WO2025264695A1 - Compositions and methods for treatment - Google Patents

Abstract

The present disclosure is directed to compositions comprising or containing a therapeutically effective amount of a veterinary active agent, preferably a JAK inhibitor, and methods of treatment of dermatological conditions using such compositions in non-human animals are provided.

Description

COMPOSITIONS AND METHODS FOR TREATMENT

TECHNICAL FIELD

[0001] The present disclosure is directed to compositions comprising or containing a therapeutically effective amount of a veterinary active agent, preferably a JAK inhibitor, and methods of treatment using such compositions.

BACKGROUND

[0002] Canine atopic dermatitis (cAD) is a progressive, chronic condition that requires lifelong treatment for most affected dogs. Interleukin-31 (IL-31) is a cytokine involved in dermatitis, pruritic skin lesions, allergy and airway hypersensitivity. It is mainly produced by activated T helper (Th)2 cells, but is also produced in mast cells and macrophages. IL- 31 binds a co-receptor composed of IL-31 receptor A (IL-31 RA) and the oncostatin M receptor (OSMR). Receptor activation results in phosphorylation of STAT through JAK receptor(s). Expression of the co-receptor has been shown in macrophages, keratinocytes and in dorsal root ganglia.

[0003] IL-31 has been implicated in the induction of pruritus associated with cAD. Janus Kinase Inhibitors (JAKi) have been shown to significantly inhibit IL-31-induced pruritus in dogs. In 2013, the first veterinary JAKi, Oclacitinib (Apoquel®) received marketing authorization in Europe for the treatment of pruritus associated with allergic dermatitis in dogs, and the treatment of clinical manifestations of atopic dermatitis in dogs.

However, for safety reasons, the dose of oclacitinib must be reduced from twice daily to once daily at day 14 of treatment, which can lead to an increase in pruritus (rebound effect) in many dogs. Further, around one third of the cAD population may be non- responsive, or minimally responsive, to therapy with this drug. Therefore, there is a need for novel drugs for treatment of cAD and related skin conditions.

SUMMARY

[0004] The present disclosure is directed to compositions comprising or containing a therapeutically effective amount of a veterinary active agent, preferably a JAK inhibitor, and methods of treatment using such compositions. In some embodiments, the agent used in the methods of the present invention is a compound which can inhibit the activity of one or more Janus kinases (JAKs). The JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2), as well as the Signal T ransducers and Activators of Transcription (STATs), are engaged in the signaling of a wide range of cytokines. Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression.

[0005] It has been found that once daily administration of JAK inhibitor, I lu nocitinib and Oclacitinib, induced a rapid decrease in pruritic behaviour in cAD dogs. With disruption of the vicious itch-scratch cycle, skin lesion scores improved as well. Surprisingly, the inventors found a significantly higher percentage of ilunocitinib-treated dogs had >50% reduction of skin lesions after 28 days of treatment, indicating improvement in the condition of the dogs, while oclacitinib-treated dogs had significantly higher CADESI-4 scores compared to the ilunocitinib group from Day 28 onwards, indicating worsening of the condition in the oclacitinib treated dogs. The relatively rapid and sustained improvement in skin lesions observed in the ilunocitinib treated dogs demonstrates the advantageous nature of ilunocitinib in treatment of pruritis in dogs.

[0006] Accordingly, the present disclosure also provides for methods of treating a dermatological condition (e.g., allergic dermatitis, atopic dermatitis, pruritus, etc.) comprising, administering to a non-human animal in need thereof a pharmaceutical composition as disclosed herein. [0007] In some embodiments, the pharmaceutical composition comprises at least one active pharmaceutical ingredient comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-l-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof.

[0008] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the composition further comprises an additional active pharmaceutical ingredient.

[0009] In some embodiments, the composition is a solid pharmaceutical composition. In some embodiments, the composition is an oral dosage form.

[0010] In some embodiments, the composition comprises about 1 mg to about 150 mg, preferably about 1 mg to about 100 mg, more preferably about 1 mg to about 75 mg, more preferably 1 mg to about 50 mg the active pharmaceutical ingredient. In some embodiments, the composition comprises about 10 mg to 30mg, preferably about 10 mg to 25 mg, more preferably about 10 mg to 20 mg of the active pharmaceutical ingredient. In some embodiments, the composition is a pill, a tablet, a capsule, a chewable tablet, or a powder. In some embodiments, the composition is a tablet. In some embodiments, the composition is a capsule.

[0011] Methods of treatment of dermatological conditions in non-human animals are also provided. In some embodiments, the method comprises administering a therapeutically effective amount of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl)-l-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof, to a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effect amount of the composition of any one of the preceding embodiments to a subject in need thereof. [0012] In some embodiments, the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, pruritis associated with atopic dermatitis, and allergic reactions. [0013] In some embodiments, the non-human animal is dog.

[0014] In some embodiments, the dermatological condition is atopic dermatitis. In some embodiments, the dermatological condition is pruritis. [0015] In some embodiments, the administration is oral.

[0016] In some embodiments, the administration is once daily. In some embodiments, the administration is twice daily.

[0017] In some embodiments, the administration is daily for at least 7 days, preferably at least for 14 days, more preferably at least for 30 days, more preferably at least for 90 days, more preferably at least for 110 days, or more preferably at least for 120 days. In some embodiments, the administration is daily for at least 7 consecutive days, preferably at least for 14 consecutive days, more preferably at least for 30 consecutive days, more preferably at least for 90 consecutive days, more preferably at least for consecutive 110 days, or more preferably at least for consecutive 120 days.

[0018] In some embodiments, the pruritis is reduced by at least about 1% as measured by the PVAS. In some embodiments, the pruritis is reduced by at least about 10% as measured by the PVAS.

[0019] In some embodiments, the pruritis is reduced by at least about 1.0 cm. In some embodiments, the pruritis is reduced by at least about 2.0 com.

[0020] In some embodiments, the pruritis is reduced by at least about 1% as measured by the CADESI-4. In some embodiments, the pruritis is reduced by at least about 10% as measured by the CADESI-4.

[0021] In some embodiments, the pruritis is reduced by at least about 1% as measured by the PVAS and the CADESI-4. In some embodiments, the pruritis is reduced by at least about 10% as measured by the PVAS and the CADESI-4.

