Methods for treating non-infectious uveitis with brepocitinib

Abstract

The present disclosure provides methods for treating non-infectious uveitis in a subject in need of treatment thereof. In particular, the present disclosure provides methods for the oral administration of brepocitinib or a pharmaceutically acceptable salt thereof, for the treatment of non-infectious uveitis.

Description

Atty. Docket No. PRIOV- 44858.101METHODS FOR TREATING NON-INFECTIOUS UVEITIS WITH BREPOCITINIBRELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Application No. 63 / 778,720 filed on March 27, 2025, the contents of which are herein incorporated by reference.FIELD

[0002] The present disclosure provides methods for treating non-infectious uveitis in a subject in need of treatment thereof. In particular, the present disclosure provides methods for the oral administration of brepocitinib or a pharmaceutically acceptable salt thereof once daily, for the treatment of non-infectious uveitis.BACKGROUND

[0003] Non-infectious uveitis (NIU) is a group of sight-threatening conditions characterized by inflammation of the uvea, the middle layer of the eye, which includes the iris, ciliary body, and choroid. Unlike infectious uveitis, NIU is not caused by pathogens such as bacteria or viruses but is often associated with autoimmune or systemic inflammatory diseases. It can also occur as an isolated ocular condition without a known systemic association. NIU accounts for 67-90% of uveitis cases in developed countries and is a leading cause of irreversible blindness among working-age adults.

[0004] The symptoms of NIU include eye pain, redness, sensitivity to light, blurred vision, floaters, and potential vision loss. The condition can affect different parts of the eye, leading to classifications such as anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. The pathophysiology is thought to involve T-cell-mediated autoimmune processes and pro-inflammatory cytokines such as TNF-a, IL-6, IFN-gamma, IL-12, and IL-23.

[0005] The primary goal of treatment for NIU is to control inflammation, prevent recurrences, preserve vision, and minimize medication-related side effects. The therapeutic approach typically follows a stepwise progression. Corticosteroids are the first-line treatment and can be administered topically, periocularly, intravitreally, or systemically. Examples include triamcinolone acetonide injections and long-acting implants like fluocinolone acetonideAtty. Docket No. PRIOV- 44858.101(Retisert® or Yutiq®) and dexamethasone (Ozurdex®). While effective in controlling acute inflammation, prolonged use of corticosteroids is associated with significant side effects such as cataracts, glaucoma, diabetes mellitus, hypertension, and bone thinning. For patients requiring long-term treatment or those intolerant to corticosteroids, immunomodulatory therapies (IMT) are employed. Common agents include methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, and tacrolimus. These drugs help reduce corticosteroid dependency but carry risks such as liver toxicity, kidney damage, and increased susceptibility to infections. Biologies targeting specific cytokines have been used in NIU treatment in recent years. Tumor necrosis factor-alpha (TNF-a) inhibitors like adalimumab (Humira®), the only FDA-approved biologic for NIU, are used to manage refractory cases. Other off-label biologies include infliximab and golimumab. While these agents are effective in controlling inflammation and reducing steroid use, they are expensive and can lead to side effects such as reactivation of latent infections (e g., tuberculosis), malignancies, or immune dysregulation.

[0006] Despite advancements in therapy options for NIU, several challenges remain. Specifically, long-term use of corticosteroids leads to systemic complications like osteoporosis and diabetes, as well as ocular issues like cataracts and glaucoma. Immunosuppressant drugs increase the risk of infections and organ toxicity while requiring close monitoring. Biologies may lose efficacy over time due to immunogenicity or require dose adjustments. There is a critical need for therapies with improved efficacy, reduced side effects, and compatibility with combination treatments to improve outcomes for patients with NIU.SUMMARY

[0007] In one embodiment, the present disclosure relates to a method for treating non-infectious uveitis (NIU). In one aspect, the method comprises administering to a subject suffering from NIU and in need of treatment thereof a therapeutically effective amount [(1 S)-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)HAtty. Docket No. PRIOV- 44858.101

[0008] or a pharmaceutically acceptable salt thereof, wherein the brepocitinib or a pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

[0009] In some aspects of the above method, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0010] In some aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.

[0011] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

[0012] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for at least 24 weeks.

[0013] In yet further aspects of the above method, the subject is a mammal. In additional aspects, the mammal is a human.

[0014] In another embodiment, the present disclosure relates to a method of treating macular edema in a subject suffering from non-infectious uveitis. In one aspect, the method comprises the step of administering to a subject suffering from NIU and macular edema and in need of treatment thereof a therapeutically 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

[0015] or a pharmaceutically acceptable salt thereof, wherein the brepocitinib or a pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

[0016] In some aspects of the above method, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0017] In some aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.Atty. Docket No. PRIOV- 44858.101

[0018] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

[0019] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 48 weeks.

[0020] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 40 weeks.

[0021] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 32 weeks.

[0022] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 28 weeks.

[0023] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 24 weeks.

[0024] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 20 weeks.

[0025] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 16 weeks.

[0026] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 12 weeks.

[0027] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 8 weeks.

[0028] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 6 weeks.

[0029] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 4 weeks.

[0030] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 3 weeks.

[0031] In still further aspects of the above method, the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 40 weeks, 48 weeks, or 52 weeks.

