Pyrrolopyrimidine compositions for treatment of atopic dermatitis

Abstract

The present disclosure relates methods for treating skin disorders caused by an immune deficiency with oral formulations comprising 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (Compound I) or pharmaceutically acceptable derivative thereof. In particular, the oral formulations described herein may be used to treat atopic dermatitis.

Description

Attorney Docket No.: 145688-005702 PYRROLOPYRIMIDINE COMPOSITIONS FOR TREATMENT OF ATOPIC DERMATITIS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 643,899 filed May 7, 2024. The disclosure of the application is incorporated herein by reference. SUMMARY

[0002] The present disclosure is directed to a method of treating a skin condition caused by an immune deficiency in a human subject in need thereof, said method comprising orally administering to the human subject an oral dose selected from about 1 mg / day to about 80 mg / day of Compound Ior a derivative thereof to treat said skin condition.

[0003] Another aspect of the disclosure is directed to a method for reducing severity and extent of skin lesions caused by an immune deficiency. This method comprises administering orally, to a human subject having the immune deficiency, a composition comprising about 1 mg / day to about 80 mg / day of 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one having the structure of Compound I (above) or a salt thereof. DETAILED DESCRIPTION Definitions

[0004] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments herein, the preferred methods, devices, and materials are 1 1620037251.1Attorney Docket No.: 145688-005702 now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein are not entitled to antedate such disclosure by virtue of prior invention.

[0005] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to an “ITK inhibitor” is a reference to one or more ITK inhibitors and equivalents thereof known to those skilled in the art, and so forth.

[0006] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, non-recited elements or method steps. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. The compositions and methods of the present disclosure can comprise, consist essentially of, or consist of, the components or steps disclosed.

[0007] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50 mg means in the range of 45 mg to 55 mg.

[0008] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with an ITK inhibitor compound, can include, but is not limited to, providing an ITK inhibitor compound into or onto the target tissue; providing an ITK inhibitor compound systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue.

[0009] As used herein, the term “a derivative thereof” refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form 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, a mixture of tautomers thereof, an enantiomer 2 1620037251.1Attorney Docket No.: 145688-005702 thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0010] The term “substantially free” as used herein, alone or in combination, refers to the absence of isomers within the limits of detection of analytical methods such as nuclear magnetic resonance (NMR), gas chromatography / mass spectroscopy (GC / MS), high performance liquid chromatography (HPLC), or liquid chromatography / mass spectroscopy (LC / MS).

[0011] The term “condition” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “disease”, in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0012] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0013] The term “ITK inhibitor” is used herein to refer to a compound that exhibits an IC50with respect to ITK activity of no more than about 100 ^M and more typically not more than about 50 ^M, as measured in the ITK enzyme assay described generally herein. IC50is that concentration of inhibitor that reduces the activity of an enzyme (e.g., ITK) to half- maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against ITK. In certain embodiments, compounds will exhibit an IC50with respect to ITK of no more than about 10 ^M; in further embodiments, compounds will exhibit an IC50with respect to ITK of no more than about 5 ^M; in yet further embodiments, compounds will exhibit an IC50with respect to ITK of not more than about 1 ^M; in yet further embodiments, compounds will exhibit an IC50with respect to ITK of not more than about 200 nM, as measured in the ITK binding assay described herein.

[0014] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. The 3 1620037251.1Attorney Docket No.: 145688-005702 term “pharmaceutically acceptable salts” embraces salts commonly used to form alkali metal salts and to form 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 derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.

[0015] Suitable pharmaceutically acceptable acid addition salts of the Compound I of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compound of embodiments herein by treating, e.g., the compound with the appropriate acid or base.

[0016] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ȕ-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1,5- naphthalenedisulfonic acid) and the like.

[0017] Salts derived from pharmaceutically-acceptable inorganic bases suitable for the formulations as described herein include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0018] Other preferred salts according to embodiments herein are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids (e.g., chloride, bromide, iodide, sulfate, 4 1620037251.1Attorney Docket No.: 145688-005702 nitrate, phosphate), or an anion of an organic acid (e.g., acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, p- toluenesulfonate). X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulfonate.

[0019] The Compound I of embodiments herein may exist in both non-solvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, Compound I of embodiments herein in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the Compound I of embodiments herein, such as a hydrate.

[0020] In some embodiments herein one solvent molecule can be associated with one molecule of the compound described herein, such as a hydrate. In some embodiments, more than one solvent molecule may be associated with one molecule of the compound described herein, such as a dihydrate. Additionally, in some embodiments herein less than one solvent molecule may be associated with one molecule of the compound described herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of the compound described herein that retain the biological effectiveness of the non-solvate form of the compounds.

[0021] Embodiments herein also includes isotopically-labeled Compound I of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the Compound I of embodiments herein include isotopes of hydrogen, such as2H and3H carbon, such as11C,13C and14C, chlorine, such as31Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and 15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled Compound I of embodiments herein, e.g., those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium,3H, and carbon-14,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier 5 1620037251.1Attorney Docket No.: 145688-005702 isotopes such as deuterium,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0022] Isotopically-labeled Compound I of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0023] Preferred isotopically-labeled compounds include deuterated derivatives of the Compound I of embodiments herein. As used herein, the term deuterated derivative embraces Compound I of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

[0024] Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.

[0025] Typically, a deuterated derivative of a compound of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope (the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).

[0026] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.

[0027] The term “subject” as used herein and interchangeably with “patient”, includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm 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 6 1620037251.1Attorney Docket No.: 145688-005702 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 another embodiment, 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 transgenic pig.

[0028] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0029] The term “therapeutically acceptable” refers to those compounds, and a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0030] The term “BID” as used herein refers to “bis in die” or “twice a day”.

[0031] The term “TID” as used herein refers to “ter in die” or “three times a day”.

[0032] The terms “treat,” “treated,” “treating”, or “treatment” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean 7 1620037251.1Attorney Docket No.: 145688-005702 prevention of progression of a disease to a later stage of the disease and prolonging disease- free survival as compared to disease-free survival if not receiving treatment and prolonging disease-free survival as compared to disease-free survival if not receiving treatment.

[0033] Compound I is an orally available, small molecule, covalent inhibitor of Interleukin 2-Inducible T Cell kinase (ITK; also known as EMT or TSK), tyrosine protein kinase TXK (also known as Resting Lymphocyte Kinase or RLK) and Janus kinase (JAK) 3 for treatment of T cell-mediated autoimmune disease. ITK and TXK are two members of the subfamily of the non-receptor protein tyrosine kinases represented by its first member (Tec) of tyrosine kinases which consists of five family members: Tec, Bruton’s tyrosine kinase (BTK), bone marrow-expressed kinase (BMX), TXK, and ITK. These kinases are central to the regulation of hematopoietic cell biology and more specifically to the development and activity of lymphocytes and myeloid cells. The roles of ITK and TXK in T cell function have been delineated through genetic knockdown / kinase inactivation of these genes in rodents. Janus kinase 3 is a key signaling molecule downstream of the common Ȗ-chain family of cytokine receptors, which include interleukin (IL) 2, 4, 7, 9, 15, and 21. These cytokines are involved in the autoimmune response. The proven efficacy of orally (PO) dosed JAK1 / JAK3 inhibitors such as tofacitinib provide proof of concept for targeting this pathway in the treatment of various autoimmune conditions such as rheumatoid arthritis (RA) (Xeljanz USPI). Compound I has been designed to specifically inhibit all three kinases with a single drug and, thereby, prevents the activation and survival of T cells. By covalently modifying these targets, Compound I may drive highly specific, dual pathway inhibition, which may allow for a favorable benefit to risk ratio. Due to known efficacy of drugs with similar mechanisms of action (baricitinib, cyclosporine) in atopic dermatitis (AD), Compound I is anticipated to have efficacy in AD.

[0034] AD is a chronic, relapsing pruritic inflammatory skin disease involving inflammation and skin barrier defects, worsened by environmental stimuli. It is currently estimated that 10% to 30% of children and 0.3% to 14% of adults in developed countries are affected by the disorder. In the United States, the prevalence of AD in adults is approximately 2±7%, ie, 6.6±23.2 million patients as calculated from 2020ௗUS census data. Among these patients, the proportion of moderate to severe AD is approximately 30%. The disorder results in significant morbidity and adversely affects quality of life. Intense itching characteristic of the disease often leads to skin trauma and significant sleep disturbances. Among skin diseases, AD has the highest disease burden globally as measured by disability-adjusted life-years. AD 8 1620037251.1Attorney Docket No.: 145688-005702 poses detrimental effects on patients’ lives by impacting health and quality of life (QoL) as well as psychological, social, and occupational aspects. A recent US population-based survey reported that adults with AD (vs. those without AD) were more likely to rate their overall health as ‘only fair’ / ’poor’, and satisfaction with life as ‘somewhat dissatisfied’ / ’very dissatisfied’. The prevalence of self-reported healthcare-diagnosed anxiety or depression is also higher in adults with AD vs. those without AD (40.0% vs.17.5%). Patients with AD in the US have also reported lower QoL and higher absenteeism, presenteeism, and overall work and activity impairment than matched non-AD controls.

[0035] Among AD treatments, topical agents such as corticosteroids, calcineurin inhibitors, and phosphodiesterase-4 inhibitors are often baseline therapeutic options, while phototherapy and systemic immunomodulatory agents such as cyclosporine, azathioprine, mycophenolate mofetil, methotrexate and systemic corticosteroids may be considered if topical treatments inadequately control AD, or if the patient’s QoL is substantially impacted. In the past five years, several treatments for AD have been approved by the Food and Drug Administration. These include biologics such as dupilumab and tralokinumab, oral small molecules such as upadacitinib and abrocitinib, and the topical small molecule ruxolitinib. Additionally, many agents administered via injectable, oral, or topical route for AD treatment are being investigated. Although treatment options are expanding, patients’ satisfaction with traditional topical and systemic treatment options is low, and studies exploring or discussing newer treatment options are limited. It has been found that the treatment satisfaction with topical and systemic medications generally decreased with increasing disease severity which emphasizes the need for effective treatments in AD, especially in those with more severe disease.

[0036] Also provided are embodiments wherein any embodiment described herein may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive. Compositions for Oral Administration

[0037] In any embodiment, Compound I can be administered orally as disclosed herein comprises a free base. In any embodiment, Compound I can be administered orally as disclosed herein comprises a pharmaceutically acceptable salt.