[0022] In some embodiments, the recurrence of pruritis is reduced as compared to treatment with oclacitinib.

BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1. Least Square Means (LSM) PVAS scores over time. Data presented are the LSM ± SEs. * Indicates a significant difference (p <0.05)

[0024] Figure 2. Proportion of Dogs in clinical remission from pruritus (PVAS <2). Data presented are percentage of dogs with PVAS <2 (normal). * Indicates a significant difference (p <0.05) Figure 3. Mean Canine Atopic Dermatitis Extent and Severity Index (CADESI)-4 scores. Data presented are the LSM ± SEs.* Indicates a significant difference (p <0.05)

DETAILED DESCRIPTION

[0025] The present disclosure is directed to various pharmaceutical compositions containing an active pharmaceutical ingredient, such as a Janus Kinase (JAK) inhibitor, and methods of treatment using such pharmaceutical compositions.

[0026] Before the subject disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present disclosure will be established by the appended claims.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0028] As used in the description and the appended claims, the terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or"). The term "about," as used herein when referring to a measurable value such as an amount of dose, time, temperature, or other activity and the Like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount. The present disclosure also contemplates other embodiments "comprising," "consisting of" and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not.

[0029] It should be understood that while the use of words such as preferable, preferably, preferred or more preferred utilized in the description indicates that the feature so described may be more desirable, it nonetheless may not be necessary and examples lacking the same may be contemplated as within the scope of the invention, the scope being defined by the claims that follow. In reading the claims, it is intended that when words such as "a," "an," or "at least one," are used there is no intention to limit the claim to only one item unless specifically stated to the contrary in the claim. [0030] The term "acceptable excipient" refers to those typically used in preparing veterinary and pharmaceutical compositions and should be pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others. [0031] The term "dermatological conditions" includes skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, pruritis associated with atopic dermatitis, and allergic reactions.

[0032] The term "effective amount" refers to the amount or dose of compound of the invention, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient or non-human mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0033] The term "dosing regimen" refers to the frequency of administration of the active pharmaceutical ingredient, or the composition comprising the active pharmaceutical ingredient, the duration of time over which the active pharmaceutical ingredient, or the composition comprising the active pharmaceutical ingredient is administered, the amount or dose of the active pharmaceutical ingredient, or the composition comprising the active pharmaceutical ingredient, or a combination thereof. The terms "patient," "subject," and "non-human mammal" refers to a warm-blooded animal, such as dogs, cats, mice, rats, guinea pigs, rabbits, cows, horses, sheep, goats, and pigs. Particular non-human mammals are pets or companion animals, such as dogs and cats and also mice, guinea pigs, and rabbits. Preferred non-human mammals are dogs and cats. Preferably, the non-human mammal is a canine. A particularly preferred non-human mammal is the dog.

[0034] The embodiments of the present invention described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present invention.

Compositions

[0035] In some embodiments, the compositions are solid pharmaceutical compositions. In some embodiments, the solid pharmaceutical composition is provided, comprising, consisting essentially of, or consisting of an active pharmaceutical ingredient; and at least one excipient. [0036] In some embodiments, the solid pharmaceutical composition is an oral dosage form. In some embodiments, the solid pharmaceutical composition is a pill, tablet, capsule, chewable tablet, or powder. The oral dosage form may be sustained-release, extended -release, rap Id -re lease, or a combination thereof. The chewable tablet may be a soft chewable tablet, or a hard chewable tablet, or a combination thereof.

[0037] In some embodiments, the composition comprises, consists essentially of or consists of one or more active pharmaceutical Ingredients. In some embodiments, the pharmaceutical composition may comprise about 95 wt.%, about 90 wt.%, about 85wt.%, about 80 wt.%, about 75wt.%, about 70 wt.%, about 65wt.%, about 60 wt.%, about 55wt.%, about 50 wt.%, about 45wt.%, about 40wt.%, about 35 wt.%, about 30 wt.%, about 25 wt.%, about 20 wt.%, about 15 wt.%, about 10 wt.%, about 5 wt.%, about 2.5 wt.%, about 1 wt.%, about 0.5 wt.%, or about 0.1 wt.% of the active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition may comprise from about 0.1 wt.% to about 99 wt.%, from about 1 wt.% to about 99 wt.%, from about 5 wt.% to about 75 wt.%, from about 5 wt.% to about 50 wt.%, from about 5 wt.% to about 40 wt.%, from about 0.1 wt.% to about 40 wt.%, from about 0.1 wt.% to about 20 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 2.5 wt.%, from about 10 wt.% to about 70 wt.%, from about 10 wt.% to about 50 wt.%, from about 10 wt.% to about 40 wt.%, from about 10 wt.% to about 30 wt.%, from about 0.5 wt.% to about 3 wt.%, from about 1 wt.% to about 5 wt.%, from about 1.5 wt.% to about 5 wt.%, from about 2 wt.% to about 5 wt.%, from about 2.5 wt.% to about 5 wt.%, from about 3 wt.% to about 15 wt.%, or from about 30 wt.% to about 50 wt.%, of the active pharmaceutical ingredient.

[0038] In some embodiments, the pharmaceutical composition may comprise from about 1 mg to about 150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, from about 4 mg to about 20 mg, from about 5 mg to 25 mg, from about 5 mg to 30 mg, from about 10 mg to 30 mg, from about 10 mg to 20 mg or from about 7 mg to 30 mg of the active pharmaceutical ingredient.

[0039] In some embodiments, the active pharmaceutical ingredient comprises a JAK inhibitor, wherein the JAK inhibitor comprises a pyrrolopyrimidine or pyrrolopyridine scaffold. In some embodiments, at least one active pharmaceutical ingredient is a JAK inhibitor. In some embodiments, the active pharmaceutical ingredient comprises at least one JAK inhibitor.

[0040] In some embodiments, the JAK inhibitor comprises a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and/or a TYK2 inhibitor. In some embodiments, the active pharmaceutical ingredient comprises Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, I lu nocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and/or Decernotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the active pharmaceutical ingredient consists or consists essentially of Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, llunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and/or Decernotinib, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the JAK inhibitor is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl)-l-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof.

