine, fluorouracil, cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

[0259] The solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet described herein and method are contemplated to include embodiments including any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures), unless stated otherwise.EXAMPLES

[0260] The following examples are provided for illustration and are not intended to limit the scope of the invention.Summary of abbreviations:

[0261] SDD = spray-dried dispersion; SDNC = spray-dried nanocrystals; SDI = spray-dried intermediate; SIF = simulated intestinal fluid; 0.5 SIF = 6.7 mM sodium taurocholate (NaTC) and 6.7 mM egg lecithin; FaSSIF = fasted state simulated intestinal fluid; FeSSIF = fed state simulated intestinal fluid; FaSGF = fasted state simulated gastric fluid; PBS = phosphate buffered saline; N2 = nitrogen gas; g = grams; mg = milligrams; kg = kilograms; mgA / mL = milligrams active substance per milliliter; pgA / mL = micrograms active substance per milliliter; pm = micrometer; pL = microliters; mL = milliliter; mm = millimeter; nm = nanometers; mM = millimolar; M = molar; N = normality; MPa = megapascal; slpm = standard liters per minute; psi = pounds per square inch; g = RCF = relative centrifugal force; G = G- force; deg =0= degrees; kV = kilovolts; mA = milliamps; A = angstroms; hr = hours; min = minutes; sec = seconds; wt% = weight percent; Tg = glass transition temperature; Tm = melting temperature; GB = gastric buffer; IB = intestinal buffer; HPLC = high performance liquid chromatography; SEM = scanning electron microscopy; XRPD and PXRD = powder x-ray diffraction; mDSC = modulated differential scanning calorimetry; TGA = thermalgravimetric analysis; DLS = dynamic light scattering; HPMCAS-L = hydroxypropyl methylcellulose acetate succinate (L-grade); HPMCAS-M = hydroxypropyl methylcellulose acetate succinate(M-grade); HPMCAS-H = hydroxypropyl methylcellulose acetate succinate (H-grade); PVP- VA64=PVPVA= poly(vinylpyrrolidone-co-vinyl acetate); SLS = sodium lauryl sulfate; HPC SSL = hydroxypropylcellulose (grade SSL); PVP K25 = polyvinylpyrrolidone (K25); HPMC E3 = hydroxypropyl methylcellulose (E3-grade); TFA = trifluoroacetic acid.Methods

[0262] A brief summary of the characterization methods used throughout the examples is provided in Tables 1-3 below. mDSCTable 1: Modulated Differential Scanning Calorimetry (mDSC) Method ParametersPXRD

[0263] PXRD analysis was carried out on a Rigaku Miniflex 600 X-ray diffractometer, scanning the samples between 3 and 40° 29. The material was gently ground and loaded into a 0.2 mm zero background cup. The cup was then placed into the diffractometer and analyzed using Cu K radiation (al X = 1.54060 A; a2 = 1.54443 A; P = 1.39225 A; al :a2 ratio = 0.5) running in transmission mode (step size 0.0200° 29) using 40 kV / 15 mA generator settings.Table 2: Powder X-Ray Diffraction (PXRD) Method ParametersSEMTable 3: Scanning Electron Microscopy (SEM) Method ParametersMicrocentrifuge (MCT) Dissolution Test Protocol

[0264] The wet and secondary dried SDDs of Example 2 and SDNCs of Example 3 were evaluated in a non-sink gastric to intestinal buffer (G-IB) dissolution test to evaluate various aspects of the compositions. The samples were added to 2.0 mL microcentrifuge tubes and dosed under the conditions listed below. All samples were kept at 37 °C. Samples were taken at different time points and drug concentration was measured by HPLC after centrifugation in a microcentrifuge and an ultracentrifuge. The ultracentrifuge test was performed at select timepoints during the test, and it consisted of a centrifugation step at 300,000 x g to remove any colloidal species that are present, leaving only the free dissolved drug and drug in micelle species.Table 4: MCT Dissolution Parametersu=ultracentrifuged sampleTable 5: HPLC MethodTable 6: HPLC Gradient ProgramExample 1: Characterization of Compound (I)PXRD

[0265] The powder X-ray diffractogram of crystalline Compound (I) is shown in Fig. 1.The XRPD peaks are listed in Table 7 below.Table 7T and Tm

[0266] The melting point of crystalline Compound (I) was measured using an OptiMelt Melting Point Apparatus. Crystalline Compound (I) was loaded into a glass capillary and heated at 2.5°C / minute up to 320°C. The OptiMelt determines the melting point when theamount of light transmitted through the sample increases above 50% (called the “single point”). Crystalline Compound (I) exhibited a sharp melting range between 245°C and 255°C. The single melting point was determined to be 250°C.

[0267] To quantify the degradation temperature of Compound (I), approximately 5 mg of the compound was heated in a TGA, in which the sample mass was monitored while the sample was heated. The compound was heated at a rate of 2.5°C / minute up to 300°C. The compound showed a loss of approximately 1% weight at the melting point, which likely reflects solvent molecules that are liberated with increased degrees of freedom in the compound crystals. The conservative onset of degradation was approximately 265°C, the temperature at which the weight began to drop following this initial solvent loss.

