WO2024150110A1 - Compositions et méthodes pour le traitement et/ou la prévention du diabète de type 1 - Google Patents

Compositions et méthodes pour le traitement et/ou la prévention du diabète de type 1 Download PDF

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Publication number
WO2024150110A1
WO2024150110A1 PCT/IB2024/050163 IB2024050163W WO2024150110A1 WO 2024150110 A1 WO2024150110 A1 WO 2024150110A1 IB 2024050163 W IB2024050163 W IB 2024050163W WO 2024150110 A1 WO2024150110 A1 WO 2024150110A1
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days
diabetes
subject
weeks
once
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PCT/IB2024/050163
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English (en)
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Christopher BANFIELD
Jeremy GALE
Michael Steven Vincent
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Pfizer Inc.
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Publication of WO2024150110A1 publication Critical patent/WO2024150110A1/fr

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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present disclosure relates to the treatment and/or prevention of Type 1 diabetes.
  • Type 1 diabetes mellitus is an immune-mediated disease in which insulinproducing p cells are completely or almost completely destroyed, resulting in life-long dependence on exogenous insulin therapy.
  • T1D is a chronic and potentially disabling disease that represents a major public health and clinical concern. The number of individuals being diagnosed with T1D is increasing each year. What is needed are compositions and methods for the treatment and/or prevention of Type 1 diabetes.
  • the present disclosure provides methods for the treatment or prevention of Type 1 diabetes, comprising administering to a patient or subject in need a therapeutically effective amount of a JAK 1 inhibitor. In one embodiment, the present disclosure provides methods for the treatment or prevention of Type 1 diabetes, comprising administering to a patient or subject in need a therapeutically effective amount of a JAK1 inhibitor, wherein the JAK1 inhibitor is administered in an amount of about 40 mg to about 300 mg.
  • the JAK1 inhibitor can be abrocitinib.
  • the abrocitinib can be administered orally at a single or twice daily dose for up to 8 weeks, 52 weeks or indefinitely.
  • the abrocitinib can be administered at a single or twice daily dose, wherein the total daily dosage is about 200 mg total.
  • the abrocitinib can be administered with one or more additional therapies, for example, insulin.
  • the present disclosure provides methods for the treatment or prevention of Type 1 diabetes, comprising administering to a patient or subject in need a therapeutically effective amount of a JAK3/TEC inhibitor. In one embodiment, the present disclosure provides methods for the treatment or prevention of Type 1 diabetes, comprising administering to a patient or subject in need of a therapeutically effective amount of a JAK3/TEC inhibitor, wherein the JAK3/TEC inhibitor is administered in an amount of about 50 mg to about 150 mg.
  • the JAK3/TEC inhibitor can be ritlecitinib.
  • the ritlecitinib can be administered orally at a single or twice daily dose for up to 8 weeks, 52 weeks or indefinitely.
  • the ritlecitinib can be administered at a single or twice daily dose, wherein the total daily dosage is about 100 mg total.
  • the ritlecitinib can be administered with one or more additional therapies, for example, insulin.
  • the present disclosure provides methods of treating and/or preventing Type 1 diabetes, comprising administering to a patient or subject a therapeutically effective amount of abrocitinib, wherein the abrocitinib is administered orally at a single or twice daily dose of about 200 mg total.
  • the present disclosure provides methods of treating and/or preventing Type 1 diabetes, comprising administering to a patient or subject a therapeutically effective amount of ritlecitinib, wherein the ritlecitinib is administered orally at a single or twice daily dose of about 100 mg total.
  • the present disclosure provides uses of a JAK1 inhibitor for treating and/or preventing Type 1 diabetes.
  • the JAK 1 inhibitor can be abrocitinib.
  • the present disclosure provides uses of a JAK3/TEC inhibitor for treating and/or preventing Type 1 diabetes.
  • the JAK3/TEC inhibitor can be ritlecitinib.
  • the present disclosure provides methods wherein, during the duration of the treatment, the patient or subject has HbAlc levels within the currently recommended American Diabetes Association age-specific target range in the absence of clinically significant or severe hypoglycemia or diabetic ketoacidosis.
  • Figures 1A-1B relates to cyclophosphamide-enhanced T1D in NOD mice in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 1A is a graph of cyclophosphamide-enhanced T1D model in Study 1, in an exemplary embodiment of the present disclosure.
