Method of administering belumosudil for the treatment of chronic graft-versus-host disease

Abstract

The present disclosure provides a method of administering belumosudil mesylate salt to a patient with cGVHD.

Description

Technical Field

[0001] The present disclosure relates to a method of administering belumosudil mesylate (REZUROCK™) to a patient for the treatment of chronic graft-versus-host disease (cGVHD).

Background Art

[0002] Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potential serious complication after solid organ transplantation and allogeneic hematopoietic cell transplantation (alloHCT). cGVHD affects up to 70% of all alloHCT recipients, with an incidence of 20% - 50% in children. It is the main cause of non-relapse mortality beyond 2 years after alloHCT. The estimated prevalence of cGVHD is 14,000 patients in the United States (as of 2016). (Bachier CR et al: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. ASH 2019, Orlando, FL, December 7 - 10, 2019, published in 2019) (“Bachier et al.”)

[0003] Patients with cGVHD have substantial impairments in quality of life (QOL), as evaluated by the Lee Symptom Scale (LSS) that measures the impact of cGVHD on the patient's function and well-being. Only one-third of patients with cGVHD who initiate systemic treatment are reported to survive, achieve remission, and discontinue immunosuppressive therapy by 5 years. (Lee SJ et al: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transpl 24:555 - 562, 2018) (“Lee et al.”).

[0004] The pathophysiology of cGVHD can be divided into three phases: early inflammation due to tissue damage, dysregulation of the adaptive immune system, and abnormal tissue repair due to chronic inflammation and fibrosis.

[0005] The first-line treatment for moderate to severe chronic graft-versus-host disease (cGVHD) as defined by the US National Institutes of Health (NIH) is corticosteroids alone, or in combination with sirolimus or calcineurin inhibitors. However, up to 70% of patients require additional treatment regimens. (Bachier CR et al). Furthermore, long-term use of corticosteroids is associated with significant side effects. (Lee et al).

[0006] The management of cGVHD has continued to evolve with the emergence of targeted therapies. cGVHD is characterized by the overproduction of the pro-inflammatory cytokines IL-21 and IL-17, and the overactivation of follicular helper T cells and B cells, which leads to the overproduction of antibodies.

[0007] In 2017, the US Food and Drug Administration approved the Bruton-type Tyr kinase inhibitor ibrutinib for the treatment of adults with cGVHD after failure of one or more prior systemic therapies. In a study of patients with cGVHD who were required to have either an erythematous rash covering more than 25% of the body surface area or an NIH mouse score of more than 4, an overall response rate (ORR) of 67% and a discontinuation rate due to treatment-emergent adverse events (TEAE) of 43% were reported for treatment with ibrutinib. (Waller EK, et al: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b / 2 study. Biol Blood Marrow Transpl 25:2002-2007, 2019). Summary of the Invention Problems to be Solved by the Invention

[0008] There remains an opportunity to study other treatment options for patients with cGVHD, including those who have failed treatment for one or more lines.

[0009] The present disclosure provides a method of administering besremi (REZUROCKTM) to a patient for the treatment of cGVHD.

Means for Solving the Problems

[0010] In one embodiment, the present disclosure provides the use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound), and / or besremi, for use in a patient who has experienced one or more treatment-related adverse reactions while being administered a compound comprising the following compound at a clinically recommended dose. If the patient experiences at least one adverse reaction at grade 3 or higher, discontinue administration of the compound to the patient; if at least one adverse reaction does not escalate to grade 4 and the patient recovers to grade 1 or lower after discontinuation of treatment, resume administration of the compound to the patient at a clinically recommended dose.

[0011] In one embodiment, the present disclosure provides the use of a compound or besremi, and / or a method of treating a subject for cGVHD, comprising administering a compound to a patient at a clinically recommended dose for the patient; monitoring the patient for adverse reactions; discontinuing administration of the compound to the patient if the patient experiences at least one adverse reaction at grade 3; and resuming administration of the compound to the patient if at least one adverse reaction of the patient recovers to grade 1 or lower.

[0012] In another embodiment, the present disclosure provides permanently discontinuing administration of the compound to the patient if the patient experiences at least one adverse reaction at grade 4.

[0013] The present disclosure and further embodiments can be more fully understood by reference to the following detailed description and examples, which are intended to illustrate, but not limit, the non-limiting embodiments.

Brief Description of the Drawings

[0014]

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Mode for Carrying Out the Invention

[0015] Overview Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 inhibition acts on the dysregulated adaptive immune system and fibrosis resulting from abnormal tissue repair. Belumosudil inhibits ROCK2 and ROCK1 at IC 50 values of approximately 100 nM and 3 μM, respectively.

[0016] Belumosudil downregulated pro-inflammatory responses via modulation of STAT3 / STAT5 phosphorylation and a shift in the Th17 / Treg balance in ex vivo or in vitro human T cell assays. Belumosudil also inhibited abnormal profibrotic signaling in vitro. By controlling ROCK2 activity, belumosudil mediates signaling in immune cell function and fibrosis pathways, thereby alleviating the effects caused by this debilitating disease, such as inflammation and fibrotic changes in multiple tissues involving several organs including the lung, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0017] In vivo, belumosudil has shown activity in an animal model of chronic GVHD.

[0018] The mesylate salt of belumosudil is marketed as REZUROCK™ in the United States and other countries for the treatment of patients with chronic GVHD (cGVHD), optionally after failure of at least two prior lines of systemic therapy. The compound belumosudil has the chemical name: 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound belumosudil is also known as KD025. The active pharmaceutical ingredient of REZUROCK™ has the molecular formula C 27 H 28 N6O5S and is the belumosudil mesylate salt having the chemical name 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1).

[0019] The chemical structure of the belumosudil mesylate salt is as follows.

Chemical formula

[0020] The methods for making belumosudil and the compound are described in the following U.S. patents. U.S. Patent No. 8,357,693, U.S. Patent No. 9,815,820, U.S. Patent No. 10,183,931, and U.S. Patent No. 10,696,660.

[0021] The present disclosure provides a method of administering belumosudil mesylate (REZUROCK™) to a patient having risk management steps to address potential adverse reactions.

[0022] Definitions As used herein, "about" includes the exact amount modified by the term "about" and amounts expected to be within experimental error, such as within 15%, 10%, or 5%. For example, "about 200 mg" means "200 mg" and also means a range of mg within experimental error, such as ±15%, 10%, or 5% of 200 mg. As used herein, the term "about" can be used to modify ranges and specific values.

[0023] As used herein (including the use of this term in connection with stopping and / or restarting the administration of an API, such as a compound or vermoxnil, to a subject), "administer" or "administered" refers to the act of prescribing a medicament containing an API for a subject to ingest during treatment, the act of dispensing the medicament to the subject, and / or the act of physically receiving or ingesting the medicament. Thus, an API (such as a compound or vermoxnil) can be "administered" by a physician or other medical professional writing a prescription for the medicament. And / or by a pharmacist filling in the prescription, and / or by a pharmacist dispensing the medicine to the subject; and / or provided by a patient or subject ingesting the medicament, and / or by their partner or caregiver providing the medicament to the subject, each of whom can also "stop" and / or "restart" the administration of the API.

[0024] "Adverse reaction" means a physiological reaction resulting from treatment with an API that is undesirable, harmful, or unpleasant for the patient or the treatment process. In certain embodiments, adverse reactions include, but are not limited to, infectious diseases, gastrointestinal disorders, respiratory disorders, thoracic or mediastinal disorders, vascular disorders, musculoskeletal or connective tissue disorders, nervous system disorders, metabolic disorders, and / or skin and subcutaneous disorders.

[0025] In other embodiments, more general adverse reactions can include, but are not limited to, weakness, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, phosphate reduction, increased gamma-glutamyltransferase, lymphopenia, and hypertension. Adverse reactions can be detected directly or indirectly.

[0026] "API" means "active pharmaceutical ingredient".

[0027] "Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" and "allogeneic hematopoietic cell transplantation (allo-HCT)", also known as bone marrow transplantation and stem cell transplantation, refer to the technique of transplanting donor-derived hematopoietic cells into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some situations, cord blood can be used. The donor and recipient can be matched by the human leukocyte antigen (HLA) gene, such as siblings. The donor and recipient can be a parent and child who are only half-matched (haplotype-matched).

[0028] When the term "belumosudil" is used in this specification, it should be understood that, unless the context clearly indicates otherwise, this term can include any form of the compound belumosudil as well as its pharmaceutically acceptable salts. The term "belumosudil" refers to both the compound belumosudil (e.g., in free base form, amorphous form or crystalline form), the pharmaceutically acceptable salts of belumosudil, such as the mesylate form used as (trademark) REZUROCK, and any form of belumosudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0029] "Discontinue" or "discontinuing", when used with respect to the administration of an API, means that the API is no longer being administered to the patient, either temporarily or permanently. For example, if a patient experiences a treatment-related grade 3 adverse reaction, the administration of the API can probably be "discontinued" temporarily (to be resumed if the patient recovers to grade 0 or 1), or if a patient experiences a treatment-related grade 4 adverse reaction, the administration of the API should be permanently discontinued or stopped.

[0030] "Clinical endpoint" or "trial endpoint" refers to an event or outcome in a clinical trial that can be objectively measured to determine the outcome and potential beneficial effects of a drug or dosing protocol designed in a clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) is the percentage of people in a test or treatment group who have a partial response (PR) or complete response (CR) to treatment within a certain period. Failure-free survival (FFS) means the time from the first dose of belumosudil to the event of failure, or the interval from the start of belumosudil to the addition of a new cGVHD therapy, recurrence of the underlying disease, or time to non-relapse mortality (NRM). Overall survival (OS) means the length of time from the date of diagnosis or start of treatment of the disease. Duration of response (DOR) means the time from the point of initial response (e.g., PR or CR) to documented progression from the best response of cGVHD, to the start of additional systemic cGVHD therapy from the initial response, or to death. Time to next treatment (TTNT) means the time to the start of subsequent systemic cGVHD therapy.

