WO2024150110A1

WO2024150110A1 - Compositions and methods for the treatment and/or prevention of type 1 diabetes

Info

Publication number: WO2024150110A1
Application number: PCT/IB2024/050163
Authority: WO
Inventors: Christopher BANFIELD; Jeremy GALE; Michael Steven Vincent
Original assignee: Pfizer Inc.
Priority date: 2023-01-11
Filing date: 2024-01-08
Publication date: 2024-07-18

Abstract

The present disclosure relates to the field of Type 1 diabetes. More specifically, the present disclosure provides pharmaceutical compositions and methods for treating and/or preventing Type 1 diabetes. In certain embodiments, pharmaceutical compositions and methods comprise administering to a patient or subject a therapeutically effective amount of a JAK1 inhibitor, for 5 example, abrocitinib. In certain embodiments, pharmaceutical compositions and methods comprise administering to a patient or subject a therapeutically effective amount of a JAK3/TEC inhibitor, for example ritlecitinib.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT AND/OR PREVENTION OF TYPE 1 DIABETES

FIELD

The present disclosure relates to the treatment and/or prevention of Type 1 diabetes.

BACKGROUND

Type 1 diabetes mellitus (T1D) 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.

SUMMARY

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 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. In an embodiment, the abrocitinib can be administered with one or more additional therapies, for example, insulin.

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 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. In an embodiment, the ritlecitinib can be administered with one or more additional therapies, for example, insulin.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the present disclosure provides uses of a JAK1 inhibitor for treating and/or preventing Type 1 diabetes. The JAK 1 inhibitor can be abrocitinib. In one embodiment, 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.

In an embodiment, 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.

BRIEF DESCRIPTION OF THE FIGURES

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.

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.

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. DETAILED DESCRIPTION

It is understood that the present disclosure is not limited to the particular methods and components, etc., described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to a “protein” is a reference to one or more proteins, and includes equivalents thereof known to those skilled in the art and so forth. Specific methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure.

All publications cited herein are hereby incorporated by reference including all journal articles, books, manuals, published patent applications, and issued patents. In addition, the meaning of certain terms and phrases employed in the specification, examples, and appended claims are provided. The definitions are not meant to be limiting in nature and serve to provide a clearer understanding of certain aspects 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.

The terms “patient,” “subject,” or “host” are used interchangeably herein, and refer 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.

As used herein, the terms “treatment,” “treating,” “treat” and the like, refer 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.

As used herein, 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. As would be appreciated by one of ordinary skill in the art, 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.

The pharmaceutical 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. The term “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).

As used herein, the term “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).

Other 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. In an embodiment, the pharmaceutical composition can comprise a Janus protein tyrosine kinase 1 (JAK1) inhibitor. The present disclosure also provides use of a JAK1 inhibitor for treating Type 1 diabetes and/or preventing Type 1 diabetes. In one embodiment, 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. In an embodiment, the JAK1 inhibitor is abrocitinib.

The pharmaceutical 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.

In a specific embodiment, 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.

The pharmaceutical 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. In certain embodiments, 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. In certain embodiments, the route of administration for the present pharmaceutical compositions may be oral. In some embodiments, 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, can be administered to a patient at a single daily dose or twice daily dose. In an embodiment, the total daily dosage of a JAK1 inhibitor, for example abrocitinib, administered to a patient can be about 40 mg to about 300 mg. In a specific embodiment, the abrocitinib is administered in a total daily amount of about 150 mg to about 250 mg. In another embodiment, the abrocitinib is administered in a total daily amount of about 200 mg. In other embodiments, 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, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg. In one embodiment, the dosage of abrocitinib can be about 200mg daily.

In other embodiments, the present pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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 about 4 months, for about 5 months, for about 6 months, for about 7 months, for about 8 months, for about 9 months, for about 10 months, for about 11 months, for about 12 months, for about 1 year, for about 2 years, for about 3 years, for about 4 years or for about 5 years. In an embodiment, the JAK1 inhibitor, for example abrocitinib, can be administered to a patient indefinitely.