[0038] In any embodiment, the pharmaceutically acceptable salt is an acid addition salt. Suitable acid addition salts include those formed with both organic and inorganic acids. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, 9 1620037251.1Attorney Docket No.: 145688-005702 hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ȕ-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like.

[0039] In any embodiment, the pharmaceutically acceptable salt is a basic addition salt. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'- dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0040] In any embodiment, oral administration of Compound I is a non-solvated form or in a solvated form. In any embodiment herein one solvent molecule can be associated with one molecule of Compound I as described herein, such as a hydrate. In some embodiments, more than one solvent molecule may be associated with one molecule of Compound I as described herein, such as a dihydrate. Additionally, in some embodiments herein less than one solvent molecule may be associated with one molecule of Compound I as described herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of Compound I as described herein that retain the biological effectiveness of the non-solvate form of Compound I.

[0041] In any embodiment, the compositions of Compound I for oral administration of the present disclosure comprises Compound I as disclosed herein formulated by admixture with a pharmaceutically acceptable carrier or excipient. In certain embodiments, pharmaceutical 10 1620037251.1Attorney Docket No.: 145688-005702 compositions include the therapeutically effective amount of Compound I and a physiologically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition further includes one or more additional therapeutic components and / or adjuvants.

[0042] In any embodiment, the compositions of Compound I for oral administration disclosed herein may further comprise pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for preparation and administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Banker, G. S., & Rhodes, C. T. (2002). Modern pharmaceutics. New York: Marcel Dekker.; and Goodman, L. S., Brunton, L. L., Chabner, B., & Knollmann, B. C. (2011). Goodman & Gilman's pharmacological basis of therapeutics. New York: McGraw-Hill. can be consulted.

[0043] The compositions of Compound I for oral administration as disclosed herein can be formulated readily by combining Compound I with pharmaceutically acceptable carriers well known in the art. Such carriers enable the Compound I of embodiments herein to be formulated as nanoparticles, nanoparticle suspension, tablets, troches, pills, dragees, capsules, powders, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Compositions of Compound I for oral administration can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutical preparations for oral administration can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate.

[0044] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, PVP, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic 11 1620037251.1Attorney Docket No.: 145688-005702 solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0045] Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient in an admixture with one or more fillers (e.g., lactose), one or more binders (e.g., starches), and / or one or more lubricants (e.g., talc or magnesium stearate) and, optionally, one or more stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid PEG. In addition, stabilizers can be added. All compositions for oral administration should be in dosages (e.g., about 1 mg to about 100 mg) suitable for such administration.

[0046] In some embodiments, the compositions of Compound I for oral administration may take the form of, e.g., lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, PVP or HPMC); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, e.g., sugars, films or enteric coatings. Additionally, the pharmaceutical compositions containing Compound I as disclosed herein can be in any form suitable for oral use, including, e.g., troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0047] In one embodiment, the pharmaceutical composition of Compound I for oral administration as disclosed herein is a tablet. Tablets may contain Compound I in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., corn starch, or alginic acid); binding agents (for example starch, gelatin or acacia); and lubricating agents (for example magnesium stearate, stearic acid or talc). The tablets may 12 1620037251.1Attorney Docket No.: 145688-005702 be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. In some embodiments, the tablet is formulated for immediate release. In some embodiments, the tablet is formulated for controlled release. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions.

[0048] In some embodiments, the composition of Compound I for oral administration comprises Compound I and a buffer. In some embodiments, the buffer may be selected from the group consisting of citric acid monohydrate, sodium phosphate, water, and a combination thereof. In some embodiments, the oral composition comprises Compound I and a stabilizer. In some embodiments, the stabilizer is selected from a group consisting of povidone, sodium benzoate, water, sodium lauryl sulfate, and a combination thereof. In some embodiments, the oral composition further includes a buffer, an acid, sodium benzoate, sodium phosphate, citric acid, or a combination thereof. In some embodiments, the composition of Compound I for oral administration comprises Compound I and a stabilizer and a buffer. In some embodiments, the oral composition further comprises a lubricant, a pH modifier, a binder, a diluent, a granulating agent, a glidant, a disintegrant, a filler, a sorbent, an anti-adherent, a coloring agent, a compression aid, a coating material, a sweetener, a preservative, an antioxidant, or a combination thereof. In some embodiments, Compound I is in a therapeutically effective amount (e.g., about 5 mg to about 100 mg). In some embodiments, the composition of Compound I for oral administration is a suspension, tablet, capsule, nanoparticle powder, nanoparticle suspension, cachet, pellet, pill, powder, granules, or a combination thereof.

[0049] In some embodiments, the lubricant may be selected from the group consisting of stearic acid or its salts (e.g., magnesium stearate, calcium stearate), sodium lauryl sulfate, PEG, mineral oil, sodium benzoate, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, and a combination thereof.

[0050] In some embodiments, the pH modifier may be an acid (e.g., hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, or a combination thereof).

[0051] In some embodiments, the binder may be selected from the group consisting of a natural or synthetic polymer (e.g., starches, sugars, sugar alcohols, or cellulose derivatives) such as gelatin, glucose, lactose, sorbitol, xylitol, maltitol, methyl cellulose, microcrystalline 13 1620037251.1Attorney Docket No.: 145688-005702 cellulose (MCC), ethyl cellulose, HPMC, hydroxypropyl cellulose (HPC), starch, PVP, PEG, sodium alginate, CMC, and a combination thereof.

[0052] In some embodiments, the compression aid may be selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, a physical mixture of MCC-colloidal silicon dioxide, and a combination thereof.

[0053] In some embodiments, the disintegrant may be selected from the group consisting of starch, cellulose derivatives and alginates, PVP, croscarmellose sodium, sodium starch glycolate, and a combination thereof.

[0054] In some embodiments, the filler may be selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, plant cellulose, dibasic calcium phosphate, dibasic sodium phosphate, vegetable fats and oils, and a combination thereof.

[0055] In some embodiments, the diluent may be selected from the group consisting of sugar compounds (e.g., sucrose, lactose, dextrin, glucose, sorbitol, or the like), inorganic compounds (e.g., silicates, calcium salts, or magnesium salts), sodium chloride, potassium chloride, and a combination thereof.

[0056] In some embodiments, the preservative may be selected from the group consisting of an antioxidant (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), an amino acid (e.g., cysteine, or methionine), citric acid, sodium citrate, a synthetic preservative (e.g., a paraben such as methyl paraben or propyl paraben), and a combination thereof.

[0057] In some embodiments, the glidant may be selected from the group consisting of colloidal anhydrous silicon and other silica compounds, such as fumed silica, magnesium carbonate, colloidal silicon dioxide (AEROSIL®), cornstarch, talc, and a combination thereof.

[0058] In some embodiments, the composition for oral administration comprising Compound I is a capsule. In some embodiments, the capsule comprises an inner coating made from a high fat emulsion. In some embodiments, the capsule comprises a high fat coating that is either on the inside or the outside of the capsule. In some embodiments, the capsule comprises HPMC. In some embodiments, the capsule may be a HPMC capsule. In some embodiments, the capsule may be enteric coated. In some embodiments, the capsule may be a silica capsule, such as silica sold under the trade name SYLOID®. In some embodiments, the capsule comprises cyclodextrin. In some embodiments, the capsule may be a cyclodextrin complex enteric capsule. 14 1620037251.1Attorney Docket No.: 145688-005702

[0059] In some embodiments, the oral formulation comprising Compound I is a tablet. In some embodiments, the tablet contains Compound I in the form of nanoparticles. In some embodiments, the tablet may be coated. In some embodiments, the tablet may be coated with an enteric coating. In some embodiments, the tablet may be coated with a coating selected from a sugar coating, film coating, organic film coating, aqueous film coating, pan coating, dip coating, electrostatic coating, compression coating, plasticizer dry coating, heat dry coating, electrostatic dry coating, or the like. Some ingredients used for coating may include aqueous acrylic enteric system such as that sold under the trade name ACRYL-EZE®, film coating system sold under the trade name OPADRY®, HPMC, methyl hydroxyethyl cellulose, ethylcellulose, povidone, cellulose acetate phthalate, acrylate polymers (such as those sold under the trade name EUDRAGIT® L & EUDRAGIT® S), HPMC phthalate, or a combination thereof.

[0060] In some embodiments, the composition for oral administration comprises Compound I in the form of a nanoparticle suspension (nanosuspension). In some embodiments, the nanosuspension comprises Compound I, a stabilizer, and a buffer. In some embodiments, the nanosuspension may further comprise a pH modifier. In some embodiments, the pH modifier may be selected from a group consisting of hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, and a combination thereof. In some embodiments, the pH modifier may be hydrochloric acid. In some embodiments, the hydrochloric acid may be 1.0N hydrochloric acid. In some embodiments, the stabilizer may be selected from the group consisting of povidone, sodium lauryl sulfate, sodium benzoate, WFI quality water such as that sold under the trade name HYCLONE^, or a combination thereof. In some embodiments, the buffer solution may include WFI quality water, sodium phosphate (dibasic, 7-hydrate, crystal), citric acid monohydrate, or a combination thereof.

[0061] The nanoparticle suspension may be manufactured by suspending particles of the active in the excipients, reducing particles to the desired particle size using grinding media in a mill, and then diluting the suspension to the final volume. In some embodiments, the grinding media used may be selected from ceramic, agate, silicon nitride, sintered corundum, zirconia, stainless steel, chrome steel, Cr–Ni steel, tungsten carbide, glass (yttrium-stabilized), cross- linked polystyrene resins, plastic polyamide, pearls, or a combination thereof. In some embodiments, the mill may be a stationary agitated vessel or a recirculating mill.

[0062] A tablet may be manufactured by spraying the nanosuspension (above) onto sucrose to form a spray granulate intermediate, granulating the spray granulate intermediate 15 1620037251.1Attorney Docket No.: 145688-005702 with excipients to form a final granulation, and compressing the final granulation to form a tablet. The sucrose could be any sugar, including, e.g., glucose, fructose, maltose, galactose, lactose, or the like. In some embodiments, the excipients for the tablet formulation may include lactose monohydrate, PVP, silicified microcrystalline cellulose (e.g., sold under the trade name PROSOLV® SMCC HD 90), magnesium stearate, or a combination thereof. In some embodiments, the tablet comprises about 1 mg to about 100 mg of Compound I.

[0063] In some embodiments the composition of Compound I for oral administration as described herein is a dry powder. In some embodiments, the dry powder may be encapsulated or made into a suspension. In some embodiments, the suspension may be a nanoparticle suspension or a milled suspension.