[0268] A melt quench experiment was performed to confirm the melting point of neat Compound (I) and to measure the glass transition temperature after quenching with liquid nitrogen. Compound (I) was brought past the melt on the DSC furnace at a heating rate of 10°C / minute. After the melt was completed, the sample was removed from the furnace and submerged in liquid nitrogen for at least one minute. The sample was then placed back on the DSC furnace, and the glass transition was measured using a heating rate of 2.5°C / minute with ±1.5°C / minute modulation. The initial heating scan of Compound (I) exhibited a sharp endothermic melting peak, centered at 250°C, which aligns with the previously determined melting point. After quenching in liquid nitrogen and reheating, the sample showed a Tgat 112°C based on reversing heat flow signal.Crystalline Aqueous Solubility

[0269] Aqueous media were saturated with crystalline Compound (I) at approximately 1 mgA / mL. The aqueous media were 0.01 N HC1 (pH = 2), 66 mM phosphate buffered saline (pH = 6.5, lx PBS), 0.5% SIF in lx PBS, and 2% SIF in lx PBS. Aliquots of 1 mL were removed after 90 minutes and 24 hours. Samples were centrifuged at 300,000 x g for 8 minutes (ultracentrifuge). Fractions of each supernatant were diluted for HPLC analysis. All samples were measured in duplicate.

[0270] The results of the solubility testing in aqueous media are summarized in Table 8 below.Table 8: Aqueous Solubility of Crystalline Compound (I)SIF refers to FaSSIF / FeSSIF / FaSGF V.l powder from Biorelevant comprising an equimolar ratio of sodium taurocholate (NaTC) and egg lecithin.Amorphous Aqueous Solubility

[0271] A stock solution of Compound (I) in acetonitrile at 15 mg / mL was prepared. The solution was loaded into 1 mL syringes and dosed into 10 mL of either lx PBS or lx PBS with 0.5 % SIF using a syringe pump at 30 pL / min. UV-Vis spectral data was recorded using fiber optic probes from 200-720 nm. The scattering was monitored over a wavelength range of 500- 550 nm. The concentration reported was determined by monitoring the second derivative of the absorbance at 300-310 nm. The amorphous solubility corresponds to the amount of drug added at the point that scattering rises above initial baseline. This indicates that the solution is supersaturated with compound and crystals start to form.

[0272] Amorphous solubilities in PBS with or without SIF were approximately 160 and 150 pg / mL, respectively (see Table 1). The amorphous solubilities represent a nearly 10-fold improvement over crystalline solubilities.Example 2: Development of Spray-Dried Dispersions (SDDs)Polymer sustainment

[0273] The ability of a variety of pharmaceutically acceptable polymers to sustain supersaturated concentrations of Compound (I) was investigated. The same method described for the amorphous aqueous solubility (see Example 1) was used, except that the 0.5% SIF receiving media contained 0.25 mg / mL pharmaceutically acceptable polymer. The pharmaceutically acceptable polymers tested were HPMCAS-L, HPMCAS-M, HPMCAS-H, and PVP-VA64.

[0274] The sustainment plot is shown in Fig. 2. All tested polymers demonstrated improved Cmax and Compound (I) concentration sustainment compared to the 0.5% SIF control.Initial Composition and Process

[0275] Five initial spray-dried dispersions (SDDs) were prepared for screening of performance, physical stability, and chemical stability. In this example, and throughout the following examples, SDDs are identified using a nomenclature wherein the weight ratio of Compound (I) to pharmaceutically acceptable polymer(s) is identified, followed Compound (I) and the particular pharmaceutically acceptable polymer(s) “polymer,” below. As an example, “25 / 75 Compound (I) / HPMCAS-M SDI” refers to a SDD prepared using 25% by weight Compound (I) and 75% by weight HPMCAS-M. Stated another way, 100% of the weight of the solids used to produce the dispersion can be attributed to Compound (I) and HMPCAS-M, and the Compound (I) and HMPCAS-M are in a 1 :3 weight ratio. The SDD produced may not contain exactly 25% by weight Compound (I) and 75% by weight HPMCAS-M, however, as residual solvent, water and impurities may account for some of the SDD’s weight. The SDDs were manufactured on a Bend Lab Dryer with 35 kg / hr drying gas capacity (BLD-35). The SDD compositions screened are summarized in Table 9 below.Table 9: SDD Compositions for Screening

[0276] The spray solutions were prepared by dissolving Compound (I) and pharmaceutically acceptable polymer in acetone. The solution was fed to a nozzle and atomized into droplets that were rapidly dried into particles by a hot nitrogen gas stream. The droplet drying kinetics were selected to minimize the changes of Compound (I) recrystallizing once in this state. The particles were collected by a cyclone that separated them from the drying gas exhaust.

[0277] The five SDD compositions were manufactured with high yields. After spray drying, the SDDs were secondary dried in the vacuum tray dryer at 40 °C for approximately 22 hours. A manufacturing summary is provided in Table 10 below.Table 10: Manufacturing Summary for SDD CompositionsSDD Characterization

[0278] The particle morphology of all SDD compositions was assessed with SEM. Representative images are shown in Fig. 3 and Fig. 4. All SDDs exhibit particle morphologies consisting of collapsed / whole / shattered spheres, with particles ranging from 5-50 pm. No signs of crystallinity were observed by SEM. For comparison, images of crystalline Compound (I) are shown in Fig. 5. Crystalline Compound (I) consists of large cube-like / geometric structures ranging from 100-400 pm.

[0279] Each SDD was analyzed by PXRD (Fig. 6) to examine the degree of crystallinity. The diffractogram for each SDD was consistent with amorphous material.

[0280] The SDDs were characterized by modulated differential scanning calorimetry (mDSC) to probe the physical state and glass transition of the composition. The data are summarized in Table 11. The HPMCAS compositions showed consistent Tg values at approximately 104°C, while the PVP-VA64 composition had a Tg of approximately 114°C.Table 11: DSC Data for Compound (I) SDDsDissolution Testing

[0281] The SDDs were evaluated in a non-sink gastric to intestinal (G-IB) transfer microcentrifuge dissolution test (see the full microcentrifuge dissolution test protocol described above).