[0042] In some embodiments, the JAK inhibitor is llunocitinib. llunocitinib is known by the chemical name 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l- (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. llunocitinib is also known by the names 2-[l~cyclopropylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3- yl]acetonitrile and 2-(l-cyclopropylsulfonyl-3-pyrazol-l-yl-(4-(7H-pyrrolo[2,3- d]pyrimidin azetidin-3-yl)acetonitrile and for clarity is the compound of the formula (I), below:

[0043] In some embodiments, the pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient described herein such as a filler, a disintegrant, a glidant, a lubricant, a complexing agent, a solubilizer, a stabilizer, a preservative, a surfactant, a polymer, and combinations thereof.

Methods of treatment

[0044] The present disclosure also provides for methods of treating or preventing a dermatological condition comprising, consisting essentially of, or consisting of, for example, administering to an animal (particularly a non-human animal) in need thereof the pharmaceutical composition as disclosed in the paragraphs vide supra.

[0045] In some embodiments, the condition may comprise at least one condition selected from the group consisting of atopic dermatitis, pruritus, skin rash, skin irritation, skin sensitization, skin lesions, allergic reactions, psoriasis, and combinations thereof. In some embodiments, the dermatological condition may comprise atopic dermatitis. In some embodiments, the dermatological condition may comprise skin lesions. The dermatological condition may comprise pruritus.

[0046] In some embodiments, the dermatological condition is atopic dermatitis. In some embodiments, the dermatological condition is skin lesions. In some embodiments, the dermatological condition is pruritis.

[0047] In some embodiments, the non-human animal may comprise a mammal. In some embodiments, the non-human animal may comprise a dog. In some embodiments, the non-human animal is a dog. [0048] In some embodiments, the method comprises administering to the animal a therapeutically effective amount of a JAK inhibitor. In some embodiments, the method comprises administering to the animal a pharmaceutical composition comprising therapeutically effective amount of at least one JAK inhibitor.

[0049] In some embodiments, method comprises a dosing regimen. In some embodiments, the pharmaceutical composition may be administered once per day. In some embodiments, the pharmaceutical composition may be administered twice per day. In some embodiments, the pharmaceutical composition may be administered thrice per day. In some embodiments, the pharmaceutical composition may be administered once per week. In some embodiments, the pharmaceutical composition may be administered twice per week. In some embodiments, the pharmaceutical composition may be administered once per 12 hours. In some embodiments, the pharmaceutical composition may be administered once per 24 hours.

[0050] In some embodiments, the pharmaceutical composition is administered daily for at least 7 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 14 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 30 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 60 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 90 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 120 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 155 consecutive days. In some embodiments, the pharmaceutical composition is administered daily for at least 110 consecutive days.

[0051] In some embodiments, the pharmaceutical composition is administered for at least 7 days. In some embodiments, the pharmaceutical composition is administered for at least 14 days. In some embodiments, the pharmaceutical composition is administered for at least 30 days. In some embodiments, the pharmaceutical composition is administered for at least 60 days. In some embodiments, the pharmaceutical composition is administered for at least 90 days. In some embodiments, the pharmaceutical composition is administered for at least 120 days. In some embodiments, the pharmaceutical composition is administered for at least 155 days. In some embodiments, the pharmaceutical composition is administered for at least 110 days.

[0052] In some embodiments, the pharmaceutical composition is parenterally administered. In some embodiments, the pharmaceutical composition is administered orally.

[0053] In some embodiments, the treatment reduces pruritis as measured by validated pruritis analog scale (PVAS). In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 1%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 2%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 5%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 10%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 20%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 30%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 40%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 50%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 60%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 70%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 80%. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 90%.

[0054] In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 0.5 cm. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 1.0 cm. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 1.5 cm. In some embodiments, the treatment reduces pruritis as measured by the PVAS by at least about 2.0 cm.

[0055] In some embodiments, the treatment reduces pruritis as measured by the scores of Canine Atopic Dermatitis Extent and Severity Index version 4 (CADESI-4) by at least about 1%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 2%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 5%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 10%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 20%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 30%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 40%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 50%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 60%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 70%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 80%. In some embodiments, the treatment reduces pruritis as measured by the CADESI-4 by at least about 90%.

[0056] In some embodiments, the treatment prevents a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib by at least about 1%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib by at least about 2%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib by at least about 3%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib by at least about 4%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to oclacitinib by at least about 5%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to ociacitinib by at Least about 6%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to ociacitinib by at least about 7%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to ociacitinib by at least about 8%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to ociacitinib by at least about 9%. In some embodiments, the treatment reduces the occurrence of a reoccurrence of chronic pruritus in the subject or reduces frequency of acute pruritus in the subject as compared to ociacitinib by at least about 10%.

[0057] While illustrative examples of the disclosure have been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only certain examples have been shown and described and that all changes and modifications that come within the spirit of the claimed invention are desired to be protected.

[0058] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0059] Following from the above description and invention summaries, it should be apparent to those of ordinary skill in the art that, while the methods and compositions herein described constitute exemplary embodiments of the present invention, the invention contained herein is not limited to this precise embodiment and that changes may be made to such embodiments without departing from the scope of the invention as defined by the claims. Additionally, it is to be understood that the invention is defined by the claims and it is not intended that any limitations or elements describing the exemplary embodiments set forth herein are to be incorporated into the interpretation of any claim element unless such limitation or element is explicitly stated. Likewise, it is to be understood that it is not necessary to meet any or all of the identified advantages or objects of the invention disclosed herein in order to fall within the scope of any claims, since the invention is defined by the claims and since inherent and/or unforeseen advantages of the present invention may exist even though they may not have been explicitly discussed herein.

[0060] EXAMPLES

[0061] Example 1. Evaluation of the efficacy and safety of ilunocitinib, in comparison to oclacitinib, for the control of cAD in a randomized, blinded trial

[0062] The objective of this study was to evaluate the efficacy and safety of ilunocitinib, in comparison to oclacitinib, for the control of cAD in a randomized, blinded trial. Dogs (n = 338) with confirmed diagnosis of cAD were randomized to receive oclacitinib (0.4- 0.6 mg/kg twice daily for 14 days; then once daily), or ilunocitinib (0.6 to 0.8mg/kg once daily), for up to 112 days. Owners assessed pruritus using an enhanced visual analog scale (PVAS). Clinicians assessed skin lesions using the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4).