In a specific embodiment, the JAK1 inhibitor, for example abrocitinib, 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. In a specific embodiment, the JAK1 inhibitor, for example abrocitinib, 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 200 mg total for up to 8 to 52 weeks or indefinitely.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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 30 days, or every other day for about 31 days or more.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, 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. In certain embodiments, the pharmaceutical compositions comprising a JAK1 inhibitor, for example abrocitinib, can be administered in 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. In an embodiment, 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.

In an embodiment, methods of treating and/or preventing Type 1 diabetes are provided, wherein the methods can comprise 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. In an embodiment, the additional therapy can comprise insulin.

In an embodiment, during the duration of the treatment comprising a JAK1 inhibitor, for example abrocitinib, 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.

In an embodiment, 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.

In an embodiment, methods for the treatment and/or prevention of Type 1 diabetes comprising a JAK1 inhibitor, for example abrocitinib, can comprise the patient or subject is free of, or substantially free of one or more of the following criteria: (i) current or ongoing use of noninsulin pharmaceuticals or medication that affect glycemic control or glucose homeostasis within prior seven days of screening; (ii) untreated hypothyroidism or active Graves’ disease; (iii) concurrent treatment with one or more immunosuppressive agents; (iv) active acute or chronic infection requiring treatment with oral antibiotics, antivirals, antiparasitics, antiprotozoals, or antifimgals within four (4) weeks prior to Day 0 or superficial skin infection within one (1) week prior to Day 0; (v) significant trauma or major surgery within one (1) month of signing informed consent; (vi) considered in imminent need for surgery or with elective surgery scheduled to occur during treatment; (vii) history of disseminated herpes zoster, disseminated herpes simplex or a recurrent (more than one episode of) localized, dermatomal herpes zoster; (viii) prior or current tuberculosis infection as assessed by purified protein derivative (PPD) test, interferon gamma release assay or by history; (ix) current or past HIV, Hepatitis B infection; (x) active Hepatitis C infection; (xi) COVID-19 infection; (xii) history of thromboembolic events comprising one or more of DVT, PE and inherited coagulopathies; (xiii) any present malignancies or history of malignancies; (xiv) history of any lymphoproliferative disorder comprising one or more of Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, history of leukemia, and signs and symptoms suggestive of current lymphatic or lymphoid disease; (xv) one or more of the following screening laboratory values: (a) Leukocytes < 3,000/pL; (b) Neutrophils <1,500 / pL; (c) Lymphocytes <800 /pL; (d) Platelets <100,000 /pL; (e) Haemoglobin <6.2 mmol/L (10.0 g/dL); (f) Potassium >5.5 mmol/L or <3.0 mmol/L; (g) Sodium >150mmol/L or < 130mmol/L; (h) AST or ALT >2.5 times the upper limits of normal; (i) Bilirubin > 1.5 times upper limit of normal; and (j) any other laboratory abnormality that might, in the judgment of the investigator, place the subject at unacceptable risk for participation in this trial; (xvi) vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks, except 2 weeks for flu vaccine; (xvii) currently pregnant, lactating, or anticipate getting pregnant within the duration of the treatment; (xviii) currently participating in another type 1 diabetes treatment regimen; (xix) patient or subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the trial; (xx) any complicating medical issues or abnormal clinical laboratory results that may interfere with the treatment or cause increased risk; (xxi) any condition that adversely affects the treatment or may compromise the treatment results; and (xxii) currently smoking or history of smoking. The target patient population of the present pharmaceutical compositions and methods may include different or additional criteria.

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. In an embodiment, 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. In one embodiment, 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. In an embodiment, the JAK3/TEC inhibitor is ritlecitinib.

In a specific embodiment, 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.

The pharmaceutical 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. In certain embodiments, 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. In certain embodiments, the route of administration for the present pharmaceutical compositions may be oral.

In some embodiments, 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.

