Medication plans for the treatment of autoimmune and inflammatory diseases using LY3871801

Abstract

This specification discloses a method for treating a subject having an autoimmune or inflammatory disease, and a related formulation comprising administering to the patient a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt is administered in doses of approximately 12.5 mg to approximately 125 mg of the free base equivalent of the compound per dose, and related formulations.

Description

[Technical Field]

[0001] This application relates to a regimen of receptor-interacting protein-1 kinase ("RIP1") inhibitors for the treatment of autoimmune and inflammatory diseases and / or other conditions associated with RIP1 abnormalities. In particular, this application relates to a regimen of compound 1 for the treatment of autoimmune diseases and inflammatory disorders, such as rheumatoid arthritis, psoriasis, and ulcerative colitis. [Background technology]

[0002] Receptor-interacting protein-1 kinases (hereinafter interchangeably referred to as "RIP1" or "RIPK1") belong to the tyrosine kinase-like family and are serine / threonine protein kinases involved in innate immune signaling. RIP1 plays a central role in regulating cellular signaling, and its role in programmed cell death is associated with a variety of inflammatory diseases, including inflammatory bowel disease, psoriasis, and other diseases and / or conditions associated with inflammatory and / or necrotizing cell death.

[0003] For example, rheumatoid arthritis (RA) is a common systemic autoimmune inflammatory disease characterized by synovitis that leads to pain, swelling, stiffness, and progressive destruction and deformation of small and large joints. Patients experience impairments in physical function, social participation, and health-related quality of life. Current expert recommendations for the treatment of RA include timely initiation and modification of DMARD therapy to achieve the goal of sustained low disease activity (LDA) or remission (Fraenkel et al. 2021; Smolen et al. 2022). Achieving these goals improves short- and long-term patient health outcomes, including the prevention of progressive, irreversible structural joint damage (Smolen et al. 2022). Treatment goals can be met in most patients using currently available treatment options, including csDMARDs, bDMARDs, and tsDMARDs. However, 20%–30% of RA patients do not respond to current therapy. These patients require new treatment options (Smolen et al. 2022).

[0004] Similarly, psoriasis is a common chronic inflammatory skin disease characterized by erythema and scaly patches, often associated with other systemic diseases. Although several treatment options are available, a significant proportion of patients with psoriasis are untreated or poorly treated due to long-term safety concerns, poor tolerability, failure to achieve or maintain treatment goals, patient preference / tolerance regarding the route of administration, medication costs, and / or access and reimbursement issues (Armstrong et al. 2013).

[0005] However, currently, there are no RIPK1 inhibitors that have achieved market approval, and it appears that none have achieved proof of concept. Compound I, (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide: [ka] It is a novel, potent, and selective inhibitor of receptor-interacting protein kinase 1 that blocks downstream inflammatory cell death of receptors such as the TNF receptor and Fas / CD95.

[0006] Compound I has been previously reported as a potential treatment option for autoimmune and inflammatory disorders (International Publication No. 2021046437, U.S. Patent No. 11,332,451). Compound I has been found to have linear pharmacokinetics (PK) over the test dose range up to 1000 mg, to be potent after single and multiple doses, generally safe, and well-tolerated (Yan L. et al. Poster presented at: ASCPT 2021 Annual Meeting; March 2021). Nevertheless, improved administration methods and treatment plans are still needed for the advantageous treatment of autoimmune and inflammatory diseases.

[0007] Successful dosing and treatment regimens require careful design of, among other things, dosage amount, dosing frequency, route of administration, crystallinity, particle size, excipients, and carriers in order to achieve a balanced efficacy and toxicity profile for a particular indication. It has been reported that determination of successful dosing and treatment regimens for RIPK1 inhibitors is unpredictable.

[0008] This unpredictability is best demonstrated by the related RIPK1 inhibitor known as GSK2982772, or 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide having the following structure.

Chemical Structure

[0009] GSK2982772 was tested in a multi-center, randomized, double-blind, placebo-controlled clinical trial in patients with mild-to-moderate plaque psoriasis under 60 mg oral b.i.d. and 60 mg oral t.i.d. treatment regimens. The sponsor observed "limited" clinical improvement over placebo and suggested that "higher systemic exposure" may be required. (Weisel et al. Clin Pharmacol Ther. 2020 Oct;108(4):808-816). The sponsor then evaluated some modified-release formulations of GSK2982772 and was able to achieve a once-daily pharmacokinetic profile (e.g., 80% of GSK2982772 released over 12 hours) in the fasting state, but this profile was not maintained with a standard meal or a high-fat meal (Tompson et al. Pharmaceutical Research volume 38, pages 1235-1245 (2021)). The sponsor then used its proprietary DiffCORE MR and enteric-coated formulations to overcome the effect of food without sacrificing tolerability (Tomsson et al. Pharmaceutical Research volume 39, pages 153-165 (2022)). One of these modified-release formulations was then subjected to a Phase 1 trial at 960 mg once daily for up to 84 days. (ClinicalTrials.gov identifier: NCT04316585. Updated November 11, 2021. Accessed April 11, 2023. https: / / clinicaltrials.gov / ct2 / show / NCT04316585).

[0010] Meanwhile, GSK2982772 was also investigated in patients with moderate to severe RA under 84-day treatment plans of 60 mg oral bid and 60 mg oral tid. No significant differences were observed compared to the placebo group in terms of disease activity, radiological progression, or inflammatory markers. The sponsor concluded that "inhibition of RIPK1 activity at the evaluated GSK2982772 exposure levels does not lead to meaningful clinical improvement in RA" (Weisel et al., Arthritis Research & Therapy (2021) 23:85). Furthermore, GSK2982772 was investigated in patients with moderate to severe RA under 84-day treatment plans of 60 mg oral tid. The trial sponsor found that "this drug did not produce a difference in measures of histological disease activity or clinical efficacy compared to placebo," and that "RIPK1 may not be a promising therapeutic target in UC when GSK2982772 is used as monotherapy." (Weisel et al. BMJ Open Gastroenterology 2021;8:e000680).

[0011] GSK2982772 was removed from the sponsor's clinical pipeline as of February 2022, after nine clinical trials were extended over a seven-year period. [Overview of the Initiative]

[0012] In some embodiments, the Disclosure provides therapeutically advantageous formulations, doses, and dosing regimens of compound I or a pharmaceutically acceptable salt thereof for the treatment of autoimmune or inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory colitis, ulcerative colitis, psoriatic arthritis, sweat gland abscess, spondyloarthritis, Crohn's disease, cutaneous lupus erythematosus, lupus nephritis, systemic lupus erythematosus, cutaneous lupus erythematosus, and atopic dermatitis, or for the treatment of autoimmune or inflammatory diseases modulated by receptor-interacting protein (RIP) kinase 1. The doses and dosing regimens include a range of fixed doses and dosing regimens for treating such diseases with efficacy and persistence without causing excessive toxicity concerns.

[0013] The aforementioned and other purposes and features of this disclosure will become more apparent from the following detailed description. [Modes for carrying out the invention]

[0014] The following explanations of terms and methods are provided to better describe this disclosure and to guide those skilled in the art in the practice of this disclosure. The singular forms “a,” “an,” and “the” refer to one or more unless explicitly indicated otherwise in the context. The term “or” refers to a single element or a combination of two or more elements of the alternative elements described, unless explicitly indicated otherwise in the context. As used herein, “comprises” means “includes.” Thus, “comprises A or B” means “comprises A, B, or A and B” without excluding any additional elements. All references cited herein, including patents and patent applications, are incorporated by reference.

[0015] Unless otherwise specified, all figures representing quantities, molecular weights, percentages, temperatures, times, etc., of components used herein or in the claims should be understood to be modified by the term “approximately.” Therefore, unless otherwise explicitly or implicitly indicated, the numerical parameters described are approximations that may depend on the desired properties and / or detection limits under standard testing conditions / methods. Where embodiments are directly and explicitly distinguished from the prior art considered, the numerical values ​​of embodiments are not approximations unless the word “approximately” is explicitly stated.

[0016] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains. Similar or equivalent methods and materials may be used in carrying out or testing the disclosure, but preferred methods and materials are described below. These materials, methods, and examples are illustrative and not intended to limit the scope of this disclosure.

[0017] "Target" generally refers to mammals and other animals, especially humans.

[0018] As used herein, “patient” specifically refers to a person who requires treatment for, for example, one of the diseases, disorders, or conditions described herein.

[0019] "Pharmacologically acceptable excipients" refer to substances other than the active ingredient that are included in a composition containing the active ingredient. As used herein, excipients may be incorporated into the particles of the pharmaceutical composition or may be physically mixed with the particles of the pharmaceutical composition. Excipients may be used, for example, to dilute the active ingredient and / or to modify the properties of the pharmaceutical composition. Examples of excipients include, but are not limited to, antifouling agents, binders, coatings, enteric coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, flow enhancers, adsorbents, preservatives, carriers, or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, sugars and derivatives of sugars such as disaccharides, polysaccharides, and sugar alcohols, proteins, synthetic polymers, crosslinked polymers, antioxidants, amino acids, or preservatives. Examples of excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, taltrazine, aspartum, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0020] An "adjuvant" is a component that modifies the effects of other drugs, typically the active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effects of active ingredients by increasing the immune response. Adjuvants can also act as stabilizers of formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, dead bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as complete or incomplete Freund's adjuvants.

[0021] "Pharmacologically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspension aid, solubilizer, or aerosolizing aid. (Incorporated herein by reference: Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21) st Edition (2005) describes exemplary compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0022] Generally, the properties of the carrier will depend on the specific mode of administration used. For example, parenteral formulations typically contain an injectable fluid, such as water, saline, equilibrium salt solution, aqueous dextrose, or glycerol, as the vehicle, which is a pharmaceutically and physiologically acceptable fluid. In some cases, the pharmaceutically acceptable carrier may be sterilized to be suitable for administration to the subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to a biologically neutral carrier, the administered pharmaceutical composition may contain small amounts of non-toxic auxiliary substances, such as sodium acetate or sorbitan monolaurate, including wetting agents or emulsifiers, preservatives, and pH buffers.

[0023] "Pharmacologically acceptable salts" refer to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions, as would be known to those skilled in the art, including, for example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and, if the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. "Pharmacologically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological efficacy of a free base while being formed by an acid partner. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and xinafoic acid. "Pharmacologically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of pharmaceutically acceptable salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.Exemplary organic bases include isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, SMBerge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference). In certain disclosed embodiments, the compound may be a formate, trifluoroacetate, hydrochloride, or sodium salt.

[0024] As used herein, “solid dispersion” refers to a dispersion of an active pharmaceutical ingredient (API) in a solid inert matrix or inert carrier. A solid dispersion can be prepared by dissolving the API together with the matrix or carrier in a solution and then drying it. Alternatively, a solid dispersion may be prepared by any other suitable method, such as melting or solvent melting.

[0025] A “solvate” refers to a complex formed by a combination of a solvent molecule and a solute molecule or ion. The solvent may be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides, e.g., N,N-dialiphatic amides, e.g., N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides, e.g., dimethyl sulfoxide; water; and combinations thereof. The compounds described herein may exist in both unsolvated and solvated forms when combined with pharmaceutically acceptable or unacceptable solvents such as water and ethanol. The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein. When the solvent is water, a solvate is also called a “hydrate.”

[0026] As used herein, “to treat” or “treatment” refers to the treatment of a patient or subject, specifically a person having the disease or condition of interest, and includes, but is not limited to, the following: (i) To inhibit a disease or condition, for example, to prevent or delay its onset. (ii) Relieving a disease or condition, for example, reducing its symptoms, or causing a regression of the disease or condition or its symptoms, or (iii) including stabilizing a disease or condition.

[0027] Furthermore, the term "treatment" used in descriptions of methods specifically refers to treatment performed using that particular method.

[0028] As used herein, the terms “disease,” “disorder,” and “condition” may be used interchangeably, or they may differ in that a particular disease or condition may not have a known causative substance (and therefore its etiology has not yet been determined), and therefore not yet recognized as a disease, but only as an undesirable condition or syndrome for which a certain set of symptoms has been identified by a clinician.

[0029] As used herein, “dosage” or “amount of medication” refers to the total amount of compound I or its pharmaceutically acceptable salt administered in a single dose.

[0030] When used herein in conjunction with "dose," "free base equivalent" or "free drug equivalent" refers to the dose of the free base form of compound I that may be formed. For example, compound I administered at a dose equal to its free base equivalent is administered at that dose. The solvate of compound I administered at a dose equal to its free base equivalent is administered at a slightly higher dose to adjust for the amount of solvent molecules present that may not contribute to pharmaceutically effective. Similarly, a pharmaceutically acceptable salt of compound I administered at a dose equal to its free base equivalent is administered at a slightly higher dose to adjust for the amount of counterions present that may not contribute to pharmaceutically effective.

[0031] As used herein, “the majority” refers to more than 50% of the total amount.

[0032] As used in this specification, "primarily" refers to a probability greater than 50%.

[0033] When used herein, "once a day" means administration every 24 hours. Other terms are interpreted similarly. For example, as used herein, "once every two days" means administration every 48 hours. As used herein, "once every three days" means administration every 72 hours. As used herein, "twice a day" means administration every 12 hours. As used herein, "three times a day" means administration every 8 hours.

[0034] When used before a number, such as a dosage, "approximately" refers to + / - 0.5 mg. For example, a dosage of "approximately 12.5 mg" refers to 12 mg to 13 mg.

[0035] Compounds and pharmaceutical compositions In this specification, (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or referred to herein as Compound I, [ka] The administration regimens of its pharmaceutically acceptable salts in the treatment of autoimmune and inflammatory diseases are disclosed. Compound I is interchangeable with 5-benzyl-N-[(3S)-7-(3-hydroxy-3-methyl-buta-1-inyl)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepine-3-yl]-1H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-[(3S)-7-(3-hydroxy-3-methyl-buta-1-inyl)-4-keto-5-methyl-2,3-dihydro-1,5-benzoxazepine-3-yl]-1H-124-triazole -3-carboxamide, N-[(3S)-5-methyl-7-(3-methyl-3-oxidanyl-buto-1-inyl)-4-oxidanidene-2,3-dihydro-1,5-benzoxazepine-3-yl]-5-(phenylmethyl)-1H-1,2,4-triazole-3-carboxamide, 5-benzyl-N-[(3S7-(3-hydroxy-3-methylbuta-1-inyl)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepine-3-yl]-1H-1 Compound I may be interchangeably called 1H-1,2,4-triazole-3-carboxamide, or N-[(3S)-7-(3-hydroxy-3-methylbuta-1-inyl)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepine-3-yl]-5-(phenylmethyl)-1H-1,2,4-triazole-3-carboxamide. Compound I is 1H-1,2,4-triazole-5-carboxamide, 3-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro- It may also be called 7-(3-hydroxy-3-methyl-1-butyne-1-yl)-5-methyl-4-oxo-1,5-benzoxazepine-3-yl). References to "compound I" do not include salts of compound I, e.g., pharmaceutically acceptable salts of compound I. Compound I is also referred to alternatively and interchangeably as the "free base" or "free base form" of compound I. Compound I can be prepared according to the method of Example 2 of International Publication No. 2019213447, or any other suitable method.

[0036] Although not expressly described throughout this disclosure, Compound I may exist in tautomeristic forms in which the hydrogen atom bonded to the triazole ring shifts position among the three triazole nitrogen atoms. References to Compound I encompass these tautomeristic forms of Compound I. Furthermore, Compound I or its pharmaceutically acceptable salts may exist in one or more crystalline or amorphous forms. References to Compound I encompass all such forms unless otherwise specified. In addition, Compound I or its pharmaceutically acceptable salts may exist in solvated (e.g., hydrated) or non-solvated forms, respectively. References to any methods, uses, compositions, kits, etc., containing Compound I also intend to include the solvated form of Compound I (in addition to the non-solvated form).

[0037] Therapy may involve using a composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one additional component such as a pharmaceutically acceptable excipient, adjuvant, or any combination thereof. Pharmacologically acceptable excipients may be included in the pharmaceutical composition for a variety of purposes, such as diluting the pharmaceutical composition for delivery to a target, facilitating the handling of the formulation, providing favorable material properties to the formulation, promoting dispersion from the delivery device, stabilizing the formulation (e.g., an antioxidant or buffer), or providing a pleasant or palatable taste or consistency to the formulation. Pharmacologically acceptable excipients may include pharmaceutically acceptable carriers. Exemplary excipients, but are not limited to, monosaccharides, disaccharides, and polysaccharides, sugar alcohols, and other polyols, such as lactose, glucose, raffinose, melegitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof.Surfactants such as sorbitol, diphosphatidylcholine, and lecithin; fillers; buffers such as phosphate buffer and citrate buffer; anti-sticking agents such as magnesium stearate; binders, e.g., sugars (including disaccharides such as sucrose and lactose), polysaccharides (starch, cellulose, microcrystalline cellulose, cellulose ether (hydroxypropylcellulose, etc.)), gelatin, synthetic polymers (polyvinylpyrrolidone, polyalkylene glycol, etc.); coatings (e.g., cellulose ether containing hydroxypropyl methylcellulose, shellac, corn protein zein, and gelatin); release agents (e.g., enteric coating); disintegrants (crospovidone, cross-linked carboxymethylcellulose sodium, starch glycolate sodium, etc.); fillers (e.g., second ri Calcium carbonate, vegetable oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, etc.); flavorings and sweeteners (mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla, etc.); lubricants (minerals exemplified by talc or silica, plant stearin, fats exemplified by magnesium stearate or stearic acid, etc.); preservatives (e.g., antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids exemplified by cysteine ​​and methionine, parabens exemplified by citric acid and sodium citrate, methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0038] Compound I can be formulated as a pharmaceutical composition itself, or as a pharmaceutically acceptable salt, tautomer, or solvate thereof. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases may also be formed. A pharmaceutical composition may contain Compound I or a pharmaceutically acceptable salt thereof in a total weight percentage from more than 0% to 99%. More typically, a pharmaceutical composition containing one or more of the disclosed compounds contains about 1 to about 20 total weight percent of Compound I or a pharmaceutically acceptable salt thereof, and about 80 to about 99 weight percent of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may further contain an adjuvant.

[0039] Pharmaceutical compositions can be manufactured by any suitable method, such as mixing, dissolving, granulation, sugar-coated tablet preparation, powdering, emulsification, encapsulation, encapsulation, or lyophilization processes. Pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or adjuvants), one or more adjuvants, or a combination thereof, to provide preparations that can be used pharmaceutically.

[0040] A suitable pharmaceutical composition can take a form suitable for virtually any mode of administration, including, for example, a form suitable for topical, ocular, oral, oral, systemic, nasal, intravenous or intravenous injection, transdermal, rectal, vaginal, or inhalation or inhalation. For oral administration, the pharmaceutical composition may take the form of lozenges, tablets, or capsules, prepared by conventional means with pharmaceutically acceptable excipients such as, for example, binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art, for example, with sugar, film, or enteric coating.

[0041] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or may be presented as dry products to be mixed with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); water and aqueous solutions mixed with water (e.g., water, aqueous solutions mixed with water); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, Cremophore®, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). Preparations may also contain buffer salts, preservatives, flavorings, colorings, and sweeteners as needed.

[0042] Preparations for oral administration can be suitably formulated to provide controlled release of the active compound, as is well known. Alternatively, other pharmaceutically acceptable delivery systems may be used.

[0043] Diseases, disorders, and conditions Compound I, its pharmaceutically acceptable salts, and combinations and / or pharmaceutical compositions, in particular according to the dosage regimens described herein, may be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo. They may be used to improve or treat a variety of diseases and / or disorders. In certain embodiments, Compound I, its pharmaceutically acceptable salts, and combinations and / or pharmaceutical compositions, in particular according to the dosage regimens described herein, may be useful in treating conditions where inhibition of RIP1 or the pathways in which RIP1 is involved is therapeutically beneficial. In some embodiments, Compound I, or its pharmaceutically acceptable salts, directly inhibits RIP1 kinase activity. In certain embodiments, Compound I, its pharmaceutically acceptable salts, and combinations and / or pharmaceutical compositions, in particular according to the dosage regimens described herein, may be useful in treating autoimmune or inflammatory diseases.

[0044] In certain embodiments, compound I or its pharmaceutically acceptable salts, as well as combinations and / or pharmaceutical compositions thereof, particularly according to the dosage regimen described herein, are useful for treating rheumatoid arthritis, psoriasis, inflammatory colitis, ulcerative colitis, psoriatic arthritis, sweat gland abscess, spondyloarthritis, or Crohn's disease.

[0045] In certain embodiments, compound I or its pharmaceutically acceptable salts, as well as combinations and / or pharmaceutical compositions thereof, particularly according to the dosage regimen described herein, are useful for treating cutaneous lupus erythematosus, lupus nephritis, systemic lupus erythematosus, or atopic dermatitis.

[0046] In certain embodiments, compound I or its pharmaceutically acceptable salts, and combinations and / or pharmaceutical compositions thereof, particularly according to the dosage regimens described herein, are useful for treating anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), otulin-associated autoinflammatory syndrome (ORAS), A20 haploinsufficiency (HA20), rippling-resistant RIPK1-induced autoinflammatory syndrome (CRIA), NEMO deficiency syndrome, fibrous disease, vacuole, E1 enzyme, X-linked autoinflammatory syndrome and somatic (VEXAS) syndrome, tank-binding kinase 1 (TBK1) and optinulin (OPTN) deficiency, familial amyotrophic lateral sclerosis (fALS), or sporadic amyotrophic lateral sclerosis (sALS).

[0047] In certain embodiments, compound I or its pharmaceutically acceptable salts, as well as combinations and / or pharmaceutical compositions thereof, particularly according to the dosage regimens described herein, are useful for treating autoimmune or inflammatory diseases regulated by receptor-interacting protein (RIP) kinase 1.

[0048] For example, rheumatoid arthritis (RA) typically presents with generalized swelling, pain, loss of movement, and tenderness of target joints. RA is characterized by a chronically inflamed synovial membrane densely packed with lymphocytes. Typically the thickness of a single cell layer, the synovial membrane appears to have a morphology similar to lymphoid tissue, with cells strengthened and containing clusters of dendritic cells, T, B, and NK cells, macrophages, and plasma cells. This process, along with numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformation, permanent loss of function, and / or bone erosion in or near the joint.

[0049] Compound I or its pharmaceutically acceptable salts, as well as combinations and / or pharmaceutical compositions thereof, in particular according to the dosage regimens described herein, may be used to treat or improve any one, some, or all of these symptoms of RA. Therefore, in the context of RA, Compound I or its pharmaceutically acceptable salts, in particular according to the dosage regimens described herein, are considered to provide a therapeutic benefit if a reduction or improvement of any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment results in the underlying concomitant treatment of RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0050] According to the revised criteria of the American College of Rheumatology (ACR) (Hochberg et al. 1992), rheumatoid arthritis (RA) can be classified into four classes based on the patient's functional capacity. Class I RA patients have "full functional capacity, capable of performing all usual tasks without handicap." Class II RA patients have "sufficient functional capacity to perform normal activities despite handicaps such as discomfort or limited mobility in one or more joints." Class III RA patients have "sufficient functional capacity to perform little or no usual occupational or self-care tasks." Class IV RA patients are "almost or completely incapacitated," and the patient is "bedridden or wheelchair-bound and little or no ability to perform self-care."

[0051] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criteria for 20% clinical improvement), requires a 20% improvement in the number of tender and swollen joints, as well as a 20% improvement in three of the following five parameters: overall patient assessment, overall physician assessment, patient pain assessment, degree of disability, and level of acute-phase reactions. These criteria are extended to ACR50 and ACR70 for 50% and 70% improvement, respectively. Other criteria include Paulu's criteria and progression on radiographic data (e.g., Sharp score).

[0052] In some embodiments, the therapeutic benefit in patients with RA is achieved when the patient presents with an ACR of 20. In certain embodiments, an ACR improvement of ACRC50 or even ACR70 can be achieved.

[0053] In some embodiments, subjects have moderate to severe active RA, defined by the presence of ≥6 swollen joints based on a 66-joint count and ≥6 tender joints based on a 68-joint count. (1) Note that distal interphalangeal joints should be evaluated but not included in the total number for determining eligibility. (2) If a participant has received corticosteroid treatment according to exclusion criteria

[29] , the treated joints should be excluded from the joint count.

[0054] As another example, psoriasis is a common chronic inflammatory skin disease characterized by erythema and scaly patches, often associated with other systemic diseases. Moderate to severe chronic psoriasis vulgaris is determined by the following criteria: psoriasis vulgaris with 10% or more of the body surface area (BSA) of the affected skin and an absolute psoriasis area and severity index (PASI) score of 12 or higher, or a physician's static overall assessment (sPGA) score of 3 or higher. Compound I or its pharmaceutically acceptable salts provide therapeutic benefits to subjects with psoriasis, e.g., subjects with moderate to severe chronic psoriasis vulgaris, particularly according to the dosage regimen described herein.

[0055] As yet another example, ulcerative colitis is a major form of chronic inflammatory bowel disease (IBD). Ulcerative colitis is characterized by abdominal pain and bloody stools (diarrhea with blood). Currently available treatments typically seek to control inflammation through anti-inflammatory and immunosuppressant agents, but do not address the underlying cause of chronic inflammation. Compound I or its pharmaceutically acceptable salts provide therapeutic benefits to subjects with ulcerative colitis, particularly according to the dosing regimen described herein.

[0056] Medication plan In one embodiment, a method for treating a subject having an autoimmune or inflammatory disease is provided herein, comprising administering to the patient a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt is administered in doses of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose. As further described below in Examples 1 and 2, for example, the disclosed dose range is advantageous in that it provides a combination of efficacy and tolerability among other therapeutic factors. For example, within this dose range, therapeutically effective concentrations can be maintained throughout the entire treatment window, particularly in the trough between two doses. Furthermore, within this dosage range, toxicity concerns are significantly reduced, as demonstrated, for example, by a sufficient safety margin.