[0063] Dogs diagnosed with cAD in accordance with the recommendations of Hensel et al. were enrolled at 25 veterinary clinics in 4 EU countries (Germany, Hungary, Ireland and Portugal). The study was initially designed as a 56 day prospective double blinded, randomized, oclacitinib-controlled, field study to demonstrate the non -inferiority of ilunocitinib for the treatment of skin lesions and pruritus associated with cAD. During the in-life phase, the protocol was amended to include an optional continuation phase, wherein dogs would continue in the treatment group assigned in the original randomisation for up to a total study duration of 112 days.

[0064] A sample size estimate of at least 272 evaluable subjects (136 in each treatment arm) was calculated to be sufficient to demonstrate non -inferiority with a power of 85% and a non-inferiority margin of 20%, based on unpublished data from a previous pilot field study as well as published data for the positive control. [0065] Inclusion Criteria: Client-owned dogs of any breed, of either sex, greater than 12 months of age, and weighing > 3.0 kg were eligible to enroll into the study. Other than a confirmed diagnosis of cAD, the dog must have been physically healthy and free of serious or systemic disease that would have interfered with the objectives of the study. The dog must have had at least moderate pruritus as assessed by owners using a validated pruritus analog scale (PVAS score > 6.0, corresponding to moderate to severe itchingand at least a moderate skin lesion score (> 35, based on CADESI-4 assessed by the Investigator). Dogs had no evidence of flea infestation at enrolment and continuous use of flea control throughout the study.

[0066] Dogs with conditions that required concomitant medications could be enrolled if the treatment remained consistent prior to the study, no change in treatment would be made during the study (e.g. NSAIDs), and/or the medication was not likely to interfere with evaluations (e.g. parasiticides and vaccinations). Withdrawal times for prohibited concurrent medications or those which were conditionally allowed are summarized in Table 1.

[0067] Table 1: Conditionally Allowed/Prohibited Medications

[0068] Exclusion Criteria: Exclusion criteria included the following: pregnanlactation or lactating dogs, or if the dog was intended to be used for breeding purposes; evidence of malignant neoplasia, demodicosis or immune suppression such as hyperadrenocorticism; known sensitivity to JAK inhibitors; ongoing treatment with prohibited concomitant medications within the last 90 days. Dogs with clinically significant abnormalities in complete blood counts, serum chemistry, or urinalysis conducted at enrolment were withdrawn from the study.

[0069] Enrollment, randomization, and masking: Animals that met the study inclusion criteria were blocked and randomized (block size 4, 2 per group) in a 1:1 ratio based on order of enrolment at each clinic to receive daily oral doses of ilunocitinib or oclacitinib using SAS Version 9.4 (SAS Institute Inc., Cary NC, USA). The individual dog was the experimental unit. To maintain investigator blinding, each site designated one or more persons as a "dispenser" who was responsible for treatment distribution. Owners were not informed about treatment group assignment or drug name and both treatments were packaged in identical study specific packaging.

[0070] Each treatment was dosed with or without food, at the owner's choice, as listed in Table 2. Owners were instructed to give the tablets at approximately the same time each day. [0071] Table 2: Treatment Groups: The dogs were randomly allotted to two groups, Group 1 received ilunocitinib tablets and Group 2 received oclacitinib tablets.

Abbreviations: BW = Body Weight; SID = semil in die, once dally; BID = bis in die, twice dally

[0072] Schedule of study activities: Baseline data (clinical history, concomitant therapies, body weight, physical examinations, and assessments of pruritus and skin lesions) were collected for each dog at Day 0. Further clinic visits were carried out on Day 14 (±2), 28 (±2), 56 (±3), and for dogs entering the continuation phase, 84 (±3), and 112 (±3). At each follow up visit data were collected regarding body weight, physical examination, Owner assessment of pruritus (PVAS score), Investigator assessment of skin lesions (CADESI-4 score), and both the Owner and Investigator (independently recorded) overall response to treatment (RTT). RTT was assessed using a simple VAS scale graded from "no improvement" at 0 cm and "excellent improvement" at 10 cm (designated ORTT- VAS and IRTT-VAS, respectively). Owners kept a daily log of feeding, dosing, and observations - including any possible adverse events.

[0073] Blood samples (complete blood count and serum chemistry) were collected on Day 0 (prior to dosing) and on days 14, 28, 56, 84 and 112. All blood samples were sent to a central laboratory.

[0074] Effectiveness Assessments

[0075] There were two equal primary endpoints: percentage reduction from baseline (Day 0) on Day 28 in owner assessed PVAS scores and percentage reduction from baseline on Day 28 in Investigator assessed CADESI-4 scores. Further effectiveness assessments included evaluation of: (i) the change in PVAS or CADESI-4 over time; (ii) the proportion of dogs with > 50% decrease in PVAS or CADESI-4; (ill) the proportion of dogs with > 2 cm decrease in PVAS; (tv) frequency of dogs with remission of clinical signs of cAD - i.e. scores in the range of <2 for PVAS or <10 for CADESI-4; and (v) Owner and Investigator independent evaluations of Response to Treatment (ORTT and IRTT respectively).

[0076] Safety Assessments

[0077] Clinical safety was assessed via Adverse Events (AEs), physical examinations, and clinical pathology (haematology and serum chemistry). An abnormal clinical sign occurring at any time during the study after dosing on Day 0 was documented as an AE regardless of treatment group.

[0078] The study was conducted according to applicable European and national regulatory requirements and in compliance with VICH GL9 (Good Clinical Practice, June 2000), in support of the registration for a new Marketing Authorization by the European Medicines Agency. Animal owners gave written informed consent to allow each dog to participate in the study.

[0079] Clinical Success/Clinical Remission

[0080] Over the past 20 years, in many trials evaluating the efficacy of drugs to treat cAD, clinical success was defined as >50% decrease in either PVAS or CADESI-4. Ideally, a truly efficacious therapeutic would return a dog to a clinical condition resembling an unaffected dog. A state where the disease severity has been reduced to a minimum and does not significantly adversely impact a patient's daily life, with an itch or CADESI-4 score of "normal" (PVAS < 2), (CADESI-4 < 10), is defined as clinical remission.