  • Figure IB is a graph of a potential positive control in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 2A is a timeline for cyclophosphamide-accelerated diabetes study in NOD mice in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 2B is a table showing treatment, selectivity and dosing for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figures 3A and 3B shows disease outcome for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 3A is a graph showing survival of diabetes onset/high blood glucose levels in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 3B is a graph of blood glucose level post cyclophosphamide injection in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4A is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4B is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4C is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4D is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4E is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 4F is a graph showing splenocyte cytometry at take down in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figures 5A-5E are graphs that demonstrate that JAKi and FTY720 decreased IL-10, IL2p70, and IFNa, IFNy, and IL-21 cytokine response to anti-CD3/28 ex vivo challenge in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figures 6A-6B show an example of histology methods, i.e., digital image analysis (DIA) of pancreas sections stained for insulin or glucagon by IHC and whole slides were scanned for DIA in Study 1, according to an exemplary embodiment of the present disclosure.
  • DIA digital image analysis
  • Figure 6A is an example of whole slide image containing pancreas stained for insulin by IHC.
  • Figure 6B is an example of region of interest (ROI; green) selection in whole slide images for quantification of IHC signal by DIA.
  • ROI region of interest
  • Figures 7A-7B are graphs showing the islet infiltration results of Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 7A is a graph showing islet infiltration severity scores in 3 step sections of pancreas -200 um apart from each animal (scored by pathologist on HE-stained slides) in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 7B is a graph showing number of islets (HE) normalized to the total measured pancreas area in whole slide images containing 3 step sections (L1-L3) of pancreas -200 um apart, from each animal in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figures 8A-8C are images and graphs showing the immunohistochemistry (IHC) results of Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 8A is an image demonstrating that increased severity of inflammatory cell infiltrates was associated with reduced insulin positive area in the pancreatic islets in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 8B is a graph of percent area insulin+ IHC/islet in whole slide images of 3 step sections of pancreas from each mouse in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 8C is a graph of percent area glucagon+ IHC/islet in whole slide images of 3 step sections of pancreas from each mouse in Study 1, according to an exemplary embodiment of the present disclosure.
  • Figure 9A is a timeline for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 2, according to an exemplary embodiment of the present disclosure.
  • Figure 9B is a table showing treatment and dosing for the cyclophosphamideaccelerated diabetes study in NOD mice in Study 2, according to an exemplary embodiment of the present disclosure.
  • Figures 10A-10B show the disease outcome in Study 2, according to an exemplary embodiment of the present disclosure.
  • Figure 10A is a graph showing survival of diabetes onset and blood glucose levels in Study 2, according to an exemplary embodiment of the present disclosure.
  • Figure 1 OB is a graph showing blood glucose levels post cyclophosphamide injection in Study 2, according to an exemplary embodiment of the present disclosure.
  • Figure 11A is a timeline for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 3, according to an exemplary embodiment of the present disclosure.
  • Figure 11B is a table showing treatment and dosing for the cyclophosphamideaccelerated diabetes study in NOD mice in Study 3, according to an exemplary embodiment of the present disclosure.
  • Figures 12A-12B show the disease outcome in Study 3, according to an exemplary embodiment of the present disclosure.
  • Figure 12A is a graph showing survival of diabetes onset and blood glucose levels in Study 3, according to an exemplary embodiment of the present disclosure.
  • Figure 12B is a graph showing blood glucose levels post cyclophosphamide injection in Study 3, according to an exemplary embodiment of the present disclosure.
  • Agent or “active ingredient” refers to any materials that may be used as or in pharmaceutical compositions that can generate a pharmaceutical effect, for example compounds such as small synthetic or naturally derived organic compounds, nucleic acids, polypeptides, antibodies, fragments, isoforms, variants, or other materials that may be used independently for such purposes, all in accordance with the present disclosure.
  • Antagonist refers to an agent that suppresses or inhibits at least one bioactivity, for example of a protein, cell or physiologic system.
  • An antagonist can be a compound which inhibits or decreases the interaction between a protein or cellular receptor and another molecule, e.g., a target peptide or enzyme substrate.
  • An antagonist may also be a compound that down-regulates expression of a gene or which reduces the amount of expressed protein related to the bioactivity to be antagonized.
  • patient refers to any individual human or animal to be treated by the present methods, for example a human or non-human primate, bovine, ovine, porcine, feline, canine or rodent.
  • treatment refers to obtaining a desired pharmacologic or physiologic effect.
  • the pharmacologic and/or physiologic effect can be prophylactic, for example by completely or partially delaying or preventing a particular outcome relating to a disease or disorder, or a symptom thereof, or may be therapeutic, for example by ameliorating or causing a partial or complete cure for a disease or disorder /or symptom or adverse effect thereof.
  • an “effective amount” or a “therapeutically effective amount” is used interchangeably and refers to an amount of a pharmaceutical composition of the present disclosure which provides the desired treatment of a subject.
  • the therapeutically effective amount of the present pharmaceutical compositions to treat a given disease, disorder or condition will vary from subject to subject, depending on factors such as age, general condition of the subject, the severity of the condition being treated, the particular compound and/or composition administered, and the like.