[0057] In some embodiments, autoimmune or inflammatory diseases are diseases regulated by receptor-interacting protein (RIP) kinase 1.

[0058] In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory colitis, ulcerative colitis, psoriatic arthritis, sweat gland abscess, spondyloarthritis, Crohn's disease, cutaneous lupus erythematosus, lupus nephritis, systemic lupus erythematosus, atopic dermatitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), OTULIN-associated autoinflammatory syndrome (ORAS), A20 haploinsufficiency (HA20), transection-resistant RIPK1-induced autoinflammatory syndrome (CRIA), NEMO deficiency syndrome, fibrous disease, vacuole, E1 enzyme, X-linked autoinflammatory syndrome and somatic syndrome (VEXAS), TANK-binding kinase 1 (TBK1) and optinulin (OPTN) deficiency, familial amyotrophic lateral sclerosis (fALS), or sporadic amyotrophic lateral sclerosis (sALS).

[0059] In some embodiments, administration is carried out using the free base form of the compound.

[0060] In some embodiments, administration is carried out using the amorphous form of the compound. Surprisingly, as will be further described below, it has been found that by preparing compound I in an amorphous state, such as in a solid dispersion, the bioavailability is significantly improved compared to the corresponding preparation having compound I in a crystalline form. This allows for therapeutic efficacy in a lower dose range than required by other methods. Therefore, a suitable pharmaceutical composition mainly comprises compound I in an amorphous form. The composition may take the form of an amorphous tablet, such as a solid dispersion tablet. The solid dispersion tablet may be prepared, for example, by spray-drying technology, where a solution of compound I and a solution of a suitable polymer are mixed and dried to form a solid dispersion. The suitable polymer may assist in the dispersion and stabilization of compound I in the amorphous state. A suitable pharmaceutical composition may also take the form of a liquid formulation of compound I mainly in an amorphous form. For example, the composition may take the form of a solid dispersion oral suspension.

[0061] In one embodiment, a method is provided herein for treating a subject with an autoimmune disease or inflammatory disease, comprising administering to a patient a compound in an amorphous form of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl-1H-1,2,4-triazole-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt is administered in a dose of approximately 12.5 mg to approximately 125 mg of the free base equivalent of the compound per dose.

[0062] In some embodiments, the amorphous form of the compound is part of a solid dispersion.

[0063] In some embodiments, the solid dispersion is a spray-dried dispersion.

[0064] In some embodiments, the solid dispersion comprises a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4 (also known as PVP / VA 64 or 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate), povidone K30 (also known as PVP K30 or polyvinylpyrrolidone K30), and hydroxypropyl methylcellulose (HPMC). In some embodiments, the weight ratio (w / w) of the free base equivalent of the compound to the polymer is about 1:4 to about 1.2:1.

[0065] In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate.

[0066] In some embodiments, the weight ratio (w / w) of the free base equivalent of the compound to the polymer (e.g., hydroxypropyl methylcellulose acetate succinate) is about 1:4 to about 1.2:1. In some embodiments, the weight ratio (w / w) is about 1:3 to about 1:1. Weight ratios within this range allow for a balanced dose-potency suitable for administration without excessive patient compliance difficulties.

[0067] In some embodiments, the dose is approximately 25 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 106.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 81.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 68.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 62.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 56.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 43.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 37.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 31.25 mg of the compound's free base equivalent per dose.

[0068] In some embodiments, the dose is approximately 50 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 106.50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 81.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 68.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 62.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 56.50 mg of the compound's free base equivalent per dose.

[0069] In some embodiments, the dose is approximately 75 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 106.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 81.75 mg of the compound's free base equivalent per dose.

[0070] In some embodiments, the dose is approximately 100 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 106.25 mg of the compound's free base equivalent per dose.

[0071] In some embodiments, the dose is approximately 20 mg to 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg to 30 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg, 25 mg, or 30 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 45 mg to 55 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 70 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg, 55 mg, 60 mg, 65 mg, or 70 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 70 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or 125 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg to approximately 110 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, or 110 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg to approximately 90 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, or 90 mg of the compound per dose. In some embodiments, the dose is approximately 90 mg to 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 90 mg, 95 mg, 100 mg, 105 mg, or 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 110 mg of the compound's free base equivalent per dose.In some embodiments, the dose is approximately 100 mg, 105 mg, or 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 110 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 110 mg, 115 mg, 120 mg, or 125 mg of the compound's free base equivalent per dose.

[0072] In some embodiments, the dose is approximately 25 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 75 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 100 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 125 mg of the free base equivalent of the compound per dose.

[0073] In one embodiment, the Specified provides a method for treating a subject having an autoimmune or inflammatory disease, comprising administering to a patient an amorphous form of the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 25 mg to approximately 125 mg of the free base equivalent of the compound per dose.

[0074] In some embodiments, the maximum daily dose is approximately 25 mg to 125 mg of the free base equivalent of the compound. In some embodiments, the maximum daily dose is approximately 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg of the free base equivalent of the compound.

[0075] In some embodiments, the dose is administered once daily for any of the above-mentioned doses.

[0076] In some embodiments, with respect to any of the above doses, the dose is administered twice daily. In some embodiments, the dose is administered twice daily, and the dose is approximately 12.5 mg to approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is administered twice daily, and the dose is approximately 25 mg to approximately 50 mg of the free base equivalent of the compound per dose.

[0077] In some embodiments, with respect to any of the above doses, the dose is administered three times a day. In some embodiments, the dose is administered three times a day, and the dose is approximately 12.5 mg to approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is administered three times a day, and the dose is approximately 25 mg to approximately 50 mg of the free base equivalent of the compound per dose.

[0078] In some embodiments, with respect to any of the above doses, the dose is administered once every two days.

[0079] In some embodiments, with respect to any of the above doses, the dose is administered once every three days.

[0080] In one embodiment, a method for treating a subject with an autoimmune disease or inflammatory disease is provided herein, comprising administering to a patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl-1H-1,2,4-triazole-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 25 mg to approximately 125 mg of the free base equivalent of the compound per dose, and the dose is administered once daily.

[0081] In some embodiments, with respect to any of the above-mentioned doses, the dose is administered orally.

[0082] In some embodiments, an autoimmune or inflammatory disease is an inflammatory disease.

[0083] In some embodiments, an autoimmune disease or inflammatory disease is an autoimmune disease.

[0084] In some embodiments, the autoimmune or inflammatory disease is a tumor necrosis factor (TNF)-driven disease.

[0085] In some embodiments, the autoimmune or inflammatory disease is rheumatoid arthritis. In some embodiments, rheumatoid arthritis is class I, class II, or class III rheumatoid arthritis according to the revised ACR criteria (Hochberg et al. 1992). In some embodiments, rheumatoid arthritis is moderate to severely active rheumatoid arthritis. In some embodiments, the subject has been previously treated with at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and either one biological disease-modifying antirheumatic drug (bDMARD) or one targeted synthetic disease-modifying antirheumatic drug (tsDMARD) treatment.

[0086] In some embodiments, with respect to any of the above methods targeting rheumatoid arthritis, the method further comprises administering one or more oral conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In some embodiments, the method further comprises administering methotrexate (MTX).

[0087] In some embodiments, with respect to any of the above methods for targeting rheumatoid arthritis, the method further comprises administering one or more bio-disease-modifying antirheumatic drugs (bDMARDs) to the subject. In some embodiments, with respect to any of the above methods for targeting rheumatoid arthritis, the method further comprises administering a tumor necrosis factor (TNF) inhibitor to the subject.

[0088] In some embodiments, with respect to any of the above methods targeting rheumatoid arthritis, the method further comprises administering one or more targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).

[0089] In some embodiments, with respect to any of the above methods targeting rheumatoid arthritis, the subject achieves low disease activity after 12 weeks of treatment, as defined below: (a) Clinical disease activity index (CDAI) ≤10; (b) The simplified disease activity index (SDAI) is 11 or less; (c) Disease activity score - Highly sensitive C-reactive protein (DAS28-hsCRP) is 3.2 or less; or (d) Disease activity score erythrocyte sedimentation rate (DAS28-ESR) is 3.2 or less.

[0090] In some embodiments, with respect to any of the above methods for treating rheumatoid arthritis, the subject achieves remission after 12 weeks of treatment, as defined below: (a) Clinical disease activity index (CDAI) ≤2.8; (b) The simplified disease activity index (SDAI) is 3.3 or less; (c) Disease activity score - Highly sensitive C-reactive protein (DAS28-hsCRP) is ≤2.6; (d) Disease activity score erythrocyte sedimentation rate (DAS28-ESR) is 2.6 or less.

[0091] In some embodiments, with respect to any of the above methods for rheumatoid arthritis, the subject achieves ACR70 after 12 weeks of treatment according to the American College of Rheumatology criteria.

[0092] In some embodiments, with respect to any of the above methods for rheumatoid arthritis, the subject achieves ACR50 after 12 weeks of treatment according to the American College of Rheumatology criteria.

[0093] In some embodiments, with respect to any of the above methods for rheumatoid arthritis, the subject achieves ACR20 after 12 weeks of treatment according to the American College of Rheumatology criteria.

[0094] In some embodiments, with respect to any of the above-mentioned related methods, the autoimmune disease or inflammatory disease is psoriasis.

[0095] In some embodiments, with respect to any relevant method described above, the autoimmune or inflammatory disease is psoriasis vulgaris. In some embodiments, psoriasis vulgaris is defined as moderate to severe psoriasis vulgaris with ≥10% body surface area (BSA) and an absolute psoriasis area and severity index (PASI) score ≥12; and / or a physician's static overall assessment (sPGA) score ≥3.

[0096] In some embodiments, patients achieve a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a score of 0 (clear) or 1 (nearly clear) on the Physician Static Overall Assessment (sPGA) scale after 12 weeks of treatment.

[0097] In some embodiments, the autoimmune disease or inflammatory disease is inflammatory bowel disease.

[0098] In some embodiments, the autoimmune disease or inflammatory disease is ulcerative colitis.

[0099] In some embodiments, the autoimmune or inflammatory disease is Crohn's disease.

[0100] In some embodiments, the autoimmune disease or inflammatory disease is psoriatic arthritis.

[0101] In some embodiments, the autoimmune or inflammatory disease is a sweat gland abscess.

[0102] In some embodiments, the autoimmune or inflammatory disease is axial spondyloarthritis.

[0103] In some embodiments, the autoimmune or inflammatory disease is not driven by tumor necrosis factor (TNF).

[0104] In some embodiments, the autoimmune or inflammatory disease is cutaneous lupus erythematosus.

[0105] In some embodiments, the autoimmune disease or inflammatory disease is lupus nephritis.

[0106] In some embodiments, the autoimmune disease or inflammatory disease is systemic lupus erythematosus.

[0107] In some embodiments, the autoimmune disease or inflammatory disease is cutaneous lupus erythematosus.

[0108] In some embodiments, the autoimmune or inflammatory disease is atopic dermatitis.

[0109] In some embodiments, the autoimmune or inflammatory disease is an OTULIN-associated autoinflammatory syndrome (ORAS).

[0110] In some embodiments, autoimmune or inflammatory diseases are A20 haploinsufficiency (HA20). A20 is also known as TNF-α-inducible protein 3 (TNFAIP3).

[0111] In some embodiments, the autoimmune or inflammatory disease is amputation-resistant RIPK1-induced autoinflammatory syndrome (CRIA).

[0112] In some embodiments, autoimmune or inflammatory diseases are NEMO deficiency syndromes.

[0113] In some embodiments, the autoimmune or inflammatory disease is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

[0114] In some embodiments, the autoimmune disease or inflammatory disease is a fibrous disease.

[0115] In some embodiments, the autoimmune or inflammatory disease is vacuolar, E1 enzyme, X-linked autoinflammatory syndrome, and somatic (VEXAS) syndrome.

[0116] In some embodiments, the autoimmune or inflammatory disease is a TANK-binding kinase 1 (TBK1) / optineurin (OPTN) deficiency.

[0117] In some embodiments, the autoimmune or inflammatory disease is familial amyotrophic lateral sclerosis (fALS) or sporadic amyotrophic lateral sclerosis (sALS).

[0118] In one embodiment, a method for treating a patient having rheumatoid arthritis is provided herein, comprising administering to the patient a compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 12.5 mg to about 125 mg per dose.

[0119] In one embodiment, a method for treating a patient having rheumatoid arthritis is provided herein, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily in doses of about 25 mg to about 125 mg per dose.

[0120] In one embodiment, a method for treating a patient having psoriasis is provided herein, comprising administering to the patient a compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 12.5 mg to about 125 mg per dose.

[0121] In one embodiment, a method for treating a patient having psoriasis is provided herein, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily in doses of about 25 mg to about 125 mg per dose.

[0122] In one embodiment, a method for treating a patient having ulcerative colitis is provided herein, comprising administering to the patient a compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 12.5 mg to about 125 mg per dose.

[0123] In one embodiment, a method for treating a patient having ulcerative colitis is provided herein, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily in doses of about 12.5 mg to about 125 mg per dose.

[0124] In one embodiment, a pharmaceutical composition is provided herein comprising a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, wherein the composition contains about 12.5 mg to about 125 mg of the compound in free base equivalents per dose, and the composition is administered to a patient having an autoimmune disease or an inflammatory disease, and the administration comprises administering to the patient the compound or a pharmaceutically acceptable salt thereof according to any of the above embodiments and examples.

[0125] In one embodiment, a pharmaceutical composition for use in the treatment of an autoimmune or inflammatory disease in a patient is provided herein, comprising a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof, comprising about 12.5 mg to about 125 mg of the compound in free base equivalents per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0126] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (2) a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC).

[0127] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, and (2) a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC).

[0128] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide in an amorphous form, and (2) a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC).

[0129] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide in amorphous form, and (2) a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC), wherein the weight ratio (w / w) of the compound to the polymer is about 1:4 to about 1.2:1.

[0130] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide in an amorphous form, and (2) hydroxypropyl methylcellulose acetate succinate (HPMC-AS), wherein the weight ratio (w / w) of the compound to HPMC-AS is about 1:4 to about 1.2:1.

[0131] In one embodiment, a pharmaceutical composition is provided herein comprising (1) an amorphous compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, and (2) hydroxypropyl methylcellulose acetate succinate (HPMC-AS), wherein the weight ratio (w / w) of the compound to HPMC-AS is about 1:3 to about 1:1.

[0132] In one embodiment, a pharmaceutical composition is provided herein comprising (1) a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (2) a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC), wherein the composition contains approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose, and the weight ratio (w / w) of the compound's free base equivalent to the polymer's is approximately 1:4 to approximately 1.2:1.

[0133] In some embodiments, the polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMC-AS). In some embodiments, the weight ratio (w / w) of the free base equivalent of the compound to the hydroxypropyl methylcellulose acetate succinate is about 1:3 to about 1:1.

[0134] In some embodiments, the composition further comprises a pharmaceutically acceptable diluent or carrier.

[0135] In one embodiment, the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of autoimmune or inflammatory diseases in patients, wherein the compound or a pharmaceutically acceptable salt thereof is administered in doses of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0136] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide is provided herein for use in the treatment of autoimmune or inflammatory diseases in patients, wherein the compound is administered in doses of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0137] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide is provided herein for use in the treatment of autoimmune or inflammatory diseases in patients, wherein the compound is administered in an amorphous state at a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the above embodiments and methods.

[0138] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide is provided herein for use in the treatment of rheumatoid arthritis, wherein the compound is administered in an amorphous state at a dose of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0139] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide is provided herein for use in the treatment of psoriasis in patients, wherein the compound is administered in an amorphous state at doses of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0140] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide is provided herein for use in the treatment of ulcerative colitis in patients, wherein the compound is administered in an amorphous state at a dose of about 12.5 mg to about 125 mg of the compound's free base equivalent per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0141] In one embodiment, the use of the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of an autoimmune or inflammatory disease in a patient, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 12.5 mg to approximately 125 mg of the free base equivalent of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0142] In one embodiment, the use of the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical for the treatment of an autoimmune or inflammatory disease in a patient, wherein the compound is administered in doses of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0143] In one embodiment, the use of the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical for the treatment of an autoimmune or inflammatory disease in a patient, wherein the compound is administered in an amorphous state at a dose of about 12.5 mg to about 125 mg of the compound's free base equivalent per dose, is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0144] In one embodiment, the use of the compound (S)-5-benzyl-N-7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical for the treatment of rheumatoid arthritis in a patient, wherein the compound is administered in an amorphous state at a dose of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose, is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0145] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical for the treatment of psoriasis in a patient, wherein the compound is administered in an amorphous state at a dose of about 25 mg to about 125 mg of the compound's free base equivalent per dose, is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0146] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical for the treatment of ulcerative colitis in a patient, wherein the compound is administered in an amorphous state at a dose of about 12.5 mg to about 125 mg of the compound's free base equivalent per dose, and such use is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0147] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof is provided herein for use in the manufacture of a medicament for the treatment of autoimmune or inflammatory diseases in patients, wherein the medicament contains a free base equivalent titer of the compound at approximately 12.5 mg per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0148] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof is provided herein for use in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament contains a free base equivalent titer of the compound at approximately 25 mg per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and models.

[0149] In one embodiment, the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof is provided herein for use in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament contains a free base equivalent titer of the compound at approximately 62.5 mg per dose. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0150] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 12.5 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0151] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 25 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and embodiments.

[0152] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 62.5 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0153] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 12.5 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0154] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 25 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and embodiments.

[0155] In one embodiment, the use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease in a patient, wherein the medicament comprises a free base equivalent titer of about 62.5 mg of the compound per dose, the use of which is provided herein. In some embodiments, the treatment follows any of the methods of the above embodiments and examples.

[0156] In some embodiments, autoimmune or inflammatory diseases are diseases regulated by receptor-interacting protein (RIP) kinase 1.

[0157] In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory colitis, ulcerative colitis, psoriatic arthritis, sweat gland abscess, spondyloarthritis, Crohn's disease, cutaneous lupus erythematosus, lupus nephritis, systemic lupus erythematosus, atopic dermatitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), OTULIN-associated autoinflammatory syndrome (ORAS), A20 haploinsufficiency (HA20), transection-resistant RIPK1-induced autoinflammatory syndrome (CRIA), NEMO deficiency syndrome, fibrous disease, vacuole, E1 enzyme, X-linked autoinflammatory syndrome and somatic syndrome (VEXAS), TANK-binding kinase 1 (TBK1) and optinulin (OPTN) deficiency, familial amyotrophic lateral sclerosis (fALS), or sporadic amyotrophic lateral sclerosis (sALS).

[0158] In some embodiments, the treatment uses the free base form of the compound.

[0159] In some embodiments, treatment is carried out using an amorphous form of the compound.

[0160] In some embodiments, the treatment is the treatment of a patient having an autoimmune or inflammatory disease and comprises administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt is administered in doses of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

[0161] In some embodiments, the amorphous form of the compound is part of a solid dispersion.

[0162] In some embodiments, the solid dispersion is a spray-dried dispersion.

[0163] In some embodiments, the solid dispersion comprises a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4 (also known as PVP / VA 64 or 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate), povidone K30 (also known as PVP K30 or polyvinylpyrrolidone K30), and hydroxypropyl methylcellulose (HPMC). In some embodiments, the weight ratio (w / w) of the free base equivalent of the compound to the polymer is about 1:4 to about 1.2:1.

[0164] In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate.

[0165] In some embodiments, the weight ratio (w / w) of the free base equivalent of the compound to the polymer (e.g., hydroxypropyl methylcellulose acetate succinate) is about 1:4 to about 1.2:1. In some embodiments, the weight ratio (w / w) is about 1:3 to about 1:1. Weight ratios within this range allow for a balanced dose-potency suitable for administration without excessive patient compliance difficulties.

[0166] In some embodiments, the dose is approximately 25 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 106.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 81.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 68.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 62.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 56.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 43.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 37.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 25 mg to 31.25 mg of the compound's free base equivalent per dose.

[0167] In some embodiments, the dose is approximately 50 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 106.50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 81.25 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 68.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 62.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 56.50 mg of the compound's free base equivalent per dose.

[0168] In some embodiments, the dose is approximately 75 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 106.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 100 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 93.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 87.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 75 mg to 81.75 mg of the compound's free base equivalent per dose.

[0169] In some embodiments, the dose is approximately 100 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 118.75 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 112.5 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 106.25 mg of the compound's free base equivalent per dose.

[0170] In some embodiments, the dose is approximately 20 mg to 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg to 30 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 20 mg, 25 mg, or 30 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 45 mg to 55 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg to 70 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 50 mg, 55 mg, 60 mg, 65 mg, or 70 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 70 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or 125 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg to approximately 110 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, or 110 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg to approximately 90 mg of the compound per dose. In some embodiments, the dose is approximately 70 mg, 75 mg, 80 mg, 85 mg, or 90 mg of the compound per dose. In some embodiments, the dose is approximately 90 mg to 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 90 mg, 95 mg, 100 mg, 105 mg, or 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 100 mg to 110 mg of the compound's free base equivalent per dose.In some embodiments, the dose is approximately 100 mg, 105 mg, or 110 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 110 mg to 125 mg of the compound's free base equivalent per dose. In some embodiments, the dose is approximately 110 mg, 115 mg, 120 mg, or 125 mg of the compound's free base equivalent per dose.

[0171] In some embodiments, the dose is approximately 25 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 75 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 100 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is approximately 125 mg of the free base equivalent of the compound per dose.

[0172] In some embodiments, the treatment is the treatment of a patient having an autoimmune or inflammatory disease and comprises administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt is administered in doses of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose.

[0173] In some embodiments, the maximum daily dose is approximately 25 mg to 125 mg of the free base equivalent of the compound. In some embodiments, the maximum daily dose is approximately 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg of the free base equivalent of the compound.

[0174] In some embodiments, the dose is administered once daily for any of the above-mentioned doses.

[0175] In some embodiments, with respect to any of the above doses, the dose is administered twice daily. In some embodiments, the dose is administered twice daily, and the dose is approximately 12.5 mg to approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is administered twice daily, and the dose is approximately 25 mg to approximately 50 mg of the free base equivalent of the compound per dose.

[0176] In some embodiments, with respect to any of the above doses, the dose is administered three times a day. In some embodiments, the dose is administered three times a day, and the dose is approximately 12.5 mg to approximately 50 mg of the free base equivalent of the compound per dose. In some embodiments, the dose is administered three times a day, and the dose is approximately 25 mg to approximately 50 mg of the free base equivalent of the compound per dose.

[0177] In some embodiments, with respect to any of the above doses, the dose is administered once every two days.

[0178] In some embodiments, with respect to any of the above doses, the dose is administered once every three days.

[0179] In some embodiments, the treatment is the treatment of a patient having an autoimmune or inflammatory disease and comprises administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl-1H-1,2,4-triazole-3-carboxamide, the compound or a pharmaceutically acceptable salt of which is administered in doses of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose, and the dose is administered once daily.

[0180] In some embodiments, with respect to any of the above-mentioned doses, the dose is administered orally.

[0181] In some embodiments, an autoimmune or inflammatory disease is an inflammatory disease.

[0182] In some embodiments, an autoimmune disease or inflammatory disease is an autoimmune disease.

[0183] In some embodiments, the autoimmune or inflammatory disease is a tumor necrosis factor (TNF)-driven disease.

[0184] In some embodiments, the autoimmune or inflammatory disease is rheumatoid arthritis. In some embodiments, rheumatoid arthritis is class I, class II, or class III rheumatoid arthritis according to the revised ACR criteria (Hochberg et al. 1992). In some embodiments, rheumatoid arthritis is moderate to severely active rheumatoid arthritis. In some embodiments, the subject has been previously treated with at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and either one biological disease-modifying antirheumatic drug (bDMARD) or one targeted synthetic disease-modifying antirheumatic drug (tsDMARD) treatment.

[0185] In some embodiments, with respect to rheumatoid arthritis, the treatment further comprises administering one or more oral conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In some embodiments, the treatment further comprises administering methotrexate (MTX) as the target.

[0186] In some embodiments, with respect to rheumatoid arthritis, the treatment further comprises administering one or more bio-disease-modifying antirheumatic drugs (bDMARDs). In some embodiments, with respect to rheumatoid arthritis, the treatment further comprises administering tumor necrosis factor (TNF) inhibitors.

[0187] In some embodiments, with respect to rheumatoid arthritis, treatment further comprises administering one or more targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).

[0188] In some embodiments, with respect to rheumatoid arthritis, the subjects achieve low disease activity after 12 weeks of treatment, as defined below: (a) Clinical disease activity index (CDAI) ≤10; (b) The simplified disease activity index (SDAI) is 11 or less; (c) Disease activity score - Highly sensitive C-reactive protein (DAS28-hsCRP) is 3.2 or less; or (d) Disease activity score erythrocyte sedimentation rate (DAS28-ESR) is 3.2 or less.

[0189] In some embodiments, with respect to rheumatoid arthritis, the subjects achieve remission after 12 weeks of treatment, as defined below: (a) Clinical disease activity index (CDAI) ≤2.8; (b) The simplified disease activity index (SDAI) is 3.3 or less; (c) Disease activity score - Highly sensitive C-reactive protein (DAS28-hsCRP) is ≤2.6; (d) Disease activity score erythrocyte sedimentation rate (DAS28-ESR) is 2.6 or less.

[0190] In some embodiments, with respect to rheumatoid arthritis, subjects achieve ACR70 after 12 weeks of treatment according to American College of Rheumatology criteria.

