Topical formulations of JAK1 / 3 inhibitors and methods of use for the treatment of atopic dermatitis and other skin conditions - Patents.com

Abstract

The present disclosure relates to a method of treating skin disorders caused by immune deficiency with a topical formulation comprising ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Compound I) or a pharma- ceutically acceptable derivative thereof. In particular, the topical formulations described herein may be used to treat atopic dermatitis, alopecia areata, or vitiligo.

Description

[Technical field]

[0001] (Priority Claim) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 150,610, filed February 18, 2021, U.S. Provisional Patent Application No. 63 / 197,463, filed June 6, 2021, U.S. Provisional Patent Application No. 63 / 197,888, filed June 7, 2021, and U.S. Provisional Patent Application No. 63 / 221,706, filed July 14, 2021, which are incorporated by reference in their entireties herein.

[0002] (Field) The present disclosure is directed to the preparation and use of topical formulations containing JAK inhibitors, and the use of those formulations to treat skin conditions, particularly atopic dermatitis. Summary of the Invention

[0003] A first aspect of the present disclosure is directed to a method for treating a skin condition caused by an immune deficiency in a subject in need thereof. The method comprises administering to the subject an amount of Compound I: The present invention includes topically administering a composition containing about 0.5% to about 4% of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate or a salt thereof, having the structure TIFF2024509383000002.tif5374.

[0004] Another aspect of the present disclosure is directed to a method for reducing the severity and extent of skin lesions caused by an immune deficiency, comprising topically administering to a subject having an immune deficiency a composition comprising about 0.5% to about 4% of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate having the structure of Compound I (above) or a salt thereof.

[0005] Another aspect of the present disclosure is directed to a topical pharmaceutical formulation comprising about 0.1 w / w% to about 4 w / w% of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Compound I), a salt thereof, or a solvate thereof. The formulation further comprises a primary solvent comprising one or both of polyethylene glycol and diethylene glycol monoethyl ether having an average molecular weight of about 100 g / mol to about 400 g / mol; a co-solvent comprising one or more of benzyl alcohol, ethanol, and phenoxyethanol, dimethyl isosorbide:propylene glycol:glycerol:, and an antioxidant. The topical pharmaceutical formulation of the present disclosure has an apparent viscosity of about 10 mPa·S to about 100 mPa·S.

[0006] In yet another aspect, the present disclosure is directed to a sprayable topical pharmaceutical formulation comprising about 0.5 w / w% to about 2 w / w% of a compound of the structure of Compound I, a salt thereof, or a solvate thereof; about 65 w / w% to about 70 w / w% of a primary solvent comprising one or both of polyethylene glycol and diethylene glycol monoethyl ether having an average molecular weight of about 100 g / mol to about 400 g / mol; about 15 w / w% of dimethyl isosorbide; about 5 w / w% of propylene glycol; about 8 w / w% to about 10 w / w% of glycerol; and about 0.05 w / w% to about 0.5 w / w% of an antioxidant, wherein the topical pharmaceutical formulation has an apparent viscosity of about 10 mPa·S to about 100 mPa·S.

[0007] Topical delivery has many advantages, especially for treating skin conditions such as AD as described herein: the ability to deliver pharmaceutical substances more selectively to specific sites, avoiding fluctuations in drug levels, inter- and intra-patient variation, improving compliance, and improving suitability for self-medication.However, many of the current topical therapies for AD and other inflammatory skin conditions (e.g., alopecia areata, vitiligo) face challenges such as incomplete efficacy, difficulty in application, side effects from long-term topical use (especially steroid treatment), and local site reactions.For topical therapy, the formulation of the vehicle is as important as the active agent itself, since the interaction of the vehicle with the skin and the active ingredient can change the effect of the active ingredient.In addition to conducting thorough research into the therapeutic effect of JAK inhibitors to treat inflammatory skin conditions, thorough formulation development must also be performed to ensure that the JAK inhibitor molecule is delivered to the appropriate superficial site (e.g., epidermis / dermis, avoiding systemic introduction) and that the completeness of dosage, drug transport, and duration of activity, as well as at least patient acceptance and compliance, are maintained.

[0008] As described herein, ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Compound I) is designed to act locally in the skin and to be metabolically unstable; It results in short-term circulating drug concentrations in plasma that provide efficacy and minimize the risk of systemic toxicity. When administered for 4 weeks to subjects suffering from moderate to severe atopic dermatitis, analysis of pharmacokinetic plasma samples in the treatment group showed that over 86% of plasma samples had concentrations of the active compound that were less than 1 ng / ml, and the mean drug concentration was less than the IC50 of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. 50The study showed that the reduction in eczema area and severity did not exceed 5%. Subjects treated with ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate reported a 74.4% reduction in the primary efficacy endpoint, modified Eczema Area and Severity Index (mEASI) score at week 4. Additionally, favorable trends were observed in key secondary efficacy endpoints.

[0009] For a more complete understanding of the nature and advantages of the present invention, reference should be made to the following detailed description taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the percent change in Eczema Area and Severity Index (EASI) from baseline for subjects treated with Compound I and vehicle on days 8, 15, and 28. [Diagram 2] FIG. 2 shows EASI50, EASI75, and EASI90 response data on day 28 of the study for Compound I and vehicle treated subjects. [Diagram 3] FIG. 3 shows the change in Peak Pruritus Numerical Rating Score (PP-NRS) scores from baseline in both Compound I and vehicle treated subjects on days 8, 15, and 28 of the study. [Figure 4] FIG. 4 shows the percentage of subjects (Compound I and vehicle treatment) who showed an improvement of 2 or more points during the study and had an Investigator's Global Assessment (IGA) treatment response of 0 or 1. [Diagram 5] FIG. 5 shows the change from baseline in disease-affected body surface area (BSA) in Compound I and vehicle treated subjects on days 8, 15, and 28, respectively. [Figure 6]FIG. 6 is a table summarizing the number of patients who achieved a 50% improvement in Eczema Area and Severity Index (EASI) score on days 8, 15, and 28 of the study. [Figure 7] FIG. 7 is a table summarizing the number of patients who achieved a 75% improvement in EASI score on days 8, 15, and 28 of the study. [Figure 8] FIG. 8 is a table summarizing the number of patients who achieved a 90% improvement in EASI score on days 8, 15, and 28 of the study. [Figure 9] FIG. 9 is a table summarizing the actual values ​​and changes from baseline in Peak Pruritus Numeric Rating Scale (PP-NRS) for Compound I and vehicle treated subjects over the course of the study. [Figure 10] 10A-10B are graphs showing the permeation of various formulations described herein into the dermis and epidermis in an ex vivo / in vitro permeation assay, as described herein. [Figure 11] 11A-11B are graphs showing the permeation of Compound I with formulations of the present disclosure as measured in the ex vivo / in vitro permeability assays described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] (Detailed Description) definition Before describing the compositions and methods of the present invention, it is to be understood that the scope of the present invention is not limited to the specific processes, compositions, or methodologies described, as they may vary. It is also to be understood that the terminology used herein is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. 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. Although any methods or materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference with respect to the aspects identified as described. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0012] It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "JAK inhibitor" is a reference to one or more JAK inhibitors and equivalents thereof known to those of skill in the art, and so forth.

[0013] The transition term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transition term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transition term "consisting essentially of" limits the scope of the claim to those materials or steps specified that "do not materially affect the basic and novel characteristics" of the claimed invention. In embodiments or claims using the term "comprising" as a transition term, such embodiments may be envisioned replacing the term "comprising" with the term "consisting of" or "consisting essentially of." The compositions and methods of the present disclosure may comprise, consist essentially of, or consist of the disclosed components.

[0014] As used herein, the term "about" means plus or minus 10% of the number with which it is used, so about 50% means a range of 45% to 55%.

[0015] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent to a patient, where the therapeutic agent has a beneficial effect on the targeted tissue. Thus, as used herein, the term "administering," when used in conjunction with the JAK inhibitor compounds described herein, includes, but is not limited to, delivering the JAK inhibitor compound into or onto the targeted tissue.

[0016] As used herein, the term "a derivative thereof" refers to a salt thereof, a pharma- ceutically acceptable salt thereof, an ester thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0017] The compounds described herein may contain asymmetric centers and therefore may exist as enantiomers. When compounds according to embodiments herein have two or more asymmetric centers, they may exist as diastereomers. It is to be understood that the present invention encompasses all stereochemical isomeric forms, including d- and l-isomers, as well as diastereomeric, enantiomeric, and epimeric forms, and mixtures thereof. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting materials of a particular stereochemistry are commercially available or can be prepared and separated by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, with all tautomers being provided by the present invention. Additionally, compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0018] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or separation of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture was separated by chromatography and / or fractional crystallization, and one or both of the diastereomeric isomers were converted to the corresponding pure enantiomer by methods well known to those skilled in the art. The chiral compounds of embodiments herein (and their chiral precursors) were obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of 0-50% isopropanol, typically 2-20%, and 0-5% alkylamine, typically 0.1% diethylamine, in a hydrocarbon, typically heptane or hexane. The eluate is concentrated to give the enriched mixture. The stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).

[0019] As used herein, the term "substantially free," alone or in combination, refers to the absence of isomers within the detection limits of analytical methods such as nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GG / MS), high performance liquid chromatography (HPLC), or liquid chromatography / mass spectrometry (LC / MS).

[0020] As used herein, the term "condition" is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "disease," in that it reflects an abnormal state of the human or animal body or parts thereof that impairs normal functioning, is typically manifested by characteristic signs or symptoms, and causes a decrease in the duration or quality of the human or animal's life.

