Methods for treating sarcoidosis with brepocitinib

Abstract

The present disclosure provides methods related to the treatment of a chronic immune-mediated disease affecting the skin and associated tissues. In particular, the present disclosure provides methods for the oral administration of a JAK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of sarcoidosis.

Description

Atty. Docket No. PRIOV- 43983.601METHODS FOR TREATING SARCOIDOSIS WITH BREPOCITINIBRELATED APPLICATION INFORMATION

[0001] This application claims priority to U. S. Application No. 63 / 755,304 filed on February 6, 2025, the contents of which are herein incorporated by reference.FIELD

[0002] The present disclosure provides methods related to the treatment of a chronic immune-mediated disease affecting the skin and associated tissues. In particular, the present disclosure provides methods for the oral administration of a JAK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of sarcoidosis.BACKGROUND

[0003] Sarcoidosis is a rare, immune-mediated inflammatory disorder characterized by the formation of non-caseating granulomas that can affect multiple organs, including the skin, lungs, lymph nodes, and eyes, with an estimated prevalence of 8-9 cases per 100,000 people in the United States (Baughman, 2016). Cutaneous sarcoidosis, a subtype that primarily affects the skin, has an incidence of approximately 1 per 100,000 individuals in the U. S. (Ungprasert, 2016). Skin involvement in sarcoidosis is highly variable, manifesting as plaques, papules, lupus pernio, subcutaneous nodules, and other dermal lesions that can affect hair, mucous membranes, and nails. While pulmonary involvement is the most common and accounts for significant morbidity, cutaneous sarcoidosis can remain chronically active even when extracutaneous symptoms are controlled, profoundly impacting quality of life. Currently, there are no FDA-approved treatments specifically for cutaneous sarcoidosis, although prednisone and corticotropin gel are approved for pulmonary forms of the disease. Treatment options for cutaneous sarcoidosis generally involve the use of topical or intralesional corticosteroids, systemic corticosteroids, immunosuppressants, and combinations of off-label drugs (Sanchez, 2015; Abdelghaffar, 2024). These treatments manage symptoms but often do not address underlying disease mechanisms, leading to reduced quality of life and challenges such as increased infection risk, dependence on corticosteroids (and their longterm side effects). There is a critical need for therapies with improved efficacy, reduced side effects, and compatibility with combination treatments to improve outcomes for patients with chronic cutaneous sarcoidosis.Atty. Docket No. PRIOV- 43983.601SUMMARY

[0004] Embodiments of the present disclosure include a method for treating sarcoidosis, the method comprising administering to a subject in need of treatment thereof an effective amount [(lS)-2,2-difluorocyclo-propyl] [(lR,5S)-3-{2-[(l-methyl-lH-pyrazol-4-yl) amino] pyrimidin-4-yl}-3,8-diazabicyclo [3.2.1] oct-8-yl] methanone (Brepocitinib)H

[0005] or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered in a dosage of about 10 mg to about 200 mg.

[0006] Embodiments of the present disclosure also include the administration of an effective amount of Brepocitinib to the subject has one or more effects selected from the group consisting of: decreases or inhibits one or more cytokine signaling pathways implicated in sarcoidosis; decreases or inhibits cytokine activity mediated by IFN-I and INF-II activity in the subject; decreases or inhibits cytokine activity mediated by interleukin (IL)-6, IL-12, IL-15, IL-21, IL-22, IL-23 activity in the subject; and interferes with and / or reduces sarcoidosis activity and morphology.

[0007] In some embodiments, the sarcoidosis includes, but is not limited to, pulmonary sarcoidosis, ocular sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, musculoskeletal sarcoidosis, hepatic sarcoidosis, renal sarcoidosis, splenic sarcoidosis, lymphatic sarcoidosis, endocrine sarcoidosis, gastrointestinal sarcoidosis, multisystem sarcoidosis or any combination thereof.

[0008] In some embodiments, the sarcoidosis is cutaneous sarcoidosis.

[0009] In some embodiments, the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, plaque sarcoidosis, nodular sarcoidosis, scar sarcoidosis, tattoo sarcoidosis, subcutaneous sarcoidosis (Darier-Roussy sarcoidosis), or hypopigmented sarcoidosis.

[0010] In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0011] In some embodiments, the compound is administered orally.

[0012] In some embodiments, the compound is administered in a dosage of about 45 mg.Atty. Docket No. PRIOV- 43983.601

[0013] In some embodiments, the compound is administered in a dosage of about 15 mg.

[0014] In some embodiments, the compound administered is taken daily.

[0015] In some embodiments, the compound administered is in divided doses administered two, three or four times per day.

[0016] In some embodiments, the compound is administered for less than or about 64 weeks.

[0017] In some embodiments, the compound is administered for more than or about 4 weeks.

[0018] In some embodiments, the subject is a mammal.

[0019] In some embodiments, the mammal is a human.

[0020] Embodiments of the present disclosure also include the use of Brepocitinib for the manufacture of a medicament for the treatment of sarcoidosis in a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0022] Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

[0023] FIG. 1: A schema of the study design fortesting Brepocitinib for the treatment of cutaneous sarcoidosis.DETAILED DESCRIPTION1. Definitions

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. The phrase “in some embodiments” as used herein does not necessarily refer to the same embodiment, though it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention. All publications, patent applications, patents and other referencesAtty. Docket No. PRIOV- 43983.601mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0025] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0026] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0027] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0028] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0029] As used herein, the term “sarcoidosis” refers to a chronic inflammatory disease characterized by the formation of granulomas — clusters of immune cells — in various organs, most commonly the lungs, lymph nodes, and skin. In cases of cutaneous sarcoidosis, the disease primarily affects the skin, presenting with various types of lesions such as lupus pernio (purplish-red, raised lesions on the face), papular sarcoidosis (small, raised papules), plaque sarcoidosis (firm, raised plaques), and other forms including nodular, scar-associated, and hypopigmented sarcoidosis. These cutaneous manifestations can vary widely in appearance and distribution, potentially affecting the face, limbs, trunk, and areas of prior injury or tattoos.Atty. Docket No. PRIOV- 43983.601

[0030] Diagnosis of sarcoidosis includes a clinical evaluation of symptoms and a range of tests, such as blood tests to identify markers of inflammation and elevated levels of angiotensinconverting enzyme (ACE) or calcium. Biopsy of affected tissues, such as skin lesions or lymph nodes, is performed to confirm the presence of granulomas. Additional diagnostic tools include imaging, such as chest X-rays or CT scans, to detect organ involvement, and pulmonary function tests to assess lung function if respiratory involvement is suspected.

[0031] Embodiments of the present disclosure include a method of administering Brepocitinib or another JAK inhibitor, or a pharmaceutically acceptable salt thereof, for treating sarcoidosis, including cutaneous sarcoidosis, pulmonary sarcoidosis, ocular sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, musculoskeletal sarcoidosis, hepatic sarcoidosis, renal sarcoidosis, splenic sarcoidosis, lymphatic sarcoidosis, endocrine sarcoidosis, gastrointestinal sarcoidosis, multisystem sarcoidosis and the like.

[0032] As used herein, the terms “providing,” “administering,” and “introducing,” are used interchangeably herein and refer to the placement of the proteins or systems of the disclosure into a subject by a method or route which results in at least partial localization to a desired site. Administration can use any appropriate route which results in delivery to a desired location in the subject.

