WO2025235366A1 - Compositions de pyrrolopyrimidine pour le traitement de la dermatite atopique - Google Patents

Compositions de pyrrolopyrimidine pour le traitement de la dermatite atopique

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Publication number
WO2025235366A1
WO2025235366A1 PCT/US2025/027723 US2025027723W WO2025235366A1 WO 2025235366 A1 WO2025235366 A1 WO 2025235366A1 US 2025027723 W US2025027723 W US 2025027723W WO 2025235366 A1 WO2025235366 A1 WO 2025235366A1
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Prior art keywords
compound
day
study
composition
therapeutically effective
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English (en)
Inventor
David Randolph ANDERSON
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Aclaris Therapeutics Inc
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Aclaris Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • 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.
  • compositions and methods of the present disclosure can comprise, consist essentially of, or consist of, the components or steps disclosed.
  • 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.
  • 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.
  • 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 1620037251.1 Attorney 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.
  • an isotope thereof e.g., tritium, deuterium
  • NMR nuclear magnetic resonance
  • GC/MS gas chromatography/mass spectroscopy
  • HPLC high performance liquid chromatography
  • LC/MS liquid chromatography/mass spectroscopy
  • 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.
  • 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.
  • ITK inhibitor is used herein to refer to a compound that exhibits an IC 50 with 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.
  • IC 50 is 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.
  • compounds will exhibit an IC 50 with respect to ITK of no more than about 10 ⁇ M; in further embodiments, compounds will exhibit an IC 50 with respect to ITK of no more than about 5 ⁇ M; in yet further embodiments, compounds will exhibit an IC 50 with respect to ITK of not more than about 1 ⁇ M; in yet further embodiments, compounds will exhibit an IC 50 with respect to ITK of not more than about 200 nM, as measured in the ITK binding assay described 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.
  • 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.
  • 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.
  • 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, ⁇ -hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, ace
  • 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,
  • X- may be an anion of various mineral acids (e.g., chloride, bromide, iodide, sulfate, 4 1620037251.1 Attorney 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).
  • mineral acids e.g., chloride, bromide, iodide, sulfate, 4 1620037251.1 Attorney Docket No.: 145688-005702 nitrate, phosphate
  • an organic acid e.g., acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methane
  • 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.
  • the Compound I of embodiments herein may exist in both non-solvated and solvated forms.
  • 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.
  • 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.
  • 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.
  • isotopes suitable for inclusion in the Compound I of embodiments herein include isotopes of hydrogen, such as 2 H and 3 H carbon, such as 11 C, 13 C and 14 C, chlorine, such as 31 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • 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, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier 5 1620037251.1 Attorney Docket No.: 145688-005702 isotopes such as deuterium, 2 H 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 as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the Compound I of embodiments 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 or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • 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.
  • 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).
  • 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 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 1620037251.1 Attorney 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.
  • the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.
  • 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.
  • 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.
  • BID as used herein refers to “bis in die” or “twice a day”.
  • TID refers to “ter in die” or “three times a day”.
  • treatment 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.
  • 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.
  • 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 1620037251.1 Attorney 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.
  • 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 Interleukin 2-Inducible T Cell kinase
  • TSK tyrosine protein kinase TXK
  • RLK Resting Lymphocyte Kinase
  • Java Janus kinase
  • 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 ⁇ -chain family of cytokine receptors, which include interleukin (IL) 2, 4, 7, 9, 15, and 21. These cytokines are involved in the autoimmune response.
  • IL interleukin
  • PO orally
  • 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.
  • 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 2020 ⁇ US census data.
  • QoL quality of life
  • 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.
  • 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.
  • several treatments for AD have been approved by the Food and Drug Administration.
  • 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 1620037251.1 Attorney 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, ⁇ -hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothe
  • 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.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, eth
  • oral administration of Compound I is a non-solvated form or in a solvated form.
  • one solvent molecule can be associated with one molecule of Compound I as described herein, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of Compound I as described herein, such as a dihydrate.