[0031] "Clinically recommended amount" or "clinically recommended dose" refers to the amount or dose of an API that is recommended and / or approved for administration to a patient by a person skilled in the art of pharmaceutical chemistry for treating the disease state in question after a clinical trial, as described, for example, in Examples 1 and 2 of this specification. In some embodiments, the clinically recommended dose of belumosudil mesylate is 200 mg / day. In some embodiments, it is 200 mg / day and is administered orally with food.

[0032] "CYP3A" refers to the CYP3A family of p-450 isoenzymes, including CYP3A4.

[0033] When the term "grade" is used to refer to the grade level of an adverse reaction, it is intended that this term be defined according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 scale. The CTCAE shows grades 1 - 5, which have a unique clinical description of the severity of each adverse reaction based on general guidelines: Grade 1 - Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; no indicated intervention); Grade 2 - Moderate (minimal indicated local or non-invasive intervention); Grade 3 - Severe (medically significant but not immediately life-threatening; indicated hospitalization or extension of hospitalization; disabling; limitation of self-care); Grade 4 - Life-threatening (indicating urgent intervention); and Grade 5 - Death.

[0034] "Immunosuppressive therapy" (IST) refers to therapy that is typically administered for at least 6 months after allogeneic HSCT in an attempt to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine.

[0035] The Lee Symptom Scale (LSS) summary score measures the impact on a patient's function and health. The Lee Symptom Scale is a 30-item scale developed to measure symptoms of cGVHD and is described in Lee SJ, et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease. Biol Blood Marrow Transplant 2002;8:444-452.

[0036] "Treatment line" or "line of treatment" describes the order or sequence in which different treatments are given to a patient as their disease progresses. The first treatment (primary treatment) may or may not work well and may stop functioning after a certain period. After the first-choice therapy is discontinued, a second, different treatment (second-choice therapy) may be administered. Subsequent treatment lines may be administered if the second treatment does not work or stops functioning. Some patients may receive multiple treatment lines over the course of their disease.

[0037] The first-choice therapy for moderate to severe chronic graft-versus-host disease (cGVHD) as defined by the US National Institutes of Health (NIH) can be corticosteroids alone or in combination with sirolimus or a calcineurin inhibitor. (Carpenter PA, et al.: A phase II / III randomized, multicenter trial of prednisone / sirolimus versus prednisone / sirolimus / calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 103:1915-1924, 2018).

[0038] Examples of corticosteroid therapies for the treatment of cGVHD include, but are not limited to, prednisone, prednisolone, methylprednisolone, and budesonide. Examples of prior systemic therapies for treating cGVHD include, but are not limited to, prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib, and ofatumumab.

[0039] "Monitoring" as related to the evaluation of adverse reactions means observing, confirming, and / or evaluating the progression of one or more adverse reactions over at least two time points. In some embodiments, over a period of time; in some embodiments, monthly; in some embodiments, at least monthly. Monitoring can be performed directly or indirectly via examinations, patient self-reports, visual observations, physical examinations, use of devices, laboratory tests, and / or any other means for detecting adverse reactions. As defined above, anyone who may be involved in the administration of an API to a subject may be involved in monitoring for adverse reactions.

[0040] "Myeloablative transplantation" refers to a transplantation process that uses very high doses of chemotherapy or radiation prior to transplantation with autologous or allogeneic hematopoietic stem cells. Reduced-intensity or non-myeloablative transplantation includes patients who have less intensive chemotherapy prior to transplantation with allogeneic hematopoietic stem cells.

[0041] The "NIH Lung Symptom Score" or "NIH cGVHD Lung Score" is a clinically-based score in the range of 0 - 3. Score 0 is used for no symptoms, score 1 is used for shortness of breath on stairs, score 2 is used for shortness of breath on flat ground, and score 3 is used for shortness of breath at rest or shortness of breath requiring oxygen.

[0042] "Or" is used in an inclusive sense (equivalent to "and / or") unless the context requires otherwise.

[0043] As used herein, "patient" or "subject" includes animals or humans, in one embodiment humans.

[0044] "Pharmaceutical composition" means a mixture of substances suitable for administration to an individual containing a pharmaceutical agent. For example, a pharmaceutical composition may contain a sterile aqueous solution or an API formulated into an oral dosage form such as a tablet or capsule.

[0045] "Pharmaceutically acceptable salt" means a physiologically and pharmaceutically acceptable salt of the compounds provided herein. "Pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines. Alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0046] For example, "risk" as used herein with respect to an adverse event means that there is a possibility, even if slight or remote, that an adverse event may occur.

[0047] "Side effect" means any physiological response resulting from treatment with an API other than the disease or disorder for which the API is being administered. Side effects can include "adverse events" (or AEs) or "adverse reactions", or can even be harmless or beneficial side effects.

[0048] "Steroid-resistant" (SR) cGVHD is defined as the progression of cGVHD during steroid or corticosteroid administration. In one embodiment, prednisone is being administered.

[0049] "Treatment is urgent" when used with respect to an adverse reaction or adverse event means that an adverse reaction or event or its symptoms occurred during the period in which the patient was exposed to the API (e.g., that appeared during the course of treatment).

[0050] "Treatment-related", when used with respect to an adverse reaction or adverse event, means that an adverse reaction that manifests under treatment occurs or worsens during the exposure period to the API and is more likely to be attributable to the exposure to the API than to other causes or existing conditions (other than the disease state for which the treatment is being provided), based on the clinical evaluation of the patient's diagnosis, condition, and / or physiological profile. For example, if the clinical evaluation of the patient indicates that the adverse reaction is related to an existing disease or disorder and is unlikely to be related to the API, the adverse reaction is not considered "treatment-related".

[0051] The "therapeutically effective amount" of an API means an amount sufficient to effect the treatment of a disease state being treated when administered to a human (e.g., cGVHD). When applied to cGVHD in humans, "treating" or "treatment" includes (1) reducing the risk of developing cGVHD and / or inhibiting cGVHD, i.e., stopping or reducing the development of cGVHD or its clinical symptoms. (2) Reducing cGVHD, i.e., causing regression, recovery, or improvement of cGVHD, or reducing the number, frequency, duration, or severity of its clinical symptoms.

[0052] The therapeutically effective amount of an API can vary depending on the health and condition of the subject being treated, the degree of disease progression, the evaluation of the medical situation, and other relevant factors. It is expected that the therapeutically effective amount can be within the range that can be determined through testing and with reference to clinical trial data and results, as described, for example, in Examples 1 and 2 of this specification and in the scientific literature.

[0053] Exemplary Embodiments In one embodiment, the disclosure is directed to the use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) in a patient experiencing one or more treatment-related adverse reactions while being administered a clinically recommended dose of a compound comprising the following: If a patient experiences at least one adverse reaction at grade 3 or higher, discontinue the administration of the compound to the patient; and If at least one adverse reaction does not escalate to grade 4 and the patient recovers to grade 1 or lower after discontinuation of treatment, resume the administration of the compound at the clinically recommended dose for the patient.

[0054] In one embodiment, the present disclosure is the use of a compound or vemurafenib mesylate, administering the compound to the patient at the clinically recommended dose for the patient; monitoring the patient for adverse reactions; if the patient experiences at least one adverse reaction at grade 3, discontinue the administration of the compound to the patient; and resuming the administration of the compound to the patient if at least one adverse reaction of the patient has recovered to grade 1 or lower.

[0055] In some embodiments, at least one adverse reaction of the patient recovers to grade 0 after discontinuation of compound administration, and administration is resumed.

[0056] In some embodiments, at least one adverse reaction of the patient is grade 4, and the administration of the compound to the patient is permanently discontinued.

[0057] In some embodiments, the patient is monitored for adverse reactions over a period of time. In some embodiments, the monitoring is performed monthly. In some embodiments, it is performed at least monthly.

[0058] In some embodiments, the present disclosure provides the use of a clinically recommended dose of 200 mg per day for a patient before and after the patient experiences one or more treatment-related adverse reactions.

[0059] In some embodiments, the present disclosure provides for the use of a clinically recommended dose for a patient of 200 mg, taken once daily with food, either before and / or after one or more adverse reactions.

[0060] In some embodiments, the present disclosure provides for the use of a clinically recommended dose for a patient of 400 mg once daily, before and after a patient experiences one or more treatment-related adverse reactions. In some aspects, this dose is administered to the patient when the patient is also administered one or more PPIs and / or CYP3A inducers, and in some aspects one or more strong CYP3A4 inducers.

[0061] In some embodiments, the present disclosure provides for the use of a clinically recommended dose for a patient that decreases after the patient recovers to grade 1 or lower and administration of the compound is restarted, as compared to the clinically recommended dose administered to the patient prior to the occurrence of at least one adverse reaction.

[0062] In some embodiments, the present disclosure provides for the use of a clinically recommended dose for a patient that is in the range of 200 mg to 400 mg per day.

[0063] In some embodiments, the patient is being treated for chronic graft-versus-host disease (cGVHD). In some aspects, the patient is being treated for cGVHD and has failed at least two prior lines of systemic therapy for cGVHD.

[0064] In some embodiments, the present disclosure provides for the use of the Common Terminology Criteria for Adverse Events (CTCAE) to assess or grade the severity of a patient's adverse reactions. In some embodiments, the CTCAE version is 5.0.

[0065] In some embodiments, the patient experiences at least one adverse reaction that is an infectious disease, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, phosphate reduction, increased gamma-glutamyltransferase, lymphopenia, or hypertension.

[0066] In some embodiments, the patient experiences at least one adverse reaction that is a viral infection, a bacterial infection, or an infection by an unspecified pathogen.

[0067] In some embodiments, the patient experiences at least one adverse reaction that is an infection by an unspecified pathogen that is acute rhinitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, rhinitis, airway infection, bronchitis, sepsis, or septic shock.

[0068] In some embodiments, the patient experiences at least one adverse reaction that is asthenia, edema, or fever.