[0021] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to a patient, such as a mammal. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Such salts can be obtained from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0022] Suitable pharma- ceutically acceptable acid addition salts of the compounds of the embodiments herein may be prepared from inorganic acids or organic acids. All of these salts may be prepared by conventional means from the corresponding compounds of the embodiments herein, for example, by treating the compound with the appropriate acid or base.

[0023] Pharmaceutically acceptable acids include inorganic acids, such as hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric, and diphosphoric acid; and organic acids, such as formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, malonic, galactic, carboxylic, carboxylic acids ... acid), galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, ascorbic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), napadisilic acid (1,5-naphthalenedisulfonic acid), and others.

[0024] Other preferred salts according to embodiments herein are quaternary ammonium compounds, with the corresponding anion (X - ) is associated with the positive charge of the N atom. X - X can be the anions of various inorganic acids, such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or the anions of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. - is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. More preferably, X - is the chloride, bromide, trifluoroacetate, or methanesulfonate.

[0025] The compounds of the embodiments herein may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the embodiments herein and one or more pharma-ceutically acceptable solvent molecules. The term hydrate is used when the solvent is water. Examples of solvate forms include, but are not limited to, compounds of the embodiments herein associated with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. In the embodiments herein, it is specifically contemplated that one solvate molecule can be associated with one molecule of the compounds of the embodiments herein, such as a hydrate.

[0026] In some embodiments herein, one solvent molecule may be associated with one molecule of the compounds described herein, such as hydrate.In some embodiments herein, more than one solvent molecule may be associated with one molecule of the compounds described herein, such as dihydrate.Furthermore, in some embodiments herein, less than one solvent molecule may be associated with one molecule of the compounds described herein, such as hemihydrate.Furthermore, the solvent of the embodiments herein is considered as the solvate of the compounds described herein, which retains the biological effectiveness of the unsolvated form of the compounds.

[0027] The term "subject" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild animals, domestic animals, and agricultural animals. In certain embodiments, the subject described herein is an animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or a transgenic pig.

[0028] The phrases "therapeutically effective" or "therapeutically effective amount" or "effective amount" of a composition are a predetermined amount calculated to achieve a desired effect (e.g., reducing discomfort and / or the appearance of skin abnormalities). The activity contemplated by the method of the present invention includes both medical and / or prophylactic treatment, as appropriate. The specific dose of a compound administered according to the present invention to achieve a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. A therapeutically effective amount of a compound of the present invention is typically an amount that is sufficient to achieve an effective local concentration in a tissue when administered in a composition of a physiologically acceptable vehicle.

[0029] Unless otherwise indicated, the term "skin" means the outer envelope or layer of the body, consisting of the stratum corneum, the epidermis and the dermis, and overlying the subcutaneous tissue.

[0030] As used herein, the terms "treat", "treated", or "treating" refer to both medical treatment and prophylactic or preventative measures, the purpose being to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes of this invention, a beneficial or desired clinical result includes, but is not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder, or disease; stabilization (i.e., not worsening) of the state of a condition, disorder, or disease; delay in onset or slowing of progression of a condition, disorder, or disease; amelioration of a condition, disorder, or disease; and reversal (whether partial or total), or enhancement or amelioration of a condition, disorder, or disease, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without undue side effects.

[0031] Embodiments herein are directed to compounds and pharmaceutical compositions that inhibit JAK1 and / or JAK3 activity, and methods of using the compounds. Some embodiments include a method of treating a disease in a patient by topically administering the JAK1 and / or JAK3 inhibitor compounds described herein.

[0032] Treatment methods In one aspect, the disclosure provides a method of treating a skin condition resulting from immune deficiency in a human subject, the method comprising topically administering to an area of ​​the subject affected by the skin condition a composition comprising about 0.5% to about 4% of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate having the structure of Compound I (hereinafter referred to as "Compound I") or a pharma- ceutically acceptable derivative thereof. TIFF2024509383000003.tif6287

[0033] Topical administration of a composition of Compound I is therapeutically effective to achieve a desired effect, which may include, but is not limited to, improvement in one or more of the following: size of skin lesions, total body area affected, severity, redness, flakiness, discomfort, itchiness, and pain associated with a skin condition.

[0034] Another aspect of the present disclosure provides a method for reducing the severity and extent of skin lesions resulting from immune deficiency in a human subject, the method comprising topically administering to a human subject having an immune deficiency a composition comprising about 0.5%-4% of Compound I or a pharma-ceutically acceptable derivative, salt, or solvate thereof. The topical administration of the composition of Compound I is therapeutically effective to achieve a desired effect, e.g., prevention or reduction of skin lesion formation, prevention or reduction of the severity of skin lesion formation.

[0035] According to these aspects of the disclosure, the skin condition treated according to the methods and formulations disclosed herein is selected from atopic dermatitis, vitiligo, or alopecia areata. Atopic dermatitis (AD) is a common and chronic skin disorder resulting from complex genetic, immunological, and environmental interactions. AD is a chronic, recurrent, pruritic, inflammatory skin disease with inflammation and skin barrier impairment associated with environmental stimuli. In AD, the outer layer of the skin (the stratum corneum), which normally acts to prevent foreign substances such as bacteria, viruses, and allergens from entering the body, is weakened and more susceptible to inflammation caused by the body's immune cells reacting to these foreign substances. AD can be characterized as mild, moderate, or severe based on the skin extent and severity of symptoms. Mild AD affects small areas of the skin and may be accompanied by occasional itching and redness. However, moderate and severe AD cover large areas of the skin and are often accompanied by itching, with periods of intense itching.

[0036] Lesioned skin of AD patients contains high levels of proinflammatory cytokines and cellular infiltrates of CD4+ T cells that propagate the pathophysiology of the disease. The cytokine microenvironment in AD is complex, and patients display distinct cytokine signatures at different stages of the disease.

[0037] As described herein, the Janus kinase (JAK) family of signal transducers is an advantageous therapeutic target since various cytokines exert their biological effects through the JAK signal transducer and activator of transcription (STAT) pathway. The JAK family includes four cytoplasmic tyrosine kinases: JAK1, JAK2, JAK3, and TYK2; and seven STAT proteins: STAT 1, 2, 3, 4, 5a, 5b, and 6. The JAK-STAT signaling molecules interact downstream with a number of cytokines involved in autoimmune and inflammatory responses. AD is caused by cytokines such as IL-4, IL-13, IL-15, and interferon gamma, among others. All of these cytokines are primarily restricted by JAK1 and JAK3. Therefore, administration of the JAK1 / 3 inhibitor, i.e., compound I, described herein, is particularly valuable in controlling the associated inflammation seen in AD and restoring skin barrier function. The JAK1 / 3 inhibitors described herein are also useful for treating other chronic skin conditions such as alopecia, in which the immune system attacks hair follicles, causing hair loss, and vitiligo, which involves loss of melanocytes and skin pigmentation.

[0038] The following disclosure and description is provided based at least in part on clinical observations that topical administration to the skin of a therapeutically effective amount of a composition comprising Compound I, a potent inhibitor of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), is effective in treating atopic dermatitis, vitiligo, and alopecia areata. Compound I competes with adenosine triphosphate for a binding site within the kinase domain, thereby inhibiting JAK phosphorylation and activation, STAT recruitment, and downstream effects of gene expression. In parallel, various formulations were developed that ensure Compound I is delivered to the appropriate target site, and that maintain dosage integrity, drug transport, and duration of activity, and are sufficient to improve patient symptoms. Additional studies were performed to ensure physical and chemical stability, as well as to evaluate aesthetic appeal to potential end users.

[0039] Compound I is disclosed in U.S. Patent Application No. 20190135808 (Example 117), the entire contents of which are incorporated herein by reference. Compound I is 18 H 21 It has the chemical formula of N5O3 and a molecular weight of 335.40 g / mol.

[0040] As used herein, "Compound I" refers to ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, and includes both the free base form and any pharma- ceutically acceptable salts of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. For example, Compound I may be administered to a subject as an acid addition salt, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, or an organic acid, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. As used herein, "Compound I" includes crystalline, semi-crystalline, or amorphous Compound I. Crystalline or semi-crystalline Compound I may be in the form of a pharma- ceutically acceptable polymorph of Compound I or a mixture of polymorphs of Compound I.

[0041] The therapeutically effective amount or therapeutic application of the described compositions of Compound I includes an amount of Compound I effective to reduce the severity and extent of AD-related symptoms according to the EASI (Eczema Area and Severity Index) or modified versions thereof (e.g., excluding evaluation of specific body sites such as the head (neck, face, scalp), palms, soles, groin, and genitals). Modified versions of the EASI may, for example, include evaluation of the trunk, upper extremities (arms), and lower extremities (feet). The extent of symptoms may be measured by giving each evaluated body site a score of 0 to 6 based on the percentage of involvement in that site. For example, Area Scores may be given as follows: (0): 0%; (1): 1% to 9%; (2): 10% to 29%; (3): 30% to 49%; (4): 50% to 69%; (5): 70% to 89%; (6): 90% to 100%. The severity may be measured according to four specific symptoms: erythema (S erythema ), edema / papules (S edema / papulation ), exfoliation (S excoriation ), and lichenification (Slichenification ) may be measured on a scale of 0 (minimum) to 3 (maximum), providing the severity of each.

