WO2021124095A1 - Treatment of ulcerative colitis with kinase inhibitors - Google Patents

Treatment of ulcerative colitis with kinase inhibitors Download PDF

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Publication number
WO2021124095A1
WO2021124095A1 PCT/IB2020/061956 IB2020061956W WO2021124095A1 WO 2021124095 A1 WO2021124095 A1 WO 2021124095A1 IB 2020061956 W IB2020061956 W IB 2020061956W WO 2021124095 A1 WO2021124095 A1 WO 2021124095A1
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pyrazol
subject
pyrazin
cyanomethyl
cyclobutane
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PCT/IB2020/061956
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French (fr)
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Jyoti Padmini RAMAKRISHNA
Christopher Vujic TEHLIRIAN
Dahong YU
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Pfizer Inc.
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Publication of WO2021124095A1 publication Critical patent/WO2021124095A1/en

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides methods for treating ulcerative colitis using compounds and analogues which inhibit certain kinases including Janus Kinase (JAK) in particular inhibitors of Tyk2, and more particularly, the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof.
  • JK Janus Kinase
  • Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility implicated in the aforementioned and related diseases.
  • JAK1 , JAK2, JAK3, and Tyk2 cellular protein tyrosine kinases
  • JAK1 , JAK2, JAK3, and Tyk2 cellular protein tyrosine kinases
  • cytokine signaling Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression.
  • STAT signal transducer and activator of transcription
  • Numerous cytokines are known to activate the JAK family.
  • cytokines include, the interferon (IFN) family (IFN-alpha, IFN-beta, IFN- omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11 , OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1 , Leptin, IL-12, IL-23), gamma C family (IL-2, IL-7, TSLP, IL- 9, IL-15, IL-21 , IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1 , HGF), and G-protein coupled receptors (AT1).
  • IFN interferon
  • gp130 family IL-6, IL-11 , OSM, LIF,
  • Tyk2 pairs with JAK1 to mediate type I interferon (IFN) signaling and with JAK2 to transmit interleukin (IL) IL-12 and IL-23 signaling. Both of these key cytokines are implicated in the pathophysiology of inflammatory bowel disease (IBD) Allocca M, etal., Best Practice & Research Clinical Gastroenterology 2018; 32-33; 95-102.
  • IBD inflammatory bowel disease
  • IL-12 and IL-23 require Tyk2 for signal transduction, raising the strong possibility that inhibition of Tyk2 mediated signaling could be efficacious in the treatment of UC.
  • Floss DM et al., Mol Biol Cell. 2016; 27(14):2301-16.
  • the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile is an orally bioavailable highly selectve Tyk2 inhibitor (Tyk2i).
  • (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H- pyrazol-1-yl)cyclobutane-1-carbonitrile is expected to target the T-helper 1 (Th1), T-helper 17 (Th17), and Types I IFN signaling pathways directly by inhibiting Tyk2. This should provide therapeutic benefit in the treatment of inflammatory conditions driven by Th1/Th17 and interferon immune responses.
  • 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).
  • Subjects 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., Gastroenterology, 2004; 126(2):451 -9.
  • UC ulcerative colitis
  • 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.
  • Disclosed herein is the discovery that compounds and analogues which inhibit certain kinases such as Tyk2 and particularly the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile are useful for treating UC. Accordingly, described herein are methods of reducing the severity of UC symptoms in a human subject, with more rapid onset of action and lower incidence of adverse effects.
  • the present invention provides a method for treating ulcerative colitis in a subject, comprising admistering to the subject in need thereof any of the compounds disclosed herein which inhibit JAK such as Tyk2.
  • the invention provides provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject comprising:
  • the invention provides the use of a JAK inhibitor, (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, in the manufacture of a medicament for use in the treatment of ulcerative colitis as set forth herein.
  • a JAK inhibitor (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile
  • subject refers to humans.
  • AE reverse effect
  • QD or “Q.D.” means one administered dose per day.
  • treating means an alleviation of symptoms associated with a disease, disorder or condition, or halt of further progression or worsening of those symptoms.
  • treatment may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the present invention in combination with other therapies.