[0191] In some embodiments, with respect to rheumatoid arthritis, subjects achieve ACR50 after 12 weeks of treatment according to American College of Rheumatology criteria.

[0192] In some embodiments, with respect to rheumatoid arthritis, subjects achieve ACR20 after 12 weeks of treatment according to American College of Rheumatology criteria.

[0193] In some embodiments, the autoimmune or inflammatory disease is psoriasis.

[0194] In some embodiments, the autoimmune or inflammatory disease is psoriasis vulgaris. In some embodiments, psoriasis vulgaris is defined as moderate to severe psoriasis vulgaris with ≥10% body surface area (BSA) and an absolute psoriasis area and severity index (PASI) score ≥12; and / or a physician's static overall assessment (sPGA) score ≥3.

[0195] In some embodiments, patients achieve a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. In some embodiments, patients achieve a score of 0 (clear) or 1 (nearly clear) on the Physician Static Overall Assessment (sPGA) scale after 12 weeks of treatment.

[0196] In some embodiments, the autoimmune disease or inflammatory disease is inflammatory bowel disease.

[0197] In some embodiments, the autoimmune disease or inflammatory disease is ulcerative colitis.

[0198] In some embodiments, the autoimmune or inflammatory disease is Crohn's disease.

[0199] In some embodiments, the autoimmune disease or inflammatory disease is psoriatic arthritis.

[0200] In some embodiments, the autoimmune or inflammatory disease is a sweat gland abscess.

[0201] In some embodiments, the autoimmune or inflammatory disease is axial spondyloarthritis.

[0202] In some embodiments, the autoimmune or inflammatory disease is not driven by tumor necrosis factor (TNF).

[0203] In some embodiments, the autoimmune or inflammatory disease is cutaneous lupus erythematosus.

[0204] In some embodiments, the autoimmune disease or inflammatory disease is lupus nephritis.

[0205] In some embodiments, the autoimmune disease or inflammatory disease is systemic lupus erythematosus.

[0206] In some embodiments, the autoimmune disease or inflammatory disease is cutaneous lupus erythematosus.

[0207] In some embodiments, the autoimmune or inflammatory disease is atopic dermatitis.

[0208] In some embodiments, the autoimmune or inflammatory disease is an OTULIN-associated autoinflammatory syndrome (ORAS).

[0209] In some embodiments, autoimmune or inflammatory diseases are A20 haploinsufficiency (HA20). A20 is also known as TNF-α-inducible protein 3 (TNFAIP3).

[0210] In some embodiments, the autoimmune or inflammatory disease is amputation-resistant RIPK1-induced autoinflammatory syndrome (CRIA).

[0211] In some embodiments, autoimmune or inflammatory diseases are NEMO deficiency syndromes.

[0212] In some embodiments, the autoimmune or inflammatory disease is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

[0213] In some embodiments, the autoimmune disease or inflammatory disease is a fibrous disease.

[0214] In some embodiments, the autoimmune or inflammatory disease is vacuolar, E1 enzyme, X-linked autoinflammatory syndrome, and somatic (VEXAS) syndrome.

[0215] In some embodiments, the autoimmune or inflammatory disease is a TANK-binding kinase 1 (TBK1) / optineurin (OPTN) deficiency.

[0216] In some embodiments, the autoimmune or inflammatory disease is familial amyotrophic lateral sclerosis (fALS) or sporadic amyotrophic lateral sclerosis (sALS).

[0217] In some embodiments, the treatment is the treatment of a patient having rheumatoid arthritis and comprises administering to the patient the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, which is administered once daily in doses of about 12.5 mg to about 125 mg per dose.

[0218] In some embodiments, the treatment is the treatment of a patient having rheumatoid arthritis and comprises administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, the compound being administered once daily in doses of about 25 mg to about 125 mg per dose.

[0219] In some embodiments, the treatment is a method for treating a patient having psoriasis, comprising administering to the patient the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, which is administered once daily in doses of about 12.5 mg to about 125 mg per dose.

[0220] In some embodiments, the treatment is a method for treating a patient having psoriasis, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, the compound being administered once daily in doses of about 25 mg to about 125 mg per dose.

[0221] In some embodiments, the treatment is a method for treating patients with ulcerative colitis, comprising administering to the patient the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, which is administered once daily in doses of about 12.5 mg to about 125 mg per dose.

[0222] In some embodiments, the treatment is a method for treating a patient having ulcerative colitis, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, the compound being administered once daily in doses of about 12.5 mg to about 125 mg per dose.

[0223] In one embodiment, a pharmaceutical unit dose composition containing approximately 12.5 mg to approximately 125 mg of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is provided herein.

[0224] In one embodiment, a pharmaceutical unit dose composition containing approximately 25 mg to approximately 125 mg of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is provided herein.

[0225] In one embodiment, pharmaceutical unit dose compositions comprising approximately 12.5 mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 100 mg, 112.5 mg, or 125 mg of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide are provided herein.

[0226] In one embodiment, a pharmaceutical unit dose composition is provided herein, comprising approximately 12.5 mg to approximately 125 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, wherein the unit dose composition is suitable for oral administration.

[0227] In one embodiment, a pharmaceutical unit dose composition is provided herein, comprising approximately 12.5 mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 100 mg, 112.5 mg, or 125 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, wherein the unit dose composition is suitable for oral administration.

[0228] In one embodiment, a pharmaceutical unit dose composition is provided herein, comprising approximately 25 mg to approximately 125 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, wherein the unit dose composition is suitable for oral administration.

[0229] In some embodiments, the pharmaceutical unit dose composition contains about 12.5 mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, or 75 mg of the compound.

[0230] In one embodiment, a pharmaceutical unit dose composition is provided herein, which contains approximately 12.5 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, and the unit dose composition is suitable for oral administration.

[0231] In one embodiment, a pharmaceutical unit dose composition is provided herein, comprising approximately 25 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, wherein the unit dose composition is suitable for oral administration.

[0232] In one embodiment, a pharmaceutical unit dose composition is provided herein, which contains approximately 62.5 mg of amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound, and the unit dose composition is suitable for oral administration.

[0233] In some embodiments, the pharmaceutical unit dose composition is used according to any of the methods or uses described above.

[0234] Example 1 Compound I was tested in a Phase 1 single-center trial to investigate the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of Compound I in healthy volunteers. The trial consisted of three parts: a single escalating dose (Part 1A), multiple escalating doses (Part 2), and formulation evaluation (Parts 1B and 3). The dosing regimen administered in the trial is shown in Table 1.

[0235] Table 1. Dosage plan for compound I in first-in-human trials [Table 1] Abbreviations: ALT = Alternative; IMP = Investigational drug; LIPID = Lipid oral solution; NA = Not applicable; QD = Once daily. IMP Guide: ALT1 suspension = Compound I alternative formulation 1 administered as an oral suspension; ALT2 suspension = Compound I alternative formulation 2 administered as an oral suspension; LIPID = Compound I lipid oral solution, free drug equivalent. a Free drug equivalent. b To mask the taste, Listerine strips were administered immediately before LIPID, ALT1 suspension, and ALT2 suspension formulations. c ALT1 and ALT2 are spray-dried dispersion powders for oral suspension, and were administered as oral suspensions (ALT1 suspension and ALT2 suspension, respectively) according to the dosage instructions specific to the study. d The high-fat breakfast, in accordance with FDA guidelines, consisted of one hash brown, two rusher Sainsbury's streak bacon (grilled), one small egg (45g) fried in 10g of butter, two slices of white medium slice bread with 20g of butter, and 240mL of whole-fat milk.

[0236] Exposure to compound I increased proportionally over the dose range of 12–1000 mg. The highest exposure to compound I in this study was observed after a single dose of 1000 mg of ALT1 suspension, with a geometric mean AUC. 0-∞ and C 最大 The values ​​were 499,000 ng × h / mL and 26,000 ng / mL, respectively, which were below the NOAEL exposure of 1,000 mg / kg / day from a 28-day GLP toxicity study in monkeys.

[0237] Exposure to compound I was determined after 14 days of 180 mg QD and 500 mg QD. The highest exposure was determined at 500 mg QD, with a geometric mean AUC. τ The glycemic index was 213,000 ng × h / mL, and the Cmax was 15,100 ng / mL. Analysis of the plasma obtained on day 14 showed the presence of one major metabolite, β-hydroxylated compound I.

[0238] Based on the AUC geometric mean ratio being within the acceptable limits of biological equivalence (80% - 125%), similar exposures were observed between the ALT1 suspension and the ALT1 tablet, and between the ALT1 tablet with or without food.

[0239] On the other hand, Compound I has been found to have a half-life of approximately 13 - 15 hours in human subjects, which is much longer than other RIPK1 inhibitors in the art (e.g., 2 - 3 hours for GSK2982772).

[0240] Example 2 Compound I was tested in multiple toxicology studies conducted over periods of up to 6 months in rats and 9 months in monkeys. Minimal effects were observed in rats, but mortality related to secondary infections was observed in monkeys at doses of 250 mg / kg / day and above. The safety pharmacology and genotoxicity battery found no effects on human safety. Furthermore, the developmental and reproductive toxicology studies conducted in rats and rabbits revealed no concerns for pregnant women. Surprisingly, the NOAEL / NOEL and corresponding safety margins established from each study (Table 2) support a human dose of only approximately 125 mg.

[0241] Table 2: Limits of safety for oral administration of Compound I based on human exposure estimates

Table 2

[0242] Example 3 Compound I was further tested in a Phase 1 open-label single-dose fixed-sequence study to evaluate the pharmacokinetics, safety, and tolerability of a single 125 mg dose administered as a solid dispersion oral suspension and crystalline free base tablets in healthy participants. Each participant received both formulations during two separate dosing periods.

[0243] Table 3 shows the PK parameters of compound I after oral administration of crystalline free base tablets and solid dispersion oral suspensions. Surprisingly, compared to the oral suspension, the AUC(0-t) of the tablets was higher. last ) and AUC(0-∞) are approximately 70%, C max There was a statistically significant decrease of 77% for the median t. max The duration was longer for tablets compared to oral suspensions. (Geometric mean t) 1 / 2 The following were similar across formulations: For compound I, the amount of drug excreted that did not change between 0 and 24 hours post-administration (Ae(0-24)) and the percentage of the dose excreted that did not change between 0 and 24 hours post-administration (Fe(0-24)) were lower in tablets compared to oral suspensions due to greater plasma exposure in oral suspensions, but CLr was comparable across formulations. AUC(0-t last ), AUC(0-∞), and Cmax The inter-participant CV for tablets was higher for tablets compared to oral suspensions. The CV ranged from 33.3% to 34.0% for tablet formulations and from 21.3% to 23.2% for oral suspension formulations. AUC for tablets 0∞ ) and C max When each formulation was administered as a single oral dose of 125 mg, the levels were approximately 70% and 77% lower, respectively, than those of the suspension.

[0244] Table 3. Summary of pharmacokinetic parameters [Table 3] Abbreviation:%AUC(t last -∞) = Percentage of extrapolated AUC(0-∞); Ae(0-24) = Amount of drug excreted that does not change between time 0 and 24 hours after administration; AUC(0-24) = Area under the concentration-time curve from time 0 to 24 hours after administration during one dosing interval (i.e., 24 hours); AUC(0~∞) = Area under the concentration-time curve from time 0 to infinity; AUC(0~t last ) = Area under the concentration-time curve from time 0 to time t, where t is the last time point at a measurable concentration; CL / F = Apparent total clearance of the drug calculated after extravasation; CL r = Renal clearance; C max =Maximum observed drug concentration;CV = Coefficient of variation (%);Fe(0-24) = Percentage of the dose excreted without change between time 0 and 24 hours after administration;n = Number of participants with valid observations;N = Number of participants;T 1 / 2 =Apparent final emission half-life; t max = Time to maximum observed drug concentration; Vss / F = Apparent volume of distribution at steady state after extravascular administration; Vz / F = Apparent volume of distribution during the terminal phase after extravascular administration; Presents the geometric mean (CV) [n] statistic; t max For this, present the median (minimum-maximum)[n] statistic; t 1 / 2 We present the geometric mean (minimum - maximum) [n] for this.

[0245] Example 4 Protocol overview: Adaptive design Phase 2a / 2b randomized, double-blind, placebo-controlled trial of compound I in adult participants with moderate to severe active rheumatoid arthritis.

[0246] basis This adaptive design Phase 2a / 2b trial aims to evaluate the efficacy and safety of compound I at multiple dose levels in adult participants with moderate to severe active rheumatoid arthritis (RA). This is the first trial of compound I in RA.

[0247] Objective, endpoint, and estimation: [Table 4-1]

[0248] (Continuation of the table above) [Table 4-2] Abbreviations: ACR = American College of Rheumatology; CDAI = Clinical Disease Activity Index; DAS28-hsCRP = Disease Activity Score - Highly Sensitive C-Reactive Protein; FACIT-F = Functional Assessment of Chronic Disease Treatment - Fatigue; HAQ-DI = Disability Index Using Health Assessment Questionnaire; LDA = Low Disease Activity; PaGADA = Patient-Wide Assessment of Disease Activity; PhGADA = Physician-Wide Assessment of Disease Activity; SDAI = Simplified Disease Activity Index; SF-36 = Shortened 36 Version 2 Health Survey Acute Form; VAS = Visual Analog Scale.

[0249] Main estimate Phase 2a The main clinical problems addressed are as follows: Assuming no changes to permitted concomitant medications and no violations of restrictions regarding the use of prohibited therapies, and assuming all participants adhere to the study intervention, what is the difference in mean change from baseline at week 12 between compound I and placebo in the target patient population?

[0250] The presumption is described by the following attributes. ● Population: Participants with moderate to severe active RA defined by the presence of ≥6 swollen joints based on 66 joint counts at screening (Visit 1) and ≥6 tender joints based on 68 joint counts at randomization (Visit 2 / baseline). ● Endpoint: Change from baseline in the Disease Activity Score - high sensitivity C-reactive protein (DAS28-hsCRP). ● Intervention-related events (ICE) related to the trial intervention include the use of prohibited drug therapies, changes in permitted concomitant medications, and early discontinuation from the trial or trial intervention. A hypothetical imputation strategy is used; that is, data collected after the first occurrence of ICE are excluded from the analysis, and the treatment effect is imputed for all participants who did not use prohibited drug therapies, did not change permitted concomitant medications, and adhered to the treatment. ● Summary at the population level: Difference in the mean change from baseline to week 12 between the trial intervention conditions. ● Principle of imputation: Data collected after treatment discontinuation, initiation of prohibited dosing, or change in permitted concomitant medications will not show the true efficacy effect.

[0251] [[ID=1 4]]Phase 2b The main clinical question of interest is as follows. What is the difference between Compound I and placebo in the target patient population when achieving response at week 12 without changing permitted concomitant medications, without receiving prohibited drug therapies, or without discontinuing the trial intervention?

[0252] The presumption is described by the following attributes. ● Population: Participants with moderate to severe active RA defined by the presence of ≥6 swollen joints based on 66 joint counts at screening (Visit 1) and ≥6 tender joints based on 68 joint counts at randomization (Visit 2 / baseline). ● Endpoint: American College of Rheumatology (ACR) 50 at week 12. ●ICEs related to the trial intervention include the use of prohibited drug therapies, changes in permitted concomitant medications, and early termination of the trial or trial intervention. A combined strategy is used; that is, participants with ICEs are considered non-responders because they are assumed not to have benefited from the intervention. ●Summary at the group level: Difference in the proportion of participants who achieved a response at week 12 between the trial intervention conditions. ● Principle of estimation: Data collected after treatment discontinuation, initiation of prohibited drug therapy, or change of permitted concomitant medications are classified as treatment failures, as it is assumed that the participant did not benefit from the intervention.

[0253] Overall design: This study is an adaptive-design, phase 2a / 2b, multicenter, randomized, double-blind trial to evaluate the efficacy and safety of compound I at multiple dose levels in adult participants with moderate to severe active rheumatoid arthritis (RA). This table summarizes the key features of the two phases of the study.

[0254] [Table 5] Abbreviations: bDMARD = Biological Disease Modified Antirheumatic Drug; CDAI = Clinical Disease Activity Index; csDMARD = Conventional Synthetic Disease Modified Antirheumatic Drug; SJC = Number of Swollen Joints; TJS = Number of Tender Joints; tsDMARD = Targeted Synthetic Disease Modified Antirheumatic Drug. a A history of failure = insufficient response, intolerance, or loss of response. b SOC treatment includes all csDMARDs and b / tsDMARDs.

[0255] Exam period Both Phase 2a and Phase 2b have the following test periods. ●Period I: Screening (1 visit) ●Period II: Double-blind, placebo-controlled treatment ●Period III: Treatment ●Period IV: Post-treatment follow-up (visits 801 and 802)

[0256] Treatment period This table summarizes the key features of the treatment period for both phases of the trial. The trial intervention is self-administered by the participants at home on days other than the trial visit days.

[0257]

Table 6

[0258] Summary of the trial: The aim of this trial is to evaluate the efficacy and safety of Compound I compared to placebo in adults with moderate to severe active RA.

[0259] For each of the two phases of the trial ● The trial period is up to 32 weeks. ● The treatment period is up to 24 weeks.

[0260] During the treatment period, the visit frequency is ● Phase 2a: every 2 weeks, and ● Phase 2b: every 2 - 4 weeks.

[0261] Trial population: Individuals included in this trial ● 18 years of age or older ● Diagnosed with RA as an adult at least 3 months before screening ● Currently have moderate to severe active RA ● Have a history of failure (insufficient response, intolerance, or loss of response) to at least one csDMARD and either one bDMARD or one tsDMARD treatment.

[0262] Number of participants: Approximately 100 participants will be randomly assigned to the trial intervention (placebo or 50 mg QD) in Phase 2a.

[0263] If the higher-dose cohort is activated in Phase 2a, up to approximately 100 additional participants can be randomly assigned to the study intervention (placebo or a higher dose not exceeding 125 mg).

[0264] Approximately 280 participants will be randomly assigned to the Phase 2b trial intervention.

[0265] Intervention group and duration: These tables list the interventions used in the different phases of this clinical trial. For both phases 2a and 2b of the trial, the treatment duration is ● For double-blind, placebo-controlled treatment, the period was 12 weeks, and ● 24 weeks for the entire treatment period (including placebo-controlled treatment).

[0266] As outlined in the "Overall Design" section of this summary, the following participants may be selected at the discretion of the principal investigator: ● Phases 2a and 2b: Standard of Care (SOC) therapy at week 14

[0267] [Table 7] a Based on the results of the interim analysis and the recommendations of the sponsor's Internal Assessment Committee (IAC), higher-dose cohorts may be added during Phase 2a at doses not exceeding 125 mg.

[0268] [Table 8] a The final dose of compound I in Phase 2b will be determined based on the interim analysis from Phase 2a of this study and the recommendations of the sponsor's Investigative Advisory Committee (IAC).

[0269] [Table 9]

[0270] Abbreviations: CDAI = Clinical Disease Activity Index; ED = Early Termination; IAC = Internal Review Committee; PBO = Placebo; QD = Once Daily; SOC = Standard Treatment; SP = Trial Period. a Screening is performed between 1 and ≤42 days after the patient's first visit. b Post-treatment follow-up (V801) is conducted 4 weeks after the last treatment visit or ED; V802 occurs 8 weeks after the last treatment visit or ED. c For definitions of primary endpoints, see Section 3.

[0271] Activity Schedule (SoA) Planned activities for Phase 2a of this trial ● The procedure for visit 1 may be carried out for more than one day, provided that all activities are completed within the acceptable range of visits. ●For early discontinuation occurring before the final visit during the treatment period, please refer to the activities listed under ED in this table.

[0272] [Table 10-1]

[0273] (Continuation of the table above) [Table 10-2]

[0274] (Continuation of the table above) [Table 10-3]

[0275] (Continuation of the table above) [Table 10-4]

[0276] (Continuation of the table above) [Table 10-5]

[0277] (Continuation of the table above) [Table 10-6]

[0278] (Continuation of the table above) [Table 10-7]

[0279] (Continuation of the table above) [Table 10-8]

[0280] Planned activities for Phase 2b of this trial ● The procedure for visit 1 may be carried out for more than one day, provided that all activities are completed within the acceptable range of visits. ●For early discontinuation occurring before the final visit during the treatment period, please refer to the activities listed under ED in this table.

[0281] [Table 11-1]

[0282] (Continuation of the table above) [Table 11-2]

[0283] (Continuation of the table above) [Table 11-3]

[0284] (Continuation of the table above) [Table 11-4]

[0285] (Continuation of the table above) [Table 11-5]

[0286] (Continuation of the table above) [Table 11-6]

[0287] (Continuation of the table above) [Table 11-7]

[0288] (Continuation of the table above) [Table 11-8] Abbreviations: ACTH = adrenocorticotropic hormone; AESI = adverse events for a specific purpose; anti-HBc = hepatitis B core antibody; CKD-EPI = collaborative epidemiological study of chronic kidney disease; C-SSRS = Colombian Suicide Severity Rating Scale; DHEA-S = dehydroepiandrosterone sulfate; ECG = electrocardiogram; ED = early discontinuation; FACIT-F = functional assessment of treatment for chronic diseases - fatigue; HIV = human immunodeficiency virus; ICF = informed consent form; IWRS = interactive web response system; MRI = magnetic resonance imaging; NRS = numerical rating scale; PRO = patient-reported outcome; RA = rheumatoid arthritis; VAS = visual analog scale; WOCBP = women of possible pregnancy.

[0289] Objective, endpoint, and estimation Unless otherwise specified, the objectives and endpoints in this table apply to both Phase 2a and Phase 2b of this study.

[0290] [Table 12-1]

[0291] (Continuation of the table above) [Table 12-2] Abbreviations: ACR = American College of Rheumatology; CDAI = Clinical Disease Activity Index; DAS28-ESR = Disease Activity Score Erythrocyte Sedimentation Rate; DAS28-hsCRP = Disease Activity Score - Highly Sensitive C-Reactive Protein; FACIT-F = Functional Assessment of Chronic Disease Treatment - Fatigue; HAQ-DI = Health Assessment Questionnaire-Based Disability Index; LDA = Low Disease Activity; MRI = Magnetic Resonance Imaging; PaGADA = Patient-Based Assessment of Disease Activity; PhGADA = Physician-Based Assessment of Disease Activity; RAMRIS = Rheumatoid Arthritis Magnetic Resonance Imaging Score; SDAI = Simplified Disease Activity Index; SF-36 = Shortened SF-36 Version 2 Health Survey Acute Form; VAS = Visual Analog Scale.

[0292] Main estimate Phase 2a The main clinical problems addressed are as follows: Assuming no changes to permitted concomitant medications and no violations of restrictions regarding the use of prohibited therapies, and assuming all participants adhere to the study intervention, what is the difference in mean change from baseline at week 12 between compound I and placebo in the target patient population?

[0293] The estimation is described by the following attributes: ●Group: Participants with moderate to severe active RA (see Section 5.1). ● Endpoint: Change from baseline in DAS28-hsCRP ● ICEs related to trial interventions include the use of prohibited drug therapies, changes in permitted concomitant medications, and early termination of the trial or trial intervention. An assumption-based estimation strategy is used; that is, data collected after the first occurrence of an ICE are excluded from the analysis, and the treatment effect is estimated to have occurred assuming that no prohibited drug therapies were used, permitted concomitant medications remained unchanged, and all participants adhered to treatment. ●Population-level summary: Mean difference in change from baseline to week 12 between trial intervention conditions. ● Principle of estimation: Data collected after discontinuation of treatment, initiation of prohibited medications, or change of permitted concomitant medications may not show true efficacy.

[0294] Phase 2b The main clinical problems addressed are as follows: What is the difference between compound I and placebo in the target patient population in achieving a response at week 12, without changing approved concomitant medications, receiving prohibited therapies, or discontinuing the trial intervention?

[0295] The estimation is described by the following attributes: ●Group: Participants with moderate to severe active RA (see Section 5.1). ● Endpoint: ACR50 at week 12 ●ICEs related to the trial intervention include the use of prohibited drug therapies, changes in permitted concomitant medications, and early termination of the trial or trial intervention. A combined strategy is used; that is, participants with ICEs are considered non-responders because they are assumed not to have benefited from the intervention. ●Summary at the group level: Difference in the proportion of participants who achieved a response at week 12 between the trial intervention conditions. ● Principle of estimation: Data collected after treatment discontinuation, initiation of prohibited drug therapy, or change of permitted concomitant medications are classified as treatment failures, as it is assumed that the participant did not benefit from the intervention.

[0296] Secondary estimation Unless otherwise specified, the information in this section applies to both phases of this examination.

[0297] Secondary estimation of category endpoints For secondary objectives with categorized endpoints analyzed by week 12, the clinical questions for the objectives are as follows: What is the difference between compound I and placebo in the target patient population in achieving a response at week 12, without changing approved concomitant medications, receiving prohibited therapies, or discontinuing the trial intervention?

[0298] The estimation is described by the following attributes: ●Group: Participants with moderate to severe active RA (see Section 5.1). ● Endpoints: The following secondary endpoints ○ ACR20 ○ ACR50 (for phase 2a only), and ○ ACR70. ●ICE is explained using the same estimation strategy as the primary estimation for Phase 2b. ●Summary at the group level: Difference in the proportion of participants who achieved a response at week 12 between the trial intervention conditions.

[0299] Secondary estimation for continuous endpoints For secondary objectives with continuous endpoints analyzed up to week 12, the clinical question of the objective is: Assuming no changes to permitted concomitant medications and no violations of restrictions regarding the use of prohibited therapies, and assuming all participants adhere to the study intervention, what is the difference in mean change from baseline at week 12 between compound I and placebo in the target patient population?