[0042] The EASI score, for example, when assessing the trunk, upper extremities, and lower extremities, can be calculated as follows: TIFF2024509383000004.tif22169

[0043] Thus, according to the methods disclosed herein, topical administration of a composition comprising about 0.5% to about 4% Compound I to an area of ​​a subject afflicted with a skin condition, such as AD, results in at least a 25%, at least a 30%, at least a 35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, at least a 75%, or greater improvement in the subject's EASI score from the baseline score, i.e., the score before treatment began.

[0044] In another embodiment, a therapeutically effective amount of Compound I is an amount effective to reduce the discomfort of a skin condition caused by itch according to a self-reported PP-NRS (Peak Pruritus Numeric Rating Scale). The PP-NRS is designed to measure peak itch or worst itch over a 24-hour period based on a scale of 0 (no itch) to 10 (worst itch). In some embodiments, topical administration of a composition comprising about 0.5% to about 4% Compound I to a site of a subject suffering from a skin condition such as AD results in at least a 1-point reduction, at least a 2-point reduction, at least a 3-point reduction, or more than a 3-point reduction on the PP-NRS scale.

[0045] In another embodiment, the therapeutically effective amount of compound I is an amount effective to reduce the total amount of body surface area (BSA) affected by a skin condition. The BSA affected by a skin condition, such as AD, is estimated by a clinician or clinical researcher, physician, or other medical professional using the handprint method, which estimates that the area of ​​the patient's entire handprint (fingers and thumb combined) constitutes 1% of the total BSA. In some embodiments, topical administration of a composition comprising about 0.5% to about 4% compound I to the site of a subject suffering from a skin condition, such as AD, results in a significant reduction in the total BSA of the subject suffering from the condition.

[0046] In another embodiment, a therapeutically effective amount of compound I is an amount that improves the overall appearance of the lesion as assessed by an independent person, such as a clinician or clinical researcher, physician, or other medical professional (e.g., Investigator's Global Assessment or IGA). IGA scoring can provide a numerical representation of appearance, for example, based on the following criteria:

[0047] 0- Clear: No inflammatory signs of atopic dermatitis (no erythema, no edema / papule, no lichenification, no oozing / crusting). Post-inflammatory hyperpigmentation and / or hypopigmentation may be present. 1 - Almost clear: barely perceptible erythema, barely perceptible edema / papule, and / or minimal lichenification. No weeping or crusting. 2-Mild: Mild but distinct erythema (pink), mild but distinct edema / papule, and / or mild but distinct lichenification. No weeping or crusting. 3-Moderate: Clearly perceptible erythema (dark red), clearly perceptible edema / papule, and / or clearly perceptible lichenification. Weeping or crusting may be present. 4-Severe: Marked erythema (deep red or bright red), marked edema / papulation, and / or marked lichenification. Disease is widespread. Weeping or crusting may be present.

[0048] In some embodiments, topical administration of a composition comprising about 0.5% to about 4% Compound I to a site of a subject suffering from a skin condition, such as AD, results in a decrease in the subject's IGA score. In some embodiments, treatment with a composition of Compound I described herein results in a decrease of at least 1 point in the subject's IGA score.

[0049] Additionally, or alternatively, a therapeutically effective amount of Compound I is an amount sufficient to reduce the frequency or severity of lesion occurrence, e.g., smaller lesions, fewer lesions, or less itchy or noticeable lesions.

[0050] The therapeutically effective amount of Compound I is an amount that is sufficient to achieve effective local concentration in skin tissue when administered in topical formulation.In any embodiment, the therapeutically effective amount of Compound I reduces the level of proinflammatory cytokines and the cellular infiltrate of CD4+T cells at or near the administration site.In any embodiment, the therapeutically effective amount of Compound I reduces the level of one or more of IL-4, IL-13, IL-15, and interferon gamma at or near the administration site.In any embodiment, the therapeutically effective amount of Compound I increases filaggrin expression at or near the administration site.

[0051] Specific dosages and dosing regimens may vary from subject to subject depending on variables such as, but not limited to, severity of lesions, sensitivity to inactive ingredients, sensitivity to Compound I, frequency of lesion occurrence, frequency and / or severity of adverse events, weight, age, sex, comorbidity with other diseases or conditions, use of adjuvant therapies to treat AD, use of other non-AD related medications, etc.

[0052] For example, Compound I can be administered to a subject in need thereof at about 20 mg / day to about 320 mg / day, including about 40 mg / day to about 280 mg / day, about 80 mg / day to about 240 mg / day, about 120 mg / day to about 200 mg / day, about 40 mg / day to about 160 mg / day, about 80 mg / day to about 160 mg / day, or about 160 mg / day to about 320 mg / day. Compound I can be administered once a day, twice a day, three times a day, or more frequently. In any embodiment, the daily dosage as described above can be divided by the number of daily administrations to obtain the dosage per administration. For example, a dosage of about 40 mg / day to about 320 mg / day corresponds to a dosage of about 20 mg / administration to about 160 mg / administration when applied twice a day.

[0053] Alternatively, dosing instructions may be provided for each administration. Thus, in yet another embodiment, the present disclosure provides a method for treating atopic dermatitis, vitiligo, or alopecia areata in a subject in need thereof, comprising topically administering to the subject about 10 mg to about 160 mg of Compound I or a pharma- ceutically acceptable derivative, salt, or solvate thereof per administration. Administration of Compound I by topical administration may be once a day, twice a day, three times a day, or more frequently. Each interval between administrations may be the same as or different from the other intervals. For example, when administered twice a day, the second administration may be administered about 12 hours after the first administration. Alternatively, the administration may be administered at equal intervals only during waking hours, such as between 6:00 a.m. and 10:00 p.m. Suitable dosage amounts include about 10 mg to about 180 mg per administration, including about 20 mg / administration, about 60 mg / administration, about 80 mg / administration, about 100 mg / administration, about 120 mg / administration, and about 140 mg / administration. One of skill in the art will be able to optimize the dosage amount and administration interval to achieve a favorable treatment for the subject to whom Compound I is administered.

[0054] Compound I may be administered to a subject in the form of a topical formulation, such as, but not limited to, a topical solution, ointment, cream, gel, gel cream, foam, etc. For example, the topical formulation may be a topical solution. The topical formulation may be applied, for example, directly to the skin at the site of the skin lesion or where the lesion normally appears. The topical formulation may be applied to the skin, for example, through the use of a dropper. Optionally and if necessary, the pumping mechanism may further provide a plastic bottle / cap, which is securely replaced with a pumping mechanism that removes the cap and delivers the topical formulation as a spray. Upon administration, the topical formulation may be rubbed into the skin to facilitate absorption of Compound I into the affected area and skin layers. The amount of topical formulation to be administered topically to the skin may be calculated based on the desired dosage of Compound I and the concentration of Compound I in the formulation. Generally, about 0.25 mL to about 8 mL per administration of a topical formulation containing Compound I may be administered topically to a subject.

[0055] Compound I may be present in the topical formulation at a concentration of about 0.01% w / w to the maximum concentration that represents the maximum equilibrium saturated solubility at room temperature in the selected vehicle or vehicle. Those skilled in the art may easily determine the maximum equilibrium saturated solubility of compound I in any selected solvent or mixture of solvents. In a particularly useful embodiment, compound I may be present at a concentration that represents about 85% of its maximum equilibrium saturated solubility or less. In particular, compound I may be present in the topical formulation at a concentration of about 0.01% w / w to about 10% w / w, for example, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w. Compound I may be present in the topical formulation at a concentration of from about 0.01% w / w to about 4% w / w, e.g., from about 0.5% w / w to about 4% w / w, from about 0.5% w / w to about 3.5% w / w, from about 0.5% w / w to about 2% w / w, from about 1.5% w / w to about 2.5% w / w, or from about 1% w / w to about 2% w / w. In any embodiment, Compound I is administered at about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, It may be present in the topical formulation at a concentration of about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, or about 5.0% w / w. As used herein, and unless otherwise specified, % w / w refers to the % by weight of the named component compared to the total weight of the formulation of which it is a part, where the total weight of the formulation is 100% w / w.Compound I may be present in the topical formulation in any physical form, including, but not limited to, as a free base or a salt, a solvated form, an unsolvated form, or a complexed form.

[0056] In one embodiment, topical compound I may be administered chronically to treat one or more of atopic dermatitis, vitiligo, and alopecia areata in a subject in need of treatment, for example, to prevent lesion formation or reduce the severity of lesions that do form, as compared to untreated lesions, for ongoing treatment and prevention of skin condition symptoms.In another embodiment, administration may be administered as needed when symptoms occur or are predicted to occur.In any embodiment, compound I may be administered chronically, with additional administration and / or increased administration upon onset of symptoms.Examples of symptoms include, but are not limited to, dry and / or scaly skin, itching, redness of skin, skin infection, and skin bleeding or weeping.In any embodiment, dosage may be increased or decreased based on the severity of symptoms.

[0057] One exemplary dosing regimen for the treatment of atopic dermatitis involves topical administration of about 1 mL to about 8 mL of a 2% Compound I formulation twice daily to an area of ​​a subject affected by atopic dermatitis, comprising application of: a) about 1 mL of a 2% w / w Compound I formulation twice daily; b) about 2 mL of a 2% w / w Compound I formulation twice daily; c) about 3 mL of a 2% w / w Compound I formulation twice daily; d) about 4 mL of a 2% w / w Compound I formulation twice daily; e) about 5 mL of a 2% w / w Compound I formulation twice daily; f) about 6 mL of a 2% w / w Compound I formulation twice daily; g) about 7 mL of a 2% w / w Compound I formulation twice daily; and h) about 8 mL of a 2% w / w Compound I formulation twice daily.