  • An appropriate therapeutically effective amount of the present pharmaceutical compositions suitable for any individual subject can be readily determined by one of ordinary skill in the art from the information provided herein.
  • compositions of the present disclosure are in biologically compatible form suitable for administration to subjects, for example to humans.
  • the pharmaceutical compositions can further comprise a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable means suitable for use in humans or animals, for example as approved by a governmental regulatory agency (such as the US Food and Drug Administration) or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, or which are generally recognized as safe (GRAS).
  • excipient refers to a carrier or vehicle (including any suitable diluent, adjuvant or the like) with which the active ingredient is administered.
  • suitable pharmaceutically acceptable excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be a pharmaceutically acceptable excipient when the pharmaceutical composition is administered orally.
  • Sterilized water, saline, aqueous dextrose, glycerol, lactated Ringer’s solution and the like can be pharmaceutically acceptable excipients when the pharmaceutical composition is injected, such as administered subcutaneously, intramuscularly, or intravascularly (for example intravenously).
  • Suitable pharmaceutically acceptable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried slim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the pharmaceutical composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • JAK1 Inhibitor e.g., Abrocitinib
  • the present disclosure provides pharmaceutical compositions and methods for treating Type 1 diabetes and/or preventing Type 1 diabetes.
  • the pharmaceutical composition can comprise a Janus protein tyrosine kinase 1 (JAK1) inhibitor.
  • JAK1 inhibitor for treating Type 1 diabetes and/or preventing Type 1 diabetes.
  • the JAK1 inhibitor is abrocitinib.
  • the present disclosure also provides a method comprising administering to a patient or subject in need a therapeutically effective amount of a JAK1 inhibitor.
  • the JAK1 inhibitor is abrocitinib.
  • compositions of the present disclosure can take any suitable form for administration to a subject, such as a human subject, for example solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the present pharmaceutical composition can also, for example, be formulated as a suppository, with traditional pharmaceutical excipients such as triglycerides.
  • Oral pharmaceutical formulations of the disclosure can include standard carriers as pharmaceutical excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • a pharmaceutical composition of the disclosure comprises an effective amount of abrocitinib together with a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the patient, for example by oral administration.
  • compositions of the present disclosure can be administered by any suitable route of administration, for example oral, parenteral, subcutaneous, intramuscular, intravenous, intra-arterial, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intraosseous, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means.
  • routes of administration for example oral, parenteral, subcutaneous, intramuscular, intravenous, intra-arterial, intr
  • the routes of administration for the present pharmaceutical compositions are oral administration or by injection, for example by subcutaneous, intramuscular, or intravascular (for example intravenous or intra-arterial) injection.
  • the route of administration for the present pharmaceutical compositions may be oral.
  • the pharmaceutical compositions of the disclosure comprising a JAK1 inhibitor, e.g., a formulation comprising abrocitinib without any other active ingredient, or in concert with at least one other active ingredient at appropriate dosages of the at least one other active ingredient as are known in the art to achieve a desired treatment, for example as defined by routine testing in order to obtain optimal efficacy while minimizing any potential toxicity.
  • Suitable therapeutically effective amounts and dosage regimens utilizing a pharmaceutical composition of the disclosure can be selected by the ordinarily skilled clinician in accordance with a variety of factors, including species, age, weight, sex, and overall medical condition of the patient; the condition to be treated and its severity or penetration; the route of administration; the renal and hepatic function of the patient; and the particular pharmaceutical composition employed.
  • the present disclosure provides methods for the treatment of Type 1 diabetes.
  • the JAK1 inhibitor for example abrocitinib
  • the total daily dosage of a JAK1 inhibitor, for example abrocitinib, administered to a patient can be about 40 mg to about 300 mg.
  • the abrocitinib is administered in a total daily amount of about 150 mg to about 250 mg.
  • the abrocitinib is administered in a total daily amount of about 200 mg.
  • the daily dosage can be about 40 mg, about 45 mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about lOOmg, about 105mg, about 1 lOmg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg,
  • the present pharmaceutical compositions comprising a JAK1 inhibitor can be administered to a patient at a single daily dose or twice daily dose (BID): for about 2 days, for about 3 days, for about 4 days, for about 5 days, for about 6 days, for about 7 days, for about 8 days, for about 9 days, for about 10 days, for about 11 days, for about 12 days, for about 13 days, for about 14 days, for about 15 days, for about 16 days, for about 17 days, for about 18 days, for about 19 days, for about 20 days, for about 21 days, for about 22 days, for about 23 days, for about 24 days, for about 25 days, for about 26 days, for about 27 days, for about 28 days, for about 29 days, for about 30 days, for about 31 days, for about 1 week, for about 2 weeks, for about 3 weeks, for about 4 weeks, for about 5 weeks, for about 6 weeks, for about 7 weeks for about 8 weeks, for about 1 month, for about 2 months, for about 3 months, for
  • the JAK1 inhibitor for example abrocitinib
  • the JAK1 inhibitor is administered to a patient for the treatment of Type 1 diabetes and/or the prevention of Type 1 diabetes orally at a single or twice daily dose of about 150 mg to about 250 mg total for up to 8 to 52 weeks or indefinitely.
