US20190046527A1 - Methods of treating crohn's disease and ulcerative colitis - Google Patents

Methods of treating crohn's disease and ulcerative colitis Download PDF

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US20190046527A1
US20190046527A1 US15/917,013 US201815917013A US2019046527A1 US 20190046527 A1 US20190046527 A1 US 20190046527A1 US 201815917013 A US201815917013 A US 201815917013A US 2019046527 A1 US2019046527 A1 US 2019046527A1
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weeks
patient
pharmaceutically acceptable
acceptable salt
pyrazin
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Roopal B. Thakkar
Steven JUNGERWIRTH
Ana Paula Machado de LACERDA
Anne M. ROBINSON
Jose Jeffrey V. ENEJOSA
Aileen L. Pangan
Mohamed-Eslam F. Mohamed
Ahmed A. Othman
Ben Klünder
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AbbVie Inc
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Assigned to AbbVie Deutschland GmbH & Co. KG reassignment AbbVie Deutschland GmbH & Co. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KLÜNDER, BEN
Assigned to ABBVIE INC. reassignment ABBVIE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AbbVie Deutschland GmbH & Co. KG
Publication of US20190046527A1 publication Critical patent/US20190046527A1/en
Assigned to ABBVIE INC. reassignment ABBVIE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NORDSTROM, FREDRIK LARS, ALLIAN, AYMAN D., MARROUM, Patrick J., MAYER, PETER T., MULHERN, MATHEW M., SHEIKH, AHMAD Y., BORCHARDT, THOMAS B., JAYANTH, JAYANTHY
Priority to US17/115,833 priority patent/US20210361647A1/en
Priority to US17/712,008 priority patent/US11607411B2/en
Priority to US17/732,070 priority patent/US11564922B2/en
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present disclosure is directed to methods for treating inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, and in particular, to methods for inducing clinical remission and endoscopic improvement of Crohn's disease or a clinical remission and endoscopic improvement of ulcerative colitis, using a JAK1 inhibitor.
  • the patient is administered an induction dose of the JAK1 inhibitor to induce clinical remission and/or endoscopic improvement of the Crohn's disease or a clinical remission of ulcerative colitis, followed by administration of at least one maintenance dose of the JAK inhibitor thereafter.
  • IBD Inflammatory bowel disease
  • IBD involves chronic inflammation of a patient's digestive tract. IBD includes both Crohn's disease and ulcerative colitis. The exact cause of IBD is not known.
  • the IBD can be idiopathic IBD.
  • CD Crohn's Disease
  • CD has been characterized by significant morbidity including abdominal pain, diarrhea, weight loss/malnutrition, fatigue and a progressive nature that leads to complications such as fistulas, strictures and abscesses.
  • a substantial number of patients demonstrated a structuring or penetrating phenotype at 10 years after diagnosis (Solberg I C, Vatn M H, Hoie O, et al; IBSEN Study Group. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Heptaol. 2007; 5(12):1430-8).
  • UC Ulcerative colitis
  • IBD idiopathic inflammatory bowel disease
  • UC ulcerative colitis
  • Extraintestinal complications include arthritis (peripheral or axial involvement), dermatological conditions (erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum), inflammation of the eye (uveitis), and liver dysfunction (primary sclerosing cholangitis).
  • Patients with UC are at an increased risk for colon cancer, and the risk increases with the duration of disease as well as extent of colon affected by the disease.
  • Rutter M Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. ( Gastroenterology, 2004; 126(2):451-9).
  • the aim of medical treatment in UC is to control inflammation and reduce symptoms.
  • Available pharmaceutical therapies are limited, do not always completely abate the inflammatory process, and may have significant adverse effects.
  • Therapies for mild to moderate active UC include 5-aminosalicylic acid derivatives and immunosuppressants.
  • Corticosteroids are used in patients with more severe UC symptoms but are not useful for longer term therapy. (Truelove S C, Witts L J, Cortisone and corticotrophin in ulcerative colitis. Br Med J. 1959; 1(5119):387-94). The frequency and severity of corticosteroid toxicities are significant, including infections, emotional and psychiatric disturbances, skin injury, and metabolic bone disease. Corticosteroids are not effective for the maintenance of remission and the UC practice guidelines from the American College of Gastroenterology recommend against chronic steroid treatment. (Kornbluth A, Sachar D B; Practice Parameters Committee of the American College of Gastroenterology.
  • Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for IBD.
  • Infliximab, adalimumab, and golimumab are successfully being used for the treatment of UC.
  • vedolizumab an anti-adhesion therapy, has been approved for the treatment of UC by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and clinical development is ongoing in Japan.
  • FDA US Food and Drug Administration
  • EMA European Medicines Agency
  • Anti-TNF therapies are an effective treatment for patients who are steroid refractory or steroid dependent, who had inadequate response to a thiopurine, or who are intolerant to these medications.
  • Potential risks with anti-TNF therapies include infusion or injection site reactions, serious infections, lymphoma, heart failure, lupus-like syndromes, and demyelinating conditions (Sandborn W J. State-of-the-art: immunosuppression and biologic therapy. Dig Dis. 2010; 28(3):536-42).
  • Despite the beneficial results achieved with the available biologic agents only 17% to 45% of patients who receive them are able to achieve clinical remission.
  • the therapeutic strategy is to reduce symptoms, improve quality of life, reduce endoscopic evidence of inflammation, and minimize short- and long term toxicity and complications (Lichtenstein G R, Hanauer S B, Sandborn W J; Practice Parameters Committee of American College of Gastroenterology, Management of Crohn's disease in adults. Am J Gastroenterol., 2009, 104(2):465-83).
  • Adverse events (AEs) associated with short-term use of corticosteroids include acne, moon face, edema, skin striae, glucose intolerance, and sleep/mood disturbances, while potential AEs observed with longer term use (usually 12 weeks or longer but sometimes shorter durations) include posterior subcapsular cataracts, osteoporosis, osteonecrosis of the femoral head, myopathy, and susceptibility to infection (Irving P M, Gearry R B, Sparrow M P, et al., Review article: appropriate use of corticosteroids in Crohn's disease, Aliment Pharmacol Ther., 2007, 26(3):313-29; Rutgeerts P J, Review article: the limitations of corticosteroid therapy in Crohn's disease, Aliment Pharmacol Ther., 2001, 15(10):1515-25).
  • azathioprine and 6-mercaptopurine include pancreatitis, bone marrow depression, infectious complications, and malignant neoplasms (Sandborn, W J, State-of-the-art: immunosuppression and biologic therapy, Dig Dis., 2010, 28(3):536-42).
  • MTX may be associated with nausea, bone marrow depression and liver and pulmonary toxicity (Siegel, et al., Review article: Practical Management of Inflammatory Bowel Disease Patients Taking Immunosuppressants. Aliment Pharmacol Ther., 2005, 22:1-16).
  • Natalizumab a humanized monoclonal antibody to ⁇ 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrins, showed promise for patients with prior exposure to anti-TNF- ⁇ therapy; more than half of the patients had a response to the induction regimen (Sandborn, et al., “Natalizumab induction and maintenance therapy for Crohn's disease,” N. Engl. J. Med., 2005, 353(18):1912-25).
  • PML progressive multifocal leukoencephalopathy
  • Vedolizumab is specific to the ⁇ 4 ⁇ 7 integrin, which does not affect lymphocyte trafficking to the brain. Therefore, it is presumed to not have the PML risk associated with natalizumab. However, it does not fulfill many of the unmet needs of patients who have failed treatment with anti-TNFs, such as the improvement of extra-intestinal manifestations (Rubin, et al., Inflammatory Bowel Diseases, 2016, 22 Suppl. 1:S42-S43).
  • the present disclosure addresses the above needs and provides methods for treating Crohn's disease and ulcerative colitis.
  • the present disclosure provides methods for treating Crohn's disease in patients that have moderately to severely active Crohn's disease.
  • the present disclosure provides methods for treating ulcerative colitis in patients that have moderately to severely active ulcerative colitis.
  • the patient may have had an inadequate response to or experienced intolerance to conventional treatment, such as aminosalicylates, corticosteroids or immunosuppressants, or to a previous treatment with an anti-TNF therapy or another biologic agent.
  • the patient is an adult with moderately to severely active Crohn's disease and has had an inadequate response to, or were intolerant to, corticosteroid, immunomodulator, or biologic therapy.
  • the present disclosure is directed to a method of inducing clinical remission of Crohn's disease in a patient, said method comprising: a) administering to the patient at least one induction dose of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib), or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method further comprises maintaining the clinical remission of Crohn's disease, wherein the method further comprises b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose once daily thereafter.
  • the present disclosure is directed to a method of inducing endoscopic improvement of Crohn's disease in a patient, said method comprising: a) administering to the patient at least one induction dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method further comprises maintaining the endoscopic improvement of Crohn's disease, wherein the method further comprises b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose once daily thereafter.
  • the present disclosure is directed to a method of inducing clinical remission of Crohn's disease in a patient, said method comprising: a) administering to the patient at least one induction dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable or solid state form salt thereof.
  • the method further comprises maintaining the clinical remission of Crohn's disease, wherein the method further comprises b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose once daily thereafter.
  • the present disclosure is directed to a method of inducing endoscopic remission of Crohn's disease in a patient, said method comprising: a) administering to the patient at least one induction dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method further comprises maintaining the endoscopic remission of Crohn's disease, wherein the method further comprises b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose once daily thereafter.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with a corticosteroid, an immunosuppressant, or a biologic agent. In one embodiment, the patient had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent. In one embodiment, the patient had moderately to severely active Crohn's disease prior to administration of the induction dose.
  • the induction dose is administered orally to the patient. In one embodiment, the induction dose is administered once daily to the patient.
  • clinical remission is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, clinical remission is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • endoscopic improvement is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, endoscopic improvement is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • clinical remission is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, clinical remission is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • endoscopic remission is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, endoscopic remission is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient's Simplified Endoscopic Score for Crohn's Disease is greater than a 50% decrease or endoscopic remission versus the patient's baseline SES-CD. In one embodiment, after administration of at least one induction dose, the patient's Simplified Endoscopic Score for Crohn's Disease (SES-CD) is at least a 2 point reduction versus the patient's baseline SES-CD. In one embodiment, after administration of at least one induction dose, the patient achieves an endoscopic remission. In one embodiment, after administration of at least one induction dose, the patient achieves a clinical response. In one embodiment, the patient achieves a clinical response as early as two weeks from the first induction dose. In one embodiment, after administration of at least one induction dose, the patient achieves a CDAI score of less than 150.
  • the first maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the first maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the at least one additional maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the at least one additional maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • first maintenance dose and said at least one additional maintenance dose are administered orally. In one embodiment, the first maintenance dose and said at least one additional maintenance dose are administered once daily.
  • the patient maintains clinical remission. In one embodiment, the patient maintains endoscopic improvement. In one embodiment, the patient maintains endoscopic remission.
  • the patient maintains a Simplified Endoscopic Score for Crohn's Disease (SES-CD) that is greater than a 50% decrease or endoscopic remission versus the patient's baseline SES-CD. In one embodiment, the said patient maintains a Simplified Endoscopic Score for Crohn's Disease (SES-CD) that is at least a 2 point reduction versus the patient's baseline SES-CD. In one embodiment, the patient maintains an endoscopic remission. In one embodiment, the patient maintains a CDAI score of less than 150. In one embodiment, the patient maintains a clinical response.
  • SES-CD Simplified Endoscopic Score for Crohn's Disease
  • SES-CD Simplified Endoscopic Score for Crohn's Disease
  • CDAI score of less than 150. In one embodiment, the patient maintains a clinical response.
  • the patient achieves a CDAI score of less than 150 before administration of the first maintenance dose. In one embodiment, the patient achieves a clinical response before administration of the first maintenance dose.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • the first maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • the at least one additional maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • the first maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • the at least one additional maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily.
  • the induction dose is in a once-daily, modified release formulation.
  • the first maintenance dose and the at least one additional maintenance dose are each in a once-daily, modified release formulation.
  • the present disclosure is directed to a method for treating Crohn's disease comprising administering to a patient 15 mg to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method comprising administering 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method comprising administering 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method comprising administering 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof is administered orally to the patient. In one embodiment, upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof is administered once daily to the patient.
  • the present disclosure is directed to a method for treating Crohn's disease comprising: a) administering to a patient at least one induction dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method further comprises b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose to the patient once daily thereafter.
  • the first maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the first maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the first maintenance dose is administered orally.
  • the at least one additional maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment the at least one additional maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the at least one additional maintenance dose is administered orally.
  • the patient maintains a CDAI score of less than 150.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with a corticosteroid, an immunosuppressant, or a biologic agent. In one embodiment, the patient had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the patient achieves a clinical remission after administration of at least one induction dose. In one embodiment, the patient achieves an endoscopic improvement after administration of at least one induction dose. In one embodiment, the patient achieves an endoscopic remission after administration of at least one induction dose. In one embodiment, the patient achieves a clinical response after administration of at least one induction dose.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • said first maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • said at least one additional maintenance dose comprises 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • said first maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily
  • said at least one additional maintenance dose comprises 15 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, administered orally once daily.
  • the induction dose is in a once-daily, modified release formulation.
  • the first maintenance dose and the at least one additional maintenance dose are each in a once-daily, modified release formulation.
  • the patient had moderately to severely active Crohn's disease prior to administration of the induction dose.
  • the present disclosure is directed to a method of inducing remission in a patient having moderately to severely active Crohn's disease, the method comprising administering 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof, to the patient.
  • the patient had an inadequate response to or was intolerant to aminosalicylates, corticosteroids, immunosuppressants, biologic agents, anti-TNF agents, or combinations thereof.
  • the present disclosure is directed to a method of inducing clinical remission in a patient having moderately to severely active Crohn's disease the method comprising administering 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof, to the patient.
  • the patient had an inadequate response to or was intolerant to aminosalicylates, corticosteroids, immunosuppressants, biologic agents, anti-TNF agents, or combinations thereof.
  • the present disclosure is directed to a method of inducing endoscopic improvement in a patient having moderately to severely active Crohn's disease the method comprising administering 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof to the patient.
  • the patient had an inadequate response to or was intolerant to aminosalicylates, corticosteroids, immunosuppressants, biologic agents, anti-TNF agents, or combinations thereof.
  • the present disclosure is directed to a method of treating a refractory patient having moderately to severely active Crohn's disease the method comprising administering 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, to the patient.
  • clinical remission is induced within 16 weeks of administering the initial dose of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • endoscopic improvement is induced within 12 weeks or within 16 weeks of administering the initial dose of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction dose comprises 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the first maintenance dose and/or the at least one additional maintenance doses comprise 15 mg to 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure is directed to a method of inducing a clinical response in a patient with moderately to severely active ulcerative colitis, said method comprising: a) administering to the patient at least one induction dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein said induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical response is a clinical response is wherein the patient has a decrease from a baseline Adapted Mayo score greater than or equal to 2 points and greater than or equal to 30% accompanied by a decrease in rectal bleeding subscore of greater than or equal to 1 or an absolute rectal bleeding subscore of 0 or 1.
  • the clinical response is a clinical response is wherein the patient has a decrease from a baseline Full Mayo score greater than or equal to 3 points and greater than or equal to 30% accompanied by a decrease in rectal bleeding subscore from baseline of greater than or equal to 1 or an absolute rectal bleeding subscore of 0 or 1.
  • the method further comprising maintaining the clinical response, said method further comprising: b) administering a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose once daily thereafter.
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the first maintenance dose and/or the at least one additional maintenance dose comprises 15 mg to 30 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the method of the present disclosure is a method of inducing clinical remission of Crohn's disease in a patient, the method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 12 weeks of administration of the first induction dose.
  • clinical remission of Crohn's disease is induced within 4 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing clinical response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 2 weeks and comprises 45 mg of upadacitinib or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical response.
  • the clinical response of Crohn's disease is induced within 4 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the clinical response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing endoscopic remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 12 weeks of administration of the first induction dose.
  • the endoscopic remission of Crohn's disease is induced within 4 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the endoscopic remission of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing endoscopic response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic response within 12 weeks of administration of the first induction dose.
  • the endoscopic response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing corticosteroid-free remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves steroid-free remission within 4 weeks of administration of the first induction dose.
  • the patient is an adult with moderately to severely active Crohn's disease.
  • the patient experiences a CDAI reduction of greater than 150 within 12 weeks of administration of the first induction dose.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with a corticosteroid, an immunosuppressant, or a biologic agent.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the patient had an inadequate response to or experienced intolerance to an infliximab, adalimumab or certolizumab pegol.
  • the patient has had a diagnosis of Crohn's disease for more than ten years and has had an inadequate response to or experienced intolerance to one or more previous treatments.
  • the previous treatments are selected from the group consisting of corticosteroids, immunosuppressants, antibiotics and biologic therapies.
  • the method comprises a method of inducing and maintaining clinical remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 12 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically
  • the method comprises a method of inducing and maintaining clinical response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 2 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical response within 2 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically
  • the clinical response of Crohn's disease is induced within 4 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the clinical response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method comprises a method of inducing and maintaining endoscopic remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 12 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib
  • the endoscopic remission of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing and maintaining endoscopic response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic response within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a
  • the endoscopic response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing and maintaining corticosteroid-free remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves steroid-free remission within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered and; d) administering at least one additional maintenance dose to the patient of
  • the patient is an adult with moderately to severely active Crohn's disease.
  • the patient experiences improvement in stool frequency one week after the first induction dose. In one embodiment the patient experiences improvement in abdominal pain at 8 weeks after the first induction dose.
  • the patient experiences a CDAI reduction of greater than 150 within 12 weeks of administration of the first induction dose.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with a corticosteroid, an immunosuppressant, or a biologic agent.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the anti-TNF agent is infliximab, adalimumab or certolizumab pegol.
  • the patient has had a diagnosis of Crohn's disease for more than ten years and has had an inadequate response to or experienced intolerance to a previous treatment.
  • the previous treatments are selected from corticosteroids, immunosuppressants, antibiotics and biologic therapies.
  • the method is a method of inducing and maintaining clinical remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or
  • the method is a method of inducing and maintaining clinical response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 2 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical response within 2 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically acceptable
  • the clinical response of Crohn's disease is induced within 4 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the clinical response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing and maintaining endoscopic remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib
  • the method is a method of inducing and maintaining endoscopic remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib
  • the endoscopic remission of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing and maintaining endoscopic response of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic response within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutical
  • the endoscopic response of Crohn's disease is induced within 12 weeks of the first induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof.
  • the method is a method of inducing and maintaining corticosteroid-free remission of Crohn's disease in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves steroid-free remission within 12 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered and; d) administering at least one additional maintenance dose to the patient of
  • the patient is an adult with moderately to severely active Crohn's disease.
  • the patient experiences a CDAI reduction of >150 within 12 weeks of administration of the first induction dose.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with a corticosteroid, an immunosuppressant, or a biologic agent.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the patient had an inadequate response to or experienced intolerance to a previous treatment anti-TNF agent is infliximab, adalimumab or certolizumab pegol.
  • the patient has had a diagnosis of Crohn's disease for more than ten years and has had an inadequate response to or experienced intolerance to one or more previous treatment.
  • the method comprises a method wherein the previous treatments are selected from corticosteroids, immunodulators, antibiotics and biologic therapies.
  • the method comprises inducing clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 4 weeks of administration of the first induction dose.
  • the method comprises inducing clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 6 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 6 weeks of administration of the first 45 mg induction dose.
  • the method comprises inducing clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 8 weeks of administration of the first 45 mg induction dose.
  • the method comprises a method of inducing endoscopic improvement of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof, and b) wherein said patient achieves endoscopic improvement within 8 weeks of administration of the first induction dose.
  • the method comprises a method of inducing endoscopic remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 8 weeks of administration of the first 45 mg induction dose.
  • the patient has moderately to severely active ulcerative colitis.
  • the patient is taking corticosteroids at the time of the first induction dose.
  • the clinical remission, endoscopic improvement or endoscopic remission is corticosteroid free.
  • the patient demonstrated an inadequate response to, loss of response to or intolerance to one or more corticosteroids, immunosuppressants or biologic therapies.
  • the immunosuppressants are selected form oral azathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.
  • the biologic therapy is selected from infliximab, adalimumab, golimumab and vedolizumab.
  • the inadequate response in said patient taking corticosteroids is defined as said patient experiencing signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ⁇ 40 mg/day orally for 3 to 4 weeks or intravenously for one week.
  • the patient is unable to taper corticosteroid below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease.
  • the intolerance of said patient to corticosteroids leads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia, insominia or infection.
  • the patient experiencing the inadequate response to immunosuppressants experienced signs and symptoms of persistently active disease despite a history of at least one 90-day regimen of oral azathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.
  • the patient experiencing the inadequate response to immunosuppressants experienced nausea, vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia or infection.
  • the patient experiencing the inadequate response to biologic therapies experienced signs and symptoms of persistently active disease despite a history of a) at least one 6-week induction regimen of infliximab comprising a ⁇ 5 mg/kg intravenous dose at 0, 2 and 6 weeks; b) at least one 4-week induction regimen of adalimumab comprising one 160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose at least two weeks apart; c) at least one 2-week induction regimen of golimumab comprising one 200 mg subcutaneous dose followed by one 100 mg subcutaneous dose at least 2 weeks apart); d) at least one 6-week induction regimen of vedolizumab comprising a 300 mg intravenous dose at 0, 2 and 6 weeks.
  • the patient experiencing inadequate response to biologic therapies experienced recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit.
  • the patient experiencing intolerance to biologic therapies experienced infusion-related reaction, demyelination, congestive heart failure or infection.
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 4 weeks of administration of the first induction dose) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically acceptable
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 6 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 6 weeks of administration of the first 45 mg induction dose; and c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib,
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 8 weeks of administration of the first 45 mg induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib,
  • the method is inducing and maintaining endoscopic improvement of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic improvement within 8 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically acceptable salt thereof
  • the method comprises inducing and maintaining endoscopic remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 8 weeks of administration of the first 45 mg induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 30 mg of upadacitinib, or a 30 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutically
  • the method comprises inducing and maintaining endoscopic remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 8 weeks of administration of the first 45 mg induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or
  • the patient has moderately to severely active ulcerative colitis. In one embodiment the patient is an adult. In one embodiment, the patient has had an inadequate response corticosteroid, immunomodulatory or biologic therapy. In one embodiment, the patient has had loss of response to aminosalicylate, corticosteroid, immunomodulatory or biologic therapy. In one embodiment, the patient was intolerant to corticosteroid, immunomodulatory or biologic therapy. In one embodiment, the patient is an adult and has moderately to severely active ulcerative colitis and has had an inadequate response to, loss of response to, or was intolerant to aminosalicylate, corticosteroid, immunomodulatory (IMM), or biologic therapy.
  • IMM immunomodulatory
  • the patient is taking corticosteroids at the time of the first induction dose.
  • the clinical remission, endoscopic improvement or endoscopic remission is corticosteroid free.
  • the patient demonstrated an inadequate response to, loss of response to or intolerance to one or more corticosteroids, immunosuppressants or biologic therapies.
  • the immunosuppressants are selected form oral azathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.
  • the biologic therapy is selected from infliximab, adalimumab, golimumab and vedolizumab.