[0069] In some embodiments, the patient experiences at least one adverse reaction that is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is nausea, diarrhea, abdominal pain, or dysphagia.

[0070] In some embodiments, the patient experiences at least one adverse reaction that is a disorder of the respiratory, thoracic, or mediastinal organs. In some embodiments, it is dyspnea, cough, or nasal congestion.

[0071] In some embodiments, the patient experiences at least one adverse reaction that is a vascular disorder. In some embodiments, it is bleeding or hypertension.

[0072] In some embodiments, the patient experiences at least one adverse reaction that is a musculoskeletal disorder or a connective tissue disorder. In some embodiments, the musculoskeletal or connective tissue disorder is musculoskeletal pain, muscle spasm, or joint pain.

[0073] In some embodiments, the patient experiences at least one adverse reaction that is a neurological disorder. In some embodiments, it is a headache or migraine.

[0074] In some embodiments, the patient experiences at least one adverse reaction that is a metabolic disorder. In some embodiments, the metabolic disorder is anorexia.

[0075] In some embodiments, the patient experiences a skin or subcutaneous disorder. In some embodiments, the skin or subcutaneous disorder is a rash or pruritus.

[0076] In other embodiments, the present disclosure provides a method for treating a patient who experiences one or more treatment-related adverse reactions while being administered a clinically recommended dose of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound), comprising: discontinuing administration of the compound to the patient if the patient experiences at least one adverse reaction at grade 3 or higher; and resuming administration of the compound to the patient at a clinically recommended dose if at least one adverse reaction does not escalate to grade 4 and the patient recovers to grade 1 or lower after treatment is discontinued.

[0077] In some embodiments, the method provided by the present disclosure comprises a patient who experiences at least one adverse reaction at grade 3 and resuming administration of the compound to the patient if at least one of the patient's adverse reactions has recovered to grade 1 or lower.

[0078] In some embodiments, the method provided by the present disclosure comprises a patient who experiences at least one adverse reaction at grade 4 and permanently discontinuing administration of the compound to the patient.

[0079] In embodiments of the disclosure provided herein, including the therapeutic uses and methods, the clinically recommended dosage for a patient can be in the range of 200 mg to 400 mg per day. In some embodiments, the clinically recommended dosage for a patient is 200 mg per day; in some embodiments, the clinically recommended dosage for a patient is a reduced dosage after the patient has recovered to Grade 1 or below and the administration of the compound has been restarted, as compared to the clinically recommended dosage administered before the patient experienced at least one adverse reaction.

[0080] In some embodiments, the subject has undergone an allogeneic hematopoietic stem cell transplantation that is a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplantation is a haploidentical HSCT.

[0081] In some embodiments, the belumosudil treatment is continued based on the patient's tolerance until the active cGVHD symptoms resolve or progress. The number of treatment cycles and duration depend on the patient. In some embodiments, belumosudil is administered to the patient in 28-day cycles.

[0082] In some embodiments, the number of cycles is from 3 to 15. In some embodiments, the number of cycles is in the range of 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments, the number of cycles is in the range of 5 to 11. In some embodiments, the number of cycles is in the range of 6 to 12. In some embodiments, the number of cycles is in the range of 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the number of cycles is 5 to 7. In some embodiments, the number of cycles is in the range of 5 to 6. In some embodiments, the number of cycles is 5. In some embodiments, the number of cycles is 6. In some embodiments, the number of cycles is 7. In some embodiments, the number of cycles is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0083] In some embodiments, the number of cycles ranges from 3 cycles to loss of response. In some embodiments, the number of cycles ranges from 4 cycles to loss of response. In some embodiments, the number of cycles ranges from 5 cycles to loss of response. In some embodiments, the number of cycles ranges from 6 cycles to loss of response. In some embodiments, the number of cycles ranges from 7 cycles to loss of response. In some embodiments, the number of cycles ranges from 8 cycles to loss of response. In some embodiments, the number of cycles is greater than 3, 4, 5, 10, 15, 20, 25, or 30, or until a desired response is achieved.

[0084] In some embodiments, the subject experiences improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences at least a 7-point decrease in the LSS score. In some embodiments, the subject experiences at least a 10-point decrease in the LSS score. In some embodiments, the improvement is maintained over at least two consecutive evaluations. In some embodiments, the LSS score is evaluated on the first day of each cycle starting from the baseline and the first day of cycle 2.

[0085] In some embodiments, the subject has chronic graft-versus-host disease and has failed one to three prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed two to five prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has failed at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten prior lines of systemic therapy for chronic graft-versus-host disease.

[0086] In some embodiments, the subject experienced a complete response to the last treatment for graft-versus-host disease prior to belumosudil. In some embodiments, the subject experienced a partial response to the last treatment for graft-versus-host disease prior to belumosudil. In some embodiments, the subject experienced stable disease during the last treatment for graft-versus-host disease prior to belumosudil.

[0087] In some embodiments, prior lines of systemic therapy for chronic graft-versus-host disease have been discontinued.

[0088] In some embodiments, prior lines of systemic therapy are selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0089] In some embodiments, cGVHD is steroid-refractory (SR) cGVHD. In some embodiments, the subject is refractory to the last treatment line prior to belumosudil treatment.

[0090] In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from the group consisting of prednisone, prednisolone, methylprednisolone, and budesonide. In some embodiments, the concomitant corticosteroid therapy is prednisone. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased after at least one cycle of belumosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% after at least one cycle of belumosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased by about 10% to about 70%, about 15% to about 65%, about 20% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to about 60%, or about 45% to about 55% after at least one cycle of belumosudil treatment. In some embodiments, the concomitant corticosteroid therapy is discontinued after at least one cycle of belumosudil treatment.

[0091] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0092] In some embodiments, the subject has involvement of at least four organs. In some embodiments, the subject has involvement of at least three organs. In some embodiments, the subject has involvement of at least two organs.

[0093] Belumosudil tablets In one embodiment, belumosudil is formulated into tablets for oral administration. Belumosudil mesylate is a yellow powder that is substantially insoluble in water. Belumosudil tablets can be prepared for oral administration. Each tablet contains 200 mg of the free base corresponding to 242.5 mg of belumosudil mesylate. The tablets may also contain the following inactive ingredients. Microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide. Each 200 mg tablet is a pale yellow film-coated oval tablet with "KDM" debossed on one side and "200" debossed on the other side. The tablets are stored at room temperature, 20°C to 25°C (68°F to 77°F); excursions are permitted at 15°C and 30°C (59°F to 86°F).

[0094] Overview The following abbreviations may be useful in considering the examples and descriptions herein.

[0095] [Table 1] Examples

[0096] Example 1: Phase IIa Open-Label Dose Escalation Study of Belumosudil Subject Eligibility Eligible patients were ≥18-year-old allogeneic bone marrow transplant or allogeneic hematopoietic cell transplant (alloHCT) recipients with persistent cGVHD symptoms after receiving 1 - 3 previous lines of systemic therapy, who had received corticosteroid treatment with or without calcineurin inhibitors and / or concomitant extracorporeal photopheresis. Belumosudil was continued until cGVHD progression or unacceptable toxicity.

[0097] Study Design and Treatment Patients were enrolled in three consecutive cohorts: Cohort 1 received 200 mg of belumosudil once daily, Cohort 2 received 200 mg of belumosudil twice daily, and Cohort 3 received 400 mg of belumosudil once daily. (Figure 1) Before enrolling subsequent cohorts, after 8 patients reached 2 months of treatment, the safety data of each previous cohort were analyzed to confirm the absence of safety signals. The 2-month time frame was selected because all previously clinically significant belumosudil-related adverse events (AEs) had occurred within ≤ 36 days from the start of belumosudil. No safety concerns were identified, allowing for planned dose escalation.

[0098] Belumosudil was administered orally in 28-day cycles until disease progression or unacceptable toxicity occurred. Progression was defined according to the 2014 NIH cGVHD consensus criteria. Long-term follow-up was performed every 8 weeks until the end of the study. Four weeks after belumosudil therapy, corticosteroid therapy could be tapered at the discretion of the treating investigator. Screening was performed within 28 days of the first study dose. Response was first evaluated after 2 cycles; however, this was amended to evaluate response on day 1 of each cycle, starting from day 1 of cycle 2.

[0099] Study endpoints The primary efficacy endpoint was the ORR defined as the percentage of patients who achieved either complete response (CR) or partial response (PR) at any time according to the 2014 NIH cGVHD consensus criteria. Only response evaluations before the next treatment line after belumosudil were counted towards the ORR. All responses were evaluated by the treating investigators. Secondary endpoints included the number and percentage of patients with steroid-dependent cGVHD with best response of PR or CR, duration of response (DOR), response rate by organ system, LSS score, corticosteroid dose reduction, time to next treatment (TTNT), failure-free survival (FFS), and overall survival (OS). The safety and tolerability of belumosudil were evaluated throughout the study by AE assessment, physical examination, vital sign measurement, laboratory tests, and electrocardiograms. Pretreatment samples were collected for pharmacodynamic (PD) evaluation including assessment of immune cell subtypes in peripheral blood.

[0100] Statistical Analysis With a sample size of 16 patients per cohort, this study had >90% probability of having ≥1 study participant experiencing an AE with a baseline rate ≥14%, derived from the probability calculation of the assumed sample size of the study participants. Assuming a clinically meaningful best ORR of 25%, this study was expected to have approximately 90% probability of showing a response in ≥2 patients per cohort. This study was not powered to show a significant difference between cohorts for efficacy, AE, or PD analysis. The primary analysis was performed using the safety population defined as enrolled patients who received ≥1 dose of the study drug. The two-sided 95% CI for the ORR was constructed using the Clopper-Pearson (exact) method. The Kaplan-Meier (K-M) method was used to calculate the estimates of FFS and OS.