  • the JAK1 inhibitor for example abrocitinib
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered every other day for about 2 days, every other day for about 3 days, every other day for about 4 days, every other day for about 5 days, every other day for about 6 days, every other day for about 7 days, every other day for about 8 days, every other day for about 9 days, every other day for about 10 days, every other day for about 11 days, every other day for about 12 days, every other day for about 13 days, every other day for about 14 days, every other day for about 15 days, every other day for about 16 days, every other day for about 17 days, every other day for about 18 days, every other day for about 19 days, every other day for about 20 days, every other day for about 21 days, every other day for about 22 days, every other day for about 23 days, every other day for about 24 days, every other day for about 25 days, every other day for about 26 days, every other day for about 27 days, every other day for about 28 days, every other day for about 29 days, every other day for about 20 days, every other day for about 21 days
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered at a single daily dose or twice daily dose about every day, about every 2 days (also sometimes stated herein as once every other day), about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 days, about every 9 days, about every 10 days, about every 11 days, about every 12 days, about every 13 days, about every 14 days, about every 15 days, about every 16 days, about every 17 days, about every 18 days, about every 19 days, about every 20 days, about every 21 days, about every 22 days, about every 23 days, about every 24 days, about every 25 days, about every 26 days, about every 27 days, about every 28 days, about every 29 days, about every 30 days, or about every 31 days.
  • a JAK1 inhibitor for example abrocitinib
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered at a single daily dose or twice daily dose about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, or about once every 20 weeks.
  • a JAK1 inhibitor for example abrocitinib
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered about once every month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, about once every 6 months, about once every 7 months, about once every 8 months, about once every 9 months, about once every 10 months, about once every 11 months, or about once every 12 months.
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered at least once a week for about 2 weeks, at least once a week for about 3 weeks, at least once a week for about 4 weeks, at least once a week for about 5 weeks, at least once a week for about 6 weeks, at least once a week for about 7 weeks, at least once a week for about 8 weeks, at least once a week for about 9 weeks, at least once a week for about 10 weeks, at least once a week for about 11 weeks, at least once a week for about 12 weeks, at least once a week for about 13 weeks, at least once a week for about 14 weeks, at least once a week for about 15 weeks, at least once a week for about 16 weeks, at least once a week for about 17 weeks, at least once a week for about 18 weeks, at least once a week for about 19 weeks, or at least once a week for about 20 weeks.
  • a JAK1 inhibitor for example abrocitinib
  • the pharmaceutical compositions comprising a JAK1 inhibitor can be administered at least once a week for about 1 month, at least once a week for about 2 months, at least once a week for about 3 months, at least once a week for about 4 months, at least once a week for about 5 months, at least once a week for about 6 months, at least once a week for about 7 months, at least once a week for about 8 months, at least once a week for about 9 months, at least once a week for about 10 months, at least once a week for about 11 months, or at least once a week for about 12 months.
  • a JAK1 inhibitor for example abrocitinib
  • the pharmaceutical compositions comprising a JAK1 inhibitor for example abrocitinib
  • a dosing regimen or treatment method comprising administering the pharmaceutical composition to a patient who has Type 1 diabetes or as a prevention of Type 1 diabetes.
  • the present disclosure provides methods of treating and/or preventing Type 1 diabetes in a patient comprising administering to a patient or subject a therapeutically effective amount of abrocitinib, wherein the abrocitinib is administered orally at a single or twice daily dose of about 200 mg total.
  • the present disclosure also provides use of a JAK1 inhibitor for treating and/or preventing Type 1 diabetes, comprising administering to a patient or subject a therapeutically effective amount of abrocitinib.
  • the abrocitinib may be administered orally at a single or twice daily dose of about 200 mg total.
  • the present disclosure also provides dosing regimens for the treatment and/or prevention of Type 1 diabetes, the dosing regimen comprising administering to a patient or subject a therapeutically effective amount of abrocitinib, wherein the abrocitinib is administered orally at a single or twice daily dose of about 200 mg total.
  • the present disclosure also provides a package or kit comprising a JAK1 inhibitor formulated for oral administration to a patient, and instructions for administering the JAK11 inhibitor for the treatment and/or prevention of Type 1 diabetes, the instructions comprising administering to a patient or subject a therapeutically effective amount of the JAK1 inhibitor, for example abrocitinib, wherein the JAK inhibitor, for example abrocitinib, is administered orally at a single or twice daily dose of about 200 mg total.