The present disclosure provides methods for the treatment of Type 1 diabetes. The JAK3/TEC inhibitor, for example ritlecitinib, can be administered to a patient at a single daily dose or twice daily dose. In an embodiment, the total daily dosage of a JAK3/TEC inhibitor, for example ritlecitinib, administered to a patient can be about 50mg to about 200 mg. In a specific embodiment, the ritlecitinib is administered in a total daily amount of about 50 mg to about 150 mg. In another embodiment, the ritlecitinib is administered in a total daily amount of about 100 mg. In other embodiments, 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. In one embodiment, the dosage of ritlecitinib can be about lOOmg daily.

In other embodiments, the present pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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 about 4 months, for about 5 months, for about 6 months, for about 7 months, for about 8 months, for about 9 months, for about 10 months, for about 11 months, for about 12 months, for about 1 year, for about 2 years, for about 3 years, for about 4 years or for about 5 years. In an embodiment, the JAK3/TEC inhibitor, for example ritlecitinib, can be administered to a patient indefinitely.

In a specific embodiment, the JAK3/TEC inhibitor, for example ritlecitinib, 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. In a specific embodiment, the JAK3/TEC inhibitor, for example ritlecitinib, 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 100 mg total for up to 8 to 52 weeks or indefinitely.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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 30 days, or every other day for about 31 days or more.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In other embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In certain embodiments, the pharmaceutical compositions comprising a JAK3/TEC inhibitor, for example ritlecitinib, can be administered in 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. In an embodiment, 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.

In an embodiment, methods of treating and/or preventing Type 1 diabetes are provided, wherein the methods can comprise 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. In an embodiment, the additional therapy can comprise insulin.

In an embodiment, during the duration of the treatment comprising a JAK3/TEC inhibitor, for example ritlecitinib, 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.

In an embodiment, 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.

In an embodiment, methods for the treatment and/or prevention of Type 1 diabetes comprising a JAK3/TEC inhibitor, for example ritlecitinib, can comprise the patient or subject is free of, or substantially free of one or more of the following criteria: (i) current or ongoing use of non-insulin pharmaceuticals or medication that affect glycemic control or glucose homeostasis within prior seven days of screening; (ii) untreated hypothyroidism or active Graves’ disease; (iii) concurrent treatment with one or more immunosuppressive agents; (iv) active acute or chronic infection requiring treatment with oral antibiotics, antivirals, antiparasitics, antiprotozoals, or antifimgals within four (4) weeks prior to Day 0 or superficial skin infection within one (1) week prior to Day 0; (v) significant trauma or major surgery within one (1) month of signing informed consent; (vi) considered in imminent need for surgery or with elective surgery scheduled to occur during treatment; (vii) history of disseminated herpes zoster, disseminated herpes simplex or a recurrent (more than one episode of) localized, dermatomal herpes zoster; (viii) prior or current tuberculosis infection as assessed by purified protein derivative (PPD) test, interferon gamma release assay or by history; (ix) current or past HIV, Hepatitis B infection; (x) active Hepatitis C infection; (xi) COVID-19 infection; (xii) history of thromboembolic events comprising one or more of DVT, PE and inherited coagulopathies; (xiii) any present malignancies or history of malignancies; (xiv) history of any lymphoproliferative disorder comprising one or more of Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, history of leukemia, and signs and symptoms suggestive of current lymphatic or lymphoid disease; (xv) one or more of the following screening laboratory values: (a) Leukocytes < 3,000/pL; (b) Neutrophils <1,500 / pL; (c) Lymphocytes <800 /pL; (d) Platelets <100,000 /pL; (e) Haemoglobin <6.2 mmol/L (10.0 g/dL); (f) Potassium >5.5 mmol/L or <3.0 mmol/L; (g) Sodium >150mmol/L or < 130mmol/L; (h) AST or ALT >2.5 times the upper limits of normal; (i) Bilirubin > 1.5 times upper limit of normal; and (j) any other laboratory abnormality that might, in the judgment of the investigator, place the subject at unacceptable risk for participation in this trial; (xvi) vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks, except 2 weeks for flu vaccine; (xvii) currently pregnant, lactating, or anticipate getting pregnant within the duration of the treatment; (xviii) currently participating in another type 1 diabetes treatment regimen; (xix) patient or subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the trial; (xx) any complicating medical issues or abnormal clinical laboratory results that may interfere with the treatment or cause increased risk; (xxi) any condition that adversely affects the treatment or may compromise the treatment results; and (xxii) currently smoking or history of smoking.