[0101] Results Subjects A total of 54 patients were enrolled in the consecutive cohorts: 17 patients in cohort 1, 16 patients in cohort 2, and 21 patients in cohort 3 (Figure 1). At the time of data cutoff for this analysis, the median follow-up period was 36 months in cohort 1, 32 months in cohort 2, and 24 months in cohort 3. The median follow-up period for the entire follow-up period was 29 months (range, 1 - 39 months).

[0102] Demographics and baseline characteristics were comparable across the cohorts (Tables 1, 2). The median age at baseline was 52 years (range, 20 - 75 years). The median time from cGVHD diagnosis to treatment was longest in cohort 1 at 26 months (compared to 18 months and 16 months in cohorts 2 and 3, respectively). By the assessment of the treating physicians, 78% of the patients had severe cGVHD. Half of the patients had involvement of ≥4 organs, and more patients in cohort 3 had lung involvement (48%) compared to patients in cohorts 1 (24%) and 2 (19%). The median baseline corticosteroid dose (mg / kg / d prednisone equivalent) was 0.22, 0.19, and 0.17 across the cohorts, respectively. Patients in cohort 1 had received a median of 3 prior lines of therapy, while patients in cohorts 2 and 3 had received 2 prior lines of treatment. 73% of the patients (35 out of 48, data not available for 6 patients) were refractory at the last line of therapy before study enrollment. The CONSORT diagram (Figure 1) shows the patient disposition. The median treatment period was 8.5 months (range, 2 - 39 months) in cohort 1, 7.5 months (range, 1 - 35 months) in cohort 2, and 9 months (range, 1 - 29 months) in cohort 3. 28% of the patients received belumosudil for >18 months. Reasons for discontinuation of belumosudil included progressive cGVHD (n = 22), voluntary withdrawal by the patient (n = 8), recurrence of underlying disease (n = 7), decision by the treating physician (n = 3), AEs that may be treatment-related (n = 3), and death (n = 2). LTFU means long-term follow-up.

[0103]

Table 2

[0104]

Table 3

[0105]

Table 4

[0106] Efficacy Overall response rate. In the safety population (N = 54), the ORR (95% CI) was 65% (51%–77%). The ORR (95% CI) was similar across cohorts: 65% (38%–86%) in cohort 1, 69% (41%–89%) in cohort 2, and 62% (38%–82%) in cohort 3 (Table 3). Efficacy data for subgroups and secondary endpoints are presented as pooled data across the cohorts.

[0107]

Table 5

[0108] Responses were achieved across all important subgroups, with an ORR of 60% (25 / 42) in patients with severe cGVHD, 66% (23 / 35) in patients who had received ≥2 prior systemic therapy lines before enrollment, 63% (22 / 35) in patients who were refractory to the last treatment line before enrollment, and 70% (19 / 27) in patients with ≥4 involved organs (Figure 2). All responses at the patient level were PRs, but organ-specific analysis showed that CR was achieved across all affected organs except the lung, and PR was the best response achieved (Figures 3A and 3B). Figure 3B shows the best response by organ, with three partial responses achieved in the lung at a dose of 400 mg once daily.

[0109] Responses were generally rapid, with over 75% of all responses achieved by the first response assessment at week 8 (Figure 4A). Four out of 35 responses occurred after 24 weeks of belumosudil treatment, and late organ responses were observed in the lungs, joints and / or fascia, and eyes (Figure 4B).

[0110] Among responders, the Kaplan-Meier (K-M) median duration of response (DOR) was 35 weeks (Figure 5A). The K-M median DOR was 38 weeks for patients who received two or more prior systemic therapies.

[0111] Time to next treatment. The K-M median time to next treatment (TTNT) was 14 months (Figure 5B). Subsequent systemic cGVHD therapies included tacrolimus, sirolimus, ibrutinib, ruxolitinib, extracorporeal photopheresis, and mycophenolate mofetil.

[0112] FFS and OS. The FFS rates (95% CI) were 76% (62% - 85%), 47% (33% - 60%), and 33% (21% - 46%) at 6, 12, and 24 months, respectively (Figure 5C). FFS was defined as the time from the first dose of belumosudil to the failure event. Reasons for failure included initiation of a new systemic therapy (n = 27), recurrence of underlying disease (n = 7), and death (n = 2). The key endpoint was the proportion of patients who achieved FFS with response (CR / PR) at 12 months, which was 24% in this study. The OS rates (95% CI) were 91% (79% - 96%) and 82% (69% - 90%) at 12 and 24 months, respectively (Figure 5D).

[0113] QOL assessment. Clinically meaningful improvement in the LSS score, defined as a decrease of ≥7 points in the LSS summary score, was observed in 50% of patients during belumosudil treatment. 35% of all patients (37% of responders and 32% of non-responders) reported a clinically significant improvement in the LSS score on serial assessments.

[0114] Corticosteroid sparing. During belumosudil treatment, 67% of patients reduced their corticosteroid dose and 19% discontinued corticosteroid therapy completely. The mean corticosteroid dose decreased by 45%. The median time to corticosteroid therapy discontinuation was 29 weeks (range, 8 - 77 weeks). The mean reduction in corticosteroid dose was 55% in responders and 26% in non - responders (Table 3).

[0115] Safety Belumosudil had good tolerability, with >56 patient - years of belumosudil exposure. The median relative dose intensity was 98% overall. The percentages of patients with relative dose intensity >95% were 77%, 63%, and 71% for the entire cohort, respectively. Dose reduction occurred in 9% of patients, and the median reduction period was 97 days (range, 21 - 859 days). Dose interruption occurred in 41% of patients, and the median interruption period was 10 days (range, 2 - 39 days).

[0116] AEs were consistent with those expected in a population of patients with advanced cGVHD receiving corticosteroid therapy. AEs reported in >20% of patients were upper respiratory tract infection (46%), diarrhea (33%), fatigue (33%), nausea (33%), elevated liver function test values (33%), dyspnea (30%), headache (24%), peripheral edema (24%), cough (22%), and hypertension (20%) (Table 4). Serious AEs were reported in 43% of patients, and serious AEs reported in >1 patient were dyspnea (7%), pulmonary infection (6%), hypoxia (4%), and influenza - like illness (4%). 61% of patients had grade 3 or higher AEs, and the most common ones were dyspnea (13%), elevated liver function test values (7%), hyperglycemia (7%), and hypoxemia (7%) (Table 4). Grade ≥3 cytopenias were reported in 2 patients (4%). These occurred at the recurrence of the underlying malignancy in patients who had maintained normal blood counts by other means during belumosudil treatment.

[0117]

Table 6

[0118] Cases of cytomegalovirus (CMV) infection or reactivation were not reported in belumosudil. Three patients discontinued belumosudil due to drug-related possible AEs (cohort 1: diarrhea and headache; cohort 3: fatigue). All four patients belonging to cohort 3 died during the trial (relapse of leukemia, pneumonia (unknown pathogen), cardiac arrest, and subsequent progression of cGVHD), but these deaths could not be attributed to belumosudil. There was no dose-response for the observed AEs.

[0119] PD analysis In exploratory PD analysis of peripheral blood mononuclear cells across the entire cohort, the percentage of CD4+ Tregs showed an increasing trend at an early stage by day 1 of cycle 2 of belumosudil treatment. A concomitant decrease in Th17 cells was also observed. Th17 cells continued to decrease through C4D1 and C6D25. The percentage of CD4+ Tregs continued to increase through C4D1 and C7D1, as shown in Figures 6A - 6C. Due to the small sample size, correlation data with steroid doses were limited in the statistical analysis.

[0120] This trial was the first to evaluate belumosudil treatment in human patients with cGVHD. All phenotypes of cGVHD that did not require inflammatory or fibrotic symptoms were included. Progressive multi-organ cGVHD patients treated with belumosudil achieved an ORR of 65%, and improvements in QOL, reduction in corticosteroid doses, and toxicity were limited. With a relatively small sample size, there was no difference in ORR between cohorts.

[0121] Belmosulimab achieved a meaningful and consistent response rate across the overall subgroup, including patients with severe cGVHD, patients who had received ≥2 prior lines of systemic therapy, patients who were refractory in the last line of therapy prior to registration, and patients with ≥4 involved organs. The ORR in patients with non-severe cGVHD was 83%, suggesting that further studies are warranted to show how belmosulimab may benefit patients earlier in the disease. All responses at the patient level were PRs; CRs were not achieved. However, given the severity and extent of fibrotic cGVHD symptoms in this patient population, some advanced fibrotic changes in the eyes, mouth, lungs, or joints and / or fascia may be irreversible, so achieving CRs in all organs was not expected. CRs were observed in all organs except the lungs, where PRs were achieved.

[0122] Belmosulimab response kinetics suggest that most responders achieved a response rapidly, within 8 weeks after belmosulimab administration. Belmosulimab had good tolerability, with a median DOR of 35 weeks across all responders. The ability to continue therapy depended on the safety and long-term tolerability profile of the intervention. The median treatment duration was 8 months (range, 1 to 39 months). Twenty-eight percent of patients remained on belmosulimab for >18 months. Despite 57% of patients being CMV seropositive, CMV infection or reactivation was not reported. The incidence of TEAE and grade ≥3 TEAE was similar across cohorts. The combination of a highly tolerable therapy and efficacy in response induction translated into an 82% 2-year OS rate, a median TTNT of 14 months, and FFS rates of 76% and 47% at 6 and 12 months, respectively.

[0123] In a prospective trial conducted by the cGVHD Consortium, the 12-month FFS rate with response (CR / PR) after first-line therapy was 12% - 15%. (Martin PJ, Storer BE, Inamoto Y, et al: An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease. Blood 130:360 - 367, 2017) In this trial (after 1 - 3 prior lines of therapy), the 12-month FFS rate with response was 24%.