[0032] In some aspects of the above method, the subject exhibits a decrease in central subfield thickness (CST) relative to baseline through week 48 of treatment.Atty. Docket No. PRIOV- 44858.101

[0033] In still further aspect, the subject exhibits a decrease in CST relative to baseline through a period selected from the group consisting of week 3, week 4, week 6, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

[0034] In still further aspects of the above method, baseline is defined as the best CST value achieved at day 1 of treatment.

[0035] In yet still further aspects of the above method, the decrease in CST is observed in at least one eye.

[0036] In yet still further aspects of the above method, the decrease in CST is observed in each eye having a CST equal to or greater than 325 pm at baseline.

[0037] In yet still further aspects of the above method, the decrease in CST relative to baseline is at least 10 pm.

[0038] In yet still further aspects of the above method, the decrease in CST relative to baseline is at least 20 pm, at least 30 pm, at least 40 pm, at least 50 pm, at least 75 pm, at least 100 pm, at least 125 pm, at least 150 pm, at least at 175 pm, at least 200 pm, or at least 250 pm.

[0039] In yet still further aspects of the above method, the decrease in CST relative to baseline is in the range of about 10 pm to about 250 pm.

[0040] In yet still further aspects of the above method, the decrease in CST relative to baseline is in the range of about 20 pm to about 200 pm.

[0041] In yet still further aspects of the above method, the decrease in CST is sufficient to reduce the subject's CST to less than 325 pm as measured by optical coherence tomography.

[0042] In yet still further aspects of the above method, the optical coherence tomography is performed using a Cirrus OCT machine or a Spectralis machine. A Cirrus OCT machine is a high-speed, spectral-domain OCT machine used for diagnosing and monitoring retinal diseases and glaucoma. A Spectralis machine is a multimodal imaging platform that combines confocal scanning laser ophthalmoscopy with spectral domain OCT.

[0043] In yet still further aspects of the above method, the decrease in CST is sufficient to achieve resolution of macular edema in the subject.

[0044] In yet still further aspects of the above method, the subject achieves resolution of macular edema by week 48 of treatment, wherein resolution is defined as a central subfield thickness (CST) of less than 325 pm as measured by optical coherence tomography.Atty. Docket No. PRIOV- 44858.101

[0045] In yet still further aspects of the above method, the subject achieves resolution of macular edema by a time point selected from the group consisting of week 3, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

[0046] In yet still further aspects of the above method, the subject achieves resolution of macular edema within a period selected from the group consisting of about 1 to about 3 weeks, about 1 to about 4 weeks, about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 20 weeks, about 1 to about 24 weeks, about 1 to about 28 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, or 1 to about 48 weeks following initiation of treatment.

[0047] In yet still further aspects of the above method, the resolution of macular edema is sustained for a period of at least 3 weeks.

[0048] In yet still further aspects of the above method, the resolution of macular edema is sustained for a period of at least 3 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 32 weeks, at least 40 weeks, or at least 48 weeks.

[0049] In yet still further aspects of the above method, the sustained resolution of macular edema is maintained for a period selected from the group consisting of about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 24 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, and about 1 to about 48 weeks.

[0050] In yet still further aspects of the above method, the resolution of macular edema, once achieved, is maintained without relapse through week 24 of treatment.

[0051] In yet still further aspects of the above method, the resolution of macular edema, once achieved, is maintained without relapses through week 48 of treatment.

[0052] In yet still further aspects of the above method, the resolution of macular edema is defined as a CST of less than 325 pm as measured using optical coherence tomography.

[0053] In yet still further aspects of the above method, the macular edema is present at baseline, and wherein baseline is defined as the CST value at day 1 of treatment.

[0054] In yet still further aspects of the above method, the subject has a CST equal to or greater than 300 pm at baseline.

[0055] In yet still further aspects of the above method, the resolution of macular edema is achieved in at least one eye.Atty. Docket No. PRIOV- 44858.101

[0056] In yet still further aspects of the above method, the resolution of macular edema is achieved in each eye having a CST equal to or greater than 300 pm at baseline.

[0057] In yet further aspects of the above method, the subject is a mammal. In additional aspects, the mammal is a human.

[0058] In another embodiment, the present disclosure relates to the use of brepocitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of non-infectious uveitis in a subject in need thereof. In some aspects of this use, the subject is also suffering from macular edema.BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The patent or application fde 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.

[0060] 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:

[0061] FIG. 1 shows the median time-to-Treatment Failure of subjects suffering from NIU treated with 15 mg (N=9) and 45 mg (N=17) of brepocitinib once daily compared to patients treated with the standard of care which is adalimumab (Humira®, Abb Vie) as reported in Jaffe Glenn J. et al., “Adalimumab in Patients with Active Noninfectious Uveitis,” N. Engl. J. Med., 375: 10932-943 (September 8, 2016) also known as the “Visual I” study. In this figure, the higher median time-to-treatment failure indicates a greater treatment benefit to the patients.

[0062] FIG. 2 shows the dose-dependent benefit on posterior segment inflammation in patients with NIU, treated as described in Example 1. Measurement of posterior segment inflammation was performed using wide-field fluorescein angiography (FA) score change from baseline at week 24 and week 52 and centrally assessed using ASUWOG, a multi-domain, semi-quantitative scoring system.

[0063] FIG. 3 shows the benefit of brepocitinib (45 mg administered once daily) on preventing and treating macular edema in patients with NIU in patients treated for 24 and 52 weeks, respectively, as described in Example 1.Atty. Docket No. PRIOV- 44858.101DETAILED DESCRIPTION1. Definitions

[0064] 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 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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, theAtty. Docket No. PRIOV- 44858.101term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0069] As used herein, the terms “administering,” “introducing,” and “providing” 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.