[0058] Another exemplary dosing regimen involves topical administration of about 1 mL to about 6 mL of a 2% w / w Compound I formulation three times per day to an area of ​​a subject affected with atopic dermatitis, including application of: a) about 1 mL of a 2% w / w Compound I formulation three times per day; b) about 2 mL of a 2% w / w Compound I formulation three times per day; c) about 3 mL of a 2% w / w Compound I formulation three times per day; d) about 4 mL of a 2% w / w Compound I formulation three times per day; e) about 5 mL of a 2% w / w Compound I formulation three times per day; and d) about 6 mL of a 2% w / w Compound I formulation three times per day.

[0059] Another exemplary dosing regimen involves more frequent administration of smaller amounts of Compound I, for example, topical administration of about 1 mL to about 6 mL of a 0.5% w / w Compound I formulation three times per day to an area of ​​a subject suffering from atopic dermatitis, including application of: a) about 1 mL of a 0.5% w / w Compound I formulation three times per day; b) about 2 mL of a 0.5% w / w Compound I formulation three times per day; c) about 3 mL of a 0.5% w / w Compound I formulation three times per day; d) about 4 mL of a 0.5% w / w Compound I formulation three times per day; e) about 5 mL of a 0.5% w / w Compound I formulation three times per day; f) about 6 mL of a 0.5% w / w Compound I formulation three times per day; g) about 7 mL of a 2% w / w Compound I formulation three times per day; and h) about 8 mL of a 2% w / w Compound I formulation three times per day.

[0060] Yet another exemplary dosing regimen involves topical administration of about 1 mL to about 8 mL of a 0.5% w / w Compound I formulation four times per day to an area of ​​a subject affected with atopic dermatitis, including application of: a) about 1 mL of a 0.5% w / w Compound I formulation twice per day; b) about 2 mL of a 0.5% w / w Compound I formulation twice per day; c) about 3 mL of a 0.5% w / w Compound I formulation twice per day; d) about 4 mL of a 0.5% w / w Compound I formulation twice per day; e) about 5 mL of a 0.5% w / w Compound I formulation twice per day; f) about 6 mL of a 0.5% w / w Compound I formulation twice per day; g) about 7 mL of a 0.5% w / w Compound I formulation twice per day; and about 8 mL of a 0.5% w / w Compound I formulation twice per day.

[0061] In any embodiment, compound I can be used as a combination therapy or adjuvant therapy of another AD-related therapy.For example, the method for treating atopic dermatitis, vitiligo or alopecia areata in a subject in need thereof comprises topically administering to the subject a therapeutically effective amount of compound I or its pharma-ceutically acceptable derivative, salt or solvate in combination with one or more of immunosuppressants, antihistamines, corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, dupilumab, antibacterial agents, and the humanized monoclonal antibody that blocks interleukin (IL)-4 / IL-13 signal transduction.

[0062] Pharmaceutical preparations Another aspect of the present disclosure is directed to a topical formulation comprising ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Compound I) or a pharma- ceutically acceptable derivative, salt, or solvate thereof, and a vehicle comprising a primary solvent and one or more co-solvents. The formulation may further comprise one or more antioxidants, one or more antibacterial agents, or any other desired excipients, such as, but not limited to, diluents, surfactants, emulsifiers, emollients, stabilizers, viscosity modifiers, colorants, fragrances, or any combination thereof. In a particularly useful embodiment, the topical formulation comprises an emollient.

[0063] Compound I may be present in the topical formulation at a concentration of about 0.01% w / w to a maximum concentration that represents the maximum equilibrium saturated solubility at room temperature in a selected vehicle or vehicle. Those skilled in the art may easily determine the maximum equilibrium saturated solubility of compound I in any selected solvent or mixture of solvents. In a particularly useful embodiment, compound I may be present at a concentration that represents about 85% of its maximum equilibrium saturated solubility or less. In particular, compound I may be present in the topical formulation at a concentration of about 0.01% w / w to about 10% w / w, for example, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w. Compound I may be present in the topical formulation at a concentration of from about 0.01% w / w to about 4% w / w, e.g., from about 0.5% w / w to about 4% w / w, from about 0.5% w / w to about 3.5% w / w, from about 0.5% w / w to about 2% w / w, from about 1.5% w / w to about 2.5% w / w, or from about 1% w / w to about 2% w / w. In any embodiment, Compound I is present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2.1 w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w , about 2.8% w / w, about 2.9% w / w, about 3.0 w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9 w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8 w / w, about 4.9% w / w, or about 5.0% w / w. As used herein, and unless otherwise specified, % w / w refers to the % by weight of the named component compared to the total weight of the formulation of which it is a part, where the total weight of the formulation is 100% w / w.Compound I may be present in the topical formulation in any physical form, including, but not limited to, as a free base or a salt, a solvated form, an unsolvated form, or a complexed form.

[0064] As will be appreciated by those skilled in the art, some excipients can perform multiple functions. For example, PEG-400 can function as a solvent and an emollient. The combination of formulation components disclosed herein is selected to maximize solubility, moisturizing / emollient effect while balancing the need for sprayability and therefore spreadability.

[0065] The topical formulations described herein may include a primary solvent. Examples of suitable primary solvents include one or more of polyethylene glycols (e.g., PEG-400, PEG-300), diethylene glycol monoethyl ether (e.g., TRANSCUTOL, PEG-400, PEG-300), and / or PEG-400 (e.g., PEG-400, PEG-300). TM P or HP), or any combination thereof.

[0066] In a particularly useful embodiment, the primary solvent comprises polyethylene glycol. As used herein, the term "polyethylene glycol" refers to a polymer comprising ethylene glycol monomer units of the formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxy group at each end of the polymer molecule, or may have one or more hydroxy groups etherified with a lower alkyl (e.g., methyl group). Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200 (PEG-200), polyethylene glycol-300 (PEG-300), and polyethylene glycol-400 (PEG-400). In one embodiment, the polyethylene glycol solvent is primarily PEG-400 or comprises a mixture of PEG-400 and diethylene glycol monoethyl ether. The number following the dash in the name refers to the average molecular weight of the polymer (i.e., PEG-400 has an average molecular weight of about 400 g / mol). In some embodiments, SUPER REFINED POLYETHYLENE GLYCOL from Croda (Edison, NJ, USA) is used. TM Use the grade.

[0067] The primary solvent may comprise at least about 50 w / w% of the topical formulation. For example, the primary solvent of the topical formulation may comprise from about 50 w / w% to about 90 w / w%, from about 65 w / w% to about 90 w / w%, from about 60 w / w% to about 80 w / w%, or from about 65 w / w% to about 70 w / w%, and any concentration or range of concentrations therein. When the primary solvent comprises a mixture of polyethylene glycol and diethylene glycol monoethyl ether, the primary solvent may comprise about 40% to about 50% by weight of polyethylene glycol (e.g., about 40 w / w%, about 42 w / w%, about 44 w / w%, about 46 w / w%, about 48 w / w%, or about 50 w / w%, and any range therebetween, such as about 40 w / w% to 42 w / w%, about 42 w / w% to about 44 w / w%, about 44 w / w% to about 46 w / w%, and about 46 w / w% to about 48 w / w%, and about 48 w / w% to about 50 w / w%). Additionally or alternatively, the ratio of polyethylene glycol to diethylene glycol monoethyl ether may be about 0.7:1 to about 1:1.

[0068] One or more co-solvents may also be included in the topical formulation. Examples of suitable co-solvents include, but are not limited to, dimethyl isosorbide, benzyl alcohol, ethanol, phenoxyethanol, propylene glycol, propylene carbonate, dimethyl sulfoxide, water, and any mixtures thereof. In particularly useful embodiments, the topical formulation may comprise about 10 w / w% to about 20 w / w% (e.g., about 10 w / w%, about 11 w / w%, about 12 w / w%, about 13 w / w%, about 14 w / w%, about 15 w / w%, about 16 w / w%, about 17 w / w%, about 18 w / w%, about 19 w / w%, or about 20 w / w%) dimethyl isosorbide; about 3 w / w% to about 6 w / w% (e.g., about 3 w / w%, about 4 w / w%, about 5 w / w%, or about 6 w / w%) propylene glycol; and about 1 w / w% to about 3 w / w% (e.g., about 1 w / w%, about 2 w / w%, or about 3 w / w%) benzyl alcohol. In total, the one or more co-solvents may comprise from about 20% w / w to about 30% w / w of the topical formulation.

[0069] Suitable topical formulations may include one or more emollients. In one embodiment, the emollient is glycerol. Other suitable emollients include, but are not limited to, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopherol acetate, cetyl acetate, tocopherol linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentyl glycol dicaprylate / dicaprate, caprylyl glycol, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, octyl dodecanol, sucrose fatty acid esters, and octyl hydroxystearate. The one or more emollients may be included in the topical formulation at about 6 w / w% to about 10 w / w% (e.g., about 6 w / w%, about 7 w / w%, about w / w%, about 9 w / w%, or about 10 w / w%).

[0070] The antioxidant may be included in the topical formulation at a concentration of about 0.01 w / w% to about 1 w / w%, for example, about 0.1 w / w% to about 0.5 w / w%. Examples of suitable antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin C and its derivatives, vitamin E and its derivatives, and propyl gallate. In a particularly useful embodiment, the antioxidant includes butylated hydroxytoluene.