[0124] In the trial of this example, the belumosudil therapy was associated with a corticosteroid-sparing effect. In the trial of this example, the belumosudil therapy was associated with a corticosteroid-sparing effect. Since the side effect profile of corticosteroid therapy contributes to the patient's symptom burden, the use of corticosteroid therapy is linked to quality of life. A decrease in corticosteroid dosage was observed in both responders and non-responders to belumosudil. Approximately 20% of patients were able to discontinue corticosteroid therapy during belumosudil treatment. Even in the absence of an NIH-defined response, patients experienced clinical benefit, as demonstrated by improvement in the LSS score or a decrease in corticosteroid dosage.

[0125] In this trial, responses were achieved in patients with fibrotic manifestations in the lung, joints and / or fascia, and eyes. These responses were sometimes observed after 24 weeks of treatment, further highlighting the advantage of continuing effective treatment to achieve clinical benefit, particularly in patients with treatment-refractory diseases. In the study described in Example 2, the 200 mg twice-daily dosage was further compared to a 200 mg once-daily dosage to evaluate dosage recommendations, as the lower 200 mg once-daily belumosudil was equally safe and effective.

[0126] Example 2: Phase II Randomized Trial of Belumosudil The study of this Example 2 was a randomized, open-label, multi-center study of belumosudil mesylate for the treatment of chronic GVHD patients who had received 2 to 5 prior lines of systemic therapy and required additional treatment. Patients were excluded from the trial if they had platelets < 50 × 10 9 / L; absolute neutrophil count < 1.5 × 10 9 / L; AST or ALT > 3 × ULN; total bilirubin > 1.5 × ULN. QTc(F) > 480 ms; eGFR < 30 mL / min / 1.73 m 2 ; or FEV1 ≤ 39%. Sixty-six patients were treated with REZUROCK 200 mg orally once daily. Concurrent treatment with supportive therapy for chronic GVHD was permitted. Concurrent treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapy was permitted as long as the subject had been on a stable dose for at least 2 weeks prior to the study. Initiation of new systemic chronic GVHD treatment during the study was not permitted.

[0127] Subject Eligibility Eligible subjects were allogeneic hematopoietic cell transplant recipients aged ≥ 12 years with persistent cGVHD symptoms after having previously received 2 to 5 lines of systemic therapy. Subjects had to have received stable corticosteroid therapy for 2 weeks prior to screening and a Karnofsky or Lansky performance status score of ≥ 60. Certain concomitant immunosuppressive medications were permitted as no drug-drug interactions were anticipated. Subjects were excluded if they had a recurrence of the underlying malignancy, a forced expiratory volume in 1 second (FEV1) of ≤ 39% or a NIH pulmonary symptom score of 3, had developed post-transplant lymphoproliferative disorder, had liver transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) > 3 times the upper limit of normal, had total bilirubin > 1.5 times the upper limit of normal for any reason, or were currently receiving ibrutinib.

[0128] Study Design and Treatment Screening for eligibility was conducted within 14 days of day 1 of cycle 1. Treatment consisted of oral belumosudil at 200 mg once daily (arm A) or 200 mg twice daily (arm B) in subjects with cGVHD (Figure 7). Randomization was stratified (1:1) by cGVHD severity and prior exposure to ibrutinib. Belumosudil was administered continuously in 28-day treatment cycles until clinically significant progression of cGVHD or unacceptable progression of toxicity. Progression was defined using organ-specific cGVHD response assessments as defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD, known as the 2014 NIH Consensus Criteria. After ≥ 2 weeks on belumosudil, corticosteroid therapy could be tapered at the discretion of the treating investigator. Subjects who did not achieve a response after 12 cycles of belumosudil treatment should be discontinued if, in the judgment of the treating investigator, there is no evidence of clinical benefit.

[0129] Study Endpoints The primary endpoint was the best ORR at any time point, defined as the percentage of subjects who achieved complete response (CR) or partial response (PR) according to the 2014 NIH Consensus Criteria. All responses were evaluated by the principal investigator of the study site. Secondary endpoints included duration of response (DOR), time to response, change in LSS summary score, failure-free survival (FFS), corticosteroid dose reduction, and overall survival (OS). DOR was measured from the time of initial PR or CR until documented progression from the best response of cGVHD, until the start of additional systemic cGVHD therapy from the initial response, or until death. The 7-day LSS summary score was calculated based on the developer's recommendations and compared to the baseline score. An improvement of ≥7 points was considered clinically meaningful. FFS was defined as the interval between the start of belumosudil and the addition of new cGVHD therapy, recurrence, or NRM. The safety of belumosudil was evaluated by adverse event (AE) and serious AE (SAE) assessments. Relative dose intensity (RDI) was used as a surrogate measure of drug tolerance and defined as actual dose intensity / planned dose intensity, where dose intensity was defined as cumulative dose (mg / d) over the exposure period. Actual dose intensity captured the total actual dose received during the exposure period and incorporated dose reductions and / or interruptions.

[0130] Statistical Analysis The sample size was based on the primary efficacy endpoint (best ORR), with a planned interim analysis once and a target ORR of 55%. Using a target sample size of 63 subjects per treatment arm and an estimated dropout rate of 10%, each treatment arm was estimated to have approximately 90% power to provide a 95% confidence interval (CI) for the ORR excluding 30% as the lower limit. Based on agreement with the principal opinion leaders, an ORR of 30% was considered clinically meaningful in this heavily pretreated population with cGVHD and unmet medical needs. The Hochberg procedure was used for multiplicity adjustment of the primary endpoint of the best ORR. The primary analysis was performed using the modified intention-to-treat (mITT) population defined as randomized subjects who received ≥ 1 dose of belumosudil. After registering 126 subjects in the mITT population, interim analysis, primary analysis, and follow-up analysis were planned at approximately 2, 6, and 12 months, respectively. Here, the results of the 12-month analysis are reported. The CI was calculated using the Clopper-Pearson interval (exact) method.

[0131] Results Characteristics of the Subjects A total of 132 subjects were enrolled in the clinical trial. Overall, the baseline demographics and clinical characteristics were comparable between the treatment groups (Table 5). At enrollment, the median age of the subjects was 56 years (range, 21 - 77). The median time from cGVHD diagnosis to enrollment was 28 months (range, 2 - 162). Based on the 2014 NIH Consensus Criteria, 31% of the subjects had moderate cGVHD at screening, 67% had severe cGVHD, and 52% had involvement of ≥4 organs. 36% of the subjects had lung involvement at baseline, and 38% of these subjects had an NIH lung symptom score of 2. The subjects had been previously treated with a median of 3 lines of systemic therapy. 72% (n = 79) of the subjects had cGVHD refractory to the last line of systemic therapy, 34% (n = 45) had previously received ibrutinib, 29% (n = 38) had previously received ruxolitinib, and 72% (n = 95) had received at least ≥3 prior lines of therapy. The median baseline corticosteroid dose was 0.2 mg / kg / day of prednisone equivalent (range, 0.03 - 1.07). The mean baseline corticosteroid dose was 0.25 mg / kg / day of prednisone equivalent (range, 0.03 - 1.07).

[0132]

Table 7

[0133]

Table 8

[0134]

Table 9

[0135]

Table 10

[0136] The CONSORT diagram (Figure 7) shows the allocation of participants. The median treatment period was 10 months (range, 0.4 - 22.0), and the median follow-up was 14 months (range, 1 - 22). 44% of the participants received treatment for ≥12 months. At the time of data analysis, 37% of the participants continued to receive belumosudil. Reasons for discontinuation included progression of cGVHD (n = 21), voluntary withdrawal (n = 13), AE (n = 16), physician's decision (n = 11), progression of underlying malignancy (n = 5), death due to underlying malignancy or disease progression (n = 4), other (n = 7), and non-compliance with the investigational drug (n = 3).

[0137] Efficacy The best ORR for belumosudil 200 mg once daily and 200 mg twice daily was 74% (95% CI, 62 - 84) and 77% (95% CI, 65 - 87), respectively (Table 6). High ORRs (61 - 85%) were observed in all subgroups (Figure 8). Pooled responses across the entire arm were used unless otherwise specified. The efficacy of belumosudil was maintained regardless of previous ibrutinib (n = 46) or ruxolitinib (n = 38) therapy. The ORR in the subgroup with previous ruxolitinib therapy was 68% (95% CI, 51 - 83). The ORR (95% CI) in the subgroup with previous ibrutinib therapy was 74% (95% CI, 59 - 86).

[0138]

Table 11

[0139] The best ORR including CR was evaluated across all affected organs. In the mITT population, organ-specific analysis demonstrated the best ORR of 37% in the skin, 42% in the eye, 55% in the mouth, 39% in the liver, 26% in the lung, 71% in the joint / fascia, 52% in the upper gastrointestinal (GI) tract, 69% in the lower GI tract, and 45% in the esophagus (Figure 9; Table 7). Overall, 7 subjects achieved CR in all affected organs. Among the 12 subjects with a lung response, 3 were scored as CR based on the normalization of FEV1 (median increase, 23%; range, 18–25), and an additional 3 CR were added based on a decrease in the 1–0 NIH lung symptom score in the absence of pulmonary function tests. Six additional subjects had PR, with an increase in FEV1 of ≥10% (median increase in all subjects achieving PR, 10%; range, 0–15), or a decrease in the NIH lung symptom score of 1 point if pulmonary function tests were not available. Among the 41 subjects with a skin response, 11 had a decrease in sclerotic features, 15 had a decrease in body surface area involvement, and 13 had an improvement in both body surface area involvement and sclerotic features. Two subjects had a skin response according to the clinical evaluation of the treating investigator, not in accordance with the 2014 NIH consensus criteria.

[0140]

Table 12

[0141] The median overall time to response was 5 weeks (range, 4–66) (Figure 10A). 91% of responses occurred within 6 months of treatment, and the remaining 9% of responses were seen 6–12 months after treatment. 59% of responders maintained a response for ≥20 weeks. The median DOR was 54 weeks in the responder population. The overall FFS rates were 75% (95% CI, 66–81) and 56% (95% CI, 47–64) at 6 and 12 months, respectively (Figure 10B). Overall, low rates of non-relapse mortality (NRM) (7%) and relapse (3%) were observed. The most common failure event was the initiation of a new systemic cGVHD therapy (38%). The 2-year OS rate was 89% (95% CI, 82–93) (Figure 10C).