[0033] As used herein, the term “life cycle” is used to refer to the stages and progression of a particular disease from its initial introduction or onset through its development, transmission, effects on the host or population, and, in some cases, resolution. The life cycle of a disease encompasses the complete course of a disease, including its origin, spread, impact, and potential outcomes. The life cycle phases of a disease would include: the disease onset, transmission of the disease, the incubation period, the symptomatic phase, the recovery or chronic phase, the spread or outbreak of the disease, the immunity or resistance period of the disease, the immunity or resistance period of the disease, the decline and elimination of the disease as well as the potential resurgence of the disease.

[0034] As used herein, the phrase “pharmaceutically acceptable carrier” is used to refer to a material that is compatible with a recipient subject, such as a mammal, more particularly a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk / benefit ratio for the intended use of the active agent.Atty. Docket No. PRIOV- 43983.601

[0035] The terms “carrier”, “adjuvant”, or “vehicle” are used interchangeably herein, and include any and all solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy. 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, pyrogen-free water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth; malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, alginic acid, isotonic saline, Ringer's solution, alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, and glycerol, cyclodextrins, lubricants such as sodium lauryl sulfate and magnesium stearate, petroleum hydrocarbons such as mineral oil and petrolatum. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.Atty. Docket No. PRIOV- 43983.601

[0036] As used herein, the phrase, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., humans and other mammals) without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. In some embodiments, a pharmaceutically acceptable salt of Brepocitinib is derived from an inorganic or organic acid or base. For reviews of suitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) and Remington: The Science and Practice of Pharmacy. 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000. Examples of suitable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, mesylate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0037] Suitable base addition salts include, without limitation, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine, and choline, and salts with amino acids such as arginine, lysine, and so forth.

[0038] Also, basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

[0039] As used herein, the terms "subject" and "patient" are used interchangeably irrespective of whether the subject has or is currently undergoing any form of treatment. As used herein, the terms "subject" and "subjects" may refer to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgus or rhesus monkey, chimpanzee, etc.) and a human). In some embodiments, the subject may be a human or a non-human.Atty. Docket No. PRIOV- 43983.601

[0040] The phrase “therapeutically effective” and “effective amount” refer to a benefit including, but not limited to, the treatment or amelioration of symptoms of sarcoidosis as discussed herein. It will be appreciated that the therapeutically effective amount or the amount of one or more agents required to provide a therapeutic effect will vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual subject), which can be readily determined by a person of skill in the art. For example, an amount of Brepocitinib is therapeutically effective if it is sufficient to affect the treatment or amelioration of symptoms of sarcoidosis as discussed herein.

[0041] As used herein, whether by themselves or in conjunction with another term or terms, "treats," "treating," "treated," and "treatment," refer to and include ameliorative, palliative, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylactically, that is, preventatively. It should be understood that "prophylaxis" or a prophylactic use or result do not refer to nor require absolute or total prevention (i.e., a 100% preventative or protective use or result). As used herein, prophylaxis or a prophylactic (preventative) use or result refers to uses and results in which administration of a compound, therapeutic agent or composition diminishes or reduces the severity of a particular condition, symptom, disorder, or disease described herein; diminishes or reduces the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing.

[0042] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.Oral administration of BrepocitinibAtty. Docket No. PRIOV- 43983.601

[0043] Embodiments of the present disclosure include a method for treating sarcoidosis, the method comprising administering to a subject in need of treatment thereof an effective amount [(lS)-2,2-difluorocyclo-propyl] [(! R,5S)-3-{2-[(l-methyl-lH-pyrazol-4-yl) amino] pyrimidin-4-yl}-3,8-diazabicyclo [3.2.1] oct-8-yl] methanone (Brepocitinib)H

[0044] or a pharmaceutically acceptable salt thereof. The Brepocitinib (referred to interchangeably herein as “the compound”) or a pharmaceutically acceptable salt thereof can be administered to a subject in a dose of about 10 mg to about 200 mg. For example, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 150 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 150 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 100 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 90 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 80 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 70 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 60 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 50 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 40 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg to about 30 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage of about 10 mg to about 20 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 20 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 30 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a doseAtty. Docket No. PRIOV- 43983.601of about 40 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 50 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 60 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 70 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 80 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg to about 200 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dose of about 150 mg to about 200 mg.

[0045] In some embodiments, the pharmaceutically acceptable pharmaceutically acceptable salt is p-toluenesulfonic acid pharmaceutically acceptable salt. In some embodiments, p-toluenesulfonic acid pharmaceutically acceptable salt is (lS)-2,2-difluorocyclopropyl] [3- [2- [(1-methyl-lH pyrazol-4-yl)amino]-4-pyrimidinyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-methanone,4-methylbenzenesulfonate (1:1) with the structure:

[0046] Methods for making Brepocitinib are described at least in WO 2016 / 027195 and U. S. Patent No. 9,663,526, the contents of which are herein incorporated by reference.

[0047] Embodiments of the present disclosure also include the administration of an effective amount of Brepocitinib to the subject has one or more effects selected from the group consisting of: decreases or inhibits one or more cytokine signaling pathways implicated in sarcoidosis; decreases or inhibits cytokine activity mediated by IFN-I and INF-II activity in the subject;Atty. Docket No. PRIOV- 43983.601decreases or inhibits cytokine activity mediated by interleukin (IL)-6, IL-12, IL-15, IL-21, IL-22, IL-23 activity in the subject; and interferes with and / or reduces sarcoidosis activity and subsequent damage and changes in morphology.

[0048] In some embodiments, the sarcoidosis includes, but is not limited to, pulmonary sarcoidosis, ocular sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, musculoskeletal sarcoidosis, hepatic sarcoidosis, renal sarcoidosis, splenic sarcoidosis, lymphatic sarcoidosis, endocrine sarcoidosis, gastrointestinal sarcoidosis or multisystem sarcoidosis. In some embodiments, the sarcoidosis is cutaneous sarcoidosis. In some embodiments, the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, plaque sarcoidosis, nodular sarcoidosis, scar sarcoidosis, tattoo sarcoidosis, subcutaneous sarcoidosis (Darier-Roussy sarcoidosis), hypopigmented sarcoidosis, or any combination thereof. In some embodiments, the sarcoidosis is pulmonary sarcoidosis. In other embodiments, the sarcoidosis is ocular sarcoidosis. In other embodiments, the sarcoidosis is cardiac sarcoidosis. In other embodiments, the sarcoidosis is neurosarcoidosis. In other embodiments, the sarcoidosis is musculoskeletal sarcoidosis. In other embodiments, the sarcoidosis is hepatic sarcoidosis. In other embodiments, the sarcoidosis is renal sarcoidosis. In other embodiments, the sarcoidosis is splenic sarcoidosis. In other embodiments, the sarcoidosis is lymphatic sarcoidosis. In other embodiments, the sarcoidosis is endocrine sarcoidosis. In other embodiments, the sarcoidosis is gastrointestinal sarcoidosis. In other embodiments, the sarcoidosis is multisystem sarcoidosis. In some embodiments, the sarcoidosis is cutaneous sarcoidosis. In some embodiments, the cutaneous sarcoidosis is lupus pernio. In other embodiments, the sarcoidosis is papular sarcoidosis. In other embodiments, the sarcoidosis is plaque sarcoidosis. In other embodiments, the sarcoidosis is nodular sarcoidosis. In other embodiments, the sarcoidosis is scar sarcoidosis. In other embodiments, the sarcoidosis is tattoo sarcoidosis. In other embodiments, the sarcoidosis is subcutaneous sarcoidosis (Darier-Roussy sarcoidosis). In other embodiments, the sarcoidosis is hypopigmented sarcoidosis.

[0049] In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0050] In some embodiments, the compound is administered orally.