[0064] In some embodiments, liquid preparations for oral administration may take the form of, e.g., elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, CREMOPHORE® or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.

[0065] Pharmaceutical compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (e.g., PEG). Methods of Use

[0066] In one aspect, the present disclosure provides a method of treating a skin condition caused by an immune deficiency in a human subject. The method involves orally administering to the subject affected by the skin condition a composition comprising about 1 mg / day to about 80 mg / day of a 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one having a structure of Compound I (hereafter “Compound I”) or a pharmaceutically acceptable derivative thereof. 16 1620037251.1Attorney Docket No.: 145688-005702Compound I

[0067] Oral administration of a Compound I composition is therapeutically effective to achieve a desired effect. A therapeutically desired effect may include, without limitation, an improvement in one or more of the size, overall body area affected, severity, redness, flakiness, scaliness, discomfort, itchiness, or soreness of a skin lesion associated with the skin condition.

[0068] Another aspect of the present disclosure provides a method of reducing the severity and extent of skin lesions caused by an immune deficiency in a human subject. The method involves orally administering to a human subject having the immune deficiency a composition comprising about 1 mg to about 80 mg of Compound I or a pharmaceutically acceptable derivative, salt, or solvate thereof. Oral administration of the Compound I composition is therapeutically effective to achieve a desired effect, e.g., prevent or reduce skin lesion formation, prevent or reduce the severity of the skin lesion formation.

[0069] In accordance with these aspects of the disclosure, the skin condition treated in accordance with the methods and formulations disclosed herein is atopic dermatitis.

[0070] Atopic dermatitis (AD) is a common, chronic skin disorder caused by complex genetic, immunological, and environmental interactions. AD is a chronic, relapsing pruritic inflammatory skin disease involving inflammation and skin barrier defects in relation to environmental stimuli. In AD, the outer layer of skin (the corneal layer), which normally acts to keep foreign substances such as bacteria, viruses, and allergens from getting into the body, is weak and more susceptible to inflammation caused by immune cells in the body reacting to these foreign substances. AD can be characterized as mild, moderate, or severe, based on skin coverage and severity of symptoms. Mild AD affects a small area of skin and may be itchy or red once in a while. However, moderate and severe AD cover larger areas of skin and are itchy more often, with periods of intense itching.

[0071] Lesional skin from patients with AD contains elevated levels of pro-inflammatory cytokines and cellular infiltrates of CD4+ T cells that propagate disease pathophysiology. The cytokine microenvironment in AD appears complex, with patients presenting with different cytokine signatures at different stages of the disease.

[0072] Compound I is disclosed in U.S. Patent No. 11,021,482, which is hereby incorporated by reference in its entirety. 17 1620037251.1Attorney Docket No.: 145688-005702

[0073] As used herein, “Compound I” refers to 1-((2S,5R)-5-((5-((R)-2,2- difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop- 2-en-1-one. For example, Compound I may be administered to a subject as an acid addition salt of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, 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 any pharmaceutically acceptable polymorph of Compound I or mixtures of polymorphs of Compound I.

[0074] A therapeutically effective amount or therapeutic application of a Compound I composition as described encompasses the 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 a modified version thereof (e.g., excluding evaluation of particular body areas such as head (neck, face, scalp), palms of hands, soles of feet, groin, and genitalia). Modified versions of the EASI may include evaluation, for example, of trunk, upper extremities (arms), and lower extremities (legs). Extent of symptoms may be measured by providing each body region evaluated with a score of 0 to 6, based on the percentage involvement of that region. For example, the following Area Scores may be given: (0): 0%; (1): 1% - 9%; (2):10% - 29%; (3): 30% - 49%; (4): 50% - 69%; (5): 70% - 89%; (6): 90% - 100%. The severity may be measured on a scale of 0 (least) to 3 (most) by providing the severity of each of four particular symptoms: erythema (Serythema), edema / papulation (Sedema / papulation), excoriation (Sexcoriation), and lichenification (Slichenification).

[0075] EASI score may be calculated by the following formulas, for example, when evaluating the trunk, upper extremities, and lower extremities: Strunk= (Serythema+ Sedema / papulation+ Sexcoriation+ Slichenification) x Area Score x 0.3 Supper extremities= (Serythema+ Sedema / papulation+ Sexcoriation+ Slichenification) x Area Score x 0.2 Slower extremities= (Serythema+ Sedema / papulation+ Sexcoriation+ Slichenification) x Area Score x 0.4 EASI score = Strunk+ Supper extremities+ Slower extremities

[0076] Thus, in accordance with the methods disclosed herein, oral administration of a composition comprising about 1 mg to about 80 mg Compound I to a subject affected by a skin condition, such as AD, results in an improvement of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, 18 1620037251.1Attorney Docket No.: 145688-005702 at least 75%, or greater than 75% in the subject’s EASI score from the baseline score, i.e., the score prior to commencing treatment.

[0077] In another embodiment, a therapeutically effective amount of Compound I is the amount effective to reduce the discomfort of the skin condition caused by itchiness according to a self-reporting PP-NRS (Peak Pruritus Numerical Rating Scale). The PP-NRS is designed to measure peak pruritus or worst itch over a 24-hour period based on a scale of 0 (no itch) to 10 (worst itch). In some embodiments, oral administration of a composition comprising about 1 mg to about 80 mg Compound I results in a reduction of at least one point, at least two points, at least three points, or a reduction of greater than three points on the PP-NRS scale.

[0078] In another embodiment, a therapeutically effective amount of Compound I is the amount effective to reduce the overall amount of body surface area (BSA) affected by the skin condition. The BSA affected by the skin condition, for example, AD, may be estimated by a clinician or clinical investigator, doctor, or other medical professional using the handprint method, which estimates that the area of a patient’s full handprint (fingers and thumbs together) constitutes 1% of their total BSA. In some embodiments, oral administration of a composition comprising about 1 mg to about 80 mg Compound I to a subject affected by a skin condition, such as AD, results in a significant reduction of their total BSA affected by the condition.

[0079] In another embodiment, a therapeutically effective amount of Compound I is the amount that improves the overall appearance of lesions as assessed by an independent person (e.g., Investigator’s Global Assessment or IGA), such as a clinician or clinical investigator, doctor, or other medical professional. IGA scoring may be based, for example, on the following criteria to provide a numerical representation of appearance.

[0080] 0 – clear: no inflammatory signs of atopic dermatitis (no erythema, no induration / papulation, no lichenification, no oozing / crusting). Post-inflammatory hyperpigmentation and / or hypopigmentation may be present.

[0081] 1 – almost clear: barely perceptible erythema, barely perceptible induration / papulation, and / or minimal lichenification. No oozing or crusting.

[0082] 2 – mild: slight but definite erythema (pink), slight but definite induration / papulation, and / or slight but definite lichenification. No oozing or crusting.

[0083] 3 – moderate: clearly perceptible erythema (dull red), clearly perceptible induration / papulation, and / or clearly perceptible lichenification. Oozing and crusting may be present. 19 1620037251.1Attorney Docket No.: 145688-005702

[0084] 4 – Severe: marked erythema (deep or bright red), marked induration / papulation, and / or marked lichenification. Disease is widespread in extent. Oozing or crusting may be present.

[0085] In some embodiments, oral administration of a composition comprising about 1 mg to about 80 mg Compound I to a subject affected by a skin condition, such as AD, results in a reduction in the IGA score of the subject. In some embodiments, treatment with the Compound I composition as described herein results in at least a reduction in the IGA score of the subject of at least one point.

[0086] Additionally, or alternatively, a therapeutically effective amount of Compound I is an amount sufficient to reduce the frequency or severity of lesion outbreaks, for example, smaller lesions, fewer lesions, or less itchy or noticeable lesions.

[0087] A therapeutically effective amount of Compound I is an amount such that when it is administered in an oral formulation, it is sufficient to achieve an effective systemic concentration. In any embodiment, a therapeutically effective amount of Compound I reduces the levels of pro-inflammatory cytokines and cellular infiltrates of CD4+ T cells at or near the site of administration. In any embodiment, a therapeutically effective amount of Compound I reduces the levels of one or more of IL-4, IL-13, IL-15, and interferon gamma at or near the site of administration. In any embodiment, a therapeutically effective amount of Compound I increases filaggrin expression at or near the site of administration.

[0088] In one aspect, treatment of one or more of atopic dermatitis in a subject in need thereof with oral administration of Compound I may be performed on a chronic basis, for example, for ongoing treatment and prevention of symptoms of the skin condition, such as preventing the formation of lesions or reducing the severity of lesions that form when compared to untreated lesions. In another aspect, administration may be performed as needed as symptoms arise or are predicted to arise. In any embodiment, Compound I may be administered on a chronic basis with additional administrations and / or increased dosing upon occurrence of symptoms. Examples of symptoms include, but are not limited to, dry and / or scaly skin, itching, reddening of the skin, skin infections, and bleeding or oozing skin. In any embodiment, dosing may be increased or decreased based on severity of symptoms.

[0089] Particular dosing amounts and regimens may vary from subject to subject depending on variables such as, but not limited to, severity of lesions, sensitivities to inactive ingredients, sensitivity to Compound I, frequency of lesion outbreaks, frequency and / or 20 1620037251.1Attorney Docket No.: 145688-005702 severity of adverse events, weight, age, gender, co-morbidity with other diseases or conditions, use of adjuvant therapies to treat AD, use of other non-AD related medications, and the like.

[0090] In any embodiment, Compound I may be used as a co-therapy or adjuvant therapy to another AD-related therapy. For example, a method of treating atopic dermatitis in a subject in need thereof comprising orally administering to the subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable derivative, salt, or solvate thereof in combination with one or more of an immunosuppressant, an antihistamine, a corticosteroid, a calcineurin inhibitor, a phosphodiesterase-4 inhibitor, dupilumab, an antimicrobial, and a humanized monoclonal antibody that blocks signaling of interleukin (IL)-4 / IL-13. Dosing Regimen

[0091] Compound I, or an oral pharmaceutical composition comprising the same, is administered to a human subject in an oral dose of about 1 mg / day to about 80 mg / day of Compound I. Human subjects in need of such therapy are disclosed above. In some embodiments, the human subject is one having atopic dermatosis (AD). In accordance with the methods disclosed herein, a therapeutically effective amount of about 1 mg / day to about 80 mg / day of Compound I. The dosage to be administered to a particular subject will depend on the characteristics of the subject being treated, e.g., the particular subject treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).