  • the inadequate response in said patient taking corticosteroids is defined as said patient experiencing signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone 240 mg/day orally for 3 to 4 weeks or intravenously for one week.
  • the patient is unable to taper corticosteroid below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease.
  • the intolerance of said patient to corticosteroids leads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia, insomnia or infection.
  • the patient experiencing the inadequate response to immunosuppressants experienced signs and symptoms of persistently active disease despite a history of at least one 90-day regimen of oral azathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.
  • the patient experiencing the inadequate response to immunosuppressants experienced nausea, vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia or infection.
  • the ulcerative colitis or Crohn's disease patient experiencing the inadequate response to biologic therapies experienced signs and symptoms of persistently active disease despite a history of a) at least one 6-week induction regimen of infliximab comprising a ⁇ 5 mg/kg intravenous dose at 0, 2 and 6 weeks; b) at least one 4-week induction regimen of adalimumab comprising one 160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose at least two weeks apart; c) at least one 2-week induction regimen of golimumab comprising one 200 mg subcutaneous dose followed by one 100 mg subcutaneous dose at least 2 weeks apart; d) at least one 6-week induction regimen of vedolizumab comprising a 300 mg intravenous dose at 0, 2 and 6 weeks.
  • the patient experiencing inadequate response to biologic therapies experienced recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit.
  • the patient experiencing intolerance to biologic therapies experienced infusion-related reaction, demyelination, congestive heart failure or infection.
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 4 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 6 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; b) wherein said patient achieves clinical remission within 6 weeks of administration of the first 45 mg induction dose; and c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or
  • the method is a method of inducing and maintaining clinical remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves clinical remission within 8 weeks of administration of the first 45 mg induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib,
  • the method is a method of inducing and maintaining endoscopic improvement of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic improvement within 8 weeks of administration of the first induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitinib, or a pharmaceutical
  • the method is a method of inducing and maintaining endoscopic remission of ulcerative colitis in a patient, said method comprising: a) administering to the patient an induction dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said induction dose is administered orally once a day for at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg free base equivalent amount of a pharmaceutically acceptable salt thereof; and b) wherein said patient achieves endoscopic remission within 8 weeks of administration of the first 45 mg induction dose; c) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt thereof, wherein said first maintenance dose is administered orally once a day and comprises 15 mg of upadacitinib, or a 15 mg free base equivalent amount of a pharmaceutically acceptable salt thereof after the last induction dose is administered; d) administering at least one additional maintenance dose to the patient of upadacitini
  • the patient has moderately to severely active ulcerative colitis.
  • the patient is taking corticosteroids at the time of the first induction dose.
  • the clinical remission, endoscopic improvement or endoscopic remission is corticosteroid free.
  • the patient demonstrated an inadequate response to, loss of response to or intolerance to one or more corticosteroids, immunosuppressants or biologic therapies.
  • the immunosuppressants are selected form oral azathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.
  • the biologic therapy is selected from infliximab, adalimumab, golimumab and vedolizumab.
  • the inadequate response in said patient taking corticosteroids is defined as said patient experiencing signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ⁇ 40 mg/day orally for 3 to 4 weeks or intravenously for one week.
  • the patient is unable to taper corticosteroid below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease.
  • the intolerance of said patient to corticosteroids leads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia, insomnia or infection.
  • the patient experiencing the inadequate response to immunosuppressants experienced signs and symptoms of persistently active disease despite a history of at least one 90-day regimen of oral azathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.
  • the patient experiencing the intolerance to immunosuppressants experienced nausea, vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia or infection.
  • the patient experiencing the inadequate response to biologic therapies experienced signs and symptoms of persistently active disease despite a history of a) at least one 6-week induction regimen of infliximab comprising a ⁇ 5 mg/kg intravenous dose at 0, 2 and 6 weeks; b) at least one 4-week induction regimen of adalimumab comprising one 160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose at least two weeks apart; c) at least one 2-week induction regimen of golimumab comprising one 200 mg subcutaneous dose followed by one 100 mg subcutaneous dose at least 2 weeks apart; d) at least one 6-week induction regimen of vedolizumab comprising a 300 mg intravenous dose at 0, 2 and 6 weeks.
  • the patient experiencing inadequate response to biologic therapies experienced recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit.
  • the patient experiencing intolerance to biologic therapies experienced infusion-related reaction, demyelination, congestive heart failure or infection.
  • FIG. 1 is a schematic representation of the study design for the clinical study described in Example 8.
  • FIG. 2 is a schematic representation of the 36 week extension phase for the clinical study described in Example 8. Patients who did not adequately respond during the double-blind portion of the extension phase were eligible to receive open-label therapy.
  • FIGS. 3A-3I are graphs depicting the relationship between upadacitinib plasma concentration and clinical response (Week 16; FIG. 3A ), (NRI) clinical remission (Week 16; FIG. 3B ), modified clinical remission (Week 16; FIG. 3C ); decrease in CDAI ⁇ 70 (Week 16; FIG. 3D ); decrease in CDAI ⁇ 100 (Week 16; FIG. 3E ); CDAI ⁇ 150 (Week 16; FIG. 3F ); endoscopic response (Week 12 or Week 16; FIG. 3G ); endoscopic improvement (Week 16; FIG. 3H ); and endoscopic remission (Week 12 or Week 16; FIG. 3I ) as determined in the Example 8 clinical study. Arrows indicate the median exposure (in mg) for each immediate release dose. The maximum and minimum plasma concentrations for each exposure bin are indicated in brackets.
  • FIGS. 4A-4F are graphs depicting the model-predicted efficacy (NRI) for different upadacitinib doses for immediate-release (IR) BID formulations or modified-release (MR) QD formulations (simulating for 200 patients/arm) at Weeks 12 or 16.
  • the predicted results are based on the exposure-response relationships as determined in the Example 8 study.
  • FIGS. 5A-5H are graphs depicting the relationship between upadacitinib plasma concentration and the change from baseline for select measured laboratory parameters at week 16 (LOCF) of the Example 8 clinical study. The maximum and minimum plasma concentrations for each data point are indicated in brackets.
  • FIGS. 6A and 6B are graphs depicting the percent of subjects who achieved clinical response or clinical remission at week 12 of the Example 8 study.
  • FIG. 6A shows results for subjects who were not on steroids at baseline
  • FIG. 6B shows results for subjects who were on steroids at baseline, and who underwent mandatory taper of steroid dose, starting at week 2 of the Example 8 clinical study.
  • FIG. 7 shows the upadacitinib mean plasma concentration versus time following administration of 6 mg twice daily immediate release capsules (Regimen K) or a 15 mg once-daily modified release tablet (Regimen L) for seven days under fasting conditions.
  • FIG. 8 shows the upadacitinib mean plasma concentration versus time following administration of 12 mg twice daily immediate release capsules (Regimen M) or a 30 mg once-daily modified release tablet (Regimen N) for seven days under fasting conditions.
  • FIG. 9 shows the clinical remission and endoscopic response in a refractory patient population administered upadacitinib or placebo in the Example 8 Crohn's disease clinical study.
  • FIGS. 10A-10E are graphs depicting the percentage of subjects who achieved modified clinical remission at week 2 ( FIG. 10A ), week 4 ( FIG. 10B ), week 8 ( FIG. 10C ), week 12 ( FIG. 10D ) and week 16 ( FIG. 10E ) of the Example 8 study.
  • FIGS. 11A-11E are graphs depicting the percentage of subjects who achieved enhanced clinical response at week 2 ( FIG. 11A ), week 4 ( FIG. 11B ), week 8 ( FIG. 11C ), week 12 ( FIG. 11D ) and week 16 ( FIG. 11E ) of the Example 8 study.
  • FIG. 12 shows the mean change in hs-CRP (percentage over baseline) versus time (weeks) following administration of placebo (PBO), upadacitinib at 3, 6, 12, 24 mg twice daily (BID) and 24 mg once daily (QD) for 16 weeks. Modified clinical remission was analyzed in patients with SF ⁇ 4. AP ⁇ 2.0 at baseline.
  • FIG. 13 is a schematic representation of the study design for the ulcerative colitis clinical study described in Example 12.
  • FIG. 14 schematically illustrates one method of preparing the Amorphous Freebase.
  • FIG. 15 schematically illustrates one method of preparing the Freebase Hydrate Form C.
  • FIG. 16 schematically illustrates one method of preparing the Tartrate Hydrate.
  • FIGS. 17A and 17B are powder X-ray diffraction patterns corresponding to the Amorphous Freebase (via precipitation) and the Amorphous Freebase (via dehydration), respectively.
  • FIG. 18 is a powder X-ray diffraction pattern corresponding to the Freebase Solvate Form A (Isopropyl Acetate/Water Solvate).
  • FIG. 19 is a powder X-ray diffraction pattern corresponding to the Freebase Hydrate Form B.
  • FIG. 20 is a powder X-ray diffraction pattern corresponding to the Freebase Hydrate Form C.
  • FIG. 21 is a powder X-ray diffraction pattern corresponding to the Tartrate Hydrate.
  • the experimental PXRD pattern is shown at the bottom of FIG. 21 and the calculated PXRD pattern is shown at the top of FIG. 21 .
  • FIG. 22 is a powder X-ray diffraction pattern corresponding to the Freebase Anhydrate Form D.
  • FIGS. 23A-23F are graphs depicting the exposure-response model-predicted efficacy for clinical and endoscopic endpoints for extended-release formulation QD regimens.
  • FIG. 23A is the percentage of subjects predicted to achieve clinical response at week 12;
  • FIG. 23B is the percentage of subjects predicted to achieve modified clinical remission at week 12;
  • FIG. 23C is the percentage of subjects expected to achieve CDAI remission at week 12;
  • FIG. 23D is the percentage of subjects predicted to achieve endoscopic response at week 12/16;
  • FIG. 23E is the percentage of patients predicted to achieve endoscopic improvement at week 12/16;
  • FIG. 23F is the percentage of patients predicted to achieve endoscopic remission at week 12/16.
  • each intervening number within the range is explicitly contemplated with the same degree of precision.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated.
  • all recited ratios also include all sub-ratios falling within the broader ratio.
  • Adapted Mayo or “Adapted Mayo score” when used in connection with ulcerative colitis refers to the Mayo Scoring System for Assessment of Ulcerative Colitis Activity, excluding the Physician's Global Assessment subscore.
  • adult refers to a person 16 years of age or older.
  • AE refers to adverse event
  • alkyl refers to straight chained or branched hydrocarbons which are completely saturated.
  • examples of alkyls include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and isomers thereof.
  • alkenyl refers to a hydrocarbon moiety containing two to eight carbons, including straight chained or branched hydrocarbons which contain one or more double bonds.
  • alkenyls are ethenyl, propenyl, and butenyl.
  • amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).
  • anhydrate as applied to a compound refers to a solid state wherein the compound contains no structural water within the crystal lattice.
  • AP refers to abdominal pain score.
  • the AP measurement discussed herein is an unweighted average of daily AP scores for seven days.
  • the AP measurements are calculated by averaging the daily AP score used in calculating the CDAI (discussed below), without the weighting factor applied.
  • aryl refers to a mono-, bi-, or tricyclic aromatic hydrocarbon radical. Examples include phenyl, naphthyl, biphenyl, and 1,2,3,4-tetrahydronaphthyl.
  • AUC 24 refers to the area under the plasma concentration time curve from time zero to twenty-four hours after administration of the referent drug following a single dose.
  • baseline refers to the day of first dosing with the JAK1 inhibitor, and is also referred to herein as “Day 1” or “Week 0”.
  • BID twice a day
  • BL means baseline
  • C 12 is the plasma concentration of the referent drug observed 12 hours after administration of a single dose, or the indicated number of doses, of the referent drug.
  • C 24 is the plasma concentration of the referent drug observed 24 hours after administration of a single dose, or the indicated number of doses, of the referent drug.
  • C ave refers to the average plasma concentration of a drug during a dosage interval at steady-state (multiple-dosing).
  • CDI carbonyldiimidazole
  • CI confidence interval
  • CDAI Crohn's Disease Activity Index
  • the term “clinical remission” when used in connection with Crohn's disease means average daily liquid/very soft stool frequency ⁇ 2.8 and not greater than baseline and average daily abdominal pain ⁇ 1.0 and not greater than baseline.
  • the phrase “not greater than baseline” means the average daily SF or average daily AP score is not higher than the average daily SF score or average daily AP score, respectively, at baseline (i.e., prior to treatment).
  • Clinical remission when used in connection with ulcerative colitis means a stool frequency (SF) subscore ⁇ 1, a rectal bleeding subscore (RBS) of 0, and an endoscopic subscore of ⁇ 0.
  • SF subscore, rectal bleeding subscore, and endoscopic subscore refer to the subscores used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. This is also referred to as “clinical remission per Adapted Mayo Score”.
  • Clinical response when used in connection with Crohn's disease is defined as an average daily liquid/very soft SF score reduction of at least 30% from BL (i.e., ⁇ 30% decrease from BL) and an average daily AP not greater than BL and/or “clinical response” is defined as an average daily AP score reduction of at least 30% from BL (i.e., ⁇ 30% decrease from BL), and an average daily liquid/very soft SF score not greater than at BL (i.e., prior to treatment).
  • Clinical response when used in connection with ulcerative colitis is defined as a decrease from baseline in the Adapted Mayo score ⁇ 2 points and ⁇ 30% from baseline accompanied by a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1.
  • impaired clinical response when used in connection with Crohn's disease is defined as ⁇ 60% decrease in average daily SF and/or ⁇ 35% decrease in average daily AP and both not greater than baseline, and/or clinical remission.
  • C max refers to the plasma concentration of the referent drug at T max , expressed herein as ng/mL, produced by the oral ingestion of a single dose, or indicated number of doses, of the dosage form or pharmaceutical composition, such as the dosage forms and compositions of the present disclosure. Unless specifically indicated, C max refers to the overall maximum observed concentration.
  • C min refers to the minimum concentration of drug in blood plasma.
  • corticosteroid-free means a patient who was taking corticosteroids at the time of the first induction dose of upadacitinib and has completely discontinued use of corticosteroids.
  • C p refers to plasma drug concentration at any time t.
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).
  • crystallization can refer to crystallization and/or recrystallization depending upon the applicable circumstances relating to the preparation of the compound.
  • a “disorder”, as used herein, is any condition that would benefit from treatment with a JAK1 inhibitor described herein. This includes chronic and acute disorders or diseases including those pathological conditions that predispose a mammal to the disorder in questions.
  • endoscopic healing means an SES-CD ulcerated surface subscore of 0 in subjects with SES-CD ulcerated surface subscore ⁇ 1 at baseline.
  • endoscopic improvement when used in connection with Crohn's disease means decrease in SES-CD>50% from baseline (or for subjects with an SES-CD of 4 at baseline of the induction study, at least a 2 point reduction from baseline).
  • endoscopic improvement when used in connection with ulcerative colitis means an endoscopic subscore ⁇ 1 at week 8 during the induction phase and an endoscopic subscore of 0 at week 8 during the maintenance phase.
  • the endoscopic subscore refers to the subscore used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • endoscopic remission when used in connection with Crohn's disease, unless otherwise indicated, means an SES-CD of ⁇ 4 ( ⁇ 2 for patients with isolated ileal CD) and at least a two point reduction in SES-CD versus BL and no subscore >1 in any individual variable used to calculate the SES-CD.
  • endoscopic remission by IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) definition, when used in connection with Crohn's disease, means SDS ⁇ 2.
  • endoscopic remission when used in connection with ulcerative colitis means an endoscopic subscore of 0.
  • the endoscopic subscore refer to the endoscopic subscore used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • endoscopic response when used in connection with Crohn's disease means at least a 50% reduction in SES-CD score from BL.
  • EtOAc ethyl acetate
  • EtOH refers to ethanol
  • Gaboes score means a histological score based on measurement of fecal calprotein and high-sensitivity C-reactive protein.
  • ulcerative colitis when used in connection with ulcerative colitis means a decrease from baseline in Geboes score.
  • HDL high density lipoprotein
  • Hgb hemoglobin
  • HOAc acetic acid
  • HPMC hydroxypropyl methylcellulose
  • the term “inducing” or “induced”, when used in connection with a particular therapeutic effect, means the therapeutic effect has been achieved.
  • the therapeutic effect is induced in a patient previously suffering from a disease condition, such as in a patient having moderately to severely active Crohn's disease or moderately to severely active ulcerative colitis.
  • inducing a particular therapeutic effect when used in connection with Crohn's disease, means the patient is brought from a state where the patient has 1) an average daily liquid/very soft stool frequency score ⁇ 2.5 or average daily abdominal pain score ⁇ 2, 2) CDAI ⁇ 220 and ⁇ 450 or 3) Simplified Endoscopic Score for Crohn's disease (SES-CD) ⁇ 6 (or ⁇ 4 for subjects with disease limited to the ileum) and bringing the patient to a state where the patient achieve the parameters for the specified therapeutic effect (e.g., endoscopic remission, clinical remission, endoscopic response, clinical response).
  • SES-CD Simplified Endoscopic Score for Crohn's disease
  • IPAc isopropyl acetate
  • IR immediate release
  • JK1 inhibitor or “upadacitinib” refers to the compound (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.
  • LDL low density lipoprotein
  • LOCF last observation carried forward method
  • Mayo means the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • the term “moderately to severely active Crohn's disease”, unless otherwise indicated, is defined as average daily very soft or liquid/soft stool frequency ⁇ 4 and/or average daily abdominal pain score ⁇ 2.0 and evidence of mucosal inflammation, defined as Simplified Endoscopic Score of or CD (SES-CD) ⁇ 6 ( ⁇ 4 for subjects with isolated ileal disease), excluding the presence of narrowing component.
  • SES-CD Simplified Endoscopic Score of or CD
  • modified clinical remission when used in connection with Crohn's disease is defined as an average daily liquid/very soft SF score of ⁇ 2.8 and not greater than BL and an average daily AP score of ⁇ 1.0 and not greater than BL.
  • the phrase “not greater than baseline” means that average daily liquid/very soft SF score or average daily AP score is not higher than the average daily liquid/very soft SF score or average daily AP score, respectively, at baseline (i.e., prior to treatment).
  • MR means modified release
  • MTX methotrexate
  • patient or “subject”, used interchangeably herein, refers to a human patient or subject.
  • NK cells refers to natural killer cells.
  • NAI non-responder imputation method
  • PBO placebo
  • Pd/C refers to palladium on carbon
  • Pd(OH 2 )/C refers to palladium hydroxide on carbon.
  • pharmaceutically acceptable refers to a material that is compatible with administration to a human subject, e.g., the material does not cause an undesirable biological effect.
  • pharmaceutically acceptable salts are described in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • pharmaceutically acceptable excipients are described in the “Handbook of Pharmaceutical Excipients,” Rowe et al., Ed. (Pharmaceutical Press, 7th Ed., 2012).
  • pTsOH refers to p-toluene sulfonic acid.
  • PVA polyvinyl acetate
  • PXRD powder X-ray diffraction
  • QD means once daily.
  • RBC red blood cells
  • RBS rectal bleeding subscore.
  • the rectal bleeding subscore refers to the subscore used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • refractory patient means a patient with moderately to severely active Crohn's disease, who has had Crohn's disease for more than ten years and who has failed several treatments, including biologic treatments.
  • remission when used in connection with Crohn's disease is defined as both endoscopic remission and clinical remission.
  • response when used in connection with Crohn's disease is defined as both endoscopic response and clinical response.
  • SC subcutaneous
  • (S)-Segphos Ru(OAc) 2 refers to diacetato[(S)-( ⁇ )5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II).
  • SES-CD refers to the Simplified Endoscopic Score for Crohn's disease, which is calculated using the parameters listed in Table 2 below.
  • SF refers to stool frequency.
  • the SF measurement discussed herein when used in connection with Crohn's disease is an unweighted average of daily liquid/very soft SF scores for seven days.
  • the SF measurements are calculated by averaging the daily liquid/very soft SF scores used in calculating the CDAI (discussed below), without the weighting factor applied.
  • the SF measurement discussed herein when used in connection with ulcerative colitis refers to the stool frequency subscore used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • therapeutically effective amount is used to refer to an amount of an active agent that relieves or ameliorates one or more of the symptoms of the disorder being treated.
  • therapeutically effective amount refers to a target serum concentration that has been shown to be effective in, for example, slowing disease progression. Efficacy can be measured in conventional ways, depending on the condition to be treated.
  • 6-TGN refers to 6-tioguanine (thioguanine) nucleotides.
  • THF tetrahydrofuran
  • T max refers to the time to peak plasma concentration of the referent drug after oral ingestion of a single dose, or indicated number of doses, of the referent drug.
  • treating are meant to include therapeutic as well as prophylactic, or suppressive measures for a disease or disorder leading to any clinical desirable or beneficial effect, including but not limited to alleviation or relief of one or more symptoms, regression, slowing or cessation of progression of the disease or disorder.
  • treatment includes the administration of an agent prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder.
  • the term includes the administration of an agent after clinical manifestation of the disease to combat the symptoms of the disease.
  • administration of an agent after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises “treatment” or “therapy” as used herein.
  • treatment or “therapy” as used herein.
  • compositions of the disclosure either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of the JAK1 inhibitor composition, the result should be considered an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not.
  • TNF tumor necrosis factor
  • t 1/2 refers to the terminal half-life of the referent drug after oral ingestion of a single dose, or indicated number of doses, of the referent drug.
  • UC ulcerative colitis
  • the present disclosure provides methods for treating and/or inducing clinical remission, endoscopic improvement, and/or endoscopic remission of Crohn's disease. In another aspect, the present disclosure provides methods for treating ulcerative colitis and/or for inducing a clinical remission of ulcerative colitis. In one aspect, the methods comprise administering a JAK1 inhibitor to the patient.
  • JAK Janus activated kinase
  • RA rheumatoid arthritis
  • CD rheumatoid arthritis
  • the activation of the JAK signaling initiates expression of survival factors, cytokines, chemokines, and other molecules that facilitate leukocyte cellular trafficking and cell proliferation, which contribute to inflammatory and autoimmune disorders.
  • CD Crohn's disease
  • the JAK comprises four family members: JAK1, 2, 3, and Tyrosine kinase 2 (Tyk2). These cytoplasmic tyrosine kinases transduce cytokine-mediated signals, and are associated with membrane cytokine receptors such as common gamma-chain (CGC) receptors and the glycoprotein 130 (gp130) trans-membrane proteins.
  • CGC common gamma-chain
  • gp130 glycoprotein 130
  • JAK3 and JAK1 are components of the CGC cytokine receptor complexes and blockade of either inhibits signaling by the inflammatory cytokines IL-2, -4, -7, -9, -15 and -21.
  • Cytokines such as IL-6 bind to gp130 and transduce its signal predominantly via JAK1.
  • Targeting the IL-6 receptor (IL-6R) is a promising approach given the fact that expression of IL-6 and soluble IL-6 receptors is elevated in patients with active CD. Further, a proof of concept study in patients with active CD with tocilizumab, a humanized monoclonal antibody against IL-6R, showed an encouraging clinical response.
  • inhibition of JAK1 is expected to attenuate the signaling of IL-6 and other pro-inflammatory cytokines (i.e. IFN-g), that are involved in development of CD.
  • the present disclosure provides a compound useful in the treatment of Crohn's Disease and ulcerative colitis.
  • the JAK1 inhibitor used in the methods of the present disclosure is the compound (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (C 17 H 19 F 3 N 6 O), or a pharmaceutically acceptable salt or solid state form thereof.