[0300] The estimation is described by the following attributes: ●Group: Participants with moderate to severe active RA (see Section 5.1). ● Endpoint: Change from baseline ○ DAS28-hsCRP (Phase 2b only) ○SDAI ○ CDAI ○ ACR component 68 is the number of tender joints. ○ ACR component 66 number of swollen joints ○ ACR component PhGADA_VAS ○ PaGADA_VAS ○ Evaluation of patients with arthritis pain (VAS) ○ Assessment of physical function by patients using HAQ-DI ○ Duration and severity of morning joint stiffness ○ FACIT-F score in week 12 ○ SF-36 domain ○ SF-36 Body Components Summary, and ○ Summary of SF-36 mental components. ●ICE is explained using the same estimation strategy as the primary estimation for Phase 2a. ●Summary at the population level: The difference in mean change from baseline to week 12 between intervention conditions.

[0301] supportive estimate Further details regarding supporting estimates for primary and secondary objectives are provided in SAP.

[0302] Test design Overall design: This study is an adaptive-design, phase 2a / 2b, multicenter, randomized, double-blind trial to evaluate the efficacy and safety of multiple dose levels of compound I in adult participants with moderate to severe active rheumatoid arthritis (RA).

[0303] This table summarizes the key features of the two phases of the test.

[0304] [Table 13] Abbreviations: bDMARD = Biological disease-modifying antirheumatic drugs; csDMARD = Conventional synthetic disease-modifying antirheumatic drugs; tsDMARD = Targeted synthetic disease-modifying antirheumatic drugs. a A history of failure = insufficient response, intolerance, or loss of response.

[0305] Exam period Both Phase 2a and Phase 2b have the following test periods. ●Period I: Screening (1 visit) ●Period II: Double-blind, placebo-controlled treatment ●Period III: Treatment ●Period IV: Post-treatment follow-up (visits 801 and 802)

[0306] For details regarding the duration of the trial period, refer to the schema (Section 1.2) and the SoA (Section 1.3).

[0307] Screening period The criteria for participation in this study are the same for both Phase 2a and Phase 2b of this study. See Sections 5.1 and 5.2.

[0308] Treatment period This table summarizes the key characteristics of the treatment duration for both phases of the study. For the dosage of compound I, see Section 6.1. As described in the SoA, the study intervention is self-administered by participants at home, except for the day of the study visit.

[0309] [Table 14]

[0310] Visit structure Some trial visits have the same numbering for both Phase 2a and Phase 2b. The content of the visits may differ for each phase (see SoA, Section 1.3). Furthermore, the interval between visits differs by 2 p60 hash.

[0311] [Table 15]

[0312] Joint and Safety Evaluator This study included blinded joint and safety assessors (see Sections 6.4 and 8).

[0313] Appropriateness of the test population Patients with rheumatoid arthritis (RA) are treated with the oral csDMARD methotrexate (MTX) alone or in combination with other therapies as first-line treatment (Fraenkel et al. 2021; Smolen et al. 2022). If the therapeutic target is not achieved with the initial csDMARD strategy, treatment modifications often involve the use of a bDMARD containing a TNF inhibitor or a targeted synthetic tsDMARD in combination with a csDMARD (Fraenkel et al. 2021; Smolen et al. 2022).

[0314] Number of placebo-controlled options and treatment groups The double-blind, placebo-controlled design of this study limits potential bias in the investigator's assessment and allows for a clearer interpretation of the active drug's effects compared to placebo.

[0315] The use of multiple active dose levels in this study, as determined by the interim analysis from Phase 2a (Section 9.4), allows for the evaluation of safety and efficacy across a wide dose range and therefore provides information to guide dose selection for future studies.

[0316] Placebo-controlled trials are justified when sound methodological considerations support them and placebo use does not expose research participants to the risk of unacceptable harm. The placebo-controlled trial design was selected to minimize bias in both the investigator and the participants. A randomized, double-blind, placebo-controlled period of approximately three months allows for an objective assessment of the efficacy and safety of compound I in participants with RA. Given the magnitude and variability of placebo responses in RA trials, control for placebo responses is necessary to enable a clear interpretation of drug effects. The placebo-controlled study design used is supported by FDA and EMA guidance for the development of drugs and biological products for RA (FDA 2013; EMA 2017).

[0317] Duration of the follow-up period An 8-week follow-up period is considered acceptable to assess safety and investigate biomarker durability and changes in clinical disease activity achieved during the treatment period.

[0318] Primary endpoints Phase 2a: Change from baseline in DAS28-hsCRP as the primary endpoint. The primary endpoint of this study was the change from baseline at week 12 in DAS28-hsCRP (Sections 3 and 8.1.12), which is a continuous scale that allows for assessment across multiple time points.

[0319] Phase 2b: Percentage of participants who achieved ACR50 at week 12 The ACR50 is widely used in RA clinical trials and remains an approved measure for demonstrating reduced RA disease activity (FDA 2013), and is a suitable primary outcome measure for early dose-ranging studies.

[0320] Independent joint and safety evaluators To prevent potential bias from observed efficacy or laboratory changes, use a "dual-rater" approach to assess efficacy and safety (see Section 8).

[0321] MRI MRI allows for detailed evaluation of synovial joints. MRI features are frequently used as an outcome measure in RA clinical trials. The RA MRI Scoring System (RAMRIS), an outcome measure in rheumatoid arthritis clinical trials (OMERACT), outlines the semi-quantitative scoring of five RA conditions: bone erosion, joint stenosis, synovitis, tenosynovitis, and bone marrow edema in the wrist and metacarpophalangeal joints.

[0322] Both phases of this study will evaluate the efficacy of compound I in reducing inflammation in the joints. Enrolling participants with active synovitis, as determined by MRI, will support the overall evaluation of compound I in reducing inflammation. An exploratory assessment of the change in RAMRIS synovitis score at week 12 will provide an objective measure of inflammation reduction.

[0323] Dosage justification The relationship between dose and efficacy of RIPK1 inhibitors has not been established for rheumatoid arthritis (RA). This study evaluates the effect of multiple doses of compound I on clinical outcomes in participants with moderate to severe active RA.

[0324] The planned dose for Phase 2a of this study is 50 mg QD, and additional doses up to 125 mg QD can be evaluated based on the interim analysis (Section 9.4). The planned doses of compound I for Phase 2b of this study are 25, 50, and 125 mg.

[0325] Phase 2a and 2b doses were selected based on factors such as human safety, tolerability, and PK data from Phase 1 SAD and MAD evaluations, in vitro assays, in vivo pharmacological models in rodents, and nonclinical toxicology. In the Phase 1 clinical trial, single doses up to 1000 mg and multiple doses of 180 mg and 500 mg QDs were evaluated.

[0326] The 25 mg QD dose in humans is predicted to achieve plasma concentrations suitable for RIPK1 inhibition, based on in vitro assays and in vivo pharmacological models. At the highest dose of compound I (125 mg) in this study, the exposure factor (ratio of animal exposure to human exposure) is estimated to be 7 for AUC, based on a 9-month NOAEL of 150 mg / kg.

[0327] For Phase 2b, the number and amount of dose levels will be modified based on the results from the Phase 2a interim analysis or any other relevant data that may become available, but the maximum dose in Phase 2b will not exceed 125 mg.

[0328] Definition of the end of the exam The end of the trial is defined as the last visit date of the final participant. ●If phase 2b is not started, phase 2a or ●If initiated, it will be phase 2b.

[0329] A participant is considered to have completed the exam if they complete the entire duration of the exam, including the final scheduled procedure shown in the SoA.

[0330] Test group Proactive approval of protocol deviations from adoption and registration criteria, also known as protocol abandonment or exemption, is not permitted.

[0331] Inclusion criteria Participants are eligible for inclusion in the study only if they meet all of the following criteria.

[0332] age [1] The person must be 18 years of age or older at the time of signing the informed consent form.

[0333] Gender and contraceptive requirements [2] Male or female. Both women who may become pregnant (WOCBP) and women who are not of pregnancy potential (WNOCBP) can participate in this clinical trial. Participant use of contraceptives should be consistent with local regulations regarding contraception for participants in clinical trials. See Appendix 10.4 for definitions and contraceptive requirements in this protocol.

[0334] body weight [3] BMI of 18-40 kg / m² 2 It is within the range (including both ends).

[0335] Participant types and disease characteristics [4] Having a diagnosis of adult-onset RA in at least three months prior to screening, as defined by the 2010 ACR / EULAR classification criteria (Aletaha (Barton) et al., 2010).

[0336] [5] Having moderate to severe active RA at screening (visit 1) and randomization (visit 2 / baseline), which is defined as having the following: ●Based on the number of 66 joints, ≥6 swollen joints, ● Based on the number of joints (68), ≥ 6 tender joints. Note: The distal interphalangeal joints should be evaluated, but they are not included in the total number used to determine eligibility. If a participant receives corticosteroid treatment according to the exclusion criteria

[29] , the treated joint should be excluded from the joint count.

[0337] [6] Having at least one of the following: ● Positive test results for rheumatoid factor or anti-citrullinated peptide antibodies during screening or ● Previous X-ray images documenting bone erosion of the hand or foot consistent with rheumatoid arthritis (RA).

[0338] [7] Each central laboratory has an hsCRP > 1.2 times ULN at the time of screening.

[0339] [8] Active synovitis in a joint of the hand or wrist of ≥1 at the time of screening, as demonstrated by an MRI synovitis RAMRIS score of ≥1 determined from the central read of the image (φstergaard et al. 2017).

[0340] [9] Current vaccination status assessment in accordance with local or national guidelines (including ACR or EULAR guidelines; ACR 2022, Furer et al., 2020); in particular, having had influenza, pneumonia, SARS-CoV-2, and herpes zoster (see criteria

[34] for timing of vaccination). Note: The principal investigator should document discussions with any potential participants, including decisions regarding vaccination.

[0341]

[10] Having clinical laboratory results within the normal reference range or with an acceptable deviation that were judged by the principal investigator at the time of screening to be clinically insignificant. This table outlines clinical laboratory results that are within the range necessary to be included in this study.

[0342] [Table 16]

[0343] Preceding treatment

[11] A history of failure (insufficient response, intolerance, or loss of response) to at least one csDMARD and one bDMARD or one tsDMARD treatment, which is defined as signs and symptoms of active disease despite receiving these treatments in accordance with local standard care. ● Azathioprin ● Methotrexate ● Hydroxychloroquine ● Chloroquine ● Leflunomide ● Sulfasalazine ●bDMARD, or ●tsDMARD.

[0344] If the dose is stable for ≥28 days prior to the screening MRI, refer to Section 6.9.2 for permitted treatments during the study.

[0345] Note the sites of EU member states: See Section 10.10.1.1 for country-specific modifications to the inclusion criteria

[11] .

[0346] Informed consent

[12] Signed informed consent may be given as set out in Appendix 10.1, Section 10.1.3, including compliance with the requirements and limitations listed in the ICF and this Protocol.

[0347] Exclusion criteria Participants will be excluded from the test if any of the following criteria apply.

[0348] Medical condition

[13] It has class IV RA according to the revised ACR criteria (Hochberg et al. 1992).

[14] Clinically significant ECG abnormalities, including corrected QT interval, Fridericia correction >450 milliseconds for males and >470 milliseconds for females.

[15] A history of further risk factors for torsades de pointe, such as heart failure or hypokalemia, or a family history of long QT syndrome.

[16] Having a clinically relevant abnormal blood pressure or heart rate as determined by the principal investigator.

[17] The presence of one or more significant comorbidities, as determined by the principal investigator, including, but not limited to, the following: ● Poorly controlled diabetes or hypertension ● Chronic kidney disease stage III a or b, IV, or V ●Symptomatic heart failure classified as New York Heart Association Class II, III, or IV ● Myocardial infarction, unstable angina, stroke, or transient ischemic attack within the 12 months prior to randomization. ● Severe chronic lung disease, such as those requiring oxygen therapy. ●Major chronic inflammatory diseases or connective tissue diseases other than rheumatoid arthritis, including, but not limited to, the following: ○ Systemic lupus erythematosus ○ Psoriatic arthritis ○Axial spondylitis, including ankylosing spondylitis and axial spondylitis without radiographic findings. ○Reactive arthritis ○Gout ○ Scleroderma ○Polymyositis ○Dermatomyositis ○ Active fibromyalgia, or Multiple sclerosis.

[18] Having a history of chronic alcohol abuse, IV drug abuse, cannabis use disorder, or illicit drug abuse within the year prior to screening. Note: The use of cannabis is prohibited during participation in this examination, regardless of local laws, or if used for medical purposes (Section 6.9.3). CBD products may be used during testing if they are derived exclusively from hemp. Participants using hemp-based CBD products must take a stable dose for at least 10 days prior to randomization, and must continue taking that stable dose throughout the trial (Section 6.9.2).

[19] Having had the idea of ​​C-SSRS within one month prior to screening, or having any suicidal behavior within three months prior to screening, and having either the idea or suicidal behavior during the screening before randomization.

[20] Diagnosis or history of malignant disease within 5 years prior to baseline, except: ● Basal cell or squamous cell carcinoma of the skin excised without evidence of metastatic disease for 3 years, or ● Cervical carcinoma in situ with no evidence of recurrence within the past 5 years prior to baseline.

[21] Based on serum creatinine levels using the CKD-EPI creatinine formula (2021), eGFR <60 mL / min is present.

[22] Any surgical procedure within 12 weeks prior to screening, or any planned surgical procedure scheduled to be performed during the study, except for minor surgeries requiring local anesthesia or not requiring anesthesia and without complications or sequelae.

[23] Within three months of screening, had any of the following types of infection, or had developed any of these infections prior to randomization visit: ●Serious (requiring hospitalization and / or treatment with IV or equivalent oral antibiotics) ● Opportunistic (as defined in Appendix 10.8) ● Chronic (symptoms, signs, and / or duration of treatment lasting 6 weeks or more) ● Recurrent (including, but not limited to, herpes simplex, herpes zoster, recurrent cellulitis, and chronic osteomyelitis). ○Note: Herpes zoster is considered active and progressing until all the vesicles dry up and form scabs. ○Exception: If the principal investigator determines that a participant with cellulitis or a recurrent, non-serious infection such as herpes simplex or genital herpes without complications does not have an increased risk of complications.

[24] Having any of these infections ●HIV infection ● Current infection by HBV, i.e., HBsAg-positive and / or HBV DNA-positive PCR ●Current infection with HCV, i.e., HCV RNA positive, or ●Active TB.

[25] In accordance with Section 8.2.9, such treatment had or had LTBI that was not treated in a full course of appropriate treatment as defined by the WHO or the U.S. CDC, unless it was ongoing.

[26] At screening or baseline, participants must have a current or recent acute active infection or a fever of 100.5°F (38°C) or higher. For at least 30 days prior to screening, participants must have had symptoms and / or signs of a confirmed or suspected infection and must have completed any appropriate anti-infective treatment. Note: Participants with upper respiratory tract infections, vaginal candidiasis, or oral candidiasis who are being treated symptomatically only and do not require systemic antiinfective therapy may be considered for enrollment if other eligibility criteria are met. Enrollment of participants with local infections without other complications should be discussed with the sponsor's designated medical monitor.

[27] Women who are currently pregnant or breastfeeding, or who are expected to become pregnant or breastfeed at any point during the study or within 28 days after receiving the last dose of the study intervention.

[0349] Previous / Combination Therapy

[28] More than three advanced therapies, including bDMARDs and tsDMARDs, have failed.

[29] You are currently receiving or have received any of these therapies within 28 days prior to the MRI screening.

[0350] [Table 17]

[0351]

[30] You have received any of these treatments prior to the MRI screening, or you are scheduled to receive any of these bioimmunosuppressive treatments during the trial.

[0352] [Table 18] Note: Other bioagents may be permitted after discussion with the clinical trial sponsor.

[0353]

[31] In the investigator's assessment, the patient had not had a primary response (i.e., a response within the first 12 weeks of treatment) to the most recent TNF-α antagonist treatment.

[32] Use of any drug, supplement, or food substance that is a potent CYP3A4 inhibitor or inducer within 14 days prior to the planned use of these drugs at baseline or during the study (see Section 6.9.3).

[33] Plan to receive treatment with a drug that is a sensitive CYP3A substrate or a P-gp substrate with a narrow therapeutic index (see Section 6.9.3).

[34] Patients who have received or intend to receive a live vaccine, including a live attenuated vaccine, within four weeks prior to screening, and whose vaccine is within five half-lives of the last dose of the intervention. exception: ● Non-live or inactivated vaccines received at least two weeks prior to baseline or after the last trial visit. ● Inactivated influenza vaccines, pneumococcal vaccines, SARS-CoV-2 vaccines, and non-live herpes zoster vaccines approved by local regulatory bodies may be administered at any point during the trial.

[35] Either the participant has received the BCG vaccine or treatment within four weeks prior to randomization, or is scheduled to receive the BCG vaccine or treatment during the study, or has received the last dose of the study intervention within the last five half-lives.

[0354] Previous / Current Clinical Trial Experience

[36] Previously, they were enrolled in clinical trials investigating RIPK1 compound I, or any other molecule targeting RIPK1, including Phase 2a of this study, for the treatment of autoimmune or autoinflammatory conditions.

[37] Participated in a clinical trial involving a trial intervention within the past 30 days. If the previous trial intervention had a long half-life, 3 months or 5 half-lives (whichever is longer) should have elapsed prior to screening.

[38] Previously completed or discontinued this examination.

[39] Currently enrolled in any other clinical trial, including any other type of medical research, including any investigational product or any other type of medical research that is deemed scientifically or medically incompatible with this study.

[0355] Other exclusion criteria

[40] Contraindications to MRI; for example. ● Claustrophobia, pacemakers, aneurysm clips, and intraocular metal fragments; or ●IV gadolinium-based contrast agents, but not limited to them, including moderate or severe renal failure or previous allergic reactions to gadolinium-containing contrast agents.

[41] Hypersensitivity to either the active substance or the excipient of compound I was experienced.

[42] Provided more than one unit of blood within four weeks prior to randomization, or intended to provide blood during the study.

[43] Personnel of the research facility directly involved in this study and / or their immediate family members. Immediate family members are defined as spouse, parent, child, or sibling, whether biological or legally adopted.

[44] Lilly employees or employees of third-party organizations involved in the testing must exclude their employees.

[45] The principal investigator or sponsor has determined that, for any reason, the subject may be impairing participant safety or complicating data interpretation, and is therefore inappropriate for inclusion in the study.

[0356] Trial interventions and combination therapies A trial intervention is defined as any clinical trial intervention, marketed product, placebo, or medical device that is administered to / intended to a trial participant in accordance with the trial protocol.

[0357] The administered experimental intervention As described in the Statement of Instructions (SoA), the study intervention will be self-administered by the participant at home, except on the day of the study visit. On the day of the visit, the participant will receive the study invention after collecting a blood sample as specified in the SoA.

[0358] These tables list the interventions used in the different phases of this clinical trial.

[0359] [Table 19] a To ensure that higher dose levels do not exceed a maximum of 125 mg in the cohort, additional doses may be added during Phase 2a based on the results of the interim analysis and the sponsor's IAC recommendation (Section 9.4).

[0360] [Table 20] a The final dose of compound I in Phase 2b will be determined based on the interim analysis from Phase 2a of this study and the recommendations of the sponsor's Investigative Advisory Committee (IAC) (Section 9.4).

[0361] Packaging and labeling The trial intervention will be provided by the sponsor or its designated agent in accordance with current Good Manufacturing Practices. The trial intervention will be marked as compliant with national requirements.

[0362] standard treatment All placebo participants may, at the discretion of the principal investigator, initiate SOC therapy at week 14. SOC therapy includes all csDMARDs and b / tsDMARDs.

[0363] Participants who were randomly assigned to compound I at baseline and did not achieve LDA at week 14 (CDAI ≤ 10) will no longer receive the study intervention and may receive SOC therapy at the discretion of the principal investigator.

[0364] For SOC therapy, the name and administration plan must be recorded.

[0365] Intra-articular joint injection and bursal injection These may be administered at the discretion of the principal investigator, in terms of dosage and interval. If a participant receives an intra-articular injection, the treated joint should be recorded as “not evaluable” in subsequent joint-specific evaluations for the remainder of the study.

[0366] Assignment to trial intervention Assignments to treatment groups within this protocol are determined by computer-generated random sequencing using IWRS. See Section 4.1 for randomization ratios.

[0367] Participants will be stratified by baseline as follows: ●Geographical area: ○ North America Central and South America ○ Europe ○The rest of the world. ● History of failures with bDMARDs or tsDMARDs (intolerance, inadequate response, or loss of response), total number (1, >1), and ● SJC66 increases by more than 20% from screening to baseline compared to less than 20%.

[0368] Blinding Some of the treatment periods for this study will be double-blinded. Blinding will be maintained throughout the conduct of the study, as described in the separate blinded and open-label plans.

[0369] Blinded joint and safety evaluators To minimize bias due to observed efficacy or laboratory variations, a "double-rater" approach is used to evaluate efficacy and safety. See Example 8.

[0370] Emergency open-labeling The IWRS is programmed with a blinding break order. In emergency situations, the principal investigator has sole responsibility to determine whether deblinding of participant intervention assignments can be guaranteed. Participant safety must always be the primary consideration when making such decisions.

[0371] If participant intervention assignments are unblinded, the sponsor must be notified immediately within 24 hours of this occurrence. The date and reason for the blinding violation must be recorded.

[0372] Discontinuation of trial intervention in cases where blinding is not performed. If the principal investigator, the on-site personnel performing the evaluation, or the participant is not blinded, the participant must discontinue the trial intervention (Section 7.1.2).

[0373] Adherence to the trial intervention Participant adherence to the trial intervention will be assessed by counting the tablets returned at each visit.

[0374] A participant will be considered significantly non-compliant if they miss more than 20% of the prescribed dose of the trial intervention during the trial, unless the participant's trial intervention is withheld by the principal investigator for safety reasons. Similarly, a participant will be considered significantly non-compliant if the principal investigator determines that they have taken 20% more of the prescribed dose of the medication during the trial.

[0375] Participants will receive counseling from the study staff as needed regarding the importance of carrying out the study intervention as prescribed.

[0376] The number of tablets dispensed to and taken by each participant must be recorded and adjusted along with the trial intervention and compliance records. The start and end dates of the intervention (including the date of intervention discontinuation) must also be recorded in the CRF.

[0377] Dosage change This protocol does not allow for dose adjustment.

[0378] Continued access to trial interventions after the trial has ended Trial interventions are not available to participants after the completion of the trial unless required by local regulations.

[0379] Previous and concurrent treatments Overall Considerations Participants should consult with the principal investigator or other appropriate trial staff before taking any new medications or supplements during the trial.

[0380] Avoid prescribing additional medications during the trial unless necessary to treat an adverse event (AE) or an ongoing medical condition. Principal investigators should follow local guidelines for managing dyslipidemia.

[0381] As described in Section 7.1.2, if the need arises for other concomitant medications, the intervention or discontinuation of the participant from the trial will be at the discretion of the principal investigator in consultation with the sponsor or nominated participant.

[0382] Clinical drug-drug interaction studies have not yet been conducted using compound I. However, based on in vitro studies, compound I may inhibit drugs metabolized by CYP2C8, CYP2C9, CYP2D6, and CYP3A, and may induce CYP3A5. Compound I may also inhibit drugs that are substrates of the P-gp, BCRP, OATP1B3, OCT1, and OATP2B1 transporters (see IB for further information).

[0383] Information regarding concomitant medications that are prohibited due to potential drug interactions is provided in Section 6.9.3.

[0384] Guidance for prescribing the following medications: The principal investigator should carefully consider the concomitant use of the following BCRP-sensitive substrates while participants are undergoing the study intervention: coumestrol, daidzein, genistein, prazosin, and rosuvastatin.

[0385] Combination therapy data collection Any medications or vaccines, including commercially available or prescription drugs, vitamins, and / or herbal supplements, that a participant is taking at the time of registration or during the study must be recorded along with the following: ● Name of drug, vaccine, or therapy ●Reason for use ● Route of administration, and ● The administration dates, including the start and end dates.

[0386] Test personnel should collect additional medication information, including dosage and frequency, for the following purposes: ● Phase 2a and Phase 2b: Approved RA therapies

[0387] If you have any questions regarding concurrent or prior treatments, you should contact your medical monitor.

[0388] Approved combination drugs Unless otherwise specified, this table outlines the adjunctive therapies permitted during the trial, provided the dose has been stable for at least 28 days prior to MRI screening. These approved adjunctive medications should be maintained stable unless otherwise specified in the table.

[0389] [Table 21]

[0390] Prohibited combination drugs This table outlines the prohibited concomitant medications during the study. Unless otherwise specified, this table applies to both Phase 2a and Phase 2b of this study.

[0391] If any of the prohibited treatments listed here are necessary, the trial intervention should be permanently discontinued (Section 7.1.2).

[0392] [Table 22] Abbreviation: DDI = Drug-Drug Interaction.

[0393] Discontinuation of trial intervention and withdrawal / withdrawal of participants This section explains the reasons for the participants' i-th reason. ● Temporary or permanent discontinuation of the trial intervention (Section 7.1), ●Cancellation from the examination (Cancellation) (Section 7.2).

[0394] The discontinuation of a specific site or the entire trial is treated as part of Appendix 10.1. Furthermore, Appendix 10.1 lists the criteria related to the suspension of enrollment in the trial.

[0395] Unless otherwise specified, the discontinuation criteria apply to both Phase 2a and Phase 2b of this study.

[0396] Interruption of the trial intervention Temporary continuation of the trial intervention Infection-related criteria for temporary suspension of trial interventions

[0397] [Table 23]

[0398] Abnormal liver function test results See Section 7.1.3.

[0399] QTc stop criteria See Section 7.1.4.