[0071] Optionally, an antimicrobial preservative may be present. Examples of suitable antimicrobial preservatives include benzyl alcohol (which may also be considered a solvent), benzalkonium chloride, benzoic acid, cetrimide, chlorocresol, chlorobutanol, glycerin, propylene glycol, phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben, and combinations thereof.

[0072] The topical formulations described herein preferably have an apparent viscosity of about 100 mPa·s or less, more preferably 80 mPa·s or less. For example, the topical formulations described herein may have an apparent viscosity of about 1 mPa·s to about 100 mPa·s, about 1 mPa·s to about 80 mPa·s, about 5 mPa·s to about 60 mPa·s, about 10 mPa·s to about 80 mPa·s, about 10 mPa·s to about 40 mPa·s, or about 15 mPa·s to about 50 mPa·s.

[0073] Various therapeutically effective topical formulations are contemplated within the scope of the present invention. In one embodiment, a suitable topical formulation comprises a therapeutically effective amount of Compound I, a salt thereof, or a solvate thereof; a primary solvent comprising one or both of a mixture of polyethylene glycol and diethylene glycol monoethyl ether having an average molecular weight of about 200 g / mol to about 400 g / mol; a co-solvent comprising one or more of benzyl alcohol, ethanol, and phenoxyethanol; dimethyl isosorbide; propylene glycol; glycerol; and an antioxidant. Such a formulation may have an apparent viscosity of about 1 mPa·s to about 100 mPa·s.

[0074] In any embodiment, a suitable topical formulation of the present disclosure comprises about 0.5 w / w% to about 3.5 w / w% of Compound I or a pharma- ceutically acceptable derivative thereof; about 68 w / w% to about 70 w / w% of a primary solvent, including one or both of a mixture of polyethylene glycol and diethylene glycol monoethyl ether having an average molecular weight of about 200 g / mol to about 400 g / mol; about 2 w / w% of benzyl alcohol; about 15 w / w% of dimethyl isosorbide; about 5 w / w% of propylene glycol; about 8 w / w% to about 10 w / w% of glycerol; and about 0.05 w / w% to about 0.5 w / w% of an antioxidant. Such a formulation may have an apparent viscosity of about 10 mPa·sec to about 100 mPa·sec.

[0075] In any embodiment, a suitable topical formulation of the present disclosure comprises about 0.5 w / w% to about 3.5 w / w% of Compound I or a pharma- ceutically acceptable derivative thereof; about 28 w / w% to about 34 w / w% of a mixture of polyethylene glycols having an average molecular weight of about 300 g / mol to about 400 g / mol; about 35 w / w% to about 40 w / w% of diethylene glycol monoethyl ether; about 2 w / w% of benzyl alcohol; about 15 w / w% of dimethyl isosorbide; about 5 w / w% of propylene glycol; about 8 w / w% to about 10 w / w% of glycerol; and 0.05 w / w% to about 0.5 w / w% of an antioxidant such as butylated hydroxytoluene. Such a formulation may have an apparent viscosity of about 1 mPa·sec to about 40 mPa·sec.

[0076] In any embodiment, a suitable topical formulation of the present disclosure comprises about 0.5 w / w% to about 3.5 w / w% of Compound I or a pharma- ceutically acceptable derivative thereof; about 68 w / w% to about 70 w / w% of a primary solvent consisting of polyethylene glycol having an average molecular weight of about 300 g / mol to about 400 g / mol; about 2 w / w% of benzyl alcohol; about 15 w / w% of dimethyl isosorbide; about 5 w / w% of propylene glycol; about 8 w / w% to about 10 w / w% of glycerol; and about 0.05 w / w% to about 0.5 w / w% of an antioxidant, such as butylated hydroxytoluene. Such formulations may have an apparent viscosity of about 1 mPa·sec to about 100 mPa·sec.

[0077] Additional exemplary topical formulations of the present disclosure are provided in Table 1 of the Examples herein. The topical formulation is provided in a plastic bottle (e.g., HDPE) or glass bottle closed with a plastic cap (e.g., polypropylene, HDPE). The topical formulation can be applied to the skin, for example, using a dropper. Optionally and if necessary, a pumping mechanism can be further provided in the plastic bottle / cap, the cap can be removed, and securely replaced with a pumping mechanism that delivers the topical formulation as a spray. Thus, the sprayable formulation should exhibit a viscosity that is compatible with the pumping / spraying mechanism utilized, as described above. Those skilled in the art will be familiar with the various commercially available pump / spray actuators that can be used for topical delivery of the formulations disclosed herein. Application of the topical formulation can be controlled via a valve that provides a continuous or metered spray.

[0078] The topical formulations disclosed herein have demonstrated long-term chemical and physical stability under various storage conditions. For example, various topical formulations disclosed herein have been found to be stable for up to 6 months when stored at 25°C and 60% relative humidity (RH) and 40°C and 75% RH, as measured by HPLC. In particular, the recovery of Compound I in one or more formulations described herein can reach about 95% to about 100% after 6 months of storage at both 25°C / 60% RH and 40°C / 75% RH. The macroscopic and microscopic appearances after storage under these conditions can remain unchanged.

[0079] The method of preparation of the topical formulation disclosed herein can be any suitable one known to those skilled in the art.For example, the topical formulation as disclosed herein can be prepared by weighing alcohol and glycol-containing solvent / co-solvent (e.g., benzyl alcohol, ethanol, phenoxyethanol, polyethylene glycol, diethylene glycol monoethyl ether) together with additional optional antioxidant (e.g., BHT) and / or antibacterial agent.These components can generally be mixed in any order to form a substantially homogeneous mixture.If necessary, the mixture can be heated to promote dissolution.

[0080] The topical formulations disclosed herein may be useful for treating conditions involving Janus kinase signaling, particularly Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3) signaling pathways. Examples of such conditions include, but are not limited to, atopic dermatitis, vitiligo, and alopecia areata. Suitable formulations may include a therapeutically effective amount of Compound I.

[0081] Advantageously, the topical formulations have been developed to meet a complex set of criteria. First, the topical formulations described herein exhibit excellent physical and chemical stability, both in the formulation and in the compound I in the formulation, to maintain potency throughout storage. In addition, the formulations have been developed with effective amounts of penetrants (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, and propylene glycol) to effect sufficient penetration of compound I into the skin while minimizing tissue introduction. Furthermore, the formulations have been developed with patient compliance and comfort in mind. The inclusion of an emollient provides a formulation that is easy to use, relieves symptoms of the underlying disease being treated with compound I, and thus increases the likelihood of patient use of the product. Each of these aspects, when combined, provides a useful topical formulation for the treatment of various skin disorders and conditions using compound I that are not currently available.

[0082] As mentioned above, the combination of formulation components disclosed herein is selected to maximize solubility, moisturizing / emollient effect while balancing the need for sprayability and therefore spreadability.In certain embodiments, application of the formulation in the absence of Compound I results in a reduction in the severity and extent of skin lesions caused by immune deficiency in human subjects.In certain embodiments, the formulation can include Compound I and can further include a vehicle that can include a primary solvent and one or more co-solvents.The formulation can further include one or more antioxidants, one or more antibacterial agents, antifungal agents, or any other desired excipients, such as, but not limited to, one or more diluents, fillers, lubricants, surfactants, emulsifiers, emollients, stabilizers, viscosity modifiers, colorants, fragrances, or any combination thereof.In particularly useful embodiments, the topical formulation includes an emollient.

[0083] In another embodiment, the formulation lacking Compound I comprises about 68 w / w% to about 70 w / w% of a primary solvent comprising one or both of a mixture of polyethylene glycol and diethylene glycol monoethyl ether having an average molecular weight of about 200 g / mol to about 400 g / mol; about 2 w / w% benzyl alcohol; about 15 w / w% dimethyl isosorbide; about 5 w / w% propylene glycol; about 8 w / w% to about 10 w / w% glycerol; and about 0.05 w / w% to about 0.5 w / w% antioxidant. Such formulations may have an apparent viscosity of about 10 mPa·sec to about 100 mPa·sec.

[0084] In another embodiment, the formulation lacking Compound I comprises a mixture of about 28 w / w% to about 34 w / w% polyethylene glycol having an average molecular weight of about 300 g / mol to about 400 g / mol; about 35 w / w% to about 40 w / w% diethylene glycol monoethyl ether; about 2 w / w% benzyl alcohol; about 15 w / w% dimethyl isosorbide; about 5 w / w% propylene glycol; about 8 w / w% to about 10 w / w% glycerol; and about 0.05 w / w% to about 0.5 w / w% antioxidant, such as butylated hydroxytoluene. Such formulations may have an apparent viscosity of about 1 mPa·sec to about 40 mPa·sec.

[0085] In yet another embodiment, the formulation lacking Compound I comprises about 68 w / w% to about 70 w / w% of a primary solvent consisting of polyethylene glycol having an average molecular weight of about 300 g / mol to about 400 g / mol; about 2 w / w% benzyl alcohol; about 15 w / w% dimethyl isosorbide; about 5 w / w% propylene glycol; about 8 w / w% to about 10 w / w% glycerol; and about 0.05 w / w% to about 0.5 w / w% of an antioxidant, such as butylated hydroxytoluene. Such formulations may have an apparent viscosity of about 1 mPa·sec to about 100 mPa·sec. In order to facilitate a better understanding of the embodiments of the present specification, the following preferred or representative embodiments are presented. The following examples should in no way be read to limit or define the scope of the present invention.