[0051] In some embodiments, the compound is administered in a dosage of about 45 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 40 mg. In yet other embodiments, embodiments, the compound, or pharmaceutically acceptable salt thereof is administered in a dosage that is about 30 mg. In someAtty. Docket No. PRIOV- 43983.601embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 25 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 20 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 15 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 10 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 5 mg.

[0052] In some embodiments, the compound is administered in a dosage of about 15mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 10 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is about 5 mg.

[0053] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 50 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 40 mg. In yet other embodiments, embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 30 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 25 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 20 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 15 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 10 mg. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered in a dosage that is less than about 5 mg.

[0054] In some embodiments, the compound or pharmaceutically acceptable salt thereof administered is taken daily. In some embodiments, the compound or pharmaceutically acceptable salt thereof is taken once daily in the dosages recited above. In some embodiments, the compound or pharmaceutically acceptable salt thereof administered is in divided doses administered two, three or four times per day in the dosages recited above.

[0055] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 70 weeks. For example, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 60 weeks. In some embodiments, theAtty. Docket No. PRIOV- 43983.601compound or pharmaceutically acceptable salt thereof is administered for less than or about 50 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 40 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 30 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 20 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 10 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 5 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 4 weeks. In some embodiments, the compound is administered for less than or about 3 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 2 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for less than or about 1 week.

[0056] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 4 weeks. For example, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 5 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 6 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 7 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 8 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 9 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 10 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 20 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 30 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 40 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 50 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 60 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 70 weeks.Atty. Docket No. PRIOV- 43983.601

[0057] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, about 60 weeks, about 61 weeks, about 62 weeks, about 63 weeks or about 64 weeks.

[0058] The Brepocitinib or pharmaceutically acceptable salt can be administered by any methods known to one skilled in the art. For example, Brepocitinib or pharmaceutically acceptable salt thereof can be administered in the form of a composition, such as, for example, a pharmaceutical composition of Brepocitinib or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, such as those described herein. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet for oral administration, such as an enteric coated tablet. In some other embodiments, the pharmaceutical composition is a liquid dosage form for oral administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0059] The pharmaceutical compositions described herein can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may optionally contain solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, stabilizers and preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0060] In some embodiments, pharmaceutical compositions are formulated for pharmaceutical administration to a mammal, such as a human or a canine. Such pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intravenously, or subcutaneously. The formulations of the present disclosure may be designed to be short-acting, fast-releasing, or long-acting. StillAtty. Docket No. PRIOV- 43983.601further, compounds can be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0061] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0062] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions formulated for parenteral administration may be injected by bolus injection or by timed push or may be administered by continuous infusion.

[0063] In order to prolong the effect of a compound or therapeutic agent (e.g., Brepocitinib or pharmaceutically acceptable salt thereof), it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may dependAtty. Docket No. PRIOV- 43983.601upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0064] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the osimertinib and / or alisertib with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0065] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the therapeutic agent is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents such as phosphates or carbonates.

[0066] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents andAtty. Docket No. PRIOV- 43983.601can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0067] The Brepocitinib or pharmaceutically acceptable salt can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0068] Dosage forms for topical or transdermal administration of the therapeutic agents described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0069] Compositions for use in the method of the present disclosure may be formulated in unit dosage form for ease of administration and uniformity of dosage. The phrase “unit dosage form”Atty. Docket No. PRIOV- 43983.601as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and pharmaceutical compositions described herein will be decided by the attending physician within the scope of sound medical judgment. A unit dosage form for parenteral administration may be in ampoules or in multi-dose containers.Example 1

[0070] Overall Design. This is a prospective, randomized, double-blind, placebo-controlled, doseranging study. The population selected for this study comprises individuals with active, moderate to severe cutaneous sarcoidosis. After an up to 4-week Screening Period, eligible participants will be centrally randomized 3:2:2 to 1 of 3 intervention groups to receive blinded investigational medicinal product (IMP) of either Brepocitinib 45 mg, Brepocitinib 15 mg, or matching placebo, both administered orally once daily (QD).

[0071] Brief Summary. The purpose of this study is to measure clinical safety and efficacy of oral Brepocitinib in adult participants with cutaneous sarcoidosis. Study details include:a. Up to 30 days for screening (Screening Period), thenb. 16 weeks of treatment with double-blinded treatment with either Brepocitinib 45 mg, Brepocitinib 15 mg, or placebo (Treatment Period), thenc. 4 weeks for safety follow-up (Off-Drug Follow-Up), andd. the visit frequency is every 4 weeks.

[0072] Ongoing standard of care (that meet eligibility criteria requirements) will be maintained during the Treatment Period. Participants receiving oral corticosteroids at baseline will undergo a mandatory taper (starting Day 15, Week 2) and discontinue oral corticosteroids on or before Day 57 (Week 8). The schema of the study design is shown in Figure 1.

[0073] Number of Participants. Approximately 28 participants will be enrolled at up to 20 sites in the US.

[0074] Screening Period. The Screening Period may last up to 30 days prior to baseline (Day 1 / Visit 2). The primary purpose of the Screening Visit is to identify individuals with active, cutaneous sarcoidosis without clinically significant extracutaneous sarcoidosis manifestations that may increase the risk of non-compliance with protocol procedures.

[0075] Treatment Period. The Treatment Period begins at baseline (Day 1 / Visit 2) and ends at Week 16 / Visit 6, which is the primary analysis timepoint. After final confirmation of studyAtty. Docket No. PRIOV- 43983.601eligibility, participants will be randomized 3:2:2 to Brepocitinib 45 mg, Brepocitinib 15 mg, or placebo.

[0076] Ongoing standard of care (that meet eligibility criteria requirements) will be maintained during the Treatment Period. Participants receiving oral corticosteroids at baseline will undergo a mandatory taper (starting Day 15, Week 2) and discontinue oral corticosteroids on or before Day 57 (Week 8).

[0077] Off-Drug Follow-Up Period. To assess safety over the 4-week, Off-Drug Follow-Up, participants will receive a phone contact or return to the clinic at Week 20 for the Off-Drug Follow-Up Visit.

[0078] Duration of Treatment. The total duration of treatment will be up to 16 weeks.

[0079] Scientific Rationale for Study Design. This is a 16-week, randomized, double-blind, placebo-controlled study to investigate efficacy and safety of oral Brepocitinib in adults with cutaneous sarcoidosis. Efficacy and safety will be evaluated by changes in assessments from baseline through Week 16.

[0080] There are no FDA approved therapies for cutaneous sarcoidosis. A number of efficacy endpoints (e.g., the cutaneous sarcoidosis activity and morphology instrument (CSAMI; Table 1 ), and a cutaneous sarcoidosis activity investigator global assessment (CSA-IGA; Table 2)) and patient reported outcomes (PROs) are included in the study to explore the efficacy profile and clinical meaningfulness of changes observed in this study and to inform potential later phase trials. Due to the exploratory nature of these efficacy endpoints, the primary endpoint will be an assessment of the safety and tolerability of Brepocitinib in cutaneous sarcoidosis.