  • therapeutically-effective indicates the capability of an agent to prevent, or improve the severity of the disorder, while avoiding adverse side effects typically associated with alternative therapies.
  • terapéuticaally-effective is to be understood to be equivalent to the phrase “effective for the treatment, prevention, or amelioration”, and both are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of disease, or pain or other symptom thereof, and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • “Pharmaceutically acceptable” means suitable for use in a “subject.”
  • ulcerative colitis is defined as having an Adapted Mayo score of 5 to 9, with an endoscopy subscore of 2 or 3. www.clinicaltrials.gov/ct2/show/NCT039342t6 ⁇
  • Clinical remission is based on 12-point total Mayo score: total Mayo score ⁇ 2 with noindividual subscore >1 .
  • clinical response is a decrease from baseline of at least 3 points in total Mayo score with at least 30% change, accompanied by at least one point decrease or absolute score of 0 or 1 in rectal bleeding subscore.
  • endoscopic remission refers to a Mayo endoscopy subscore 0.
  • endoscopic response refers to a Mayo endoscopy subscore 0 or 1 .
  • endoscopic improvement refers to a decrease of >1 point in Mayo endoscopy subscore or an absolute endoscopy score of ⁇ 1.
  • symptomatic remission refers to a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and both rectal bleeding and stool frequency subscores of 0.
  • deep remission refers to a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a 0 on both endoscopic and rectal bleeding subscore.
  • Mayo means the Mayo Scoring System for Assessment of Ulcerative Colitis Activity.
  • Adaptive Mayo Score refers to the Adaptive Mayo Score systemwhich has 3 subscores of the Mayo Score ranging from 0 to 9 without PGA subscore.
  • the present invention relates to a method for treating ulcerative colitis in a subject, comprising admistering to the subject in need thereof compounds which inhibit certain JAK, such as Tyk2.
  • the present invention further provides pharmaceutical compositions comprising such inhibitors.
  • the present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject comprising:
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In some embodiments, the amount in step (ii) is 200 or 400 mg QD.
  • the present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, the comprising:
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
  • the present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission,
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
  • the present invention provides said latter method further comprising maintaining clinical remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1r,3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains clinical remission for at least
  • the present invention provides a method of achieving clinical response of moderate to severe ulcerative colitis in a subject, comprising:
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
  • the present invention provides a method of achieving clinical response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H- pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; whereby the subject achieves clinical response, and wherein clinical response is a
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
  • the present invention provides said latter method, further comprising maintaining clinical response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains clinical response for at least 52 weeks
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
  • the present invention provides said latter method, further comprising maintaining endoscopic remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains endoscopic remission of moderate
  • the present invention provides a method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising:
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
  • the present invention provides a method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic improvement, and where
  • the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
  • the present invention provides said latter method further comprising maintaining endoscopic improvement of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains endoscopic improvement for at least 52 weeks (1 r
  • the present invention provides a method of achieving endoscopic response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; whereby the subject achieves endoscopic response, and wherein endoscopic response, and where
  • the amount is 100 mg QD. In other particular embodiments, the amount is 200 mg QD. In some embodiments, the amount is 300 mg QD. In certain embodiments, the amount is 400 mg QD. In certain other embodiments, the amount is 600 mg QD.
  • the present invention provides the latter method, further comprising maintaining endoscopic response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6- (1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent, wherein the subject maintains endoscopic response for at least 52 weeks (1 r
  • the present invention provides use of the compound (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, ora pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of ulcerative colitis according to any of the methods set forth hereinabove.
  • a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally.
  • Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area.
  • Topical administrations include the treatment of skin or organs readily accessible by local application, for example, eyes or ears. It also includes transdermal delivery to generate a systemic effect.
  • the rectal administration includes the form of suppositories.
  • the preferred routes of administration are oral, topical and parenteral.
  • compositions of the present invention may be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, drageemaking, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991).
  • the formulations of the invention can be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing.
  • the pharmaceutical formulations can also be formulated for controlled release or for slow release.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration.
  • the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
  • the compounds of the invention may be prepared by any method known in the art.