[0092] In any embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 100 mg / day or any amount in between. In an embodiment, the therapeutically effective amount of Compound I is about 2 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 3 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 4 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 5 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 10 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 15 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 20 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 25 mg / day to about 100 mg / day. In an embodiment, the therapeutically effective amount of Compound I is about 30 mg / day to about 100 mg / day. 21 1620037251.1Attorney Docket No.: 145688-005702

[0093] In an embodiment, the therapeutically effective amount of Compound I comprises about 0.5 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 1 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 2 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 3 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 4 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 5 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 6 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 7 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 8 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 9 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 10 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 11 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 12 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 13 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 14 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 15 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 16 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 17 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 18 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 19 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 20 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 21 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 22 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 23 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 24 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 26 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 27 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 28 mg / day. In an embodiment, the therapeutically 22 1620037251.1Attorney Docket No.: 145688-005702 effective amount of Compound I comprises about 29 mg / day. In an embodiment, the therapeutically effective amount of Compound I comprises about 30 mg / day.

[0094] In any embodiment, the therapeutically effective amount of 5 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein. In any embodiment, the therapeutically effective amount of 10 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein. In any embodiment, the therapeutically effective amount of 15 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein. In any embodiment, the therapeutically effective amount of 25 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein. In any embodiment, the therapeutically effective amount of 40 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein.

[0095] In an embodiment, the therapeutically effective amount of Compound I comprises about 1 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 2 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 3 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 4 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 5 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 6 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 7 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 8 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 9 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 10 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 11 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 12 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 13 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 14 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 15 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about mg 16 BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 17 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 18 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 23 1620037251.1Attorney Docket No.: 145688-005702 19 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 20 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 21 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 22 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 23 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 24 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 25 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 26 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 27 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 28 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 29 mg BID. In an embodiment, the therapeutically effective amount of Compound I comprises about 30 mg BID. In an embodiment, the therapeutically effective amount of

[0096] The dosage administered is a therapeutically effective amount of the composition sufficient to result in amelioration of a symptom or symptoms, and can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode of administration; age, sex, health and weight of the subject; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired.

[0097] In some embodiments, the oral composition comprising Compound I as described herein can be administered to the subject once (e.g., as a single dose or application). In some embodiments, the oral composition of embodiments herein is administered at least once daily, such as at least two, three or four times daily. In some embodiments, the oral composition of embodiments herein may be administered daily, twice daily, three times daily, weekly, twice weekly, every two weeks, every three weeks, monthly, as needed, or as otherwise directed by a physician. The oral composition of embodiments herein may be administered at any interval to achieve the therapeutically desired effect, e.g., induction or maintenance of remission, prevention or relief of a symptom or symptoms. In some embodiments, the oral composition of embodiments herein may be administered to a subject for a period of 1, 2, 3, 4, 5, 6 days, about a week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about two months, about three months, about four months, about five months, about six months, or a range of any two of these values. In some embodiments, treatment may be continued for at least a week, a month, a year, or as otherwise directed by a physician. In some 24 1620037251.1Attorney Docket No.: 145688-005702 embodiments, treatment may extend over multiple years, the duration of disease, or the lifetime of the subject.

[0098] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

[0099] The disclosure is further illustrated by the following examples. A list of abbreviations is provided in Table 1. Table 125 1620037251.1Attorney Docket No.: 145688-00570226 1620037251.1Attorney Docket No.: 145688-005702EXAMPLES EXAMPLE 1: A Phase 2a Open-label Study to Investigate the Safety, Tolerability, Pharmacokinetics, Efficacy, and Pharmacodynamics of Compound I Administered Over 12 Weeks in Participants with Moderate to Severe Atopic Dermatitis

[0100] Study Rational - Based on preclinical data, mechanism of action of Compound I (ITK / TXK and JAK3 inhibitor) and known efficacy of drugs with similar mechanisms of action, Compound I is anticipated to have efficacy in atopic dermatitis (AD). This study would pave way for further development of Compound I in AD and other immuno-inflammatory indications.

[0101] Primary Objectives - To investigate the safety of Compound I in participants with AD. 27 1620037251.1Attorney Docket No.: 145688-005702

[0102] Primary Endpoints: Incidence and severity of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events leading to treatment discontinuation (DAE). Change from baseline in laboratory tests, vital signs, physical examination, electrocardiogram (ECGs) over the treatment period.

[0103] Secondary Objectives – To investigate the pharmacokinetics (PK) of Compound I in participants with AD. To investigate the efficacy of Compound I in participants with AD as measured by clinical endpoints.

[0104] Secondary Endpoints: Peak concentration (1-hour post-dose) after first dose and at steady state of Compound I. Trough concentration of Compound I at steady state. Change from baseline Eczema Area and Severity Index (EASI) at week 12 and over time. Proportions of participants who achieve 50%, 75%, and 90% improvement in EASI (EASI-50, EASI-75, and EASI-90, respectively) at week 12 and over time. Proportion of participants achieving Investigator’s Global Assessment-Treatment Success (IGA-TS) defined as a Validated Investigator Global Assessment (vIGA) score of 0 to 1 combined with an improvement of 2 or more points from baseline at week 12 and over time. Change from baseline in IGA score at week 12 and over time. Change from baseline in AD Body Surface Area (BSA) at week 12 and over time. Change from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 12 and over time.

[0105] Tertiary Objectives – To investigate the efficacy of Compound I in participants with AD as measured by patient reported outcomes. To investigate the pharmacodynamics (PD) of Compound I in participants with AD in blood and tissue samples. To investigate the efficacy of Compound I in participants with AD as determined by photographic changes in the involved areas of skin.

[0106] Tertiary Endpoints: Change from baseline in Patient-Oriented Eczema Measure (POEM) total score and POEM sleep score. Change from baseline in Dermatology Life Quality Index (DLQI) total score. 28 1620037251.1Attorney Docket No.: 145688-005702 Biomarkers for ITK / TXK and JAK pathway inhibition, and other PD markers from skin samples. Immunohistochemistry on skin samples. Change from baseline in median hsCRP levels over time. Blood PD biomarkers including antiCD3 / antiCD28 ex vivo-stimulated IL-2 mRNA and IFNȖ mRNA in whole blood, IL-15 ex vivo-stimulated IFNȖ protein in whole blood, select immunophenotyping in whole blood, and endogenous cytokines / chemokines in plasma or serum. Proportion of participants with improvement in AD from baseline, based on the analyses of photographs. Overall Study Design and Plan

[0107] Study Design – This will be an open-label, single-arm study. Moderate to severe AD participants between the ages of 18 and 60 years (inclusive), without any prior exposure to systemic JAK inhibitors, will be enrolled. The study will consist of an up to 30-day Screening Period, a 12-week Treatment Period, and a 14 (± 3) days Follow-up Period. There will be a minimum of 7 days between Screening and Day 1 Treatment visit during which the Sponsor Medical Monitor will ensure that the participant meets the protocol-specified eligibility criteria. Treatment will be with Compound I 10 mg twice daily (BID) for 12 weeks. All participants will have skin sampling via tape strips from one lesional area and one non-lesional area on days specified. A skin biopsy (optional) of from one lesional area and one non-lesional area before the start of study drug, and from lesional area only after 12 weeks of treatment will also be collected. Note: Skin biopsy will be mandatory in approximately one third of participants in the study. There will be a follow-up period of 14 days, after the last dose of the study drug, for safety follow-up.

[0108] Approximately 15 male and female participants aged between 18 and 60 years inclusive, with moderate to severe AD will be enrolled.

[0109] Study Design – The maximum duration of the study for each participant will be 132 days including: Screening Period: Up to 30 days Treatment Period: 12 weeks (85 days) Follow-up Period: 14 (± 3) days 29 1620037251.1Attorney Docket No.: 145688-005702

[0110] The start of the study will be the date on which the first participant provides informed consent, and the end of the study will be after the Follow-up Visit, 14 days (± 3) after the last dose of last participant.

[0111] Dosage and Mode of Administration: Dose form: 5 mg tablet Mode of administration: Oral Dosage: 10 mg (two [2] × 5 mg oral tablets) BID. BID dosing will typically be morning and evening, approximately 12 hours (±2 hours) apart.

[0112] Sample Size – Approximately 15 participants will be enrolled. The sample size for this study is not based upon a formal power computation but on feasibility constraints. Since there are no planned inferential analyses, 15 participants will be adequate to assess the safety, and to summarize efficacy, PK, and PD parameters.

[0113] Statistical Methods – All study data will be summarized using descriptive statistics unless otherwise specified. Individual participant data will be presented in the listings.

[0114] Analysis Sets – The following analysis sets will be used in the statistical analyses. Safety Population: All participants who have been administered at least 1 dose of study medication. The safety analyses will be conducted on the safety population on observed data. The efficacy summaries will also be conducted on safety population where missing data, and the data after intercurrent event will be imputed using multiple imputation. Per-Protocol Population: All participants who have been administered at least 1 dose of study medication and have not discontinued the treatment before Day 85 with no major protocol deviations. Major protocol deviations will be determined prior to database lock. Pharmacokinetic Population: All participants who take at least 1 dose of study drug and have at least 1 evaluable PK measurement. Pharmacodynamic Population: All participants who take at least 1 dose of study medication and have at least 1 evaluable PD measurement.

[0115] Safety Analyses – The safety population will be used for the analysis of safety data (Aes, clinical laboratory values, vital signs, physical examination results, and ECGs). The Aes will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The TEAEs will be presented by system organ class and preferred term in frequency tables. 30 1620037251.1Attorney Docket No.: 145688-005702 Participants with multiple Aes will be counted only once within each preferred term and system organ class. Key participant information for participants with an AE with an outcome of death, participants with SAEs, and participants with an AE leading to discontinuation of study drug will be listed. For the laboratory data (hematology, serum chemistry, coagulation, and urinalysis), observed values and changes from baseline will be presented descriptively. Laboratory data outside study-specific reference ranges will be listed. Vital signs and ECG parameters will be presented descriptively.