[0081] Table 1: Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI)Atty. Docket No. PRIOV- 43983.601Sfinatliactitain escft M rtsas>Aerswvresist22 23 *■WSolo„o®L..AbdomenTotal activity score hrO-i sfeffia go score >MsrphoSegic type:D stuoiw D tfce^wU ^vpark^tfec [J L" J?<hfeo<ifai' mD P$nriy$fem Q > w».«wxW _ _>

[0082] Table 2: Cutaneous Sarcoidosis Activity Investigator Global Assessment (CSA-IGA)Atty. Docket No. PRIOV- 43983.601Cutaneous Sarcoidosis Activity investigator’s Global Assessment Rate the severity of sarcoidosis-related skin activity seen today, using the definitionsprovided below for erythema and lesion thickness. Also rate the extent of disease and involvement of cosmetically significant areas (e.g., face, hands)Note: Post-inflammatory' hypa- / hyper-pigmentation and scarring should not be considered.Characteristic Score Score Features0 = No erythemaErythema (E) 1 = Barely perceptible erythema( averaged o ver the 2 = Slight but definite pink or light pink erythemaaffected areas) 3 = Pink to red erythema4 = Bright red., deep red, or violaceous erythema0 = No induration or depressionLesion Thickness ( L) 1 = Barely perceptible lesion thickness(averaged over the 2 = < 1 mm lesion thickness of most lesionsaffected areas) 3 = 1-2 ir>rn thickness of most lesions4 = > 2 mm thickness of most lesionsAverage of E and L scoresActivity Score (E + L) / 2Rounded up to nearest whole number.0 = No inflammatory lesions in any area1 = MinimalExtent of ActiveDisease (B) 2 = Moderate3 = Widespread4 = Very widespread0 = No involvementActive Disease in 1 = Very limited involvementCosmetically 2 = Slight involvementSignificant Areas (C) 3 = Moderate involvement4 = Major Involvement

[0083] Due to the historically rapid onset of action of JAK inhibitors, this duration of treatment is expected to be sufficient to demonstrate any treatment-related efficacy of Brepocitinib, also as evidenced in an open-label study of another JAK inhibitor, tofacitinib, in cutaneous sarcoidosis patients [Damsky 2022],

[0084] This study will evaluate two dose levels of Brepocitinib (45 mg QD and 15 mg QD) compared to placebo. The inclusion of a placebo arm is justified by allowing all participants to continue any ongoing non-steroid oral background therapy (e.g., immunomodulatory, immunosuppressive, antimalarial, tetracycline therapy) in addition to study drug. ParticipantsAtty. Docket No. PRIOV- 43983.601using oral corticosteroids at baseline will be tapered per-protocol to evaluate a potential steroid-sparing effect of Brepocitinib.

[0085] Justification for Dose. Oral Brepocitinib has been administered in 15 completed studies from across the Phase 1 and Phase 2 development program at single doses up to 200 mg and multiple doses up to 100 mg QD. Refer to the current Brepocitinib IB for a summary of safety and efficacy across the clinical development program. Collectively, these data support 16-week administration of Brepocitinib at 45 mg QD and 15 mg QD dose levels.

[0086] Completed Phase 2 studies in psoriasis, psoriatic arthritis, alopecia areata, hidradenitis suppurativa, non-infectious uveitis (NIU), Crohn’s disease, and ulcerative colitis have evaluated Brepocitinib dose levels ranging from of 10 to 60 mg QD. Consistent dose-dependent effects on key efficacy endpoints were observed across these studies, with doses in the 30 to 60 mg range providing maximal efficacy (refer to the current Brepocitinib IB for study summaries). Based on these results, a high-level of target engagement is expected at the 45 mg QD dose level, as recently demonstrated in participants with NIU.

[0087] The Brepocitinib 15 mg QD dose level was selected to further elucidate potential doseresponse relationships for safety and efficacy in cutaneous sarcoidosis. Efficacy has been noted in prior studies using a dose level of 10 mg QD, albeit reduced, and therefore a dose of 15 mg QD was selected for the current study to explore the Brepocitinib dose-response. This dose has also shown pharmacologic efficacy supported by dose-dependent reductions in interferon gammainduced protein 10 (IP- 10, also known as C-X-C motif chemokine ligand 10 [CXCL10]) that have been observed in Phase 1 and Phase 2 studies. In healthy subjects, reductions in IP- 10 were observed by Day 2 and separated from placebo at doses ≥ 10 mg. In participants with psoriasis, reductions in IP-10 were also observed.

[0088] Importantly, there is considerable overlap between cutaneous sarcoidosis and the completed Phase 2 studies in plaque psoriasis and hidradenitis suppurativa, in not only the cytokines implicated in their pathogenesis (type II IFN, IL-12, IL-13, and IL-23), but also the cutaneous symptoms caused by these diseases (skin inflammation, scarring). Collectively, these data suggest Brepocitinib 45 mg QD and Brepocitinib 15 mg QD are appropriate doses for the current 16-week study in participants with cutaneous sarcoidosis.Atty. Docket No. PRIOV- 43983.601

[0089] Study Population.

[0090] Inclusion Criteria. An individual will be eligible for participation in this study only if all of the following inclusion criteria are met:

[0091] Age and Sex. Male or female, and the participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent form (ICF).

[0092] Type of Participant and Disease Characteristics. A screening skin biopsy histology consistent with cutaneous sarcoidosis and presentation of cutaneous sarcoidosis symptoms for ≥ 6 months where other possible etiologies (e g. infection) have been reasonably excluded. If results from historic biopsy are available, a skin biopsy does not have to be performed at screening unless participating in optional biopsy biomarker collection. A CSAMI activity score of ≥ 10 at screening and baseline (Day 1 / Visit 2).

[0093] Weight. Participants weighing > 40 kg to < 130 kg, and with a body mass index (BMI) < 40 kg / m2.

[0094] Informed Consent. Participants who are able and willing to understand and comply with the study requirements and capable of giving signed informed consent.

[0095] Prior / Concomitant Therapy. Current therapy consisting of > 25 mg / day of prednisone or equivalent or a change in corticosteroid dose in the 4 weeks prior to baseline [Day 1 / Visit 2],

[0096] Current or planned treatment with prohibited concomitant medications, including biologic therapy (e.g., TNF inhibitors) and investigational agents during the study. Prior treatment is permitted provided the specified discontinuation period is met prior to baseline (Day 1 / Visit 2), including:

[0097] Use of topical JAK inhibitors or topical calcineurin inhibitors within 12 weeks prior to baseline (Day 1 / Visit 2);

[0098] Intralesional corticosteroids administered within 4 weeks prior to baseline (Day 1 / Visit 2).

[0099] If receiving immunomodulatory, antimalarial, or tetracycline antibiotic therapy (up to 1 of each is permitted):

[0100] Receiving more than 1 of the immunomodulatory therapies, or an immunomodulatory therapy at a dose higher than that listed in Table 3;

[0101] Receiving more than 1 of the antimalarial therapies, or an antimalarial therapy at a dose higher than that listed in Table 3;Atty. Docket No. PRIOV- 43983.601

[0102] Receiving more than 1 of the tetracycline antibiotics, or a tetracycline antibiotic at a dose higher than that listed in Table 3.

[0103] Table 3: Allowed Non-Steroid Immunomodulatory TherapyDrug Maximally allowed stable dose as concomitant therapy:Immunomodulatory TherapyAzathioprine 2.5 mg / kg daily; Cyclosporine 5 mg / kg dailyi Leflunomide 20 mg dailyi Methotrexate 25 mg weeklyi Mycophenolate mofetil (MMF) 3000 mg dailyMycophenolic acid (MPA) 2160 mg daily; Sulfasalazine 3000 mg dailyi Tacrolimus 0.2 mg / kg dailyi Antimalarialsi Chloroquine 250 mg dailyi Hydroxychloroquine 400 mg dailyTetracyclinesMinocycline or doxycycline 100 mg twice dailyIf receiving therapies listed above, it must have been taken for at least 12 weeks and the dose must have been stable for at least 4 weeks, prior to baseline (Day 1 / Visit 2), and the dose must be anticipated to remain stable for the duration of the study.Prior exposure to Brepocitinib or participation in a Brepocitinib clinical trial.History of hypersensitivity to any constituents of the IMP formulation or other JAK inhibitors.