[0070] As used herein, the term “best CST value" or "best state achieved" when used in reference to central subfield thickness refers to the lowest CST measurement recorded for a given eye over the specified time period. Because a lower CST value indicates reduced macular thickening and decreased fluid accumulation, the lowest recorded CST value represents the best (i.e., most improved) retinal anatomical state achieved by the subject. For example, where baseline is defined as the best CST value achieved at or prior to Week 6 (43 days) of treatment, the baseline CST for a given eye is the lowest CST measurement recorded at any post-baseline visit at or prior to Week 6 (34 days) of treatment. Baseline CST may also be defined as the CST value on the first day of treatment.

[0071] 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,Atty. Docket No. PRIOV- 44858.101glycine, 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.

[0072] As used herein, the term “macular edema” refers to swelling or thickening of the macula, the central part of the retina responsible for sharp, detailed central vision. Macular edema occurs due to the accumulation of fluid in the macula, typically caused by the leakage of blood vessels in the retina. The fluid disrupts the normal retinal structure, leading to blurred or distorted central vision and, in severe cases, significant visual impairment. In patients with non-infectious uveitis, macular edema can develop as a complication and is a leading cause of vision loss. It occurs due to chronic inflammation that disrupts the blood-retinal barrier (BRB), a critical structure that regulates fluid exchange between the retina and the blood vessels. This breakdown leads to increased vascular permeability and leakage of fluids into the macula.

[0073] Macular edema is diagnosed using several techniques to assess retinal structure and detect fluid accumulation. The primary diagnostic methods include: (1) a dilated retinal exam (e.g., a special lens is used to examine the macula for swelling or cystic changes); (2) fluorescein angiography (e.g., a sodium-based dye is injected into a vein, which highlights retinal blood vessels, allowing detection of leakage or abnormalities in the macula); and / or (3) optical coherence tomography or “OCT” (e.g., a non-invasive imaging technique provides detailed cross-sectional images of the retina, measuring its thickness and identifying fluid accumulation). OCT isAtty. Docket No. PRIOV- 44858.101considered the gold standard for diagnosing macular edema due to its sensitivity and reproducibility. Central subfield thickness or “CST” is a key parameter measured using OCT imaging. It refers to the average retinal thickness within a 1-mm diameter circular area centered on the fovea, the central part of the macula responsible for sharp vision. CST is widely used as an objective marker to: (1) quantify macular thickening in conditions like macular edema; (2) monitor disease progression and response to treatment; and / or (3) serve as a secondary endpoint in clinical trials. An increase in CST typically indicates fluid accumulation in the retina, as seen in conditions such as diabetic macular edema, retinal vein occlusion, or uveitic macular edema. In some aspects, a subject having NIU is considered to have macular edema when the subject’s CST is equal to or greater than 300 pm (using a Cirrus OCT machine). In still other aspects, a subject having NIU is considered not to have macular edema when the subject’s CST is less than 300 pm (using a Cirrus OCT machine).

[0074] As used herein, the term “non-infectious uveitis” or “NIU” as used interchangeably herein, refers to a group of intraocular inflammatory disorders that affect the uvea, the middle layer of the eye, which includes the iris, ciliary body, and choroid. Unlike infectious uveitis, NIU is not caused by pathogens such as bacteria or viruses but instead results from autoimmune, inflammatory, or idiopathic mechanisms. The inflammation in non-infectious uveitis is primarily driven by immune system dysfunction, often involving T-cell-mediated autoimmune processes. Cytokines such as IL-17, IL-23, IL-6, IL-2, TNF-a, INF-y, and IL-12 have been implicated in its pathogenesis. Genetic predispositions, including mutations in HLA-B27 and other immune-related genes (e.g., IL23R), play a role in susceptibility to certain forms of non-infectious uveitis. Non-infectious uveitis can occur as a localized ocular condition or as part of systemic autoimmune diseases. Common associated conditions include: (1) autoimmune diseases, such as, rheumatoid arthritis, psoriatic arthritis, Behcet’s disease; (2) systemic inflammatory conditions, such as sarcoidosis, Crohn’s disease and / or ulcerative colitis; ocular diagnoses such as Vogt-Koyanagi-Harada disease and birdshot chorioretinopathy; and / or (4) idiopathic cases, where the exact cause is unknown. Symptoms of NIU include, but are not limited to, eye pain, redness, sensitivity to light (photophobia), blurred vision, floaters, and / or progressive vision loss.

[0075] 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 ofAtty. Docket No. PRIOV- 44858.101the 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.

[0076] 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. Set. 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.

[0077] 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 di cyclohexylamine, N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine, and choline, and salts with amino acids such as arginine, lysine, and so forth.

[0078] 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.

[0079] 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,Atty. Docket No. PRIOV- 44858.101chimpanzee, etc.) and a human). In some embodiments, the subject may be a human or a nonhuman.

[0080] The phrase “therapeutically effective” or “effective amount” as used interchangeably herein refer to a benefit including, but not limited to, the treatment or amelioration of symptoms of NIU or NIU and macular edema 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 NIU or NIU and macular edema as discussed herein.

[0081] 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.