[0116] Efficacy Analyses – Descriptive statistics will be provided for all efficacy endpoints at all scheduled visits on the safety population and separately on the Per-Protocol Population. For the summary on the safety population, multiple imputation will be used to impute missing data or data following an intercurrent event. Observed data, not imputing missing data, will be used for the Per-Protocol efficacy summaries. Continuous measures will be summarized using n, mean, standard deviation, median, minimum and maximum. For the EASI, IGA, AD BSA, PP-NRS, POEM and DLQI the observed value, the change from baseline and the percent change from baseline will be summarized at each scheduled timepoint. For hsCRP median percent change from baseline will be summarized at each scheduled timepoint. For binary responder type endpoints such as EASI-50, EASI-75, EASI-90, and IGA-TS, the number and percent of participants meeting each criterial will be presented at each scheduled timepoint. Since the efficacy endpoints are secondary in nature, there will not be a formally defined estimand for this study.

[0117] Pharmacokinetic Analyses – All PK summaries will be performed using the PK population. Plasma concentrations of Compound I will be summarized by day and sample time.

[0118] Pharmacodynamic Analyses – All PD summaries will be performed using the PD population. PD endpoints will be summarized by day and sample time.

[0119] Benefit / Risk Assessment – With Compound I, the key risk observed in preclinical toxicology studies to date was diarrhea associated with opportunistic infection, observed in Beagle dogs and Cynomolgus monkeys but not in SD rats. The incidence and severity of this finding appeared to be dose-dependent in monkeys and dogs. In healthy human participants administered daily doses of Compound I for up to 2 weeks, however, there were only 2 transient episodes of diarrhea, observed in 1 participant administered 5 mg BID. This finding resolved before the cessation of dosing and was not observed in other participants receiving doses of up to 40 mg BID. The relevance of dose-limiting infectious diarrhea observed in some preclinical 31 1620037251.1Attorney Docket No.: 145688-005702 species to human safety is, therefore, unclear; however, this finding is easily monitorable in the clinic setting.

[0120] Safety data from the SAD and MAD studies were reassuring and did not reveal any clinically meaningful signal at doses up to 80 mg per day. In the SAD study, there were only 17 TEAEs documented during the study (16 / 17 were mild), and all had resolved during the observation period. There were no SAEs, no treatment discontinuations, and no lab abnormalities that were clinically significant as determined by the investigator. In the MAD study, there were only 15 TEAEs, no SAEs, and of the several AESIs, only the episode of zoster re-activation after treatment completion was noted to possibly be related to Compound I.

[0121] Efficacy data for Compound I in any clinical indication are not yet available. Available preclinical models and PD data from human phase 1 study suggest a possible role of Compound I in the treatment of immunoinflammatory disorders.

[0122] Overall, based on the available preclinical and clinical data and prior knowledge, the risk benefit profile of Compound I is judged acceptable for initial proof of concept studies.

[0123] Study Population – Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0124] Inclusion Criteria – Participants must meet the following criteria to be eligible for participation in the study: 1. Able to comprehend and willing to sign the Institutional Review Board (IRB) approved informed consent form (ICF) prior to administration of study-related procedures. 2. Male or female participants between the ages 18 to 60 years (inclusive), at the time of informed consent. 3. Willing to follow the contraceptive requirements with protocol specified contraception methods. Males must follow contraceptive guidelines from Screening to 90 days after last dose of study drug, and females must follow the contraceptive guidelines from Screening to 30 days after the last dose of the study drug. 4. Have a diagnosis of AD fulfilling the specified diagnostic criteria of Hanifin and Rajka. 5. Have at least a 1-year history of AD prior to the Screening Visit, and no significant AD flares for the 4 weeks prior to the Screening Visit as determined by the Investigator upon review of participant medical history. 6. Have had no prior exposure to systemic (oral) JAK inhibitors or TYK inhibitors at any time prior to Screening. 32 1620037251.1Attorney Docket No.: 145688-005702 7. Participant meets all of the following disease activity criteria: EASI ^ 16 at the Screening and Baseline Visits vIGA-AD score ^ 3 at the Screening and Baseline Visits. At least a third of participants should have a vIGA score of 4 at the Baseline Visit. ^ 10% BSA of AD involvement at the Screening and Baseline Visits 8. Willing to return to the clinic, follow all study instructions, attend all study visits, and complete study procedures. 9. If the participant is on systemic anti-histaminics, the dose is stable for at least 2 weeks before Day 1, and the participant is willing to stay on the same dose / regimen throughout the study. 10. Participant must be using an emollient / moisturizer of their choice (non-urea containing) regularly (once or twice daily) for at least 1 week before Day 1. He / she should use the same emollient / moisturizer throughout the study, at the same frequency. The participant should not use an emollient for 12 hours before any clinic visit. 11. In good general health and free of any known disease state or physical condition that, in the investigator’s opinion, might impair evaluation of the participant or that might expose the participant to an unacceptable risk by study participation.

[0125] Inclusion Criteria – Participants with any of the following are excluded from the study: 1. Use of any of the following treatments within the indicated washout period prior to Day 1 (start of the study drug): Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy) within 4 weeks prior to Day 1. Systemic biologic immunosuppressant or immunomodulatory therapy (eg, etanercept, alefacept, infliximab, dupilumab) within 12 weeks (or 5 half-lives of the product, whichever is longer) prior to Day 1. Non-biologic systemic immunosuppressants (eg, prednisone, methotrexate, retinoids, calcineurin inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine) within 4 weeks prior to Day 1. Note: Intranasal, inhaled, and topical ocular corticosteroids are allowed). Cytostatic agents (e.g. mycophenolate) within 4 weeks prior to Day 1. 33 1620037251.1Attorney Docket No.: 145688-005702 Topical disease modifying treatments for AD (corticosteroids, calcineurin inhibitors, crisaborole, JAK inhibitors) within 1 week prior to Day 1. Topical antihistaminics within 2 weeks prior to Day 1. Antibiotics – topical or systemic within 2 weeks prior to Day 1. Other investigational product (IP) within 30 days or 5 half-lives (whichever is longer) prior to Day 1. Doxepin and topical products containing urea within 1 week prior to Day 1. Intravenous immunoglobulin (IVIg) therapy within 12 weeks prior to Day 1. 2. Live attenuated vaccine treatment within 4 weeks prior to Day 1 3. Unstable course of AD (spontaneously improving or rapidly deteriorating) based on the participant history or as determined by the investigator during the Screening Period. 4. Refractory AD (ie, AD that required frequent hospitalizations and / or frequent intravenous treatment for skin infections within the year before the Screening Visit). 5. Any signs or symptoms associated with AD therapy (eg, history of anaphylaxis, hypersensitivity reactions, skin atrophy, striae, pigmentary changes) that, in the investigator’s opinion, might impair evaluation of the AD or that exposes the participant to unacceptable risk by study participation. 6. Concomitant skin disease or clinically infected AD or presence of other skin disease that may interfere with study assessments. 7. Clinically significant laboratory abnormalities at the Screening Visit that, in the opinion of the investigator, could affect interpretation of study data or the safety of the participant’s participation in the study, including any laboratory values that meet criteria below (out of range labs may be rechecked once, after consultant with the Medical Monitor, before participant is considered a screen failure): White blood cell (WBC) count <2.5×109 / L ANC <1500 / μL Platelet count <100,000 / μL Hemoglobin <10 g / dL AST or ALT >2×ULN Lymphocyte count <0.5×109 / L 34 1620037251.1Attorney Docket No.: 145688-005702 Alkaline phosphatase (ALP) > 3 × ULN Total bilirubin level > 2 × ULN unless participant has been diagnosed with Gilbert syndrome, and this is clearly documented. 8. Significant renal impairment defined as estimated glomerular filtration rate (eGFR) < 40 mL / min / 1.73 m2 based on Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation. 9. Investigator-assessed history of, or current physical findings of, severe, progressive, or uncontrolled immunologic, hepatic, gastrointestinal, pulmonary, cardiovascular, genitourinary (renal), hematological, neurologic or cerebral disorders, infectious disease or coagulation disorders that, as determined by the investigator, could affect the safety of the participant’s participation in the study or would preclude participation in and completion of study assessments. 10. Participant has a known immune deficiency or is immunocompromised. 11. History of, current, or suspected systemic or cutaneous malignancy and / or lymphoproliferative disease within the last 5 years, other than participants with a history of adequately treated and well healed and completely cleared nonmelanoma skin cancers (ie, basal or squamous cell carcinoma) or cervical carcinoma in situ treated successfully at least 1 year prior to the Screening Visit with no evidence of disease. 12. Evidence of active, chronic, or latent infections at the time of enrollment or a significant skin infection or a systemic infection including but not limited to a history of treated infection (eg, pneumonia, septicemia) within 3 months prior to Baseline. 13. Participant has a known active tuberculosis at any time (treated or untreated). 14. Participant has a history of incompletely treated or untreated latent tuberculosis. Participants with a history of latent tuberculosis must have documented adequate treatment verified by the investigator. Participants who demonstrate evidence of latent tuberculosis infection (positive QuantiFERON®Tuberculosis Gold Test) will only be allowed to participate in the study if there is documented evidence of a completed adequate treatment course for latent tuberculosis, and active tuberculosis is excluded per the investigator’s judgment. 15. Positive serological test for HIV (antibody), hepatitis C virus (antibody), hepatitis B surface antigen, or hepatitis B core antigen antibody. 35 1620037251.1Attorney Docket No.: 145688-005702 16. Herpes zoster or cytomegalovirus infection that resolved less than 2 months prior to the Screening Visit. Participants with a history of frequent outbreaks of herpes simplex virus (defined as 4 or more outbreaks a year). 17. Clinically significant ECG findings such as, but not limited to, baseline mean QTcF >450 msec for males or >470 msec for females, a new or unstable arrhythmia, or a heart block. Before excluding a participant based on an ECG finding, confirm the findings with a repeat ECG. 18. Prior major adverse cardiovascular event (MACE) e.g. stroke, acute myocardial infarction, or coronary stenting, or transient ischemic attack or unstable angina within 6 months of the Screening Visit. 19. Deep venous thromboembolism within 6 months of the Screening Visit. 20. Known allergy to any of the inactive ingredients in the study drug. 21. Female participants who are pregnant, nursing, or planning to become pregnant during the study. 22. Legal incapacity or limited legal capacity. 23. Major surgery within 3 months of the Screening Visit or a major surgery planned during the study. 24. Any other condition that precludes adequate understanding, cooperation, and compliance with study procedures or any condition that could pose a risk to the participant’s safety, as per the investigator’s judgment. 25. Use of potent and moderate inhibitors of cytochrome P4503A4 such as (but not limited to) clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit that the participant can’t stop. 26. Use of potent and moderate inducers of cytochrome P4503A4 that the participant can’t stop. 27. Use of medications that are sensitive CYP3A4 substrates and have a narrow therapeutic index such as (but not limited to) alfentanil and tacrolimus that the participant can’t stop. 28. Current or any recent (within last 12 months prior to screening) substance (including alcohol) abuse disorder. 29. Donation or loss of blood or blood product in excess of 500 mL within 56 days prior to Screening, plasma or platelet within 7 days prior to Screening. 36 1620037251.1Attorney Docket No.: 145688-005702

[0126] Meals and Dietary Restrictions – The consumption of grapefruit, or grapefruit- containing products, star fruit, Seville oranges and marmalade, is not allowed from Screening through the end of treatment. No restrictions on caffeine, alcohol, and tobacco.