[0142] During treatment with belumosudil, 65% of the subjects had a reduction in corticosteroid dose. The mean corticosteroid dose decreased by 45% in the mITT population and by 54% on average in responders. 21% of the subjects discontinued corticosteroid therapy. In addition, 22% of these subjects successfully discontinued calcineurin inhibitor (CNI) therapy, and 20% and 21% of the subjects discontinued sirolimus and mycophenolate mofetil, respectively.

[0143] Clinically meaningful improvements (≥ 7-point decrease) in the 7-day LSS summary score from baseline with 200 mg once daily and 200 mg twice daily of belumosudil were observed in 59% and 62%, respectively, of their ITT populations. This improvement was observed in 69% and 71% of responders and 29% and 33% of non-responders in the 200 mg once daily and 200 mg twice daily belumosudil arms, respectively.

[0144] Safety Belmosul was well tolerated, with a median RDI of 99.7%. 81% of the subjects received an RDI > 95%. The AEs were consistent with those expected in cGVHD patients receiving corticosteroid therapy and other immunosuppressive therapies (IST) (Table 8). 38% of the subjects had ≥1 SAE, and the most common was pneumonia (7%). The most common (≥5%) grade 3 or 4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%). 24% of the subjects had an increase in liver function tests (LFT), and at baseline, 5% of the subjects had an increase in gamma-glutamyltransferase (GGT), 5% of the subjects had an increase in AST, 3% of the subjects had an increase in ALT, 3% of the subjects had an increase in LFT, and 1% of the subjects had an increase in bilirubin. The most common liver-related AE was an increase in GGT (12%). Among the 83 subjects who discontinued treatment, 28 (21%) discontinued due to overall AEs, 16 (12%) discontinued due to possible drug-related AEs, 5 (4%) discontinued due to progression of the underlying malignancy disease, and 21 (16%) discontinued due to progression of cGVHD. 14 subjects died during the trial; 2 due to possible multi-organ failure and infection related to belmosul, 2 due to cardiac arrest, 2 due to respiratory failure, 1 due to hemothorax resulting from lung biopsy, 1 due to relapse of acute myeloid leukemia, and 6 during long-term follow-up (LTFU) (>28 days after the last dose). Grade ≥3 anemia was reported in 3% of the subjects, neutropenia was reported in 2% of the subjects, and thrombocytopenia was reported in 2% of the subjects. There was 1 case of Epstein-Barr virus viremia and 1 case of cytomegalovirus (CMV) reactivation requiring treatment; both were unrelated to belmosul treatment.

[0145]

Table 13

[0146] The trial of this Example 2 demonstrated the promising efficacy and favorable safety profile of belumosudil therapy in patients with steroid-refractory (SR) cGVHD. The trial population consisted of subjects with severe cGVHD with multi-organ involvement and fibrotic manifestations, treated in a median of 3 previous systemic therapy lines, and achieved best ORRs of 74% and 77% in the 200 mg once-daily and 200 mg twice-daily treatment arms, respectively.

[0147] The response to belumosudil was sustained and clinically significant regardless of response to previous treatment, severity of cGVHD, and number of organs involved. Responses were observed in all organs, which was clinically significant as CR and PR were achieved in treatment-refractory organs such as the lung and liver, as well as in fibrotic manifestations such as the skin. cGVHD significantly reduces quality of life, especially in patients with fibrotic multi-organ involvement, which can be difficult to treat. The observed CR and PR, along with improvement in LSS, limited interactions, and absence of drug toxicity, are promising results demonstrating that belumosudil treatment may have the potential to improve the overall health status of patients. Seven subjects achieved CR in all affected organs. CR in all affected organs can be difficult to achieve in cGVHD. This is due to irreversible changes that occur in some organs, particularly the eyes and lungs. The clinical benefit and tolerability of belumosudil therapy demonstrate the potential to halt the expected cycles of cGVHD treatment seen in clinical practice. The response persisted in 59% of responders for ≥20 weeks in the 12-month analysis. The median DOR was 54 weeks in responders in the 12-month analysis.

[0148] In patient populations vulnerable to infection due to AE and immunosuppressive therapy (IST), belumosudil was well tolerated, and most subjects were able to continue treatment to achieve clinically meaningful results and improvements in quality of life, which could be maintained by continuous treatment. Only 12% of subjects discontinued belumosudil due to possible drug-related AEs. The median treatment duration was 10 months (range, 0.4 - 22.0), and 37% of subjects continued to receive belumosudil after this time point. AEs were manageable, and there were few grade ≥3 SAEs attributable to belumosudil. The SAE rate was equivalent between the two treatment arms. Many of the current cGVHD treatment options are immunosuppressive and as a result can increase the risk of infection and cause hematotoxicities including neutropenia, anemia, and thrombocytopenia. Grade ≥3 cytopenias were present in <4% of subjects, and there was only one reported reactivation of cytomegalovirus (CMV) unrelated to belumosudil treatment. Cytopenias and CMV infections are present as serious complications of cGVHD and cGVHD therapeutics; therefore, the low rates of grade ≥3 cytopenias and CMV infections are promising features of the safety profile of belumosudil.

[0149] In this trial, all subjects received belumosudil. It was not appropriate to require randomization to the best available therapy because subjects had previously progressed after ≥2 lines of systemic therapy with historically low response rates. In fact, subjects in this trial had already tried a median of 3 prior lines of the best available therapy for cGVHD before enrollment and had used agents such as ECP (48%), ibrutinib (34%), ruxolitinib (29%), and rituximab (21%). The best ORR was 75% in subjects refractory to the last line of therapy.

[0150] Example 3: Side Effect Risk Management In the clinical trials in the previous Examples 1 and 2, 83 adult patients with chronic GVHD were treated with 200 mg of belumosudil once daily. The median treatment duration was 9.2 months (range 0.5 to 44.7 months). A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure. A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure.

[0151] Permanent discontinuation of belumosudil due to adverse reactions occurred in 18% of patients. Adverse reactions that led to permanent interruption of belumosudil in more than 3% of patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of patients. Adverse reactions resulting in discontinuation of administration at 2% or more were infections (11%), diarrhea (4%), asthenia, dyspnea, bleeding, hypotension, abnormal liver function tests, nausea, fever, edema, and renal failure (2% each).

[0152] The most common (≥20%) adverse reactions, including clinical laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, phosphate reduction, gamma-glutamyltransferase increase, lymphopenia, and hypertension.

[0153] Table 9 summarizes the non-laboratory adverse reactions.

[0154]

Table 14

[0155]

Table 15

[0156] Table 10 summarizes the clinical laboratory abnormalities of belumosudil.

[0157]

Table 16

[0158] Table 11 summarizes the recommended dosage changes of belumosudil for adverse reactions.

[0159]

Table 17

[0160] Example 4: US REZUROCK (trademark) (belumosudil) FDA label Indications and Usage REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. (1)

[0161] Dosage and Administration Recommended Dosage: 200 mg orally once daily with food. (2.1)

[0162] Dosage Form and Strength Tablets: 200 mg. (3)

[0163] Contraindications None. (4)

[0164] Warnings and Precautions Embryo-Fetal Toxicity: May cause fetal harm. Advise females of the potential risk to the fetus with respect to reproductive potential and use effective contraception. (5.1, 8.1, 8.3)

[0165] Drug Interactions Strong CYP3A Inducers: Increase the REZUROCK dosage up to 200 mg twice daily. (7.1) Proton Pump Inhibitors: Increase the REZUROCK dosage up to 200 mg twice daily. (7.1)

[0166] Adverse Reactions The most common (≥20%) adverse reactions including clinical laboratory abnormalities were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension. (6.1)

[0167] Use in Specific Populations Lactation: Advise not to breastfeed. (8.2) For patient count information and FDA-approved patient labeling, see 17.

[0168] Full Prescribing Information 1 Indications and Use REZUROCK is indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0169] 2 Dosage and Administration 2.1 Recommended Dosage The recommended dose of REZUROCK is 200 mg orally once daily until progression of chronic GVHD requiring new systemic therapy.

[0170] Instruct the patient as follows. · Swallow the REZUROCK tablets whole. Do not cut, crush, or chew the tablets. · Take REZUROCK approximately at the same time each day with food [see Clinical Pharmacology (12.3)]. · If the dose of REZUROCK is missed, instruct the patient not to take an additional dose to make up for the missed dose.

[0171] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)].

[0172] 2.2 Dose Modification for Adverse Reactions Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly. Modify the REZUROCK dosage according to Table 12 for adverse reactions.

[0173]

Table 18

[0174] 2.3 Dose Modification Due to Drug Interactions Strong CYP3A Inducers If co-administered with a strong CYP3A inducer, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0175] Proton Pump Inhibitors If co-administered with a proton pump inhibitor, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0176] 3 Dosage Forms and Strengths Each 200 mg tablet is a light yellow film-coated rectangular tablet debossed with "KDM" on one side and "200" on the other side.

[0177] 4 Contraindications None.

[0178] 5 Warnings and Precautions 5.1 Embryo-Fetal Toxicity Based on findings in animals and their mechanisms of action, REZUROCK can cause harm to the fetus when administered to pregnant women. In animal reproductive studies, administration of belumosudil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and malformations, at maternal exposures (AUC) lower than those in patients at the recommended dose. Inform pregnant women of the potential risk to the fetus. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

[0179] 6 Adverse Reactions 6.1 Clinical Trial Experience Clinical trials are conducted under widely varying conditions, and the rates of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates actually observed.

[0180] Chronic graft-versus-host disease In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Trials (14.1)]. The median treatment duration was 9.2 months (range 0.5 to 44.7 months).

[0181] A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure.