[0104] Diagnostic Assessments. Confirmed positive screening result for hepatitis B (hepatitis B surface antigen [HBsAg] positive; HBsAg negative, hepatitis B core antibody [HBcAb] positive, and hepatitis B surface antibody [HBsAb] negative; or HBV deoxyribonucleic acid [DNA] positive on reflex testing), hepatitis C (hepatitis C virus antibody [HCVAb] positive and hepatitis C virus [HCV] RNA positive on reflex testing), or human immunodeficiency virus [HIV] infection.

[0105] Note: HBsAg negative, HBcAb positive, HBsAb positive participants will be eligible if HBV DNA is negative on reflex testing.

[0106] Impaired kidney function, defined as serum creatinine-based eGFR< 30 mL / min / 1.73 m2 at screening (and confirmed by repeat test, if deemed necessary), or renal disease associated with clinically meaningful proteinuria or interstitial nephritis.Atty. Docket No. PRIOV- 43983.601

[0107] Lifestyle Considerations

[0108] Contraception: Female Participants. Participants who are WOCBP must understand that they should avoid becoming pregnant during the study. The investigator or designee, in consultation with the participant (WOCBP), will confirm that the participant has selected an appropriate method of contraception for the individual participant from the permitted list of contraception methods and will confirm that the participant has been instructed in its consistent and correct use. As indicated, throughout the study, the investigator or designee will inform the participant of the need to use highly effective contraception consistently and correctly and document the conversation and the participant’s affirmation in the participant’s chart (participants need to affirm their consistent and correct use of at least one of the selected methods of contraception). In addition, the investigator or designee will instruct the participant to call immediately if the selected contraception method is discontinued or if pregnancy is known or suspected in the participant.

[0109] Contraception: Male Participants. No contraception methods are required for male participants in this study, as the calculated safety margin is > 100-fold between the estimated maternal exposure due to seminal transfer and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.

[0110] Other Requirements. Participants must be made aware of the following lifestyle guidelines and restrictions that apply during the study:• Avoid strenuous exercise within 24 hours prior to a scheduled study visit and maintain adequate hydration, if possible.• On study visit days, take prescribed permitted concomitant medication(s), as needed, prior to the study visit.• On the day of Visit 3 / Week 4, do not take the dose of IMP at home, as it will be administered in the clinic after the first pre-dose PK sample.• One the day of Visit 6 / Week 16, do not take the dose of IMP at home. The final dose of IMP should be the day before Visit 6.• If applicable, the first reduction in dose of the oral corticosteroid taper should occur on Day 15.• Contact the study site investigator if there are any changes or additions to concomitant medications.Atty. Docket No. PRIOV- 43983.601• A participant may withdraw from the trial at any time without any resulting detriment and without having to provide any justification. The participant is not obliged to give their reason(s) for withdrawing prematurely from the trial, and may withdraw without penalty or loss of benefits to which the participant is otherwise entitled; however, all participants who enroll should be encouraged to remain in the study through to the end of the Treatment Period for safety and efficacy assessments, whether or not they continue to receive IMP or are switched to non-protocol treatment; this is in order to reduce missing data as much as possible. It is expected that the only reasons for which a participant will withdraw from the study will be for withdrawal of consent or lost to follow-up. This was specifically requested by a regulatory authority to minimize missing data in participants who prematurely discontinue IMP.

[0111] Screen Failures. A screen failure occurs when a participant who consents to participate in the clinical study does not subsequently receive IMP. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs.

[0112] Individuals who otherwise meet all inclusion criteria and no exclusion criteria except for laboratory values are not automatically considered screen failures and may undergo repeat laboratory testing, without the need to repeat other eligibility assessments. If repeat laboratory testing still excludes participation, this will be considered screen failure, and the participant may rescreen at a later date.

[0113] Rescreening. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened. Rescreening is allowed no more than 2 times for an individual participant. Rescreened participants should be re-consented and assigned a new participant number (Subject Identification [ID] number).

[0114] Criteria for Temporarily Delaying Enrollment. An extension of the Screening Period may be granted after consultation between the investigator and sponsor. Reasons for extending the Screening Period include, but are not limited to, the following:Atty. Docket No. PRIOV- 43983.601

[0115] Results of laboratory tests or other assessments required to determine eligibility are pending (e.g., if a skin biopsy or chest x-ray is required and has been performed, but results have not been reported within the designated Screening Period).

[0116] Clinic visit scheduling is delayed or shipment of supplies to the site (e.g., IMP or laboratory kits) are delayed due to a global crisis or other unforeseeable reasons.

[0117] Study Assessments and Procedures. Protocol waivers or exemptions are not allowed.

[0118] Study procedures and their timing are summarized in the Schedule of Activities (Table 1). Additional unscheduled visits or assessments may be arranged as needed for participants with any study-related safety concerns.

[0119] Immediate safety concerns should be discussed with the medical monitor and / or sponsor upon occurrence or awareness to determine if the participant should continue or discontinue study participation.

[0120] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm study eligibility or record reasons for screening failure, as applicable.

[0121] Procedures conducted as part of the participant’s routine clinical management (e.g., chest x-ray) and obtained before signing of the ICF may be utilized for screening or baseline purposes provided the procedures meet the protocol-specified criteria. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.

[0122] Administrative Procedures. It is strongly encouraged that study assessments (when applicable to a visit) be performed in the following order:1. Informed consent2. Patient-reported outcome (PRO) questionnaires (i.e., participant-completed assessments)3. Vital signs and ECG4. AE collection5. Concomitant medication6. Investigator-completed assessments7. It is strongly encouraged that the investigator-completed assessments be performed in the following order: CSAMI (activity and damage), CSA-IGA, PhGI-S, PhGI-CAtty. Docket No. PRIOV- 43983.6018. Skin photography9. Blood draws10. Urinalysis11. IMP administration (i.e., the witnessed dose at baseline [Day 1 / Visit 2] and for PK sampling [Week 4 / Visit 3])

[0123] Note: For WOCBP, a negative pregnancy test result (urine test) must be obtained prior to IMP dosing in the clinic at baseline (Day 1 / Visit 2).

[0124] At applicable visits, a skin biopsy should be completed after skin photography.

[0125] For visits that include PK sampling, pre-dose and post-dose samples should be collected at times relative to IMP administration.

[0126] Informed Consent. The investigator (or appropriate delegate at the site) must obtain a signed and dated ICF from each potential participant prior to performing any study-specific procedures.

[0127] Demographic and Baseline Characteristics. The following demographics will be recorded: year of birth, sex (as assigned at birth), race, and ethnicity. These data will be used to characterize the study population and may be used to evaluate any differences in safety or efficacy based on demographic variables.

[0128] Medical History / Prior Medications. Medical / surgical and medication history (including vaccinations and sarcoidosis medications) will be assessed during screening (Visit 1) and baseline (Visit 2 / Day 1). However, if additional information about the participant’s medical / surgical or medication history is learned during the course of the study, this will also be recorded in the eCRF, even if this history is obtained after baseline.