[0127] Activity – Participants will abstain from strenuous exercise for 12 hours before each blood collection for clinical laboratory tests.

[0128] Other Restrictions: Participants avoid excessive sun exposure or the use of tanning salons during the study. Participants should not donate blood or blood products from Screening, up to 90 days after the end of treatment with study drug. Male participants must refrain from donating sperm for the duration of the study and for 90 days after the last dose of study drug. Female participants must refrain from retrieving eggs for the duration of the study and for 30 days after the last dose of study drug.

[0129] Study Interventions – Study interventions are all pre-specified, investigational and non-investigational medicinal products, medical devices and other interventions (eg, surgical and behavioral) intended to be administered to the study participants during the study conduct.

[0130] Dose Modifications – If a participant is not tolerating the 10 mg BID dose well, the dose of the study medication should be decreased to 5 mg BID, and the action along with reason should be recorded in the participant’s source documents and the electronic case report form (eCRF). However, before the dose change, there must be a discussion (preferably over the phone, but potentially by email) between the investigator and the Medical Monitor, and this discussion will be documented in participant’s source documents.

[0131] Allowed Medications: Allowed medications include basic skin care (cleansing and bathing), emollients, topical anesthetics. Note that bleach baths are not allowed. Systemic antihistaminics are allowed if the participant is already on a stable dose for 2 weeks prior to Day 1 and willing to stay on the same dose / regimen throughout the study. Note that new systemic antihistaminic medications are not allowed.) Antibiotics (topical or systemic) may be used for an active skin infection that happens during the study, after discussion with Medical Monitor. Up to 2 weeks of systemic 37 1620037251.1Attorney Docket No.: 145688-005702 antibiotics are allowed during the study; if a participant needs more than two weeks of systemic antibiotics, study drug should be withdrawn.

[0132] Prohibited Medications – The following are prohibited from Screening to the Follow up Visit: Live vaccination New systemic antihistaminic medications are not allowed. Use of any of the following treatments is prohibited: o Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy) o Systemic biologic immunosuppressant or immunomodulatory therapy (eg, etanercept, alefacept, infliximab, dupilumab) o Non-biologic immunosuppressants (e.g,, methotrexate, retinoids, calcineurin inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine). o JAK inhibitors (systemic and topical) o Systemic or topical corticosteroids (Intranasal, inhaled, and topical ocular corticosteroids are allowed if used to treat other medical conditions.) o Cytostatic agents o Crisaborole o Other disease-modifying medicated topical treatments for AD (e.g. corticosteroids, calcineurin inhibitors) o Prescription or active-ingredient moisturizers that attempt to repair the skin barrier, such as the ones containing ceramides, hyaluronic acid, urea, filaggrin degradation products and similar products o Topical antihistaminics o Any other topical or systemic treatment that will affect AD Strong or moderate CYP3A4 inhibitors (Table 2), including grapefruit juice Strong or moderate CYP3A4 inducers (Table 3) Sensitive CYP3A4 substrates (Table 4) Strong or moderate P-glycoprotein inhibitors (Table 5) 38 1620037251.1Attorney Docket No.: 145688-005702 Sensitive P-glycoprotein substrates including (dabigatran etexilate, digoxin, edoxaban, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, talinolol, vinblastine) BCRP inhibitors: curcumin, cyclosporine, darolutamide, eltrombopag, febuxostat, fostamatinib, rolapitant, sofosbuvir (velpatasvir, voxilaprevir), teriflunomide

[0133] Use of these medications during the study may or may not be defined as a major violation for analysis purposes (intercurrent event), depending upon their likely impact on efficacy assessments.

[0134] Note that the use of weak inhibitors or inducers of CYP3A4, or moderate sensitive CYP3A4 substrates, is allowed with caution and closer monitoring for adverse events. Table 2: List of CYP3A4 InhibitorsAUC = Area under plasma drug concentration; CYP = Cytochrome P450; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ^ 5-fold, ^ 2 to < 5-fold, and ^ 1.25 to < 2-fold, respectively.aInhibitor of P-gp (defined as those increasing AUC of digoxin to ^ 1.25-fold).bRitonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities.cThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation- dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (eg, high-dose, double-strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low-dose, single-strength).dThe classification is based on studies conducted with intravenously administered conivaptan.eDiltiazem increased AUC of certain sensitive CYP3A substrates (eg, buspirone) more than 5-fold.fStrong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A g Strong inhibitor of CYP1A2 and CYP2C19, moderate inhibitor of CYP3A, and weak inhibitor of CYP2D6 39 1620037251.1Attorney Docket No.: 145688-005702 Table 3: List of CYP3A4 InducersAUC = Area under plasma drug concentration; CYP = Cytochrome P450 Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ^ 80%, ^ 50% to < 80%, and ^ 20% to < 50%, respectively.aStrong inducer of CYP2B6, CYP3A, and weak inducer of CYP2C9bStrong inducer of CYP3A and moderate inducer of CYP2C9 and CYP2C19cStrong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9dStrong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19eThe effect of St. John’s wort varies widely and is preparation-dependent.fModerate inducer of CYP2B6, CYP2C19, and CYP3A.gBased on the effect of 200 mg / day modafinil; a higher dose (400 mg / day) of modafinil had a larger induction effect on CYP3A. Table 4: List of CYP3A4 SubstratesAUC = Area under plasma drug concentration; CYP = Cytochrome P450; DDI = Drug-drug interactionaUsually administered to participants in combination with ritonavir, a strong CYP3A inhibitor Sensitive substrates are drugs that demonstrate an increase in AUC of ^ 5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ^ 2 to < 5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Table 5: List of P glycoprotein inhibitorsData from US FDA Drug Development and Drug Interactions, www.fda.gov / drugs / drug-interactions- labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-ind

[0135] Study Assessments and Procedures: Protocol waivers or exemptions are not allowed. 40 1620037251.1Attorney Docket No.: 145688-005702 Immediate safety concerns should be discussed with the Medical Monitor immediately upon occurrence or awareness to determine if the participant should continue, temporarily discontinue, or discontinue study treatment. Adherence to the study design requirements is essential and required for study conduct. All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable. For the participants who are not screen failures, whom the investigator plans to dose, all their screening data should be entered into CRF within 5 business days of the Screening Visit to permit Medical Monitor review in a timely fashion before dosing. Every effort should be made to ensure that investigator-completed assessments for any one participant are performed by the same evaluator throughout the study to minimize inter-observer variation. If same evaluator is not going to be available throughout the study, a backup rater should be trained and familiar with the method of assessment of the primary rater. In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate strategies for participant visits, assessments, medication distribution and monitoring may be implemented by the sponsor or the investigator, as per local health authority / ethics requirements. The maximum amount of blood collected from each participant over the duration of the study, not including any extra assessments that may be required, will be specified in the ICF. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.

[0136] Medical History – Any relevant past medical history, including diagnosis of AD and any relevant ongoing illnesses prior to Screening, will be recorded in the participant’s source documents and eCRF, with the start date and stop date (if applicable) of the illness / condition, and medication(s) taken.

[0137] Any pre-study surgical procedures will be recorded in the participant’s source documents and eCRF as part of the medical history assessment.

[0138] Detailed AD history including number of flares in the past 1 year, will also be captured in addition to general medical history. Following factors which impact AD treatment and side effects should be captured: 41 1620037251.1Attorney Docket No.: 145688-005702 History of shingles at any time prior to Screening. History of shingles vaccination at any time prior to Screening. Presence / absence of diabetes should also be recorded and if present, date of diagnosis should also be recorded.

[0139] Any medical events (with the exception of SAE) happening between Screening and first dose of study drug should be recorded as medical history.

[0140] Demographics – Demographic data, including the age, sex at birth, race, and ethnicity, will be recorded in the participant’s source documents and eCRF.

[0141] Viral Serology – Blood samples for serology testing will be collected at Screening for the measurement of HIV-1 and HIV-2 antibodies, HbsAg, HBcAb, and anti-HCV antibodies.

[0142] Tuberculosis Test – An interferon-gamma release assay / QuantiFERON TB Gold Test for active / latent TB will be performed at Screening. Participants with a negative test result will be eligible for the study. In case of indeterminate results, the test may be repeated once. The participant can be included in the study if the repeat test is negative; however, if the repeat test is positive or indeterminate, the participant will be excluded from the study. Efficacy Assessments

[0143] Body Surface Area - The total percentage of the participant’s AD-affected BSA will be estimated by the investigator or designee using the handprint method, which estimates that the area of a participant’s full handprint (fingers and thumbs together) constitutes 1% of their total BSA.

[0144] The BSA should be calculated for each EASI regions and will be summed up to get total percentage estimates. The estimation should be done to the nearest whole number. Maximum possible percentage (number of handprints) for each area are: Head and Neck: 10 (ie 10% of total body area) Trunk (including genitalia): 30 (ie 30% of total body area) Upper extremities: 20 (ie 20% of total body area) Lower extremities: 40 (ie 40% of total body area)

[0145] Eczema Area and Severity Index - The investigator will perform the EASI assessment; the same individual should conduct the extent and severity evaluations at each visit on a given participant, especially baseline visit and Day 29 and Day 85 visits. The extent and 42 1620037251.1Attorney Docket No.: 145688-005702 severity of AD will be assessed using EASI scoring system. The EASI uses a formula to grade the severity of AD and the extent of the skin affected.

[0146] Regions: The EASI will evaluate AD in each of 4 body regions: head and neck, trunk (including genitalia), upper extremities, and lower extremities.