[0082] As used herein, the term “Treatment Failure” refers to worsening of NIU signs and symptoms, defined by the following criteria shown in Table 1 :Table 1: Treatment Failure Criteria11Failure Criteria Failure Criteria Parameter at 6 weeks of treatment after 6 weeks of treatment New chorioretinal and / or New active, inflammatory lesions New active, inflammatory lesions retinal vascular lesions’3relative to baseline relative to baselineAtty. Docket No. PRIOV- 44858.101Anterior chamber cell> 2-step increase relative to best (ACC) grade Inability to achieve < 0.5+state achieved(SUN grading)0Vitreous haze > 2-step increase relative to best Inability to achieve < 0.5+(NEI / SUN grading) state achieved0Worsening of BCVA by Worsening of BCVA by Best Corrected Visual> 15 letters relative to best state > 15 letters relative to best state Acuity (ETDRS chart)achieveddachieved0

[0083] Treatment failure is defined as meeting failure criteria for at least 1 of the parameters in at least 1 eye.

[0084] ) For a new lesion to be identified, the location must have been visible at baseline with no lesion present (i.e., visualization was not precluded by poor image quality or field, or significant vitreous haze).

[0085] c Best state achieved refers to best state achieved at or prior to Week 6. A 2-step increase is defined as a change of Grade 0 to Grade 2+ or higher; or Grade 0.5+ to Grade 3+ or higher.

[0086] d Best state achieved refers to the best measure recorded at visits prior to Week 6.

[0087] Abbreviations: ACC = anterior chamber cell; BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; NEI = National Eye Institute; SUN = Standardization of Uveitis Nomenclature Working Group.

[0088] 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 provided for illustrative purposes only and should not be considered limiting.Administration of Brepocitinib

[0089] Embodiments of the present disclosure include a method for treating non-infectious uveitis or NIU. In some aspects, the method comprising administering to a subject suffering from NIU and in need of treatment thereof a therapeutically 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”)

[0090] or a pharmaceutically acceptable salt thereof.Atty. Docket No. PRIOV- 44858.101

[0091] Brepocitinib (referred to interchangeably herein as “the compound”) or a pharmaceutically acceptable salt thereof can be administered to a subject suffering from NIU and in need of treatment thereof in a dose of approximately 15 mg or approximately 45 mg, respectively. In some aspects, the subject suffering from NIU is a human subject. In some aspects, the human subject suffering from NIU is administered about 15 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily. In other aspects, the human subject suffering from NIU is administered about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily. In yet other aspects, the human subject suffering from NIU is orally administered about 15 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily. In still other aspects, the human subject suffering from NIU is orally administered about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily.

[0092] In some aspects, the subject suffering from NIU is also suffering from macular edema (e.g., the subject has a CST equal to or greater than 300 pm). In these aspects, it has been found that administering about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily can treat macular edema in such subjects (See, for example, FIG. 3). Specifically, it has been found that administering about 45 mg of brepocitinib or a pharmaceutically acceptable salt completely resolves macular edema subjects suffering from NIU and macular edema. As shown in FIG. 3, the resolution rates were better than those provided by the standard of care for NIU and macular edema, which is adalimumab (HUMIRA®, Abb Vie).

[0093] More specifically, subjects suffering from NIU and macular edema, upon administration of about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily as described herein, have been found to achieve resolution of macular edema, wherein resolution is defined as a CST of less than 325 pm as measured by optical coherence tomography (e.g., using a Spectralis machine). In further aspects, resolution of macular edema is achieved in each eye having a CST equal to or greater than 325 pm at baseline.

[0094] In some aspects, subjects suffering from NIU and macular edema, upon administration of about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily as described herein, have been found to achieve resolution of macular edema, wherein resolution is defined as a CST of less than 325 pm as measured by optical coherence tomography (e.g., using a Spectralis machine). In still further aspects, subjects suffering from NIU and macular edema, upon administration of about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof onceAtty. Docket No. PRIOV- 44858.101daily as described herein, have been found to achieve resolution of macular edema, wherein resolution is defined as a C ST of less than 300 pm as measured by optical coherence tomography (e.g., using a Cirrus OCT machine). In some aspects, the resolution of macular edema is achieved in at least one eye. In other aspects, resolution of macular edema is achieved in both eyes. In further aspects, resolution of macular edema is achieved in each eye having a CST equal to or greater than 325 pm at baseline. In other aspects, resolution of macular edema is achieved in each eye having a CST equal to or greater than 300 pm at baseline.

[0095] In some aspects, the macular edema is present in the subject at baseline, where baseline is defined as the subject’s CST value at day 1 of treatment. In some aspects, the subject has a CST equal to or greater than 325 pm at baseline. In other aspects, the subject has a CST equal to or greater than 300 pm at baseline.

[0096] In some further aspects, resolution of macular edema is sustained for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, or at least 48 weeks. In other aspects, sustained resolution of macular edema is maintained for a period of about 1 to about 4 weeks, about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 20 weeks, about 1 to about 24 weeks, about 1 to about 28 weeks, about 1 to about 32 weeks, about 1 to about 36 weeks, about 1 to about 40 weeks, about 1 to about 44 weeks, or about 1 to about 48 weeks. In still other aspects, each intervening weekly integer within any of the foregoing ranges is expressly contemplated.