  • “Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalic acid, tartaric acid such as mono tartaric acid (e.g., (+) or ( ⁇ )-tartaric acid or mixtures thereof), amino acids (e.g., (+) or ( ⁇ )-amino acids or mixtures thereof), and the like.
  • These salts can be prepared by methods known to those skilled in the art
  • the present disclosure is directed to methods for the treatment of Crohn's disease.
  • the present disclosure provides methods for treating Crohn's disease, in particular methods comprising administering a JAK1 inhibitor to a patient in certain amounts and/or at certain intervals.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides a JAK1 inhibitor for use in the treatment of Crohn's disease, by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for the treatment of Crohn's disease, by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure is directed to methods for inducing clinical remission and/or endoscopic remission of Crohn's disease.
  • the present disclosure provides methods for inducing clinical remission and/or endoscopic remission of Crohn's disease, in particular methods comprising administering a JAK1 inhibitor to a patient in certain amounts and/or at certain intervals.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides a JAK1 inhibitor for use in inducing clinical remission and/or endoscopic remission of Crohn's disease by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for inducing clinical remission and/or endoscopic remission of Crohn's Disease by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure is directed to methods for inducing clinical remission and/or endoscopic improvement of Crohn's disease, in particular, methods comprising administering a JAK1 inhibitor to a patient in certain amounts and/or at certain intervals.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides a JAK1 inhibitor for use in inducing clinical remission and/or endoscopic improvement of Crohn's disease by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for inducing clinical remission and/or endoscopic improvement of Crohn's disease, by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the disease is moderately to severely active Crohn's disease.
  • a patient is na ⁇ ve to, or was previously treated with immunosuppressants (e.g., methotrexate), aminosalicylates, corticosteroids, and/or a biologic agent (e.g., vedolizumab, ustekinumab, natalizumab, etc.).
  • a biologic agent e.g., vedolizumab, ustekinumab, natalizumab, etc.
  • the patient is na ⁇ ve to, or was previously treated with an anti-TNF therapy (e.g., infliximab, adalimumab, certolizumab pegol, golimumab, etc.).
  • a patient was previously treated with one, two, three or more TNF antagonist(s) (also referred to herein as anti-TNF agents).
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a TNF antagonist.
  • a patient was previously treated with one, two, three or more biologic(s).
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a biologic agent.
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a TNF antagonist, aminosalicylates, corticosteroids, immunosuppressants, and/or a biologic agent.
  • the patient is a refractory patient who has moderately to severely active Crohn's disease.
  • the patient is either na ⁇ ve to or has stopped using corticosteroids prior to treatment with the JAK1 inhibitor.
  • CDAI Crohn's Disease Activity Index
  • SES-CD Simplified Endoscopic Score for CD
  • SF average daily liquid/very soft stool frequency
  • AP average daily abdominal pain
  • IBDQ Inflammatory Bowel Disease Questionnaire
  • the IBDQ is a well-known 32 item validated questionnaire that assesses a patient's inflammatory bowel disease symptoms, general well-being, and mood, and may be used as a tool to evaluate a patient's quality of life (Guyatt, et al., Gastroenterology, 1989, 96:804-810).
  • the IBDQ questionnaire is described in further detail below.
  • CDAI is a composite score used to quantify symptoms of patients with Crohn's disease.
  • the index consists of eight factors added together after adjusting for a predefined weighting factor (see Table 1 below).
  • CDAI scores range from 0 to 600. Index values of 150 and below are associated with quiescent disease; values above 150 are associated with active disease, and values above 450 are seen with extremely severe disease.
  • a patient to be treated by a method according to the present disclosure has a CDAI score of 220 to 450 prior to treatment, which may be indicative of moderately to severely active CD.
  • SES-CD is calculated using the following parameters listed in Table 2:
  • the patient to be treated has moderately to severely active Crohn's disease.
  • Moderately to severely active Crohn's disease is characterized by a SES-CD of greater than or equal to 6 (or a SES-CD of greater than or equal to 4 for patients with disease limited to the ileum).
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a conventional therapy (e.g., aminosalicylates, corticosteroids, immunosuppressants), or to a biologic agent.
  • a conventional therapy e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a TNF antagonist.
  • anti-TNF agents include infliximab, adalimumab, and certolizumab pegol. Criteria for determining if a patient has had an inadequate response to or experienced intolerance to previous treatment with an anti-TNF agent is defined as:
  • the patient is one who has previously been treated with, or is currently being treated with aminosalicylates, immunosuppressants, corticosteroids, and/or a biologic agent.
  • CDAI or any of the evaluations described in the Examples herein below is/are used to assess the efficacy of upadacitinib in the treatment of Crohn's disease, for example moderately to severely active Crohn's disease.
  • the treatment of a patient or the induction of clinical remission and/or endoscopic remission in a patient or the induction of clinical remission and/or endoscopic improvement in a patient comprises an induction phase and a maintenance phase.
  • one or more doses of the JAK1 inhibitor for example referred to herein as induction doses
  • the maintenance phase a first dose of the JAK1 inhibitor, for example referred to herein as the maintenance dose, is administered to the patient followed by at least one additional dose of the JAK1 inhibitor, for example, also referred to herein as a maintenance dose.
  • the maintenance doses are, for example, administered orally.
  • the JAK1 inhibitor may be, for example, upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. Examples of induction phases and maintenance phases are described herein.
  • a certain therapeutic result is achieved by the patient during or at the end of the induction phase, for example clinical remission, endoscopic remission, or both clinical remission and endoscopic remission (referred to herein as “remission”).
  • the patient achieves clinical remission during or by the end of the induction phase.
  • the patient achieves endoscopic remission during or by the end of the induction phase.
  • a certain therapeutic result is achieved by the patient during or at the end of the induction phase, for example clinical remission, endoscopic improvement, or both clinical remission and endoscopic improvement.
  • the patient achieves clinical remission during or by the end of the induction phase.
  • the patient achieves endoscopic improvement during or by the end of the induction phase
  • the induction phase lasts for up to 16 weeks (e.g., for up to 16 weeks following initiation of administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction phase is 16 weeks.
  • the induction phase optionally lasts for less than 16 weeks, for instance, for 2 weeks, for 4 weeks, for 5 weeks, for 6 weeks, for 7 weeks, for 8 weeks, for 9 weeks, for 10 weeks, for 11 weeks, for 12 weeks, for 13 weeks, for 14 weeks, or for 15 weeks.
  • the patient achieves an endoscopic remission within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a clinical remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one aspect, the patient achieves an endoscopic improvement within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one aspect, the patient achieves a clinical remission within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves clinical remission within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves both 1) average daily liquid/very soft SF score of ⁇ 1.5 and not worse than BL, and 2) average daily AP score of ⁇ 1.0 and not worse than baseline within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the phrase “not worse than baseline” means that the average daily liquid/very soft SF score or average daily AP score is not higher than the average daily liquid/very soft SF score or average daily AP score, respectively, at baseline (i.e., prior to treatment).
  • the patient achieves both 1) average daily liquid/very soft SF score of ⁇ 1.5 and not worse than BL, and 2) average daily AP score of ⁇ 1.0 and not worse than baseline within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the phrase “not worse than baseline” means that the average daily liquid/very soft SF score or average daily AP score is not higher than the average daily liquid/very soft SF score or average daily AP score, respectively, at baseline (i.e., prior to treatment).
  • the patient achieves endoscopic remission and/or endoscopic improvement within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves endoscopic remission and/or endoscopic improvement within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves corticosteroid-free remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves at least one therapeutic result selected from the group consisting of:
  • the patient achieves either a clinical remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, or an endoscopic remission within 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and combinations thereof.
  • the induction phase is 16 weeks.
  • the induction phase is 12 weeks, and the patient achieves either a clinical remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, or an endoscopic remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 2), 3), 5), 6), 7), 8), 10), 11), 13), 14), 15), 16), 18), 19), 20), 22), 23), 25), 26), 28), 29), and combinations thereof, wherein the therapeutic result is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 4 weeks, and the patient achieves either a clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, or an endoscopic remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 3), 6), 8), 11), 14), 16), 19), 20), 23), 26), 29), and combinations thereof, wherein the therapeutic result is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a clinical remission within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and combinations thereof.
  • the induction phase is 16 weeks.
  • the induction phase is 12 weeks, and the patient achieves a clinical remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 2), 3), 5), 6), 7), 8), 10), 11), 13), 14), 15), 16), 18), 19), 20), 22), 23), 25), 26), 28), 29), and combinations thereof, wherein the therapeutic result is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 16 weeks, and the patient achieves a clinical remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and combinations thereof, wherein the therapeutic result is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 4 weeks, and the patient achieves a clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 3), 6), 8), 11), 14), 16), 19), 20), 23), 26), 29), and combinations thereof, wherein the therapeutic result is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a clinical remission within 4 weeks, 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 4 weeks, 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves an additional therapeutic result selected from the group consisting of a CDAI of less than 150 within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a CDAI of less than 150 within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a CDAI of less than 150 within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically
  • the induction phase is 16 weeks
  • the additional therapeutic result is selected from the group consisting of a CDAI of less than 150 within 16 weeks, or within 12 weeks, or within 4 weeks, or within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, an endoscopic remission within 16 weeks or within 12 weeks or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 16 weeks or within 12 weeks or within 4 weeks, or within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; and combinations thereof.
  • the induction phase is 12 weeks
  • the additional therapeutic result is selected from the group consisting of a CDAI of less than 150 within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; and combinations thereof.
  • the additional therapeutic result may further be a clinical remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, wherein the patient has an average daily liquid/very soft SF score of greater than or equal to 2.5 and an average daily AP score of greater than or equal to 2.0 at baseline.
  • the additional therapeutic result may be selected from the group consisting of a CDAI score of less than 150 within 16 weeks of initiating administration of upadacitinib.
  • the additional therapeutic result may further be remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient achieves a CDAI score of less than 150 during or by the end of the induction phase.
  • the patient may achieve an additional therapeutic result selected from the group consisting of a clinical remission (i.e., average daily SF score ⁇ 2.8 and not greater than baseline and average daily AP score ⁇ 1.0 and not greater than baseline) within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement (i.e., SES-CD score that is greater than a 50% decrease from baseline or at least a 2 point reduction in SES-CD score from baseline or endoscopic remission) within 4 weeks, within 6 weeks, within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; and combinations thereof.
  • a clinical remission i.e., average daily SF score ⁇ 2.8 and not greater than baseline and average daily AP score ⁇ 1.0 and not greater than baseline
  • an endoscopic improvement i.e., SES-CD score that is greater than a 50% decrease from baseline or at least a 2
  • the patient may achieve an additional therapeutic result selected from the group consisting of a decrease in CDAI score from baseline of greater than or equal to 70, and a decrease in CDAI score from baseline of greater than or equal to 100.
  • the induction phase is 16 weeks and the decrease in CDAI occurs within 16 weeks or within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 12 weeks and the decrease in CDAI occurs within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 16 weeks, and the patient achieves a clinical remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement (i.e., SES-CD score that is greater than a 50% decrease from baseline or at least a 2 point reduction in SES-CD score from baseline, or endoscopic remission) within 4 weeks, within 6 weeks, within 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; and combinations thereof.
  • an endoscopic improvement i.e., SES-CD score that is greater than a 50% decrease from baseline or at least a 2 point reduction in SES-CD score from baseline, or endoscopic remission
  • the induction phase is 12 weeks, and the patient achieves a clinical remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; or combinations thereof.
  • the patient is administered upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, for at least 52 weeks.
  • the administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof may include an induction phase (e.g., an induction phase of up to 16 weeks), and additional weeks (e.g., 36 weeks or longer) of a maintenance phase (discussed hereinafter).
  • the administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof may include a shorter induction phase (e.g., up to 2 weeks, up to 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.), and a longer maintenance phase (e.g., a 12 week induction phase and a 40 week or longer maintenance phase).
  • a shorter induction phase e.g., up to 2 weeks, up to 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.
  • a longer maintenance phase e.g., a 12 week induction phase and a 40 week or longer maintenance phase.
  • the patient may achieve at least one therapeutic result selected from the group consisting of: remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; endoscopic remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; clinical remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; endoscopic improvement within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; response within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; endoscopic response within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof pharm; clinical response within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof pharm;
  • the additional therapeutic result may be selected from the group consisting of a CDAI of less than 150 within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and an endoscopic remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; and combinations thereof.
  • the additional therapeutic result may be selected from the group consisting of a CDAI of less than 150 within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical
  • a patient is evaluated during or at the end of the induction phase for a therapeutic result selected from the group consisting of clinical remission, endoscopic improvement, endoscopic remission, endoscopic response, clinical response, CDAI, average daily liquid/very soft SF score, average daily AP score, fecal calprotectin level, hs-CRP, IBDQ score, and combinations thereof.
  • a patient is evaluated for clinical remission during or at the end of the induction phase.
  • a patient is evaluated for endoscopic improvement during or at the end of the induction phase.
  • a patient is evaluated for endoscopic remission during or at the end of the induction phase.
  • the patient is administered at least 14 doses, at least 28 doses, at least 42 doses, at least 70 doses, or at least 84 doses, or at least 112 doses, or at least 140 doses, or at least 168 doses, or at least 224 doses, or 70 doses, or 84 doses, or 112 doses, or 140 doses, or 168 doses, or 224 doses of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, during the induction phase.
  • a certain therapeutic result is maintained by the patient during the maintenance phase.
  • the maintenance phase may last for an indefinite period of time.
  • the maintenance phase is at least 36 weeks, including at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the maintenance phase is at least 40 additional weeks.
  • the therapeutic result maintained by the patient during the maintenance phase is selected from the group consisting of clinical remission, endoscopic remission, and combinations thereof.
  • the therapeutic result maintained by the patient during the maintenance phase is selected from the group consisting of clinical response, endoscopic improvement, and combinations thereof.
  • a patient maintains a CDAI score of less than 150 during the maintenance phase.
  • a patient maintains a SES-CD that is greater than a 50% decrease versus the patient's baseline SES-CD.
  • the patient maintains a SES-CD that is at least a 2 point reduction versus the patient's baseline SES-CD.
  • the therapeutic result maintained by the patient during the maintenance phase is clinical response.
  • the therapeutic result maintained by the patient during the maintenance phase is endoscopic remission.
  • a patient is evaluated for clinical remission during the maintenance phase. In one embodiment, a patient is evaluated for endoscopic improvement during the maintenance phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for endoscopic remission during the maintenance phase.
  • the present disclosure provides a method for treating an inflammatory disease, in one aspect for treating Crohn's Disease, comprising (a) administering to a patient a dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) at week 0 and once daily (QD) thereafter for 16 weeks, wherein the dose is 45 mg QD.
  • the method further comprises (b) administering to the patient additional doses once daily thereafter for at least 36 additional weeks, wherein the dose is 15 mg or 30 mg QD.
  • the dose is administered orally.
  • a patient is evaluated for clinical remission (average daily liquid/very soft SF score ⁇ 2.8 and not worse than baseline and average daily AP score ⁇ 1.0 and not worse than baseline) and/or for endoscopic remission (SES-CD ⁇ 4 (or SES-CD ⁇ 2 for patients with isolated ileal CD) and at least a two point reduction in SES-CD versus BL and no subscore >1 in any individual variable used to calculate SES-CD).
  • a patient is evaluated for clinical remission and/or for endoscopic remission.
  • a patient is evaluated for clinical remission (average daily liquid/very soft SF score ⁇ 2.8 and not worse than baseline and average daily AP score ⁇ 1.0 and not worse than baseline) and/or for endoscopic remission (SES-CD ⁇ 4 (or SES-CD ⁇ 2 for patients with isolated ileal CD) and at least a two point reduction in SES-CD versus BL and no subscore >1 in any individual variable used to calculate SES-CD).
  • clinical remission average daily liquid/very soft SF score ⁇ 2.8 and not worse than baseline and average daily AP score ⁇ 1.0 and not worse than baseline
  • SES-CD ⁇ 4 or SES-CD ⁇ 2 for patients with isolated ileal CD
  • a patient is evaluated for remission, for example defined as reaching clinical remission (average daily liquid/very soft SF score ⁇ 2.8 and not worse than baseline and average daily AP score ⁇ 1.0 and not worse than baseline) and endoscopic remission (SES-CD ⁇ 4 (or SES-CD ⁇ 2 for patients with isolated ileal CD) and at least a two point reduction in SES-CD versus BL and no subscore >1 in any individual variable used to calculate SES-CD).
  • clinical remission average daily liquid/very soft SF score ⁇ 2.8 and not worse than baseline and average daily AP score ⁇ 1.0 and not worse than baseline
  • SES-CD ⁇ 4 or SES-CD ⁇ 2 for patients with isolated ileal CD
  • a patient is evaluated for clinical remission and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission and/or for endoscopic improvement.
  • the present disclosure provides a method for treating Crohn's disease, comprising (a) administering to a patient a dose of a JAK inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) at week 0 and once daily thereafter via an oral route, wherein the doses of the JAK1 inhibitor comprise 15 mg, 30 mg, or 45 mg QD, or any combination thereof.
  • a JAK inhibitor e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof
  • the present disclosure provides a method for treating Crohn's disease, comprising administering to a patient 15 mg to 45 mg of a JAK1 inhibitor. In one embodiment, the present disclosure provides a method for treating Crohn's disease, comprising administering to a patient orally 15 mg of a JAK1 inhibitor QD. In one embodiment, the present disclosure provides a method for treating Crohn's disease, comprising administering to a patient orally 30 mg of a JAK1 inhibitor QD. In one embodiment, the present disclosure provides a method for treating Crohn's disease, comprising administering to a patient orally 45 mg of a JAK1 inhibitor QD.
  • the JAK1 inhibitor may be upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In any such embodiment, the JAK1 inhibitor may be in a once daily modified release formulation. In any such embodiment, the patient may have moderately to severely active Crohn's disease prior to treatment.
  • a JAK1 inhibitor according to the present disclosure is further described in the Examples herein below or in FIG. 1 .
  • the present disclosure provides a method for treating Crohn's disease, said method comprising a) administering at least one induction dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) to a patient, wherein said induction dose comprises 45 mg of the JAK 1 inhibitor.
  • a JAK1 inhibitor e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof
  • the induction dose is administered orally.
  • the induction dose is administered QD.
  • the induction dose is administered for 12 weeks.
  • the induction dose is administered for 16 weeks.
  • the induction dose is administered for up to 16 weeks, including for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.
  • the induction dose comprises 45 mg of the JAK1 inhibitor administered QD.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction dose is in a once daily modified release formulation.
  • the method further comprises b) administering a first maintenance dose of a JAK1 inhibitor (e.g., upadacitinib, or pharmaceutically acceptable salt or solid state form thereof), to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose to the patient once daily thereafter.
  • a JAK1 inhibitor e.g., upadacitinib, or pharmaceutically acceptable salt or solid state form thereof
  • the first maintenance dose comprises 15 mg to 30 mg of the JAK1 inhibitor. In one aspect, the first maintenance dose comprises 15 mg or 30 mg of the JAK1 inhibitor. In one aspect, the first maintenance dose is smaller than the induction dose. In one aspect, the first maintenance dose is administered QD. In one aspect the first maintenance dose is 15 mg. In one aspect the first maintenance dose is 30 mg. In one aspect, the first maintenance dose is administered orally. In one aspect, the first maintenance dose is in a once daily modified release formulation.
  • the at least one additional maintenance dose comprises 15 mg to 30 mg of the JAK 1 inhibitor. In one aspect, the at least one additional maintenance dose comprises 15 mg or 30 mg. In one aspect, the at least one additional maintenance dose is administered orally. In one aspect, the at least one additional maintenance dose is administered QD. In one embodiment, the at least one additional maintenance dose comprises 15 mg of the JAK1 inhibitor administered QD. In one embodiment, the at least one additional maintenance dose comprises 30 mg of the JAK1 inhibitor administered QD. In one aspect, the at least one additional maintenance dose is in a once daily modified release formulation.
  • the JAK1 inhibitor may be upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient maintains a CDAI score of less than 150.
  • the patient is one who had an inadequate response to or experienced intolerance to conventional treatment (e.g., amninosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent.
  • conventional treatment e.g., amninosalicylates, corticosteroids, immunosuppressants
  • the patient is one who had an inadequate response to or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the patient is a refractory patient.
  • the patient is one who is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid an immunosuppressant, a biologic agent or an anti-TNF agent.
  • the patient is one who had moderately to severely active Crohn's disease prior to treatment or administration of the induction dose.
  • the present disclosure further provides a method for inducing clinical remission of Crohn's Disease in a patient, said method comprising a) administering to the patient at least one induction dose of a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mg QD.
  • the method further comprises maintaining clinical remission of Crohn's disease, said method further comprising b) administering a first maintenance dose of said JAK1 inhibitor to the patient after the last induction dose is administered and c) administering at least one additional maintenance dose to the patient as described above or herein. In one embodiment, the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the additional maintenance doses are administered once daily for at least 40 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has a CDAI score of 220 to 450 before administration of the first induction dose. In one embodiment, the patient has moderately to severely active Crohn's disease prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent, and/or an anti-TNF agent.
  • the clinical remission is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical remission is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the clinical remission is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves a CDAI score of less than 150 before administration of the first maintenance dose. In one embodiment, the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure provides a method for inducing endoscopic remission of Crohn's disease, the method comprising (a) administering to a patient at least one induction dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof), wherein the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • a JAK1 inhibitor e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mg QD.
  • the method further comprises maintaining endoscopic remission of Crohn's disease, said method further comprising (b) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, after the last induction dose is administered, and (c) administering at least one additional maintenance dose once daily thereafter.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the additional maintenance doses are administered once daily for at least 40 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has a CDAI score of 220 to 450 before administration of the first induction dose. In one embodiment, the patient has moderately to severely active Crohn's disease prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic and/or an anti-TNF agent.
  • conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, an anti-TNF agent and/or a biologic agent.
  • the endoscopic remission is achieved within 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the endoscopic remission is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a CDAI score of less than 150 before administration of the first maintenance dose.
  • the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure further provides a method for inducing endoscopic improvement of Crohn's Disease in a patient, said method comprising a) administering to the patient at least one induction dose of a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction dose comprises 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mg QD.
  • the method further comprises maintaining endoscopic improvement of Crohn's disease, said method further comprising b) administering a first maintenance dose of said JAK1 inhibitor to the patient after the last induction dose is administered and c) administering at least one additional maintenance dose to the patient as described above or herein. In one embodiment, the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the additional maintenance doses are administered once daily for at least 40 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has a CDAI score of 220 to 450 before administration of the first induction dose. In one embodiment, the patient has moderately to severely active Crohn's disease prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the endoscopic improvement is achieved within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the endoscopic improvement is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the endoscopic improvement is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves a CDAI score of less than 150 before administration of the first maintenance dose. In one embodiment, the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure further provides a method of maintaining clinical remission of Crohn's Disease in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is a once-daily, modified release formulation.
  • the present disclosure further provides a method of maintaining endoscopic improvement of Crohn's Disease in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is a once-daily, modified release formulation.
  • the present disclosure further provides a method of maintaining endoscopic remission of Crohn's Disease in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is a once-daily, modified release formulation.
  • the present disclosure further provides a method of maintaining remission of Crohn's Disease in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt form thereof is in a once-daily, modified release formulation.