[0081] Statistical Analysis

[0082] All assessments were evaluated at two-tailed 0.05 level of significance, except for for the tests for non-inferiority with a 20% margin. This margin was set following statistical Guideline EMA/CVMP/EWP/81976/2010 recommendations. All statistical analyses were conducted using SAS for Windows (version 9.4, or higher, Cary, NC).

[0083] Efficacy data was analysed from two populations of animals: 1. Intention To Treat - those dogs that were enrolled, received at least one dose of medication, and at least one post-baseline measurement was obtained. 2. Per Protocol - those dogs that were enrolled and completed the study without major deviations from the study. As both populations were very similar, efficacy conclusions presented below were based on the results from the Per Protocol analyses. All dogs that received at least one dose of assigned medication were included in the evaluation of product safety, regardless of whether they completed the study.

[0084] Non-inferiority

[0085] The analyses were conducted using a linear mixed effect model for repeated measures (MM RM), which included baseline as a covariate, treatment, time, and treatment by time interaction as fixed effects. The model included site, treatment-by- site and animal as random effects.

[0086] For both PVAS and CADESI-4, the difference in percentage change from baseline in scores, between the two treatment groups, assessed at Day 28, was calculated. To adjust for multiple testing of the two primary efficacy variables, a Bonferroni corrected significance level of 2.5% and confidence intervals (Cl) of 97.5% was used. Noninferiority of ilunocitinib to oclacitinib, was concluded if the upper limit of the 97.5% Cl for the difference of oclacitinib minus ilunocitinib was less than 20%.

[0087] Efficacy Assessments

[0088] Assessments with a binary response were analysed using a generalized linear mixed model for repeated measures with a logit link and binomial error. The model included treatment, time, and treatment-by-time as fixed effects, and site, treatment-by- site, and animal as random effects. Model-derived estimates of the treatment success rates, and 95% Cis were calculated for each treatment group.

[0089] Continuous efficacy assessments were analysed using a linear mixed model for repeated measures including fixed effects of treatment, time and treatment-by-time interaction. Site, treatment-by-site and animal were included as a random effect. Baseline CADESI-4 scores were included in the CADESI-4 model and baseline PVAS scores were included in the ORTT and IRTT models as a covariate. For continuous secondary endpoints, data were also summarized by treatment group for each study visit.

[0090] Dogs withdrawn from the study on or before each day of assessment due to worsening signs of cAD (lack of efficacy), or an AE potentially related to the study drug, were considered as treatment failures for each binary response variable. For continuous variables, the last time point that data was available was used for subsequent time points. [0091] Results [0092] Demographics

[0093] There were 338 dogs enrolled in the study. Of these, 169 were randomized into the ilu nocitinib group and 169 in the oclacitinib group. The mean age was 5.5 years and mean body weight (BW) was 19.1 kg. Female and purebred dogs were more frequently enrolled. Demographics of the study population are presented in Table 3. A total of 154 dogs entered the continuation phase (75 ilunocitinib, 79 oclacitinib).

[0094] Table 3. Demography and Breed Summary

[0095] Efficacy Analyses

[0096] Test of Non-lnferiority

[0097] Primary Endpoints: Pruritus Visual Analogue Score (PVAS) [0098] The mean percentage reduction from baseline on Day 28 was 68.2% for ilunocitinib and 59.4% for oclacitinib. Ilunocitinib demonstrated non -inferiority to oclacitinib, and the difference between treatment groups was statistically significant (p = 0.003). The percentage reduction from baseline in the owner-assessed pruritus at Day 28 compared to baseline is shown in Table 4.

[0099] Table 4: Percentage reduction of PVAS score from baseline linear mixed model for repeated measures (MMRM)

Model estimates

Treatment Study_LSMean Standard _gg group Day Oclacitinib

Ilunocitinib 28 68.2 2.65 (63.04, 73.43) 0.003

Oclacitinib 59.4 2.67 (54.20, 64.69)

[0100] Canine Atopic Dermatitis Extent and Severity Index (CADESI-4)

[0101] The percentage reduction from baseline in the investigator-assessed skin lesions at Day 28 compared to baseline is shown in Table 5. The Day 28 estimate of the mean percentage reduction from baseline was 73.3% for ilunocitinib and 68.773% for oclacitinib.

[0102] Table 5: Percentage reduction of CADESI-4 score from baseline linear mixed model for repeated measures (MMRM)

Model estimates

Treatment Study _LSMea„ Standard _{gg% c|} P group Day error Oclacitinib

Ilunocitinib 28 73.2 3.10 (67.15, 79.32) 0.056

Oclacitinib 69.0 3.11 (62.86, 75.08) [0103] Owner-Assessed Pruritus Scores (PVAS)

[0104] Over the first 7 days of treatment, there was a rapid drop in mean PVAS to approximately half of baseline for both treatment groups, and PVAS scores continued to improve through Day 14. On Day 28, there was an increase in PVAS (rebound effect)5 for oclacitinib-treated dogs, while ilunocitinib-treated dogs demonstrated continuous improvement in PVAS scoring. Mean PVAS scores for ilunocitinib-treated dogs were significantly lower than for oclacitinib-treated dogs on Days 28 through 112 (p < 0.003, Figure 1).

[0105] A greater percentage of ilunocitinib-treated dogs achieved >50% reduction from baseline in PVAS from Day 28 onward, with significantly greater numbers on Days 28 through 84 (p < 0.03) compared to oclacitinib-treated dogs. A similar finding was observed for a >2.0 cm reduction from baseline in PVAS, with significantly greater numbers on Days 56 and 84 (p < 0.043).

[0106] As shown in Figure 2, a higher proportion of dogs treated with ilunocitinib reached clinical remission from pruritus (PVAS <2) from Day 14 onwards compared to dogs treated with oclacitinib, with the difference being significant on Days 56 and 112 (p<0.04). By Day 112, 77% percent of ilunocitinib-treated dogs were in clinical remission versus 53% of oclacitinib-treated dogs.