  • the compounds of the invention can be prepared by the procedures described by reference to the prior art references in which they are disclosed.
  • the study consists of a screening period up to 4 weeks, an 8-week induction treatment period, a 52-week open label extension treatment period, and a 4-week safety follow-up period.
  • eligible participants will be randomly assigned to receive either (1 r,3r)- 3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile 600 mg once daily (QD), 300 mg QD, 100 mg QD or matched placebo at overall 2:2:1 : 1 randomization ratio and stratified based on previous exposure to biologic treatments for UC and oral corticosteroid use at baseline.
  • Endoscopy (colonoscopy or flexible sigmoidoscopy) must be performed during the screening period preferably after all other eligibility criteria have been verified and within 5 to 7 days (not exceeding 10 days) prior to baseline to allow centrally read endoscopic subscore to be available at baseline visit for total Mayo score calculation.
  • the endoscopic subscore by the Central Reader must be available at the baseline visit.
  • the assessment by the Central Reader will be used to derive the total Mayo score for study eligibility.
  • the stool frequency, rectal bleeding and centrally-read endoscopic subscores based on diary data and the endoscopy performed during the screening period and the Physician Global Assessment (PGA) obtained at baseline will be used to determine eligibility.
  • the endoscopic report and pathology report must be available in the source documents.
  • Endoscopy is also performed during the Week 8 and Week60/early withdrawal visit where possible but may be performed up to - 7 days prior to the site visit if necessary.
  • a bowel prep should be conducted as per local routine.
  • the position of the endoscope will be based on the length of the instrument at various levels of insertion as well as the morphological features of the intestine as seen during screening endoscopy.
  • the endoscopy report and any photographs and/or video recordings taken during the procedure should be filed in the participant’s chart.
  • Endoscopy subscores will be reported per Mayo score based on Central Reader, and for Mayo endoscopy subscore of 1 , presence or absence of friability will be noted. Participants who meet either of the 2 criteria below are considered at risk for colorectal cancer and must have a colonoscopy prior to randomization. The colonoscopy and pathology reports (if biopsies obtained) must be available in the source documentation:
  • Participant Stool Diary Study participants will use an electronic diary in order to record the following information on a daily basis beginning at Screening Visit and throughout the study:
  • the Subject Global Impression of Severity (PGIS) Question rates the severity of your ulcerative colitis over the past 24 hours.
  • participants should enter diary data beginning at Screening Visit and continuously throughout the study. Instructions for completing the diary will be provided to participants at screening and reviewed at subsequent visits.
  • the Mayo Score is a tool designed to measure disease activity for UC.
  • the Mayo scoring system consists of 4 subscores, each graded 0 to 3 with the higher score indicating more severe disease activity (See below and Section 10.9.3).
  • the total Mayo score is a summary of all 4 subscores ranging from 0 to 12 points.
  • Calculation of the Mayo Score requires an assessment of the participant’s stool frequency and any amount of blood in the stool.
  • the Mayo scores will be calculated based on the participant’s stool diary most recently recorded 3 valid and consecutive days closest to the study visit. Investigator sites will be trained on the diary usage and will train participants on use of the diary. Diary data entered by the participant will be reviewed by the site at each visit.
  • the IBDQ is a psychometrically validated PRO instrument for measuring the disease- specific quality of life in participants with IBD, including UC.
  • the IBDQ is comprised of 32-items, which are grouped into 4 dimensions: bowel function, emotional status, systemic symptoms and social function. The 4 domains are scored as follows: ⁇ Bowel symptoms: 10 to 70.
  • the total IBDQ score ranges from 32 to 224. Forthe total score and each domain, a higher score indicates better quality of life. A score of at least 170 corresponds to clinical remission and an increase of at least 16 points is considered to indicate a clinically meaningful improvement.

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Abstract

Method for treating ulcerative colitis using compounds and analogues which inhibit certain kinases including Janus Kinase (JAK), said method comprising the step of administering to the subject in need thereof (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-5pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

Description

TREATMENT OF ULCERATIVE COLITIS WITH KINASE INHIBITORS
FIELD OF THE INVENTION
The present invention provides methods for treating ulcerative colitis using compounds and analogues which inhibit certain kinases including Janus Kinase (JAK) in particular inhibitors of Tyk2, and more particularly, the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility implicated in the aforementioned and related diseases.
Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1 , JAK2, JAK3, and Tyk2) play a central role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1 ; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the interferon (IFN) family (IFN-alpha, IFN-beta, IFN- omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11 , OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1 , Leptin, IL-12, IL-23), gamma C family (IL-2, IL-7, TSLP, IL- 9, IL-15, IL-21 , IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1 , HGF), and G-protein coupled receptors (AT1).
Tyk2 pairs with JAK1 to mediate type I interferon (IFN) signaling and with JAK2 to transmit interleukin (IL) IL-12 and IL-23 signaling. Both of these key cytokines are implicated in the pathophysiology of inflammatory bowel disease (IBD) Allocca M, etal., Best Practice & Research Clinical Gastroenterology 2018; 32-33; 95-102. Clinical study results from both induction and maintenance phases show that treatment with either ustekinumab (monoclonal antibody against the p40 sub-unit of I L-12/IL-23 receptor) or mirikizumab (monoclonal antibody against the p19 sub-unit of IL-23 receptor) induced and maintained clinical remission in a significant proportion of ulcerative colitis (UC) subjects with moderate to severe disease activity. Sandborn WJ, etal., J Crohn’s and Colitis 2018; 13 (Supp. 1):S024-26; Sandborn WJ, et al., Gastroenterology 2018; 154(6):Supp. 1 :S1360-S1361. IL-12 and IL-23 require Tyk2 for signal transduction, raising the strong possibility that inhibition of Tyk2 mediated signaling could be efficacious in the treatment of UC. Floss DM, et al., Mol Biol Cell. 2016; 27(14):2301-16.
The compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile is an orally bioavailable highly selectve Tyk2 inhibitor (Tyk2i). (1 r,3r)-3-(Cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile is being investigated in participants with plaque psoriasis and other autoimmune diseases. Based on its cytokine inhibition profile, (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H- pyrazol-1-yl)cyclobutane-1-carbonitrile is expected to target the T-helper 1 (Th1), T-helper 17 (Th17), and Types I IFN signaling pathways directly by inhibiting Tyk2. This should provide therapeutic benefit in the treatment of inflammatory conditions driven by Th1/Th17 and interferon immune responses.
There is still an unmet need for an effective, safe, and well tolerated treatment in subjects with moderate to severe ulcerative colitis. The hallmark clinical symptoms of UC include bloody diarrhea associated with rectal urgency and tenesmus. The clinical course is marked by exacerbation and remission. The diagnosis of UC is suspected on clinical grounds and supported by diagnostic testing, and elimination of infectious causes. Dignass A, Eliakim R, Magro F, et al., J Crohn's Colitis. 2012; 6(10):965-90). The most severe intestinal manifestations of UC are toxic megacolon and perforation. 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). Subjects 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., 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. Disclosed herein is the discovery that compounds and analogues which inhibit certain kinases such as Tyk2 and particularly the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile are useful for treating UC. Accordingly, described herein are methods of reducing the severity of UC symptoms in a human subject, with more rapid onset of action and lower incidence of adverse effects. SUMMARY OF THE INVENTION
The present invention provides a method for treating ulcerative colitis in a subject, comprising admistering to the subject in need thereof any of the compounds disclosed herein which inhibit JAK such as Tyk2.
In some embodiments, the invention provides provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject comprising:
(i) orally administering to the subject for up to 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 - methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, wherein subject achieves an endoscopic response.
In another embodiment, the invention provides the use of a JAK inhibitor, (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, in the manufacture of a medicament for use in the treatment of ulcerative colitis as set forth herein.
The present invention will be further understood from the following description given by way of example only. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through the following discussion and the examples.
As used herein, “subject” refers to humans.
The term “adverse effect” (AE) is any untoward medical occurrence in a subject or clinical study participant, temporally associated with the administration of the JAK inhibitor.
The term “QD” or “Q.D.” means one administered dose per day.