  • induction doses for the methods disclosed herein are administered for 12 weeks in a dose regimen described in Table 3. In one aspect, induction doses are administered for 16 weeks in a dose regimen described in Table 3. In one aspect, maintenance doses are administered for 36 weeks or more in a dose regimen described in Table 3. In one aspect, induction doses for the methods disclosed herein are administered for 16 weeks and the maintenance doses are administered for 36 weeks in a dosing regimen as described in Table 3.
  • BID Induction Frequency of Maintenance Frequency of Dose
  • induction doses dose mg
  • maintenance dose 3 BID 3 BID 6 BID 3 BID 6 BID 6 BID 12 BID 3 BID 12 BID 6 BID 12 BID 12 BID 24 BID 3 BID 24 BID 6 BID 24 BID 12 BID 24 QD 1 3 BID 24 QD 1 6 BID 24 QD 1 12 BID 1
  • the 24 mg QD dose is two 12 mg tablets administered simultaneously.
  • the induction doses for the methods disclosed herein are administered for 2 weeks in a dose regimen described in Table 4. In one aspect, the induction doses for the methods disclosed herein are administered for 4 weeks in a dose regimen described in Table 4. In one aspect, induction doses for the methods disclosed herein are administered for 12 weeks in a dose regimen described in Table 4. In one aspect, induction doses are administered for 16 weeks in a dose regimen described in Table 4. In one aspect, maintenance doses are administered for 36 weeks or more in a dose regimen described in Table 4. In one aspect, induction doses for the methods disclosed herein are administered for 2 weeks and the maintenance doses are administered for 36 or 40 weeks in a dosing regimen as described in Table 4.
  • induction doses for the methods disclosed herein are administered for 4 weeks and the maintenance doses are administered for 36 or 40 weeks in a dosing regimen as described in Table 4. In one aspect, induction doses for the methods disclosed herein are administered for 12 weeks and the maintenance doses are administered for 36 or 40 weeks in a dosing regimen as described in Table 4. In one aspect, induction doses for the methods disclosed herein are administered for 16 weeks and the maintenance doses are administered for 36 or 40 weeks in a dosing regimen as described in Table 4.
  • the induction dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • the induction dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 15 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • the maintenance and induction doses are in once-daily, modified release formulations.
  • the present disclosure is directed to methods for the treatment of ulcerative colitis.
  • the present disclosure provides methods for treating ulcerative colitis, in particular methods comprising administering a JAK1 inhibitor to a patient in certain amounts and/or at certain intervals.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides a JAK1 inhibitor for use in the treatment of ulcerative colitis, by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for the treatment of ulcerative colitis, by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure is directed to methods for inducing clinical remission and/or endoscopic remission of ulcerative colitis.
  • the present disclosure provides methods for inducing clinical remission and/or endoscopic remission of ulcerative colitis, in particular methods comprising administering a JAK1 inhibitor to a patient in certain amounts and/or at certain intervals as described herein.
  • the present disclosure is further directed to methods for inducing clinical remission wherein the patient has a SF score ⁇ 1, RBS of 0 and endoscopy score ⁇ 1 at week 48 following administration of the JAK1 inhibitor.
  • the patient achieves clinical remission per Full Mayo score ⁇ 2 with no subscore >1) plus fecal calprotectin below 150 mg/kg at Week 8 following administration of the JAK1 inhibitor.
  • the patient has an increase of IBDQ ⁇ 16 from baseline at week 8 following administration of the JAK1 inhibitor.
  • the patient has a RBS ⁇ 1 or an absolute RBS ⁇ 1 at week 8 following administration of the JAK1 inhibitor.
  • the patient has a SF subscore ⁇ 1 at week 8 following administration of the JAK1 inhibitor.
  • the patient achieves a RBS of 0 at week 8.
  • the patient achieves a fecal calprotectin below 150 mg/kg at week 8 following administration of the JAK1 inhibitor. In one aspect the patient achieves histologic improvement at week 8 following administration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides a JAK1 inhibitor for use in inducing clinical remission of ulcerative colitis by administration in certain amounts and/or at certain intervals as described herein.
  • the present disclosure provides a JAK1 inhibitor for use in inducing clinical remission and/or clinical response and/or endoscopic improvement and/or endoscopic remission of ulcerative colitis by administration in certain amounts and/or at certain intervals as described herein.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for inducing clinical remission of ulcerative colitis by administration in certain amounts and/or at certain intervals as described herein. In one aspect, the present disclosure provides for the use of a JAK1 inhibitor for the preparation of a medicament for inducing clinical remission and/or clinical response and/or endoscopic improvement and/or endoscopic remission of ulcerative colitis by administration in certain amounts and/or at certain intervals as described herein. In one aspect, the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the disease is moderately to severely active ulcerative colitis.
  • a patient is na ⁇ ve to, or was previously treated with immunosuppressants (e.g., methotrexate), aminosalicylate, corticosteroid, and/or a biologic agent (e.g., vedolizumab, ustekinumab, natalizumab, etc.).
  • a biologic agent e.g., vedolizumab, ustekinumab, natalizumab, etc.
  • the patient is na ⁇ ve to, or was previously treated with an anti-TNF therapy (e.g., infliximab, adalimumab, certolizumab pegol, golimumab, etc.).
  • a patient was previously treated with one, two, three or more TNF antagonist(s) (also referred to herein as anti-TNF agents).
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a TNF antagonist.
  • a patient was previously treated with one, two, three or more biologic agent(s).
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a biologic agent.
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a TNF antagonist, aminosalicylates, corticosteroids, immunosuppressants, and/or a biologic agent.
  • the patient is a refractory patient who has moderately to severely active ulcerative colitis.
  • the patient is either na ⁇ ve to or has stopped using corticosteroids prior to treatment with the JAK1 inhibitor.
  • ulcerative colitis may be measured using a variety of indexes, including the Mayo Scoring System for Assessment of Ulcerative Colitis Activity (“Full Mayo”), the Adapted Mayo Score (consisting of the stool frequency subscore, rectal bleeding subscore and endoscopy subscore of the Full Mayo), the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score system, the Inflammatory Bowel Disease Questionnaire (IBDQ), the Work Productivity and Activity Impairment Questionnaire for Ulcerative Colitis (version 2.0) (WPAI:UC), the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L), the Short Form 36 Item (SF-36) Health Survey (version 2), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Ulcerative Colitis Symptoms Questionnaire (UC-SQ), and the Patient Global Impression of Change (PGIC).
  • Full Mayo the Adapted Mayo Score (consisting of the stool frequency subscore, rec
  • the Mayo Scoring System for Assessment of Ulcerative Colitis Activity is a composite of the following subscores: Stool Frequency Subscore, Rectal Bleeding Subscore (RBS), Endoscopy Subscore, and Physician's Global Assessment Subscore.
  • the IBDQ is a well-known 32 item validated questionnaire that assesses a patient's inflammatory bowel disease symptoms, general well-being, and mood, and may be used as a tool to evaluate a patient's quality of life (Guyatt, et al., Gastroenterology, 1989, 96:804-810).
  • the IBDQ questions and answer options are set forth below in Table 6.
  • WPAI:UC The Work Productivity and Activity Impairment Questionnaire for Ulcerative Colitis
  • WPAI:CD Crohn's Disease
  • WPAI:UC has six items covering four domains: Absenteeism (work time missed), measured as the number of hours missed from work in the past 7 days due to a condition related problem. Scores are expressed as impairment percentages, adjusting for hours actually worked according to the WPAI:UC or WPAI:CD scoring algorithm; Presenteeism (impairment at work/reduced on-the-job effectiveness), measured as the impact of the condition on productivity while at work (i.e., reduced amount or kind of work, or not as focused as usual).
  • ulcerative colitis affected If ulcerative colitis affected your work only a lttle, choose a low productivity while at work number. Choose a high number if ulcerative colitis affected your work a great deal. 6.
  • ulcerative colitis During the past 7 days, how much did your ulcerative colitis Select number on a scale of 0 (UC affect your ability to do your regular daily activities, other than had no effect on daily activities) to work at a job? 10 (UC completely prevented me Regular activities means usual activities such as work around from doing daily activities), the house, shopping, childcare, exercising, studying, etc. representing how much ulcerative Consider times you were limited in the amount or kind of colitis affected ability to do activities you could do and times you accomplished less than regular daily activities, other than you would like. If ulcerative colitis affected your activities only work at a job a little, choose a low number. Choose a high number if ulcerative colitis affected your activities a great deal. *Questions 2-7 are about the previous seven days, not including the day the questionnaire is completed.
  • the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) is a standardized non-disease specific instrument for describing and valuing health-related quality of life.
  • the EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problem, slight problem, moderate problem, severe problem or unable to do the activity. It also contains a Visual Analogue Scale (VAS). Subjects are asked to indicate the level that describes their current level of function or experience for each dimension. As a measure of health status, it provides a descriptive profile and can be used to generate a single index value for health status, where full health is equal to 1 and death is equal to 0. The VAS records the subject's assessment of his/her own health along a vertical 20 cm line, which has health state scores between 0 and 100.
  • the EQ-5D-5L questions and answer options are set forth in Table 8.
  • the SF-36 questionnaire is a self-administered multi-domain scale with 36 items. Eight subscales cover a range of functioning: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH).
  • the scoring yields a physical component score, a mental component summary score, and subscale scores. Higher scores represent better outcomes.
  • the concepts measured by the SF-36 are not specific to any age, disease, or treatment group, allowing comparison of relative burden of different diseases and the benefit of different treatments.
  • the SF-36 questions and answer options are set forth below in Table 9.
  • the Functional Assessment of Chronic Illness Therapy (FACIT) system is a collection of quality of life (QOL) questionnaires targeted to the management of cancer and other chronic illnesses.
  • the FACIT fatigue (FACIT-F) questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. The responses to the 13 items on the FACIT fatigue questionnaire are each measured on a 4-point Likert scale. The responses to the answers are the following: (i) not at all: 0 points; (ii) a little bit: 1 point; (iii) somewhat: 2 points; (iv) quite a bit: 3 points; and (v) very much: 4 points. Thus, the total score ranges from 0 to 52. High scores represent less fatigue.
  • the FACIT-F questions and answer options are set forth below in Table 10.
  • the Ulcerative Colitis Symptoms Questionnaire is a UC-specific instrument composed of 17 Likert-type items. UC-SQ was developed to assess UC related gastrointestinal and non-gastrointestinal symptoms such as frequent bowel movements, abdominal discomfort, nausea, loss of appetite, pain, and anemia along with the impact on patients' sleep. Each question can be answered using Likert-type options such as (i) Not at all: 0 points; (ii) A little bit: 1 point; (iii) Somewhat: 2 points; (iv) Quite a bit: 3 points; and (v) Very much: 4 points based on how the patient felt during the past week (i.e., 7 days). The total score ranges can vary from 0 to 68 with lower scores indicating improvement.
  • the UC-SQ questions and answer options are set forth below in Table 11.
  • the Patient Global Impression of Change is a self-administered instrument that assesses change in the overall symptoms due to Ulcerative Colitis.
  • the PGIC is one item in which subjects are asked to rate overall improvement since start of the treatment. Patients are asked the question “Compared to before your treatment began, how would you rate the change in your overall symptoms due to your ulcerative colitis?”, and rate their change as “Very much improved.” “Much improved,” “Minimally improved”, “No change,” “Minimally worse,” “Much worse” and “Very much worse”.
  • the patient to be treated has moderately to severely active ulcerative colitis.
  • Moderately to severely active ulcerative colitis is characterized by an Adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2 to 3.
  • the patient is a patient who had an inadequate response with, lost response, or was intolerant to a conventional therapy (e.g., aminosalicylate, corticosteroids, immunosuppressants), or to a biologic agent.
  • a conventional therapy e.g., aminosalicylate, corticosteroids, immunosuppressants
  • biologic agents e.g., aminosalicylate, corticosteroids, immunosuppressants
  • biologic therapies include infliximab, adalimumab, vedolizumab, golimumab, ustekinumab and certolizumab pegol. Criteria for determining if a patient has had an inadequate response to, lost response, or experienced intolerance to previous treatment with corticosteroids, immunosuppressants, and/or a biologic therapy are defined below:
  • the patient is one who has previously been treated with, or is currently being treated with aminosalicylate, immunosuppressants, corticosteroids, and/or a biologic agent.
  • the Mayo Scoring System for Assessment of Ulcerative Colitis Activity or any of the evaluations described hereinbefore or in the Examples herein below is/are used to assess the efficacy of upadacitinib in the treatment of ulcerative colitis, for example moderately to severely active ulcerative colitis.
  • the evaluation used to assess the efficacy of upadacitinib in the treatment of ulcerative colitis is selected from the group consisting of the Full Mayo score, the Partial Mayo score, the Adapted Mayo score, the IBDQ, the WPAI:UC, the EQ-5D-5L, the SF-36, the FACIT-F, the UC-SQ, the PGIC, and combinations thereof.
  • the treatment of a patient having ulcerative colitis, and/or the induction of clinical remission of ulcerative colitis and/or the induction of clinical response and/or endoscopic improvement and/or endoscopic remission in a patient comprises an induction phase and a maintenance phase.
  • one or more doses of the JAK1 inhibitor for example referred to herein as induction doses
  • the maintenance phase a first dose of the JAK1 inhibitor, for example referred to herein as the maintenance dose, is administered to the patient followed by at least one additional dose of the JAK1 inhibitor, for example, also referred to herein as a maintenance dose.
  • the maintenance doses are, for example, administered orally.
  • the JAK1 inhibitor may be, for example, upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. Examples of induction phases and maintenance phases are described herein.
  • a certain therapeutic result is achieved by the patient during or at the end of the induction phase, for example clinical remission.
  • the therapeutic result achieved by the patient during or at the end of the induction phase is selected from the group consisting of endoscopic subscore of 0 or 1 at week 8, endoscopic subscore of 0 at week 8, fecal calprotectin below 150 mg/kg at week 8.
  • IBDQ response increase of IBDQ ⁇ 16 from baseline
  • RBS of 0 at week 8 or RBS of 0 at week 8.
  • the patient achieves clinical remission during or by the end of the induction phase.
  • the patient achieves endoscopic remission during or by the end of the induction phase.
  • the patient achieves endoscopic improvement of ulcerative colitis during or by the end of the induction phase. In one aspect, the patient achieves clinical remission and endoscopic improvement of ulcerative colitis during or at the end of the induction phase.
  • the induction phase lasts for up to 16 weeks (e.g., for up to 16 weeks following initiation of administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction phase is 16 weeks.
  • the induction phase optionally lasts for less than 16 weeks, for instance, for 2 weeks, for 3 weeks, for 4 weeks, for 5 weeks, for 6 weeks, for 7 weeks, for 8 weeks, for 9 weeks, for 10 weeks, for 11 weeks, for 12 weeks, for 13 weeks, for 14 weeks, or for 15 weeks.
  • the patient achieves an endoscopic remission within 8 weeks, or within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one aspect, the patient achieves a clinical remission within 8 weeks, or within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one aspect, the patient achieves an endoscopic improvement within 8 weeks, or within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a clinical response within 8 weeks, or within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one aspect, the patient achieves a clinical remission within 8 weeks, or within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves clinical remission within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves clinical response within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves clinical response within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves endoscopic improvement or endoscopic remission within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves endoscopic improvement or endoscopic remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves endoscopic improvement or endoscopic remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves endoscopic improvement or endoscopic remission within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves corticosteroid-free remission within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves corticosteroid-free remission within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the corticosteroid-free remission is a clinical remission. In one embodiment, the corticosteroid-free remission is endoscopic remission.
  • the patient achieves at least one therapeutic result selected from the group consisting of:
  • the patient achieves a clinical remission within 16 weeks or within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21) and combinations thereof.
  • the induction phase is 16 weeks.
  • the additional therapeutic result is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and is selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11) and combinations thereof.
  • the induction phase is 8 weeks, and the patient achieves a clinical remission within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21) and combinations thereof.
  • the additional therapeutic result is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the additional therapeutic result is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and is selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11) and combinations thereof.
  • the induction phase is 4 weeks, and the patient achieves a clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves any combination of additional therapeutic results selected from the group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21) and combinations thereof.
  • the additional therapeutic result is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the additional therapeutic result is achieved within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and is selected from the group consisting of endoscopic improvement, clinical remission, clinical response, endoscopic remission, histologic improvement, and combinations thereof.
  • the patient achieves a clinical remission within 4 weeks, within 8 weeks, within 12 weeks, or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves an endoscopic improvement within 4 weeks, within 8 weeks, within 12 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, and further achieves an additional therapeutic result selected from the group consisting of a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; clinical response per Partial Mayo score within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus
  • the patient achieves a clinical remission within 12 weeks or within 16 weeks of initiating administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof, and/or achieves a clinical remission per Adapted Mayo score (defined as SFS ⁇ 1, RBS or 0, and endoscopy subscore ⁇ 1) within 12 weeks of initiation administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a clinical response per Adapted Mayo score (defined as decrease from BL in the Adapted Mayo score ⁇ 2 points and ⁇ 30% from BL, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 at week 12 or 16.
  • the induction phase is 16 weeks
  • the additional therapeutic result is selected from the group consisting of a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 16 weeks, within 12 weeks, within 8 weeks, within 4 weeks or within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic remission within 16 weeks, within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 16, within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement within 16 weeks, within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a
  • the induction phase is 12 weeks
  • the additional therapeutic result is selected from the group consisting of a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 12 weeks, within 8 weeks, within 4 weeks, or within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic remission within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, an endoscopic improvement within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a Full Mayo score ⁇ 2 with no subscore >
  • the induction phase is 8 weeks
  • the additional therapeutic result is selected from the group consisting of a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 48 weeks, 8 weeks, within 4 weeks, or within 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic remission within 8 weeks or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 8 weeks or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement within 8 weeks or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a Full Mayo score ⁇ 2 with no subscore >1 within 8 weeks or within 4 weeks of initiating administration of upad
  • the patient achieves clinical remission within 16 weeks, or within 12 weeks, or within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient is one who was taking corticosteroids at baseline but who discontinued corticosteroid use during treatment with the JAK1 inhibitor.
  • the additional therapeutic result may be a Full Mayo score ⁇ 2 with no subscore >1 within 16 weeks, or within 12 weeks, or within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient is one who was taking corticosteroids at baseline but who discontinued corticosteroid use during treatment with the JAK1 inhibitor.
  • the additional therapeutic result may be selected from the group consisting of an endoscopic remission within 16 weeks, within 12 weeks, within 8 weeks, or within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 16 weeks, or 12 weeks, or 8 weeks, or 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 16 weeks, or 12 weeks, or 8 weeks, or 4 weeks, or 2 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 within 16 weeks, or 12 weeks, or 8 weeks, or 4
  • the additional therapeutic result may be an Adapted Mayo score (defined as SFS ⁇ 1, RBS of 0, and endoscopy subscore ⁇ 1) at 16 weeks, or within 12 weeks, or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient is one who was taking corticosteroids at baseline but who discontinued corticosteroid use during treatment with the JAK1 inhibitor.
  • the additional therapeutic result may be selected from the group consisting of an endoscopic remission within 16 weeks, within 12 weeks, or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a clinical response within 16 weeks, or 12 weeks, or 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 16 weeks, or 12 weeks, or 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 within 16 weeks, or 12 weeks, or 8 weeks, or 4 weeks of initiating administration of upadacitinib, or
  • the induction phase is 8 weeks, and the patient achieves a clinical remission (SF subscore ⁇ 1, RBS of 0 and endoscopic subscore ⁇ 1) within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof and an endoscopic improvement (i.e., an endoscopic subscore ⁇ 1) within 6 weeks or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • SF subscore ⁇ 1, RBS of 0 and endoscopic subscore ⁇ 1 within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof
  • an endoscopic improvement i.e., an endoscopic subscore ⁇ 1
  • the induction phase is 4 weeks, and the patient achieves a clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof and an endoscopic improvement within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction phase is 8 weeks, and the patient achieves a clinical remission within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof and further achieves a full Mayo score ⁇ 2, with no subscore >1 within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement (i.e., an endoscopic subscore ⁇ 1) within 6 weeks or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; or combinations thereof.
  • an endoscopic improvement i.e., an endoscopic subscore ⁇ 1
  • the induction phase is 4 weeks, and the patient achieves a clinical remission within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof and further achieves a full Mayo score ⁇ 2, with no subscore >1 within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; an endoscopic improvement within 4 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; or combinations thereof.
  • the patient is administered upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, for at least 52 weeks.
  • the administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof may include an induction phase (e.g., an induction phase of up to 16 weeks), and additional weeks (e.g., 36 weeks or longer) of a maintenance phase (discussed hereinafter).
  • the administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof may include a shorter induction phase (e.g., up to 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.), and a longer maintenance phase (e.g., a 12 week induction phase and a 40 week or longer maintenance phase).
  • a shorter induction phase e.g., up to 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.
  • a longer maintenance phase e.g., a 12 week induction phase and a 40 week or longer maintenance phase.
  • the induction phase is 8 weeks and the maintenance phase is 44 weeks.
  • the patient may achieve at least one therapeutic result selected from the group consisting of: clinical remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; endoscopic remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; full Mayo score ⁇ 2, with no subscore >1 within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; clinical response within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; endoscopic improvement within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS
  • the patient when the patient is administered upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, for at least 52 weeks, the patient is one who was taking corticosteroids at baseline but who discontinued corticosteroid use during treatment with the JAK1 inhibitor, and the therapeutic result may be selected from the group consisting of clinical remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a endoscopic remission within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; a Full Mayo score ⁇ 2 with no subscore >1 within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; clinical response within 52 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof; decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease
  • a patient is evaluated during or at the end of the induction phase for a therapeutic result selected from the group consisting of clinical remission, a Full Mayo score ⁇ 2 with no subscore >1, endoscopic improvement, endoscopic remission, clinical response, decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1, a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time, SF sub score, rectal bleeding subscore, endoscopic subscore, histologic improvement, fecal calprotectin level, hs-CRP, IBDQ score, and combinations thereof.
  • a therapeutic result selected from the group consisting of clinical remission, a Full Mayo score ⁇ 2 with no subscore >1, endoscopic improvement, endoscopic remission, clinical response, decrease from baseline in Full Mayo score ⁇ 3 points and ⁇
  • a patient is evaluated for clinical remission during or at the end of the induction phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for endoscopic improvement during or at the end of the induction phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for achievement of Full Mayo score ⁇ 2 with no subscore >1 during or at the end of the induction phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for endoscopic remission during or at the end of the induction phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for clinical response during or at the end of the induction phase.
  • a patient in a method of the present disclosure, is evaluated for decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time during or at the end of the induction phase.
  • a patient in a method of the present disclosure, is evaluated for change in Full Mayo score from baseline during or at the end of the induction phase.
  • a patient in a method of the present disclosure, a patient is evaluated for histologic improvement during or at the end of the induction phase.
  • the induction phase is 2 weeks. In one embodiment, the induction phase is 8 weeks. In one embodiment, the induction phase is 12 weeks.