[0282] The five SDDs in Table 11 were compared to neat Compound (I). Each SDD and neat Compound (I) were added at a concentration of 600 pgA / mL in gastric buffer (GB), which was diluted to 300 pgA / mL in intestinal buffer (IB). The dissolution profiles are shown in Fig. 7, and the data summarized in Table 12. The measurements at the 90 minute and 1200 minute time point were collected by HPLC after centrifuging (C90, C1200, respectively) and ultracentrifuging (Ultrago, Ultranooo, respectively). The measurements by centrifuge are connected by lines, while the measurements by ultracentrifuge at the 90 minute and 1200 minute time points are not.

[0283] Overall, the five SDDs improve dissolution and concentration supersaturation relative to neat Compound (I).Table 12: Tabulated Dissolution Results for SDDs and Compound (I)Example 3: Development of Spray-Dried NanocrystalsNanomilling

[0284] Nine nanomilled compositions (A) - (I) were tested as described below. The tested compositions are summarized in Table 13. The Table 13 compositions are described using wt% of the components with the balance being water.Table 13: Tested Nanomilling Compositions

[0285] The compositions were all milled in a LabRam II acoustic mixer at 60 G with 0.5 mm zirconium oxide milling beads.Particle Size Characterization

[0286] The particle size of each of composition (A)-(I) was measured by DLS using a Malvern ZetaSizer every 30 minutes. The results are summarized in Table 14 below.Table 14: Particle Size by DLS of Nanomilled CompositionsScale Up Milling

[0287] Composition C was scaled up to test spray-drying feasibility. 19.5 g of Compound (I) was used to manufacture a 195 g batch of 10 wt.% active suspension with HPC SSL and SLS. The composition was milled in the LabRAM II acoustic mixer for three hours at approximately 40 G. A summary of the processing conditions is shown in Table 15.Table 15: Manufacturing Summary of Nanomilled Composition

[0288] To recover the composition from the milling vessel, a 250 pm sieve was used to separate the milling zirconia beads from the composition. A 65% yield was achieved.Spray -Dried Nanocrystal (SDNC) Compositions

[0289] From the nanomilled material, five spray-dried compositions were manufactured. The compositions were spray-dried on a Bend Lab Dryer with 35 kg / hr drying gas capacity.The composition with additional HPC SSL (Sample C in Table 16 below) was prepared to be 10wt% solids in water. All other compositions were prepared to be 15wt% solids loading in water. All compositions were spray-dried at the same conditions. A summary of the processing conditions can be found in Table 16 below.Table 16: Process summary for SDNC ManufactureSDNC Dissolution

[0290] The SDNCs were evaluated in a non-sink gastric to intestinal (G-IB) transfer microcentrifuge dissolution test (see the full microcentrifuge dissolution test protocol described above).

[0291] The SDNCs were compared to a SDD composition and to neat Compound (I). The powders were added at a concentration of 600 pgA / mL in gastric buffer (GB), which was diluted to 300 pgA / mL in intestinal buffer (IB). The dissolution data are summarized in Table 17. The dissolution profiles are shown in Fig. 8, with a zoomed in plot, comparing only the SDNC compositions and the Compound (I) control in Fig. 9. The measurements at the 90 minute and 1200 minute time point were collected by HPLC after centrifuge (C90, C1200, respectively) and ultracentrifuge (Ultrago, Ultranooo, respectively). The measurements bycentrifuge are connected by lines, while the measurements by ultracentrifuge at the 90 minute and 1200 minute time points are not.Table 17. Non-sink Dissolution Performance for SDNC Compositions, SDDComposition, and Compound (I) ReferencePXRD characterization

[0292] The crystalline profiles of the SDNC were next determined by PXRD. The peak profiles of the compositions agreed with that of Compound (I). The slightly broader, shorter signals are indicative of smaller crystals. The PXRD patterns are shown in Fig. 10.Example 4: SDD and SDNC Capsule Compositions

[0293] Two SDD compositions and two SDNC compositions were selected as spray-dried intermediates (SDIs) to be evaluated in capsules. Size 0 gelatin capsules were filled with the desired SDD or SDNC. The compositions tested are summarized in Tables 18, 19a and 19b below.Table 18: Spray-Dried Intermediates (SDI) for CapsulesTable 19a: SDD CapsulesTable 19b: SDNC Capsules

[0294] Capsules 3 and 4 were directly filled with SDI 3 and SDI 4, respectively, with no extra processing or excipients added. It was found that while SDI 3 disintegrated without issue, in order to get the appropriate amount of SDI 4 into a single capsule, the powder had to be over tamped causing the powder to form a slug with an external layer of gel during disintegration. Once the slug formed, it appeared to no longer disintegrate. To overcome this, two 25 mg active dose capsules were made in addition to one 50 mg active dose capsule. No slug wasformed when the 25 mg active capsules were disintegrated, and no adverse effects using two capsule doses were observed during dissolution.

[0295] The capsules containing the SDD compositions were granulated with an osmogen (NaCl), mixed with Cab-O-Sil® hydrophilic fumed silica as a glidant, and filled into capsules. The pregranulation blend was slugged using 0.25” Flat Face tooling targeting tensile strength of 0.6 MPa. A tensile strength of 0.6 MPa was found to yield granules with good compressibility, structural integrity, and disintegration times. The granules were then mixed with Cab-O-Sil® hydrophilic fumed silica.Disintegration Testing

[0296] All four capsules were next tested for disintegration in triplicate. Disintegration times for both SDD and SDNC capsules can be seen in Table 20 below.Table 20: SDD and SDNC Capsule DisintegrationDissolution Testing

[0297] Dissolution was performed on the capsules using a similar non-sink method to that used for the SDD and SDNC powders. Based on the data, the predicted rank order for in vivo performance is HPMCAS-M SDD capsule > HPMCAS-H SDD capsule > SDNC capsule.