Without further elaboration, it is believed that one skilled in the art, using the preceding description, can utilize the present disclosure to the fullest extent. The following examples are illustrative only, and not limiting of the remainder of the disclosure in any way whatsoever.

STUDIES AND EXAMPLES

The following studies and examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and/or methods described and claimed herein are made and evaluated and are intended to be purely illustrative and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for herein. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Celsius or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process.

STUDY 1 - Cyclophosphamide-accelerated diabetes study in NOD mice

The compounds used in Study 1 are surrogate compounds to abrocitinib and 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.

When referenced in this disclosure, PF-06263313 refers to the compound 1-

((3aR,7aR)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)prop-

2-en-l-one with the following structure:

exemplary synthesis of PF-

06263313 can be found, for example, in PCT Publication No. WO2015083028, published on June

11, 2015, which is incorporated herein by reference.

When referenced in this disclosure, PF-06667291 or PF-7291 refers to the compound

!-(((( Is, 3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl)methyl)sulfonyl)azetidine-3-carbonitrile with the following structure:

. An exemplary synthesis of PF-06667291 (or PF-7291) can be found, for example, in Canadian Patent Application No. 2899888, published on February 12, 2016, which is incorporated herein by reference.

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. When referenced in this disclosure, 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 >500um² 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), and 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 and 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.

In summary, 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. Spleen cytometry: cyclophosphamide exposure resulted in profound alteration of lymphocyte subsets- depression of Tregs has been suggested to be one of the most important for development of diabetes; and PF-06263313 and PF- 06667291 selectively and differentially reverse some of these changes, suggesting different MOA. Ex vivo antigen re-stimulation: 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.

STUDY 2 - Cyclophosphamide-accelerated diabetes study in NOD mice

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.

Conclusions from Study 2 include the following: disease Incidence: 70%; no diabetes in animals treated with FTY720; and no difference in diabetes development between vehicle- treated and untreated group and may lead to the conclusion that oral BID dosing does not have an impact on disease development. Study 3 - Cyclophosphamide-accelerated diabetes study in NOD mice

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.

Conclusions from Study 3 include the following: BID vehicle dosing reduces disease incidence relative to untreated mice; significantly lower blood glucose levels in mice with all treatments than in vehicle-treated mice; comparable to study 1.

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.

Conclusion

While the present disclosure has been discussed in terms of certain embodiments, it should be appreciated that the present disclosure is not so limited. The embodiments are explained herein by way of example, and there are numerous modifications, variations and other embodiments that may be employed that would still be within the scope of the present disclosure.

It is to be understood that the disclosed subject matter is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The disclosed subject matter is capable of other embodiments and of being practiced and carried out in various ways. The examples set forth in this document are for illustrative purposes and all elements of the example may not be required or exhaustive. Accordingly, other implementations are within the scope of the following claims. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods, and systems for carrying out the several purposes of the disclosed subject matter. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the disclosed subject matter. Although the disclosed subject matter has been described and illustrated in the foregoing exemplary embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the disclosed subject matter may be made without departing from the spirit and scope of the disclosed subject matter. For example, the steps and/or limitations in the specification, drawings, and/or claims may be performed in an order other than the order set forth in the specification, drawings, and/or claims .

In addition, it should be understood that any figures which highlight the functionality and advantages are presented for example purposes only. The disclosed methodology and system are each sufficiently flexible and configurable such that they may be utilized in ways other than that shown. For example, other steps may be provided, or steps may be eliminated, from the described flows, and other components may be added to, or removed from, the described systems.