  • a patient is evaluated during or at the end of the maintenance phase for a therapeutic result selected from the group consisting of endoscopic improvement, achievement of Full Mayo score ⁇ 2 with no subscore >1, discontinuation of corticosteroid use and clinical remission per Adapted Mayo score, maintenance of clinical remission among subjects who achieved clinical remission during the induction phase, endoscopic improvement among subjects who achieved clinical remission during the induction phase, clinical response, endoscopic remission, histologic improvement, and combinations thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by being corticosteroid-free for 44 weeks after discontinuing corticosteroids. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving clinical remission 4 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving clinical remission 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving clinical remission 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving Full Mayo score ⁇ 2 with no subscore >1 within 52 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving clinical remission defined as stool frequency subscore ⁇ 1, rectal bleeding subscore of 0, and endoscopic subscore ⁇ 1 with absence of friability within 52 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a SF subscore of 0, a RBS of 0, and endoscopic subscore of 0.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 2 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 4 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score 12 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving clinical response or a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 2 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving clinical response or a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 4 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving clinical response or a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of 1 or an absolute RBS of 0 or 1.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline, plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1 over time within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving stool frequency subscore ⁇ 1 within 2 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving stool frequency subscore ⁇ 1 within 4 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving stool frequency subscore ⁇ 1 within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving rectal bleeding subscore of 0 over time.
  • a patient is evaluated for a therapeutic result by achieving an endoscopic subscore of ⁇ 1 within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving an endoscopic improvement within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving fecal calprotectin below 150 mg/kg within 4 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving fecal calprotectin below 150 mg/kg within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving fecal calprotectin below 150 mg/kg within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving an IBDQ response (increase of IBDQ ⁇ 16 from Baseline) within 2 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving an IBDQ response (increase of IBDQ ⁇ 16 from Baseline) within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving an IBDQ response (increase of IBDQ ⁇ 16 from Baseline) within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a change from Baseline in hs-CRP within 2 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a change from Baseline in hs-CRP within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving a change from Baseline in hs-CRP within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a change in Baseline in fecal calprotectin within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving a change in Baseline in fecal calprotectin within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving a change in corticosteroid dose within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in Adapted Mayo score. Full Mayo score, Partial Mayo score and/or Mayo subscores within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change form Baseline in UCEIS scores within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by achieving histologic remission (defined as Geboes score ⁇ 2) within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • histologic remission defined as Geboes score ⁇ 2
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by achieving histologic remission (defined as Geboes score ⁇ 2) within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in histologic score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • histologic remission defined as Geboes score ⁇ 2
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in histologic score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, hematocrit, albumin, total protein concentration, and weight) within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, hematocrit, albumin, total protein concentration, and weight) within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • nutritional parameters e.g., hemoglobin, hematocrit, albumin, total protein concentration, and weight
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change in Baseline in subject-reported stool frequency (absolute values) within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change in Baseline in subject-reported stool frequency (absolute values) within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in IBDQ score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in IBDQ score within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient is evaluated for a therapeutic result by change from Baseline in EQ-5D-5L score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in EQ-5D-5L score within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in WPAI:UC scores within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in WPAI:UC scores within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change in SF-36, PCT, MCS components and domain scores within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient is evaluated for a therapeutic result by change in SF-36, PCT, MCS components and domain scores within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient is evaluated for a therapeutic result by change in PGIC score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient is evaluated for a therapeutic result by change in PGIC score within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient is evaluated for a therapeutic result by change from Baseline in FACIT-F score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in FACIT-F score within 12 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, in a method of the present disclosure, a patient is evaluated for a therapeutic result by change from Baseline in UC-SQ score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • a patient in a method of the present disclosure, is evaluated for a therapeutic result by change from Baseline in UC-SQ score within 8 weeks after initial administration of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient is administered at least 14 doses, 28 doses, or at least 42 doses, or at least 56 doses of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, during the induction phase.
  • a certain therapeutic result is maintained by the patient during the maintenance phase.
  • the maintenance phase may last for an indefinite period of time.
  • the maintenance phase is at least 36 weeks, including at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks after the patient achieves clinical remission or clinical response after the patient achieves clinical remission or clinical response.
  • the maintenance phase is at least 40 additional weeks.
  • the maintenance phase is at least 44 additional weeks after the patient achieves clinical remission or clinical response.
  • the therapeutic result maintained by the patient during the maintenance phase is selected from the group consisting of clinical remission, a Full Mayo score ⁇ 2 with no subscore >1, endoscopic remission, clinical response, a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1, endoscopic improvement, and combinations thereof.
  • the therapeutic result maintained by the patient during the maintenance phase is endoscopic remission.
  • the therapeutic result maintained by the patient during the maintenance phase is endoscopic response.
  • the therapeutic result maintained by the patient during the maintenance phase is clinical remission.
  • the therapeutic result maintained by the patient during the maintenance phase is corticosteroid-free remission.
  • a patient is evaluated for clinical remission during the maintenance phase. In one embodiment, a patient is evaluated for endoscopic improvement during the maintenance phase. In one embodiment, a patient is evaluated for clinical remission a Full Mayo score ⁇ 2 with no subscore >1 during the maintenance phase. In one embodiment, in a method of the present disclosure, a patient is evaluated for endoscopic remission during the maintenance phase.
  • a patient is evaluated for clinical response, or a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, or a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 during the maintenance phase.
  • the present disclosure provides a method for treating an inflammatory disease, in one aspect for treating ulcerative colitis, comprising (a) administering to a patient a dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) at week 0 and once daily (QD) thereafter for 8 weeks, wherein the dose is 45 mg QD.
  • the method further comprises (b) administering to the patient additional doses once daily thereafter for at least 44 additional weeks, wherein the dose is 15 mg or 30 mg QD.
  • the dose is administered orally.
  • a patient is evaluated for clinical remission and/or for a Full Mayo score ⁇ 2 with no subscore >1.
  • 8 weeks after initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof a patient is evaluated for clinical response and/or for a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, and/or for a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 and/or for endoscopic improvement and/or for endoscopic remission.
  • a patient is evaluated for clinical remission and/or a Full Mayo score ⁇ 2 with no subscore ⁇ 1 and/or for endoscopic remission.
  • a patient is evaluated for a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 and/or clinical response and/or a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 230% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission and/or for a Full Mayo score ⁇ 2 with no subscore >1 and/or for endoscopic remission.
  • a patient is evaluated for a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 and/or for clinical response and/or for a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission and/or for a Full Mayo score ⁇ 2 with no subscore >1 and/or for endoscopic remission.
  • a patient is evaluated for a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS of 0 or 1 and/or for clinical response and/or for a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30% from baseline plus a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1, and/or for endoscopic improvement.
  • a patient is evaluated for clinical remission per Adapted Mayo score (defined sa SFS ⁇ 1, RBS of 0, and endoscopy subscore ⁇ 1), clinical remission per Full Mayo score (defined as a Full Mayo score ⁇ 2 with no subscore >1), clinical remission per Partial mayo score (defined as Partial Mayo score ⁇ 2 with no subscore >1) over time, clinical remission defined as stool frequency subscore ⁇ 1, rRBS of 0 and endoscopic subscore ⁇ 1 with absence of friability and clinical response per Adapted mayo score (defined as decrease from BL in the Adapted Mayo score ⁇ 2 points and ⁇ 30% from BL, plus a decrease in RBS ⁇ 1).
  • clinical remission per Adapted Mayo score defined sa SFS ⁇ 1, RBS of 0, and endoscopy subscore ⁇ 1
  • clinical remission per Full Mayo score defined as a Full Mayo score ⁇ 2 with no subscore >1
  • the present disclosure provides a method for treating ulcerative colitis, comprising (a) administering to a patient a dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) at week 0 and once daily thereafter via an oral route, wherein the doses of the JAK1 inhibitor comprise 15 mg, 30 mg, or 45 mg QD, or any combination thereof.
  • a JAK1 inhibitor e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof
  • the present disclosure provides a method for treating ulcerative colitis, comprising administering to a patient 15 mg to 45 mg of a JAK1 inhibitor. In one embodiment, the present disclosure provides a method for treating ulcerative colitis, comprising administering to a patient orally 15 mg of a JAK1 inhibitor QD. In one embodiment, the present disclosure provides a method for treating ulcerative colitis, comprising administering to a patient orally 30 mg of a JAK1 inhibitor QD. In one embodiment, the present disclosure provides a method for treating ulcerative colitis, comprising administering to a patient orally 45 mg of a JAK1 inhibitor QD.
  • the JAK1 inhibitor may be upadacitinib or a pharmaceutically acceptable salt or solid state form thereof. In any such embodiment, the JAK1 inhibitor may be in a once daily modified release formulation. In any such embodiment, the patient may have moderately to severely active ulcerative colitis prior to treatment.
  • a JAK1 inhibitor according to the present disclosure is further described in the Examples herein below or in FIG. 13 .
  • the present disclosure provides a method for treating ulcerative colitis, said method comprising a) administering at least one induction dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof) to a patient, wherein said induction dose comprises 15 mg to 45 mg of the JAK 1 inhibitor.
  • the induction dose comprises 15 mg or 30 mg or 45 mg.
  • the induction dose comprises 45 mg.
  • the induction dose is administered orally.
  • the induction dose is administered QD.
  • the induction dose is administered for 8 weeks.
  • the induction dose is administered for 6 weeks.
  • the induction dose is administered for 4 weeks.
  • the induction dose is administered for up to 12 weeks, including for 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.
  • the induction dose comprises 45 mg of the JAK inhibitor administered QD.
  • the induction dose comprises 30 mg of the JAK1 inhibitor administered QD.
  • the induction dose comprises 15 mg of the JAK1 inhibitor administered QD.
  • the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the induction dose is in a once daily modified release formulation.
  • the method further comprises b) administering a first maintenance dose of a JAK1 inhibitor (e.g., upadacitinib, or pharmaceutically acceptable salt or solid state form thereof), to the patient after the last induction dose is administered; and c) administering at least one additional maintenance dose to the patient once daily thereafter.
  • a JAK1 inhibitor e.g., upadacitinib, or pharmaceutically acceptable salt or solid state form thereof
  • the first maintenance dose comprises 15 mg to 30 mg of the JAK1 inhibitor. In one aspect, the first maintenance dose comprises 15 mg or 30 mg of the JAK1 inhibitor. In one aspect, the first maintenance dose is smaller than the induction dose. In one aspect, the first maintenance dose is administered QD. In one aspect the first maintenance dose is 15 mg. In one aspect the first maintenance dose is 30 mg. In one aspect, the first maintenance dose is administered orally. In one aspect, the first maintenance dose is in a once daily modified release formulation.
  • the at least one additional maintenance dose comprises 15 mg to 30 mg of the JAK 1 inhibitor. In one aspect, the at least one additional maintenance dose comprises 15 mg or 30 mg. In one aspect, the at least one additional maintenance dose is administered orally. In one aspect, the at least one additional maintenance dose is administered QD. In one embodiment, the at least one additional maintenance dose comprises 15 mg of the JAK1 inhibitor administered QD. In one embodiment, the at least one additional maintenance dose comprises 30 mg of the JAK1 inhibitor administered QD. In one aspect, the at least one additional maintenance dose is in a once daily modified release formulation.
  • the JAK1 inhibitor may be upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient is one who had an inadequate response to or experienced a loss of response to or intolerance to conventional treatment (e.g., aminosalicylate, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent.
  • conventional treatment e.g., aminosalicylate, corticosteroids, immunosuppressants
  • biologic agent e.g., aminosalicylate, corticosteroids, immunosuppressants
  • the patient is one who had an inadequate response to, a loss of response to, or experienced intolerance to a previous treatment with an anti-TNF agent.
  • the patient is one who is na ⁇ ve to previous treatment with an aminosalicylate, a corticosteroid, an immunosuppressant, a biologic agent or an anti-TNF agent.
  • the patient is one who had moderately to severely active ulcerative colitis prior to treatment or administration of the induction dose.
  • the present disclosure further provides a method for inducing clinical remission of ulcerative colitis or a Full Mayo score of ⁇ 2 with no subscore >1 in a patient, said method comprising a) administering to the patient at least one induction dose of a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • a JAK1 inhibitor as described above or herein
  • the induction dose comprises 30 mg to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks), wherein the dose is 30 mg QD or 45 mg QD.
  • the method further comprises maintaining clinical remission of ulcerative colitis or a Full Mayo score of ⁇ 2 with no subscore >1, said method further comprising b) administering a first maintenance dose of said JAK1 inhibitor to the patient after the last induction dose is administered and c) administering at least one additional maintenance dose to the patient thereafter as described above or herein. In one embodiment, the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks, or at least 420 weeks.
  • the additional maintenance doses are administered once daily for at least 44 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopy subscore of 2 or 3 before administration of the first induction dose.
  • the patient has moderately to severely active ulcerative colitis prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid, an immunosuppressant, a biologic agent, and/or an anti-TNF agent.
  • the clinical remission or Full Mayo score of ⁇ 2 with no subscore >1 is achieved within 4 weeks or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the clinical remission or a Full Mayo score of ⁇ 2 with no subscore >1 is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the clinical remission or Full Mayo score of ⁇ 2 with no subscore >1 is achieved within 10 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical remission or Full Mayo score of ⁇ 2 with no subscore >1 is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a stool frequency subscore ⁇ 1, RBS of 0 and endoscopic subscore ⁇ 1 before administration of the first maintenance dose.
  • the patient achieves a full Mayo score of ⁇ 2 with no subscore >1 before administration of the first maintenance dose.
  • the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure provides a method for inducing endoscopic remission of ulcerative colitis, the method comprising (a) administering to a patient at least one induction dose of a JAK inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof), wherein the induction dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • a JAK inhibitor e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks), wherein the dose is 30 mg QD or 45 mg QD.
  • the method further comprises maintaining endoscopic remission of ulcerative colitis, said method further comprising (b) administering to the patient a first maintenance dose of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, after the last induction dose is administered, and (c) administering at least one additional maintenance dose once daily thereafter as described above or herein. In one embodiment, the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks, or at least 420 weeks.
  • the additional maintenance doses are administered once daily for at least 44 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2 or 3 before administration of the first induction dose.
  • the patient has moderately to severely active ulcerative colitis prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic and/or an anti-TNF agent.
  • the patient is na ⁇ ve to previous treatment with an aminosalicylate, a corticosteroid, an immunosuppressant, an anti-TNF agent and/or a biologic agent.
  • the endoscopic remission is achieved within 4 weeks or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the endoscopic remission is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the endoscopic remission is achieved within 10 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the endoscopic remission is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves an endoscopic subscore of 0 before administration of the first maintenance dose. In one embodiment, the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure further provides a method for inducing clinical response or inducing a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30% accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or inducing a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 in an ulcerative colitis in a patient, said method comprising a) administering to the patient at least one induction dose of a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction dose comprises 30 mg to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 8 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks), wherein the dose is 30 mg QD or 45 mg QD.
  • the method further comprises maintaining clinical response of ulcerative colitis or maintaining a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or maintaining a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1, said method further comprising b) administering a first maintenance dose of said JAK1 inhibitor to the patient after the last induction dose is administered and c) administering at least one additional maintenance dose to the patient thereinafter as described above or herein. In one embodiment, the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks, or at least 420 weeks.
  • the additional maintenance doses are administered once daily for at least 44 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2 or 3 before administration of the first induction dose.
  • the patient has moderately to severely active ulcerative colitis prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the clinical response or the decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or the decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 is achieved within 4 weeks or within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical response or the decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical response or the decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or the decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 is achieved within 10 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the clinical response, or the decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or the decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the patient achieves a decrease from baseline in Adapted Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of 0 or 1 before administration of the first maintenance dose. In one embodiment, the patient achieves a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 before administration of the first maintenance dose.
  • the patient achieves a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS from baseline of ⁇ 1 or an absolute rectal bleeding subscore of 0 or 1 before administration of the first maintenance dose.
  • the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure further provides a method for inducing endoscopic improvement of ulcerative colitis in a patient, said method comprising a) administering to the patient at least one induction dose of a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • a JAK1 inhibitor as described above or herein (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof).
  • the induction dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • an induction dose is administered at week 0 and once daily (QD) thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks) wherein the dose is 30 mg QD or 45 mg QD.
  • the method further comprises maintaining endoscopic improvement of ulcerative colitis, said method further comprising b) administering a first maintenance dose of said JAK1 inhibitor to the patient after the last induction dose is administered and c) administering at least one additional maintenance dose to the patient thereinafter as described above or herein.
  • the at least one additional maintenance dose is administered once daily.
  • the additional maintenance doses are administered once daily for at least 36 additional weeks, including for at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks, or at least 420 weeks.
  • the additional maintenance doses are administered once daily for at least 44 additional weeks.
  • the maintenance dose is 15 mg or 30 mg QD.
  • the induction and maintenance doses are administered orally.
  • the patient has active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2 or 3 before administration of the first induction dose.
  • the patient has moderately to severely active ulcerative colitis prior to administration of the first induction dose.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylate, corticosteroids, and immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylate, corticosteroids, and immunosuppressants
  • the patient is na ⁇ ve to previous treatment with an aminosalicylate a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the endoscopic improvement is achieved within 8 weeks or within 16 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the endoscopic improvement is achieved within 12 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the endoscopic improvement is achieved within 10 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the endoscopic improvement is achieved within 8 weeks of initiating administration of upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof. In one embodiment, the patient achieves an endoscopic subscore ⁇ 1 before administration of the first maintenance dose. In one embodiment, the induction and maintenance doses are in once-daily, modified release formulations.
  • the present disclosure further provides a method of maintaining clinical remission or a method of maintaining a Full Mayo score ⁇ 2 with no subscore >1 of ulcerative colitis in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, or at least 44 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is a in once-daily, modified release formulation.
  • the present disclosure further provides a method of maintaining clinical response or a method of maintaining a decrease from baseline in Full Mayo score ⁇ 3 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute RBS or 0 or 1 or a method of maintaining a decrease from baseline in Partial Mayo score ⁇ 2 points and ⁇ 30%, accompanied by a decrease in RBS of ⁇ 1 or an absolute rectal bleeding subscore of ⁇ 1 in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is a in once-daily, modified release formulation.
  • the present disclosure further provides a method of maintaining endoscopic improvement or endoscopic remission of ulcerative colitis in a patient, said method comprising administering 15 mg or 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof to the patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered once daily for at least 36 weeks, including for at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is administered orally.
  • the patient has had an inadequate response to or experienced intolerance to a conventional treatment (e.g., aminosalicylates, corticosteroids, immunosuppressants) or to a previous treatment with a biologic agent and/or an anti-TNF agent.
  • a conventional treatment e.g., aminosalicylates, corticosteroids, immunosuppressants
  • the patient is na ⁇ ve to previous treatment with aminosalicylates, a corticosteroid, an immunosuppressant, a biologic agent and/or an anti-TNF agent.
  • the patient is a refractory patient.
  • the upadacitinib or a pharmaceutically acceptable salt or solid state form thereof is a in once-daily, modified release formulation.
  • induction doses for the methods disclosed herein are administered for 8 weeks in a dose regimen described in Table 12. In one aspect, induction doses are administered for 8 weeks in a dose regimen described in Table 12. In one aspect, maintenance doses are administered for 44 weeks or more in a dose regimen described in Table 12. In one aspect, induction doses for the methods disclosed herein are administered for 8 weeks and the maintenance doses are administered for 44 weeks in a dosing regimen as described in Table 12.
  • the induction dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • the induction dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 15 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • the induction dose is 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD. In one embodiment, the induction dose is 30 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 15 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • the induction dose is 30 mg or 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 15 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD. In one embodiment, the induction dose is 30 mg or 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD, and the maintenance dose, and any additional maintenance dose administered thereafter, is 7.5 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof administered QD.
  • upadacitinib may be synthesized using synthetic transformations such as those illustrated in Schemes I-IIIa.
  • Starting materials are commercially available, may be prepared by the procedures described in U.S. patent application Ser. No. 15/295,561, by literature procedures, or by procedures that would be well known to one skilled in the an of organic chemistry (see, for example, Larock. R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd edition”, 1999, Wiley-VCH or Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3 rd Edition”, 1999, Wiley-Interscience).
  • the protecting group may be any suitable protecting group known in the art.
  • the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.
  • the protecting group is carboxybenzyl.
  • R 1 is —OR 2 , and R, is methyl or ethyl.
  • the compound of formula (IV) is a compound of formula (IVa):
  • R 2 is methyl or ethyl
  • a pharmaceutically acceptable salt of a compound of the compound of formula (I) is used in the reaction of step (a).
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of the naphthalenethane amine salt (Ia) and the dicyclohexylamine salt (Ib)
  • the pharmaceutically acceptable salt of compound (VII) is selected from the group consisting of (VIIa), (VIIb), and (VIIc)
  • step (a) of Schemes I and Ia is generally accomplished in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base.
  • a coupling agent such as carbonyldiimidazole (CDI)
  • the strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide, or combinations thereof.
  • the step (a) reaction may be conducted in any suitable solvent including, but not limited to, tetrahydrofuran, water, and methyl ten-butylether. In one embodiment, the reaction is conducted in the presence of carbonyldiimidazole and potassium tert-butoxide.
  • a solution of a compound of formula (I), (Ia), or (Ib) in solvent is slowly added (e.g., over 30 minutes) to a slurry of CDI in solvent, and the resulting mixture is stirred at room temperature for 30 minutes to 12 hours, and typically for about 1 hour.
  • the resulting solution is slowly added (e.g., over 15 minutes) to a suspension of the trimethylsulfoxonium chloride, strong base, and solvent, while maintaining the internal temperature below ⁇ 1° C.
  • the reaction is quenched and the resulting compound of formula (II) or (IIa) is isolated prior to step (b).
  • the reaction of step (a) may further involve contact of (Ia) or (Ib) with an acid prior to reaction with the trimethylsulfoxonium chloride, in order to extract the amine to obtain a compound of formula (I).
  • Suitable acids include any mineral acid or organic acid, such as phosphoric acid, hydrochloric acid (HCl), acetic acid (HOAc), citric acid, and the like.
  • the compound of formula (I) may subsequently be taken up in a suitable solvent, and reacted with trimethylsulfoxonium chloride, as described herein.
  • a pharmaceutically acceptable salt of a compound of formula (I) is used in step (a), wherein the pharmaceutically acceptable salt is (Ia) or (Ib).
  • step (b) of Schemes I and Ia a compound of formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of formula (III) or (IIIa), respectively.
  • the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid.
  • LiX may be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is conducted in lithium bromide and p-toluenesulfonic acid.
  • the reaction of step (b) may be conducted in any suitable solvent including, but not limited to tetrahydrofuran, ethyl acetate, heptanes, ethanol, water, and combinations thereof.
  • the sulfonic acid is added to a solution of the compound of formula (II) or (IIa) and LiX in a solvent.
  • the resulting mixture is warmed to about 35° C. to about 65° C. and stirred overnight. In one embodiment, the mixture is warmed to about 40° C. and stirred overnight.
  • the mixture is cooled to room temperature and washed.
  • the compound of formula (III) or (IIIa) may be isolated, or optionally used in the next step without purification.
  • step (c) of Schemes I and Ia a compound of formula (III) or (IIIa) are reacted with a compound of formula (IV) or (IVa) (prepared as described herein).
  • the step (c) reaction is conducted in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or combinations thereof.
  • the base is lithium tert-butoxide.
  • the reaction of step (c) may be conducted in any suitable solvent including, but not limited to dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, and combinations thereof.
  • the base is added to a cooled suspension of the compound of formula (III) or (IIIa) in a solvent.