[0182] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Adverse reactions that led to permanent discontinuation of REZUROCK in more than 3% of patients included nausea (4%). Adverse reactions that led to dose interruption occurred in 29% of patients. Adverse reactions that led to discontinuation of dosing in 2% or more were infections (11%), diarrhea (4%), asthenia, dyspnea, hemorrhage, hypotension, abnormal liver function tests, nausea, fever, edema, and renal insufficiency (each 2%).

[0183] The most common (≥20%) adverse reactions including clinical laboratory abnormalities were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension.

[0184] Table 13 summarizes the non-laboratory adverse reactions.

[0185] [Table 19]

[0186] [Table 20]

[0187] Table 14 summarizes the laboratory abnormalities of REZUROCK.

[0188] [Table 21]

[0189] 7 Drug Interactions 7.1 Effects of Other Drugs on REZUROCK Strong CYP3A Inducers Concomitant administration of REZUROCK with strong CYP3A inducers decreases vemurafenib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. If concomitant use with a strong CYP3A inducer is necessary, increase the dose of REZUROCK [see Dosage and Administration (2.3)].

[0190] Proton Pump Inhibitors Concomitant administration of REZUROCK and a proton pump inhibitor decreases vemurafenib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. Increase the dose of REZUROCK when administered concomitantly with a proton pump inhibitor [see Dosage and Administration (2.3)].

[0191] 8 Use in Specific Populations 8.1 Pregnancy Summary of Risks Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], REZUROCK may cause fetal harm when administered to a pregnant woman. There are no available human data regarding the use of REZUROCK in pregnant women to evaluate drug-related risks. In animal reproductive studies, administration of vemurafenib to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including changes in growth, embryo-fetal mortality, and embryo-fetal malformations, at maternal exposures (AUC) approximately 3-fold greater (rats) and 0.07-fold greater (rabbits) than the human exposure (AUC) at the recommended dose (see Animal Data). Inform pregnant women and women of reproductive potential of the potential risk to the fetus.

[0192] In the general population of the United States, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

[0193] Data Animal Data During the period of animal organogenesis, bemcentinib was administered to rats at doses of 25, 50, 150, and 300 mg / kg / day in the pilot study and 15, 50, and 150 mg / kg / day in the pivotal study to conduct embryo-fetal development studies. In the pilot study, maternal toxicity and embryo-fetal developmental effects were observed. Maternal toxicity (decrease in body weight gain) occurred at doses of 150 and 300 mg / kg / day. An increase in post-implantation loss occurred at 50 and 300 mg / kg / day. Fetal malformations were observed at ≥50 mg / kg / day and included anal and tail absence, umbilical cord tumor, and domed head. The exposure (AUC) at 50 mg / kg / day in rats is approximately 3 times that of human exposure at the recommended dose of 200 mg.

[0194] In the embryo-fetal development study in rabbits, pregnant animals orally administered bemcentinib at 50, 125, and 225 mg / kg / day during the organogenesis period resulted in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of 125 mg / kg / day and above. Embryo-fetal effects were observed at doses of ≥50 mg / kg / day and included spontaneous abortion, increased post-implantation death, decreased proportion of live fetuses, malformations, and decreased fetal body weight. Malformations included malformations of the tail (short), ribs (branching, fusion, or deformation), sternal segmentation (fusion), and neural arch (fusion, displacement, deformation). The exposure (AUC) at 50 mg / kg / day in rabbits is approximately 0.07 times that of human exposure at the recommended dose of 200 mg.

[0195] 8.2 Lactation Summary of Risks There is no data available on the presence of bemcentinib or its metabolites in human breast milk, or the effects on children who are breastfed, or on breast milk production. Due to the potential for serious adverse reactions from bemcentinib in children who are breastfed, women who are breastfeeding are advised not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose.

[0196] 8.3 Reproductive Women and Men REZUROCK can cause harm to the fetus if administered to pregnant women [see Use in Specific Populations (8.1)].

[0197] Pregnancy test Confirm the pregnancy status of women of reproductive potential before initiating treatment with REZUROCK.

[0198] Contraception Women Instruct women of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus.

[0199] Men Instruct men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK.

[0200] Infertility Women Based on findings in rats, REZUROCK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0201] Men Based on findings in rats and dogs, REZUROCK may impair male fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0202] 8.4 Use in Pediatric Patients The safety and efficacy of REZUROCK have been established in pediatric patients 12 years of age and older. Use of REZUROCK in this age group is supported by evidence from adequate and well-controlled studies of REZUROCK in adults with additional population pharmacokinetic data demonstrating that age and weight did not clinically significantly affect the pharmacokinetics of the active drug substance, that exposure to the active drug substance was expected to be similar between adults and pediatric patients 12 years of age and older, and that the disease course was sufficiently similar between adults and pediatric patients to allow extrapolation of data from adults to pediatric patients.

[0203] The safety and efficacy of REZUROCK have not been established in pediatric patients less than 12 years of age.

[0204] 8.5 Use in the Elderly Of the 186 patients with chronic GVHD in the REZUROCK clinical trials, 26% were 65 years of age or older. No clinically significant differences in the safety or efficacy of REZUROCK were observed compared to younger patients.

[0205] 11 Description Belmosulodzim is a kinase inhibitor. The active pharmaceutical ingredient is belmosulodzim mesylate, which has the molecular formula C27H28N6O5S and a molecular weight of 548.62 g / mol. The chemical name of belmosulodzim mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1). The chemical structure is as follows: [Chemical formula]

[0206] Belmosulodzim mesylate salt is a yellow powder that is poorly soluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0207] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base equivalent to 242.5 mg of besimostat mesylate and also contains the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0208] The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow.

[0209] 12 Clinical Pharmacology 12.1 Mechanism of Action Besimostat is an inhibitor of rho-associated coiled-coil containing protein kinase (ROCK) that inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 μM, respectively. Besimostat downregulated the pro-inflammatory response via the regulation of STAT3 / STAT5 phosphorylation and the shift of the Th17 / Treg balance in ex vivo or in vitro human T cell assays. Besimostat also inhibited abnormal profibrotic signaling in vitro. In vivo, besimostat showed activity in an animal model of chronic GVHD.

[0210] 12.2 Pharmacodynamics The exposure-response relationship and the time course of the pharmacodynamic response of besimostat have not been established.

[0211] 12.3 Pharmacokinetics Unless otherwise specified, the following pharmacokinetic parameters are shown for patients with chronic GVHD who received 200 mg of besimostat once daily. The mean (coefficient of variation %, CV%) steady-state AUC and Cmax of besimostat were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of besimostat increased almost proportionally over the dose range of 200 and 400 mg (1 to 2 times the recommended once-daily dose). The accumulation ratio of besimostat was 1.4.

[0212] Absorption The median Tmax of velmosdil at steady state was 1.26 to 2.53 hours after administering 200 mg once or twice daily to patients. The mean (%CV) bioavailability was 64% (17%) after a single dose of velmosdil in healthy subjects.

[0213] Dietary effect Compared with fasting in healthy subjects, after a single dose of velmosdil with a high-fat and high-calorie diet (about 50% of the total calorie content of the diet from fat, 800 - 1,000 calories), the Cmax and AUC of velmosdil increased 2.2-fold and 2-fold, respectively. The median Tmax was delayed by 0.5 hours.

[0214] Distribution The geometric mean volume of distribution of velmosdil after a single dose in healthy subjects was 184 L (geo CV% 67.7%).

[0215] The binding of velmosdil to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6% in vitro, respectively.

[0216] Elimination The mean (%CV) elimination half-life of velmosdil in patients was 19 hours (39%), and the clearance was 9.83 L / hour (46%).

[0217] Metabolism Velmosdil is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9 in vitro.

[0218] Excretion After a single oral dose of radiolabeled velmosdil to healthy subjects, 85% of the radioactivity was recovered in feces (30% unchanged), and less than 5% was recovered in urine.

[0219] Specific populations Age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥60 and <90 mL / min / 1.72 m 2 ~eGFR ≥30 and <60 mL / min / 1.72 m 2 ), no clinically significant differences in the pharmacokinetics of vemurafenib were observed. The effect of severe renal impairment on the pharmacokinetics of vemurafenib has not been studied.

[0220] Drug Interaction Studies Clinical studies and an informed approach regarding the effects of other drugs on vemurafenib Potent cytochrome P450 (CYP) 3A inhibitor: When co-administered with itraconazole in healthy subjects, there was no clinically meaningful effect on vemurafenib exposure.

[0221] Potent CYP3A inducer: Co-administration of rifampin decreased vemurafenib Cmax by 59% and AUC by 72% in healthy subjects.

[0222] Moderate CYP3A inducer: Co-administration of efavirenz is predicted to decrease vemurafenib Cmax by 32% and AUC by 35% in healthy subjects.

[0223] Proton pump inhibitor: In healthy subjects, co-administration of rabeprazole decreased vemurafenib Cmax by 87% and AUC by 80%, and omeprazole decreased vemurafenib Cmax by 68% and AUC by 47%.

[0224] Effect of vemurafenib on other drugs CYP3A substrate: Co-administration of vemurafenib is predicted to increase midazolam (a sensitive CYP3A substrate) Cmax and AUC by approximately 1.3-fold and 1.5-fold, respectively.

[0225] CYP2C9 substrate: Co-administration of vemurafenib is not expected to have a clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

[0226] CYP2C8 Substrate: Co - administration of vemurafenib is not expected to have a clinically meaningful effect on the exposure of CYP2C8 substrates that are not OATP1B1 substrates.

[0227] In Vitro Studies Transport Systems: Vemurafenib is a substrate of P - gp. Vemurafenib inhibits BCRP, P - gp, and OATP1B1 at clinically relevant concentrations. Enzyme Systems: Vemurafenib is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9.

[0228] 13 Non - clinical Toxicity 13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility Carcinogenicity studies with vemurafenib have not been conducted.

[0229] Vemurafenib was not genotoxic in in vitro bacterial mutagenicity (Ames) assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes (HPBL), or in vivo rat bone marrow micronucleus assay.