[0147] Extent: In each respective body region exact percentage involvement will be reported by the investigator as noted in BSA recording above. Each respective body region will be given a score between 0 and 6 based on the percentage involvement in that region according to Table 6. This will not be recorded separately by the investigator but calculated automatically from recorded BSA. Table 6: Extent of Atopic Dermatitis in Each Body Region

[0148] Severity: For each respective body region, the severity of each of 4 signs (erythema, edema / papulation, excoriation, lichenification) will be graded by the investigator or qualified designee on a 0- to 3-point scale ([0] none, [1] mild, [2] moderate, [3] severe) in AD-affected areas. Half scores are allowed. The average severity across AD-affected areas in each body region will be used as the score for that region.

[0149] Score Calculation: The investigator or qualified designee will enter the extent and severity values into the participant’s source documents and eCRF. The final EASI will then be calculated by an electronic data capture (EDC) system as described in Table 7. Table 7: Eczema Area and Severity Index Calculation

[0150] Score Interpretation - The severity scores for the EASI, are as follows: 0 = clear 0.1 to 1.0 = almost clear 1.1 to 7.0 = mild 43 1620037251.1Attorney Docket No.: 145688-005702 7.1 to 21.0 = moderate 21.1 to 50.0 = severe 50.1 to 72.0 = very severe

[0151] Validated Investigator’s Global Assessment - The vIGA is the investigator’s assessment of the overall appearance of the lesions at a particular point in time. At every study visit, the investigator will assess the vIGA using the scale in Table 8 and report the one score that best describes the overall appearance of the lesions. It is not necessary that all characteristics under Morphological Description be present. In indeterminate cases, please use extent to differentiate between scores. The investigator or qualified designee will enter the score into the participant’s source documents and eCRF. Whenever possible, the same individual should conduct the evaluation at each visit. The IGA-TS is defined as a vIGA score of 0 or 1 with ^ 2 grade improvement from baseline. For example: Participant with marked erythema (deep or bright red), marked papulation, and / or marked lichenification that is limited in extent, will be considered “3 – Moderate”. Table 8: IGA Scoring

[0152] Peak Pruritus Numerical Rating Scale - The PP-NRS is a single patient^reported item designed to measure peak pruritus, or ‘worst’ itch, over the previous 24 hours based on the following question: ‘On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch imaginable,” how would you rate your itch at the worst moment during the previous 24 hours?’.

[0153] Prior to study medication administration on Day 1, the study coordinator should show the PP-NRS scale to the participant, explain the scale, and ask the participant to indicate which integer best describes the worst pruritus the participant experienced for their AD over the previous 24 hours. 44 1620037251.1Attorney Docket No.: 145688-005702

[0154] The participant will complete this assessment and record in their diary each morning before taking the study drug during the Treatment Period.

[0155] The participant will report the diary rating to site staff at each visit and provide the diary to the site staff at each visit, who will enter it into the participant’s source documents and eCRF.

[0156] Patient-Oriented Eczema Measure (POEM) - The POEM is a 7-question patient-derived assessment for monitoring atopic eczema severity during the past 7 days and will be assessed.

[0157] Questionnaire - The participant will answer the following: 1. Over the last week, on how many days has your skin been itchy because of the eczema? 2. Over the last week, on how many nights has your sleep been disturbed because of the eczema? 3. Over the last week, on how many days has your skin been bleeding because of the eczema? 4. Over the last week, on how many days has your skin been weeping or oozing clear fluid because of the eczema? 5. Over the last week, on how many days has your skin been cracked because of the eczema? 6. Over the last week, on how many days has your skin been flaking off because of the eczema? 7. Over the last week, on how many days has your skin felt dry or rough because of the eczema?

[0158] For each question, the participant will choose one of the 5 answers with 0- to 4- point score ([0] no days, [1] 1-2 days, [2] 3-4 days, [3] 5-6 days, [4] every day).

[0159] The POEM is graded on a 0- to 28-point score ([0-2] clear, [3-7] mild, [8-16] moderate, [17-24] severe, [25-28] very severe).

[0160] Dermatology Life Quality Index (DLQI) - The DLQI is a simple 10-question, patient-reported assessment to measure the impact of skin disease on the patient’s quality of life for monitoring atopic eczema severity during the past 7 days and will be assessed. For each question, the participant will choose one of the 5 answers with 0- to 3-point score ([0] not relevant, [0] not at all, [1] a little, [2] a lot, [3] very much). The higher the score, the greater impact of skin disease has on the quality of life. 45 1620037251.1Attorney Docket No.: 145688-005702

[0161] Scoring - Each of the seven questions carries equal weight and is scored from 0 to 4 as follows: No days = 0 1-2 days = 1 3-4 days = 2 5-6 days = 3 Every day = 4 Note: If one question is left unanswered this is scored 0 and the scores are summed and expressed as usual out of a maximum of 28 If two or more questions are left unanswered the questionnaire is not scored

[0162] Tape Strip Skin Sampling: Skin (epidermal) samples will be taken by tape strips from one lesional area and one non-lesional area , at the specified time points. 15-20 strips will be taken from each site at each time point. Samples will be processed as specified in the lab manual and sent to the designated lab. Same lesion / area will be sampled at each visit, at the specified time points.

[0163] Skin Biopsy (Optional): Biopsies are optional for all study participants to opt-in; however, must be received from approximately one third of participants. Punch biopsies of 4.5 mm diameter will be taken during the study at the specified time points. At Baseline Visit 2, punch biopsies will be taken – one lesional and one non-lesional. The lesional biopsy should be from a representative lesion. The area and the lesion from where that biopsy is taken should be clearly noted in the participant’s source documents and eCRF. After 12 weeks of treatment (Day 85 Visit), a single punch biopsy will be taken from the same lesion near the area where the original lesional biopsy was taken. Biopsies will be processed as specified in the lab manual and sent to the designated lab. Safety Assessments

[0164] Physical Examinations - A full examination will be performed at the Screening Visit. A full examination will include general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest / lungs, heart, abdomen, lymph nodes, and extremities. A brief examination 46 1620037251.1Attorney Docket No.: 145688-005702 will be performed at visits, including any unscheduled visits (if needed), and will include disease-specific and symptom-focused assessments. A brief examination does not preclude examination of any of the other body systems as clinically indicated.

[0165] Height, Weight, BMI - Height and weight will be recorded at visits. BMI will be derived for the visits where weight is recorded.

[0166] Vital Signs - Vital signs will be taken at the specified time points. Systolic and diastolic blood pressure (BP), respiration rate, oral body temperature, and pulse rate will be recorded after the participant has been resting in a semi-supine position for at least 5 minutes. BP and pulse measurements will be assessed using an automated device. Manual techniques will be used only if an automated device is not available. Abnormal, clinically significant vital sign results will be recorded as AEs. If known, the underlying etiology for the abnormal clinically significant vital sign will be recorded as an AE rather than the vital sign itself.

[0167] Electrocardiograms - Single 12-lead ECG will be obtained using an ECG machine supplied by the site that automatically calculates the heart rate and measures PR, QRS, QT, and heart-rate corrected QT (QTc) intervals. The ECG tracing should clearly identify the participant, include the date and time of the assessment, and include the signature and date of the person who made the local interpretation; the tracing will be archived at the study site. ECG interpretation by the investigator (normal / abnormal) will be recorded in the participants source documents and eCRF. New, abnormal, clinically significant ECG results will be recorded as AEs. If there is noise or other artifacts, they will be repeated. The QTcF intervals should be reviewed based on the automatic read from the ECG machine in real time. ECGs collected at the Baseline Visit (Visit 2, prior to dosing) should be assessed locally by the Investigator for confirmation of eligibility. Screening ECGs will be collected prior to vital signs and blood samples. ECGs at other timepoints will be collected pre-dose.

[0168] Clinical Safety Laboratory Tests - All laboratory samples will be processed and shipped to the central laboratory, as described in the Laboratory Manual. The central laboratory will analyze the samples or send them to reference laboratory(ies) for analysis, as indicated in the manual. Refer to the ICF for the maximum total volume of blood to be collected per participant throughout the study.

[0169] Blood samples (non-fasting preferred, but not required) and urine samples will be collected. On dosing day(s) sampling for the analysis of clinical laboratory parameters will be performed before the administration of study drug. 47 1620037251.1Attorney Docket No.: 145688-005702

[0170] The Investigator must review the laboratory results, document this review, and record any clinically significant changes occurring during the study as an AE. The laboratory results must be retained with source documents.

[0171] Abnormal laboratory findings associated with the underlying disease are not considered clinically significant unless judged by the Investigator to be more severe than expected for the participant’s condition.

[0172] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 14 days (± 3 days) after the last dose of study drug should be repeated until the values return to normal or baseline or are no longer considered clinically significant by the Investigator or Medical Monitor. If clinically significant / any values that do not return to normal / baseline within a period judged reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. All protocol-required laboratory tests must be conducted in accordance with the laboratory manual. If laboratory values from non-protocol-specified laboratory tests performed at the institution’s local laboratory require a change in participant management or are considered clinically significant by the Investigator (eg, SAE or AE), then the laboratory value result must be recorded in source documentation and any associated SAE or AE must be recorded in the database. Other abnormal laboratory tests that are not clinically significant should not be recorded as adverse events.

[0173] Pregnancy Testing - Pregnancy testing will be conducted on all female participants at study visits. Blood samples will be collected for serum pregnancy testing at Screening, and results must be reviewed prior to dosing in the study. Urine samples will be used for all other pregnancy tests.

[0174] Adverse Events (AEs) Serious Adverse Events (SAEs), and Other Safety Reporting - The Investigator and any designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and remain responsible for following up AEs that are serious, considered related to the study drug or study procedures, or that caused the participant to discontinue study drug or the study must be reported. This 48 1620037251.1Attorney Docket No.: 145688-005702 includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).

[0175] All AEs and SAEs will be collected at the specified time points. SAE reporting will start at the time of consent. Any AE (that is not an SAE) that occurs between the time of consent and prior to dosing on Day 1 will be recorded as medical history. AEs will be collected following the first dose of study drug on Day 1 through the Follow-up Visit (14 days ±3 days after the last administration of study drug).

[0176] All SAEs will be recorded and reported to the Sponsor or designee immediately without undue delay (no later than within 24 hours).The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available.

[0177] Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study participation. However, if the Investigator learns of any SAE, including a death, at any time after a participant has been discharged from the study, and he / she considers the event to be reasonably related to the study drug or study participation, the Investigator must promptly notify the Sponsor.

[0178] Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open- ended and nonleading verbal questioning of the participant is the preferred method to inquire about AE occurrences.