  • methods of treating and/or preventing Type 1 diabetes comprising administering to a patient or subject a therapeutically effective amount of abrocitinib and one or more additional therapies.
  • the abrocitinib may be administered orally at a single or twice daily dose of about 40 mg to about 300 mg total, for example about 200mg total.
  • the additional therapy can comprise insulin.
  • the patient or subject may have HbAlc levels within the currently recommended American Diabetes Association age-specific target range in the absence of clinically significant or severe hypoglycemia or diabetic ketoacidosis.
  • methods of determining whether a patient or subject is a candidate for the treatment disclosed herein, for example treatment and/or prevention of Type 1 diabetes comprising a JAK1 inhibitor, for example abrocitinib are provided.
  • the methods can comprise determining, via a test or screen, whether the patient or subject has HbAlc levels within the currently recommended American Diabetes Association age-specific target range in the absence of clinically significant or severe hypoglycemia or diabetic ketoacidosis.
  • methods for the treatment and/or prevention of Type 1 diabetes comprising a JAK1 inhibitor, for example abrocitinib
  • JAK3/TEC Inhibitor e.g., ritlecitinib
  • the present disclosure provides pharmaceutical compositions and methods for treating Type 1 diabetes and/or preventing Type 1 diabetes.
  • the pharmaceutical composition can comprise a Janus tyrosine kinase 3 (JAK3)/TEC tyrosine-protein kinase (TEC) inhibitor.
  • the present disclosure also provides use of a JAK3/TEC inhibitor for treating Type 1 diabetes and/or preventing Type 1 diabetes.
  • the JAK3/TEC inhibitor is ritlecitinib.
  • the present disclosure also provides a method comprising administering to a patient or subject in need a therapeutically effective amount of a JAK3/TEC inhibitor.
  • the JAK3/TEC inhibitor is ritlecitinib.
  • compositions of the present disclosure can take any suitable form for administration to a subject, such as a human subject, for example solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the present pharmaceutical composition can also, for example, be formulated as a suppository, with traditional pharmaceutical excipients such as triglycerides.
  • Oral pharmaceutical formulations of the disclosure can include standard carriers as pharmaceutical excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • a pharmaceutical composition of the disclosure comprises an effective amount of ritlecitinib together with a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the patient, for example by oral administration.
  • compositions of the present disclosure can be administered by any suitable route of administration, for example oral, parenteral, subcutaneous, intramuscular, intravenous, intra-arterial, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intraosseous, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means.
  • routes of administration for example oral, parenteral, subcutaneous, intramuscular, intravenous, intra-arterial, intr
  • the routes of administration for the present pharmaceutical compositions are oral administration or by injection, for example by subcutaneous, intramuscular, or intravascular (for example intravenous or intra-arterial) injection.
  • the route of administration for the present pharmaceutical compositions may be oral.
  • the pharmaceutical compositions of the disclosure comprising a JAK3/TEC inhibitor, e.g., a formulation comprising ritlecitinib without any other active ingredient, or in concert with at least one other active ingredient at appropriate dosages of the at least one other active ingredient as are known in the art to achieve a desired treatment, for example as defined by routine testing in order to obtain optimal efficacy while minimizing any potential toxicity.
  • a JAK3/TEC inhibitor e.g., a formulation comprising ritlecitinib without any other active ingredient, or in concert with at least one other active ingredient at appropriate dosages of the at least one other active ingredient as are known in the art to achieve a desired treatment, for example as defined by routine testing in order to obtain optimal efficacy while minimizing any potential toxicity.
  • Suitable therapeutically effective amounts and dosage regimens utilizing a pharmaceutical composition of the disclosure can be selected by the ordinarily skilled clinician in accordance with a variety of factors, including species, age, weight, sex, and overall medical condition of the patient; the condition to be treated and its severity or penetration; the route of administration; the renal and hepatic function of the patient; and the particular pharmaceutical composition employed.
  • the present disclosure provides methods for the treatment of Type 1 diabetes.
  • the JAK3/TEC inhibitor for example ritlecitinib
  • the total daily dosage of a JAK3/TEC inhibitor, for example ritlecitinib, administered to a patient can be about 50mg to about 200 mg.
  • the ritlecitinib is administered in a total daily amount of about 50 mg to about 150 mg.
  • the ritlecitinib is administered in a total daily amount of about 100 mg.
  • the daily dosage can be about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about lOOmg, about 105mg, about HOmg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, or about 200mg.
  • the dosage of ritlecitinib can be about lOOmg daily.