[0086] Although the present invention has been described in some detail with reference to certain preferred embodiments thereof, other versions are possible, and therefore, the spirit and scope of the appended claims should not be limited to the description and preferred versions contained herein. EXAMPLES

[0087] Method for evaluating formulation characteristics in Examples 1 to 3 Surface tension was measured at 25° C. using a Malvern Instruments Kinexus Ultra + Rheometer S / N MAL1102043 (DeNouy Ring geometry). Viscosity was measured at 25° C.±1.0 on a Brookfield model DV 2T / LV viscometer using Rheocalc T.1.2.19 software. Storage stability was measured for various topical formulations stored in glass vials in amber glass bottles closed with polypropylene caps for up to 24 months at 25°C / 60% RH and 40°C / 75% RH for up to 6 months. Compound I content and peak purity were measured by HPLC (method described below), microscopic and macroscopic appearance was evaluated, and benzyl alcohol and butylated hydroxytoluene containing benzyl were measured.

[0088] Permeability Test: Ex Vivo / In Vitro permeability tests were performed by mounting human skin in a flow-through diffusion cell (MEDFLUX-HT®). Test formulations were placed on top of the skin, and receptor solution (citric acid / phosphate buffer pH 4.0 + 0.1% polyethylene glycol hexadecyl ether (BRIJ®)) was perfused under the skin to capture Compound I that had permeated the skin. After removal from the flow cell, the skin itself was subjected to an extraction procedure (10:90 v / v acetonitrile:water) to quantify the amount of Compound I remaining in the skin. Compound I content in the receptor solution and extraction solution was quantified by HPLC (method described below).

[0089] HPLC method: Waters TM XBRIDGE® BEH C 18 An HPLC Water Alliance equipped with a 35 μm, 150×4.6 mm column was utilized. Compound I was detected by UV at a wavelength of 235 nm. The column temperature was maintained at 40±5° C. Mobile phase A was 0.1% TFA in water, mobile phase B was 100% methanol, and samples were analyzed with gradient elution at a flow rate of 1.0 mL / min.

[0090] Example 1: Formulation example Table 1 below reports various specific examples of topical formulations that may be administered to a subject to treat skin conditions caused by immunodeficiency diseases, such as atopic dermatitis, alopecia areata, or vitiligo, some of which represent exemplary embodiments of such topical formulations.

[0091] [Table 1-1] [Table 1-2]

[0092] Example 2 Preparation of Formulation 4 23.62kg Croda SUPER REFINED TM PEG-400 and 1.75kg of SUPER REFINED TM Propylene glycol (Croda) was mixed in the mixer. 700g of benzyl alcohol and 35g of butylated hydroxytoluene (BHT) were added to the mixer. The resulting mixture was stirred until all the BHT was dissolved and a clear solution was obtained. The contents were mixed. Separately, 707.07g of Compound I and 3.25kg of SUPER REFINED TM ARLASOLVE TM Dimethyl isosorbide (Croda) was added to the container and mixed until a uniform dispersion was obtained. The dispersion was added to the clear solution in the mixer, using 2000g of additional dimethyl isosorbide to rinse the container. The combined mixture was mixed under heating until Compound I was dissolved. Then, 2.94 kg of glycerol was added to the mixed mixture while continuing to mix to obtain a uniform solution. The solution was cooled while continuing to mix at the same speed to obtain the final topical formulation.

[0093] Example 3: Ex Vivo / In Vitro Permeability Test For Ex Vivo permeability testing, 10 mg of formulations 1-12 were applied to the test layer of skin as described above. Table 2 below represents data collected from testing various embodiments of the formulations disclosed herein (formulations 1-3, 4, and 8 above). The amount applied to the skin is reported in mg and represents the amount of Compound I in the formulation applied to the skin. Figures 10A and 10B compare the dermis and epidermis penetration of formulations 1 (SOL01), 2 (SOL02), and 3 (SOL03) as a percentage of administered dose to various other Compound I containing formulations. Specific formulations included in Figures 10a and 10b are an ointment formulation (PO3), a non-aqueous gel (NA10, 11, 12, 13, and 14), an aqueous gel (AG07, 08, and 09), a cream (CR12, CR14, CR16), and a foam (F09, 10, 11, 12, and 13). Figures 11A and 11B compare the concentration of Compound I in the receptor solution for Formulation 1 (SOL01), Formulation 2 (SOL02), Formulation 3 (SOL03), Formulation 4 (SOL04), and Formulation 8 (SOL14) with various aqueous and non-aqueous gel, cream, and foam formulations.

[0094] [Table 2]

[0095] Example 4: A Phase 2a study to determine the safety, tolerability, pharmacokinetics, and efficacy of a topical JAK inhibitor for the treatment of moderate or severe atopic dermatitis. Compound I is an inhibitor of the JAK1 / 3 enzyme and has demonstrated local activity in a skin inflammation model. Compound I was designed to be pharmacologically active in the skin and to have rapid systemic clearance to limit systemic exposure.

[0096] The easy way Adult subjects with moderate or severe atopic dermatitis (AD) were randomized to Compound I topical solution 2.0% or vehicle treatment, administered twice daily (BID). The primary endpoint was the percent change in mEASI score at day 28. Other efficacy endpoints included IGA, BSA, PP-NRS. Safety assessments included Adverse Event (AE) assessments, vital signs, electrocardiogram (ECG), and laboratory assessments. PK blood sampling assessed systemic exposure.

[0097] Detailed Method Fifty subjects, both male and female, aged 18-65 years, were selected to use either a topical formulation containing 2% w / w Compound I or a placebo. The appropriate inclusion criteria for this study were: (i) a diagnosis of atopic dermatitis (AD) fulfilling the specific diagnostic criteria of Hanifin and Rajka (Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. Suppl 1980; 92: 44-7, incorporated herein by reference in its entirety); (ii) a 6-month course of AD; (iii) no significant AD inflammation for the previous 4 weeks; (iv) no more than 3 cm 3 (v) stable diagnosis of moderate or severe AD (Investigator Global Assessment (IGA) score of 3 or 4); (vi) Eczema Area and Severity Index (EASI) score of 48 or less; and (vii) having AD affecting 3% to 20% of the body surface area (BSA) (head, palms, soles, groin, and genitals).

[0098] The 50 subjects were randomly assigned to 2% Compound I treatment (n=23) and vehicle treatment (n=25) groups. Two of the subjects were randomly assigned but not treated. Of the assigned subjects, 91% (n=21) and 72% (n=18) of the Compound I treatment group completed the study. The demographic and baseline characteristics of the study subjects are provided in Table 3 below.

[0099] [Table 3]

[0100] The topical formulation was applied topically twice daily, approximately 8-12 hours apart. One mL at a time, up to a maximum of 8 mL, was applied to the subject's identified AD target area and rubbed into the subject's area to obtain a thin film on the skin. Less than 8 mL may be used if less is needed to completely cover the identified AD target area. Subjects recorded AD symptoms, such as itching, daily. Subjects were asked to refrain from washing the treatment area within 6 hours of application, to minimize sun exposure, to refrain from using moisturizers, emollients, and sunscreens on the treatment area, and to refrain from activities that would cause excessive sweating (e.g., exercise) for 6 hours after each application. The study was conducted for 4 weeks. On days 1, 8, and 15, pharmacokinetic samples (e.g., blood) were taken from each subject approximately 2 hours after application of the topical formulation. On day 28, the following pharmacokinetic samples were obtained: Subgroup 1: 1 sample before adaptation and 1 sample 0.5-2.5 hours after adaptation Subgroup 2: 1 sample 2.5-5 hours after adaptation and 1 sample at least 2 hours later Subgroup 3: 1 sample 5-8 hours after adaptation and 1 sample at least 2 hours later (before any subsequent adaptation) was collected.

[0101] Each subject's AD symptoms were assessed by EASI score, IGA, PP-NRS, and BSA on days 1, 8, 15, and 28. The primary efficacy of treatment was measured as the percentage change in EASI from baseline (EASI on day 1) to day 28. Additional measures of efficacy included percent change in EASI between Days 1, 8, 15, and 28, respectively, and baseline and / or pre-assessments of IGA, AD BSA, and PP-NRS on Days 8, 15, and 28; proportion of subjects achieving an IGA score of 0-1 combined with a 2 or more point improvement from baseline by Day 28; proportion of subjects achieving a 50%, 75%, and 90% improvement in EASI score (compared to baseline).

[0102] Quick Results Fifty subjects were enrolled in the study, of which 48 (96%) met the Full Analysis Set criteria. 39 / 48 (81.3%) subjects completed the study, and 7 (14.6%) vehicle subjects discontinued, including 3 subjects who discontinued due to AEs. Compound I was superior to the vehicle group, with a 74.4% reduction in mean mEASI at week 4 compared with 41.4% in the vehicle group (1-sided p<0.001). A beneficial trend for Compound I was observed in secondary efficacy endpoints, including mEASI50 / 75 / 90 and IGA responders, as well as IGA, BSA, and itch scores. More than 86% of plasma samples showed Compound I at or below the lower limit of quantification of 0.1 ng / mL. Mean drug concentrations were 5% or less of the IC50 of Compound I. Compound I was generally well tolerated, with similar percentages of subjects in each treatment group reporting AEs (9 / 23 in the Compound I group and 9 / 25 in the vehicle group). No deaths or SAEs were reported. Most AEs were mild or moderate in severity. Two unrelated serious events (atrial fibrillation (AF) and elevated CPK) were reported in the Compound I treatment group.

[0103] Detailed Results Figure 1 shows the percent change in EASI scores from baseline for subjects treated with Compound I and vehicle on days 8, 15, and 28. The data show a significantly greater improvement in EASI scores from baseline versus vehicle, providing conclusive evidence of efficacy in a validated and recognized endpoint in AD.