[0129] The medical history will be obtained by the investigator (or appropriately qualified delegate at the site). Medical history will include all relevant chronic, past, and ongoing conditions, regardless of the year diagnosed. At a minimum, medical history over the last 5 years should be collected. To confirm eligibility criteria, the medical history will include, but is not limited to, a review of the following: sarcoidosis history, lymphoproliferative disorders, cancers, musculoskeletal or neuro-muscular conditions, liver disease, thromboembolic conditions, cardiovascular disease, and solid organ transplant history. Alcohol and tobacco use history also will be collected at screening.Atty. Docket No. PRIOV- 43983.601

[0130] Ongoing or new non-sarcoidosis medications used during screening will be assessed as part of the participant’s medication history (including over-the-counter or prescription medications, recreational drugs, vitamins, and / or herbal supplements). Vaccination history also will be collected (e.g., hepatitis B, varicella zoster).

[0131] Clinical / Efficacy Assessments. There is no target lesion for clinical efficacy assessments. All cutaneous sarcoid lesions should be evaluated.

[0132] Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI). The CSAMI is an investigator-completed, one-page tool used to assess skin disease in cutaneous sarcoidosis [Rosenbach, 2013], The items included in this tool are used evaluate the skin in 11 anatomic locations, with 2 separate scores given based on activity (inflammation / erythema, induration or depression, surface change / scaling, and area; CSAMI -A scores range from 0-165) and damage (hypo- / hyper-pigmentation and scarring; CSAMI-D scores range from 0-22). The tool also assesses morphologic types of sarcoidosis lesions and examines the presence of specific types of lesions, including lupus pernio and erythema nodosum.

[0133] The CSAMI is a tool developed for use in clinical trials and longitudinal participant assessment. Higher CSAMI scores indicate greater disease severity. A sample of the CSAMI is provided in Table 1.

[0134] Dermatology Life Quality Index (DLQI). The DLQI is a participant-completed, 10-item questionnaire that assesses subjects’ health-related quality of life including daily activities, relationships, work and school, symptoms and feelings, and treatment [Finlay, 1994], The response scale is a 4-point scale with total scores ranging from 0 to 30 (higher scores indicate a greater impact on quality of life). It has been used extensively in dermatology clinical trials and has been shown to be responsive to change.

[0135] Fatigue Assessment Scale (FAS). The FAS is a participant-completed, 10-item questionnaire comprising questions related to physical and mental fatigue developed for use in the general population [Michielsen, 2004], The response scale is a 5-point scale (1-never to 5- always) with total scores ranging from 10-50 (higher scores indicates greater fatigue). The FAS has previously been reported to have good validity in the sarcoidosis population [De Vries, 2004],Atty. Docket No. PRIOV- 43983.601

[0136] Cutaneous Sarcoidosis Activity Investigator’s Global Assessment (CSA-IGA). The CSA-IGA is an investigator-completed verbal writing (Likert-type) assessment of the severity of the participant’s cutaneous sarcoidosis. A sample of the CSA-IGA is provided in Table 2.

[0137] King’s Sarcoidosis Questionnaire (KSQ). The KSQ is participant-completed, modular, multi-organ health status measure with five modules (general health, skin, lung, eyes, medication) that are answered based on a participant’s affected organs [Patel, 2013], The KSQ is scored using a re-ordered response scale. The organ-specific modules can be combined with the General health status module to assess overall health status.

[0138] The KSQ is a tool developed for use in sarcoidosis clinical trials and clinical practice. Lower KSQ scores indicate worse quality of life.

[0139] Patient Global Impression of Change (PGI-C). The PGLC is a participant-completed single-item, verbal writing (Likert-type) assessment of the overall change in the participant’s cutaneous sarcoidosis since starting study drug.

[0140] Patient Global Impression of Severity (PGI-S). The PGLS is a participant-completed single-item, verbal writing (Likert-type) assessment of the overall severity of the participant’s cutaneous sarcoidosis that day considering all the ways cutaneous sarcoidosis affects the participant.

[0141] Physician Global Impression of Change (PhGI-C). The PhGLC is an investigator-completed single-item, verbal writing (Likert-type) assessment of the overall change in the participant’s cutaneous sarcoidosis since starting study drug.

[0142] Physician Global Impression of Severity (PhGI-S). The PhGLS is an investigator-completed single-item, verbal writing (Likert-type) assessment of the participant’s overall dermatomyositis activity.

[0143] Rhinosinusitis Disability Index (RSDI). The RSDI is a participant-completed, 30-question tool that assesses a participant’s health related quality of life because of chronic rhinosinusitis [Benninger, 1997], Each question is scored on a 0 to 4 scale (0=never, l=almost never, 2=sometimes, 3=almost always, 4=always). At the end of the questionnaire, participants are asked to rate the overall severity of their rhinosinusitis on a scale from 0 (normal) to 7 (severe). The RSDI is calculated both for a total score and for functional, emotional, and physical domains. The total score ranges from 0 to 120, with higher scores indicating greater disability.Atty. Docket No. PRIOV- 43983.601

[0144] Sarcoidosis Assessment Tool (SAT). The SAT is a participant-completed health-related quality-of-life measure comprised of generic measures from the patient-reported outcomes measurement information system (PROMIS) as well as four sarcoidosis-specific item banks and short forms of eye problems, lung problems, skin problems and skin stigma [Victorson, 2014], SAT short forms are scored using an algorithm based on item-response theory, contain between 5 and 10 items each, and are scored using a 5-point Likert scale. The SAT is a tool developed for use in sarcoidosis clinical trials and clinical practice.

[0145] Skindex-16. The Skindex-16, is a participant-completed tool used to rate the most bothersome skin condition that occurred in the past week [Chren, 2001], It is a short 16-item tool using numerical scales, ranging from 0 (“Never Bothered”) to 6 (“Always Bothered”). Responses are categorized into 3 subscales: symptoms (4 items), emotional (7 items), and functional (5 items). The overall score averages the 3 domain scores, all of which are normalized to a 0 to 100 scale, where 0 indicates that their skin condition has no impact on quality of life and 100 represents maximal impact on quality of life for the worse.

[0146] Skin Photography. On the visit day photography assessments, participants are requested to avoid applying creams or ointments onto their skin prior to the clinic visit. An effort will be made to maintain the same photography equipment and lighting at every visit. Capture relevant skin disease and photograph the same area(s) at each visit photography is assessed. While body photography is not required. A ruler and color strip / wheel will be included in every photograph. Any new lesions during the study should also be captured. Areas photographed will be recorded, and all photographs will be maintained with the participant’s source documents. All photographs will be de-identified and may also be used in external disclosures.

[0147] Skin Biopsy. If a historic skin lesion biopsy is not available for determination of eligibility, a skin biopsy must be collected during screening. The lesion for biopsy will be selected by the investigator that is representative of the participants cutaneous sarcoidosis. Skin punch biopsy is to be performed according to standard institutional practice with regard to antiseptic preparation technique and local anesthesia. Collection of additional skin biopsies for potential assessment of exploratory biomarker research is optional.

[0148] Pulmonary Function Testing. Pulmonary function testing at screening is not required if an inclusionary test is available within the 12 months prior to screening, unless, in the judgment of the investigator, the historic test is no longer representative of the participants’ lung function.Atty. Docket No. PRIOV- 43983.601

[0149] Spirometry. Spirometry may be performed either at the study site or an external site that provides pulmonary function testing. FEV1 and FVC, absolute and percent predicted, will be documented.

[0150] Diffusion Capacity. DLCO is to be measured using the single-breath technique and obtained after participants have been sitting quietly for 5 minutes. DLCO is to be corrected for hemoglobin.