  • the present pharmaceutical compositions comprising a JAK3/TEC inhibitor can be administered to a patient at a single daily dose or twice daily dose (BID): for about 2 days, for about 3 days, for about 4 days, for about 5 days, for about 6 days, for about 7 days, for about 8 days, for about 9 days, for about 10 days, for about 11 days, for about 12 days, for about 13 days, for about 14 days, for about 15 days, for about 16 days, for about 17 days, for about 18 days, for about 19 days, for about 20 days, for about 21 days, for about 22 days, for about 23 days, for about 24 days, for about 25 days, for about 26 days, for about 27 days, for about 28 days, for about 29 days, for about 30 days, for about 31 days, for about 1 week, for about 2 weeks, for about 3 weeks, for about 4 weeks, for about 5 weeks, for about 6 weeks, for about 7 weeks for about 8 weeks, for about 1 month, for about 2 months, for about
  • BID twice daily dose
  • the JAK3/TEC inhibitor for example ritlecitinib
  • the JAK3/TEC inhibitor is administered to a patient for the treatment of Type 1 diabetes and/or the prevention of Type 1 diabetes orally at a single or twice daily dose of about 50 mg to about 150 mg total for up to 8 to 52 weeks or indefinitely.
  • the JAK3/TEC inhibitor for example ritlecitinib
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor can be administered every other day for about 2 days, every other day for about 3 days, every other day for about 4 days, every other day for about 5 days, every other day for about 6 days, every other day for about 7 days, every other day for about 8 days, every other day for about 9 days, every other day for about 10 days, every other day for about 11 days, every other day for about 12 days, every other day for about 13 days, every other day for about 14 days, every other day for about 15 days, every other day for about 16 days, every other day for about 17 days, every other day for about 18 days, every other day for about 19 days, every other day for about 20 days, every other day for about 21 days, every other day for about 22 days, every other day for about 23 days, every other day for about 24 days, every other day for about 25 days, every other day for about 26 days, every other day for about 27 days, every other day for about 28 days, every other day for about
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor can be administered at a single daily dose or twice daily dose about every day, about every 2 days (also sometimes stated herein as once every other day), about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 days, about every 9 days, about every 10 days, about every 11 days, about every 12 days, about every 13 days, about every 14 days, about every 15 days, about every 16 days, about every 17 days, about every 18 days, about every 19 days, about every 20 days, about every 21 days, about every 22 days, about every 23 days, about every 24 days, about every 25 days, about every 26 days, about every 27 days, about every 28 days, about every 29 days, about every 30 days, or about every 31 days.
  • a JAK3/TEC inhibitor for example ritlecitinib
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor for example ritlecitinib
  • a JAK3/TEC inhibitor for example ritlecitinib
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor for example ritlecitinib
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor can be administered at least once a week for about 2 weeks, at least once a week for about 3 weeks, at least once a week for about 4 weeks, at least once a week for about 5 weeks, at least once a week for about 6 weeks, at least once a week for about 7 weeks, at least once a week for about 8 weeks, at least once a week for about 9 weeks, at least once a week for about 10 weeks, at least once a week for about 11 weeks, at least once a week for about 12 weeks, at least once a week for about 13 weeks, at least once a week for about 14 weeks, at least once a week for about 15 weeks, at least once a week for about 16 weeks, at least once a week for about 17 weeks, at least once a week for about 18 weeks, at least once a week for about
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor can be administered at least once a week for about 1 month, at least once a week for about 2 months, at least once a week for about 3 months, at least once a week for about 4 months, at least once a week for about 5 months, at least once a week for about 6 months, at least once a week for about 7 months, at least once a week for about 8 months, at least once a week for about 9 months, at least once a week for about 10 months, at least once a week for about 11 months, or at least once a week for about 12 months.
  • a JAK3/TEC inhibitor for example ritlecitinib
  • the pharmaceutical compositions comprising a JAK3/TEC inhibitor for example ritlecitinib
  • a dosing regimen or treatment method comprising administering the pharmaceutical composition to a patient who has Type 1 diabetes or as a prevention of Type 1 diabetes.
  • the present disclosure provides methods of treating and/or preventing Type 1 diabetes in a patient comprising administering to a patient or subject a therapeutically effective amount of ritlecitinib, wherein the ritlecitinib is administered orally at a single or twice daily dose of about 100 mg total.
  • the present disclosure also provides use of a JAK3/TEC inhibitor for treating and/or preventing Type 1 diabetes, comprising administering to a patient or subject a therapeutically effective amount of ritlecitinib.
  • the ritlecitinib may be administered orally at a single or twice daily dose of about 100 mg total.
  • the present disclosure also provides dosing regimens for the treatment and/or prevention of Type 1 diabetes, the dosing regimen comprising administering to a patient or subject a therapeutically effective amount of abrocitinib, wherein the ritlecitinib is administered orally at a single or twice daily dose of about 100 mg total.