[0298] When comparing the powder dissolution to the capsule dissolution method, the dissolution method was scaled up to a USP II bath volume, and the samples were stirred at 75 rpm rather than mixed by vortex. 1 mL samples were removed from the vessels at each designated time point, centrifuged, and the supernatant was diluted in diluent for HPLC analysis. The remaining material in the centrifuge tube was not returned to the dissolution vessel.

[0299] The capsules containing the SDNC showed comparable dissolution performance to that of the native SDNC powder. The 50 mg capsule as a single capsule and two 25 mg capsules together (50 mg total dose) showed comparable dissolution performance. When comparing the dissolution of the capsule samples and the native powder, the native powder showed faster initial dissolution in the gastric portion of the test. Once the intestinal media was added, all thesamples sustained at approximately 20 pg / mL. The data are summarized in Table 21 below, and Fig. 11.Table 21: Tabulated dissolution data for SDNC compositions compared to the SDNC native powders

[0300] The capsules containing the granulated SDD showed slower dissolution when compared with the native SDD powder. This was attributed to the presence of the granules in the capsules, which are expected to dissolve more slowly due to the decrease in available surface area as compared to the native SDD powder. The data are summarized in Table 22 below, and Fig. 12.Table 22: Tabulated Dissolution Data for SDD Capsule Compositions Compared to SDD Native PowdersExample 5: Preparation of Tablets of Compound (I) SDDPreparation Procedure

[0301] Tablets containing the 25 / 75 Compound (I) / HPMCAS-M SDD were investigated. Tablets were prepared by blending the SDD with intragranular excipients (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, MCC-DCP (75 percent microcrystalline cellulose and 25 percent anhydrous dibasic calcium phosphate, produced using spray-dried co-processing), mannitol, lactose, croscarmellose sodium and magnesium stearate), de-lumping, lubrication, roller compaction and milling, blending with extra-granular excipients (e.g., microcrystalline cellulose and magnesium stearate), lubrication, compression and packaging. In some instances, a further coating process may be performed prior to packaging. The tablets are summarized in Table 23.Table 23: Tablets Containing SDDs of Compound (I)Example 6: Pharmacokinetics of SDD Tablets

[0302] Tablets were made as generally described in Example 5. Pharmacokinetics (PK) of SDD tablets, as compared to a capsule control, were evaluated in male beagle dogs fastedovernight prior to study drug administration. The capsule control was formulated as a white opaque size 0 hard gelatin capsule with a clear gelatin sealing band containing 10 mg of Compound (I), formulated as a semi-solid formulation containing the inactive ingredients polyethylene glycol (PEG) 1500 and PEG 400 (3:2). Whole blood samples were collected predose, and 0.5, 1, 2, 4, 8, 24, 48, and 96 hours following administration by mouth (PO) of a single dose of study drug. Compositions tested and PK data are summarized in Table 24.Table 24: Pharmacokinetics of Compound (I) Compositions in Male Beagle DogsExample 7: Stability of Compound (I) SDD Tablets

[0303] Tablet Prototype 3 of Example 4 was selected for stability studies. Tablets were packaged in 40 cc high density polyethylene (HDPE) bottles with 2 g desiccant canister and a polypropylene (PP) child-resistant closure (CRC) with induction seal, and were stored at 25°C ± 2 °C / 60% ± 5% relative humidity (RH) and 40°C ± 2 °C / 75% ± 5% RH. Tablets are sampled over time and tested for appearance, assay and impurities by HPLC, water content by Karl Fischer titration, and dissolution.

[0304] The appearance, assay, impurities, and dissolution are monitored over the course of 12 months at long-term 25 °C ± 2 °C / 60% ± 5% RH and 6 months at accelerated 40 °C ± 2 °C / 75% ± 5% RH storage conditions. The stability study protocol is summarized in Table 25 below.Table 25: Summary of Stability ProtocolX = Appearance, assay, impurity, water content, dissolution; M = microbial limit tests

[0305] No significant changes or trend in appearance, assay, related substances, dissolution, and water content were observed at 25°C / 60% relative humidity or 40°C / 75% relative humidity storage. The results of the stability tests are summarized in Tables 26 and 27 below. Stability will be monitored according to the schedule in Table 25 above.Table 26: Stability Results for Storage at 25 °C ± 2 °C / 60% ± 5% RHTable 27: Stability Results for Storage at 40 °C ± 2 °C / 75% ± 5% RHExample 8

[0306] This was an open-label, randomized, 3-treatment, 3-period crossover study to evaluate the PK of Compound (I) tablet (Prototype 3 from Example 5) and capsule (as described in Example 6) and the effect of food on the tablet formulation. Twenty-four (24) healthy, adult male (vasectomized only) and female volunteers were enrolled. Screening of volunteers occurred within 28 days prior to the first dosing.

[0307] On Day 1 of each period, a single dose of Compound (I) was administered in a 3- period crossover fashion according to the randomization sequence. Treatments are described as follows:• Treatment A: 100 mg Compound (I) (10 x 10 mg capsules) on Day 1 under fasting conditions.• Treatment B: 100 mg Compound (I) (4 x 25 mg tablets) on Day 1 under fasting conditions.• Treatment C: 100 mg Compound (I) (4 x 25 mg tablets) on Day 1, 30 minutes after the start of a high-fat meal.

[0308] PK samples for Compound (I) were taken predose and up to 168 hours postdose. There was a washout of at least 7 days between the Compound (I) doses.

[0309] Safety was monitored throughout the study by repeated clinical and laboratory evaluations.

[0310] Volunteers were housed on Day -1 of Period 1, at the time indicated by the clinical research unit (CRU), until after the 168-hour blood draw and completion of study proceduresin Period 3. At all times, a volunteer may have been required to remain at the CRU for longer at the discretion of the PI or designee.

[0311] All volunteers who received at least one dose of Compound (I) (including volunteers who terminated the study early) were asked to return to the CRU 14 (± 2) days after discharge from the CRU for follow-up procedures, and to determine if any adverse event (AE) had occurred since the last study visit.