[0107] Table 6. Percentage of Dogs with Greater than 50% Decrease in PVAS Score from Baseline

I Lunocitlnlb Oclacitinib Study LS mean LS mean p-

Day (SE) (SE) value

0

1 8 (3.2) 5 (3.1) 0.332

2 11 (3.9) 10 (3.8) 0.833

3 20 (5.2) 14 (4.8) 0.306

4 28 (6.9) 26 (6.4) 0.754

5 37 (6.9) 37 (7.7) 0.984 6 41 (7.0) 45 (7.8) 0.649

7 47 (7.1) 51 (7.3) 0.610

14 68 (6.8) 72 (6.6) 0.455

28 79 (5.8) 66 (6.0) 0.030

56 89 (3.7) 72 (5.9) 0.005

84 90 (4.6) 71 (8.2) 0.030

112 81 (6.9) 74 (6.8) 0.361

[0108] Table 7. Percentage of Dogs with at Least 2 cm Reduction in PVAS Score from Baseline llunocitinib Oclacitinib

Study LS mean LS mean p- day (SE) (SE) value

0

1 20 (5.0) 21 (5.1) 0.829

2 30 (6.0) 33 (6.4) 0.563

3 45 (6.4) 46 (6.1) 0.914

4 59 (6.6) 57 (6.9) 0.861

5 69 (5.8) 63 (7.0) 0.461

6 70 (5.4) 74 (6.0) 0.494

7 74 (5.7) 79 (5.5) 0.361

14 87 (4.0) 89 (3.6) 0.607

28 94 (2.7) 88 (3.8) 0.217

56 96 (2.2) 86 (4.7) 0.043

84 95 (2.7) 84 (4.8) 0.030

112 91 (4.0) 80 (6.1 ) 0.086

[0109] Investigator-Assessed Skin Lesion Scores (CADESI-4) [0110] For both ilunocitinib and oclacitinib, the mean CADESI-4 scores dropped rapidly over the first 14 days of treatment to less than half of the baseline scores. However, as shown in Figure 3, from Day 28 through Day 112, the mean scores of ilunocitinib- treated dogs were significantly lower than mean scores of oclacitinib-treated dogs (p < 0.02).

[0111] The percentage of dogs achieving a 50% reduction in CADESI-4 scores was similar for both treatments at Day 14. From Day 28 through Day 112, 94 to 97% of dogs dogs treated with ilunocitinibdemonstrated > 50% reduction from baseline in CADESI-4 compared to only 85 to 88% of dogs treated with oclacitinib. On Days 28 and 56 the difference was statistically significant with p 0.005. The proportion of dogs in clinical remission from skin lesions (CADESI-4 <10) was numerically higher in the ilunocitinib group compared to the oclacitinib group on Days 56 and 84. The proportions were similar for both treatment groups on Days 14, 28, and 112.

[0112] Table 8. Summary of CADESI-4 Efficacy Parameters

Bold print indicates a significant difference (p <0.05)

[0113] Owner and Investigator Assessment of Response to Treatment [0114] The comparison of ORTT and IRTT between the treatment groups on Days 14 - 112 are displayed in Tables 8 and 9, with higher scores indicating a better clinical response. On day 14 ORTT and IRTT were similar for both treatment groups. On all subsequent days, ORTT and IRTT were significantly better in the ilunocitinib group compared to the oclacitinib group (p <_ 0.002).

[0115] Table 9: Owner-assessed response to treatment (ORTT-VAS) score linear mixed model for repeated measures (LMM)

[0116] Table 10: Investigator response to treatment (IRTT)-VAS score linear mixed model for repeated measures (LMM)

[0117] Safety

[0118] Physical examination results [0119] The results of physical examinations (respiration rate, heart rate, rectal temperatures, and body weight) showed no abnormal or notable changes in both treatment groups over the study period.

[0120] Serum biochemistry results

[0121] No clinically relevant differences were seen in any of the serum biochemistry parameters in either treatment group over the study period. While in most cases mean values remained within normal laboratory reference ranges, there were decreases in mean band neutrophils (% and absolute), basophils (absolute), monocytes (absolute), eosinophils (% and absolute) and leukocytes in both treatment groups.

Haematology results

[0122] The statistical analysis of haematology parameters revealed a treatment effect for eosinophils (% and absolute), erythrocytes, haemoglobin concentration and packed cell volume (%), as well as a treatment*time effect for band neutrophils (%). However, the differences in the means of these parameters between the two study groups and between study days were small and were not considered to be of clinical relevance.

[0123] Table 11: Haematology parameters with significant treatment effects- Linear mixed model for repeated measures - Safety population

[0124] For thirteen dogs the haematocrit was below normal reference range during study. An overview of the means for haematology parameters with significant treatment effects are listed in Table 12.

[0125] Table 12: Means for Haematology parameters with significant treatment effects

[0126] Concomitant therapies

[0127] Forty-one ilunocitinib-treated dogs and 31 oclacitinib-treated dogs were administered a variety of concomitant therapies during the study. The most administered therapeutics were: parasiticides, vaccines, antibiotics, antifungals, NSAIDs, ear cleaners, sedatives/anaesthetics, and dietary supplements such as pre- and probiotics. For a complete listing, refer to Table 13. There were no drug interactions observed with the concomitantly used veterinary medicinal products in either treatment group. Table 13. Concomitant Therapies Administered During the Study

Only concomitant medications prescribed during the inlife phase are included in the table.

*All dogs were provided with ectoparasiticides at enrolment. This refers only to cases which were prescribed additionally during the in-life phase.

[0128] Adverse Events

[0129] Adverse events were monitored over the extended study period of 112 days and their frequency calculated on a per animal basis. The frequency of any observed AE was similar in both treatment groups. Most commonly observed AEs were digestive tract disorders, predominantly emesis and diarrhoea with 13.6% and 10.7% in the ilunocitinib and oclacitinib group, respectively, followed by systemic disorders (5.3% ilunocitinib; 7.1% oclacitinib) and skin/appendages disorders (5.9% ilunocitinib; 3.6% oclacitinib). [0130] Most of these AEs were evaluated by the investigators as possibly related to treatment. Clinically relevant laboratory investigation results were documented as AEs on 6 occasions (3.6%) in the ilunocitinib and on 9 occasions (5.4%) in the oclacitinib group. Most of them were evaluated as either possibly treatment related or unknown.