[0151] Vital Signs. Vital signs (blood pressure [BP], heart rate [HR], respirations, and temperature) will be measured with the participant in a quiet setting without distractions (e.g., television, cell phones). Vital sign measurements should be taken prior to any blood collections taken during the visit. BP and HR measurements should be assessed with the participant in a seated or supine position with a completely automated device; however, manual techniques may be used if an automated device is not available. The same equipment and method for assessing BP should be used at all visits for a given participant. Temperature should be assessed using the same method at all visits for a particular participant.

[0152] Height. Standing height will be measured without shoes.

[0153] Body Weight. Body weight will be measured in kilograms using a scale with appropriate range and resolution, and it must be placed on a stable, flat surface. Participants should remove their shoes and bulky layers of clothing (jacket / coat), so that only light street clothing remains. Participants should also remove the contents of their pockets and remain still during the weight measurement.

[0154] Physical Examination. A physical examination will include, at a minimum, assessments of the head, ears, eyes, nose, mouth, skin, lymph nodes as well as the cardiovascular, respiratory, gastrointestinal (includes liver and spleen), musculoskeletal, and neurological systems. A symptom-directed physical examination may include a subset of systems based on participant symptoms and the investigator’s judgement. At subsequent visits after screening / Visit 1, if no symptoms are present, a physical examination is not required. Investigators should pay special attention to clinical signs related to previous serious illnesses. Physical examinations may be conducted by a physician, trained physician’s assistant, or nurse practitioner as acceptable according to local regulations and documented on the delegation of authority log.

[0155] Electrocardiogram (ECG). ECGs (12-lead) will be obtained using an ECG machine that automatically calculates the HR and measures PR and QT (including QT corrected for heat rateAtty. Docket No. PRIOV- 43983.601[QTc]) intervals. All scheduled ECGs should be performed after the participant has rested quietly for at least 10 minutes in a supine position and prior to any blood collections. ECGs will be read centrally. The final ECG report from the central ECG vendor should be reviewed by the investigator or designee and maintained in the participant’s source documentation and will be considered the final interpretation of the ECG recording.

[0156] Chest X-Ray. A chest x-ray is required to assess participant eligibility; however, historical results from a prior chest x ray (or computed tomography [CT] or positron emission tomography [PET]-CT scan) showing no abnormalities may be used for screening purposes if the chest x-ray (or CT or PET CT scan) was performed within 6 months prior to screening / Visit 1. The official reading must be included in the source documentation and recorded in the eCRF. Chest radiography with poster-anterior and lateral views is recommended; however, local guidelines should be followed. On the screening chest x-ray, participants should have no evidence of active or prior infection with TB, general infections, atypical mycobacterial disease, cavitary lung lesions, or other exclusionary conditions.

[0157] Clinical Safety Laboratory Tests. The investigator must review the laboratory report, document this review, and record clinically significant changes occurring during the study as an AE. The laboratory reports must be filed with the source documents. The criteria for determining whether an abnormal laboratory finding should be reported as an AE include the following:1. The test result is associated with accompanying symptoms, and / or2. The test result requires additional diagnostic testing or medical / surgical intervention, and / or3. The test result leads to a change in dosing (not allowed per protocol), discontinuation from the study, significant additional concomitant drug treatment, or other therapy.

[0158] Abnormal laboratory findings associated with the underlying disease are not considered clinically significant unless judged by the investigator to be more severe than expected for the participant’s condition.

[0159] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within approximately 4 weeks after the last dose of IMP should be repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor.Atty. Docket No. PRIOV- 43983.601

[0160] If clinically significant values do not return to normal / baseline within a period of time judged reasonable by the investigator, the etiology should be identified, and the sponsor notified.

[0161] If laboratory values from non-protocol-specified laboratory tests performed at the institution’s local laboratory require a change in participant management or are considered clinically significant by the investigator (e.g., SAE or AE), then the results must be recorded.

[0162] Pregnancy Testing. WOCBP only must have a serum β-hCG pregnancy test at screening and urine β-hCG pregnancy tests at subsequent study visits. A negative urine pregnancy test is required for WOCBP prior to dosing at baseline (Day 1 / Visit 2) and Visit 3 / Week 3. Additionally, if the site staff become aware of a participant having a missed menstrual cycle between visits, the participant should come to the site for a urine pregnancy test (as an unscheduled visit if necessary).

[0163] Urine pregnancy tests (supplied by the central laboratory) will be performed at the site. A positive urine β-hCG test must be followed up with a serum β-hCG pregnancy test. A positive pregnancy test prior to randomization requires exclusion. A positive urine β-hCG test during the study after randomization requires immediate interruption of study drug until a serum β-hCG is performed and found to be negative. The participant must be permanently discontinued from study drug and followed if pregnancy is confirmed by a positive serum β-hCG.

[0164] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and appreciable, and may be made using suitable equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are merely intended only to illustrate some aspects and embodiments of the disclosure, and should not be viewed as limiting to the scope of the disclosure. The disclosures of all journal references, U. S. patents, and publications referred to herein are hereby incorporated by reference in their entireties.

[0266] The present invention has multiple aspects, illustrated by the non-limiting examples described herein.

[0267] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.Atty. Docket No. PRIOV- 43983.601

[0268] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

[0269] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0270] Clause 1. A method for treating sarcoidosis, the method comprising administering to a subject in need of treatment thereof an effective amount [(lS)-2,2-difluorocyclo-propyl] [(lR,5S)-3-{2-[(l-methyl-lH-pyrazol-4-yl) amino] pyrimidin-4-yl}-3,8-diazabicyclo [3.2.1] oct-8-yl] methanone (Brepocitinib)HI

[0271] or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered in a dosage of about 10 mg to about 200 mg.

[0272] Clause 2. The method of clause 1, wherein the administration of an effective amount of Brepocitinib to the subject has one or more effects selected from the group consisting of:

[0273] a. decreases or inhibits one or more cytokine signaling pathways implicated in sarcoidosis;

[0274] b. decreases or inhibits cytokine activity mediated by IFN-I and INF-II activity in the subject;

[0275] c. decreases or inhibits cytokine activity mediated by interleukin (IL)-6, IL-12, IL-15, IL-21, IL-22, IL-23 activity in the subject; and

[0276] d. interferes with and / or reduces sarcoidosis activity and subsequent damage and changes in morphology.

[0277] Clause 3. The method of clause 1, wherein the sarcoidosis is pulmonary sarcoidosis, ocular sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, musculoskeletal sarcoidosis, hepaticAtty. Docket No. PRIOV- 43983.601sarcoidosis, renal sarcoidosis, splenic sarcoidosis, lymphatic sarcoidosis, endocrine sarcoidosis, gastrointestinal sarcoidosis, multisystem sarcoidosis, or any combination thereof.

[0278] Clause 4. The method of clause 1, wherein the sarcoidosis is cutaneous sarcoidosis.

[0279] Clause 5. The method of clause 4, wherein the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, plaque sarcoidosis, nodular sarcoidosis, scar sarcoidosis, tattoo sarcoidosis, subcutaneous sarcoidosis (Darier-Roussy sarcoidosis), or hypopigmented sarcoidosis.

[0280] Clause 6. The method of any of clauses 1-5 wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0281] Clause 7. The method of any of clauses 1-6, wherein the compound is administered orally.

[0282] Clause 8. The method of any of clauses 1-7, wherein the compound is administered in a dosage of about 45 mg.

[0283] Clause 9. The method of any of clauses 1-7, wherein the compound is administered in a dosage of about 15mg.

[0284] Clause 10. The method of any of clauses 1-9, wherein the compound administered is taken daily.

[0285] Clause 11. The method of any of clauses 1-9, wherein the compound administered is in divided doses administered two, three or four times per day.