  • the present disclosure also provides a package or kit comprising a JAK3/TEC inhibitor formulated for oral administration to a patient, and instructions for administering the JAK3/TEC inhibitor for the treatment and/or prevention of Type 1 diabetes, the instructions comprising administering to a patient or subject a therapeutically effective amount of the JAK3/TEC inhibitor, for example ritlecitinib, wherein the JAK3/TEC inhibitor, for example ritlecitinib, is administered orally at a single or twice daily dose of about 100 mg total.
  • methods of treating and/or preventing Type 1 diabetes comprising administering to a patient or subject a therapeutically effective amount of ritlecitinib and one or more additional therapies.
  • the ritlecitinib may be administered orally at a single or twice daily dose of about 50 mg to about 150 mg total, for example about 100 mg total.
  • the additional therapy can comprise insulin.
  • the patient or subject may have HbAlc levels within the currently recommended American Diabetes Association age-specific target range in the absence of clinically significant or severe hypoglycemia or diabetic ketoacidosis.
  • methods of determining whether a patient or subject is a candidate for the treatment disclosed herein, for example treatment and/or prevention of Type 1 diabetes comprising a JAK3/TEC inhibitor, for example ritlecitinib are provided.
  • the methods can comprise determining, via a test or screen, whether the patient or subject has HbAlc levels within the currently recommended American Diabetes Association age-specific target range in the absence of clinically significant or severe hypoglycemia or diabetic ketoacidosis.
  • methods for the treatment and/or prevention of Type 1 diabetes comprising a JAK3/TEC inhibitor, for example ritlecitinib
  • Figures 1A-1B relates to cyclophosphamide-enhanced T1D in NOD mice.
  • Figure 1A is a graph of cyclophosphamide-enhanced T1D model.
  • Figure IB is a potential positive control (Transplantation. 2002 Dec 27;74(12): 1684-6).
  • Figures 1A-1B show 2x cyclophosphamide injection into NOD mice accelerates T1D model development and can lead to depletion of T-cells with stronger impact on Tregs.
  • Figure 2A is a timeline for cyclophosphamide-accelerated diabetes study in NOD mice.
  • Figure 2B is a table showing treatment, selectivity and dosing for the cyclophosphamideaccelerated diabetes study in NOD mice.
  • Figures 3A and 3B shows disease outcome for the cyclophosphamide-accelerated diabetes study in NOD mice.
  • Figure 3A is a graph showing survival of diabetes onset/high blood glucose levels.
  • Figure 3B is a graph of blood glucose level post cyclophosphamide injection.
  • Figures 4A-4F are graphs showing splenocyte cytometry at take down.
  • Figures 4A-4F demonstrate that cyclophosphamide exposure resulted in alteration of lymphocyte subsets, and depression of Tregs may be one of the most important factors for development of diabetes.
  • Figures 4A-4F demonstrate that PF-06263313 and PF-06667291 (also referred to as PF-7291) selectively and differentially reverse some of the changes, including Treg suppression and CD8+ T cell activation.
  • PF-06263313 refers to the compound 1-
  • PF-06667291 or PF-7291 refers to the compound
  • Figures 5A-5E are graphs that demonstrate that JAKi and FTY720 decreased IL- 10, IL2p70, and IFNa, IFNy, and IL-21 cytokine response to anti-CD3/28 ex vivo challenge.
  • the following interleukins do not appear to be induced and not affected by the compound: IL-2, IL-6, IL 15, IL-23, and IL27.
  • FTY720 refers to the compound with the following structure: .
  • An exemplary synthesis of FTY270 can be found, for example, in PCT Publication No. WO2020165672, published on August 20, 2020, which is incorporated herein by reference
  • Figures 6A-6B show an example of histology methods, i.e., digital image analyses (DIA) of pancreas sections stained for insulin or glucagon by IHC and whole slides were scanned for DIA.
  • a DIA algorithm was developed using Defmiens tissue studio to identify individual islets and quantify the percent area of each islet occupied by insulin or glucagon reactivity. Islets >500um 2 in 3 step sections (labeled as “LI, L2, L3”, ⁇ 200um interval) from each mouse were included in this analysis. The percent area occupied by positive stain was determined by quantifying the area of stain in each identified islet relative to the total area of the islet. Islets in 3 pancreas step sections/mouse were stained for insulin (6A) and an example of the ROI selections for the DIA algorithm is shown in green (6B); Similar analysis was performed for glucagon- stained samples.
  • Figures 7A-7B are graphs showing the islet infiltration results of Study 1.