[0400] Abnormal hematological test results See Section 7.1.5.

[0401] Permanent continuation of trial intervention If necessary, participants may permanently discontinue the trial intervention. In such cases, participants should discontinue the trial intervention (treatment), remain in the trial, and follow the procedures for all remaining trial visits as indicated in the State of Action (SoA).

[0402] Possible reasons for permanently discontinuing a trial intervention include, but are not limited to, the following: Participant selection: Participants are asked to stop participating in the trial intervention.

[0403] Principal Investigator's Opinion: In the principal investigator's opinion, the participant should be permanently discontinued from the trial intervention for safety reasons.

[0404] Pregnancy: Participants become pregnant (Sections 8.2.6 and 8.3.2).

[0405] Grade of malignancy: Participants develop a grade of malignancy (excluding basal cell or squamous cell carcinoma that is successfully treated).

[0406] HIV: Participants may develop HIV infection.

[0407] Active TB or untreated LTBI: Participants either have active TB or untreated LTBI (Section 8.2.9).

[0408] HBV or HCV: Participants will be tested for HBV DNA or HCV RNA (see sections 8.2.10 and 8.2.11 for details). Note: Prior to discontinuation of any immunomodulatory and / or immunosuppressive therapy, including the trial intervention, participants will be referred, evaluated, and managed by a specialist with expertise in the assessment and management of viral hepatitis. The timing of discontinuation from the trial intervention to initiation of any antiviral therapy for hepatitis will be based on the recommendations of a specialist consulted in conjunction with the principal investigator and aligned with medical guidelines and standard of care.

[0409] Suicidal thoughts and behaviors: Participants ● You answered "yes" to question 4 or question 5 in the "Suicidal Ideation" section of the C-SSRS, or ● The patient answered "yes" to any of the suicidal behaviors listed in the suicidal behavior section of the C-SSRS.

[0410] A psychiatrist or appropriately trained professional may assist in the decision to discontinue the participant.

[0411] Abnormal liver function tests: Section 7.1.3 describes temporary discontinuation of the study drug based on abnormal liver function tests. If liver function tests do not return to baseline after temporary discontinuation of the study drug and no self-limiting non-pharmacological etiology is identified, the study drug will be permanently discontinued.

[0412] QTc termination criteria: See Section 7.1.4.

[0413] Abnormal hematological test results: See Section 7.1.5.

[0414] Use of prohibited concomitant medications: Participants will require treatment with prohibited medications as specified in Section 6.9.3. Permanent discontinuation from the study intervention should be performed before the introduction of prohibited drug therapy.

[0415] Non-compliance: The principal investigator determines that a participant is not complying with the administration of the study drug or any other study procedure.

[0416] Deblinding: As described in Section 6.4, if the principal investigator, blinded site staff, designated person conducting a blinded assessment, or participant is deblinded for the participant's intervention assignment for emergency deblinding, the participant must permanently discontinue the study drug. If there are ethical reasons for the participant to continue the study and continue receiving the study drug, the principal investigator must obtain specific approval from the sponsor's designated medical monitor for the participant to continue.

[0417] Liver Chemotherapy Criteria Discontinuation of the investigational drug based on elevated liver function test results. If one or more of these conditions occur, the investigational drug should be discontinued and strict liver monitoring should be initiated (see Section 8.2.8).

[0418] [Table 24]

[0419] Discontinuation of study drug based on elevated liver function in participants with abnormal baseline liver function tests. In study participants with abnormal baseline liver function tests (ALT, AST, ALP ≥ 1.5 × ULN), if one or more of these conditions occur, the study drug should be discontinued:

[0420] [Table 25]

[0421] Resumption or permanent discontinuation of the investigational drug after elevated liver function tests. Resumption of the study drug should only be considered in consultation with a Lilly-designated medical monitor, and only if liver function tests return to baseline and a self-limiting non-study drug etiology is identified. Otherwise, the study drug should be discontinued.

[0422] QTc stop criteria If clinically significant findings are identified after enrollment (including, but not limited to, changes in the QT interval from baseline corrected using Fridericia's formula [QTcF]), the principal investigator or qualified nominee will determine whether the participant can continue the study intervention and whether any changes in participant management are necessary. This review of ECGs printed at the time of collection must be documented. Any new clinically relevant findings should be reported as adverse events (AEs).

[0423] Hematology Laboratory Standards If one or more of these conditions occur, the trial intervention should be interrupted or terminated.

[0424] [Table 26] Abbreviations: ANC = Absolute Neutrophil Count; WBC = White Blood Cells.

[0425] Test evaluation and procedures The test procedures and their timing are summarized in the Statement of Analysis (SoA).

[0426] Any immediate safety concerns should be discussed with the trial sponsor immediately upon occurrence or recognition, and a decision should be made on whether the participant should continue or discontinue the trial intervention.

[0427] Adherence to test design requirements, including those specified in the SoA, is essential and necessary for conducting the test.

[0428] All screening assessments must be completed and reviewed to ensure that potential participants meet all eligibility criteria. The principal investigator shall record details of all screened participants and maintain a screening log to confirm eligibility or, where applicable, to record the reasons for screening failure.

[0429] Joint and Safety Evaluator As described in Section 6.4, a “double-rater” approach is used to assess efficacy and safety in order to prevent potential bias from observed efficacy or laboratory changes.

[0430] Whenever possible, the same evaluator should conduct a joint assessment of participants throughout the trial to minimize inter-observer variability.

[0431] A backup independent joint evaluator should be identified.

[0432] It is the responsibility of the principal investigator to ensure that all evaluators are qualified in accordance with the protocol specifications, trained to conduct collaborative assessments, and that all training is documented. If an independent evaluator is unavailable, a pre-identified backup evaluator should perform such an assessment.

[0433] When the principal investigator acts as a co-evaluator, they may not have access to or discuss patient-reported assessments, PhGADA_VAS, and safety assessments with the participants. These assessments must be delegated to qualified sub-investigators and recorded in the trial delegation log. The principal investigator remains primarily responsible for monitoring the safety of all participants throughout the trial.

[0434] Joint Evaluation Department qualification Joint evaluators or nominees should be rheumatologists, nurses, medical assistants, or physicians, and skilled joint evaluators. Other qualified individuals may be considered, but must first be approved by the clinical trial sponsor.

[0435] response The joint evaluator is responsible for completing the joint count.

[0436] Co-evaluators must not access or discuss patient-reported assessments, PhGADA_VAS, or safety assessments with participants.

[0437] Access to the exam form Field staff assigned to the role of co-evaluator have access to complete the co-evaluation and co-evaluation certification forms.

[0438] Scribe Field staff assigned to the role of test coordinator have access to complete the collaborative assessment form (which functions as a scribe). If the scribe is used, the collaborative assessors must still perform the collaborative assessment for the participant, review the form entries, and complete the collaborative assessment certification.

[0439] Safety evaluator qualification Safety assessors or designated individuals should be healthcare professionals defined as follows: ● Physician (MD) ●Physician specializing in osteopathy (DO) ● Medical assistant ● Nurse (NP), or ●Registered Nurse (RN).

[0440] Other eligible individuals may be considered in consultation with the sponsor, based on their regionally defined medical roles.

[0441] response The safety assessor is responsible for accessing both safety and effectiveness data and completing PhGADA_VAS.

[0442] Safety assessors are responsible for accessing source documents, laboratory results, and CRFs, and for making treatment decisions based on participants' clinical responses and laboratory parameters.

[0443] Effectiveness evaluation For further distinctions, see Section 3: ● Primary, secondary, and exploratory measures of effectiveness and quality of life, ● Endpoints specific to Phase 2a or Phase 2b.

[0444] Unless otherwise specified, the evaluations listed in this section apply to both Phase 2a and Phase 2b of this study.

[0445] Order of evaluation Assessments reported by patients and clinicians should be completed in the order specified in the State of Assessment (SoA).

[0446] Additional calculations and evaluations In addition to the specific assessments listed in the SoA, effectiveness measurements also include the following calculations and evaluations: ●ACR response ●DAS28-hsCRP ●DAS28-ESR ●SDAI ●CDAI, and ●MRI.

[0447] Comprehensive evaluation of patients with arthritis pain using the VAS scale. The Visual Analog Scale (VAS) for Arthritis Pain is a single-item patient-reported outcome measure used to assess the current severity of pain in patients in relation to rheumatoid arthritis.

[0448] The pain VAS is a continuous scale consisting of horizontal or vertical lines ranging from 0 to 100 mm in length, fixed at both ends by two linguistic descriptors. 0 = No pain, 100 = Worst possible pain.

[0449] Participants are asked to place a line perpendicular to the VAS line at the point representing pain intensity. A higher score indicates a higher pain intensity.

[0450] pain VAS ● Takes less than 1 minute to complete. ● Used as a component of ACR, and ● Should be administered before any clinical evaluation.

[0451] Health Assessment Questionnaire - Disability Index (HAQ-DI) The HAQ-DI is a patient-reported outcome questionnaire commonly used in rheumatoid arthritis to measure disease-related impairment (assessment of physical function). It consists of 20 questions that refer to eight functional domains. ● Dressing / Grooming - 2 items ●Food-3 items ●Hygiene-3 items ●Grip - 3 items ● Occurrence - 2 items ● Walking - 2 items ●Reach - 2 items, and ●Daily activities - 3 items.

[0452] Participants rate the difficulty of the above activities over the past week on a four-item ordinal scale ranging from 0 (no problem) to 3 (unable to perform). In addition, there are four questions asking participants whether they typically require assistance from another person, aid, or device for any of the above activities (Fries et al. 1980, 1982; Fries 1983; Ramey et al. 1996).

[0453] For each domain, the score assigned to that domain is the worst score within that domain. For example, if one question scores 1 and another scores 2, the domain's score will be 2.

[0454] Furthermore, if assistance or devices are used, or if help from another individual is required, the minimum score for that domain is 2. If the domain score is already 2 or higher, no correction is made.

[0455] The scores from the eight domains are summed and divided by eight. The result is the disability index or functional impairment index. A higher score indicates greater limitations in physical function.

[0456] HAQ-DI can be completed in approximately 5 minutes.

[0457] The efficacy, reliability, and susceptibility to change of HAQ-DI have been established in numerous observational and clinical trials (Fries et al. 1980, 1982; Wells et al. 1993; Bruce and Fries 2003).

[0458] HAQ-DI should be administered before any clinical evaluation.

[0459] Comprehensive assessment of patient disease activity (RA) (PaGADA_VAS) PaGADA_VAS is a single-item, patient-reported outcome measure that asks participants how they feel about their RA today.

[0460] PaGADA_VAS is a continuous scale consisting of horizontal or vertical lines with lengths ranging from 0 to 100 mm, with two language descriptors fixed at both ends. 0 = Very good, 100 = Very bad.

[0461] Participants are asked to draw a line perpendicular to the VAS line in terms of RA activity. A higher score indicates a higher level of disease activity (Nikiphorou (Barton) et al. 2016).

[0462] PaGADA_VAS ● Used as a component of ACR, and ● should be administered before any clinical evaluation.

[0463] Shortened version - 36-item health survey acute form (SF-36v2 acute) The SF-36v2 Acute is a patient-reported, subjective, and general health-related quality of life measure consisting of 36 questions covering eight health domains. ●Body function ●Somatic pain ● Role limitations due to physical problems ● Role restrictions due to emotional issues ●General health perception ● Mental health ● Social function, and ●Vitality.

[0464] SF-36 can be scored for the eight health domains named above, as well as two overall summary scores: a physical component summary and a mental component summary (McHorney et al. 1993; Ware et al. 2007).

[0465] The emergency version of SF-36 version 2 uses the recall period from "last week" (Ware and Sherbourne 1992; Maruish 2011).

[0466] Participant responses to each domain were questioned using a Likert scale of varying length, with 3 to 6 response options per item. Each domain was scored by summing the individual items and converting the scores to a scale of 0 to 100, with higher scores indicating better health or function. Two summary scores were derived from scores from eight SF-36v2 acute domains.

[0467] Morning joint stiffness duration PRO The Duration of Joint Stiffness PRO is a single-item participant management scale designed to capture information about the self-reported length of time that participants experienced joint stiffness each day.

[0468] Participants will report the duration of joint stiffness by entering the number of hours and minutes that have occurred up to the present.

[0469] Morning joint stiffness severity NRS The Joint Stiffness Severity NRS is a single-item, participant-managed 11-point horizontal scale that captures the severity of morning joint stiffness using a scale of 0 to 10, where 0 = No joint stiffness, 10 = Extremely severe joint stiffness.

[0470] The overall severity of joint stiffness in participants is indicated by selecting the number that best represents the worst level of joint stiffness on the day of visit.

[0471] Treatment of Chronic Diseases - Functional Assessment of Fatigue (FACIT-F) The FACIT-F scale (Cella 1997) is a 13-item questionnaire that measures the severity of fatigue and its impact on daily activities and function over the past seven days.

[0472] FACIT-F uses a 5-point Likert scale for scoring. The total score ranges from 0 to 52, with higher scores indicating less fatigue.

[0473] Number of tender / swollen joints treated by clinicians (TSJC) (68 / 66) TSJC(68 / 66) managed by clinicians is performed upon hospital visit according to the State of Awareness (SoA).

[0474] The same evaluator should conduct joint evaluations of participants throughout the trial whenever possible to minimize inter-observer variability. See Section 8 for descriptions of joint evaluation, safety evaluation, and scribe.

[0475] Number of tender joints The number of tender joints is determined by examining 68 joints, 34 on each side of the participant's body.

[0476] The 68 joints that are evaluated and classified as having or not having tenderness include the following:

[0477] [Table 27]

[0478] The principal investigator will identify joints that should be excluded from evaluation at each visit. Joints that have been replaced, resected, ankylous, or arthrodetic should be marked as unassessable.

[0479] Joints that received intra-articular corticosteroid injections within four weeks prior to baseline should be excluded from evaluation during the study. The location or list of these prior procedures should be recorded in the participant's source documentation or CRF.

[0480] The number of joints is assessed by scoring the tenderness and passive movement characteristics of specific joints. Participants are asked to report pain in response to these operations, and their spontaneous pain responses are observed. Any positive response to pressure, movement, or both is converted into a single tender vs. non-tender dichotomy.

[0481] Number of swollen joints The number of swollen joints is determined by examining 66 joints, i.e., 33 joints on each side of the participant's body.

[0482] The 66 joints evaluated and classified as swollen or non-swollen are the same as those for tender joints, with the exception of two hip joints.

[0483] Swelling is defined as palpable, fluctuating synovitis of the joint.

[0484] The same method applies to mark replaced, synovectomized, ankylous, or arthrodetic joints, and recently injected joints as unassessable.

[0485] Comprehensive VAS assessment of disease activity by physicians (PhGADA_VAS) PhGADA_VAS is a single-item clinician-patient-reported outcome measure that asks physicians to assess participants' current disease activity using a horizontal VAS scale ranging from 0 to 100 mm. 0 = No disease activity, 100 = Extremely active disease.

[0486] The safety assessor is responsible for completing the PhGADA_VAS after the participant-reported assessments and the clinician-administered TSJC have been completed.

[0487] To ensure consistent PhGADA_VAS throughout the trial, the means should be evaluated by the same physician at every trial visit.

[0488] Actigraphy See Appendix 10.9.

[0489] American College of Rheumatology (ACR) criteria ACR20, ACR50, and ACR70 ACR20, ACR50, and ACR70 are defined as improvements of at least 20%, 50%, and 70% to the ACR core setting.

[0490] The improvement rate of the ACR score is determined by an improvement of at least 20%, 50%, or 70% in the number of TJCs (0-68) and SJCs (0-66), as well as an improvement of at least 20%, 50%, or 70% in at least three of these five assessments. 1. Evaluation of patients using the VAS scale for arthritis pain. 2. PaGADA_VAS 3. PhGADA_VAS 4. HAQ-DI, or 5. Acute-phase reactive substances measured by hsCRP.

[0491] Disease activity score - High-sensitivity C-reactive protein (DAS28-hsCRP) The DAS28-hsCRP measures disease activity in 28 joints using a composite numerical score of the following variables (Vander Cruyssen et al. 2005). ● Number of swollen joints (0-28) ●: Number of the tender joint (0-28) ● hsCRP, and ●PaGADA_VAS.

[0492] Of the 28 joints examined and evaluated for tenderness or lack thereof for the torso junction (TJC) and swelling or lack thereof for the sagging junction (SJC), 14 joints were included on each side of the participant's body (Smolen et al. 1995). ●2 Shoulder ●2 Elbow ●2 Wrist ●10 Metacarpophalangeal joints ●2 Interphalangeal joint of the thumb ●8 Proximal interphalangeal joints, and ●2 Knee.

[0493] DAS28-hsCRP remission is defined as DAS28-hsCRP < 2.6.

[0494] The LDA for DAS28-hsCRP is defined as DAS28-hsCRP ≤ 3.2.

[0495] Disease activity score: Erythrocyte sedimentation rate (DAS28-ESR) The DAS28-ESR measures disease activity in 28 joints using a composite numerical score of the following variables (Vander Cruyssen et al. 2005): ●TJC ●SJC ●ESR, and ●PaGADA VAS.

[0496] For a description of the 28 joints, see Section 8.1.12.

[0497] DAS28-ESR remission is defined as DAS28-ESR < 2.6.

[0498] The DAS28-ESR LDA is defined as DAS28-ESR ≤ 3.2.

[0499] Simple Disease Activity Index (SDAI) The Sustainable Developmental Aptitude Test (SDAI) is a tool for measuring disease activity in rheumatoid arthritis (RA) that integrates scales from physical examination, acute response, patient self-assessment, and assessor assessment (Aletaha and Smolen 2005). The SDAI is calculated by adding together the scores from the following assessments: ● Number of swollen joints (0-28) ● Number of tender joints (0-28) ● hsCRP, mg / dL (0.1~10.0) ●PaGADA VAS (0~100mm), and ●PhGADA VAS (0-100mm).

[0500] For a description of the 28 joints, see Section 8.1.12.

[0501] According to the definition of remission based on the ACR / EULAR index, disease remission is defined as an SDAI score ≤ 3.3 (Felson et al. 2011).

[0502] LDA is defined as an SDAI score of ≤11.

[0503] Clinical Disease Activity Index (CDAI) CDAI is similar to SDAI, but does not use test results, allowing for immediate scoring (Aletaha and Smolen 2005). CDAI is calculated by adding up the scores from the following assessments. ● Number of swollen joints (0-28) ● Number of tender joints (0-28) ●PaGADA VAS (0~100mm), and ●PhGADA VAS (0-100mm).

[0504] For a description of the 28 joints, see Section 8.1.12.

[0505] Remission is defined as a CDAI score of ≤2.8 (Felson et al. 2011).

[0506] LDA is defined as a CDAI score of ≤10.

[0507] MRI imaging and synovitis score MRI scans of the hand and wrist are performed to determine the presence of synovitis, and a synovitis score is determined using the OMERACT RAMRIS system (ostergaard et al. 2017).

[0508] Two evaluators from the central vendor read and score the screening and week 12 scans for each participant in pairs. The evaluators are not informed of the chronological order of the participant's treatments and scans. A detailed chart from the central reading laboratory outlines the MRI procedure, including image acquisition, image analysis, and data transfer.

[0509] Test evaluation Planned timeframes for all safety assessments are provided to the State of Agreement (Section 1.3).

[0510] Physical examination The physical examination is either completed or directed towards symptoms.

[0511] The principal investigator should pay special attention to clinical signs associated with a previous serious illness.

[0512] Complete physical examination A complete physical examination includes an assessment of these areas and bodily systems. ● Peripheral lymph nodes ● Thyroid palpation ●Cardiovascular ●Respiratory system ●Gastrointestinal tract, and ● Nerves.

[0513] Complete physical examination ● Unless clinically demonstrated, exclude pelvic, rectal, and chest examinations. ●Include TB evaluation, where applicable (see "TB Evaluation" below, and Section 8.2.9).

[0514] A complete physical examination may be repeated at the discretion of the principal investigator whenever a participant exhibits physical symptoms.

[0515] Physical assessment of symptoms after screening These assessments are conducted based on the participant's condition and standard treatment.

[0516] TB rating At the time of screening and approximately every three months thereafter, specific physical assessments, whether complete or symptomatic, should include a documented assessment of TB risk factors and signs of active TB, including assessment of peripheral lymph nodes (see Section 8.2.9).

[0517] Height and weight Measure and record your height and weight.

[0518] Vital signs Vital signs include body temperature, blood pressure, and pulse rate. Additional vital signs may be measured at the discretion of the principal investigator.

[0519] Timing of vital sign collection Measurement of vital signs ● After the participants have been seated for at least 5 minutes, ● Before obtaining ECG traces or blood samples for clinical testing.

[0520] electro-cardiogram ECG collections For each participant, a 12-lead digital ECG will be collected in three consecutive scans according to the System of Action (SoA). The ECG must be recorded before blood samples are taken. The patient must lie supine for approximately 5-10 minutes before ECG collection and remain supine during ECG collection, but must be awake.

[0521] ECG (triple) scans are taken at approximately one-minute intervals. Additional ECG scans may be taken at additional times if deemed clinically necessary.

[0522] ECG interpretation The ECG should be interpreted on-site by a qualified physician (principal investigator or qualified designated investigator) as soon as possible after the time of ECG collection, ideally while the participant is still present, to determine whether the participant meets the inclusion criteria at the relevant visit, and if clinically relevant findings are identified, to be interpreted for immediate participant management.

[0523] Participant evaluation after ECG If clinically significant quantitative or qualitative changes from baseline are identified after enrollment, the principal investigator will assess the participant for symptoms (e.g., palpitations, near-syncope, syncope) to determine whether the participant can continue the study (Section 7.1.4). The principal investigator or qualified nominee is responsible for determining whether a change in participant management is necessary and must document a review of one of the replicated ECGs printed at the time of collection.

[0524] Responsibility of the Central ECG Laboratory The digital ECG is electronically transmitted to a central ECG laboratory designated by the sponsor. A cardiologist at the central ECG laboratory then performs a complete overread on one of the replicated ECGs, including all intervals. A report based on the data from this overread is issued to the site of study. For each set of repetitions, the RR and QT intervals and heart rate are determined for the ECG that was not completely overread. This data is not routinely reported to the site of study. All data from the overread is placed in the sponsor's database for analysis and trial reporting purposes. Any clinically significant findings that were not present in the single fully overread ECG but were present in other replicated ECGs are reported to the principal investigator and the sponsor.

[0525] In the central ECG laboratory, if there is a difference in ECG interpretation between the principal investigator (or qualified designated investigator) and a cardiologist, the principal investigator's (or qualified designated investigator's) interpretation will be used for trial entry and immediate participant management. The interpretation from the cardiologist at the central ECG laboratory will be used for data analysis and report preparation.

[0526] The principal investigator (or qualified designated investigator) must document their review of the final overreading ECG report issued by the central ECG laboratory, as well as any warning reports.

[0527] Chest imaging High-quality, locally performed chest X-rays (postoanterior view and, if necessary, lateral view), interpreted and reported by a radiologist or pulmonologist, shall be obtained as specified in the SoA.

[0528] For each participant, chest X-ray films, images, or radiological reports must be available for review by the principal investigator before the participant is randomly assigned to treatment in this study.

[0529] Conditions for using past chest X-rays during screening In the opinion of the principal investigator, if both of these conditions are met, participants are not required to undergo a chest X-ray at the time of screening. ● A chest X-ray was performed within 3 months prior to the initial screening, and ● Documentation of chest X-rays, read by a qualified radiologist or pulmonologist, is sufficient for TB assessment in accordance with local standard treatment. Note: In some jurisdictions, the interval between X-rays must exceed three months. If this is the case, a chest X-ray taken within six months prior to visit 1 may be used.

[0530] Alternative to chest X-ray In consultation with the clinical trial sponsor's medical monitor, the results of a chest CT scan or other imaging test similar to a chest X-ray may be used instead of a chest X-ray for TB evaluation, provided they are performed within the same time window.

[0531] Liver safety monitoring Close monitoring of the liver If one or more of these conditions occur, clinical tests including ALT, AST, ALP, TBL, D.Bil, GGT, and CK (Appendix 10.6) should be repeated within 48 to 72 hours to check for abnormalities and determine whether they are elevated or decreased.

[0532] [Table 28]

[0533] If the abnormality persists or worsens, the principal investigator should consult with a Lilly-designated medical monitor to initiate clinical and laboratory monitoring and an assessment of possible causes of the abnormal liver function test. This assessment should include, at a minimum, a physical examination and a thorough medical history, including symptoms, recent illnesses (e.g., heart failure, systemic infection, hypotension, or seizures), recent travel, concomitant medications (including over-the-counter medications), herbs and dietary supplements, and a history of alcohol and other substance abuse.

[0534] Initially, symptom monitoring and liver biochemical testing should be performed 1-3 times per week, based on the participant's clinical condition and liver biochemical test results. Subsequently, once the participant's clinical condition and test results stabilize, the monitoring frequency can be reduced to once every 1-2 weeks. Monitoring of ALT, AST, TBL, and TBL should continue until levels normalize or return to approximately baseline levels.

[0535] Comprehensive liver assessment If one or more of these conditions occur, a comprehensive evaluation should be conducted to explore possible causes of liver damage.

[0536] [Table 29] a Signs or symptoms of hepatic disorders include severe fatigue, nausea, vomiting, right upper abdominal pain, fever, rash, and / or eosinophilia >5%.

[0537] At a minimum, this assessment should include a physical examination and complete medical history as outlined above, as well as PT-INR testing; testing for viral hepatitis A, B, C, or E; testing for autoimmune hepatitis; and abdominal imaging tests (e.g., ultrasound or CT scan).