[0286] Clause 12. The method of any of clauses 1-11, wherein the compound is administered for less than or about 64 weeks.

[0287] Clause 13. The method of any of clauses 1-11, wherein the compound is administered for more than or about 4 weeks.

[0288] Clause 14. The method of any clauses 1-13, wherein the subject is a mammal.

[0289] Clause 15. The method of clause 14, wherein said mammal is a human.

[0290] Clause 16. Use of brepocitinib for the manufacture of a medicament for the treatment of sarcoidosis in a subject in need thereof.REFERENCES

[0291] Abdelghaffar M, Hwang E, Damsky W. Cutaneous Sarcoidosis. Clin Chest Med. 2024 Mar;45(l):71-89. doi: 10.1016 / j.ccm.2023.08.004.Atty. Docket No. PRIOV- 43983.601

[0292] Baughman RP, Field S, Costabel U, Crystal RG, Culver DA, Drent M, Judson MA, Wolff G. Sarcoidosis in America. Analysis Based on Health Care Use. Ann Am Thorac Soc. 2016 Aug; 13(8): 1244-52.

[0293] Baughman RP, Judson MA, Teirstein A, Lower EE, Lo K, Schlenker-Herceg R, Bamathan ES. Chronic facial sarcoidosis including lupus pernio: clinical description and proposed scoring systems. Am J Clin Dermatol. 2008;9(3): 155-61

[0294] Benninger MS, Senior BA. The development of the Rhinosinusitis Disability Index. Arch Otolaryngol Head Neck Surg. 1997 Nov; 123(11): 1175-9.

[0295] Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Cutan Med Surg. 2001 Mar-Apr;5(2):105-10.

[0296] Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis. N Engl J Med. 2018 Dec 27;379(26):2540-2546.

[0297] Damsky W, Wang A, Kim DJ, Young BD, Singh K, Murphy MJ, Daccache J, Clark A, Ayasun R, Ryu C, McGeary MK, Odell ID, Fazzone-Chettiar R, Pucar D, Homer R, Gulati M, Miller EJ, Bosenberg M, Flavell RA, King B. Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis. Nat Commun. 2022 Jun 6;13(l):3140.

[0298] De Vries J, Michielsen H, Van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS). Br J Health Psychol. 2004 Sep;9(Pt 3):279-91.

[0299] Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)— a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994 May;19(3):210-6.

[0300] Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):cl79-84.

[0301] Lertnawapan R, Bian A, Rho YH, Raggi P, Oeser A, Solus JF, Gebretsadik T, Shintani A, Stein CM. Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus. Lupus. 2012 Mar;21(3):279-87.

[0302] Michielsen, H. J., De Vries, J., Van Heck, G. L., Van de Vijver, F. J. R., & Sijtsma, K. (2004). Examination of the Dimensionality of Fatigue: The Construction of the Fatigue Assessment Scale (FAS). Eur J Psychol Assessment, 20(1), 39-48.Atty. Docket No. PRIOV- 43983.601

[0303] National Cancer Institute (NCI), US Department of Health and Human Services, National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Published: November 27, 2017. Available from: https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / ctc.htm. Accessed: 10 February 2023.

[0304] Nicolaides NC, Pavlaki AN, Maria Alexandra MA, et al. Glucocorticoid Therapy and Adrenal Suppression. [Updated 2018 Oct 19], In: FeingoldKR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK279156 / . Accessed: 10 February 2023.

[0305] Patel AS, Siegert RJ, Creamer D, Larkin G, Maher TM, Renzoni EA, Wells AU, Higginson IJ, Birring SS. The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status. Thorax. 2013 Jan;68(l):57-65.

[0306] Risch L, Huber AR. Glucocorticoids and increased serum cystatin C concentrations. Clin Chim Acta. 2002 Jun;320(l-2): 133-4.

[0307] Rosenbach M, Yeung H, Chu EY, Kim EJ, Payne AS, Takeshita J, Vittorio CC, Wanat KA, Werth VP, Gelfand JM. Reliability and convergent validity of the cutaneous sarcoidosis activity and morphology instrument for assessing cutaneous sarcoidosis. JAMA Dermatol. 2013 May;149(5):550-6.

[0308] Safadi M, Whittington K, Zahner S, Rubinstein I, Tsoukas M, Sweiss N. Recalcitrant cutaneous sarcoidosis treated with upadacitinib: Case report. JAAD Case Rep. 2024 Jul 5;51:7-9.

[0309] Sanchez M, Haimovic A, Prystowsky S. Sarcoidosis. Dermatol Clin. 2015 Jul;33(3):389-416.

[0310] Talty R, Damsky W, King B. Treatment of cutaneous sarcoidosis with tofacitinib: A case report and review of evidence for Janus kinase inhibition in sarcoidosis. JAAD Case Rep. 2021 Aug 20; 16:62-64.

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Claims

Atty. Docket No. PRIOV- 43983.601CLAIMSWhat is claimed is:

1. A method for treating sarcoidosis, the method comprising administering to a subject in need of treatment thereof an effective amount [(lS)-2,2-difluorocyclo-propyl] [(lR,5S)-3-{2-[(l- methyl-lH-pyrazol-4-yl) amino] pyrimidin-4-yl}-3,8-diazabicyclo [3.2.1] oct-8-yl] methanone (Brepocitinib)Hor a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered in a dosage of about 10 mg to about 200 mg.

2. The method of claim 1, wherein the administration of an effective amount of Brepocitinib to the subject has one or more effects selected from the group consisting of:a. decreases or inhibits one or more cytokine signaling pathways implicated in sarcoidosis; b. decreases or inhibits cytokine activity mediated by IFN-I and INF-II activity in the subject;c. decreases or inhibits cytokine activity mediated by interleukin (IL)-6, IL-12, IL-15, IL-21, IL-22, IL-23 activity in the subject; andd. interferes with and / or reduces sarcoidosis activity and subsequent damage and changes in morphology.

3. The method of claim 1, wherein the sarcoidosis is pulmonary sarcoidosis, ocular sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, musculoskeletal sarcoidosis, hepatic sarcoidosis, renal sarcoidosis, splenic sarcoidosis, lymphatic sarcoidosis, endocrine sarcoidosis, gastrointestinal sarcoidosis, multisystem sarcoidosis, or any combination thereof.

4. The method of claim 1, wherein the sarcoidosis is cutaneous sarcoidosis.

5. The method of claim 4, wherein the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, plaque sarcoidosis, nodular sarcoidosis, scar sarcoidosis, tattoo sarcoidosis, subcutaneous sarcoidosis (Darier-Roussy sarcoidosis), or hypopigmented sarcoidosis.Atty. Docket No. PRIOV- 43983.6016. The method of any of claims 1-5 wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

7. The method of any of claims 1-6, wherein the compound is administered orally.

8. The method of any of claims 1-7, wherein the compound is administered in a dosage of about 45 mg.

9. The method of any of claims 1-7, wherein the compound is administered in a dosage of about 15mg.

10. The method of any of claims 1-9, wherein the compound administered is taken daily.

11. The method of any of claims 1-9, wherein the compound administered is in divided doses administered two, three or four times per day.

12. The method of any of claims 1-11, wherein the compound is administered for less than or about 64 weeks.

13. The method of any of claims 1-11, wherein the compound is administered for more than or about 4 weeks.

14. The method of any claims 1-13, wherein the subject is a mammal.

15. The method of claim 14, wherein said mammal is a human.

16. Use of brepocitinib for the manufacture of a medicament for the treatment of sarcoidosis in a subject in need thereof.

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