[0179] After the initial AE / SAE report, the investigator is required to proactively follow each participant at subsequent visits / contacts. All SAEs and non-serious AEs of special interest (AESIs) will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up.

[0180] Prompt notification by the investigator to the sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met.

[0181] The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. The sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, institutional review boards (IRBs) / independent ethics committees (IECs), and investigators.

[0182] Safety reports (eg, MedWatch) must be prepared for suspected unexpected serious adverse reactions (SUSAR) according to local regulatory requirements and Sponsor policy. 49 1620037251.1Attorney Docket No.: 145688-005702 These SUSAR reports will be submitted to regulators by the Sponsor or their designee. SUSARs will also be forwarded to Investigators as necessary.

[0183] An investigator who receives an investigator safety report describing an SAE or other specific safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it along with the IB and will notify the IRB, if appropriate according to local requirements.

[0184] Pregnancy: Details of all pregnancies in female participants and, if indicated, female partners of male participants will be collected after the start of study drug and until the time period for reporting pregnancies aligns with the time period for postintervention contraception. If a pregnancy is reported, the investigator will record pregnancy information on the appropriate form and submit it to the sponsor within 24 hours of learning of the female participant or female partner of male participant (after obtaining the necessary signed informed consent from the female partner) pregnancy. While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. The participant / pregnant female partner will be followed to determine the outcome of the pregnancy. The investigator will collect follow-up information on the participant / pregnant female partner and the neonate, and the information will be forwarded to the sponsor. Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by the investigator will be reported to the sponsor as described in Section 8.4.4. While the investigator is not obligated to actively seek this information in former study participants / pregnant female partner, he or she may learn of an SAE through spontaneous reporting. Any female participant who becomes pregnant while participating in the study will discontinue study drug. 50 1620037251.1Attorney Docket No.: 145688-005702

[0185] Adverse Events of Special Interest - The following AEs will be classified as AESI in this study based predominantly on knowledge on the mechanism of action of Compound I and medicines with related mechanisms of action: Serious infections Shingles Moderate-to-severe diarrhea MACE (stroke, acute myocardial infarction, cardiovascular death) Venous thromboembolism (Deep vein thrombosis or pulmonary embolism)

[0186] Laboratories of interest, based predominantly on knowledge on the mechanism of action and medicines with related mechanisms of action (cytopenias, transaminase increase, lipid abnormalities, creatine kinase [CK] elevations) will be analyzed as collected during the course of the study. Investigators should only report labs as AEs if they meet criteria for AEs.

[0187] Pharmacokinetics - Blood samples of approximately 2 mL each will be collected, and plasma harvested, for measurement of plasma concentrations of Compound I. The actual date and time (24-hour clock time) of each sample will be recorded in the participants’ source documents and eCRF.

[0188] In addition, a PK sample may be taken at the occurrence of a toxicity or possibly drug-related AE, at the discretion of an Investigator, if a PK sample is not already scheduled.

[0189] Each plasma sample will be divided into 2 aliquots (1 each for primary analysis and back-up). Samples collected for analyses of Compound I, and potential metabolite plasma concentrations, may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.

[0190] At visits during which blood samples for the determination of PK of Compound I will be taken, 1 sample of sufficient volume can be used. Every effort will be taken to collect the blood samples as close as possible to the scheduled time points, but a window of ± 5 minutes is permitted for each blood draw. In instances where different assessments are due at the same time point, they will be performed such that the blood samples for PK analyses will be drawn at the correct time (as long as participant safety is not compromised).

[0191] Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study team member and then archived in the Sponsor and study center study files but will not constitute a protocol 51 1620037251.1Attorney Docket No.: 145688-005702 amendment. The IRB / IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the ICF.

[0192] If a sample cannot be obtained due to insufficient blood supply from participant, this will not be considered a protocol violation as the PK analysis is an exploratory objective.

[0193] Details on sample collection, handling, storage, and shipping will be described in the Laboratory Manual.

[0194] Pharmacodynamics - All biological samples taken for study purposes will be analyzed and processed at analytical laboratory(ies) as per the outline below. Analyses for exploratory endpoints may or may not be carried out immediately after the last participant completes the dosing. Biological samples may be retained at the analytical laboratory(ies) until the study is completed and reported (or as required by local regulations). Samples may be kept and stored for research purposes until they are used, damaged, decayed, or otherwise unfit for analysis. Sponsor may store samples for up to 10 years after the end of the study to achieve study objectives. Additionally, with participants’ consent, samples may be used for further research by sponsor or others such as universities or other companies to contribute to the understanding of AD or other diseases, the development of related or new treatments, or research methods.

[0195] Blood Samples - Blood samples will be analyzed for including but not limited to the following: Analysis of pathway biomarkers and modulation of inflammatory mediators (protein and messenger ribonucleic acid [mRNA]). Ex-vivo-stimulated biomarker analysis Immunophenotyping

[0196] Punch Biopsies - Punch biopsies from skin samples will be analyzed for including but not limited to the following: Immunohistochemistry RNA analysis

[0197] Tape Strips Skin Samples - Tape strip skin samples will be analyzed for including but not limited to the following: RNA analysis Proteomics Statistical Considerations

[0198] General Considerations - There will be two reporting efforts for this study. An interim analysis will be conducted when at least 80% of enrolled participants have completed 52 1620037251.1Attorney Docket No.: 145688-005702 their Day 29 visit or have discontinued the study. A separate final analysis will be done once all data from all participants are available at the time the study ends. The statistical analysis plan will be finalized prior to interim analysis, and it will include a more technical and detailed description of the statistical analyses described in this section. This section is a summary of the planned statistical analyses of the most important endpoints, including primary and key secondary endpoints. All study data will be summarized using descriptive statistics unless otherwise specified. Individual participant data will be presented in the listings.

[0199] Primary Endpoint Analysis – The safety population will be used for the analysis of safety data (AEs, clinical laboratory values, vital signs, physical examination results, and ECGs). The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The TEAEs will be presented by system organ class and preferred term in frequency tables. Participants with multiple AEs will be counted only once within each preferred term and system organ class. Key participant information for participants with an AE with an outcome of death, participants with SAEs, and participants with an AE leading to discontinuation of study drug will be listed.

[0200] For the laboratory data (hematology, serum chemistry, coagulation, and urinalysis) observed values and changes from baseline will be presented descriptively. Laboratory data outside study-specific reference ranges will be listed. Vital signs and ECG parameters will be presented descriptively.

[0201] Secondary Endpoint Analysis – Descriptive statistics will be provided for all efficacy endpoints at all scheduled visits on the Safety population using observed values (no imputation for missing or intercurrent data). Observed data, not imputing missing data, will be used for the Per-Protocol efficacy summaries.

[0202] Continuous measures will be summarized using n, mean, standard deviation, median, minimum and maximum. For the EASI, IGA, AD BSA, and PP-NRS the observed value, the change from baseline and the percent change from baseline will be summarized at each scheduled timepoint.

[0203] For binary responder type endpoints such as EASI-50, EASI-75, EASI-90, and IGA-TS, the number and percent of participants meeting each criterial will be presented at each scheduled timepoint.

[0204] Since the efficacy endpoints are secondary in nature, there will not be a formally defined estimand for this study. 53 1620037251.1Attorney Docket No.: 145688-005702

[0205] Tertiary / Exploratory Endpoint Analysis – For the DLQI and POEM total scores, and POEM sleep score, the observed value, the change from baseline and the percent change from baseline will be summarized at each scheduled timepoint.

[0206] Interim Analysis – A formal interim analysis will be conducted once at least 80% of all enrolled participants have either complete data for the Day 29 visit or discontinued prior to Day 29. The interim analysis will include all Day 29 safety, efficacy, PK and PD endpoint summaries. Further details regarding the interim analysis will be provided in the study specific SAP. 54 1620037251.1

Claims

Attorney Docket No.: 145688-005702 CLAIMS 1. A method for treating a skin condition caused by immune deficiency in a human subject in need thereof, said method comprising: administering orally to the subject affected by the skin condition, a composition comprising about 1 mg / day to about 80 mg / day of a compound having the structure of Compound I or a pharmaceutically acceptable derivative thereof2. The method of claim 1, wherein the skin condition is atopic dermatitis.

3. The method of claim 1 or 2, wherein said administering reduces one or more of an Investigator’s Global Assessment (IGA) score, an Eczema Area and Severity Index (EASI) score, a Peak Pruritus Numerical Rating Scale (PP-NRS) score, or a Body Surface Area (BSA) measurement of the subject.

4. The method of any one of claims 1-3, wherein the composition is administered once a day.

5. The method of any one of claims 1-3, wherein the composition is administered twice a day.

6. The method of any one of claims 1-3, wherein a composition comprising 10 mg Compound I is administered twice daily.

7. The method of any one of claims 1-6 wherein the composition is a capsule, a tablet, a nanoparticle suspension or a liquid preparation.

8. The method of any one of claims 1-7, wherein the composition is a tablet.

9. The method of any one of claims 1-3 and 7-8, wherein said administering comprises oral administration of a tablet comprising 10 mg Compound I twice daily.

10. The method of any one of claims 1-9 further comprising: administering one or more of a corticosteroid, calcineurin inhibitor, a phosphodiesterase-4 inhibitor, dupilumab, and a 55 1620037251.1Attorney Docket No.: 145688-005702 humanized monoclonal antibody that blocks signaling of interleukin (IL)-4 / IL-13 to the subject.

11. A method for reducing severity and extent of skin lesions caused by an immune deficiency, said method comprising: administering orally to a human subject having the immune deficiency a composition comprising about 1 mg / day to about 80 mg / day of a compound having the structure of Compound I or a pharmaceutically acceptable derivative thereof12. The method of claim 11, wherein subject has been diagnosed with atopic dermatitis.

13. The method of claim 11 or 12, wherein the composition is administered once a day.

14. The method of claim 11 or 12, wherein the composition is administered twice a day.

15. The method of any one of claims 11-14, wherein said administering reduces one or more of an IGA score, an EASI score, a PP-NRS score, or a BSA measurement of the subject.

16. The method of any one of claims 11-12 and 15, wherein a composition comprising 10 mg Compound I is administered twice daily.

17. The method of any one of claims 11-16, wherein the composition oral administration is a capsule, a tablet, a nanoparticle suspension or a liquid preparation.

18. The method of any one of claims 11-17, wherein the composition is a tablet.

19. The method of any one of claims 11-12 and 15-18, wherein said administering comprises oral application of a solution comprising 10 mg Compound I twice daily. 56 1620037251.1

Images