[0538] Based on the patient's medical history and initial outcomes, further testing should be considered in consultation with a Lilly-designated medical monitor, including testing for HDV, CMV, EBV, acetaminophen levels, acetaminophen protein adducts, uremic screening, Wilson's disease, blood alcohol levels, urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the participant's clinical status and the investigator's assessment, the investigator should consider referring the participant to a hepatologist or gastroenterologist, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, echocardiography, or liver biopsy.

[0539] Collection of additional liver data (liver safety CRF) in trial participants with abnormal liver function tests during the trial. Additional liver safety data collection in the liver safety CRF should be performed in trial participants who meet one or more of the following five conditions: 1. Elevation of serum ALT to ≥5×ULN in 1.2 or more consecutive blood tests (if baseline ALT <1.5×ULN) ● In participants with baseline ALT ≥ 1.5 × ULN, the threshold is ALT ≥ 3 × baseline in two or more consecutive trials. 2. TBL is elevated to 2×ULN or higher (if baseline TBL < 1.5×ULN) (excluding known cases of Gilbert's syndrome) ● For participants with baseline TBL ≥ 1.5 × ULN, the threshold must be TBL ≥ 2 × baseline. 3. Elevated serum ALP to ≥2×ULN in 3.2 or more consecutive blood tests (if baseline ALP <1.5×ULN) ● In participants with baseline ALP ≥ 1.5 × ULN, the threshold is ALP ≥ 2 × baseline in two or more consecutive blood tests. 4. Liver events that may be considered SAE 5. Discontinuation of the study drug due to liver events. Note: There should be at least two days between two consecutive blood tests.

[0540] Tuberculosis testing and monitoring screening During screening, all participants will be evaluated for risk factors, symptoms, and signs of TB using all of the following: ● A thorough medical history to determine lifelong risk factors for TB infection, TB progression, and symptoms and / or signs of active TB, and ● Previous or active signs of TB as follows: ○A thorough physical examination for signs of active TB, including measurement of body temperature (Section 8.2.2) and evaluation of peripheral lymph nodes (Section 8.2.1), and ○ High-quality chest X-rays (anteroposterior views, including lateral views as needed) interpreted and reported by a radiologist or respiratory physician (Section 8.2.4).

[0541] All participants without a history of LTBI or active TB, and without a history of positive manto TST or positive M tuberculosis (Mycobacterium tuberculosis) IGRA using PPD, must undergo one of the following tests: ●PPD TST, or ● IGRA of M tuberculosis.

[0542] For details on these tests, see Appendix 10.7.

[0543] Diagnosed LTBI Participants diagnosed with LTBI are excluded unless they are candidates for LTBI treatment, have been treated for LTBI, and meet the following criteria (Section 5.2): ● After receiving at least four weeks of appropriate LTBI therapy (following WHO or US CDC guidelines), there is no evidence of hepatotoxicity (ALT / AST must remain ≤2 times ULN) or other treatment intolerance. In this case, participants may be rescreened (Section 5.4) and not excluded due to LTBI. ●Participants must continue and complete appropriate LTBI therapy to remain eligible to continue receiving the trial intervention (Section 7.1.1).

[0544] Monitoring during the test For all participants, TB monitoring will continue throughout the trial. At a minimum, each participant will have the following records at least every three months: ●A thorough medical history to determine any risk factors for TB infection and TB progression, as well as symptoms or signs of active TB, and ● A thorough physical examination for signs of active TB, including temperature measurement and evaluation of peripheral lymph nodes (Sections 8.2.1 and 8.2.2).

[0545] Hepatitis B testing and monitoring As stated in the SoA, initial testing for HBV infection includes HBsAg and anti-HBc. ● If an HbsAg test is positive, the participant will be excluded. ●Participants who test negative for HbsAg and anti-HBc will not be excluded. ●If HbsAg is negative and anti-HBc is positive, further testing for HBV DNA is necessary. ○ If the screening HBV DNA test is positive, the participant will be excluded. ○Participants who test negative for HBV DNA will not be excluded. Repeated HBV DNA testing is required at least every three months during the study period.

[0546] Management of registered participants with detectable HBV DNA during the study If HBV DNA is detected, the trial intervention will be temporarily suspended or permanently terminated, as described in sections 7.1.1 and 7.1.2, and participants should receive appropriate follow-up medical care from a hepatologist or other specialist with expertise in the evaluation and management of viral hepatitis.

[0547] Hepatitis C Test As stated in Section 1.3 of the Statement of Action (SoA), initial testing for HCV infection includes testing for anti-HCV. ●If the anti-HCV test is positive, testing for circulating HCV RNA is necessary. ● Participants will not be excluded if their HCV RNA test is negative. ● If the HCV RNA test is positive, the participant will be excluded (see Section 5.2).

[0548] Participants who have had an HCV infection and have been successfully treated as having a persistent virological response (negative HCV RNA by PCR for at least 24 weeks after completion of treatment) are not excluded on an HCV basis, provided that their HCV RNA test is negative in screening.

[0549] If HCV RNA is detected during the study, the study intervention will be discontinued, and the participant should receive appropriate follow-up medical care from a hepatologist or other specialist with expertise in the evaluation and management of hepatitis (Section 7.1.2).

[0550] Adverse events, serious adverse events, and product complaints The definitions of the following phenomena can be found in Appendix 10.3. ●AE ●SAE, and ●Product complaints (PC)

[0551] These events are reported by the participant (or, where appropriate, by a caregiver, representative, or legally authorized agent of the participant).

[0552] The principal investigator and any qualified designated investigators remain responsible for detecting, documenting, and recording events that meet these definitions, and for tracking events that are serious, are thought to be related to the study intervention or procedure, or cause a participant to discontinue the study intervention or the study (see Section 7).

[0553] Care should be taken to avoid introducing bias when detecting events. Open-ended, non-initiated oral questions from participants are a preferred method for inquiring about the occurrence of events.

[0554] Following the initial report, the principal investigator is required to proactively follow up with each participant during subsequent visits / contacts. All SAEs and special-purpose AESs (as defined in Section 8.3.3) will be followed up until resolved, stabilized, the event is otherwise explained, or the participant fails to follow up (as defined in Section 7.3). For product complaints, the principal investigator is responsible for ensuring that follow-up includes any supplementary investigations as indicated to clarify the nature and / or causality. Further information regarding follow-up procedures is provided in Appendix 10.3.

[0555] Timing and methods for collecting data on events This table describes the timing, deadline, and mechanism for collecting event data.

[0556] [Table 30] a SAEs should not be reported unless the principal investigator believes they may be related to the study treatment or participation in the study.

[0557] Adverse events for special purposes The AESI for this exam includes the following: ● Malignant tumors, and ●Serious infections, including opportunistic infections (Section 8.3.3.1) and tuberculosis (Section 8.2.9 and Appendix 10.7).

[0558] If these AESIs are reported, the site will be prompted to collect additional details and data.

[0559] No assessment is necessary for these AESIs.

[0560] Severe infectious diseases and opportunistic infections Completion of the infection CRF page is required for each infection reported as an AE or SAE. The sponsor identifies infections that are considered opportunistic based on the paper by Winthrop et al., 2015 (Appendix 10.8).

[0561] Pharmacokinetics Venous blood samples are collected to measure the plasma concentration of compound I as specified in SoA.

[0562] If justified and agreed upon between the principal investigator and the sponsor, up to three samples may be collected at further points during the trial.

[0563] Instructions for the collection and handling of biological samples will be provided by the clinical trial sponsor. The actual date and time (24-hour clock time) of each PK sample, as well as the date and time of the trial intervention administration prior to PK sample collection, must be recorded.

[0564] The pharmacokinetic properties (PK) of compound I will be evaluated using the samples. The samples collected for analysis may also be used to evaluate aspects of safety or efficacy related to concerns arising during or after the study.

[0565] Information on intervention concentrations that could be used to blind the trial will not be reported to the research site or to blinded staff.

[0566] bioanalysis Samples will be analyzed in a laboratory approved by the sponsor and stored at a facility designated by the sponsor. The concentration of compound I will be assayed using a valid bioanalytical method. Analysis of samples collected from placebo participants is not planned.

[0567] Sample retention is described in Appendix 10.1, Section 10.1.12. Any remaining samples used for PK are pooled and, if deemed appropriate, may be used for exploratory metabolic or bioanalytical experiments.

[0568] Pharmacokinetics Samples for the evaluation of exploratory PD markers, including hsCRP, ESR, and calprotectin, will be collected at the time specified in Section 1.3 of the SoA.

[0569] Sample retention is described in Appendix 10.1, Section 10.1.12.

[0570] biomarkers Blood samples are collected for exploratory biomarker studies (Appendix 10.2).

[0571] The visit and time for collecting biomarker samples are specified in Section 1.3 of the Statement of Instructions (SoA).

[0572] The sample can be stored and analyzed for research purposes related to drug targets, disease processes, disease states, mechanisms of action of compound I, or research methods, or when validating diagnostic tools or assays related to rheumatoid arthritis.

[0573] Biomarker studies are conducted to address issues related to drug dynamics, target involvement, disease progression (PD), mechanism of action, variability in participant responses (including safety), and their relevance to clinical outcomes. Sample collection is incorporated into clinical trials to allow for the examination of these issues through the measurement of biomolecules, including DNA, RNA, proteins, lipids, and other cellular components.

[0574] All samples will be coded with participant numbers. These samples and any generated data can only be linked to participants by on-site staff at the research site.

[0575] The samples will be kept at a facility selected by the clinical trial sponsor or its designated participant. The maximum retention period is specified in Appendix 10.1, Section 10.1.12.

[0576] Statistical considerations The statistical analysis plan was completed before deblinding and includes a more technical and detailed description of the statistical analysis described in this section. This section is a summary of the planned statistical analysis of the most important endpoints, including the primary endpoint and major secondary endpoints.

[0577] statistical process Phase 2a The primary objective is to demonstrate that compound I is superior to placebo in the mean change from baseline in DAS28-hsCRP at week 12. Therefore, the null hypothesis tested for the primary estimate is: As measured by the mean change in DAS28-hsCRP from baseline to week 12, there was no difference between compound I and placebo in participants with moderate to severe active RA.

[0578] Phase 2b The primary objective is to demonstrate that compound I is superior to placebo in achieving ACR50 at week 12. Therefore, the null hypothesis tested for the primary estimate is: As measured by the percentage of trial participants who achieved ACR50 at week 12, there was no difference between compound I and placebo in achieving ACR50 in participants with moderate to severe active RA.

[0579] Multiplicity adjustment Adjustments for multiple comparisons will not be used in the analysis of this study.

[0580] Analysis set The following groups are defined for the purpose of this study.

[0581] [Table 31]

[0582] Efficacy analyses will be conducted on the mITT population unless otherwise specified, and will combine efficacy data collected in Phase 2a and Phase 2b as appropriate. If deemed necessary, separate efficacy analyses by phase may be provided for the mITT population. Safety summaries will be provided for the safety population by phase and treatment duration. More detailed population definitions will be provided to the SAP.

[0583] statistical analysis Overall Considerations The statistical analysis of this study is the responsibility of the sponsor or its nominee. A detailed SAP describing the statistical methodology will be developed by the sponsor or its nominee.

[0584] The handling of missing, unused, and false data will be proactively addressed, where appropriate, within the statistical methods described in the protocol and SAP. Adjustments to the planned analysis will be described in the final CSR.

[0585] Efficacy and safety data will be analyzed and, where appropriate, summarized by phase and treatment duration. See Section 4.1 for details regarding the phases and duration of the trial.

[0586] Efficacy analyses are performed on the mITT population unless otherwise specified. Safety analyses are performed on the safety population.

[0587] For the Phase 2b efficacy analysis in Trial Period II, Phase 2a efficacy data collected during Trial Period II will be combined as appropriate to support the Phase 2b analysis. Further details are provided in SAP.

[0588] The baseline for each treatment period is defined as the day of the initial trial intervention or the last non-missing assessment prior to it. Any assessments collected after the initial medication are defined as post-baseline for the treatment period. Change from baseline is calculated by subtracting the baseline value from the value at the visit of interest. If the baseline value or the value at the visit is missing for a particular variable, the change from baseline is defined as missing.

[0589] Summary statistics for continuous variables may include the mean, standard deviation, median, and minimum and maximum values.

[0590] Categorical variables are presented as numbers and percentages. Unless otherwise specified, variables are analyzed on the original scale to which they are measured.

[0591] Unless a non-parametric analysis method, such as rank-based analysis, is more suitable, a parametric approach will be used by default for statistical analysis.

[0592] Further exploratory analysis of the data will be conducted if deemed appropriate.

[0593] Bipartite responder endpoints, including the primary endpoint, are analyzed using logistic regression models with treatment group, baseline disease activity, and stratification factors as covariates. Odds ratios and p-values ​​based on odds ratios are reported. 95% confidence intervals (CIs) of mean differences are also reported without adjustment for covariates. Missing data are imputed using non-responder imputation.

[0594] Treatment comparisons of sequential efficacy endpoints with multiple post-baseline time points are analyzed using MMRM analysis. The MMRM model includes the following: ●Treatment ●Stratification factors ● Baseline value ●The interaction between hospital visits and treatment at each visit in the model as fixed factors, and ● Participants as random factors.

[0595] The covariance structure used to model within-participant errors is unstructured. If the unstructured covariance matrix results in a lack of convergence, a heterogeneous Teplitz covariance structure, followed by a heterogeneous autoregressive covariance structure, is used.

[0596] The degrees of freedom in the denominator are estimated using the Kenward-Roger method. The type III sum of squared mean values ​​is used for statistical comparison. The 95% confidence interval is also reported. Missing data are treated as missing under random assumption. No additional imputation methods are applied to the MMRM analysis.

[0597] Where appropriate, treatment comparisons of continuous efficacy endpoints are analyzed using ANCOVA modeled with treatment group, stratification factor, and baseline values ​​as covariates. Type III sums of squares for mean LS are used for statistical comparisons between treatment groups. Mean LS differences, standard errors, p-values, and 95% CIs are also reported unless otherwise specified. Missing data imputation for ANCOVA models is carried over from the last observation.

[0598] For the Phase 2b trial analysis, dose-response modeling will be performed for primary purposes to assist in dose selection decisions. Further details are provided in the SAP.

[0599] Any changes to the data analysis methods or imputation methods described in the protocol require correction only if they alter the key features of the protocol. Other changes to the data analysis methods described in the protocol, and the justifications for making such changes, are described in SAP and CSR. Additional exploratory analysis of data may be performed as deemed appropriate.

[0600] Key endpoints / estimated analysis Phase 2a The primary endpoint is the change in DAS28-hsCRP from baseline to week 12 in the compound I treatment group compared to placebo; this is analyzed using the MMRM model. The model includes treatment, stratification factors, baseline values, visits, and treatment interactions at each visit as fixed factors, and participants as a random factor. See Section 9.3.1 for details of the methods.

[0601] Hypothetical estimation strategies are proposed for intervention events, including discontinuation of the trial intervention, taking prohibited medications, and changes in permitted combination therapies. Likelihood-based methods under missing data in a randomization assumption are used to handle missing data.

[0602] Phase 2b The primary endpoint is the proportion of participants who achieved ACR50 at week 12 in the compound I treatment group compared to placebo; this is analyzed using logistic regression adjusted for stratification factors and baseline disease activity. Baseline DAS28-hsCRP score is used as the baseline variable. See Section 9.3.1 for details of the method used to test the difference between each active treatment group and placebo.

[0603] Relevant data collected in Phase 2a will be combined with Phase 2b data for analysis.

[0604] For other ICEs, a composite strategy is proposed, including discontinuation of the trial intervention, taking prohibited medications, and modification of permitted combination therapies. Participants will be considered non-responders for visits following the occurrence of these ICEs. If data is unavailable, non-responder supplements will be used.

[0605] Secondary endpoint analysis Secondary efficacy and health outcome endpoints at week 12 will be analyzed using the statistical analysis methods described in Section 9.3.1.

[0606] Summary statistics for secondary efficacy endpoints at week 24 are provided as described in Section 9.3.1.

[0607] Further details will be provided to SAP.

[0608] Pharmacokinetics / Pharmacodynamics The plasma concentrations of compound I are presented graphically and descriptively summarized. Where guaranteed and based on data availability, the exposure-response relationship between plasma compound I concentrations and efficacy endpoints and / or safety endpoints can be investigated. Model-based approaches may be implemented to estimate PK or PD parameters.

[0609] Exploratory analysis Exploratory analysis may be further described in SAP before it is terminated due to database locking.

[0610] Safety analysis Safety analysis is assessed by evaluating exposure, adverse events (AEs), laboratory analytes, vital signs, and adverse events for specific purposes.

[0611] The duration of exposure to the treatment during the treatment period is calculated for each participant and summarized by treatment group.

[0612] AEs are coded according to MedDRA and summarized by system organ class, preferred term, severity, and relationship to the trial intervention. All AEs, including pre-existing conditions, are listed by participant, visit, preferred duration, treatment group, severity, and relationship to treatment.

[0613] A TEAE is defined as the first event to occur or worsen in severity after baseline. Baseline is defined as all pre-existing conditions recorded at visit 1 and any AEs recorded prior to the first dose of the study intervention (i.e., recorded during the interval between visits 1 and 2, and with the time of onset prior to the first dose of the study intervention). The treatment duration is used as the post-baseline period for analysis. For sex-specific events, the denominator and percentage calculations include only participants from a given sex.

[0614] Summarize the number and percentage of participants who reported TEAEs, TEAEs by maximum severity, deaths, SAEs, TEAEs related to trial interventions, treatment discontinuation due to AEs, and AESIs. Summarize TEAEs (all by maximum severity), SAEs including deaths, and AEs leading to treatment discontinuation, and analyze them using MedDRA system organ classes and preferred terminology.

[0615] Treatment-related TEAEs (i.e., TEAEs related to the trial intervention) are defined as events indicated by the principal investigator on the CRF as being treatment-related.

[0616] AESI or specific safety topics are identified by standardized MedDRA queries or sponsor-defined MedDRA preferred term lists.

[0617] This section summarizes follow-up emergency adverse events (AEs), serious adverse events (SAEs) including death, and AEs leading to trial discontinuation. All AEs, including pre-existing conditions, are listed by participant, hospital visit, favorable duration, treatment group, severity, and relationship to treatment.

[0618] Other analyses Subgroup analysis Subgroup summaries are provided. Subgroup analyses can be performed for the primary endpoint (Phase 2a: Change from baseline in DAS28-hsCRP; Phase 2b: Response rate in ACR50 at week 12); subgroups that may be evaluated include prior use of RA treatment, sex, race, geographical area, and duration of disease.

[0619] A summary and / or a detailed explanation of the statistical analysis will be provided to SAP.

[0620] interim analysis The analysis of the primary database lock for phases 2a and 2b will be performed as described in Section 9.3 once all participants in each phase have completed their 12-week visit or have discontinued the trial intervention.

[0621] Potential pre-specified interim analysis Any of the prescribed interim analyses may be conducted at the discretion of the clinical trial sponsor.

[0622] Phase 2a: The first and second interim analyses prior to the primary database lock analysis may be conducted when approximately 30%–50% and 50%–70% of participants have completed week 12 or discontinued the trial intervention, respectively. The purpose of the interim analyses is to support planning activities related to the Compound I clinical development program.

[0623] A cohort with higher dose levels, not exceeding 125 mg, may be added during Phase 2a based on the results of the interim analysis and the recommendations of the sponsor's IAC. The therapeutic dose of compound I in Phase 2b may be based on the results of the interim analysis and the recommendations of the sponsor's IAC (Section 10.1.5).

[0624] The Phase 2a interim analysis may assess measures of safety, pharmacokinetics, and / or efficacy. No adjustment for Type I errors is performed.

[0625] Phase 2b: The first and second interim analyses prior to the primary database lock analysis may be conducted when approximately 30%–50% and 50%–70% of participants have completed week 12 or discontinued the trial intervention, respectively. The purpose of the interim analyses is to support planning activities related to the Compound I clinical development program. Phase 2b interim analyses may assess measures of safety, PK, and / or efficacy. No adjustment for Type I errors is performed.

[0626] The relevant Phase 2a data will be used for the preliminary analysis in Phase 2b.

[0627] Other interim analyses may be conducted at the discretion of the sponsor. All interim analyses are used to support planning activities related to the clinical development program.

[0628] Evaluation of unblinded interim data The evaluation of unblinded interim data will be conducted by an IAC (Investigational Assessment Center) consisting of a limited number of pre-designated team members who do not have direct field contact or responsibility for data entry or verification (see Section 10.1.5). Only the IAC is permitted to evaluate the unblinded interim efficacy and safety analysis. The trial site will only receive information about the interim results if it is necessary for the safety of the participants.

[0629] Prior to the provisional or final database lock, a limited number of pre-identified individuals may gain access to unblinded data to initiate the final population PK / PD model development process for provisional or final analysis.

[0630] To minimize bias, SAP and PK / PD analysis plans are finalized and approved before any deblinding.

[0631] Details of deblinding will be specified in a separate deblinding document. Information that may allow deblinding of the study during the analysis will not be reported to the study site or the blinded study team until a pre-specified milestone for deblinding the study results is reached. The study site will only receive information about interim results if it is necessary for participant safety.

[0632] Determining sample size: Phase 2a Approximately 100 participants will be randomly assigned in a 2:1 ratio to receive either compound I 50 mg or placebo. All randomly assigned participants in the mITT population are considered evaluable.

[0633] The power calculation for the second phase (a) of the test assumes the following: ●At week 12, the compound I 50mg group had a sample size of approximately 67 participants, while the placebo group had a sample size of approximately 33 participants. ●The change in DAS28-hsCRP from baseline for the Compound I 50 mg group and the placebo group was -1.80 and -0.85, respectively, and the standard deviation is assumed to be equal to 1.25. ●Power is calculated using a two-tailed test with an error rate of α = 0.05.

[0634] Based on these assumptions, the power to reject the null hypothesis is 89%.

[0635] Additional cohorts in Phase 2a For the additional cohort, up to approximately 100 participants can be randomly assigned in a 2:1 ratio to a cohort with higher dose levels of compound I (not exceeding 125 mg) and to a placebo. All randomly assigned participants in the mITT population are considered evaluable. Participants assigned to the placebo group in the previous cohort are included.

[0636] The power calculations for the additional cohort in the Phase 2a portion of the trial assume the following: ●At the end of the trial, 50, 75, and 100 patients will be further randomized. ●The sample size of approximately 33 participants assigned to the placebo group in the previous cohort is pooled for calculation purposes. ●The change in DAS28-hsCRP from baseline for the high-dose compound I group and the placebo group was -1.80 and -0.85, respectively, with a standard deviation of 1.25. ●Power is calculated using a two-tailed test with an error rate of α = 0.05.

[0637] The power to reject the null hypothesis for treatment groups with additional sample sizes equal to 50, 75, and 100 is 84%, 94%, and 97%, respectively.

[0638] Phase 2b Approximately 280 participants will be randomly assigned to one of the following four treatment groups in a ratio of 2:1:2:2. ● Compound I of 125 mg QD ● Compound I of 50 mg QD ● Compound I in 25 mg QD, or ● Placebo.

[0639] All randomly assigned participants in the mITT population are considered evaluable.

[0640] The power calculation for the Phase 2b test assumes the following: ●At week 12, the 125 mg dose of Compound I, the 25 mg dose of Compound I, and the placebo group each had a sample size of approximately 80 participants, while the 50 mg dose of Compound I had a sample size of approximately 40 participants. ●To simplify power calculations, we assume that all three Compound I treatment groups have the same therapeutic effect. ●The true placebo response rate in ACR50 at week 12 is estimated to be approximately 10%, and the true treatment response rate in ACR50 at week 12 is estimated to be approximately 32%. ●Power is calculated using a pairwise two-tailed test with an error rate α = 0.05.

[0641] Considering these assumptions, the power to reject the null hypothesis for compound I treatment groups with sample sizes of 40 and 80 is 82% and 94%, respectively, compared to the placebo group with a sample size of 80.

[0642] Abbreviations and Definitions [Table 32-1]

[0643] (Continuation of the table above) [Table 32-2]

[0644] (Continuation of the table above) [Table 32-3]

[0645] (Continuation of the table above) [Table 32-4]

[0646] (Continuation of the table above) [Table 32-5]

[0647] Example 5 Protocol overview: A Phase 2 randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of compound I in adults with moderate to severe plaque psoriasis.

[0648] Simple title: A study to investigate the efficacy and safety of oral administration of compound I compared to placebo in adult participants aged 18 to 75 years with moderate to severe plaque psoriasis.

[0649] basis This study aims to investigate the effect of compound I on clinical outcomes in participants with moderate to severe psoriasis vulgaris. This is a Phase 1, Phase 2 trial, and the data from this study will inform the decision on the clinical development of compound I.

[0650] Objective, endpoint, and estimation: [Table 33] Abbreviations: DLQI = Dermatological Quality of Life Index; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% improvement in PASI from baseline; PASI 90 = 90% improvement in PASI from baseline; PASI 100 = 100% improvement in PASI from baseline; PatGA = Patient Assessment of Psoriasis; PSS = Psoriasis Symptom Scale; sPGA = Physician's Static Assessment.

[0651] Estimate The main clinical problem of the objective If a participant discontinues the trial intervention due to lack of efficacy or adverse events, or uses a prohibited drug therapy, and is considered a non-responder, what is the difference in PASI 75 after 12 weeks of intervention between compound I and placebo in adult participants with moderate to severe plaque psoriasis?

[0652] overview screening All participants involved will sign the appropriate informed consent document before completing any procedure.

[0653] The principal investigator will review symptoms, risk factors, and other non-invasive inclusion and exclusion criteria before any invasive procedure. If the participant is deemed eligible after this review, the site will perform the invasive procedure to confirm eligibility.