Although the term “at least one” may often be used in the specification, claims and drawings, the terms “a”, “an”, “the”, “said”, etc. also signify “at least one” or “the at least one” in the specification, claims and drawings. Finally, it is the applicant's intent that only claims that include the express language

"means for" or "step for" be interpreted under 35 U.S.C. 112(f). Claims that do not expressly include the phrase "means for" or "step for" are not to be interpreted under 35 U.S.C. 112(f) .

Claims

1. A method 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.

2. A method for the treatment or prevention of Type 1 diabetes, comprising: administering to a subject in need thereof a JAK1 inhibitor, wherein the JAK1 inhibitor is administered in an amount of about 40 mg to about 300 mg.

3. The method of claim 1 or 2, wherein the JAK1 inhibitor is abrocitinib.

4. The method of claim 3, wherein abrocitinib is administered in an amount of about 150 mg to about 250 mg.

5. The method of claim 4, wherein abrocitinib is administered in an amount of about 200 mg.

6. The method of claim 4, wherein abrocitinib is administered orally in a single daily dose or a twice daily dose.

7. The method of claim 4, wherein abrocitinib is administered for up to 8 weeks, 12 months or 52 weeks or indefinitely.

8. The method of claim 4, wherein, during the duration of the treatment, the 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.

9. A method for the treatment or prevention of Type 1 diabetes, comprising: administering to a patient or subject in need a therapeutically effective amount of an JAK3/TEC inhibitor.

10. A method for the treatment or prevention of Type 1 diabetes, comprising: administering to a subject in need thereof a JAK3/TEC inhibitor, wherein the JAK3/TEC inhibitor is administered in an amount of about 50 mg to about 200 mg.

11. The method of claim 9 or 10, wherein the JAK3/TEC inhibitor is ritlecitinib.

12. The method of claim 11, wherein ritlecitinib is administered in an amount of about 50 mg to about 200 mg.

13. The method of claim 12, wherein ritlecitinib is administered in an amount of about 100 mg.

14. The method of claim 12, wherein ritlecitinib is administered orally in a single daily dose or a twice daily dose.

15. The method of claim 11, wherein ritlecitinib is administered for up to 8 weeks, 12 months or 52 weeks or indefinitely.

16. The method of claim 11, wherein, during the duration of the treatment, the 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.

17. A method of treating and/or preventing Type 1 diabetes, comprising: administering to a patient or subject a therapeutically effective amount of abrocitinib, wherein abrocitinib is administered orally at a single or twice daily dose of about 200 mg total.

18. A method of treating and/or preventing Type 1 diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of ritlecitinib, wherein ritlecitinib is administered orally at a single or twice daily dose of about 100 mg total.

19. Use of a JAK1 inhibitor for treating and/or preventing Type 1 diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of abrocitinib.

20. Use of a JAK3/TEC inhibitor for treating and/or preventing Type 1 diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of ritlecitinib.

21. A method of determining whether a patient or subject is a candidate for a treatment recited in claims 1-20 or receives ongoing treatment recited in claims 1-20, comprising 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.

22. A method of treating and/or preventing Type 1 diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of abrocitinib and an additional therapy, wherein abrocitinib is administered orally at a single or twice daily dose of about 40 mg to about 300 mg total.

23. The method of claim 22, wherein the additional therapy is insulin.

24. The method of claim 23, wherein abrocitinib is administered orally in a single daily dose or a twice daily dose in a total amount of about 200 mg.

25. A method of treating and/or preventing Type 1 diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of ritlecitinib and an additional therapy, wherein ritlecitinib is administered orally at a single or twice daily dose of about 50 mg to about 200 mg total.

26. The method of claim 25, wherein the additional therapy is insulin.

27. The method of claim 26, wherein ritlecitinib is administered orally at a single or twice daily dose of about 100 mg total.