[0312] A total of 24 volunteers were enrolled in the study, and included in the safety and PK analyses.Pharmacokinetics

[0313] In each period, blood samples for the determination of Compound (I) plasma concentrations were collected from each volunteer before dosing (predose), followed by sampling at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose. Note that the 168-hour sample collected in Periods 1 and 2 also served as the predose sample in Periods 2 and 3, respectively.

[0314] The following non-compartmental PK parameters for plasma Compound (I) were determined for each treatment: AUCO-t, AUC0 inf, AUC%extrap, Cmax, Tmax, Tlag, z, tU, CL / F, and Vz / F.

[0315] The plasma concentrations and PK parameters of Compound (I) were listed and summarized by treatment and time point for all volunteers in the PK Population. Plasma concentrations of Compound (I) were presented with the same level of precision as received from the bioanalytical laboratory. Summary statistics, including sample size (n), arithmetic mean (mean), standard deviation (SD), coefficient of variation (CV%), standard error of the mean (SEM), minimum, median, and maximum, were calculated for all nominal concentration time points. In addition, geometric mean (Geom Mean) and geometric CV% (Geom CV%) were presented for all PK parameters.

[0316] An analysis of variance (ANOVA) was performed on the natural-log (ln)- transformed PK parameters AUCO-t, AUCO-inf, and Cmax to evaluate the relative bioavailability of 100 mg Tablets - Fasted (Treatment B) (test) versus 100 mg Capsule - Fasted (Treatment A) (reference), and the effect of food for 100 mg Tablets - Fed (Treatment C) (test) versus 100 mg Tablets - Fasted (Treatment B) (reference). The ANOVA model included treatment, period, and sequence as fixed effects and volunteer nested within sequence as a random effect. The inferential results (least-squares means [LSMs], difference between LSMs,and 90% confidence interval [CI] of the difference) were exponentiated to the original scale. Geometric LSMs, geometric mean ratios (GMRs), and 90% Cis were presented.

[0317] Nonparametric analysis of Tmax and Tlag was performed. The nonparametric Wilcoxon Signed Rank Test was performed and the p-value was presented for the following comparisons: 100 mg Tablets - Fasted (Treatment B) (test) compared to 100 mg Capsule - Fasted (Treatment A) (reference) and 100 mg Tablets - Fed (Treatment C) (test) compared to 100 mg Tablets - Fasted (Treatment B) (reference). The Hodges-Lehmann estimate for the median of the differences in Tmax and Tlag, and the 90% CI were presented for the comparisons. The Hodges-Lehmann estimator was given by the median of all possible pairwise averages (Walsh averages) of the differences in Tmax and Tlag. The CI was constructed using Walsh averages and the appropriate quantile of the Wilcoxon Signed Rank Test Statistic. Note that Tmax and Tlag were not In-transformed for these analyses.

[0318] The statistical comparisons of plasma Compound (I) PK parameters following 100 mg Tablets - Fasted (Treatment B) compared to 100 mg Capsules - Fasted (Treatment A) are summarized in the following table.Table 28: Summary of Statistical Comparisons of Plasma Compound (I) Pharmacokinetic Parameters Between 100 mg Tablets - Fasted (Treatment B) Versus 100 mg Capsules - Fasted (Treatment A) (Pharmacokinetic Population)

[0319] Based on the GMRs, total exposure of Compound (I) (AUCO-t and AUCO-inf) following 100 mg Tablets - Fasted may be considered generally equivalent to 100 mg Capsules - Fasted with 90% Cis of exposure ratio meeting the conventional reference range of 80% - 125%; however, for Cmax the upper bound of the 90% Cis slightly exceeded the upper limit of this reference range, while the lower bound was contained within the range.

[0320] The nonparametric analysis of Compound (I) Tmax and Tlag following 100 mg Tablets - Fasted (Treatment B) compared to 100 mg Capsules - Fasted (Treatment A) is presented in the table below.Table 30: Nonparametric Statistical Comparison of Plasma Compound (I) Tmax and Tlag: 100 mg Tablets - Fasted (Treatment B) Versus 100 mg Capsules - Fasted (Treatment A) (PK Analysis Population)

[0321] Based on the nonparametric statistical comparisons, the median difference in plasma Compound (I) Tlag between the tablet and capsule was 0 hours. This is in line with the observation that all volunteers had a Tlag of exactly 0 hours for both Treatments A and B (Tables 14.2.1.4 and 14.2.1.5) and as such, no p-value could be calculated for Tlag.

[0322] The median difference in plasma Compound (I) Tmax between the tablet and capsule was 1.47 hours, which was significant (p-value < 0.0001).

[0323] The statistical comparisons of plasma Compound (I) PK parameters following 100 mg Tablets - Fed compared to 100 mg Tablets - Fasted are summarized in the table below.Table 31: Summary of Statistical Comparisons of Plasma Compound (I) Pharmacokinetic Parameters Between 100 mg Tablets - Fed (Treatment C) Versus 100 mg Tablets - Fasted (Treatment B) (Pharmacokinetic Population)

[0324] Based on GMRs, total exposure of Compound (I) (AUCO-t and AUCO-inf) following 100 mg Tablets - Fed may be considered generally equivalent to 100 mg Tablets - Fasted with 90% confidence interval (CI) of exposure ratio meeting the conventional reference range of 80% - 125%; however for Cmax, the GMR was 23% lower in 100 mg Tablets - Fed, while the upper bound of the 90% Cis of Cmax was contained within the range.