  • less than one solvent molecule may be associated with one molecule of Compound I as described herein, such as a hemihydrate.
  • 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.
  • pharmaceutical 10 1620037251.1 Attorney Docket No.: 145688-005702 compositions include the therapeutically effective amount of Compound I and a physiologically acceptable diluent or carrier.
  • the pharmaceutical composition further includes one or more additional therapeutic components and/or adjuvants.
  • 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.
  • 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.
  • 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).
  • 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.
  • Dragee cores can be provided with suitable coatings.
  • 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 1620037251.1 Attorney 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.
  • 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.
  • the active compound can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid PEG.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid PEG.
  • 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.
  • 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).
  • 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
  • wetting agents e
  • 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.
  • 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.
  • 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 1620037251.1 Attorney 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.
  • the tablet is formulated for immediate release.
  • the tablet is formulated for controlled release.
  • 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 composition of Compound I for oral administration comprises Compound I and a buffer.
  • the buffer may be selected from the group consisting of citric acid monohydrate, sodium phosphate, water, and a combination thereof.
  • the oral composition comprises Compound I and a stabilizer.
  • the stabilizer is selected from a group consisting of povidone, sodium benzoate, water, sodium lauryl sulfate, and a combination thereof.
  • the oral composition further includes a buffer, an acid, sodium benzoate, sodium phosphate, citric acid, or a combination thereof.
  • the composition of Compound I for oral administration comprises Compound I and a stabilizer and a buffer.
  • 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.
  • Compound I is in a therapeutically effective amount (e.g., about 5 mg to about 100 mg).
  • 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.
  • 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.
  • the pH modifier may be an acid (e.g., hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, or a combination thereof).
  • 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 1620037251.1 Attorney Docket No.: 145688-005702 cellulose (MCC), ethyl cellulose, HPMC, hydroxypropyl cellulose (HPC), starch, PVP, PEG, sodium alginate, CMC, and a combination thereof.
  • MCC natural or synthetic polymer
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an antioxidant e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium
  • an amino acid e.g., cysteine, or methionine
  • citric acid e.g., cysteine, or methionine
  • sodium citrate e.g., sodium citrate
  • a synthetic preservative e.g., a paraben such as methyl paraben or propyl paraben
  • the glidant may be selected from the group consisting of colloidal anhydrous silicon and other silica compounds
  • the composition for oral administration comprising Compound I is a capsule.
  • the capsule comprises an inner coating made from a high fat emulsion.
  • the capsule comprises a high fat coating that is either on the inside or the outside of the capsule.
  • the capsule comprises HPMC.
  • the capsule may be a HPMC capsule.
  • the capsule may be enteric coated.
  • the capsule may be a silica capsule, such as silica sold under the trade name SYLOID®.
  • the capsule comprises cyclodextrin.
  • the capsule may be a cyclodextrin complex enteric capsule.
  • the oral formulation comprising Compound I is a tablet.
  • the tablet contains Compound I in the form of nanoparticles.
  • the tablet may be coated.
  • the tablet may be coated with an enteric coating.
  • 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.
  • composition for oral administration comprises Compound I in the form of a nanoparticle suspension (nanosuspension).
  • the nanosuspension comprises Compound I, a stabilizer, and a buffer.
  • the nanosuspension may further comprise a pH modifier.
  • 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.
  • the pH modifier may be hydrochloric acid.
  • the hydrochloric acid may be 1.0N hydrochloric acid.
  • 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.
  • the buffer solution may include WFI quality water, sodium phosphate (dibasic, 7-hydrate, crystal), citric acid monohydrate, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • the tablet comprises about 1 mg to about 100 mg of Compound I.
  • the composition of Compound I for oral administration as described herein is a dry powder.
  • the dry powder may be encapsulated or made into a suspension.
  • the suspension may be a nanoparticle suspension or a milled suspension.
  • 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).
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.
  • compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (e.g., PEG).
  • 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.
  • Compound I hereafter “Compound I”
  • 16 1620037251.1 Attorney Docket No.: 145688-005702
  • 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.