[0131] Four serious adverse events were observed and relation to treatment assessed as unlikely or unknown. Three were in the oclacitinib group (fatal road traffic accident; hepatitis; mammary gland mass) and one in the ilunocitinib group (seminoma).

[0132] Table 14: Adverse Events - Safety population [0133] This multi-site pivotal field study of once-daily administration of ilunocitinib given with or without food at a dose of 0.6 - 0.8 mg/kg for the control of cAD in client- owned dogs provided extensive product efficacy and safety data. Enrollment of 338 dogs at 25 clinics in 4 different countries with diverse climatic conditions enabled data collection in a variety of clinical settings in dogs with a broad range of environmental allergies. Demographically, the study population was well balanced between the two treatment groups and represented a spectrum of ages, breeds, pre-existing medical conditions and concomitant medication use.

[0134] Results indicate that ilunocitinib is highly efficacious when used in accordance with the stated dosing schedule. With only once daily dosing, ilunocitinib was rapidly efficacious, closely matching oclacitinib BID for reduction of pruritus and skin lesion scores over the first 14 days of the study. However, with the change in dosing schedule after Day 14 for oclacitinib-treated anumals, ilunocitinib-treated dogs were numerically or statistically significantly improved at all subsequent time points and for all pruritic indicators of efficacy when compared to oclacitinib-treated dogs.

[0135] It has been previously reported that the change to once daily dosing of oclacitinib after Day 14 leads to an increased manifestation of pruritus in many dogs. [0136] It has been previously reported that the change to once daily dosing of oclacitinib after Day 14 leads to a renewed increase of pruritus in many dogs, and this 'rebound phenomenon' was confirmed in this study. Without wishing to be bound by theory, it is hypothesized that the rebound effect is caused by increased transcription of pruritogenic cytokines following cessation of oclacitinib therapy in mice. With consistent once daily administration of ilunocitinib, this study demonstrated continuously decreasing itch levels, leading to significantly lower mean PVAS scores from Day 28 onwards, (significantly) greater percentages of dogs with > 2 cm decrease in PVAS, (significantly) more dogs with a > 50% decrease in PVAS, and ultimately to (significantly) greater numbers of dogs in clinical remission from pruritus.

[0137] Administration of JAK inhibitors in this study induced a rapid decrease in pruritic behavior. With disruption of the vicious itch-scratch cycle, skin lesion scores improved as well. By Day 14, mean CADESI-4 scores were less than half of Day 0 scores for both treatment groups. Ilunocitinib-treated dogs had significantly lower mean CADESI-4 scores compared to the odacitinib group from Day 28 onwards. On Days 28 and 56, a significantly higher percentage of ilunocitinib-treated dogs had >50% reduction of skin lesions. With the rapid and sustained improvement in skin lesions observed in this study, it is concluded that ilunocitinib also had an anti-inflammatory effect via decreased Th2 cytokine signalling.

[0138] Since the underlying disease of cAD cannot be cured with JAKi, we examined the ability of ilunocitinib to alleviate the signs of cAD. There were greater percentages of ilunocitinib-treated dogs in clinical remission from pruritus on Days 28 - 112, with this difference being statistically significant on Days 56 and 112 compared to odacitinib. There were also greater numbers of ilunocitinib-treated dogs in clinical remission from skin lesions (CADESI-4 < 10) on Days 28 - 112 but, these differences did not reach the level of statistical significance.

[0139] While odacitinib has revolutionized the treatment of allergic skin disease, there is still a subpopulation of dogs that do not respond well to therapy with odacitinib. To enroll in this study, dogs were required to have moderate to severe (M-S) pruritus (PVAS > 6). By Day 14 of treatment, both treatment groups had approximately 10% of dogs in the moderate to severe pruritus range. On Day 28, the ilunocitinib group had 4.5% M-S dogs and the odacitinib group had 12.4% (Rebound effect). By Day 112, the ilunocitinib group had decreased M-S dogs to 2.9% compared to the relatively stable odacitinib group at 9.1%. Ilunocitinib demonstrated a statistically better response to treatment compared to odacitinib. Additionally, the odacitinib group had a higher percentage of dogs in the M-S group indicating fewer odacitinib dogs responded well to treatment (+/-) compared to the ilunocitinib dogs.

[0140] In the evaluation of efficacy, it is important to consider the overall opinion of the owners and Investigators regarding the success of treatment. ORTT and IRTT scores were similar for both treatment groups on Day 14. However, at all subsequent timepoints both owners and investigators ranked ilunocitinib statistically better than odacitinib for the overall response to treatment. This clearly notable difference between the actives is highly suggestive that ilunocitinib may provide a substantial enhancement to the human-animal bond which can be damaged by ongoing signs of disease in CAD.15 [0141] I Lu nocitlnlb was well tolerated when used in accordance with the stated dosing schedule. During the study, there were no notable changes observed in the clinical safety parameters such as respiration rate, heart rate, rectal temperatures, and body weight. Similarly, there were no clinically relevant abnormalities seen in the serum chemistry results. Decreases in band neutrophils (% and absolute), basophils (absolute), monocytes (absolute), eosinophils (% and absolute) and leucocytes were seen in both treatment groups over the study period, but most of these remained within normal laboratory reference ranges. Changes in haematology parameters have previously been described for Janus Kinase Inhibitors and the clinical pathology changes observed in this study were similar to those reported previously.1,16

[0142] The most frequently observed AEs were digestive tract disorders (e.g. emesis and diarrhoea), followed by systemic disorders, and skin and appendages disorders. Similar AEs are already known and reported for the commercially marketed Janus Kinase Inhibitor. None of the four serious AEs were assessed as likely, probably, or possibly related to the experimental treatment. No drug interactions were observed with the concomitantly used veterinary medicinal products (primarily vaccines, parasiticides, and antibiotics/antifungals). Limitations of the study include that the opportunity to enter a continuation phase was only introduced several months after study start. Many dogs had already completed the study by the time of the amendment, which is why data for Days 84 and 112 includes a lower number of dogs. However, dogs were still evenly distributed to treatment groups and even with lower numbers, it was possible to demonstrate statistically significant improvement of ilunocitinib-treated dogs over oclacitinib-treated dogs in multiple parameters at these time points.