The term “treating” or “treatment” means an alleviation of symptoms associated with a disease, disorder or condition, or halt of further progression or worsening of those symptoms. Depending on the disease and condition of the subject, the term “treatment” as used herein may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the present invention in combination with other therapies. The term "therapeutically-effective" indicates the capability of an agent to prevent, or improve the severity of the disorder, while avoiding adverse side effects typically associated with alternative therapies. The phrase "therapeutically-effective" is to be understood to be equivalent to the phrase "effective for the treatment, prevention, or amelioration", and both are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of disease, or pain or other symptom thereof, and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
“Pharmaceutically acceptable” means suitable for use in a “subject.”
The term "moderate to severe ulcerative colitis" is defined as having an Adapted Mayo score of 5 to 9, with an endoscopy subscore of 2 or 3. www.clinicaltrials.gov/ct2/show/NCT039342t6·
The term “clinical remission” is based on 12-point total Mayo score: total Mayo score <2 with noindividual subscore >1 .
The term “clinical response” is a decrease from baseline of at least 3 points in total Mayo score with at least 30% change, accompanied by at least one point decrease or absolute score of 0 or 1 in rectal bleeding subscore.
The term “endoscopic remission” refers to a Mayo endoscopy subscore 0.
The term “endoscopic response” refers to a Mayo endoscopy subscore 0 or 1 .
The term “endoscopic improvement” refers to a decrease of >1 point in Mayo endoscopy subscore or an absolute endoscopy score of <1.
The term “mucosal healing” refers to a Mayo endoscopy subscore 0 or 1 and Geboes histology score 0 or 1. Aranzazu, J-E., et al. Journal of Crohn's and Colitis, Volume 11 (3), 2017, 305-313
The term “symptomatic remission” refers to a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and both rectal bleeding and stool frequency subscores of 0.
The term “deep remission” refers to a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a 0 on both endoscopic and rectal bleeding subscore.
The term “clinical remission” is based on 9-point total Mayo score: total Mayo score of <2 with rectal bleeding subscore of 0.
The abbreviation "Mayo" means the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. “Adaptive Mayo Score” refers to the Adaptive Mayo Score systemwhich has 3 subscores of the Mayo Score ranging from 0 to 9 without PGA subscore. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for treating ulcerative colitis in a subject, comprising admistering to the subject in need thereof compounds which inhibit certain JAK, such as Tyk2. The present invention further provides pharmaceutical compositions comprising such inhibitors.
The present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject comprising:
(i) orally administering to the subjectsubject for up to 8 weeks (1r,3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein the subject achieves an endoscopic response. In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In some embodiments, the amount in step (ii) is 200 or 400 mg QD.
In certain embodiments, the present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, the comprising:
(i) orally administering to the subject for up to 8 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl- 1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein clinical remission is a stool frequency subscore of less than or equal to 1 , a rectal bleeding subscore of 0, and an endoscopic subscore of less than or equal to 1 . In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
In certain other embodiments, the present invention provides a method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein clinical remission is a stool frequency subscore of less than or equal to 1 , and a rectal bleeding subscore of 0. In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
In certain embodiments, the present invention provides said latter method further comprising maintaining clinical remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1r,3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains clinical remission for at least 52 weeks. In particular embodiments, the amount is 200 or 400 mg QD.
In certain other embodiments, the present invention provides a method of achieving clinical response of moderate to severe ulcerative colitis in a subject, comprising:
(i) orally administering to the subject for up to 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl- 1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r, 3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; whereby the subject achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score of greater than or equal to 2 points and greater than or equal to 30 percent decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of greater than or equal to 1 or (ii) an absolute rectal bleeding subscore of less than or equal to 1. In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
In some embodiments, the present invention provides a method of achieving clinical response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H- pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; whereby the subject achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score of greater than or equal to 2 points and greater than or equal to 30 percent decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of greater than or equal to 1 or (ii) an absolute rectal bleeding subscore of less than or equal to 1. In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
In other embodiments, the present invention provides said latter method, further comprising maintaining clinical response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains clinical response for at least 52 weeks. In particular embodiments, the amount is 200 or 400 mg QD. In certain embodiments, the present invention provides a method of achieving endoscopic remission of moderate to severe ulcerative colitis in a subject, comprising:
(i) orally administering to the subject for at least 8 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic remission, and wherein endoscopic remission is an endoscopic subscore of 0. In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
In other embodiments, the present invention provides said latter method, further comprising maintaining endoscopic remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains endoscopic remission for at least 52 weeks. In particular embodiments, the amount is 200 or 400 mg QD.