  • 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.
  • a desired effect e.g., prevent or reduce skin lesion formation, prevent or reduce the severity of the skin lesion formation.
  • the skin condition treated in accordance with the methods and formulations disclosed herein is atopic dermatitis.
  • 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.
  • 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.
  • Lesional skin from patients with AD contains elevated levels of pro-inflammatory cytokines and cellular infiltrates of CD4+ T cells that propagate disease pathophysiology.
  • 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.
  • 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.
  • hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like
  • 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.
  • 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).
  • EASI Eczema Area and Severity Index
  • 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 (S erythema ), edema/papulation (S edema/papulation ), excoriation (S excoriation ), and lichenification (S lichenification ).
  • 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
  • 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).
  • 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.
  • 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.
  • BSA body surface area
  • the BSA affected by the skin condition for example, AD
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Compound I may be administered on a chronic basis with additional administrations and/or increased dosing upon occurrence of symptoms.
  • symptoms include, but are not limited to, dry and/or scaly skin, itching, reddening of the skin, skin infections, and bleeding or oozing skin.
  • dosing may be increased or decreased based on severity of symptoms.
  • 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 1620037251.1 Attorney 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.
  • Compound I may be used as a co-therapy or adjuvant therapy to another AD-related therapy.
  • 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.
  • 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 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.
  • the human subject is one having atopic dermatosis (AD).
  • 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).
  • 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.
  • 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 1620037251.1 Attorney 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.
  • 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.
  • 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.
  • 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 1620037251.1 Attorney Docket No.: 145688-005702 effective amount of Compound I comprises about 29 mg/day.
  • 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.
  • the therapeutically effective amount of 40 mg BID of Compound I is administered to a human subject having a skin condition disclosed herein.
  • the therapeutically effective amount of Compound I comprises about 1 mg BID.
  • the therapeutically effective amount of Compound I comprises about 2 mg BID.
  • the therapeutically effective amount of Compound I comprises about 3 mg BID.
  • the therapeutically effective amount of Compound I comprises about 4 mg BID.
  • the therapeutically effective amount of Compound I comprises about 5 mg BID.
  • the therapeutically effective amount of Compound I comprises about 6 mg BID.
  • the therapeutically effective amount of Compound I comprises about 7 mg BID.
  • 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.
  • 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 1620037251.1 Attorney 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.
  • 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.
  • the therapeutically effective amount of [0096] 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.
  • the oral composition comprising Compound I as described herein can be administered to the subject once (e.g., as a single dose or application).
  • the oral composition of embodiments herein is administered at least once daily, such as at least two, three or four times daily.
  • 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.
  • 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.
  • treatment may be continued for at least a week, a month, a year, or as otherwise directed by a physician.
  • treatment may extend over multiple years, the duration of disease, or the lifetime of the subject.
  • 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).
  • AD atopic dermatitis
  • 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.
  • 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.
  • 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 1620037251.1 Attorney 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.
  • 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.
  • 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.
  • Non-biologic systemic immunosuppressants eg, prednisone, methotrexate, retinoids, calcineurin inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine
  • Cytostatic agents e.g. mycophenolate
  • Topical disease modifying treatments for AD corticosteroids, calcineurin inhibitors, crisaborole, JAK inhibitors
  • AD therapy e.g. history of anaphylaxis, hypersensitivity reactions, skin atrophy, striae, pigmentary changes
  • AD therapy e.g. history of anaphylaxis, hypersensitivity reactions, skin atrophy, striae, pigmentary changes
  • 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 1620037251.1 Attorney 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.
  • MACE Prior major adverse cardiovascular event
  • cytochrome P4503A4 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.
  • 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.
  • 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
  • Antibiotics 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 1620037251.1 Attorney 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.
  • Prohibited Medications The following are prohibited from Screening to the Follow up Visit: Live vaccination New systemic antihistaminic medications are not allowed.