[0325] The nonparametric analysis of Compound (I) Tmax and Tlag following 100 mg Tablets - Fed (Treatment C) compared to 100 mg Tablets - Fasted (Treatment B) are presented in the table below.Table 32: Nonparametric Statistical Comparison of Plasma Compound (I) Tmax and Tlag: 100 mg Tablets - Fed (Treatment C) Versus 100 mg Tablets - Fasted (Treatment B) (PK Analysis Population)

[0326] Based on the nonparametric statistical comparisons, the median difference in plasma Compound (I) Tlag between the 100 mg Tablet - Fed and 100 mg Tablet - Fasted was not significantly different from zero (median difference = 0.00, p-value = 1.000).

[0327] The median difference in Tmax between the 100 mg Tablet -Fed and 100 mg Tablet - Fasted was 2.00 hours, which was significant (p-value < 0.0001).

[0328] Administration of Compound (I) tablets in the fasted state had no effect on total exposure (AUCs) to Compound (I), but peak exposure (Cmax) was slightly increased and Tmax was delayed compared to the capsule in the fasted state. Comparing the 90% CI of both AUC and Cmax, the tested capsule and tablet may be considered generally equivalent.

[0329] Administration of Compound (I) tablets with a high-fat meal had no effect on total exposure (AUCs) to Compound (I), but peak exposure (Cmax) was reduced and Tmax was delayed compared to tablet administration in the fasted state.Example 9: Exemplary Coated Tablet Compositions*Coating level + / -1 %w / w of target

[0330] The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention may be apparent to those having ordinary skill in the art.

[0331] Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise. The invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

Claims

What is claimed is:

1. A solid dispersion comprising Compound (I) and one or more pharmaceutically acceptable polymers, wherein Compound (I) has the structure:

2. The solid dispersion of claim 1, wherein the solid dispersion is an extrudate, a spray-dried dispersion, or a co-precipitate.

3. The solid dispersion of claim 2, wherein the solid dispersion is a spray-dried dispersion.

4. The solid dispersion of any one of claims 1-3, wherein the solid dispersion has a D50 particle size of less than 100 pm, or in a range of 1 pm to 100 pm, or 5 pm to 50 pm.

5. The solid dispersion of any one of claims 1-4, wherein the pharmaceutically acceptable polymer is characterized by a glass transition temperature (Tg) greater than 112 °C, or at least 115 °C, or at least 120 °C, or at least 125 °C, or in a range of 120 °C to 200 °C, or in a range of 120 °C to 155 °C.

6. The solid dispersion of any one of claims 1-5, wherein the pharmaceutically acceptable polymer is selected from one or more of: a) cellulose-based polymers, including cellulose esters and cellulose ethers(e.g., cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC)); b) polymethacrylates; c) pyrrolidones (e.g., polyvinyl pyrrolidine (PVP) or polyvinyl pyrrolidine and vinyl acetate (PVP / VA) copolymer); and d) polyethylene glycols (PEG).

7. The solid dispersion of any one of claims 1-6, wherein the pharmaceutically acceptable polymer is selected from HPMCAS, HMPCAS-H, HPMCAS-M, and HPMCAS-L, or from HMPCAS-H and HPMCAS-M, for example HMPCAS-M.

8. The solid dispersion of any one of claims 1-7, wherein the amount of Compound (I) in the solid dispersion is in a range of 1 wt.% to 90 wt.%, or in a range of 20 wt.% to 50 wt.%.

9. The solid dispersion of any one of claims 1-8, wherein the pharmaceutically acceptable polymer is present in the solid dispersion in a range of 10 wt.% to 90 wt.%, or in a range of 50 wt.% to 80 wt.%.

10. The solid dispersion of any one of claims 1-9, wherein the solid dispersion is characterized by a single glass transition temperature (Tg).

11. The solid dispersion of any one of claims 1-10, wherein the solid dispersion is characterized by a Tg of at least 100°C.

12. The solid dispersion of claim 11, wherein the Tg is in a range of 100°C-130°C.

13. The solid dispersion of any one of claims 1-12, wherein the solid dispersion is characterized by a x-ray powder diffraction (XRPD) pattern that is absent of discrete signals.

14. The solid dispersion of any one of claims 1-13, wherein the solid dispersion is characterized by a degree of crystallinity as determined by XRPD that is: a) no more than 5%; b) no more than 3%; c) no more than 1%; d) below the limit of quantitation (LOQ); or e) below the limit of detection (LOD).

15. The solid dispersion of any one of claims 1-14, wherein the solid dispersion provides a supersaturated concentration of Compound (I) under non-sink conditions in a gastric medium of 0.0 IN HC1, optionally a concentration of at least 100 pg / ml, or at least 200 pg / ml, or at least 300 pg / ml.

16. The solid dispersion of any one of claims 1-15, wherein the solid dispersion provides a supersaturated concentration of Compound (I) for at least 90 minutes under non-sink conditions in an intestinal buffer solution consisting of 0.5% SIF in lx PBS, optionallya concentration of at least 50 pg / ml, or at least 100 pg / ml, or at least 200 pg / ml, or in a range of 50 pg / ml to 300 pg / ml.

17. The solid dispersion of claim 16, wherein the concentration of Compound (I) in intestinal buffer solution is measured after exposure in the gastric medium of claim 15 for 30 minutes.

18. A composition comprising a nanocrystalline powder form of Compound (I), whereinCompound (I) has the structure:wherein the nanocrystalline powder form has a Z-average hydrodynamic diameter (dZ) measured by dynamic light scattering (DLS) of 500 nm or less, or 400 nm or less, or 300 nm or less.

19. The composition of claim 18, wherein the nanocrystalline powder form further comprises one or more aggregation inhibitors, optionally selected from a pharmaceutically acceptable polymer, a surfactant, or a combination thereof.