In certain embodiments, the present invention provides a method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising:
(i) orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and, (ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of less than or equal to 1 . In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD. In particular embodiments, the amount in step (ii) is 200 or 400 mg QD.
In certain other embodiments, the present invention provides a method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of less than or equal to 1 . In particular embodiments, the amount in step (i) is 100 mg QD. In other particular embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In certain embodiments, the amount in step (i) is 400 mg QD. In certain other embodiments, the amount in step (i) is 600 mg QD.
In some embodiments, the present invention provides said latter method further comprising maintaining endoscopic improvement of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains endoscopic improvement for at least 52 weeks. In particular embodiments, the amount is 200 or 400 mg QD.
In certain other embodiments, the present invention provides a method of achieving endoscopic response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; whereby the subject achieves endoscopic response, and wherein endoscopic response is a Mayo endoscopy subscore 0 or 1. In particular embodiments, the amount is 100 mg QD. In other particular embodiments, the amount is 200 mg QD. In some embodiments, the amount is 300 mg QD. In certain embodiments, the amount is 400 mg QD. In certain other embodiments, the amount is 600 mg QD.
In certain embodiments, the present invention provides the latter method, further comprising maintaining endoscopic response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6- (1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent, wherein the subject maintains endoscopic response for at least 52 weeks. In particular embodiments, the amount is 200 or 400 mg QD.
In further embodiments, the present invention provides use of the compound (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile, ora pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of ulcerative colitis according to any of the methods set forth hereinabove.
In therapeutic use for treating disorders in a subject, a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Topical administrations include the treatment of skin or organs readily accessible by local application, for example, eyes or ears. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. The preferred routes of administration are oral, topical and parenteral.
Pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, drageemaking, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulations of the invention can be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.
Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
Chemical Synthesis
The compounds of the invention may be prepared by any method known in the art. In particular, the compounds of the invention can be prepared by the procedures described by reference to the prior art references in which they are disclosed.
For those compounds which inhibit Tyk2 specifically, including (1 r,3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, preparative methods are disclosed in US Patent No. 10,144,738, the contents of which are incorporated herein in their entirety.
EXAMPLES
The following non-limiting examples are presented merely to illustrate the present invention. The skilled person will understand that there are numerous equivalents and variations not exemplified but which still form part of the present teachings.
Example 1
Methods of Treatment of Ulcerative Colitis
The study consists of a screening period up to 4 weeks, an 8-week induction treatment period, a 52-week open label extension treatment period, and a 4-week safety follow-up period. After the screening period, eligible participants will be randomly assigned to receive either (1 r,3r)- 3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile 600 mg once daily (QD), 300 mg QD, 100 mg QD or matched placebo at overall 2:2:1 : 1 randomization ratio and stratified based on previous exposure to biologic treatments for UC and oral corticosteroid use at baseline. All participants who have completed the 8-week induction treatment without safety findings or do not meet discontinuation criteria will be eligible to roll over into the 52-week open label extension treatment period. Eligible participants will receive (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile 400 mg QD with a dose de-escalation to 200 mg QD if needed in the open label treatment period.
Example 2 Endoscopy
Endoscopy (colonoscopy or flexible sigmoidoscopy) must be performed during the screening period preferably after all other eligibility criteria have been verified and within 5 to 7 days (not exceeding 10 days) prior to baseline to allow centrally read endoscopic subscore to be available at baseline visit for total Mayo score calculation.
The endoscopic subscore by the Central Reader must be available at the baseline visit. The assessment by the Central Reader will be used to derive the total Mayo score for study eligibility. The stool frequency, rectal bleeding and centrally-read endoscopic subscores based on diary data and the endoscopy performed during the screening period and the Physician Global Assessment (PGA) obtained at baseline will be used to determine eligibility. The endoscopic report and pathology report must be available in the source documents.