[0097] In some aspects, resolution of macular edema is achieved by at least by week 3, by week 4, by week 8, by week 12, by week 16, by week 20, by week 24, by week 28, by week 32, by week 40, or by week 48 of treatment. In other aspects, resolution of macular edema is achieved within a period of about 1 to about 4 weeks, about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 20 weeks, about 1 to about 24 weeks, about 1 to about 28 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, or about 1 to about 48 weeks following initiation of treatment.

[0098] In further aspects, resolution of macular edema, once achieved, is maintained without relapse through week 48 of treatment. In still further aspects, resolution of macular edema, once achieved, is maintained without relapse through week 48 of treatment.Atty. Docket No. PRIOV- 44858.101

[0099] Additionally, subjects suffering from NTU and macular edema, upon administration of brepocitinib or a pharmaceutically acceptable salt thereof as described herein, exhibit a decrease in central subfield thickness (CST) relative to baseline in each eye, wherein baseline is defined as the best CST value achieved or best state achieved at day 1 of treatment, through week 48 of treatment.

[0100] In some aspects, the decrease in CST is measured from baseline to week 48. In other aspects, the decrease in CST is measured from baseline to week 48, week 40, week 32, week 28, week 20, to week 16, to week 12, to week 8, to week 4, or week 3. In still other aspects, the decrease in CST is measured from baseline to a time point within the range of week 1 to week 48, week 1 to week 40, week 1 to week 32, week 1 to week 28, week 1 to week 24, week 1 to week 20, week 1 to week 16, week 1 to week 12, week 1 to week 8, week 1 to week 4, or week 1 to week 3.

[0101] In some aspects, baseline is defined as the best CST value achieved at day 1 of treatment. In other aspects, baseline is defined as the CST value measured on day 1 of treatment. In still other aspects, baseline is defined as the CST value measured at the screening visit.

[0102] In some aspects, the decrease in CST is observed in the study eye. In other aspects, the decrease in CST is observed in each eye meeting the threshold for macular edema at baseline. In still other aspects, the decrease in CST is observed in at least one eye.

[0103] In some aspects, the decrease in CST is at least 10 pm, at least 20 pm, at least 30 pm, at least 40 pm, at least 50 pm, at least 75 pm, at least 100 pm, at least 125 pm, at least 150 pm, at least 175 pm, at least 200 pm relative to baseline, or at least 250 pm relative to baseline. In yet further aspects, the decrease in CST relative to baseline is in the range of about 10 pm to about 250 pm. In still further aspects, the decrease in CST relative to baseline is in the range of about 20 pm to about 200 pm. Additionally, in other aspects, the decrease in CST is sufficient to reduce the subject's CST to less than 325 pm as measured using optical coherence tomography. In still other aspects, the decrease in CST is sufficient to reduce the subject's CST to less than 300 pm as measured using optical coherence tomography. In some aspects, the optical coherence tomography is a Spectralis or a Cirrus OCT machine. Further, the decrease in CST in the subjects pursuant to the methods described herein is sufficient to achieve resolution of macular edema in the subject.Atty. Docket No. PRIOV- 44858.101

[0104] Additionally, as also shown in FIG. 3, administering about 45 mg of brepocitinib or a pharmaceutically acceptable salt thereof once daily can also be used to prevent the development of macular edema in subjects with NIU.

[0105] In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt of brepocitinib. In some embodiments, p-toluenesulfonic acid 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:

[0106] In some aspects, the human subject suffering from NIU or NIU and macular edema is administered about 15 mg of the p-toluenesulfonic acid salt of brepocitinib once daily. In other aspects, the human subject suffering from NIU or NIU and macular edema is administered about 45 mg of brepocitinib of the p-toluenesulfonic acid salt once daily. In yet other aspects, the human subject suffering from NIU or NIU and macular edema is orally administered about 15 mg of the p-toluenesulfonic acid salt of brepocitinib once daily. In still other aspects, the human subject suffering from NIU or NIU and macular edema is orally administered about 45 mg of the p-toluenesulfonic acid salt of brepocitinib once daily.

[0107] 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.

[0108] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered 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.Atty. Docket No. PRIOV- 44858.101

[0109] 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, the compound 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 52 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 25 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.

[0110] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 3 weeks. 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 moreAtty. Docket No. PRIOV- 44858.101than or about 12 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 16 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 24 weeks. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for more than or about 28 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 32 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 48 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.

[0111] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, 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. In some aspects, the compound or pharmaceutically acceptable salt thereof is administered for about 24 weeks. In other aspects, the compound or pharmaceutically acceptable salt thereof is administered for 52 weeks.Atty. Docket No. PRIOV- 44858.101

[0112] The brepocitinib or pharmaceutically acceptable salt (e.g., the p-toluenesulfonic acid 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, 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.

[0113] 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.

[0114] 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. Still further, compounds can be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0115] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups andAtty. Docket No. PRIOV- 44858.101elixirs. 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.

[0116] 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.

[0117] 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 depend upon 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 compoundAtty. Docket No. PRIOV- 44858.101to 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.

[0118] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the brepocitinib or a pharmaceutically acceptable salt thereof 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.

[0119] 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) fdlers 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.

[0120] 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 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. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatinAtty. Docket No. PRIOV- 44858.101capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0121] 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.

[0122] 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.

[0123] 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” as 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 soundAtty. Docket No. PRIOV- 44858.101medical judgment. A unit dosage form for parenteral administration may be in ampoules or in multi-dose containers.