[0654] Double-blind treatment and evaluation period This is a typical series of events that occur during the treatment and evaluation period. ● Complete baseline procedures and sample collection. ● Randomize participants into the intervention group. ● Participants will undergo a trial intervention. ● Complete all efficacy evaluations, safety monitoring, and post-administration sample collection.

[0655] Post-treatment follow-up A post-treatment follow-up evaluation will be conducted 4 weeks after the last dose to assess the clinical status and adverse events (AEs).

[0656] Number of participants Approximately 125 participants were screened, resulting in approximately 105 participants who were randomly assigned to test the intervention.

[0657] Intervention group and duration: There are three intervention groups: compound I 50 mg, compound I 125 mg, and placebo.

[0658] The medication is administered once a day (QD).

[0659] Data monitoring committee: Yes The internal evaluation committee will review the provisional efficacy and safety data in an unblinded format.

[0660] [Table 34] Abbreviations: ED=early discontinuation visit; QD=once a day; V=visit; W=weeks.

[0661] Activity Schedule (SoA) [Table 35-1]

[0662] (Continuation of the table above) [Table 35-2]

[0663] (Continuation of the table above) [Table 35-3]

[0664] (Continuation of the table above) [Table 35-4]

[0665] (Continuation of the table above) [Table 35-5] Abbreviations: antiHBc = hepatitis B core antibody; C-SSRS = Colombia Suicide Severity Rating Scale; CKD-EPI = Chronic Renal Disease-Lithemia Coordination Formula; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HBsAg = hepatitis B surface antigen; IL-19 = interleukin-19; IWRS = interactive web response system.

[0666] Objective, endpoint, and estimation [Table 36] Abbreviations: DLQI = Dermatological Quality of Life Index; IL-19 = Interleukin-19; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% improvement in PASI from baseline; PASI 90 = 90% improvement in PASI from baseline; PASI 100 = 100% improvement in PASI from baseline; PatGA = Patient Assessment of Psoriasis; PSS = Psoriasis Symptom Scale; PSSI = Psoriasis Scalp Severity Index; sPGA = Physician's Static Overall Assessment.

[0667] Estimate The main clinical questions of the objective The main clinical problem of the objective If a participant discontinues the trial intervention due to lack of efficacy or adverse events, or uses a prohibited drug therapy, and is considered a non-responder, what is the difference in PASI 75 after 12 weeks of intervention between compound I and placebo in adult participants with moderate to severe plaque psoriasis?

[0668] Basis for estimation This estimation assumes that if a participant discontinues treatment due to adverse events (AEs) or lack of efficacy, the burden of treatment outweighs the benefits. It also assumes that if a participant violates concomitant medication rules, the participant did not receive sufficient benefit from the treatment. Therefore, being a responder, or demonstrating clinical improvement, requires a positive response, completion of treatment, and non-violation of concomitant medication rules.

[0669] Estimated attributes This table describes the estimated attributes.

[0670] [Table 37] Abbreviations: DLQI = Dermatological Quality of Life Index; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% improvement in PASI from baseline; PASI 90 = 90% improvement in PASI from baseline; PASI 100 = 100% improvement in PASI from baseline; PatGA = Patient Assessment of Psoriasis; PSS = Psoriasis Symptom Scale; PSSI = Psoriasis Scalp Severity Index; sPGA = Physician's Static Assessment.

[0671] Test design Overall design: This is a phase 2 randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of compound I in adults with moderate to severe plaque psoriasis.

[0672] This is a 12-week trial with a follow-up visit four weeks after the last dose of the intervention.

[0673] There are three intervention groups: compound I 50 mg, compound I 125 mg, and placebo.

[0674] Medication administration is QD.

[0675] Further participants may be added at the discretion of the sponsor to evaluate different dose levels and treatment durations, and to further test safety, efficacy, and other parameters outlined in the State of Analysis (SOA). If these changes occur, the protocol will be modified and submitted to the regulatory authority and the IRB. Modifications to the trial will be considered on-site before implementation.

[0676] Design Overview screening All participants involved will sign the appropriate informed consent document before completing any procedure.

[0677] The principal investigator will review symptoms, risk factors, and other non-invasive inclusion and exclusion criteria before any invasive procedure. If the participant is deemed eligible after this review, the site will perform the invasive procedure to confirm eligibility.

[0678] Double-blind treatment and evaluation period This is a typical series of events that occur during the treatment and evaluation period. ● Complete baseline procedures and sample collection. ● Randomize participants into the intervention group. ● Participants will undergo a trial intervention. ● Complete all efficacy evaluations, safety monitoring, and post-administration sample collection.

[0679] Post-treatment follow-up To assess the clinical status and for adverse events (AEs), a post-treatment follow-up evaluation will be conducted 4 weeks after the last dose.

[0680] Scientific basis for test design Primary endpoints PASI 75 is commonly used as the primary endpoint in clinical trials for moderate to severe plaque psoriasis.

[0681] Overall design: The 12-week treatment period is based on toxicological results from the previous 3 months. This timeframe also allows for observation of the effectiveness of the treatment for psoriasis.

[0682] A follow-up four weeks after the last dose is designed to capture any additional safety signals and assess the time to potential relapse.

[0683] A placebo is selected as the control treatment to evaluate whether the observed effect is related to the treatment or simply reflects the test conditions. A double-blind, randomized, placebo-controlled design minimizes bias in safety and tolerability assessments and allows for a more robust comparison between compound I dose and placebo.

[0684] Definition of the end of the exam The end of the trial is defined as the date of the last scheduled procedure indicated in the SoA for the last participant in the trial.

[0685] A participant is considered to have completed the exam if they complete the entire duration of the exam, including the final scheduled procedure shown in the SoA.

[0686] Test group Proactive approval of protocol deviations from adoption and registration criteria, also known as protocol abandonment or exemption, is not permitted.

[0687] Inclusion criteria Participants are eligible for inclusion in the study only if they meet all of the following criteria.

[0688] age 1. At the time of signing the informed consent form, the patient must be between 18 and 75 years of age (inclusive).

[0689] Gender and contraceptive requirements 2. The man agrees to use a highly effective / effective method of contraception, or the woman is not likely to become pregnant.

[0690] The use of contraceptives by participants should be consistent with local regulations regarding contraception for those participating in clinical trials.

[0691] The definition of participants in this study and the contraceptive requirements are provided in Section 10.4.

[0692] Participant types and disease characteristics 3. Participants who, based on a confirmed diagnosis of chronic plaque psoriasis by the principal investigator using these criteria, had moderate to severe chronic plaque psoriasis for at least 6 months prior to baseline. a. Psoriasis vulgaris with ≥10% body surface area (BSA) and absolute psoriasis area and severity index (PASI) score ≥12 in affected skin at screening visit 1 and randomization / baseline visit 2. b. A static physician comprehensive assessment (sPGA) score of 3 or higher at both the first and second visits.

[0693] Test Procedure 4. I am willing to undergo and can undergo punch biopsy. 5. Has sufficient venous access to allow blood sampling. 6. Able to swallow oral medications. 7. The candidate is trustworthy, willing to make time for themselves during the exam period, and willing to follow the exam procedures.

[0694] body weight 8.18~40 kg / m 2 Having a body mass index (BMI) within the range (including both ends).

[0695] Informed consent 9. The ability to sign the informed consent as described in Appendix 10.1, including compliance with the informed consent form (ICF) and the requirements and limitations listed in this protocol.

[0696] Clinical test results 10. The clinical laboratory results must be within the normal reference range or have an acceptable deviation, and must be judged by the principal investigator as not clinically significant. This table outlines the clinical laboratory results that are within the range necessary for inclusion in this study.

[0697] [Table 38]

[0698] Exclusion criteria Participants will be excluded from the test if any of the following criteria apply.

[0699] Medical condition 11. According to the principal investigator's assessment, the patient did not have a primary response (response within the first 12 weeks of treatment) to the most recent TNF-α antagonist treatment. 12. Having clinically significant psoriatic redness during the 12 weeks prior to baseline. 13. Having any other skin condition, other than psoriasis vulgaris, that could affect the interpretation of the data, including, but not limited to, scleroderma, eczema, drug-induced psoriasis, guttate psoriasis, pustular psoriasis, parapsoriasis, or skin as determined by the principal investigator. 14. Diagnosis of an immune-mediated condition generally associated with psoriasis requiring current systemic (oral, subcutaneous, or intravenous) immunosuppressant therapy (including corticosteroids and biologics) in the participant. 15. Manifestation of symptoms of other autoimmune diseases, such as systemic lupus erythematosus.

[0700] Infectious diseases and infectious illnesses 16. Currently or recently have an acute active infection. ● From 30 days prior to screening until randomization / baseline visit, participants must not have any significant symptoms, including a fever of 100.5°F (38°C) or higher. ● From 60 days prior to screening until randomization / baseline visit, participants must be free of signs of confirmed or suspected infection and have completed any appropriate anti-infective treatment. 17. Had any of these types of infection within 3 months prior to screening and before randomization / baseline visit. ●Severity: Requires hospitalization or treatment with intravenous or equivalent oral antibiotics. ● Opportunistic: As defined by Winthrop et al., 2015 (see Section 10.8) ● Chronic: Symptoms, signs, or duration of treatment lasting 6 weeks or more ●Recurrent: Includes, but is not limited to, herpes simplex, herpes zoster, recurrent cell inflammation, and chronic osteomyelitis. ○Herpes zoster is considered active and continues until all vesicles dry and form a crust. Participants with recurrent, mild, and uncomplicated oral herpes alone, or genital herpes, or both, may be discussed with the sponsor's designated medical monitor and may be considered for enrollment if other eligibility criteria are met. 18. Has a human immunodeficiency virus (HIV) infection. 19. Current infection with hepatitis B virus (HBV) is positive for hepatitis B surface antigen (HBsAg) and / or PCR positive for HBV DNA (see Section 8.2.7). 20. Current hepatitis C virus (HCV) infections are HCV RNA positive (see Section 8.2.7). 21. Having or having had active tuberculosis (TB) (see Section 8.2.8). 22. Having or having had latent TB infection (LTBI) that has not been treated with a full course of appropriate treatment as defined by the World Health Organization (WHO) or the U.S. Centers for Disease Control and Prevention (CDC), unless such treatment is completed (see Section 8.2.8).

[0701] Other medical conditions: 23. Clinically significant ECG abnormalities, including a corrected QT interval greater than 450 milliseconds in men and greater than 470 milliseconds in women, and correction for Fridericia. 24. A history of further risk factors for Torsades de Pointe, such as heart failure or hypokalemia, or a family history of long QT syndrome. 25. The patient has clinically relevant abnormal blood pressure (BP) or heart rate (HR) as determined by the principal investigator. 26. In the opinion of the principal investigator, any participant has an unstable or uncontrolled illness, including but not limited to cerebrovascular, cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorder, congestive heart failure, multiple sclerosis, or abnormal laboratory values ​​at screening, which could affect the safety of the participant in the study or interfere with the interpretation of the data. 27. Diagnosis or history of malignant disease within 5 years prior to baseline. exception a. Basal cell or squamous cell carcinoma of skin excised without evidence of metastatic disease for 3 years. b. Cervical carcinoma in situ with no evidence of recurrence within the past 5 years prior to baseline. 28. Having a history of or current serious mental disorder. 29. Actively attempting suicide, and considered a significant suicide risk by the principal investigator. 30. You answered "yes" to either question 4 or question 5 in the "Suicidal thoughts" section of the Columbia Suicide Severity Rating Scale (C-SSRS), or And have you ever answered "yes" to any of the suicide-related behaviors listed in the "Suicidal Behavior" section of the C-SSRS? The idea or action occurred within the past month. 31. The patient has a history of major surgery within 12 weeks prior to screening, or requires major surgery during the trial. 32. The patient has a history of severe allergy to lidocaine or its derivatives used during skin biopsy.

[0702] vaccine 33. The participant has received or intends to receive a live vaccine, including a live attenuated vaccine, within four weeks prior to screening, and the vaccine is within five half-lives of the last dose of the intervention. exception a. Non-live or inactivated vaccines received at least two weeks prior to baseline or after the last trial visit. b. Inactivated influenza vaccine and inactivated pneumococcal vaccine, c. A SARS-CoV-2 vaccine approved by a local regulatory body. 34. The participant received the Calmette-Guérin vaccine or treatment within four weeks prior to screening, or intended to receive it within five half-lives of the last dose of the intervention during the study.

[0703] Previous / Combination Therapy 35. The patient received any clinical trial intervention within 4 weeks prior to screening or within 5 half-lives, whichever is longer. 36. A history of a non-psoriatic disease requiring treatment with oral or parenteral corticosteroids for more than two weeks within 24 weeks prior to screening. 37. The patient has received biological treatment for an immune condition, such as a monoclonal antibody, including a commercially available drug, within the past 12 weeks or within 5 half-lives prior to baseline, whichever is longer. 38. Within four weeks prior to baseline, the patient received systemic non-biological treatment for immune status (see Section 10.7.2). 39. The patient has received treatment for topical psoriasis within 14 days prior to baseline (see Section 10.7.2). 40. For at least four weeks prior to baseline and during the study, excessive sun exposure or use of a tanning booth cannot or does not wish to be avoided. 41. You are currently using or planning to use medications that prolong the QT / QTc interval, except when they are used to treat depression. 42. The patient has used a potent CYP3A4 inhibitor or inducer within 14 days prior to baseline or during the planned use of such a drug in the study (see Section 10.7.2). 43. Plan to receive treatment with a drug that is a sensitive CYP3A substrate or a P-gp substrate with a narrow therapeutic index (see Section 10.7.2).

[0704] Previous / Current Clinical Trial Experience 44. You are currently enrolled in any other clinical trial, including any other type of medical research, or any investigational product that is deemed scientifically or medically incompatible with this study.

[0705] Other exclusions 45. You have a history of chronic alcohol abuse, IV drug abuse, or other illegal drug abuse within the year prior to screening. 46. ​​Provided more than 500 mL of blood within 4 weeks prior to screening. 47. Received blood products within 6 months prior to screening. 48. You are an employee of Lilly Company, or an employee of any third party involved in a test that requires the exclusion of their employees. 49. Personnel of the research facility directly involved in this study and / or their immediate family members. Immediate family members are defined as spouses, parents, children, or siblings, whether biological or legally adopted. 50. It is inappropriate to include this in the principal investigator's opinion for this study.

[0706] Trial interventions and combination therapies A trial intervention is defined as any clinical trial intervention, marketed product, placebo, or medical device that is administered to / intended to a trial participant in accordance with the trial protocol.

[0707] The administered experimental intervention Participants will take the tablets orally via QD approximately every 24 hours, with or without food.

[0708] [Table 39]

[0709] Methods to minimize bias: randomization and blinding Randomization All participants will be centrally assigned to a randomized trial intervention using an interactive web response system (IWRS). Prior to the start of the trial, IWRS login information and instructions will be provided to each site.

[0710] Participants will be stratified according to their prior treatment with biologics for the treatment of psoriasis.

[0711] The trial intervention will be dispensed at the trial visit summarized in the Statement of Analysis (SoA). Each participant will be dispensed the same number of tablets to maintain blinding.

[0712] The trial intervention that was returned should not be re-prescribed to the participant.

[0713] Emergency open-labeling The IWRS is programmed with a blinding break order. In emergency situations, the principal investigator has sole responsibility to determine whether deblinding of participant intervention assignments can be guaranteed. Participant safety must always be the primary consideration when making such decisions.

[0714] If participant intervention assignments are unblinded, the sponsor must be notified immediately within 24 hours of this occurrence. The date and reason for the blinding violation must be recorded.

[0715] Cancellation of the trial in the case of an open-label study. If the principal investigator, the on-site personnel performing the evaluation, or the participant is not blinded, the participant must discontinue the trial (Section 7.2). If there are ethical reasons to keep the participant in the trial, the principal investigator must obtain specific approval from the sponsor or nominee for the participant to continue in the trial.

[0716] Adherence to the trial intervention Participant adherence to the trial intervention will be assessed by counting the tablets returned at each visit.

[0717] A participant will be considered significantly non-compliant if they miss more than 20% of the prescribed dose of the trial intervention during the trial, unless the participant's trial intervention is withheld by the principal investigator for safety reasons. Similarly, a participant will be considered significantly non-compliant if, during the trial, the principal investigator determines that the participant intentionally or repeatedly took 20% more of the prescribed amount of medication.

[0718] Participants will receive counseling from the study staff as needed regarding the importance of carrying out the study intervention as prescribed.

[0719] The number of tablets dispensed to and taken by each participant must be recorded and adjusted along with the trial intervention and compliance records. The intervention start and end dates (including days for intervention delay) must also be recorded in the case report form (CRF).

[0720] Dosage change This protocol does not allow for dose adjustment.

[0721] Continued access to trial interventions after the trial has ended The trial intervention will not be available to participants after the trial is completed.

[0722] Combination therapy. For a list of drugs permitted or prohibited in this study, see Section 10.7.

[0723] Any medications or vaccines, including commercially available or prescription drugs, vitamins, and / or herbal supplements, that a participant is taking at the time of registration or during the study must be recorded along with the following: ●Reason for use ● The date of administration, including the start and end dates, and ● Dosage information, including dosage and frequency.

[0724] All participants should maintain their usual medication regimen for any accompanying conditions or illnesses throughout the trial, unless those medications are specifically excluded in the protocol.

[0725] Participants taking concomitant medications should maintain a stable baseline dose and keep it stable throughout the study, unless a change is necessary due to an adverse event (AE).

[0726] Participants should consult with authorized site staff before taking any new medications or supplements during the trial. Authorized site staff should consult with the sponsor's medical monitor if they have any questions about concomitant treatments during the trial.

[0727] Preliminary in vitro data suggest that compound I is a weak inducer of CYP3A. Principal investigators should be aware of the participants' concomitant use of CYP3A substrates.

[0728] Discontinuation of trial intervention and withdrawal / withdrawal of participants The discontinuation of a specific site or test is handled in Section 10.1.9.

[0729] Interruption of the trial intervention Trial interventions may be permanently discontinued or temporarily suspended during the trial.

[0730] Liver Chemotherapy Criteria If one or more of these conditions occur, the trial intervention should be interrupted or discontinued.

[0731] [Table 40]

[0732] Resumption of the trial intervention may only be considered in consultation with a Lilly-designated medical monitor, and only if liver test results return to baseline and a self-limiting non-intervention etiology is identified.

[0733] Criteria for temporary suspension (suspension) of trial interventions If a participant meets any of the criteria listed in this table, a temporary suspension of the trial intervention is required.

[0734] [Table 41]

[0735] Criteria for permanent discontinuation of trial interventions In rare cases, it may be necessary for a participant to permanently discontinue the trial intervention. If the trial intervention is permanently discontinued, the participant will remain in the trial and follow the procedures outlined in the Statement of Action (SoA).

[0736] infectious disease Participants should permanently discontinue the trial intervention if any of the following apply. ● Participants develop active TB or HIV infection during the study. ● Whether the participant is diagnosed with LTBI (regardless of whether the participant is eligible for treatment), ● Participants will test positive for HBV DNA or HCV RNA as described in Section 8.2.7.

[0737] Prior to discontinuation of the trial intervention, participants will be referred, evaluated, and managed by a specialist with expertise in the assessment and management of viral hepatitis. The timing of discontinuation from the trial intervention to initiating any antiviral treatment for hepatitis will be determined in consultation with the principal investigator, based on the recommendations of the specialist, and aligned with medical guidelines and standard treatment.

[0738] Test evaluation and procedures The test procedures and their timing are summarized in the Statement of Analysis (SoA).

[0739] Any immediate safety concerns should be discussed with the trial sponsor immediately upon occurrence or recognition, and a decision should be made on whether the participant should continue or discontinue the trial intervention.

[0740] Adherence to test design requirements, including those specified in the SoA, is essential and necessary for conducting the test.

[0741] All screening assessments must be completed and reviewed to ensure that potential participants meet all eligibility criteria. The principal investigator shall record details of all screened participants and maintain a screening log to confirm eligibility or, where applicable, to record the reasons for screening failure.

[0742] Effectiveness evaluation Primary efficacy evaluation PASI is a multi-item scale administered by the principal investigator and used to measure the severity of psoriasis (EMA 2004).

[0743] PASI is based on the applicability and severity of plaque characteristics.

[0744] Coverage area is the extent of surface lesions in four anatomical regions. ● Head and neck ●Trunk ● Upper limbs, and ●Lower limbs.

[0745] The characteristics of plaque include the following: ● Degree of desquamation (scaling) ● Erythema (redness), and ● Plaque infiltration (thickness) in each area.

[0746] This assessment results in an overall score ranging from 0 for no psoriasis to 72 for the most severe case (Fredriksson and Pettersson 1978).

[0747] The primary efficacy endpoint, PASI 75, represents at least a 75% reduction (improvement) from the baseline PASI score. A PASI 75 response is considered clinically meaningful.

[0748] Secondary efficacy evaluation PASI The secondary efficacy endpoints, PASI 90 and PASI 100, represent 90% and 100% improvement from the baseline PASI score, respectively.

[0749] body surface area The BSA percentage is a physician-administered scale used to assess the proportion of psoriasis involvement on the body surface of each participant. It is assessed on a continuous scale from 0% (no involvement) to 100% (full involvement), where 1% corresponds to the participant's hand size (including palm, fingers, and thumb) (National Psoriasis Foundation 2016).

[0750] Overall evaluation of a static physician sPGA is a multi-item scale administered by the principal investigator and used in adults. It determines the overall psoriasis lesions of a participant at a given time point.

[0751] The entire lesion is graded on a scale of 0 (complete disappearance), 1 (almost complete disappearance), 2 (mild), 3 (moderate), and 4 (severe) based on plaque elevation, scaling, and erythema (Cappelleri et al. 2013).

[0752] Psoriasis Scalp Severity Index The Psoriasis Scalp Severity Index (PSSI) is a multi-item scale administered by the principal investigator and used in adults. It measures the severity of affected scalp areas and clinical symptoms.

[0753] The PSSI is a composite score (range, 0-72) obtained by multiplying the sum of the scores for erythema, induration, and desquamation by the score for the severity of the affected scalp area. A higher score indicates a worse severity (Thaci et al. 2015).

[0754] Patient-reported outcomes DLQI The Dermatological Quality of Life Index (DLQI) is a simple, patient-reported, 10-item validated quality of life questionnaire. It covers six domains. ●Symptoms and mood ●Daily activities Leisure ● Work and school ● Personal relationships, and ●Treatment.

[0755] The recall period for this scale is over "last week". The response categories are: ●None at all (score 0) ●A little (score 1) ●Lot (Score 2), and ●Very many (score 3).

[0756] Responses that are unresponsive (or "irrelevant") are scored as 0. The score ranges from 0 to 30, with higher scores indicating a greater impairment in quality of life.

[0757] A total DLQI score of 0-1 is not considered to affect participants' health-related quality of life (Hongbo et al. 2005), and a change of 5 points from baseline is considered the threshold for the smallest clinically significant difference (Khilji et al. 2002; Basra et al. 2015).

[0758] Comprehensive evaluation of psoriasis patients The Patient Assessment of Psoriasis (PatGA) is a single-item scale reported by patients. The Patient Assessment of Psoriasis allows for a holistic assessment of disease severity or overall impact from the patient's perspective (Perez-Chada et al. 2020). Participants are asked to rank the severity of their psoriasis "today" by selecting a number on a numerical rating scale from 0 to 5 (0 indicating clear / no psoriasis, and 5 indicating severe psoriasis).

[0759] psoriasis symptom scale The Psoriasis Symptom Scale (PSS) is an eight-item patient-reported scale. It is based on the following assessments. ●4 symptoms: itching, pain, stinging, burning sensation ●Three signs: redness, scaling, and cracking ●One item related to discomfort associated with symptoms / signs (Armstrong et al. 2020).

[0760] Respondents will be asked to answer questions based on their psoriasis symptoms over the past 24 hours.

[0761] The symptom domain score ranges from 0 (no symptoms) to 40 (worst conceivable symptoms).

[0762] The symptom domain score ranges from 0 (no symptoms) to 30 (worst possible symptoms).

[0763] Each of the eight individual items is scored from 0 to 10, where 0 indicates no symptoms / signs and 10 indicates the worst possible symptoms / signs.

[0764] The overall severity of individual symptoms or signs ranges from 0 to 10.

[0765] Test evaluation Planned timelines for all safety assessments will be provided to the State of Agreement (SoA).

[0766] Vital signs Blood pressure, body temperature, and pulse rate will be measured when designated as a State of Aid (SoA) and when clinically indicated. Additional vital signs may be measured during trial visits if necessary, as determined by the principal investigator.

[0767] Vital signs should be measured after the participant has been seated for at least 5 minutes, before obtaining an ECG trace, and before collecting blood samples for clinical testing.

[0768] Physical examination Physical examination during screening A complete physical examination includes an assessment of these areas and bodily systems. ●Skin ○Head ○Abdomen ○Extremities ● Ears, eyes, nose, throat ● Lymph nodes ● Thyroid palpation ●Cardiovascular ●Respiratory system ●Gastrointestinal tract, and ● Nerves.

[0769] Height and weight will also be measured and recorded.

[0770] A complete physical examination includes evaluation of peripheral lymph nodes, assessment of TB risk factors and symptoms or signs of TB (Section 8.2.8).

[0771] Unless clinically indicated otherwise, a complete physical examination should exclude examination of the pelvis, rectum, and breasts.

[0772] Physical examination for symptoms after screening These tests should also include an assessment of TB risk factors and symptoms or signs of TB, including an evaluation of peripheral lymph nodes (Section 8.2.8).

[0773] electro-cardiogram A single 12-lead digital ECG will be collected for each participant according to the System of Analysis (SoA). The ECG should be recorded before blood is drawn. The patient should lie supine for approximately 5-10 minutes prior to ECG collection and remain supine during ECG collection, but must be awake.