[0104] Figure 6 is a table summarizing the EASI50 responder data during the study. As shown, at the end of the first week (day 8), 34.8% of the patients treated with compound I achieved a 50% improvement in EASI score, compared to 12% of the patients treated with vehicle. At the end of the second week (day 15), 69.6% of the patients treated with compound I versus 36% of the patients treated with vehicle achieved a 50% improvement in EASI score, and at the end of the fourth week (day 28), 91.3% of the patients treated with compound I versus 40% of the patients treated with vehicle achieved a 50% improvement in EASI score (see also Figure 2, which is a graph showing the percentage of EASI50, EASI75 and EASI90 responders in the patients treated with compound I and vehicle at day 28 of the study).

[0105] Figure 7 is a table summarizing the data of EASI75 responders during the study period. As shown, at the end of the first week (day 8), 13.0% of the patients treated with compound I achieved a 75% improvement in EASI score, compared to 4% of the patients treated with vehicle. At the end of the second week (day 15), 21.7% of the patients treated with compound I achieved a 75% improvement in EASI score, compared to 16% of the patients treated with vehicle, and at the end of the fourth week (day 28), 65.2% of the patients treated with compound I achieved a 75% improvement in EASI score, compared to 24% of the patients treated with vehicle (see also Figure 2).

[0106] Figure 8 is a table summarizing the data of EASI90 responders during the study period. As shown, at the end of the first week (day 8), 4.3% of the patients treated with compound I achieved a 90% improvement in EASI score, while 0% of the patients treated with vehicle achieved it. At the end of the second week (day 15), 8.7% of the patients treated with compound I achieved a 90% improvement in EASI score, while 8% of the patients treated with vehicle achieved it; and at the end of the fourth week (day 28), 30.4% of the patients treated with compound I achieved a 90% improvement in EASI score, while 20% of the patients treated with vehicle achieved it (see also Figure 2).

[0107] Figure 9 is a table summarizing the change from baseline in peak pruritus numerical rating scale (PP-NRS) by week during the study, and Figure 3 shows a graph of this change. It is noteworthy that after only one week, patients treated with Compound I experienced a mean reduction in PP-NRS scores of 1.72 versus baseline. A difference of 1.0 is considered a clinically meaningful reduction. FIG. 4 shows the percentage of subjects (Compound I and vehicle treated) with an Investigator Global Assessment (IGA) treatment response of 0 or 1 with an improvement of ≥2 points during the study. FIG. 5 shows disease-affected BSA change from baseline in Compound I and vehicle treated subjects on days 1, 8, 15, and 28, respectively.

[0108] As expected, topical administration of Compound I to subjects in the study did not result in clinically relevant plasma concentrations of Compound I in any patient. All plasma concentrations were below the IC 50 (I C 50 = 36 ng / mL). The mean plasma concentrations in subjects receiving Compound I solution on days 1, 8, and 28 were as follows: Day 1, 2 hours after administration: 1.604ng / mL Day 8, 2 hours after administration: 0.519 ng / mL Day 28, pre-dose: 0.328ng / mL It was. IC 50 Only three subjects (six samples total) had concentrations greater than one-tenth of the mean. No subjects had Compound I concentrations greater than 15 ng / mL. The limit of quantification (LLOQ) was 0.100 ng / mL. Tables 4 and 5 below show PK data for subjects with the lowest (Table 4) and highest (Table 5) plasma concentrations of Compound I during the study period.

[0109] [Table 4-1] [Table 4-2] [Table 4-3] [Table 5-1] [Table 5-2] [Table 5-3]

[0110] Adverse events (AEs) of topical administration of Compound I were observed and recorded based on severity (e.g., mild, moderate, or severe) and causality. The overall safety of the use of Compound I according to the methods disclosed herein is based on the incidence of adverse events, the subjects' vital signs, and the results of physical examinations. Table 6 shows an overall summary of adverse events that occurred during treatment and the number of subjects who experienced severe adverse events, and Table 7 shows a summary of adverse events reported by study participants. No severe adverse events were reported, and no patients in the Compound I group discontinued the study due to adverse events. Three patients in the vehicle group discontinued due to COVID-19, SARS-CoV-2, and inflammation at the application site.

[0111] [Table 6] [Table 7]

[0112] conclusion In this Phase 2a clinical trial, consisting of a 4-week treatment period and a 2-week treatment-free follow-up period, 50 subjects with moderate to severe AD were randomly assigned in a 1:1 ratio to one of two treatment arms: a topical solution of Compound I 2.0% w / w or vehicle applied twice daily. One of the key objectives of this first in human trial was to evaluate the "soft" aspect of this topical JAK inhibitor compound in subjects with moderate to severe atopic dermatitis. Preliminary measurements of pharmacokinetic plasma samples in the Compound I treatment group showed that the mean drug concentration was 4.0-5.0 vs. 4.0 vs. 1.0 ng / mL for Compound I. 50 The results showed that the mean age of the 19-year-old man did not exceed 5% of the mean age of the 19-year-old man.

[0113] The primary efficacy endpoint of this study was the percent change from baseline in Eczema Area and Severity Index (EASI) score at week 4. The EASI was modified (mEASI) to exclude assessment of body sites not treated in the study (i.e., head, palms, soles, groin, or genitals). The full analysis set (FAS), which includes subjects who were randomly assigned and received at least one dose of study medication, was used as the primary endpoint. Two subjects in the Compound I treatment group were excluded from the FAS analysis because they were lost to follow-up after the baseline survey and did not have a formal record of being administered. For statistical significance, undetected key secondary efficacy endpoints included the proportion of subjects who achieved 50% in EASI score within 4 weeks after the start of treatment (EASI-50), the change from baseline in Investigator Global Assessment (IGA) score at each study visit, the change from baseline in body surface area (BSA) at each study visit, and the change from baseline in peak pruritus numerical rating scale (PP-NRS) score over time. Only the primary efficacy endpoint was powered to detect statistically significant results.

[0114] The FAS consisted of 23 and 25 subjects who were randomly assigned and recorded at least one dose of Compound I or vehicle, respectively. The study achieved its primary endpoint with a high degree of statistical significance, with Compound I-applied subjects showing a 74.5% reduction in mEASI score from baseline at week 4, compared with a 41.4% reduction in vehicle-applied subjects. Furthermore, the pre-planned per-protocol analysis of the percentage change in EASI score, as well as the post-hoc analysis including the two randomly assigned subjects not included in the FAS, using baseline EASI score carried forward to day 28, were both statistically significant. Additionally, positive trends in favor of Compound I were observed in key secondary efficacy endpoints, including improvement in pruritus, proportion of EASI-50 responders, and reduction in body surface area affected by disease.

[0115] Compound I was generally well tolerated. Nine subjects in each treatment group reported adverse events (9 / 23 and 9 / 25 in the Compound I and vehicle treatment groups, respectively). No serious adverse events were reported. The most common adverse events (reported by more than one subject in the Compound I treatment group) were increased blood creatine phosphokinase and headache, which were judged by the clinical investigator to be unrelated to Compound I. In the FAS analysis, two subjects from Compound I withdrew from the study (one lost to follow-up, one withdrew on consent), while seven subjects withdrew from the vehicle treatment group (three due to AEs and four withdrew on consent). No thrombosis was reported. BID treatment with a topical solution of Compound I was effective in adults with moderate or severe AD. Topically applied drug resulted in systemic plasma concentrations significantly below the IC50 and, as a result, are unlikely to be clinically relevant. BID treatment with a topical solution of Compound I was generally well tolerated over the 4-week treatment period. This study supports progression to a Phase 2b trial.

[0116] Example 5: A Phase 2b Study to Determine the Safety, Tolerability, Pharmacokinetics, and Efficacy of a Topical JAK Inhibitor for the Treatment of Moderate or Severe Atopic Dermatitis (AD) Objectives and Endpoints The primary objective of this study is to evaluate the efficacy of Compound I solution in patients with moderate and severe AD, administered twice daily (BID) or once daily (QD). The primary efficacy endpoint of this study is the percent change from baseline in EASI score at week 4.

[0117] The secondary objective of this study is to further characterize the efficacy of Compound I solution by evaluating several additional endpoints. These endpoints include: (i) determining the percent change from baseline in Eczema Area and Severity Index (EASI) scores at each study visit; (ii) determining the proportion of patients who achieve Investigator Global Assessment (IGA) Treatment Success (IGA-TS), defined as an (IGA) score of 0 to 1 combined with an improvement of 2 or more points from baseline within 4 weeks of starting treatment; and (iii) determining the proportion of patients who achieve 50%, 75%, and 90% improvement in EASI scores (EASI-50, EASI-75, and EASI-90, respectively) at each study visit. In addition, changes from baseline in several endpoint measurements are evaluated. These include (iv) change from baseline in IGA score at each study visit, (v) change from baseline in body surface area (BSA) at each study visit, (vi) change from baseline in peak Pruritus Numeric Rating Scale (PP-NRS) score over time, (vii) percentage change in BSA from baseline to day 28, (viii) change in PGIC from baseline to day 28, (ix) percentage of patients with a score of either 1 or 2 on PGIC from baseline to day 28, (x) change in PP-NRS from baseline to day 28. Finally, the following additional secondary endpoints will also be evaluated: (xi) percentage of patients achieving a 4-point improvement in PP-NRS at day 28, (xii) assessment of trough pharmacokinetic (PK) concentrations of Compound I at each visit, and (xiii) safety and tolerability as assessed by observing the frequency, duration, and severity of adverse events (AEs).