[0124] 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.Example 1[00125J A Phase 11 study was conducted that evaluated the clinical safety and efficacy of oral brepocitinib in patients with active intermediate, posterior, or pan-non-infectious uveitis (NIU).

[0126] The inclusion and exclusion criteria for the patients tested were:

[0127] Inclusion Criteria:

[0128] 1. Adult subjects (18-74 years old)

[0129] 2. Diagnosis of non-infectious uveitis (intermediate uveitis, posterior uveitis, or panuveitis).

[0130] 3. Active uveitic disease as defined by the presence of at least 1 of the following parameters in at least 1 eye, as determined by the investigator:

[0131] 4. Active, inflammatory chorioretinal and / or retinal vascular lesion; OR

[0132] 5. >2+ vitreous haze grade (NEI / SUN criteria).

[0133] 6. Receiving up to one non-corticosteroid, non-biologic, immunomodulatory therapy

[0134] 7. Weight > 40 kg with a body mass index < 40 kg / m2.

[0135] Exclusion Criteria:

[0136] 1. Has isolated anterior uveitis.

[0137] 2. Has confirmed or suspected current diagnosis of infectious uveitis

[0138] 3. History of:

[0139] a. Any lymphoproliferative disorder

[0140] b. Active malignancy;Atty. Docket No. PRIOV- 44858.101

[0141] c. History of cancer within 5 years prior to screening (exceptions for basal cell carcinoma, squamous cell carcinoma, ductal carcinoma in situ of the breast, carcinoma in situ of the uterine cervix, or thyroid carcinoma.)

[0142] d. At risk of thrombosis and cardiovascular disease

[0143] e. Have a high risk for herpes zoster reactivation

[0144] f. Have active or recent infections

[0145] This study was 52-weeks and enrolled 26 patients with active NIU. The patients were randomized 2: 1 to brepocitinib 45 mg once daily (17 patients) or brepocitinib 15 mg once daily (9 patients). Patients, physicians, and the study team were blinded to dose. All subjects received 60 mg / day prednisone burst at study entry for two weeks and were tapered off the prednisone by week 8 (a six-week steroid taper).

[0146] Subjects were evaluated for Treatment Failure, a registrational composite endpoint comprising multiple measures of ocular inflammation and visual acuity. The primary efficacy endpoint was the Treatment Failure rate at week 24.

[0147] At week 24, 29.4% (5 / 17) of subjects in the brepocitinib 45 mg arm and 44% (4 / 9) of subjects in the brepocitinib 15 mg arm met the Treatment Failure criteria, with lower failure rates reflecting greater treatment benefit. The Treatment Failure rate from worsening of disease activity (discontinuations censored) was 18% in the brepocitinib 45 mg arm. When comparing the median time-to-treatment failure, these results represent approximately twice the observed benefit as seen in the corresponding registrational study for adalimumab, which is the only approved non-steroidal therapy in NIU (See, Jaffe Glenn J. et al., “Adalimumab in Patients with Active Noninfectious Uveitis,” N. Engl. J. Med., 375: 10932-943 (September 8, 2016) also known as the “Visual I” study, the contents of which are herein incorporated by reference) and as shown in FIG. 1. All week 24 secondary efficacy endpoints, including haze grades, visual acuity, and macular thickness, were also positive and dose-responsive. Of patients in the brepocitinib 45 mg arm who met the threshold for uveitic macular edema at baseline, 43% achieved resolution of macular edema by week 24 (See, FIG. 3). No patients in the brepocitinib 45 mg arm who entered the study without macular edema developed macular edema by week 24 (See, FIG. 3).

[0148] The results also showed a dose-dependent benefit on posterior segment inflammation with sustained improvement at 52 weeks. FIG. 2 shows measurement of retinal vascular leakageAtty. Docket No. PRIOV- 44858.101by wide-field fluorescein angiography (FA) score change from baseline at week 24 and week 52 which was assessed using ASUWOG, a multi-domain, semi-quantitative scoring system as described by Tugal-Tutkun I, et al., “Angiography Scoring for Uveitis Working Group (ASUWOG). Scoring of dual fluorescein and ICG inflammatory angiographic signs for the grading of posterior segment inflammation (dual fluorescein and ICG angiographic scoring system for uveitis)”, Int Ophthalmol. 2010 Oct;30(5):539-52. doi: 10.1007 / sl0792-008-9263-x. Epub 2008 Sep 16. PMID: 18795232, the contents of which are herein incorporated by reference.

[0150] 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.

[0151] 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.

[0152] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0153] Clause 1. A method for treating non-infectious uveitis (NIU), the method comprising administering to a subject suffering from NIU and in need of treatment thereof a therapeutically 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)

[0155] or a pharmaceutically acceptable salt thereof, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

[0156] Clause 2. The method of clause 1, wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.Atty. Docket No. PRIOV- 44858.101

[0157] Clause 3. The method of clause 1 or clause 2, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.

[0158] Clause 4. The method of any of clauses 1-3, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers.

[0159] Clause 5. The method of any of clauses 1-4, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

[0160] Clause 6. The method of any of clauses 1-5, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for at least 24 weeks.

[0161] Clause 7. The method of any clauses 1-6, wherein the subject is a mammal.

[0162] Clause 8. The method of clause 7, wherein said mammal is a human.