  • the resulting solution is stirred for about 30 minutes to about 12 hours, or about 30 minutes, and cooled to about ⁇ 20° C. to about 0°, or about ⁇ 10° C.
  • the solution is stirred for about 30 minutes and cooled to about ⁇ 20° C. to about 0°.
  • a solution of a compound of formula (IV) or (IVa) in a solvent is slowly added (e.g., over 30 minutes), and the resulting mixture is stirred for about 30 minutes to about 6 hours, or about 30 minutes, at a temperature of about ⁇ 20° C.
  • the resulting mixture is stirred for about 30 minutes at a temperature of about ⁇ 10° C.
  • the reaction is quenched, and, in some embodiments, the resulting product (V) or (Va) is isolated prior to step (d).
  • a compound of formula (V) or (Va) is contacted with a perfluoro acid anhydride and an organic base to form a compound of formula (VI) or (VIa), respectively.
  • suitable organic bases include pyridine, triethylamine, and combinations thereof.
  • suitable perfluoro acid anhydrides include trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, and combinations thereof.
  • the organic base is pyridine and the perfluoro acid anhydride is trifluoroacetic anhydride.
  • the organic base is triethylamine
  • the perfluoro acid anhydride is pentafluoropropionic anhydride.
  • Suitable solvents for use in step (d) include, but are not limited to acetonitrile, toluene, and combinations thereof.
  • the organic base and the perfluoro acid anhydride are charged into a solution of a compound of formula (V) or (Va) in solvent.
  • the resulting mixture is warmed to about 55° C. to about 75° C., or about 55° C. and stirred for about 4 hours to about 18 hours, or about 6 hours.
  • the mixture of perfluoro acid anhydride and the compound of formula (V) or (Va) is warmed to about 55° C. and stirred for about 4 hours to about 18 hours. In one embodiment, the mixture is stirred for about 6 hours.
  • the reaction mixture may be cooled, and concentrated prior to contacting with a hydroxide solution to quench excess reagents, and remove the tosyl protecting group.
  • Suitable hydroxide solutions include a sodium hydroxide (NaOH) solution, a potassium hydroxide (KOH) solution, and the like.
  • the resulting mixture may be stirred at room temperature to about 85° C., including at about 55° C., for about 30 minutes to about 8 hours. In one embodiment, the mixture is stirred for about 1 hour.
  • the solvent may optionally be removed and switched to methanol, ethanol, isopropanol, or other suitable solvents prior to step (e).
  • step (e) of Schemes I and Ia a compound of formula (VI) or (VIa) is deprotected, and a pharmaceutically acceptable salt of compound (VII), such as (VIIa), (VIIb), or (VIIc) is formed.
  • the protecting group on the compound of formula (VI) or (VIa) may be removed using any suitable means known in the art.
  • deprotection occurs by contacting the compound of formula (VI) or (VIa) with palladium on carbon (e.g., Pd/C or Pd(OH 2 )/C) under hydrogen pressure.
  • deprotection occurs by contacting the compound of formula (VI) or (VIa) with an acid.
  • Non-limiting examples of suitable acids include hydrochloric acid (HCl), hydrobromic acid (HBr), hydrobromic acid in acetic acid (e.g., HBr/HOAc), and the like.
  • deprotection occurs by subjecting the compound of formula (VI) or (VIa) to heating, e.g., at a temperature of from room temperature to about 85° C., including about 50° C.
  • the compound of formula (VII) is contacted with the appropriate acid (e.g., hydrochloric acid or p-toluenesulfonic acid) to form the pharmaceutically acceptable salt.
  • the appropriate acid e.g., hydrochloric acid or p-toluenesulfonic acid
  • Step (e) may occur in any suitable solvent including, but not limited to ethanol, isopropyl acetate, ethyl acetate, and combinations thereof.
  • palladium on carbon and the compound of formula (VI) or (VIa) in solvent are mixed under hydrogen pressure at about 1 psig to about 100 psig. In another embodiment, the hydrogen pressure is about 20 psig.
  • the mixture is agitated for about 2 hours to about 24 hours, including about 16 hours, at about 20° C. to about 85° C., including about 50° C. In one embodiment, the mixture is agitated for about 16 hours at about 20° C. to about 80° C. In one embodiment, the mixture is agitated for about 16 hours at about 50° C.
  • the reaction mixture is cooled and filtered, followed by addition of the appropriate acid.
  • the resulting salt is optionally isolated prior to step (f).
  • step (f) the salt produced in step (e) is reacted with 2,2,2-trifluoroethylamine to produce upadacitinib.
  • the step (f) reaction is conducted in the presence of a coupling agent, such as carbonyldiimidazole (CDT), and optionally buffers, such as dipotassium phosphate, potassium hydroxide, and combinations thereof.
  • a coupling agent such as carbonyldiimidazole (CDT)
  • optionally buffers such as dipotassium phosphate, potassium hydroxide, and combinations thereof.
  • the step (f) reaction is conducted in the presence of CDI, dipotassium phosphate, and potassium hydroxide.
  • the step (f) reaction may be conducted in any suitable solvent including, but not limited to, tetrahydrofuran, ethyl acetate, heptanes, ethanol, water, and combinations thereof.
  • 2,2,2-trifluoroethyl amine is added slowly (e.g., over 20 minutes) to a slurry of CDI in solvent, while maintaining an internal temperature of less than 30° C.
  • the resulting solution is stirred for about 10 minutes to about 12 hours, and in one embodiment for about 1 hour, to form an imidazolide solution.
  • the pH of a biphasic mixture of the pharmaceutically acceptable salt from step (e) in buffer and solvent is adjusted to about 7 to about 11, and in one embodiment to about 9, by addition of a base.
  • the imidazolide solution is added, and the resulting mixture is mixed at about 25° C. while maintaining a pH of about 9 by portionwise addition of base for about 30 minutes to about 18 hours.
  • the mixture formed after addition of the imidazolide solution is mixed at about 25° C. while maintaining a pH of about 9 by portionwise addition of base for about 1 hour. In one embodiment, upon completion, the reaction is quenched and the resulting product isolated.
  • the protecting group may be any suitable protecting group known in the art.
  • the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.
  • the protecting group is carboxybenzyl.
  • R 1 is —OR 2
  • R 2 is ethyl or methyl
  • a pharmaceutically acceptable salt of the compound of formula (I) is used in the reaction of step (a).
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of the naphthalenethane amine salt (Ia) and the dicyclohexylamine salt (Ib).
  • Steps (a)-(e) of Scheme II are conducted as described above for Scheme I, wherein following deprotection of the compound of formula (VI), deprotected compound (VII) is contacted with hydrochloric acid to form pharmaceutically acceptable salt (VIIb).
  • step (f) of Scheme II salt (VIIb) is contacted with a base to form the corresponding freebase (VII).
  • Suitable bases include, but are not limited to hydroxides, such as sodium hydroxide, potassium hydroxide, and the like, and combinations thereof.
  • the base is sodium hydroxide.
  • the reaction of step (f) may be conducted in any suitable water-containing solvent including, but not limited to, water alone or in combination with THF, 2-methyl tetrahydrofuran, ethanol, methanol, and the like.
  • step (g) compound (VII) is reacted with 2,2,2-trifluoroethylamine to produce upadacitinib.
  • the step (g) reaction is conducted in the presence of a coupling agent, such as CDI.
  • Step (g) in Scheme II is conducted using similar reagents and under similar conditions as those set forth above for step (f) of Scheme I.
  • step (h) of Scheme II upadacitinib is contacted with L-tartaric acid to form the corresponding tartrate salt (step (h)).
  • Formation of the tartrate salt advantageously aids in removal of impurities prior to isolation of the freebase.
  • the tartrate salt is subsequently converted back to the freebase form (step (i)) to produce upadacitinib.
  • the tartrate salt may be contacted with a base, such as an inorganic base, to produce the corresponding freebase.
  • Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, and the like, or combinations thereof.
  • the tartrate salt is contacted with sodium bicarbonate and sodium carbonate to produce the corresponding freebase.
  • Suitable solvents for use in step (h) include, but are not limited to, isopropyl acetate, methyl tert-butyl ether, water, isopropyl alcohol, and combinations thereof.
  • Suitable solvents for use in step (i) include, but are not limited to, ethyl acetate, ethanol, water, and combinations thereof.
  • the products of steps (d), (e), (g), and (h) of Scheme II are not isolated prior to the subsequent step.
  • the protecting group may be any suitable protecting group known in the art.
  • the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.
  • the protecting group is carboxybenzyl.
  • R 1 is —OR 2
  • R 2 is methyl or ethyl
  • the compound of formula (IV) is a compound of formula (IVa):
  • R 2 is methyl or ethyl. It has surprisingly been discovered that when R 2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which aids in purification of these intermediates. In contrast, previously known processes, which use compounds where R 2 is t-butyl, result in formation of compounds of formula (V) which are isolated as amorphous solids.
  • step (a) of Schemes III and IIIa (XIa) or (XI) (which may be prepared as described in Scheme V) is converted to (I) or (XII), respectively.
  • compound (XI) or (XIa) may be contacted with a catalyst, such as a ruthenium catalyst.
  • a catalyst such as a ruthenium catalyst.
  • Any catalyst comprising a chiral phosphine may be used.
  • a suitable catalyst is diacetato[(S)-( ⁇ )5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II) (i.e., (S)-Segphos Ru(OAc) 2 ).
  • Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine, and combinations thereof.
  • a solution of (XI) or (XIa) and the catalyst in solvent is hydrogenated at about 30° C. to about 100° C. for from about 1 hour to about 18 hours.
  • the solution of (XI) or (XIa) and the catalyst in solvent is hydrogenated at about 580 psi.
  • the solution of (XI) or (XIa) and the catalyst in solvent is hydrogenated at about 200 psi gauge (psig).
  • the solution of (XI) or (XIa) and the catalyst in solvent is hydrogenated at about 80° C. for from about 1 hour to about 8 hours, or for about 2 hours, or for about 4 hours.
  • the reaction mixture is cooled to room temperature, filtered, and concentrated.
  • step (b) of Schemes III and IIIa is generally accomplished in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base.
  • a coupling agent such as carbonyldiimidazole (CDI)
  • the strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide, or combinations thereof.
  • the step (b) reaction may be conducted in any suitable solvent including, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is conducted in the presence of carbonyldiimidazole and potassium tert-butoxide.
  • a suspension of trimethylsulfoxonium chloride, strong base, and solvent is heated (e.g., to about 35° C. to about 65° C., or to about 45° C.) for about 30 minutes to about 8 hours, or for about 1 hour, followed by cooling.
  • the suspension is cooled to a temperature of about ⁇ 1° C. or less, or to about ⁇ 5° C. or less.
  • the concentrated filtrate from step (a) is diluted with a suitable solvent (e.g., tetrahydrofuran), and to this solution is slowly added (e.g., over 30 minutes to 1 hour, or over 30 minutes) CDI.
  • a suitable solvent e.g., tetrahydrofuran
  • the resulting mixture is stirred at room temperature for 30 minutes to 12 hours, and typically for about 1 hour.
  • the resulting solution is slowly added (e.g., over 15 minutes to 1 hour, or over 1 hour) to the suspension of the trimethylsulfoxonium chloride, strong base, and solvent, while maintaining the internal temperature below ⁇ 1° C.
  • the reaction may be stirred for about 30 minutes to about 8 hours, or for about 1 hour at a temperature of below about ⁇ 1° C., or at about ⁇ 5° C.
  • the reaction is quenched and the resulting compound of formula (II) or (IIa) is isolated prior to step (c).
  • Steps (a) and (b) of Schemes III and IIIa advantageously allow for preparation of a protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid without formation and isolation of the naphthalenethane amine salt (Ia) or the dicyclohexylamine salt (Ib), or isolation of (I) or (XI).
  • step (c) of Schemes III and IIIa a compound of formula (II) or (IIa) is contacted with an anhydrous source of HBr or HCl to form a compound of formula (III) or (IIIa), respectively.
  • the anhydrous source of HBr or HCl comprises no more than 0.2% water (by volume), or no more than about 0.15% water (by volume).
  • the reaction of step (c) may be conducted in any suitable solvent including, tetrahydrofuran.
  • (II) or (IIa) is combined with the HBr or HCl in a suitable solvent.
  • the solvents are tetrahydrofuran and acetic acid.
  • the solvent comprises no more than 0.2% water (by volume).
  • (II) or (IIa) is combined with a solvent (e.g., THF) and a solution of HBr in HOAc.
  • a solvent e.g., THF
  • a solution of HBr in HOAc e.g., THF
  • the resulting mixture is warmed to about 35° C. to about 65° C., or about 40° C. and agitated.
  • the mixture is agitated for about 4 to about 12 hours, or for about 5 hours.
  • the mixture is warmed to about 40° C.
  • the mixture is cooled to room temperature (e.g., around 20° C.) and distilled, followed by washing.
  • the product (compound (III) or (IIIa)) is concentrated to dryness, and resuspended in a solvent (e.g., N,N-dimethylacetamide) to form a solution of (III) or (IIIa) for use in step (d).
  • a solvent e.g., N,N-dimethylacetamide
  • Step (c) advantageously produces the halomethyl ketone (III) or (IIIa) in higher purity than Scheme I or Ia.
  • step (d) of Schemes III and IIIa a compound of formula (III) or (IIIa) is reacted with a compound of formula (IV) or (IVa) (prepared as described herein).
  • the step (d) reaction is conducted in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or combinations thereof.
  • the base is lithium tert-butoxide.
  • the reaction of step (d) may be conducted in any suitable solvent including, but not limited to dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, and combinations thereof.
  • the base is slowly added (e.g., over about 30 minutes) to a cooled suspension of the compound of formula (IV) or (IVa) in a solvent.
  • the suspension of the compound of formula (IV) or (IVa) is cooled to about 0° C.
  • the resulting solution is stirred for about 30 minutes to about 12 hours, or about 30 minutes, and cooled to about ⁇ 20° C. to about 0° C., or about ⁇ 10° C.
  • the solution is stirred for about 30 minutes and cooled to about ⁇ 20° C. to about 0° C. or about ⁇ 10° C.
  • step (c) The halomethyl ketone solution prepared in step (c) is then slowly added (e.g., over about 1 hour), and the resulting mixture is agitated (e.g., stirred) for about 30 minutes to about 6 hours, or about 30 minutes, at a temperature of about ⁇ 20° C. to about 0° C., or about ⁇ 10° C.
  • the resulting mixture is stirred for about 30 minutes at a temperature of about ⁇ 10° C.
  • the reaction is quenched, and, in some embodiments, the resulting product (V) or (Va) is isolated prior to step (e).
  • Steps (e)-(g) of Schemes III and IIIa may be conducted as described above for steps (d)-(f) of Scheme I, respectively.
  • the present disclosure also relates to the use of solid state forms of upadacitinib in the treatment of Crohn's disease and ulcerative colitis.
  • Solid state forms include the Amorphous Freebase form of upadacitinib, Freebase Solvate Form A. Freebase Hydrate Form B, Freebase Hydrate Form C, Tartrate Hydrate, and Freebase Anhydrate Form D.
  • the solid state form is amorphous upadacitinib (the “Amorphous Freebase”).
  • the Amorphous Freebase comprises less than about 13% by weight water. In another aspect, the Amorphous Freebase comprises less than about 12% by weight water. In another aspect, the Amorphous Freebase comprises less than about 10% by weight water. In another aspect, the Amorphous Freebase comprises less than about 9% by weight water. In another aspect, the Amorphous Freebase comprises less than about 8% by weight water. In another aspect, the Amorphous Freebase comprises less than about 7% by weight water. In another aspect, the Amorphous Freebase comprises less than about 6% by weight water. In another aspect, the Amorphous Freebase comprises less than about 5% by weight water.
  • the Amorphous Freebase comprises less than about 4% by weight water. In another aspect, the Amorphous Freebase comprises less than about 3% by weight water. In another aspect, the Amorphous Freebase comprises less than about 2% by weight water. In another aspect, the Amorphous Freebase comprises less than about 1% by weight water. In another aspect, the Amorphous Freebase has a glass transition temperature onset at about 119° C. In another aspect, the Amorphous Freebase has a glass transition temperature midpoint at about 122° C. In another aspect, the Amorphous Freebase has a glass transition temperature onset at about 119° C. and a glass transition temperature midpoint at about 122° C.
  • the Amorphous Freebase generally has greater solubility, and increased bioavailability, relative to the corresponding crystalline forms of the compound.
  • the Amorphous Freebase also has acceptable chemical stability.
  • the Amorphous Freebase exhibits acceptable stability to light and peroxide.
  • the Amorphous Freebase is hygroscopic and can comprise as much as 12% by weight water at 25° C./90% relative humidity. Environmental controls potentially are required to ensure appropriate control of potency and water content during storage, dispensing, and handling of the Amorphous Freebase.
  • the Amorphous Freebase can be prepared, for example, using anti-solvent crystallization to prepare the Freebase Solvate Form A or Freebase Hydrate Form B (described below) followed by dehydration or desolvation to yield the Amorphous Freebase.
  • This crystallization/dehydration/desolvation method allows for the large-scale manufacture of the Amorphous Freebase without the need for labor-intensive and expensive techniques such as spray-drying. It also provides for appropriate control of the bulk properties of the Amorphous Freebase (i.e., particle size, flow properties etc.).
  • the Amorphous Freebase When the Amorphous Freebase is prepared by desolvation of the Freebase Solvate Form A or dehydration of the Freebase Hydrate Form B, the Amorphous Freebase generally retains the morphology of the Freebase Solvate Form A or Freebase Hydrate Form B (i.e., blades with hexagonal crystal faces when prepared by dehydration of Freebase Hydrate Form B, or irregular when desolvated from Freebase Solvate Form A).
  • the process volumes required for crystallization during the large-scale manufacture of the Freebase Solvate Form A or Freebase Hydrate Form B generally are within conventional processing volumes, but impurity rejection potentially may be lower than desired. Drying and dehydration/desolvation of the Freebase Hydrate Form B/Freebase Solvate Form A to the Amorphous Freebase generally can be carried out with standard equipment under conventional conditions and the isolated Amorphous Freebase typically can be co-milled without adversely impacting the amorphous state.
  • the solid state form is a crystalline freebase of upadacitinib.
  • the crystalline freebase is a solvate.
  • the crystalline freebase is an isopropyl acetate/water solvate (the “Freebase Solvate Form A”).
  • the crystalline freebase is a hydrate (the “Freebase Hydrate Form B”). The Freebase Solvate Form A and the Freebase Hydrate Form B are further described in the Examples of the application.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and that is further characterized by a peak at one or more of 13.7 ⁇ 0.2, 20.8 ⁇ 0.2 and 25.0 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, 12.0 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, 12.0 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, 12.0 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, 12.0 ⁇ 0.2, 13.7 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 15.1-0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2, 13.7 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2, 13.7 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2, 13.7 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 14-A ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 14-B ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the crystalline freebase solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 16-B ⁇ 0.2 degrees two theta that have a relative intensity of at least 10.0%, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the significant peak values have a variation of ⁇ 0.1 degrees two theta rather than ⁇ 0.2 degrees two theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ⁇ 0.05 degrees two theta rather than ⁇ 0.2 degrees two theta.
  • the crystalline freebase has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .
  • the Freebase Solvate Form A and Freebase Hydrate Form B are not physically stable. As discussed above, they desolvate (or dehydrate) and convert to the Amorphous Freebase upon drying. Although the Freebase Solvate Form A and Freebase Hydrate Form B generally do not exhibit pharmaceutically acceptable physical stability for use as an active ingredient in a pharmaceutical dosage form, they are useful intermediates in the preparation of other solid state forms such as the Amorphous Freebase.
  • the solid state form is a crystalline hydrate, wherein the crystalline hydrate is a hemihydrate.
  • the solid state form is crystalline hemihydrate of upadacitinib having a powder X-ray diffraction pattern corresponding to Freebase Hydrate Form C.
  • the Freebase Hydrate Form C is further described in the Examples of the application.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and that is further characterized by a peak at one or more of 7.7 ⁇ 0.2, 7.9 ⁇ 0.2, 9.6 ⁇ 0.2, 10.3 ⁇ 0.2, 13.9 ⁇ 0.2, 15.5 ⁇ 0.2, 15.9 ⁇ 0.2, 17.0 ⁇ 0.2, 17.2 ⁇ 0.2, 17.8 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 19.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.9 ⁇ 0.2, 22.2 ⁇ 0.2, 23.5 ⁇ 0.2, 24.4 ⁇ 0.2, 24.9 ⁇ 0.2, 28.2 ⁇ 0.2, and 29.5 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern that is characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern that is characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 17.0 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern that is characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 20.9 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern that is characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 15.5 ⁇ 0.2, 17.0 ⁇ 0.2, 20.9 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 14-C ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 16-C ⁇ 0.2 degrees two theta that have a relative intensity of at least 10.0%, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the significant peak values have a variation of ⁇ 0.1 degrees two theta rather than ⁇ 0.2 degrees two theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ⁇ 0.05 degrees two theta rather than ⁇ 0.2 degrees two theta.
  • the Freebase Hydrate Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 20 when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Hydrate Form C generally exhibits good chemical stability, physical stability, and solid state properties (including low hygroscopicity). Large-scale manufacture of the Freebase Hydrate Form C is relatively straightforward with minimal scaling, good yield, good impurity rejection, fast filtration, conventional drying, and minimal milling issues (even after subjecting the isolated material to high energy pinmilling). In addition, different particle sizes can be achieved through appropriate control of the crystallization process.
  • the solid state form is a crystalline anhydrate freebase of upadacitinib having a powder X-ray diffraction pattern corresponding to Freebase Anhydrate Form D.
  • the Freebase Anhydrate Form D is further described in the Examples of the application.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and that is further characterized by a peak at one or more of 4.0 ⁇ 0.2, 18.4 ⁇ 0.2, 19.0 ⁇ 0.2, 23.0 ⁇ 0.2, and 24.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 18.4 ⁇ 0.2 and 20.3 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2 and 20.3 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2 and 20.3 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 20.3 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 20.3 ⁇ 0.2, and 24.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 14.5 ⁇ 0.2, and 19.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 14.5 ⁇ 0.2, and 19.0 ⁇ 0.2 degrees two theta, and that is further characterized by a peak at one or more of 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 18.4 ⁇ 0.2, 20.3 ⁇ 0.2, 23.0 ⁇ 0.2, and 24.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ⁇ 0.2, 8.0 ⁇ 0.2, 9.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 19.0 ⁇ 0.2, and 20.3 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 6.8 ⁇ 0.2, 15.7 ⁇ 0.2, and 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 21.7 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 14-E ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks substantially at the positions listed in Table 14-E ⁇ 0.2 degrees two theta that have a relative intensity of at least 10.0%, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the significant peak values have a variation of ⁇ 0.1 degrees two theta rather than ⁇ 0.2 degrees two theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ⁇ 0.05 degrees two theta rather than ⁇ 0.2 degrees two theta.
  • the Freebase Anhydrate Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 22 when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • Freebase Anhydrate Form D is reversibly hygroscopic (up to 1.8% water at 90% RH at 25° C.), and is metastable relative to Freebase Hydrate Form C at typical environmental conditions (e.g., above 2.4% RH at 23° C.) used during storage for downstream processing.