Endoscopy is also performed during the Week 8 and Week60/early withdrawal visit where possible but may be performed up to - 7 days prior to the site visit if necessary. A bowel prep should be conducted as per local routine. The position of the endoscope will be based on the length of the instrument at various levels of insertion as well as the morphological features of the intestine as seen during screening endoscopy. The endoscopy report and any photographs and/or video recordings taken during the procedure should be filed in the participant’s chart.
Endoscopy subscores will be reported per Mayo score based on Central Reader, and for Mayo endoscopy subscore of 1 , presence or absence of friability will be noted. Participants who meet either of the 2 criteria below are considered at risk for colorectal cancer and must have a colonoscopy prior to randomization. The colonoscopy and pathology reports (if biopsies obtained) must be available in the source documentation:
• If the participant is >50 years of age, a colonoscopy within 10 years of screening is required to exclude adenomatous polyps. Participants with adenomatous polyps identified on screening endoscopy will be eligible after complete polypectomy and pathology report is negative.
• If the participant has had extensive (ie, greater than left sided) colitis for >8 years or disease limited to left side of colon (i.e., distal to splenic flexure) for >10 years, regardless of age, a colonoscopy within 1 year of screening visit is required to survey for dysplasia. Participants with dysplasia or cancer identified on biopsies will be excluded.
Example 3
Participant Stool Diary Study participants will use an electronic diary in order to record the following information on a daily basis beginning at Screening Visit and throughout the study:
• ‘Normal’ number of stools per day (when not having a flare). This question will be asked only at the screening visit.
• ‘Normal’ number of stools per day before having UC. This question will be asked only at the screening visit.
• Over the past 24 hours, how many times did subject have a bowel movement, including trips to the toilet that resulted in any of the following: blood or mucus or stool while having a bowel movement.
• Over the past 24 hours, how many times did subject experience leaking of feces, blood, mucus, or liquid from your anus when not on the toilet while having a bowel movement?
• Presence of blood in the stools (if any).
• Description of blood in the stools (if any), ONLY if presence is noted.
The Subject Global Impression of Severity (PGIS) Question rates the severity of your ulcerative colitis over the past 24 hours. In order to encourage consistent diary recording, participants should enter diary data beginning at Screening Visit and continuously throughout the study. Instructions for completing the diary will be provided to participants at screening and reviewed at subsequent visits.
Example 4
Mayo Score for Ulcerative Colitis Activity
The Mayo Score is a tool designed to measure disease activity for UC. The Mayo scoring system consists of 4 subscores, each graded 0 to 3 with the higher score indicating more severe disease activity (See below and Section 10.9.3). The total Mayo score is a summary of all 4 subscores ranging from 0 to 12 points.
• Stool frequency (Subscore 0-3).
• Rectal bleeding (Subscore 0-3).
• Findings on endoscopy (Subscore 0-3).
• Physician’s Global Assessment (Subscore 0-3).
Calculation of the Mayo Score requires an assessment of the participant’s stool frequency and any amount of blood in the stool. The Mayo scores will be calculated based on the participant’s stool diary most recently recorded 3 valid and consecutive days closest to the study visit. Investigator sites will be trained on the diary usage and will train participants on use of the diary. Diary data entered by the participant will be reviewed by the site at each visit.
If there are missing stool diary data, the average will be taken from the 3 most recently available days reported within 5 days close to (and prior to if it is a baseline visit) study visit for calculation of Mayo score. Invalid days for Mayo score calculation are dates for bowel preparation, endoscopy and 1 day after endoscopic procedure.
If there only 2 available valid days reported within the 5 days close to (and prior to if it is a baseline visit) the study visit, the average will be taken from the limited available data unless there is no diary data reported within 5 days. In this case, stool frequency and rectal bleeding subscores will be considered as missing. The rectal bleeding subscore will be rounded up if the average is between >0 to <1 .