[0163] Clause 9. A method of treating macular edema in a subject suffering from non-infectious uveitis, the method comprising administering to a subject suffering from NIU and macular edema and in need of treatment thereof a therapeutically effective amount [(1 S)-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)H1

[0165] or a pharmaceutically acceptable salt thereof, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

[0166] Clause 10. The method of clause 9, wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

[0167] Clause 11. The method of clause 9 or clause 10, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.

[0168] Clause 12. The method of any of clauses 9-11, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers.Atty. Docket No. PRIOV- 44858.101

[0169] Clause 13. The method of any of clauses 9-12, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

[0170] Clause 14. The method of any of clauses 9-13, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for at least 24 weeks.

[0171] Clause 15. The method of any clauses 9-14, wherein the subject is a mammal.

[0172] Clause 16. The method of clause 15, wherein said mammal is a human.

[0173] Clause 17. Use of brepocitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of non-infectious uveitis in a subject in need thereof.

[0174] Clause 18. The use of clause 17, wherein the subject is also suffering from macular edema.

[0175] Clause 19. The method of any of clauses 9-16, wherein the subject exhibits a decrease in central subfield thickness (CST) relative to baseline through week 48 of treatment.

[0176] Clause 20. The method of any of clauses 9-16, wherein the subject exhibits a decrease in CST relative to baseline through a period selected from the group consisting of week 3, week 4, week 6, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

[0177] Clause 21. The method of any of clauses 19-20, wherein baseline is defined as the best CST value achieved at day 1 of treatment.

[0178] Clause 22. The method of any of clauses 19-21, wherein the decrease in CST is observed in at least one eye.

[0179] Clause 23. The method of any of clauses 19-21, wherein the decrease in CST is observed in each eye having a CST equal to or greater than 325 pm at baseline.

[0180] Clause 24. The method of any of clauses 19-23, wherein the decrease in CST relative to baseline is at least 10 pm.

[0181] Clause 25. The method of any of clauses 19-23, wherein the decrease in CST relative to baseline is at least 20 pm, at least 30 pm, at least 40 pm, at least 50 pm, at least 75 pm, at least 100 pm, at least 125 pm, at least 150 pm, at least at 175 pm, at least 200 pm, or at least 250 pm.

[0182] Clause 26. The method of any of clauses 19-23, wherein the decrease in CST relative to baseline is in the range of about 10 pm to about 250 pm.Atty. Docket No. PRIOV- 44858.101

[0183] Clause 27. The method of any of clauses 19-23, wherein the decrease in CST relative to baseline is in the range of about 20 gm to about 200 pm.

[0184] Clause 28. The method of any of clauses 19-23, wherein the decrease in CST is sufficient to reduce the subject's CST to less than 325 gm as measured by optical coherence tomography.

[0185] Clause 29. The method of clause 28, wherein the optical coherence tomography is performed using a Cirrus OCT machine or a Spectralis machine.

[0186] Clause 30. The method of any of clauses 19-25, wherein the decrease in CST is sufficient to achieve resolution of macular edema in the subject.

[0187] Clause 31. The method of any of clauses 9-16, wherein the subject achieves resolution of macular edema by week 48 of treatment, wherein resolution is defined as a central subfield thickness (CST) of less than 325 pm as measured by optical coherence tomography.

[0188] Clause 32. The method of any of clauses 9-16, wherein the subject achieves resolution of macular edema by a time point selected from the group consisting of week 3, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

[0189] Clause 33. The method of any of clauses 9-16, wherein the subject achieves resolution of macular edema within a period selected from the group consisting of about 1 to about 3 weeks, about 1 to about 4 weeks, about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 20 weeks, about 1 to about 24 weeks, about 1 to about 28 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, or 1 to about 48 weeks following initiation of treatment.

[0190] Clause 34. The method of any of clauses 31-33, wherein resolution of macular edema is sustained for a period of at least 3 weeks.

[0191] Clause 35. The method of any of clauses 31-33, wherein resolution of macular edema is sustained for a period of at least 3 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 32 weeks, at least 40 weeks, or at least 48 weeks.

[0192] Clause 36. The method of any of clauses 31-33, wherein sustained resolution of macular edema is maintained for a period selected from the group consisting of about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 24 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, and about 1 to about 48 weeks.Atty. Docket No. PRIOV- 44858.101

[0193] Clause 37. The method of any of clauses 31-36, wherein resolution of macular edema, once achieved, is maintained without relapse through week 24 of treatment.

[0194] Clause 38. The method of any of clauses 31-36, wherein resolution of macular edema, once achieved, is maintained without relapses through week 48 of treatment.

[0195] Clause 39. The method of any of clauses 31-36, wherein resolution of macular edema is defined as a CST of less than 325 pm as measured using optical coherence tomography.

[0196] Clause 40. The method of any of clauses 31-39, wherein macular edema is present at baseline, and wherein baseline is defined as the CST value at day 1 of treatment.

[0197] Clause 41. The method of any of clauses 33-39, wherein the subject has a CST equal to or greater than 300 pm at baseline.

[0198] Clause 42. The method of any of clauses 33-41, wherein resolution of macular edema is achieved in at least one eye.

[0199] Clause 43. The method of any of clauses 33-42, wherein resolution of macular edema is achieved in each eye having a CST equal to or greater than 300 pm at baseline.