[0143] Another limitation of the study was that in statistical analyses for secondary efficacy parameters the level of significance was not adjusted for multiple endpoint testing to account for the potential inflation of Type I error rate. Therefore, although the overall outcome of the study was consistently in favour of ilu nocitlnlb, individual p- values should be interpreted with caution.

[0144] Based on the results of this field study in client-owned dogs, once daily administration of I lunocitinib, administered with or without food, at the dosage of 0.6 - 0.8 mg/kg, is safe and efficacious in the treatment of clinical manifestation of atopic dermatitis in dogs. Further, I Lunocitinib had no rebound effect, and a Lower nonresponder or poor responder rate. I Lu nocitinib rapidly and safely controlled cAD.

I Lu nocitinib treatment demonstrated better clinical outcomes compared to oclacitinib treatment in multiple efficacy parameters, and continuous once daily dosing reduces caregiver burden compared to products requiring a change in dosing regimen over time. Overall , ilunocitinib demonstrated significantly better control of pruritus and skin lesions associated compared to oclacitinib with more dogs achieving clinical remission of their pruritus.

Claims

1. A method of treatment of a dermatological condition in non-human animals comprising administering a therapeutically effective amount of 2-(3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(cyclopropylsulfonyl)azetidin-3- yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof, to a subject in need thereof.

2. A method of treatment of a dermatological condition in non-human animals comprising administering a therapeutically effect amount of a composition comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l- (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof, to a subject in need thereof.

3. A method of treatment of a dermatological condition in non-human animals comprising administering a therapeutically effect amount of a composition comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l- (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof, to a subject in need thereof optionally in combination with one or more additional active pharmaceutical ingredient.

4. The method of any one of claims 1-3, wherein the non-human animal is a dog.

5. The method of any one of claims 1-4, wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, pruritis associated with atopic dermatitis, and allergic reactions.

6. The method of any one of claims 1-5, wherein the dermatological condition is atopic dermatitis.

7. The method of any one of claims 1-6, wherein the dermatological condition is pruritis.

8. The method of any one of claims 1-7, wherein the method comprises a dosing regimen.

9. The method of any one of claims 1-8, wherein the administration is oral.

10. The method of any one of claims 1-9, wherein the administration is once daily.

11. The method of any one of claims 1-10, wherein the administration is twice daily.

12. The method of any one of claims 1-11, wherein the administration is daily for at least 7 days, preferably at least for 14 days, more preferably at least for 30 days, more preferably at least for 90 days, more preferably at least for 110 days, or more preferably at least for 120 days.

13. The method of any one of claims 1-11, wherein the administration is daily for at least 7 consecutive days, preferably at least for 14 consecutive days, more preferably at least for 30 consecutive days, more preferably at least for 90 consecutive days, more preferably at least for consecutive 110 days, or more preferably at least for consecutive 120 days.

14. The method of any one of claims 1-13, wherein the pruritis is reduced by at least about 5% as measured by the PVAS.

15. The method of any one of claims 1-14, wherein the pruritis is reduced by at least about 10% as measured by the PVAS.

16. The method of any one of claims 1-13, wherein the pruritis is reduced by at least about 1 cm.

17. The method of any one of claims 1-13, wherein the pruritis is reduced by at least about 2 cm.

18. The method of any one of claims 1-14, wherein the pruritis is reduced by at least about 5% as measured by the CADESI-4.

19. The method of any one of claims 1-14, wherein the pruritis is reduced by at least about 10% as measured by the CADESI-4.

20. The method of any one of claims 1-14, wherein the pruritis is reduced by at least about 5% as measured by the PVAS and the CADESI-4.

21. The method of any one of claims 1-14, wherein the pruritis is reduced by at least about 10% as measured by the PVAS and the CADESI-4.

22. The method of any one of claims 1-14, wherein the recurrence of pruritis is reduced as compared to treatment with oclacitinib.

23. A pharmaceutical composition comprising at least one active pharmaceutical ingredient comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yL)-l-(cycLopropylsuLfonyL)azetldln-3-yl)acetonitrlle, or a pharmaceutically acceptable salt, ester or hydrate thereof.

24. The composition of claim 23, further comprising a pharmaceutically acceptable excipient.

25. The composition of claims 23 or 24, further comprising at least one additional active pharmaceutical ingredient.

26. The composition of any one of claims 23-25, wherein the composition is a solid pharmaceutical composition. 1. The composition of any one of claims 23-26, wherein the composition is an oral dosage form.

28. The composition of any one of claims 23-27, wherein the composition comprises about 1 mg to about 150 mg, preferably about 1 mg to about 100 mg, more preferably about 1 mg to about 75 mg, more preferably 1 mg to about 50 mg the active pharmaceutical ingredient.

29. The composition of any one of claims 23-28, wherein the composition comprises about 10 mg to 30mg, preferably about 10 mg to 25 mg, more preferably about 10 mg to 20 mg of the active pharmaceutical ingredient.

30. The composition of any one of claims 23-29, wherein the composition is a pill, a tablet, a capsule, a chewable tablet, or a powder.

31. The composition of any one of claims 23-30, wherein the composition is a tablet.

32. The composition of any one of claims 23-31, wherein the composition is a capsule.

33. The composition of any one of claims 23-32 for use in the treatment of a dermatological condition in non-human animals.

34. The composition of any one of claims 23-32 for use in the treatment of a dermatological condition, wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, pruritis associated with atopic dermatitis, and allergic reactions.

35. The composition of any one of claims 23-32 for use in the treatment of atopic dermatitis.

36. The composition of any one of claims 23-32 for use in the treatment of pruritis.

37. Use of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l- (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, or a pharmaceutically acceptable salt, ester or hydrate thereof, for the manufacture of a medicament for the treatment of dermatological condition in non-human animals.

38. Use of the composition of any of claims 23-32 for the manufacture of a medicament for the treatment of dermatological condition in non-human animals.

39. The use of claims 37 or 38, wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g„ contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, pruritis associated with atopic dermatitis, and allergic reactions.

40. The use of any one of claims 37-39, wherein the non-human animal is dog.

41. The use of any one of claims 37-40, wherein the dermatological condition is atopic dermatitis.

42. The use of any one of claims 37-40, wherein the dermatological condition is pruritis.