20. The composition of claim 19, wherein the pharmaceutically acceptable polymer comprises one or more of hydroxypropyl cellulose (HPC), polyvinyl pyrrolidine (PVP), and hydroxypropyl methylcellulose (HPMC), and the surfactant comprises one or more of polysorbate 80, pol oxamer 188, and SLS, and further optionally wherein the HPC is characterized by a viscosity, measured as 2% aqueous solution at 20°C, of less than 6 cPs, optionally less than 4 cPs, for example in a range of 2-3 cPs.

21. The composition of claim 19 or 20, wherein the one or more aggregation inhibitors are present in an amount in a range of 0.01 wt.% to 40 wt.%, or in a range of 0.1 wt.% to 35 wt.%, or in a range of 0.5 wt.% to 30 wt.%, or in a range of 10 wt.% to 25 wt.%, or in a range of 10 wt.% to 20 wt.%, based on the total weight of Compound (I) plus aggregation inhibitors.

22. The composition of any one of claims 19-21, wherein Compound (I) is present in an amount in a range of 60 wt.% to 99.99 wt.%, or in a range of 65 wt.%. to 99.9 wt.%, orin a range of 70 wt.% to 99.5 wt.%, or in a range of 75 wt.%. to 90 wt.%, or in a range of 80 wt.% to 90 wt.%, based on the total weight of Compound (I) plus aggregation inhibitors.

23. A spray-dried dispersion comprising the composition of any one of claims 18-22.

24. A plurality of granules wherein the granules comprise the solid dispersion of any one of claims 1-17, and one or more excipients.

25. The plurality of granules of claim 24, wherein the one or more excipients comprise one or more selected from the group consisting of binders, fillers, disintegrants, lubricants, and glidants, or a combination of one or more selected from the group consisting of fillers, disintegrants, and lubricants.

26. The plurality of granules of claim 25, wherein the one or more excipients comprise one or more fillers, a disintegrant, and a lubricant.

27. The plurality of granules of claim 25 or claim 26, wherein the filler comprises one or more in the group of a pharmaceutically acceptable polymer, a mineral, a metal salt, a sugar, and a starch, optionally one or more in the group of lactose, MCC, starch, a natural starch, a modified starch, calcium phosphate, calcium carbonate, sucrose, maltodextrin, mannitol sorbitol, and, sodium chloride, optionally one or more in the group of MCC, mannitol, and lactose, optionally selected from one or both of MCC and mannitol.

28. The plurality of granules of any one of claims 25-27, wherein the disintegrant comprises one or more in the group of crospovidone, croscarmellose calcium, croscarmellose sodium, and sodium starch glycolate, for example croscarmellose sodium.

29. The plurality of granules of any one of claims 25-28, wherein the lubricant comprises one or more in the group of calcium stearate, magnesium stearate, talc, and liquid paraffin.

30. The plurality of granules of any one of claims 25-29, comprising an amount of Compound(I) in a range of 1 mg to 500 mg, or in a range of 1 mg to 200 mg, or in a range of 1 mg to 150 mg, or in a range of 1 mg to 100 mg, or in a range of 20 mg to 200 mg, for example 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg.

31. A unit dosage form comprising: a) the plurality of granules of any one of claims 24-30; andb) an extragranular composition comprising one or more excipients.

32. The unit dosage form of claim 31, wherein the one or more excipients of the extragranular composition comprise one or more of a binder, a filler, a disintegrant, a lubricant, and a glidant.

33. The unit dosage form of claim 31 or 32, wherein the one or more excipients of the extragranular composition comprise a filler and a lubricant.

34. The unit dosage form of claim 32 or claim 33, wherein the filler comprises one or more in the group of a pharmaceutically acceptable polymer, a mineral, a metal salt, a sugar, and a starch, optionally one or more in the group of lactose, MCC, starch, a natural starch, a modified starch, calcium phosphate, calcium carbonate, sucrose, maltodextrin, mannitol, sorbitol, and, sodium chloride, optionally one or more in the group of MCC, mannitol, and lactose, for example MCC.

35. The unit dosage form of any one of claims 32-34, wherein the lubricant comprises one or more in the group of calcium stearate, magnesium stearate, talc, and liquid paraffin, for example magnesium stearate.

36. The unit dosage form of any one of claims 31-35, wherein the amount of solid dispersion in the unit dosage form is in a range of 10 wt.% to 90 wt.%, or in a range of 20 wt.% to 80 wt.%., or in a range of 30 wt.% to 70 wt.%, or in a range of 40 wt.% to 70 wt.%, or in a range of 45 wt.% to 65 wt.%, or in a range of 40 wt.% to 60 wt.%, or in a range of 50 wt.% to 65 wt.%, or in a range of 55 wt.% to 60 wt.%, or in a range of 53 wt.% to 63 wt.%, for example in a range of 35 wt.% to 65 wt.%.

37. The unit dosage form of any one of claims 31-36, wherein the amount of Compound (I) in the unit dosage form is: a) in a range of 1 wt.% to 50 wt.%, or in a range of 2 wt.% to 40 wt.%., or in a range of 5 wt.% to 25 wt.%, for example in a range of 10 wt.% to 20 wt.%; or b) in an amount of 20 mg to 200 mg, or an amount of 25 mg to 100 mg, for example 25 mg, or 50 mg, or 75 mg, or 100 mg.

38. The unit dosage form of any one of claims 31-37, further comprising an extragranular component, e.g., a coating, or a capsule shell.

39. The unit dosage form of claim 38, wherein the amount of extragranular component in the unit dosage form is in a range of 1 wt.% to 20 wt.% based on the weight of the dosage form, for example 2 wt.% to 10 wt.%, 5 wt.% to 15 wt.%, or 8 wt.% to 18 wt.%.

40. The unit dosage form of any one of claims 31-39, wherein the unit dosage form is a tablet.

41. The unit dosage form of any one of claims 31-40, wherein the unit dosage form provides a plasma exposure of Compound (I), measured as AUCo-inf of at least 20,000 ng-h / mL, when administered to a human subject at a dose of 100 mg.