  • the manufacture of Freebase Anhydrate Form D requires strict control of water, as the Freebase Anhydrate Form D can be manufactured only when the water content of the crystallization solvent is low (e.g., less than 0.15% at 23° C. corresponding to a water activity of 2.4%), and will convert to Freebase Hydrate Form C in solutions at high water content.
  • Freebase Anhydrate Form D is slow to crystallize, and difficult to manufacture in higher yield.
  • the solid state form is a tartrate of upadacitinib.
  • the tartrate is amorphous.
  • the tartrate is crystalline.
  • the crystalline tartrate is a solvate.
  • the crystalline tartrate is a hydrate.
  • the tartrate is a crystalline L-tartrate.
  • the crystalline L-tartrate is a hydrate.
  • the crystalline tartrate is a tetrahydrate (the “Tartrate Hydrate”). The Tartrate Hydrate (a tetrahydrate) is further described in the Examples of the application.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, 14.1 ⁇ 0.2, 15.7 ⁇ 0.2, 21.9 ⁇ 0.2, and 25.9 ⁇ 0.2 degrees two theta when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2 and 9.3 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, and 14.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, 14.1 ⁇ 0.2, 15.7 ⁇ 0.2, 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, 14.1 ⁇ 0.2, 15.7 ⁇ 0.2, 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ⁇ 0.2, 6.8 ⁇ 0.2, 14.1 ⁇ 0.2, 15.7 ⁇ 0.2, 21.9 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 13.4 ⁇ 0.2 and 15.1 ⁇ 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ⁇ 0.2, 9.3 ⁇ 0.2, and 12.0 ⁇ 0.2 degrees two theta.
  • the significant peak values have a variation of ⁇ 0.1 degrees two theta rather than ⁇ 0.2 degrees two theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ⁇ 0.05 degrees two theta rather than ⁇ 0.2 degrees two theta.
  • the Tartrate Hydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 21 , when measured at about 25° C. with monochromatic K ⁇ 1 radiation.
  • the Tartrate Hydrate has acceptable chemical stability and exhibits acceptable stability to light and peroxide.
  • the Tartrate Hydrate has good solubility (BCS Class I) and is not hygroscopic.
  • the Tartrate Hydrate potentially will convert to an amorphous tartrate below 10% relative humidity, when heated, or when compressed or under shear.
  • the Tartrate Hydrate can be manufactured, for example, using anti-solvent crystallization. Impurity rejection during the large-scale manufacture of the Tartrate Hydrate generally is good, but scaling may be greater than desired and specific anti-solvent addition controls and process volume restrictions potentially may be required.
  • appropriate control of the filtration, washing, and drying steps may be required to minimize consolidation of the wet cake and formation of hard lumps in the isolated material. For example, control of the relative humidity (e.g., greater than 10% and less than 100% relative humidity), temperature (e.g., crystallization at about 10° C. works well), and mixing rate may be required during drying to minimize the formation of hard lumps in the isolated material.
  • control of the relative humidity e.g., greater than 10% and less than 100% relative humidity
  • temperature e.g., crystallization at about 10° C. works well
  • mixing rate may be required during drying to minimize the formation of hard lumps in the isolated material.
  • the solid state form has a pharmaceutically acceptable crystalline purity (or a pharmaceutically acceptable amorphous purity in the case of the Amorphous Freebase).
  • upadacitinib comprises at least about 75% by weight of the desired solid state form.
  • at least 80% by weight is the desired solid state form.
  • at least 85% by weight is the desired solid state form.
  • at least 90% by weight is the desired solid state form.
  • at least 95% by weight is the desired solid state form.
  • at least 96% by weight is the desired solid state form.
  • at least 97% by weight is the desired solid state form.
  • the solid state form is the Amorphous Freebase.
  • the solid state form is Freebase Anhydrate Form D.
  • the solid state form is the Freebase Hydrate Form B.
  • the solid state form is the Freebase Hydrate Form C.
  • the solid state form is the Tartrate Hydrate.
  • the present disclosure also relates to methods for preparing a solid state form of upadacitinib.
  • the solid state form prepared is the Amorphous Freebase.
  • the solid state form prepared is the Freebase Hydrate Form B.
  • the solid state form prepared is the Freebase Hydrate Form C.
  • the solid state form prepared is the Tartrate Hydrate.
  • the solid state form prepared is the Freebase Anhydrate Form D.
  • the present disclosure relates to methods for preparing the Amorphous Freebase.
  • the method comprises dehydrating the Freebase Hydrate Form B to provide the Amorphous Freebase.
  • the method comprises desolvating the Freebase Solvate Form A to provide the Amorphous Freebase.
  • a wide range of process conditions can be employed for the dehydration/desolvation. The dehydration can be conducted, for example, under ambient conditions or in a vacuum oven.
  • FIG. 14 schematically illustrates one method of preparing the Amorphous Freebase by dehydration of the Freebase Hydrate Form B.
  • the method comprises dissolving upadacitinib in a solvent or mixture of solvents; and adjusting the pH of the solvent or mixture of solvents to a pH greater than about 8 to initiate precipitation of the Amorphous Freebase.
  • the solvent or mixture of solvents comprises water.
  • the pH is adjusted to a pH greater than about 9.
  • the pH is adjusted to a pH greater than about 10.
  • the pH is adjusted to a pH greater than about 11.
  • the pH is adjusted to a pH of at least about 9.
  • the method comprises preparing the Amorphous Freebase using a method selected from the group consisting of impinging jet, spray drying, and hot-melt extrusion.
  • the present disclosure additionally relates to methods for preparing the Freebase Solvate Form A and Freebase Hydrate Form B.
  • the method comprises dissolving upadacitinib in a solvent or mixture of solvents comprising an anti-solvent; and maintaining the solvent or mixture of solvents at a temperature less than about 15° C. for an amount of time sufficient to initiate crystallization of the Freebase Solvate Form A or the Freebase Hydrate Form B.
  • the anti-solvent can comprise, for example, water.
  • the solvent or mixture of solvents can comprise a polar solvent such as a solvent is selected from the group consisting of methanol, ethanol, n-butylamine, acetone, acetonitrile, ethyl formate, methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, and isopropyl acetate.
  • the Freebase Solvate Form A and Freebase Hydrate Form B exhibit similar PXRD patterns, and are therefore isostructural.
  • the method generally is conducted at sub-ambient temperatures, for example, less than about 10° C. less than about 5° C., or less than about 0° C.
  • the process further comprises seeding the solvent or mixture of solvents with crystals of the Freebase Solvate Form A or the Freebase Hydrate Form B.
  • the present disclosure additionally relates to methods for preparing the Freebase Hydrate Form C.
  • the method comprises dissolving upadacitinib in a solvent or mixture of solvents, and initiating crystallization to provide the Freebase Hydrate Form C.
  • the solvent or mixture of solvents generally will comprise an anti-solvent (such as water) which can be present in the solvent or mixture of solvents before, or added to the solvent or mixture of solvents after, the upadacitinib is dissolved in the solvent or mixture of solvents.
  • the solvent or mixture of solvents can comprise, for example, one or more polar solvents (such as polar solvent selected from the group consisting of ethanol and ethyl acetate); one or more nonpolar solvents (such as a nonpolar solvent is selected from the group consisting of hexane and heptane); or at least one polar solvent and at least one nonpolar solvent.
  • the solvent or mixture of solvents is a ternary solvent mixture comprising ethyl acetate, heptane, and water.
  • the method generally is conducted at temperatures less than about 30° C., less than about 20° C. or less than about 10° C.
  • the initiating crystallization step comprises mixing the solvent or mixture of solvents to provide sufficient agitation to initiate crystallization. In certain aspects, the initiating crystallization step comprises seeding the solvent or mixture of solvents with crystals of the Freebase Hydrate Form C. In certain aspects, the initiating crystallization step comprises both mixing the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the Freebase Hydrate Form C.
  • upadacitinib is first prepared according to any of the methods set forth herein, a reaction mixture comprising upadacitinib is filtered, and the resulting solution is suspended in a solvent or mixture of solvents.
  • the solvent or mixture of solvents can comprise, for example, one or more polar solvents (such as polar solvent selected from the group consisting of ethanol and ethyl acetate); one or more nonpolar solvents (such as a nonpolar solvent is selected from the group consisting of hexane and heptane); or at least one polar solvent and at least one nonpolar solvent.
  • the solvent is ethyl acetate, or a mixture of ethyl acetate and water.
  • the initiating crystallization step comprises seeding the solvent or mixture of solvents with crystals of the Freebase Hydrate Form C. In one particular aspect, the crystallization occurs in a wet mill.
  • FIG. 15 schematically illustrates one method of preparing the Freebase Hydrate Form C.
  • the present disclosure additionally relates to methods for preparing the Freebase Anhydrate Form D.
  • the method comprises dissolving upadacitinib in a solvent or mixture of solvents; and initiating crystallization to provide the Freebase Anhydrate Form D.
  • the solvent or mixture of solvents will be water-free, or close to water-free.
  • the solvent or mixture of solvents will have a water content of less than about 0.15 wt %, or less than about 0.10 wt. %, or less than about 0.05 wt. %, or about 0 wt. % at 23° C.
  • the solvent or mixture of solvents will have a water activity of about 2.4% or less, or about 2.2% or less, or about 2.0% or less, or about 1.5% or less.
  • the solvent or mixture of solvents can comprise, for example, ethyl acetate (EtOAc), heptane, and combinations thereof.
  • the solvent system comprises a mixture of heptane in ethyl acetate.
  • the solvent system comprises about 10 wt. %, or about 20 wt. %, or about 30 wt. %, or about 40 wt. % heptane in ethyl acetate.
  • the method generally is conducted at temperatures of at least about 7° C.
  • the method is conducted at about 23° C.
  • the initiating crystallization step comprises mixing the solvent or mixture of solvents to provide sufficient agitation to initiate crystallization.
  • the initiating crystallization step comprises seeding the solvent or mixture of solvents with crystals of the Freebase Anhydrate Form D.
  • the initiating crystallization step comprises both mixing the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the Freebase Anhydrate Form D.
  • the present disclosure additionally relates to methods for preparing the Tartrate Hydrate.
  • the method comprises dissolving upadacitinib and L-tartaric acid in a solvent or mixture of solvents to form a crystallization solution; and crystallizing the Tartrate Hydrate from the crystallization solution.
  • the solvent or mixture of solvents can comprise, for example, water and/or, for example, one or more polar solvents (such as isopropyl acetate).
  • the solvent or mixture of solvents also can comprise an anti-solvent (such as isopropyl acetate).
  • the process further comprises seeding the solvent or mixture of solvents with crystals of the Tartrate Hydrate.
  • the crystallization generally is conducted at a temperature less than about 40° C.
  • a moderate rate of addition is employed for the anti-solvent as a faster rate of addition typically results in the precipitation of an amorphous tartrate and a slower rate of addition allows the resulting slurry to thicken.
  • Proper control of filtration, washing, and drying may be needed to avoid potential issues associated with consolidation of the filter cake, including solvent entrapment, solid properties (e.g., hard, chunky solids) and handing, and damage to equipment.
  • milling may require a mechanical impact-type of mills rather than a shear-based mill (such as a co-mill).
  • FIG. 16 schematically illustrates one method of preparing the Tartrate Hydrate.
  • One or more compounds of this disclosure can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • compositions of the present disclosure may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredient contained in the dosage unit composition is upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof.
  • the target or label amount of active ingredient (e.g., upadacitinib) provided for inclusion in the compositions of the present disclosure refers to the amount of upadacitinib freebase.
  • upadacitinib may be prepared in several solid state forms including Amorphous Freebase, crystalline solvates and hydrates (e.g., Freebase Solvate Form A, Freebase Hydrate Form B), crystalline hemihydrates (e.g., Freebase Hydrate Form C), crystalline anhydrate (e.g., Freebase Anhydrate Form D), and crystalline tartrate (e.g., Tartrate Hydrate).
  • Amorphous Freebase e.g., Freebase Solvate Form A, Freebase Hydrate Form B
  • crystalline hemihydrates e.g., Freebase Hydrate Form C
  • crystalline anhydrate e.g., Freebase Anhydrate Form D
  • crystalline tartrate e.g., Tartrate Hydrate
  • the dosage unit composition comprises, e.g., a solvate, hydrate, hemihydrate, or tartrate of upadacitinib
  • the amount of solvate, hydrate, hemihydrate, or tartrate of upadacitinib present in the dosage unit composition may be slightly higher than the target amount of upadacitinib (active ingredient), and preferably will be present in the dosage unit composition in an amount sufficient to deliver the target amount of upadacitinib freebase equivalent to a patient.
  • a dosage unit composition comprising, for example, a hydrate of upadacitinib, may comprise the hydrate in an amount sufficient to deliver 15 mg of the upadacitinib freebase equivalent.
  • the pharmaceutical composition is a tablet dosage form. In one aspect, the tablet is coated with a pharmaceutically acceptable polymer. In one embodiment, the pharmaceutical composition is a capsule dosage form.
  • tablet is a controlled-release formulation, such as an extended release tablet dosage form (also referred to herein as a modified release or sustained release formulation).
  • extended release tablet dosage form also referred to herein as a modified release or sustained release formulation.
  • Such formulations permit the sustained release of the active ingredient over an extended period of time, as compared to intermediate release solid dosage forms, which permit the release of most or all of the active ingredient over a short period of time (e.g., typically around 60 minutes or less).
  • the tablet comprises an active ingredient (e.g., upadacitinib) and at least one additive selected from the group consisting of a release control polymer, a filler, a glidant, a lubricant (e.g., for use in compacting the granules), a pH modifier, a surfactant, and combinations thereof.
  • the tablet comprises an active ingredient, a release control polymer, a filler, a glidant, and a lubricant.
  • the tablet comprises an active ingredient, a release control polymer, a filler, a glidant, a lubricant, and a pH modifier.
  • the release control polymer will be a hydrophilic polymer.
  • suitable release control polymers include, but are not limited to a cellulose derivative with a viscosity of between 1000 and 150.000 mPA-s, hydroxypropylmethyl cellulose (e.g., Hypromellose 2208 or controlled release grades of hydroxypropylmethyl cellulose, including the E, F.
  • copolymers of acrylic acid crosslinked with a polyalkenyl polyether e.g., Carbopol® polymers
  • hydroxypropyl cellulose hydroxyethyl cellulose
  • non-ionic homopolymers of ethylene oxide e.g., PolyoxTM
  • water soluble natural gums of polysaccharides e.g., xanthan gum, alginate, locust bean gum, etc.
  • crosslinked starch polyvinyl acetates, polyvinylpyrrolidone, mixtures of polyvinyl acetates and polyvinyl pyrrolidone, and combinations thereof.
  • the release control polymer is selected from the group consisting of hydroxypropylmethyl cellulose, copolymers of acrylic acid crosslinked with a polyalkenyl polyether (e.g., Carbopol® polymers), and combinations thereof.
  • suitable fillers include, but are not limited to, microcrystalline cellulose (e.g., Avicel® PH 101; Avicel® PH 102), mannitol (e.g., Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, and the like.
  • the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and combinations thereof.
  • glidants include, but are not limited to, silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate, magnesium silicate, talc, and combinations thereof. In one embodiment, the glidant is colloidal silicone dioxide.
  • suitable lubricants include, but are not limited to, polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and the like. In one embodiment, the lubricant is magnesium stearate.
  • pH modifiers include, but are not limited to, organic acids, such as tartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate; magnesium or calcium carbonate or bicarbonate; and combinations thereof.
  • the pH modifier is tartaric acid.
  • suitable surfactants include sodium lauryl sulfate.
  • the pharmaceutical composition comprises from about 10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof.
  • the formulation comprises from about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %, about 15 w/w %, about 20 w/w %, about 25 w/w % or about 30 w/w % pH modifier.
  • the pH modifier is tartaric acid.
  • Sustained peak plasma concentrations can theoretically be achieved by means of sustained release matrix systems.
  • hydrophilic polymers such as HPMC
  • a pH modifier such as tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof, is used in a hydrophilic sustained release matrix system, it allows upadacitinib or a pharmaceutically acceptable salt or solid state form thereof to be released at a steady rate regardless of the pH of the environment.
  • upadacitinib reacts with the HPMC, creating a thicker gel layer which slows the release of upadacitinib from the tablet.
  • the resulting gel layer provides an environment suitable for upadacitinib to dissolve.
  • the pharmaceutical composition of the present disclosure exhibits a pH-independent release of the active ingredient (upadacitinib).
  • active ingredient upadacitinib
  • organic acids such as a tartaric acid
  • the pH modifier and hydrophilic polymer create a microenvironment in which the active ingredient dissolves, and then is released. The release from the microenvironment occurs at approximately the same rate, regardless of pH.
  • the pH of the gastrointestinal tract may vary significantly from the stomach (e.g., pH of about 1.5-3), to the duodenum (e.g., pH of about 4-5), to the lower part of the small intestines (e.g., pH of about 6.5-7.5).
  • the pharmaceutical composition is a modified release formulation comprising upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, a hydrophilic polymer, and a pH modifier, wherein the hydrophilic polymer, in contact with water, forms a gel layer that provides an environment suitable for upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, to dissolve.
  • the environment suitable for upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, to dissolve has a pH equal to or less than about 3.8 at 37° C.
  • the environment has a pH of from about 1.5 to about 3.7, or from about 2.0 to about 3.7, or from about 2.5 to about 3.6, or from about 3.0 to about 3.6, or from about 3.0 to about 3.5.
  • the environment suitable for upadacitinib, or a pharmaceutically acceptable salt or solid state form thereof, to dissolve is as set forth above, and the modified release formulation comprises from about 10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof.
  • a pH modifier and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof.
  • the formulation comprises from about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %, about 15 w/w %, about 20 w/w %, about 25 w/w % or about 30 w/w % pH modifier.
  • the pH modifier may be selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and combinations thereof.
  • the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, and combinations thereof. In one such embodiment, the pH modifier is selected from the group consisting of tartaric acid and fumaric acid. In one embodiment, the pH modifier is tartaric acid. In one embodiment, the pH modifier is fumaric acid or citric acid.
  • the weight % tartaric acid set forth herein is by weight of the uncoated composition (e.g., uncoated tablet).
  • the hydrophilic polymer may be a cellulose derivative with a viscosity of between 1000 and 150,000 mPA-s.
  • the hydrophilic polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and mixtures or combinations thereof. In one embodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose. In one embodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose Grade E, F, or K. In one embodiment, the hydrophilic polymer is Hypromellose 2208.
  • the tablet is a compressed and/or milled tablet.
  • the tablet is formed by blending the composition components (e.g., including the active ingredient and at least one pharmaceutically acceptable carrier).
  • the composition can then be either directly compressed, or one or more of the composition components can be granulated prior to compression.
  • milling is performed using a mill fitted with any suitable size screen (e.g., a fitted with a screen size of from about 600 to about 1400 ⁇ m or about 610 ⁇ m or about 1397 ⁇ m). Compression can be done in a tablet press, such as in a steel die between two moving punches.
  • the compressed and/or milled tablet is formulated using a wet granulation process.
  • Use of wet granulation helps reduce and/or eliminate sticking that may occur when compression without wet granulation (e.g., direct compression) is used to formulate the tablets.
  • the wet granulation process may include the following steps: (a) combining the active ingredient (e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof or a solid state form of upadacitinib) and at least a portion of one additional composition component to form a dry granulation mixture; (b) contacting the dry granulation mixture with a granulation fluid to form a wet granulation mixture; (c) drying the wet granulation mixture to form a granulated material; (d) milling the granulated material to form a milled granulated material; (e) combining the milled granulation material with the remaining composition components; and (f) compressing the composition into the solid dosage unit (e.g., a tablet).
  • the active ingredient e.g., upadacitinib or a pharmaceutically acceptable salt or solid state form thereof or a solid state form of upadacitinib
  • the dry granulation mixture
  • the active ingredient may be combined with, for example, a portion of the release control polymer (e.g., HPMC), a portion of the filler (e.g., microcrystalline cellulose, such as Avicel® PH101), or both a portion of the release control polymer and a portion of the filler to form the dry granulation mixture.
  • a portion of the release control polymer e.g., HPMC
  • a portion of the filler e.g., microcrystalline cellulose, such as Avicel® PH101
  • Any suitable portion of the release control polymer may be used in step (a). In one embodiment, from about 5 to 10 wt. % or from about 6 to 8 wt. % of the total amount of the release control polymer in the composition is used in step (a).
  • the granulation fluid used in step (b) may comprise water, a suitable solvent (e.g., ethanol, isopropanol, etc.), or combinations thereof.
  • the granulation fluid comprises water.
  • the active ingredient may be combined with a portion of the filler, while a portion of the release control polymer (e.g., HPMC) is dissolved in a liquid, such as water, to form the granulation fluid.
  • the granulation fluid is sprayed on the dry granulation mixture.
  • the dried granulation material may be milled using, for example, a comill fit with any suitable screen size.
  • the screen size is from about 600 to about 900 microns, or from about 610 to about 813 microns.
  • the granulated material is milled using a comill fitted with a 610 ⁇ m screen.
  • the granulated material is milled using a comill fitted with a 813 ⁇ m screen.
  • the milled granulation material is combined with any remaining composition components, such as any remaining filler (e.g., microcrystalline cellulose, such as Avicel® PH102), any remaining release control polymer, glidants, lubricants, pH modifiers, surfactants, and the like.
  • the filler and/or release control polymer included in the granulated material may be the same or different than the filler and/or release control polymer added in step (e).
  • the filler included in the granulated material e.g., Avicel®PH101
  • the composition may be sieved, and the sieved composition blended, for example, after step (e), and prior to compressing the composition (step (f)).
  • the formulation is sieved prior to addition of any lubricant.
  • the pH modifier e.g., tartaric acid
  • the tablet further comprises a film coat.
  • a film coat on the tablet further may contribute to the ease with which it can be swallowed.
  • a film coat can also improve taste and provides an elegant appearance.
  • the film-coat includes a polymeric film-forming material such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers.
  • the film-coat may further comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. polysorbates, and optionally a pigment, e.g. titanium dioxide or iron oxides.
  • the film-coating may also comprise talc as anti-adhesive.
  • the film coat accounts for less than 5% by weight of a pharmaceutical composition of the present disclosure.
  • the pharmaceutical composition is a capsule dosage form.
  • the appropriate dosage of JAK1 inhibitor will depend on a variety of factors such as the type of disease to be treated, as defined above, the severity and course of the disease, whether the JAK1 inhibitor is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
  • the JAK1 inhibitor is suitably administered to the patient at one time or over a series of treatments.
  • the JAK1 inhibitor is formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being, treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the scheduling of administration, and other factors known to medical practitioners.
  • the “therapeutically effective amount” of the JAK1 inhibitor will be governed by such considerations.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the patient being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the composition will be a once-daily modified release formulation comprising 7.5 mg, 15 mg, 30 mg, or 45 mg of upadacitinib or a pharmaceutically acceptable salt or solid state form thereof.
  • Upadacitinib (approximately 300 g) was dissolved in water (10 L) and 50% sodium hydroxide (160 g) was added drop-wise over a two hour period to adjust the pH to greater than 12. Solids formed immediately. The solids were filtered, washed with two 500 mL aliquots of water, and then dried in a vacuum oven. The solids were equilibrated for a short period of time at ambient temperature prior to characterization. Conversion to Amorphous Freebase of upadacitinib was confirmed by PXRD analysis.