  • Phototherapy ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy
  • Systemic biologic immunosuppressant or immunomodulatory therapy eg, etanercept, alefacept, infliximab, dupilumab
  • Non-biologic immunosuppressants e.g,, methotrexate, retinoids, calcineurin inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine.
  • o JAK inhibitors systemic and topical
  • Systemic or topical corticosteroids Intranasal, inhaled, and topical ocular corticosteroids are allowed if used to treat other medical conditions.
  • Cytostatic agents o Crisaborole o
  • Other disease-modifying medicated topical treatments for AD e.g.
  • Ritonavir 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.
  • c The 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).
  • the classification is based on studies conducted with intravenously administered conivaptan.
  • e Diltiazem increased AUC of certain sensitive CYP3A substrates (eg, buspirone) more than 5-fold.
  • AUC 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.
  • 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 inhibitors Data 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 1620037251.1 Attorney 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.
  • Any pre-study surgical procedures will be recorded in the participant’s source documents and eCRF as part of the medical history assessment.
  • 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 1620037251.1 Attorney 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.
  • Any medical events (with the exception of SAE) happening between Screening and first dose of study drug should be recorded as medical history.
  • 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”.
  • 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?’.
  • the study coordinator 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.
  • 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).
  • 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 1620037251.1 Attorney 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.
  • 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
  • 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.
  • 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.
  • Blood samples (non-fasting preferred, but not required) and urine samples will be collected.
  • AEs Adverse Events
  • SAEs Serious Adverse Events
  • 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 1620037251.1 Attorney Docket No.: 145688-005702 includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).
  • 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.
  • 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.
  • 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.
  • Safety reports eg, MedWatch
  • SUSAR suspected unexpected serious adverse reactions
  • SUSAR reports will be submitted to regulators by the Sponsor or their designee. SUSARs will also be forwarded to Investigators as necessary.
  • 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.
  • 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.
  • 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.
  • 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.
  • Serious infections Shingles Moderate-to-severe diarrhea MACE stroke, acute myocardial infarction, cardiovascular death
  • Venous thromboembolism Deep vein thrombosis or pulmonary embolism
  • Laboratories of interest based predominantly on knowledge on the mechanism of action and medicines with related mechanisms of action (
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • MedDRA Medical Dictionary for Regulatory Activities
  • 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.
  • For the laboratory data hematology, serum chemistry, coagulation, and urinalysis
  • observed values and changes from baseline will be presented descriptively.

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Abstract

La présente invention concerne des procédés de traitement de troubles cutanés provoqués par une déficience immunitaire avec des formulations à administrer par voie orale comprenant de la 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-méthylpipéridin-1-yl)prop-2-en-1-one (Composé I) ou un dérivé pharmaceutiquement acceptable de celle-ci. En particulier, les formulations à administrer par voie orale décrites ici peuvent être utilisées pour traiter la dermatite atopique.
PCT/US2025/027723 2024-05-07 2025-05-05 Compositions de pyrrolopyrimidine pour le traitement de la dermatite atopique Pending WO2025235366A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200016068A1 (en) * 2016-09-08 2020-01-16 Foamix Pharmaceuticals Ltd. Compositions and methods for treating rosacea and acne
US20220348579A1 (en) * 2018-08-10 2022-11-03 Aclaris Therapeutics, Inc. Pyrrolopyrimidine itk inhibitors
WO2023110843A1 (fr) * 2021-12-15 2023-06-22 Almirall, S.A. Dérivés hétérobicycliques utilisés comme inhibiteurs de l'itk

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200016068A1 (en) * 2016-09-08 2020-01-16 Foamix Pharmaceuticals Ltd. Compositions and methods for treating rosacea and acne
US20220348579A1 (en) * 2018-08-10 2022-11-03 Aclaris Therapeutics, Inc. Pyrrolopyrimidine itk inhibitors
WO2023110843A1 (fr) * 2021-12-15 2023-06-22 Almirall, S.A. Dérivés hétérobicycliques utilisés comme inhibiteurs de l'itk

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