[0774] Electrocardiograms may be obtained at additional times if deemed clinically necessary. Collecting additional ECGs at specific points in time allows for the assurance of high-quality records.

[0775] The electrocardiogram will be interpreted on-site by a qualified physician (principal investigator or qualified designated investigator) as soon as possible after the ECG acquisition time, ideally while the participant is still present, to determine whether the participant meets the trial inclusion criteria and for immediate participant management, if any clinically relevant findings are identified.

[0776] If clinically significant findings (including, but not limited to, changes in the QT / QTc interval from baseline) are identified after enrollment, the principal investigator, together with the sponsor, will determine whether the participant can continue in the study and whether any changes to participant management are necessary.

[0777] Chest X-ray Post-anterior chest radiographs (CXRs), interpreted and reported by a radiologist or pulmonologist, will be taken at the time of screening, as specified in the Statement of Agenda (SoA).

[0778] Additionally, a lateral CXR can be obtained if the principal investigator requests a lateral view.

[0779] Based on the judgment of the principal investigator, participants are not required to have a CXR at the time of screening if both of the following two conditions are met. ●CXR was conducted within 3 months prior to the initial screening. ●CXR records read by qualified radiologists or pulmonologists are sufficient for TB assessment in accordance with local standard care.

[0780] For each participant, CXR films, images, or radiographic reports must be available for review by the principal investigator before participants are randomized. Specific findings from CXR may coincide with criteria for excluding participants from the study (see Section 5.2).

[0781] Note: Results from chest CT scans or other imaging techniques similar to CXR may be used as a substitute for CXR as described above, in consultation with the sponsor's medical monitor.

[0782] Liver monitoring Close monitoring of the liver Clinical tests including ALT, AST, ALP, TBL, direct bilirubin, GGT, and CK (Section 10.2) should be repeated within 48-72 hours if one or more of these conditions occur, in order to check for abnormalities and determine whether they are elevated or decreased.

[0783] [Table 42]

[0784] If the abnormality persists or worsens, clinical and laboratory monitoring, as well as an assessment of possible causes of the abnormal liver function test, should be initiated by the principal investigator in consultation with a Lilly-designated medical monitor. This assessment should include, at a minimum, a physical examination and a thorough medical history, including symptoms, recent illnesses (e.g., heart failure, systemic infection, hypotension, or seizures), recent travel, concomitant medications (including over-the-counter medications), herbs and dietary supplements, alcohol consumption, and other substance abuse.

[0785] Initially, symptom monitoring and liver biochemical testing should be performed 1-3 times per week, based on the participant's clinical condition and liver biochemical test results. Subsequently, once the participant's clinical condition and test results stabilize, the monitoring frequency can be reduced to once every 1-2 weeks. Monitoring of ALT, AST, TBL, and TBL should continue until levels normalize or return to approximately baseline levels.

[0786] Comprehensive liver assessment If one or more of these conditions occur, a comprehensive evaluation should be conducted to explore possible causes of liver damage.

[0787] [Table 43] † Signs / symptoms of hepatic disorders include severe fatigue, nausea, vomiting, right upper abdominal pain, fever, rash, and / or eosinophilia >5%.

[0788] At a minimum, this assessment should include a physical examination and complete medical history as outlined above, as well as PT-INR testing; testing for viral hepatitis A, B, C, or E; testing for autoimmune hepatitis; and abdominal imaging tests (e.g., ultrasound or CT scan);

[0789] Based on the participant's medical history and initial results, further testing should be considered in consultation with a Lilly-designated medical monitor, including testing for hepatitis D virus (HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, acetaminophen protein adducts, uremic screening, Wilson's disease, blood alcohol levels, urinary ethyl glucuronide, and blood phosphatidylethanol.

[0790] Based on the investigator's assessment of the situation and the participant's clinical condition, the investigator should consider referring the participant to a hepatologist or gastroenterologist, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), echocardiography, or liver biopsy.

[0791] Collection of additional liver data (liver safety CRF) in trial participants with abnormal liver function tests during the trial. Additional liver safety data collection in the liver safety CRF should be performed in trial participants who meet one or more of the following five conditions:

[0792] [Table 44] Note: There should be at least two days between two consecutive blood tests.

[0793] Hepatitis testing and monitoring Hepatitis B virus Initial testing for HBV infection includes antibodies against HbsAg and hepatitis B core antigen (anti-HBc).

[0794] [Table 45]

[0795] Hepatitis C virus The initial test for HCV infection includes testing for antibodies against HCV (anti-HCV).

[0796] [Table 46]

[0797] Tuberculosis testing and monitoring During screening, all participants will be assessed for TB risk factors, symptoms, and signs. The assessment will include the following: ● A thorough medical history to determine lifelong risk factors for TB infection, TB progression, and symptoms and / or signs of active TB, and ● Previous or active TB signs by a ○A thorough physical examination for signs of active TB, including temperature measurement and evaluation of peripheral lymph nodes, and Anterior chest X-ray (PA CXR) after interpretation and reporting by a radiologist or respiratory physician.

[0798] All participants without a history of LTBI or active TB, and without a history of positive Mantots bergurin skin test (TST) using purified protein derivatives (PPDs) or positive M tuberculosis interferon-gamma-release assay (IGRA), must undergo either a PPD TST or IGRA test.

[0799] Diagnosed LTBI Participants diagnosed with LTBI will be excluded unless they have completed appropriate LTBI treatment in accordance with World Health Organization and / or U.S. Centers for Disease Control and Prevention guidelines (Section 5.2).

[0800] TB monitoring Tracking of TB will be continued for all participants throughout the trial. At a minimum, each participant should have the following records approximately every three months. ● A thorough medical history to determine any risk factors for TB infection and TB progression, and any symptoms or signs of active TB, and ● A thorough physical examination for signs of active TB, including temperature measurement and evaluation of peripheral lymph nodes.

[0801] This table provides details about TB testing.

[0802] [Table 47]

[0803] Skin assessment using the Fitzpatrick skin type scale The Fitzpatrick Skin Type is a physician-administered skin classification scale that categorizes the typical responses of different skin types to ultraviolet light. The types range from Type I (very fair; 0-6) to Type VI (very dark; 35-36) (Fitzpatrick 1988).

[0804] Adverse events, serious adverse events, and product complaints The definitions of the following phenomena can be found in Section 10.3. ● Adverse event (Ae) ●Serious adverse events (SAEs), and ●Product complaint (PC).

[0805] These events are reported by the participant (or, where appropriate, by a caregiver, representative, or legally authorized agent of the participant).

[0806] The principal investigator and any qualified designated investigators remain responsible for detecting, documenting, and recording events that meet these definitions, and for tracking any events that are serious, considered to be related to the study intervention or procedure, or cause a participant to discontinue the study intervention or the study.

[0807] Care should be taken to avoid introducing bias when detecting events. Open-ended, non-initiated oral questions from participants are a preferred method for inquiring about the occurrence of events.

[0808] Following the initial report, the principal investigator is required to proactively follow up with each participant during subsequent visits / contacts. All SAEs are followed up until resolved, stabilized, the event is otherwise explained, or the participant fails to follow up (as defined in Section 7.3). For PCs, the principal investigator is responsible for ensuring that follow-up includes any supplementary investigations as indicated to clarify their nature and / or causal relationship. Further information regarding follow-up procedures is provided in Section 10.3.

[0809] Timing and methods for collecting data on events This table describes the timing, deadline, and mechanism for collecting event data.

[0810] [Table 48] a SAEs should not be reported unless the principal investigator believes they may be related to the study treatment or participation in the study.

[0811] Adverse event monitoring using systematic questionnaires Non-leading AE collection should be performed before C-SSRS collection.

[0812] If a suicide-related event is detected during C-SSRS but not captured during non-leading AE collection, the scene should not change the AE pattern.

[0813] If an adverse event (AE) is severe or leads to discontinuation of treatment, it must be included in the AE form, and the process for reporting SAEs must be followed.

[0814] infectious disease Completion of the infection eCRF page is required for each infection reported as an AE or SAE.

[0815] The clinical trial sponsor identifies opportunistic infections based on the paper by Winthrop et al. (2015) (Section 10.8).

[0816] Pharmacokinetics Venous blood samples are collected to measure the plasma concentration of compound I as specified in SoA.

[0817] If justified and agreed upon between the principal investigator and the sponsor, up to three samples may be collected at further points during the trial.

[0818] Instructions for the collection and handling of biological samples will be provided by the clinical trial sponsor. The actual date and time (24-hour clock time) for each sample must be recorded.

[0819] The pharmacokinetic properties (PK) of compound I will be evaluated using the samples. The samples collected for analysis may also be used to evaluate aspects of safety or efficacy related to concerns arising during or after the study.

[0820] Information on intervention concentrations that could be used to blind the trial will not be reported to the research site or to blinded staff.

[0821] bioanalysis Samples will be analyzed in a laboratory approved by the sponsor and stored at a facility designated by the sponsor. The concentration of compound I will be assayed using a valid bioanalytical method. Analysis of samples collected from placebo participants is not planned.

[0822] Sample retention is described in Section 10.1.12. Any remaining samples used for PK are pooled and, if deemed appropriate, may be used for exploratory metabolic or bioanalytical experiments.

[0823] Pharmacokinetics Refer to Section 10.2, the Statement of Information (SoA) for clinical testing and interleukin-19 (IL-19) sample collection information. Sample retention is described in Section 10.1.12.

[0824] genetic Where local regulations permit, whole blood samples should be collected for pharmacogenetic analysis. See Section 10.2, SoA for Clinical Laboratory and Sample Collection Information.

[0825] For information regarding gene research, storage, and sample retention, please refer to Section 10.5.

[0826] biomarkers Biomarker samples are collected in accordance with the SoA, and where permitted by local regulations, as detailed in Section 10.2.

[0827] Skin biopsy Baseline (pre-administration) and post-administration skin biopsies are required from participants and will be collected at the times indicated in the State of Action (SoA). A local anesthetic such as lidocaine will be applied to obtain a skin punch biopsy approximately 4 mm in size. Detailed instructions on handling the biopsy specimens after the procedure will be provided by the sponsor.

[0828] Blood and skin samples Samples are collected to measure proteins and ribonucleic acid (RNA) involved in disease processes, including the disease and its mechanism of action, and pathways related to the response to treatment with compound I, or to investigate research methods and validate diagnostic tools or assays.

[0829] The sample can be stored and analyzed for research purposes related to drug targets, disease processes, disease states, mechanisms of action of compound I, or research methods, or when validating diagnostic tools or assays related to psoriasis.

[0830] Biomarker studies are conducted to address issues related to drug predisposition, target involvement, pharmacodynamics (PD), mechanism of action, variability of subject response (including safety), and relevance to clinical outcomes. Sample collection is incorporated into clinical trials to allow for the examination of these issues through the measurement of biomolecules, including DNA, RNA, proteins, lipids, and other cellular components.

[0831] All samples will be coded with participant numbers. These samples and any generated data can only be linked to participants by on-site staff at the research site.

[0832] The samples will be kept at a facility selected by the clinical trial sponsor or its designated participant. The maximum retention period is described in Section 10.1.12.

[0833] Statistical considerations The statistical analysis plan (SAP) is completed before the initial deblinding and includes a more technical and detailed description of the statistical analysis described in this section. This section is a summary of the planned statistical analysis for the primary endpoint and major secondary endpoints.

[0834] statistical process The primary objective of this study was to evaluate whether compound I 50 and 125 mg administered via QD were superior to placebo in achieving a PASI score of 75 at week 12 in participants with moderate to severe psoriasis, excluding women of potential pregnancy.

[0835] The null hypothesis being tested for the primary estimate is that compound I50, administered at a QD dose of 125 mg, is no different from placebo in achieving a PASI of 75 at week 12.

[0836] The null hypothesis corresponding to secondary estimations is defined in SAP.

[0837] Multiplicity adjustment This study is for exploratory purposes, not confirmation, and therefore, none of the hypotheses are adjusted for multiplicity.

[0838] Analysis set [Table 49]

[0839] statistical analysis Overall Considerations The statistical analysis of this study is the responsibility of Lilly or her designated person. Unless otherwise stated in the SAP, the summary will provide information on the treatment period and follow-up period of this study. The analysis will be fully detailed in the SAP.

[0840] For efficacy analysis, treatment comparisons will be performed separately for both compound I dose and placebo.

[0841] Any changes to the data analysis methods described in the protocol require modification only if they alter the key features of the protocol. Any other changes to the data analysis methods described in the protocol, and the justification for such changes, will be documented in the Clinical Research Report (CSR). Additional exploratory analyses of data will be conducted where deemed appropriate.

[0842] Baseline data For efficacy and patient-reported outcomes (PROs), baseline is defined as the last non-missing assessment recorded at or prior to visit 2.

[0843] Missing baseline values ​​are not imputed.

[0844] A detailed definition of the baseline for safety-related analysis is provided by SAP.

[0845] Continuous data Continuous data is summarized in terms of mean, standard deviation, minimum, maximum, median, and number of observations.

[0846] Category data Categorical data is summarized as frequency and percentage.

[0847] Superiority Test Unless otherwise specified, all significance tests are two-tailed tests with an α of 0.05.

[0848] Key endpoints and estimated analysis Composite response estimation will be used to analyze a comparison of the bifurcation primary endpoint and the proportion of PASI 75 at week 12. The comparison will not include data collected after intervention events related to the study treatment, such as receiving prohibited medication or early discontinuation of the study treatment due to adverse events or lack of efficacy.

[0849] Participants who discontinued the intervention 12 weeks prior, participants who did not follow concomitant medication rules, or participants for whom data is missing for other reasons are defined as non-responders, and non-responder complementation (NRI) is used when observations are missing.

[0850] For the primary endpoint and other dichotomous efficacy endpoints, treatment comparisons of compound I 50 mg QD versus placebo and compound I 125 mg QD versus placebo will be performed using the Cochrane-Mantel-Henzel (CMH) test, adjusting for planned stratification factors for the ITT population. Common risk differences, odds ratios adjusted with 95% asymptotic confidence intervals, and p-values ​​will be reported.

[0851] Alternative estimates and sensitivity analyses for primary endpoints relative to primary estimates are defined in SAP.

[0852] Secondary endpoints and estimated analysis Sequential endpoints Composite estimation is used to analyze continuous efficacy or PRO endpoints. Comparisons do not include data collected after intervention events involving the administration of prohibited drugs or early discontinuation of the study intervention due to AEs of lack of efficacy. Data collected after these intervention events are attributed as baseline values, assuming that participants with these intervention events do not benefit from the study treatment.

[0853] Missing data Multiple imputations, or imputations of non-respondents, are used to handle missing data for reasons other than treatment discontinuation due to adverse events (AEs), lack of efficacy, or protocol deviations such as taking prohibited medications. Further details are defined in SAP.

[0854] Analysis of endpoints with more than one post-baseline measurement during the double-blind treatment period. This table describes the analyses used to evaluate the therapeutic effect of Compound I 50 mg compared to placebo or Compound I 125 mg compared to placebo.

[0855] [Table 50]

[0856] Endpoints measured only once after baseline during the double-blind treatment period. This table describes the analyses used to evaluate the therapeutic effect of Compound I 50 mg compared to placebo or Compound I 125 mg compared to placebo.

[0857] [Table 51]

[0858] Two-way endpoint The estimations used to analyze the bifid efficacy endpoint are the same as those for the primary endpoint defined in Section 9.3.2.

[0859] Safety analysis Safety population data are descriptively summarized by treatment group and include the following: ●AE ●SAE ●C-SSRS, ●QIDS-SR16, ● Vital signs, and ●Laboratory analytes.

[0860] Categorical safety measures are summarized along with incidence rates. Continuous safety measures are summarized as the mean change over visits. Exposure to the study intervention is calculated for each participant and summarized by treatment group.

[0861] AEs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC), priority term, and severity.

[0862] A TEAE is defined as the first event whose severity increased or worsened after baseline. For gender-specific events, the denominator and percentage calculations include only participants from a given gender.

[0863] The number and percentage of participants are summarized below. ●TEAE ●TEAE based on maximum severity ●TEAE related to trial interventions ● Discontinuation of trial intervention due to adverse event (AE) ●SAE, or ●Death.

[0864] We will summarize and analyze TEAEs (all based on maximum severity), SAEs including death, and AEs leading to discontinuation from the trial intervention, using MedDRA SOC and preferred terminology.

[0865] Suicide-related thoughts and behaviors occurring during treatment are summarized based on responses to the C-SSRS that are consistent with the C-SSRS Scoring and Data Analysis Guide (Columbia Lighthouse Project WWW).

[0866] Details of the safety analysis will be identified within SAP.

[0867] Pharmacokinetic and pharmacodynamic analysis The plasma concentrations of compound I are presented graphically and descriptively summarized. Where guaranteed and based on data availability, the exposure-response relationship between plasma compound I concentrations and biomarkers, efficacy, and / or safety endpoints can be investigated. Model-based approaches can be implemented using nonlinear mixed-effects modeling (NONMEM) or other appropriate software to evaluate PK or PD parameters.

[0868] Subgroup analysis Subgroup analyses of the primary endpoint or several secondary endpoints may include the following: ●Demographic factors ○Gender ○ Age ○ Geographical area, or ○Weight ● Prior exposure to biological treatments, prior exposure to TNF inhibitors, and other pre-medication measures, ● Disease characteristics such as baseline PASI category.

[0869] Details of subgroup analysis are included in SAP.

[0870] interim analysis To support development activities, an interim analysis will be planned if at least 30% of participants complete their 12-week visits or if they discontinue early. Furthermore, an interim analysis will be planned if approximately 105 participants are enrolled and complete their 12-week visits or if they discontinue early.

[0871] Additional interim analyses can be conducted as needed.

[0872] The evaluation of unblinded interim data is conducted by an Internal Assessment Committee (IAC) consisting of a limited number of pre-designated team members who do not have direct field contact or responsibility for data entry or verification (see Section 10.1.5). Only the IAC is permitted to evaluate the provisional effectiveness of unblinding.

[0873] The trial will not be terminated prematurely due to efficacy or futility. No adjustments will be made for Type I errors.

[0874] Details of deblinding are specified in the SAP Deblinding Plan section or in a separate Deblinding Plan document.

[0875] SAP will provide a more detailed explanation of the planned interim analysis.

[0876] Determining sample size: Approximately 125 participants will be screened to obtain approximately 105 participants who will be randomly assigned to test the intervention. The sample size calculation is based on the primary efficacy evaluation and its endpoint at week 12, PASI 75.

[0877] Assuming an approximately 5% PASI 75 response rate and a 5% two-sided type 1 error rate for the placebo group, and using a standard approximation method, the trial has over 90% power under a sample size of 35 per group to detect a treatment difference of 0.3.

[0878] By introducing additional participants, we can evaluate new dose levels based on the availability of new data and planned interim analyses.

[0879] Appendix 2: Clinical Tests The tests detailed in the table below will be carried out by the central laboratory or local laboratory as indicated in the table.

[0880] In situations where the clinical trial sponsor approves a local clinical laboratory instead of a central clinical laboratory (see table below), the local laboratory must be qualified in accordance with applicable local regulations.

[0881] Protocol-specific requirements for the inclusion or exclusion of participants are detailed in Section 5 of the protocol.

[0882] Additional tests may be performed at any time during the trial if deemed necessary by the principal investigator or required by local regulations.

[0883] The principal investigator must document the review of safety results in the laboratory.

[0884] Test results that can be blinded to the test will not be reported to the investigation site or other blinded personnel until the test is blinded.

[0885] [Table 52-1]

[0886] (Continuation of the table above) [Table 52-2]

[0887] (Continuation of the table above) [Table 52-3]

[0888] Appendix 6: Liver Safety: Proposed Behavioral and Follow-up Evaluations Liver evaluation tests The Lilly-designated central laboratory must complete the analysis of all selected tests except for microbiological tests.

[0889] Local testing may be performed in addition to central testing if necessary for immediate participant management.

[0890] If verified tests or calculations are available, report the results.

[0891] [Table 53] a It is not necessary if you are testing for anti-actin antibodies. b Reflex / verification that depends on regulatory requirements, the availability of inspections, or both. c It is not necessary when testing for anti-smooth muscle antibodies (ASMA). d Assays were performed only by local laboratories designated by the principal investigator; central laboratory services were not available.

[0892] Appendix 7: Permitted and Prohibited Concomitant Drugs Approved combination drugs This section lists the concomitant medications and vaccinations permitted in this study.

[0893] Other medications may be permitted if approved by the clinical trial sponsor or its designated investigator.

[0894] [Table 54] Abbreviations: PASI=Psoriasis Area and Severity Index; SARS-CoV-2=Severe Acute Respiratory Syndrome Coronavirus 2.

[0895] 1.1.1. Prohibited Concomitant Drugs and Procedures This section describes the drugs prohibited in the trial. If any of the prohibited treatments listed here are necessary, the trial intervention should be permanently discontinued (Section 7.1.3).

[0896] [Table 55-1]

[0897] (Continuation of the table above) [Table 55-2] Abbreviations: DDI = drug-drug interaction; JAK = Janus kinase; PUVA = psoralen and ultraviolet A.

[0898] Appendix 8: Examples of infections that may be considered opportunistic This table provides examples of infections that may be considered opportunistic (adapted from Winthrop et al.

[2015] ). This list is not exhaustive.

[0899] [Table 56]

[0900] Appendix 11: Abbreviations and Definitions [Table 57-1]

[0901] (Continuation of the table above) [Table 57-2]

Claims

1. A method for treating a patient having an autoimmune disease or an inflammatory disease, comprising administering to the patient a compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound, or the pharmaceutically acceptable salt, is administered in a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

2. The method according to claim 1, wherein the autoimmune or inflammatory disease is a disease regulated by receptor-interacting protein (RIP) kinase 1.

3. The method according to claim 1 or 2, wherein the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, cutaneous lupus erythematosus, lupus nephritis, systemic lupus erythematosus, and atopic dermatitis.

4. The method according to any one of claims 1 to 3, wherein the administration is performed using the amorphous form of the compound.

5. The method according to claim 4, wherein the amorphous form of the compound is part of a solid dispersion containing a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC).

6. The method according to any one of claims 1 to 5, wherein the dose is approximately 12.5 mg, 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, 43.75 mg, 50 mg, 56.25 mg, 62.5 mg, 68.75 mg, 75 mg, 81.25 mg, 87.5 mg, 93.75 mg, 100 mg, 106.25 mg, 112.5 mg, 118.75 mg, or 125 mg of the free base equivalent of the compound per dose.

7. The method according to any one of claims 1 to 5, wherein the dose is approximately 50 mg to approximately 75 mg of the free base equivalent of the compound per dose.

8. The method according to any one of claims 1 to 5, wherein the dose is approximately 25 mg to approximately 50 mg of the free base equivalent of the compound per dose.

9. The method according to any one of claims 1 to 5, wherein the dose is approximately 75 mg to approximately 100 mg of the free base equivalent of the compound per dose.

10. The method according to any one of claims 1 to 5, wherein the dose is approximately 100 mg to approximately 125 mg of the free base equivalent of the compound per dose.

11. The method according to any one of claims 1 to 10, wherein the maximum daily dose is approximately 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg of the free base equivalent of the compound.

12. A method for treating a patient having an autoimmune disease or an inflammatory disease, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound or a pharmaceutically acceptable salt is administered in a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose, and the dose is administered once daily.

13. The method according to any one of claims 1 to 12, wherein the administration of the aforementioned dose is by oral administration.

14. The method according to any one of claims 1 to 13, wherein the autoimmune or inflammatory disease is rheumatoid arthritis, psoriasis, or ulcerative colitis.

15. A method for treating a patient having rheumatoid arthritis, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 25 mg to about 125 mg per dose.

16. A method for treating a patient having psoriasis, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 25 mg to about 125 mg per dose.

17. A method for treating a patient having ulcerative colitis, comprising administering to the patient an amorphous form of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, wherein the compound is administered once daily at a dose of about 12.5 mg to about 125 mg per dose.

18. A compound of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, A polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone / vinyl acetate copolymer, 6:4, povidone K30, and hydroxypropyl methylcellulose (HPMC), is included. A pharmaceutical composition in which the weight ratio (w / w) of the compound to the polymer is about 1:4 to about 1.2:

1.

19. The pharmaceutical composition according to claim 18, wherein the polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

20. The pharmaceutical composition according to claim 19, wherein the weight ratio (w / w) of the free base equivalent of the compound to the hydroxypropyl methylcellulose acetate succinate is about 1:3 to about 1:

1.

21. A compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of autoimmune or inflammatory diseases in patients, wherein the compound is administered in a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

22. A compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of rheumatoid arthritis in patients, wherein the compound is administered in an amorphous state at a dose of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose.

23. A compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of psoriasis in patients, wherein the compound is administered in an amorphous state at a dose of approximately 25 mg to approximately 125 mg of the compound's free base equivalent per dose.

24. A compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of ulcerative colitis in patients, wherein the compound is administered in an amorphous state at a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

25. Use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment of an autoimmune disease or inflammatory disease in a patient, wherein the compound or the pharmaceutically acceptable salt is administered in a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

26. Use of the compound (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazol-3-carboxamide in the manufacture of a pharmaceutical product for the treatment of an autoimmune disease or inflammatory disease in a patient, wherein the compound is administered in a dose of approximately 12.5 mg to approximately 125 mg of the compound's free base equivalent per dose.

27. A pharmaceutical unit dose composition comprising approximately 12.5 mg to approximately 125 mg of the (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide compound in amorphous form, wherein the unit dose composition is suitable for oral administration.

28. A pharmaceutical unit dose composition according to claim 27, comprising approximately 12.5 mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, or 75 mg of the compound.

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