Claims

Atty. Docket No. PRIOV- 44858.101CLAIMSWhat is claimed is:

1. A method for treating non-infectious uveitis (NIU), the method comprising administering to a subject suffering from NIU and in need of treatment thereof a therapeutically 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 brepocitinib or pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

2. The method of claim 1, wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

3. The method of claim 1 or claim 2, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.

4. The method of any of claims 1-3, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers.

5. The method of any of claims 1-4, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

6. The method of any of claims 1-5, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for at least 24 weeks.

7. The method of any claims 1-6, wherein the subject is a mammal.

8. The method of claim 7, wherein said mammal is a human.

9. A method of treating macular edema in a subject suffering from non-infectious uveitis, the method comprising administering to a subject suffering from NIU and macular edema and in need of treatment thereof a therapeutically 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)Atty. Docket No. PRIOV- 44858.101Hor a pharmaceutically acceptable salt thereof, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 45 mg once per day.

10. The method of claim 9, wherein the pharmaceutically acceptable salt is p-toluenesulfonic acid salt.

11. The method of claim 9 or claim 10, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered orally.

12. The method of any of claims 9-11, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers.

13. The method of any of claims 9-12, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for less than or about 52 weeks.

14. The method of any of claims 9-13, wherein the brepocitinib or pharmaceutically acceptable salt thereof is administered daily for at least 24 weeks.

15. The method of any claims 9-14, wherein the subject is a mammal.

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

17. Use of brepocitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of non-infectious uveitis in a subject in need thereof.

18. The use of claim 17, wherein the subject is also suffering from macular edema.

19. The method of any of claims 9-16, wherein the subject exhibits a decrease in central subfield thickness (CST) relative to baseline through week 48 of treatment.

20. The method of any of claims 9-16, wherein the subject exhibits a decrease in CST relative to baseline through a period selected from the group consisting of week 3, week 4, week 6, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

21. The method of any of claims 19-20, wherein baseline is defined as the best CST value achieved at day 1 of treatment.

22. The method of any of claims 19-21, wherein the decrease in CST is observed in at least one eye.Atty. Docket No. PRIOV- 44858.10123. The method of any of claims 19-21, wherein the decrease in CST is observed in each eye having a CST equal to or greater than 325 gm at baseline.

24. The method of any of claims 19-23, wherein the decrease in CST relative to baseline is at least 10 gm.

25. The method of any of claims 19-23, wherein the decrease in CST relative to baseline is at least 20 gm, at least 30 gm, at least 40 gm, at least 50 gm, at least 75 gm, at least 100 gm, at least 125 gm, at least 150 gm, at least at 175 gm, at least 200 gm, or at least 250 gm.

26. The method of any of claims 19-23, wherein the decrease in CST relative to baseline is in the range of about 10 gm to about 250 gm.

27. The method of any of claims 19-23, wherein the decrease in CST relative to baseline is in the range of about 20 gm to about 200 gm.

28. The method of any of claims 19-23, wherein the decrease in CST is sufficient to reduce the subject's CST to less than 325 gm as measured by optical coherence tomography.

29. The method of claim 28, wherein the optical coherence tomography is performed using a Cirrus OCT machine or a Spectralis machine.

30. The method of any of claims 19-25, wherein the decrease in CST is sufficient to achieve resolution of macular edema in the subject.

31. The method of any of claims 9-16, wherein the subject achieves resolution of macular edema by week 48 of treatment, wherein resolution is defined as a central subfield thickness (CST) of less than 325 pm as measured by optical coherence tomography.

32. The method of any of claims 9-16, wherein the subject achieves resolution of macular edema by a time point selected from the group consisting of week 3, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 40, or week 48 of treatment.

33. The method of any of claims 9-16, wherein the subject achieves resolution of macular edema within a period selected from the group consisting of about 1 to about 3 weeks, about 1 to about 4 weeks, about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 20 weeks, about 1 to about 24 weeks, about 1 to about 28 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, or 1 to about 48 weeks following initiation of treatment.

34. The method of any of claims 31-33, wherein resolution of macular edema is sustained for a period of at least 3 weeks.Atty. Docket No. PRIOV- 44858.10135. The method of any of claims 31-33, wherein resolution of macular edema is sustained for a period of at least 3 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 32 weeks, at least 40 weeks, or at least 48 weeks.

36. The method of any of claims 31-33, wherein sustained resolution of macular edema is maintained for a period selected from the group consisting of about 1 to about 8 weeks, about 1 to about 12 weeks, about 1 to about 16 weeks, about 1 to about 24 weeks, about 1 to about 32 weeks, about 1 to about 40 weeks, and about 1 to about 48 weeks.

37. The method of any of claims 31-36, wherein resolution of macular edema, once achieved, is maintained without relapse through week 24 of treatment.

38. The method of any of claims 31-36, wherein resolution of macular edema, once achieved, is maintained without relapses through week 48 of treatment.

39. The method of any of claims 31-36, wherein resolution of macular edema is defined as a CST of less than 325 pm as measured using optical coherence tomography.

40. The method of any of claims 31-39, wherein macular edema is present at baseline, and wherein baseline is defined as the CST value at day 1 of treatment.

41. The method of any of claims 33-39, wherein the subject has a CST equal to or greater than 300 pm at baseline.

42. The method of any of claims 33-41, wherein resolution of macular edema is achieved in at least one eye.

43. The method of any of claims 33-42, wherein resolution of macular edema is achieved in each eye having a CST equal to or greater than 300 pm at baseline.

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