  • a sample of the Freebase Hydrate Form B form of upadacitinib (crystallized from ethanol/water at sub-ambient temperatures as described in Example 2, Method C below) was placed in a vacuum oven at 40° C. overnight. The solids removed from the vacuum oven were equilibrated for a short time at 23° C. prior to characterization. Conversion to Amorphous Freebase of upadacitinib was confirmed by PXRD analysis.
  • a sample of the Amorphous Freebase of upadacitinib was added to a vial followed by isopropyl acetate (125 ⁇ L) and water (10 ⁇ L). All solids dissolved at ambient temperature. The solution was placed in a freezer at ⁇ 16° C. for 4 days. The liquor was decanted and the crystallized solids were isolated. The isolated crystals were analyzed by PXRD while still wet. Conversion to Freebase Solvate Form A (isopropyl acetate/water solvate) of upadacitinib was confirmed by PXRD analysis.
  • a sample of the Amorphous Freebase of upadacitinib (164 mg) and MeOH (621 mg) were added to a vial. The components were mixed at ambient temperature until the solids dissolved. Water (approximately 680 ⁇ L) was added to the vial and the vial was placed in an ice/sodium chloride bath at approximately ⁇ 3° C. Crystal seeds comprising Freebase Hydrate Form B were added to the vial and the vial was placed in a freezer at ⁇ 16° C. A sample was pulled from the crystallized suspension and the solids were immediately analyzed with PXRD and TGA-MS. Conversion to Freebase Hydrate Form B of upadacitinib was confirmed by PXRD and TGA-MS analysis.
  • a sample of the Amorphous Freebase of upadacitinib (4.2 g) was dissolved in EtOH (15.3 g) in a jacketed reactor. Water (23.3 g) was slowly added to the reactor. The reactor solution was cooled to approximately 2° C. A small portion of a seed solution comprising the Freebase Hydrate Form B was charged to the reactor. The suspension was mixed at approximately 2° C. for 3 hours and water (36 g) in was charged to the reactor in small aliquots over several hours while maintaining the suspension at a temperature of approximately 2° C. The crystallized suspension was mixed at approximately 2° C. and the solids were isolated via filtration. Conversion to Freebase Hydrate Form B of upadacitinib was confirmed by PXRD analysis.
  • the Freebase Solvate Form A and Freebase Hydrate Form B do not readily crystallize from solution. In general, sub-ambient temperatures and sufficient water activity are needed to crystallize Freebase Solvate Form A and Freebase Hydrate Form B from solution.
  • Crystalline freebase hydrates and solvates have been isolated from several solvent systems either through primary nucleation (without seeding) or through seeding. In addition to crystallization from isopropyl acetate/water (as described in Method A above), crystalline freebase hydrates or solvates also have been isolated through primary nucleation (without seeding) from, e.g., n-butylamine/water and ethanol/water solvent systems.
  • crystalline freebase hydrates or solvates also have been isolated through seeding from, e.g., acetone/water; acetonitrile/water, ethyl formate/water; methyl acetate/water; ethyl acetate/water; methyl ethyl ketone/water, methyl isobutyl ketone/water, methyl isobutyl ketone/methyl tert-butyl ether/water; and isopropyl acetate/methyl tert-butyl ether/water solvent systems.
  • the Freebase Solvate Form A (isopropyl acetate/water solvate) prepared in Method A above, the Freebase Hydrate Form B prepared in Methods B and C above, and these other crystalline freebase solvates or hydrates that have been prepared are isostructural and exhibit similar PXRD patterns. Notably, these crystalline freebase solvates and hydrates are distinguishable from and exhibit a different PXRD pattern than Freebase Hydrate Form C (a hemihydrate), which is described below.
  • the Freebase Solvate Form A and Freebase Hydrate Form B that were prepared were not stable after isolation at ambient conditions and readily dehydrated to the Amorphous Freebase.
  • a sample of the Amorphous Freebase of upadacitinib (2 g) was transferred to a 500 mL beaker equipped with a stirring bar. EtOH (50 g) was added to the beaker and stirred until all solids dissolved.
  • the solution was transferred to a 250 mL jacketed flask equipped with a dispersing device. The solution was cooled to 6° C. Water (150 g) was added to the solution and the solution was subjected to high shear for two hours using the dispersing device. After solid formation was observed, an additional amount of water (50 g) was added to the resulting suspension. The suspension was held overnight at ambient temperature. Solids were isolated and examined on the following day. Conversion to upadacitinib Freebase Hydrate Form C was confirmed by PXRD analysis.
  • a crude reaction mixture assaying for 11.1 g of upadacitinib was taken up in 2% water in EtOAc (70 g) and seeded with Freebase Hydrate Form C (100 mg). The suspension was stirred overnight and heptane (70 g) was added. The solids were collected by filtration, washed with water saturated EtOAc/heptane (1/1, 100 mL), and dried under vacuum at 50° C. Conversion to upadacitinib Freebase Hydrate Form C was confirmed by PXRD analysis.
  • the Freebase Hydrate Form C also does not readily crystallize from solution.
  • Method A describes an initial procedure that was used to prepare the tartrate tetrahydrate.
  • Method B describes a modified procedure used to prepare the tartrate tetrahydrate at a larger scale.
  • Method C describes a further modified procedure used to prepare the tartrate tetrahydrate.
  • the modified procedure of Method C relative to the procedure of Method B further reduces solidification of the filter cake, a potential problem that potentially can impact manufacturability and downstream processing.
  • a sample of the Amorphous Freebase of upadacitinib (28.2 mg) was transferred to an amber vial.
  • the suspension was vortexed under ambient conditions until all the solids dissolved.
  • the solution in the vial was magnetically stirred at 0° C. The following day, the solids were isolated from the solution and left at ambient temperature for a short period of time prior to characterization. Conversion to the upadacitinib Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.
  • Upadacitinib (4.6 g) was added to a jacketed reactor followed by the addition of isopropanol (6.5 mL) and IPAc (7.8 mL). The slurry was mixed at ambient condition until the solids dissolved.
  • L-tartaric acid (1.96 g) was dissolved in deionized water (3.92 mL). The L-tartaric acid solution was added to the reactor followed by the addition of tartrate tetrahydrate seed crystals (28 mg). The suspension was mixed for 30 minutes under ambient conditions. IPAc (71 mL) was added in small aliquots over 2 hours. The crystallized suspension was cooled to 5° C. and equilibrated at 5° C. overnight.
  • the suspension was discharged onto a filter and the filter cake rinsed with 20 mL of water saturated IPAc.
  • the filtered solids were air-dried for two days. Conversion to the upadacitinib Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.
  • Upadacitinib (104 g) was added to a flask together with isopropanol (222.7 g) and IPAc (375.8 g). The components were mixed under ambient conditions until the solids dissolved. In a separate flask, L-tartaric acid (61.6 g) was dissolved in water (98.3 g). The contents of the two flasks were then added to a jacketed reactor. Tartrate tetrahydrate seed crystals (1.55 g) were added to the reactor solution. The resulting suspension was mixed overnight under ambient conditions. IPAc (2542 g) was charged to the reactor suspension over an 8 hour period.
  • the suspension was filtered with agitation using positive pressure until a wet cake was obtained.
  • the wet cake was dried with constant agitation at a temperature of approximately 11° C. under humidified nitrogen and positive pressure for two days. Conversion to the upadacitinib Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.
  • a sample of the Amorphous Freebase of upadacitinib was dissolved in water-free EtOAc at a concentration of 19.6% (w/w). An aliquot comprising approximately 1 mL was transferred to a 4 mL vial equipped with a magnetic stirrer. The vial was sealed with parafilm and mixed at 400 rpm on a magnetic stir plate at around 23° C. for almost 8 weeks. The resulting slurry was filtered and left at ambient conditions for a short period of time prior to characterization. Conversion to Freebase Anhydrate Form D was confirmed by PXRD analysis.
  • the solid state forms of upadacitinib listed in Table 13 were analyzed by X-ray powder diffraction (“PXRD”).
  • the PXRD data were collected with a G3000 diffractometer (Inel Corp., Artenay, France) equipped with a curved position sensitive detector and parallel beam optics.
  • the diffractometer was operated with a copper anode tube (1.5 kW fine focus) at 40 kV and 30 mA.
  • the diffractometer was calibrated using the attenuated direct beam at one-degree intervals. Calibration was checked using a silicon powder line position reference standard (NIST 640c).
  • Samples were prepared by spreading the sample powder in a thin layer on an aluminum sample holder and gently leveling with a glass microscope slide.
  • the instrument was computer controlled using the Symphonix software (Inel Corp., Artenay. France) and the data was analyzed using the Jade software (version 6.5. Materials Data. Inc., Livermore, Calif.).
  • the aluminum sample holder was mounted on the rotating sample holder of the G3000 diffractometer and the diffraction data collected at ambient conditions.
  • Tables 14-A through 14-E set out the significant parameters of the main peaks in terms of 2 ⁇ values and intensities for the crystalline forms analyzed. It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of peaks may vary according to the orientation of the sample under testing and on the type and setting of the instrument used.
  • the PXRD pattern corresponding to the Amorphous Freebase (via precipitation) and the Amorphous Freebase (via dehydration) are shown in FIGS. 17A and 17B , respectively.
  • the PXRD pattern corresponding to the Freebase Solvate Form A is shown in FIG. 18 . Peak listing of the experimental PXRD pattern with relative intensities is given in Table 14-A below.
  • the PXRD pattern corresponding to the Freebase Hydrate Form B is shown in FIG. 19 . Peak listing of the experimental PXRD pattern with relative intensities is given in Table 14-B below.
  • the PXRD pattern corresponding to the Freebase Hydrate Form C is shown in FIG. 20 . Peak listing of the experimental PXRD pattern with relative intensities is given in Table 14-C below.
  • the PXRD pattern corresponding to the Tartrate Hydrate is shown in FIG. 21 .
  • Peak listing of the experimental PXRD pattern with relative intensities is given in Table 14-D below.
  • the experimental PXRD pattern is shown at the bottom of FIG. 21 and the calculated PXRD pattern is shown at the top of FIG. 21 .
  • the PXRD pattern corresponding to the Freebase Anhydrate Form D is shown in FIG. 22 . Peak listing of the experimental PXRD pattern with relative intensities is given in Table 14-E below.
  • This trial was a multicenter, randomized, double-blind placebo-controlled study of upadacitinib for the induction of symptomatic and endoscopic remission in patient with moderately to severely active Crohn's disease who have inadequately responded to or are intolerant to immunosuppressants or anti-TNF therapy.
  • the trial consisted of a screening period of up to 30 days, a 16 week double blind induction period, re-randomization at week 16, a 36 week double blind and open label phase and a 30 day follow up period.
  • the 16 week induction period began at the BL visit (week 0) and ended at the week 16 visit.
  • the randomization at BL was stratified by endoscopic disease severity (SES-CD ⁇ 15 and ⁇ 15). Safety and efficacy evaluations were performed through the end of the study. The end of the study was defined as the date the last patient completed the last follow up visit.
  • Each treatment group received the corresponding dose of upadacitinib or placebo orally twice daily.
  • Patients receiving the 24 mg QD dose were administered two 12 mg capsules simultaneously orally once daily.
  • patients were evaluated for clinical remission (average daily SF ⁇ 1.5 and not worse than baseline and average daily AP ⁇ 1.0 and not worse than baseline).
  • Patients were randomly assigned (1:1) to have an endoscopy at either week 12 or at week 16, and were evaluated for endoscopic remission (SES-CD ⁇ 4 and at least a two point reduction in SES-CD versus BL and no subscore >1 in any individual variable used to calculate SES-CD) at week 12 or week 16.
  • the central reader endoscopic score was used for calculating the endoscopic response for the evaluation of the efficacy endpoints. However, for stratification at the time of re-randomization, the endoscopic score at BL from central reader and the endoscopic score at week 12 or week 16 from site local reader were used in order to determine response status.
  • the study comprised two treatment periods: a 16 week double-blind induction period and a 36 week double-blind extension phase.
  • induction period patients with a diagnosis of ileal, colonic, or ileocolonic Crohn's disease for ⁇ 3 months prior to BL and confirmed by endoscopy during the screening period, a CDAI ⁇ 220 and ⁇ 450, and who have inadequately responded to or experienced intolerance to previous treatment with an anti-TNF agent (e.g. infliximab, adalimumab or certolizumab pegol), were assigned to receive one of the following doses of upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD or placebo.
  • the co-primary endpoints were endoscopic remission at week 12 or week 16 and clinical remission at week 16. Secondary endpoints included CDAI ⁇ 150 at week 16 and endoscopic response at week 12 or 16.
  • Eligible patients were aged 18 to 75 years. They had a diagnosis of CD for at least three months and at screening had moderate-to-severe CD, defined as a 1) SES-CD ⁇ 6 (or ⁇ 4 for patients with disease limited to the ileum), 2) a CDAI of 220-450, and 3) an average daily liquid/soft SF score ⁇ 2.5 or an average daily AP score ⁇ 2.0. Patients had inadequately responded to or experienced intolerance to previous treatment with an anti-TNF agent. Patients with a current diagnosis of ulcerative colitis, collagenous colitis or indeterminate colitis as well as patients with previous exposure to a JAK inhibitor were excluded. See Table 15 below for key demographics and BL characteristics.
  • **24 mg QD dose is two 12 mg doses given simultaneously 1 Clinical remission: average daily SF ⁇ 2.8 and not greater than Baseline AND average daily AP ⁇ 1.0 and not greater than Baseline 2
  • Endoscopic improvement SES-CD > 50% reduction from BL or at least a 2 point reduction in SES-CD from BL or endoscopic remission
  • the steroid taper consisted of a weekly decrease by 5 mg/day of prednisone (or equivalent) for doses >10/mg/day of prednisone (or equivalent) until a 10 mg/day (or equivalent) dose was reached, then a weekly decrease by 2.5 mg/day (or equivalent) until discontinuation.
  • Upadacitinib was shown to induce clinical remission as early as week 12.
  • Clinical response was achieved at week 16 by 43.6%, 56.8%, 47.2%, 61.1% and 48.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 32.4% of patients treated with placebo.
  • Endoscopic response was achieved at week 12 or week 16 by 23.1%, 43.2%, 38.9%, 50.0% and 48.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 13.5% of patients treated with placebo.
  • Clinical remission and endoscopic remission was achieved at week 16 by 2.6%, 5.4%, 2.8%, 8.3% and 5.7% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 0% of patients treated with placebo.
  • Clinical and endoscopic response was achieved at week 16 by 15.4%, 32.4%, 27.8%, 38.9% and 34.3% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 2.70/o of patients treated with placebo. Results are shown in Table 17.
  • Clinical remission was achieved at week 12 by 10.3%, 29.7%, 13.9%, 25.0%/0 and 8.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 10.8% of patients treated with placebo.
  • Clinical response was achieved at week 12 by 53.8%, 64.9%, 52.8%, 55.6% and 51.4% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 35.1% of patients treated with placebo. Results are shown in Table 17.
  • the percentage of patients achieving clinical response at week 12 is shown in FIG. 6A (patients not on baseline steroids) and FIG. 6B (patients who were on steroids at baseline, and underwent mandatory taper of steroid dose starting at week 2).
  • Endoscopic improvement was achieved at week 12 or week 16 by 12.8%, 18.9%, 27.8%, 36.1%, and 25.7% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with 3.0% of patients treated with placebo. Results are shown in Table 18. Of the patients who were evaluated for endoscopic improvement at week 12, 10.5%, 13.3%, 25%, 33.3%, and 12.5% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, achieved endoscopic improvement by week 12, compared with 0% of patients treated with placebo.
  • Table 15 above shows the number of patients in the study that received prior anti-TNF treatment, treatment with prior non-anti-TNF biologics, treatment with vedolilzumab, and who were being treated with steroids at baseline, as well as the average duration of Crohn's disease at baseline.
  • the efficacy of each treatment progressively decreases.
  • the results for refractory patients in the study are shown in FIG. 9 .
  • refractory patients treated with upadacitinib achieved clinical remission and endoscopic response at unprecedented rates.
  • 15.8% of refractory patients treated with 3 mg BID of upadacitinib achieved clinical remission.
  • 30.3% of refractory patients treated with 6 mg BID of upadacitinib achieved clinical remission.
  • 26.5% of refractory patients treated with 12 mg BID of upadacitinib achieved clinical remission.
  • 36.7% of refractory patients treated with 24 mg QD (two 12 mg BID doses given simultaneously) achieved clinical remission.
  • a surprising proportion of refractory patients treated with upadacitinib achieved endoscopic remission at 12 or 16 weeks.
  • FIGS. 3A-3I The relationship between upadacitinib plasma concentrations and the primary endpoints and certain secondary and additional endpoints is set forth in FIGS. 3A-3I . Exposure-response relationships were observed for clinical response, clinical remission, CDAI remission (CDAI ⁇ 150), endoscopic response, endoscopic improvement, and endoscopic remission.
  • upadacitinib plasma concentration was determined, and the results shown in FIGS. 5A-5H .
  • Exposure-response relationships for effects of upadacitinib on NK cells, neutrophils, LDL and HDL cholesterol in Crohn's patients were generally consistent with those previously observed in RA patients. Compared to RA patients (data not shown), subjects with Crohn's had lower decreases in hemoglobin ( FIG. 5A ).
  • Example 8 Based on the data obtained in Example 8 for administration of an immediate release (IR) formulation of upadacitinib BID, the exposure-response relationships (simulating for 200 patients/arm) for 15 mg, 30 mg, and 45 mg modified-release QD doses of upadacitinib, for placebo, for 6 mg, 12 mg, 18 mg, and 24 mg IR BID doses of upadacitinib, and for 24 mg IR QD doses of upadacitinib was predicted. The full time-course for the different clinical endpoints was analyzed using Markov analyses. The Marko models allowed transition between response, no response, and dropouts.
  • IR immediate release
  • the results are set forth in FIGS. 4A-4F .
  • Example 10 Clinical Study for Crohn's Disease: Long-Term Efficacy and Safety of Upadacitinib in Moderate to Severe Crohn's Disease
  • Example 10 the extension phase of the Example 8 clinical study was studied and discussed.
  • the trial was a multicenter, randomized, double-blind placebo-controlled study of upadacitinib for the induction of symptomatic and endoscopic remission in patient with moderately to severely active Crohn's disease who have inadequately responded to or are intolerant to immunosuppressants or anti-TNF therapy.
  • the trial consisted of a screening period of up to 30 days, a 16 week double blind induction period, re-randomization at week 16, a 36 week double blind and open label phase and a 30 day follow up period.
  • the 16 week induction period began at the BL visit (week 0) and ended at the week 16 visit.
  • the randomization at BL was stratified by endoscopic disease severity (SES-CD ⁇ 15 and ⁇ 15). Safety and efficacy evaluations were performed through the end of the study. The end of the study was defined as the date the last patient completed the last follow up visit.
  • the re-randomization was stratified by dose received during the first 16 weeks and overall response (responder versus non-responder) at week 16.
  • Each treatment group received the corresponding dose of upadacitinib orally once or twice daily.
  • Patients receiving the 24 mg QD dose were administered two 12 mg capsules simultaneously orally once daily.
  • patients were evaluated for clinical remission (average daily SF ⁇ 1.5 and not worse than baseline and average daily AP ⁇ 1.0 and not worse than baseline), CDAI ⁇ 150, modified clinical remission (SF ⁇ 2.8 and AP ⁇ 1.0, both not worse than BL in patients with SF ⁇ 4.
  • the study comprised two treatment periods: a 16 week double-blind induction period and a 36 week double-blind extension phase.
  • induction period patients with a diagnosis of ileal, colonic, or ileocolonic Crohn's disease for ⁇ 3 months prior to BL and confirmed by endoscopy during the screening period, a CDAI ⁇ 220 and ⁇ 450, and who have inadequately responded to or experienced intolerance to previous treatment with an anti-TNF agent (e.g. infliximab, adalimumab or certolizumab pegol), were assigned to receive one of the following doses of upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD or placebo.
  • an anti-TNF agent e.g. infliximab, adalimumab or certolizumab pegol
  • the co-primary endpoints were endoscopic remission at week 12 or week 16 and clinical remission at week 16. Secondary endpoints included CDAI ⁇ 150 at week 16 and endoscopic response at week 12 or 16.
  • patients who completed the 16-week induction phases were re-randomised 1:1:1 to double-blind upadacitinib at 3 mg twice daily (BID), 12 mg BID or 24 mg daily (QD) for 36 weeks.
  • BID twice daily
  • QD 24 mg daily
  • Clinical response was achieved at week 52 by 50%, 71%, 62%, and 42% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.
  • Enhanced clinical response was achieved at week 52 by 47%, 71%, 62%, and 42% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID and 24 mg QD, respectively, of upadacitinib. Results are shown in Table 20.
  • endoscopic response was achieved at week 52 by 50.0%, 50.0%, 68.8%, and 30.0% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.
  • endoscopic response was achieved at week 52 by 34.4%, 35.7%, 44.8%, and 36.8% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib. Results are shown in Table 20.
  • endoscopic response was achieved at week 52 by 34.4, 35.7, 44.8 and 36.8% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID and 24 mg QD, respectively.
  • modified clinical remission was achieved at week 52 by 41.2%, 62.5%, 73.3%, and 40.0% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.
  • modified clinical remission was achieved at week 52 by 28.6%, 42.9%, 51.9%, and 38.9% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib. Results are shown in Table 20.
  • Proportion of patients with modified clinical remission and enhanced clinical response both defined in Figure, mean change from baseline in C-reactive protein (CRP) and faecal calprotectin (FC) were assessed over time in all patients unless otherwise mentioned. Comparisons between each upadacitinib dose with PBO was tested by Cochran-Mantel-Haenszel test stratified by SES-CD at BL. Non-responder imputation was applied to patients who received open-label upadacitinib or prematurely discontinued prior to Week 16 or initiated corticosteroids or had dose increase higher than baseline.
  • CRP C-reactive protein
  • FC faecal calprotectin
  • This trial is a multicenter, randomized, double-blind placebo-controlled study of upadacitinib for the induction and maintenance of clinical remission (using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity, excluding Physician's Global Assessment [i.e., Adapted Mayo score]) in patients with moderately to severely active ulcerative colitis.
  • the trial consists of a screening period of up to 35 days, an 8 week double blind induction period (Substudy 1), a second 8 week double blind and open label induction period (Substudy 2), re-randomization at week 8, a 44 week double blind and open label maintenance phase (Substudy 3), and a 30 day follow up period.
  • the first 8 week induction period begins at the BL visit (week 0) and ends at the week 8 visit.
  • an analysis of efficacy and safety of upadacitinib versus placebo will be performed. Based on this analysis, one induction dose of upadacitinib (Dose A) will be identified for further evaluation in Substudy 2.
  • Dose A one induction dose of upadacitinib
  • approximately 100 additional subjects will continue to be randomized into Groups 3 and 4 of Substudy 1 to receive either 30 mg QD or 45 mg QD treatment (50 patients per dose group).
  • Substudy 2 consists of two parts. In Part 1, approximately 375 patients with moderately to severely active ulcerative colitis are randomized in a 2:1 ratio to one of the double-blinded induction treatment arms as shown in FIG. 13 : upadacitinib Dose A mg QD or placebo QD. Dose A is the dose determined in Substudy 1 for further evaluation. Part 2 of Substudy 2 is open label. Approximately 330 subjects will be enrolled in Part 2 of Substudy 2 to receive open-label upadacitinib Dose A QD. This second 8 week induction period begins at the BL visit (week 0) and ends at the week 8 visit.

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