42. A tablet comprising Compound (I):and one or more excipients.

43. The tablet of claim 42, wherein Compound (I) is present as a spray-dried dispersion comprising Compound (I) and a pharmaceutically acceptable polymer.

44. The tablet of claim 42 or 43, wherein the one or more excipients comprise one or more fillers, a disintegrant, one or more lubricants, and optionally a coating.

45. The tablet of claim 44, wherein: a) the one or more fillers is MCC and / or mannitol; b) the disintegrant is croscarmellose sodium; c) the lubricant is magnesium stearate; and d) the optional coating comprises polyvinyl alcohol or a copolymer thereof.

46. The tablet of claim 45, comprising about 56.5 wt.% of the spray-dried dispersion, about24.5 wt.% MCC, about 13.0 wt.% mannitol, about 5.0 wt.% croscarmellose sodium, and about 1.0 wt.% magnesium stearate.

47. The tablet of claim 46, comprising about 54.3 wt.% of the spray-dried dispersion, about23.5 wt.% MCC, about 12.5 wt.% mannitol, about 4.8 wt.% croscarmellose sodium, about 1.0 wt.% magnesium stearate, and about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof.

48. The tablet of any one of claims 43-47, wherein the pharmaceutically acceptable polymer isHPMCAS-M.

49. The tablet of claim 48, wherein the spray-dried dispersion comprises about 25.0 wt.%Compound (I), and about 75.0 wt.% HPMCAS-M.

50. A pharmaceutical composition comprising Compound (I):and a means for improving dissolution of Compound (I) and / or bioavailability of Compound (I).

51. A tablet comprising: a) about 56.5 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I):about 75 wt.% HPMCAS-M; b) about 24.5 wt.% MCC; c) about 13.0 wt.% mannitol; d) about 5.0 wt.% croscarmellose sodium; and e) about 1.0 wt.% magnesium stearate.

52. A tablet comprising: a) about 54.3 wt.% of a solid dispersion, wherein the whole of the solid dispersion comprises about 25 wt.% Compound (I):about 75 wt.% HPMCAS-M; b) about 23.5 wt.% MCC;c) about 12.5 wt.% mannitol; d) about 4.8 wt.% croscarmellose sodium; e) about 1.0 wt.% magnesium stearate; and f) about 3.8 wt.% of a coating comprising polyvinyl alcohol or a copolymer thereof.

53. A method of treating a disease, disorder, or condition mediated at least in part by HIF-2a, said method comprising administering the unit dosage form, tablet, or pharmaceutical composition of any one of claims 31-52, to a subject in need thereof.

54. The method of claim 53, wherein the disease, disorder, or condition is cancer.

55. The method of claim 54, wherein the cancer is a solid tumor, optionally wherein the solid tumor is associated with von Hippel-Lindau (VHL) disease.

56. The method of claim 54, wherein the cancer is kidney cancer, liver cancer, prostate cancer, bladder cancer, breast cancer, gynecological cancer, gastrointestinal (GI) cancer, or is a neuroendocrine tumor.

57. The method of claim 54, where the cancer is renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma, pancreatic neuroendocrine tumors (pNETs), esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), optionally wherein the cancer is associated with von Hippel-Lindau (VHL) disease.

58. The method of any one of claims 53-57, wherein the method comprises use of the solid dispersion, composition, pharmaceutical composition, unit dosage form, or tablet in combination with one or more than one additional therapy.

59. The method of claim 58, wherein each of the one or more than one additional therapy is independently selected from a kinase inhibitor, an immune checkpoint inhibitor, an ATP-adenosine axis-targeting agent, a chemotherapeutic agent, and radiation therapy.

60. The method of claim 59, wherein the one or more than one additional therapy comprises: one or more kinase inhibitors that inhibit one or more kinases selected from the group consisting of mTOR, VEGF, VEGFR, EGFR, HER-2, HER-3, BRAF, RET, MET, MER, TYRO3, ALK, MEK, ERK, FLT-3, JAK, PI3K, AKT, FGFR, KIT, and AXL; one or more immune checkpoint inhibitors selected from a CTLA-4 antagonist, a PD-(L)1 antagonist, a PD-1 antagonist, a TIGIT antagonist, a TIM-3antagonist, a LAG-3 antagonist, and a BTLA antagonist; one or more ATP-adenosine axis-targeting agents selected from an adenosine receptor (e.g., A2A and / or A2B receptor) antagonist, a CD73 inhibitor, and a CD39 inhibitor; and / or one or more chemotherapeutic agents selected from a platinum-based, taxoid- based, or anthracycline-based chemotherapeutic agent.

61. The method of claim 59 or claim 60, wherein the kinase inhibitor inhibits one or more kinases selected from the group consisting of mTOR, VEGF, VEGFR, MET, RET, TYRO3, AXL, and MER.

62. The method of any one of claims 60-61, wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

63. The method of claim 62, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiplimab, envafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab.

64. The method of claim 63, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-Ll is zimberelimab.

65. The method of any one of claims 60-64, wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of TIGIT.

66. The method of claim 65, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, domvanalimab, etigilimab, ociperlimab, tiragolumab, or vibostolimab.

67. The method of claim 65, wherein the immune checkpoint inhibitor is domvanalimab orAB308.

68. The method of any one of claims 60-67, wherein the one or more ATP-adenosine axistargeting agents are selected from the group consisting of AB598, etrumadenant,inupadenant, taminadenant, caffeine citrate, imaradenant, ciforadenant, and quemliclustat.

69. The method of claim 68, wherein the one or more ATP-adenosine axis-targeting agents areAB598, etrumadenant, and / or quemliclustat.

70. The method of any one of claims 59-69, wherein the chemotherapeutic agent comprises one or more of gemcitabine, fluorouracil, cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

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