Example 5 Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ is a psychometrically validated PRO instrument for measuring the disease- specific quality of life in participants with IBD, including UC. The IBDQ is comprised of 32-items, which are grouped into 4 dimensions: bowel function, emotional status, systemic symptoms and social function. The 4 domains are scored as follows: · Bowel symptoms: 10 to 70.
• Systemic symptoms: 5 to 35.
• Emotional function: 12 to 84.
• Social function: 5 to 35.
The total IBDQ score ranges from 32 to 224. Forthe total score and each domain, a higher score indicates better quality of life. A score of at least 170 corresponds to clinical remission and an increase of at least 16 points is considered to indicate a clinically meaningful improvement.

Claims

CLAIMS What is claimed is:
1 . A method of achieving clinical remission of moderate to severe ulcerative colitis in a subject comprising:
(i) orally administering to the subject for up to 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 - methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein the subject achieves an endoscopic response.
2. A method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, the comprising:
(i) orally administering to the subject for up to 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6- (1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r, 3r)-3-(cyanomethyl)-3- (4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein clinical remission is a stool frequency subscore of less than or equal to 1 , a rectal bleeding subscore of 0, and an endoscopic subscore of less than or equal to 1 .
3. A method of achieving clinical remission of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1- methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical remission, and wherein clinical remission is a stool frequency subscore of less than or equal to 1 , and a rectal bleeding subscore of 0.
4. The method of claim 3, further comprising maintaining clinical remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin- 4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)- 3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent, wherein the subject maintains clinical remission for at least 52 weeks.
5. A method of achieving clinical response of moderate to severe ulcerative colitis in a subject, the method comprising:
(i) orally administering to the subject for up to 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 - methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score of greaterthan or equal to 2 points and greater than or equal to 30 percent decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of greater than or equal to 1 or (ii) an absolute rectal bleeding subscore of less than or equal to 1 .
6. A method of achieving clinical response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6- (1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent; whereby the subject achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score ofgreaterthan or equal to 2 points and greater than or equal to 30 percent decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of greater than or equal to 1 or (ii) an absolute rectal bleeding subscore of less than or equal to 1 .
7. The method of claim 6, further comprising maintaining clinical response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains clinical response for at least 52 weeks.
8. A method of achieving endoscopic remission of moderate to severe ulcerative colitis in a subject, comprising:
(i) orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic remission, and wherein endoscopic remission is an endoscopic subscore of 0.
9. The method of claim 8, further comprising maintaining endoscopic remission of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1-carbonitrile free base equivalent, wherein the subject maintains endoscopic remission for at least 52 weeks.
10. A method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising:
(i) orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6- (1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; and,
(ii) orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile free base equivalent; whereby the subject achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of less than or equal to 1 .
11. A method of achieving endoscopic improvement of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl- 1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)- 1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent; whereby the subject achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of less than or equal to 1 .
12. The method of claim 11 , further comprising maintaining endoscopic improvement of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H- pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the subject maintains endoscopic improvement for at least 52 weeks.
13. A method of achieving endoscopic response of moderate to severe ulcerative colitis in a subject, comprising orally administering to the subject for at least 8 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl- 1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)- 1 H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg of (1 r,3r)-3-(cyanomethyl)-3-(4- (6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 - carbonitrile free base equivalent; whereby the subject achieves endoscopic response, and wherein endoscopic response is a Mayo endoscopy subscore 0 or 1 .
14. The method of claim 13, further comprising maintaining endoscopic response of moderate to severe ulcerative colitis in the subject, comprising orally administering to the subject for at least 52 weeks (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 , 5- a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600 or 1200 mg QD of (1 r,3r)-3- (cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 - yl)cyclobutane-1 -carbonitrile free base equivalent, wherein the subject maintains endoscopic response for at least 52 weeks.
15. Use of the compound (1 r,3r)-3-(cyanomethyl)-3-(4-(6-(1 -methyl-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1 H-pyrazol-1 -yl)cyclobutane-1 -carbonitrile, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of ulcerative colitis according to any of claims 1-14.
PCT/IB2020/061956 2019-12-18 2020-12-15 Treatment of ulcerative colitis with kinase inhibitors WO2021124095A1 (en)

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