[0118] In addition to the above, the study will also investigate the following research objectives: (i) to evaluate the time to achieve an IGA score of "clear" (0) or "almost clear" (1); (ii) to evaluate the time to achieve a 50%, 70%, and 90% improvement in the EASI; and (iii) to evaluate the time to achieve an improvement in the PP-NRS score of at least 2, 3, or 4 points. Safety will be assessed through the following outcomes: (i) recording the occurrence of treatment-emergent AEs (TEAEs) and SAEs, (ii) tracking patients' routine laboratory values, (iii) tracking patients' vital signs, (iv) performing physical examinations of patients, and (v) monitoring patients with 12-lead electrocardiograms. In assessing the pharmacokinetics of Compound I solution, a sparse sampling approach will be adopted since clinically relevant crystalline concentrations are not expected to be observed. PK samples will be taken prior to application of study drug on Days 1, 15, and 28.

[0119] Study design This is a randomized, double-constrained, vehicle-controlled, parallel-group study to determine the safety, tolerability, pharmacokinetics, and efficacy of Compound I solution following application twice daily (BID) or once daily (QD) to target sites in patients with moderate to severe AD. The study will consist of a screening period of up to 30 days, a treatment period of 4 weeks, and a follow-up period of 2 weeks. The total duration of the study for patients remaining at final follow-up will be up to 42 days. Patients will undergo screening assessments to determine eligibility up to 30 days prior to randomization. Patients who meet all inclusion criteria will be randomized on Day 1. Study drug will be administered for 4 weeks, with the final dose of study drug administered on the morning of Day 28. Patients will be seen on Days 8 and 28 for safety, efficacy, and PK / PD assessments. Patients will return for a Post-Treatment Follow-Up Visit 2 weeks after the last dose of study drug to assess safety. All assessments will be performed as detailed in the Schedule of Events (SOE).

[0120] Patients will undergo screening for up to 30 days, followed by 4 weeks of treatment and 2 weeks of PTFU. The start of the study will be the date the first patient provided informed consent and the end of the study will be the date of the patient's last evaluation. Approximately 240 patients are planned to be enrolled. Patients will be randomly assigned to receive Compound I topical solution (0.5, 1.0, 2.0% w / w) BID (twice daily) or vehicle (topical vehicle solution without Compound I) BID, or Compound I topical solution (2.0% w / w) QD (once daily) or vehicle QD 2;2;2;1;2:1.

[0121] Target population Eligible inclusion criteria for the study were: (i) patients with a diagnosis of AD meeting the specific diagnostic criteria of Hanifin and Rajka (Hanifin and Rajka 1980); (ii) patients with a history of AD for at least 6 months prior to the screening visit and no significant AD inflammation in the 4 weeks prior to the screening visit; (iii) patients with a cerebral adenomatosis of at least 3 cm at the screening visit and on Day 1 prior to the first dose of study medication. 2 (iv) patients with a diagnosis of moderate or severe AD (IGA score 3 or 4) at the screening visit; and (v) patients with AD affecting 10% or more of the BSA (not including the scalp with hair, palms, soles, groin, or genitals) at the screening visit.

[0122] The appropriate exclusion criteria for this study are: patients with any of the following will be excluded from the study; (i) an unstable course of AD (spontaneously improving or rapidly worsening) based on the patient's medical history or as determined by the investigator during the screening period; (ii) refractory AD (i.e., AD that required frequent hospitalizations and / or intravenous treatment for frequent skin infections within the year prior to the screening visit); (iii) AD of such severity that the patient is not a candidate for vehicle control (EASI>48); (iv) some signs or symptoms related to AD treatment (e.g., history of anaphylaxis, hypersensitivity reactions, skin atrophy, striae, pigmentary changes) that the investigator determines may compromise the evaluation of AD or that would expose the patient to unacceptable risk from study participation; (v) concomitant skin disease or clinically infected AD, or (vi) the presence of other skin disorders in the dosing area that may interfere with study evaluation; (vi) any of the following treatments within the indicated washout period prior to Day 1: Phototherapy (ultraviolet A therapy, ultraviolet B therapy, or psoralen and ultraviolet A therapy) within 4 weeks prior to Day 1 Systemic biologic immunosuppressive or immunomodulatory therapy (e.g., etanercept, alefecept, infliximab, dupilumab) within 12 weeks (or 5 half-lives of the product, whichever is longer) prior to Day 1 Non-biologic immunosuppressants (e.g., methotrexate, retinoids, calcineurin inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine) within 4 weeks prior to Day 1 Janus kinase (JAK) inhibitors (systemic and topical) within 4 weeks prior to Day 1 Systemic corticosteroids within 2 weeks prior to Day 1 (intranasal, inhaled, and topical ophthalmic corticosteroids are permitted) -Cytostatics within 4 weeks prior to the first day Crisaborole within 2 weeks prior to Day 1 -Systemic antibiotics within 30 days prior to Day 1 Topical treatment for AD within 2 weeks prior to Day 1 (corticosteroids, calcineurin inhibitors, topical H1 and H2 antihistamines, topical antibacterials, and other medicinal topicals) Live attenuated vaccine within 12 weeks prior to day 1 - Other investigational drugs within 30 days or 5 half-lives (whichever is longer) from Day 1 This includes the use of any of the following:

[0123] Safety Analysis: The FAS will be used for analysis of safety data (AEs, clinical laboratory values, vital signs, laboratory results, and ECGs). Plasma Drug Concentrations: Plasma drug concentrations of Compound I will be summarized at nominal time points and days.

Claims

1. A composition for treating a skin condition caused by an immune deficiency in a human subject in need thereof, comprising: The composition comprises the following compound (I): or a pharma- ceutically acceptable derivative thereof, A composition, wherein said treatment comprises topically administering said composition to the subject's area afflicted with said skin condition.

2. The composition of claim 1 , wherein the skin condition is atopic dermatitis.

3. 3. The composition of claim 1 or 2, wherein the administration reduces one or more of the subject's Investigator Global Assessment (IGA) score, Eczema Area and Severity Index (EASI) score, Peak Pruritus Numeric Rating Scale (PP-NRS) score, or Body Surface Area (BSA) measurement.

4. A composition described in any one of claims 1 to 3, wherein the treatment comprises topically administering the composition to a skin lesion caused by a skin condition of the subject.

5. A composition described in any one of claims 1 to 4, wherein the treatment comprises administering the composition once a day.

6. The composition described in any one of claims 1 to 4, wherein the treatment comprises administering the composition twice daily.

7. The composition of any one of claims 1 to 4 and 6, wherein the treatment comprises administering the composition containing 2% w / w compound (I) twice daily.

8. The composition of claim 1, wherein the treatment comprises topically administering to the subject about 0.25 mL to about 8 mL of a composition comprising about 2% w / w compound (I).

9. The composition of claim 1, which is a cream, gel, gel-cream, foam, or solution.

10. The composition of claim 1, which is a solution.

11. The composition according to any one of claims 1 to 4 and 6 to 10, wherein said administration comprises twice daily topical application of a solution containing 2% w / w of compound (I).

12. The composition of any one of claims 1 to 11, wherein the treatment further comprises administering to the subject one or more of a corticosteroid, a calcineurin inhibitor, a phosphodiesterase-4 inhibitor, dupilumab, and a humanized monoclonal antibody that blocks interleukin (IL)-4 / IL-13 signaling.

13. A composition for the treatment of reducing the severity and extent of skin lesions caused by immune deficiency, The composition comprises the following compound (I): or a pharma- ceutically acceptable derivative thereof, A composition, wherein said treatment comprises topically administering said composition to a human subject having said immunodeficiency.

14. The composition of claim 13, wherein the subject has been diagnosed with atopic dermatitis.

15. The composition described in claim 13 or 14, wherein the treatment comprises administering the composition once a day.

16. The composition described in claim 13 or 14, wherein the treatment comprises administering the composition twice daily.

17. 17. The composition of any one of claims 13 to 16, wherein said administration reduces one or more of the subject's IGA score, EASI score, PP-NRS score, or BSA measurement.

18. The composition of any one of claims 13-14 or 16-17, wherein the treatment comprises administering the composition containing 2% w / w compound (I) twice daily.

19. The composition of any one of claims 13 to 18, which is a cream, gel, gel-cream, foam, or solution.

20. The composition of any one of claims 13 to 19, which is a solution.

21. The composition according to any one of claims 13 to 14 and 16 to 20, wherein the administration comprises twice daily topical application of a solution containing 2% w / w of compound (I).

22. The composition of any one of claims 13 to 21, wherein the treatment comprises topically administering to the subject about 0.25 mL to about 8 mL of the composition comprising about 2% w / w compound (I).

23. A topical formulation comprising ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, or a pharma- ceutically acceptable derivative, salt, or solvate thereof, and a vehicle.

24. The topical formulation of claim 23, wherein the ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate or a pharma- ceutically acceptable derivative, salt, or solvate thereof is present in the topical formulation at a concentration of about 0.5% w / w.

25. The topical formulation of claim 23, wherein the ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate or a pharma- ceutically acceptable derivative, salt, or solvate thereof is present in the topical formulation in a concentration of about 2.0% w / w.

26. The topical formulation of claim 23, wherein the vehicle comprises a primary solvent and one or more co-solvents.

27. The topical formulation of claim 23, further comprising an emollient.

28. The topical formulation of claim 23, further comprising an antioxidant.

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