  • Figure 7A is a graph showing islet infiltration severity scores in 3 step sections of pancreas ( ⁇ 200 um interval) from each animal (scored by pathologist on HE-stained slides)
  • 7B is a graph showing number of islets normalized to the total measured pancreas area in whole slide images containing 3 HE- stained step sections (L1-L3, -200 um interval) of pancreas from each animal.
  • Inflammatory cell infiltration around and into islets was present in naive NOD mice, and severity was slightly higher in cyclophosphamide-induced animals although this trend was not statistically significant due to the variability in these groups.
  • the severity of islet inflammatory cell infiltration was significantly lower in cyclophosphamide-induced animals treated with FTY720 or PF-7291 compared to vehicle (veh).
  • the number of recognizable islets relative to the total area of pancreas on the slides was also statistically greater in these groups relative to cyclophosphamide-challenged/veh NOD mice alone.
  • Figures 8A-8C are images and graphs showing immunohistochemistry (IHC) results of Study 1.
  • Figure 8A is an image demonstrating that increased severity of inflammatory cell infiltrates (based on histology score assigned by a pathologist) was associated with reduced insulin positive area in the islets; histology scores ( Figure 7) and insulin positive area were improved in pancreases from cyclophosphamide-challenged mice treated with PF-7291 or FTY720 compared to veh.
  • Figure 8B is a graph of percent area insulin+ IHC/islet
  • Figure 8C is a graph of percent area glucagon+ IHC/islet in whole slide images of 3 step sections of pancreas from each mouse.
  • the area of insulin positive IHC staining in the islets was significantly greater in cyclophosphamide-treated NOD mice administered FTY720 or PF-7291 compared to vehicle alone. There were no significant differences in glucagon positive area across groups.
  • Study 1 demonstrated the following. Disease: low disease incidence; no diabetes in animals treated with PF-06667291; and significantly lower blood glucose levels in mice treated with FTY720, PF-06667291 or PF-06263313.
  • T1D peptide stimulation had low cytokine responses relative to unstimulated cells (low dynamic range); CD3/28 stimulation was robust and could be better used to identify effects of compounds- probably on cell populations as a whole; and JAKi selectively decreased IL-10, IL-12p70, IFNa, and IFNy along with marginal impact on IL-21 (PF-06263313). No effects observed with other cytokines measured.
  • Histology and IHC severity of islet inflammatory cell infdtration was significantly lower and number of islets and insulin positive staining in islets was significantly higher in cyclophosphamide-challenged animals treated with FTY720 or PF-7291 compared to vehicle.
  • the compounds used in Study 2 are surrogate compounds to abrocitinib and ritlecitinib.
  • the goal of Study 2 was to determine if oral BID dosing reduces diabetes incidence in cyclophosphamide-accelerated T1D model.
  • Figure 9A is a timeline for the cyclophosphamideaccelerated diabetes study in NOD mice in Study 2.
  • Figure 9B is a table showing treatment and dosing for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 2.
  • Figures 10A-10B show the disease outcome in Study 2.
  • Figure 10A is a graph showing survival of diabetes onset and blood glucose levels.
  • Figure 10B is a graph showing blood glucose levels post cyclophosphamide injection.
  • the compounds used in Study 3 are surrogate compounds to abrocitinib and ritlecitinib.
  • Figure 11A is a timeline for the cyclophosphamide-accelerated diabetes study in NOD mice in Study 3.
  • Figure 1 IB is a table showing treatment and dosing for the cyclophosphamideaccelerated diabetes study in NOD mice in Study 3.
  • Figures 12A-12B show the disease outcome in Study 3.
  • Figure 12A is agraph showing survival of diabetes onset and blood glucose levels.
  • Figure 12B is a graph showing blood glucose levels post cyclophosphamide injection.
  • a clinical Phase 2 multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of subtype-selective JAK inhibitors for preservation of pancreatic P cell function in newly diagnosed Type 1 Diabetes Mellitus may be conducted.

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Abstract

La présente divulgation concerne le domaine du diabète de type 1. Plus spécifiquement, la présente divulgation concerne des compositions pharmaceutiques et des méthodes de traitement et/ou de prévention du diabète de type 1. Dans certains modes de réalisation, des compositions pharmaceutiques et des méthodes comprennent l'administration à un patient ou à un sujet d'une quantité thérapeutiquement efficace d'un inhibiteur de JAK1, par exemple, l'abrocitinib. Dans certains modes de réalisation, des compositions pharmaceutiques et des méthodes comprennent l'administration à un patient ou à un sujet d'une quantité thérapeutiquement efficace d'un inhibiteur de JAK3/TEC, par exemple le ritlecitinib.
PCT/IB2024/050163 2023-01-11 2024-01-08 Compositions et méthodes pour le traitement et/ou la prévention du diabète de type 1 WO2024150110A1 (fr)

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