[0230] In a combined male and female rat fertility study, male rats treated with vemurafenib were mated with untreated females or untreated male rats were mated with vemurafenib - treated females. Vemurafenib was orally administered at doses of 50, 150, or 275 mg / kg / day to male rats for 70 days prior to and throughout the mating period and to female rats for 14 days prior to mating and up to gestational day 7. At the dose of 275 mg / kg / day, adverse findings in female rats (either treated with vemurafenib or untreated but mated with treated males) included increased pre - or post - implantation losses and decreased viable embryo numbers. Administration of vemurafenib to male rats at a dose of 275 mg / kg / day resulted in abnormal sperm findings (decreased motility, decreased count, and increased proportion of abnormal sperm) and changes in the testis / epididymis organs (weight loss and degeneration).

[0231] Fertility was decreased in both male and female treated at a dose of 275 mg / kg / day, reaching statistical significance in males. Adverse changes in male and female genitalia also occurred in the general toxicity studies. Findings included sperm degeneration at a dose of 35 mg / kg / day of vermoxir in dogs and decreased ovarian follicular development at 275 mg / kg / day in rats. During the recovery period, the changes were partially or completely reversed. Exposure (AUC) at doses of 35 mg / kg / day in dogs and 275 mg / kg / day in rats were 0.5-fold and 8 - 9-fold, respectively, of the clinical exposure at the recommended dose of 200 mg daily.

[0232] 14 Clinical Trials 14.1 Chronic Graft-versus-Host Disease The KD025-213 trial (NCT03640481) was a randomized, open-label, multi-center trial of REZUROCK for the treatment of patients with chronic GVHD who had received 2 - 5 prior lines of systemic therapy and required further treatment. Patients were excluded from the trial if platelets were < 50 × 10 9 / L; absolute neutrophil count < 1.5 × 10 9 / L; AST or ALT > 3 × ULN; total bilirubin > 1.5 × ULN. Patients with QTc(F) > 480 ms; eGFR < 30 mL / min / 1.73 m 2 ; or FEV1 ≤ 39% were also excluded. Sixty-six patients were treated with REZUROCK 200 mg orally once daily. Concurrent treatment with supportive therapy for chronic GVHD was permitted. Concurrent treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapy was permitted provided the subject had been on a stable dose for at least 2 weeks prior to the study. Initiation of new systemic chronic GVHD treatment during the study was not permitted.

[0233] Demographics and baseline characteristics are summarized in Table 15.

[0234]

Table 22

[0235]

Table 23

[0236] The efficacy of REZUROCK was based on the overall response rate (ORR) up to day 1 of cycle 7, where overall response included complete or partial response according to the 2014 NIH response criteria. The results of the ORR are shown in Table 16. The ORR was 75% (95% CI: 63, 85). The median duration of response calculated from the first response to new systemic therapy for progression, death, or chronic GVHD was 1.9 months (95% CI: 1.2, 2.9). 1. The median time to first response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, death or initiation of new systemic therapy did not occur in 62% (95% CI: 46, 74) of patients for at least 12 months after response.

[0237]

Table 24

[0238] The results of the ORR were supported by an exploratory analysis of the bothersomeness of reported symptoms showing a decrease of at least 7 points in the Leeds Symptom Scale Summary Score up to day 1 of cycle 7 in 52% (95% CI: 40, 65) of patients.

[0239] 16 Supply method / Storage method and Handling method REZUROCK 200 mg tablets are supplied as pale yellow film-coated rectangular tablets containing 200 mg of belumosudil (equivalent to 242.5 mg of belumosudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other side and is packaged as follows.

[0240] 200 mg tablets in a 30-count bottle: NDC 79802-200-30

[0241] Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0242] Dispense to patients in original container only. Store in original container to protect from moisture. Always replace cap securely after each opening. Do not discard desiccant.

[0243] 17 Patient Count Information Advise patients to read FDA-approved Patient Information.

[0244] Embryo-Fetal Toxicity · Inform females of reproductive potential, including pregnant females, of the potential risk to the fetus. Advise females regarding reproductive potential and inform healthcare providers of known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. · Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Warnings and Precautions (5.1)]. · Instruct males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.3)].

[0245] Lactation · Instruct females not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.2)].

[0246] Infertility · Inform males and females that REZUROCK may impair fertility [see Use in Specific Populations (8.3)].

[0247] Administration · Instruct the patient to take REZUROCK orally once daily with food as directed by the physician, and advise that the oral dosage (tablets) should be swallowed whole with a glass of water at approximately the same time each day without cutting, crushing, or chewing the tablets [see Dosage and Administration (2.1)]. · Advise the patient that if they miss a dose of REZUROCK, they should return to their normal schedule the next day and take the missed dose as soon as possible on the same day. The patient should not take an additional dose to make up for the missed dose [see Dosage and Administration (2.1)].

[0248] Drug Interactions · Advise the patient to inform their healthcare provider of all concomitant medications, including prescription drugs, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

[0249]

Table 25

[0250]

Table 26

[0251] The invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, but the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are hereby expressly incorporated by reference in their entirety.

Claims

1. The use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound) in a patient who experiences one or more treatment-related adverse reactions while being administered a compound comprising the following clinically recommended dosages: when the patient experiences at least one adverse reaction at grade 3 or higher, discontinuing the administration of the compound to the patient; and when the at least one adverse reaction does not increase to grade 4 and the patient recovers to grade 1 or lower after treatment is discontinued, restarting the administration of the compound to the patient at the clinically recommended dosage.

2. (a) administering the compound to the patient at the clinically recommended dosage; (b) monitoring the patient for adverse reactions; (c) when the patient experiences at least one adverse reaction at grade 3, discontinuing the administration of the compound to the patient; and (d) restarting the administration of the compound to the patient when at least one adverse reaction of the patient has recovered to grade 1 or lower, the use according to Claim 1.

3. The use according to Claim 1 or 2, wherein at least one adverse reaction of the patient has recovered to grade 0 after discontinuation of compound administration.

4. The use according to Claim 1, comprising the step of permanently discontinuing the administration of the compound to the patient when the patient experiences at least one adverse reaction at grade 4.

5. The use according to any one of Claims 2 to 3, wherein the patient is monitored for adverse reactions at least monthly.

6. The use according to any one of Claims 1 to 5, wherein the compound is the besmoterol mesylate salt.

7. The use according to any one of Claims 1 to 6, wherein the clinically recommended dosage for the patient is 200 mg per day before and after the patient experiences at least one treatment-related adverse reaction.

8. The use according to any one of Claims 1 to 7, wherein the clinically recommended dosage for the patient is 200 mg taken once a day with food.

9. The use according to any one of claims 1 to 6, wherein the clinically recommended dose for the patient is 400 mg per day before and after the patient experiences at least one treatment-related adverse reaction.

10. The use according to any one of claims 1 to 3 or claims 5 to 9, wherein after the patient recovers to grade 1 or lower and the administration of the compound is restarted, the clinically recommended dose for the patient is reduced.

11. The use according to any one of claims 1 to 10, wherein the clinically recommended dose for the patient is in the range of 200 mg to 400 mg per day.

12. The use according to any one of claims 1 to 11, wherein the patient has chronic graft-versus-host disease (cGVHD).

13. The use according to claim 12, wherein the patient has failed at least two prior lines of systemic therapy for the cGVHD.

14. The use according to any one of claims 1 to 13, wherein at least one adverse reaction of the patient is graded according to the Common Terminology Criteria for Adverse Events (CTCAE).

15. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is an infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, phosphate reduction, increased gamma-glutamyltransferase, lymphopenia, or hypertension.

16. The use according to claim 14, wherein the at least one adverse reaction is a viral infection, a bacterial infection, or an infection by an unspecified pathogen.

17. The use according to claim 16, wherein the infection by the unspecified pathogen is acute rhinosinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, rhinosinusitis, airway infection, bronchitis, sepsis, or septic shock.

18. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is asthenia, edema, or fever.

19. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a gastrointestinal disorder.

20. The use according to claim 19, wherein the gastrointestinal disorder is nausea, diarrhea, abdominal pain, or dysphagia.

21. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a disorder of the respiratory, thoracic, or mediastinal organs. Claim 22 Use according to claim 21, wherein the disorder of the respiratory organs, chest or mediastinal organs is dyspnea, cough or nasal congestion. Claim 23 Use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a vascular disorder. Claim 24 Use according to claim 23, wherein the vascular disorder is bleeding or hypertension. Claim 25 Use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a musculoskeletal disorder or a connective tissue disorder. Claim 26 Use according to claim 25, wherein the musculoskeletal disorder or connective tissue disorder is musculoskeletal pain, muscle spasm or joint pain. Claim 27 Use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a nervous system disorder. Claim 28 Use according to claim 27, wherein the nervous system disorder is headache or migraine. Claim 29 Use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a metabolic disorder. Claim 30 Use according to claim 29, wherein the metabolic disorder is anorexia. Claim 31 A method of treating a patient who experiences one or more treatment-related adverse reactions while being administered 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof at a clinically recommended dose, wherein when the patient experiences at least one adverse reaction at grade 3 or higher, terminating the administration of the compound to the patient; and wherein when the at least one adverse reaction does not increase to grade 4 and the patient recovers to grade 1 or lower after termination of treatment, restarting the administration of the compound to the patient at a clinically recommended dose. Claim 32 The method according to claim 31, comprising restarting the administration of the compound to the patient when the patient experiences at least one adverse reaction at grade 3 and at least one adverse reaction of the patient recovers to grade 1 or lower. Claim 33 The method according to claim 31, comprising permanently stopping the administration of the compound to the patient when the patient experiences at least one adverse reaction at grade 4. Claim 34 The method according to claim 31 or 32, wherein the clinically recommended dose for the patient is in the range of 200 mg to 400 mg per day.

35. The method according to any one of claims 31 to 34, wherein the clinically recommended dose for the patient is in the range of 200 mg to 400 mg per day.

36. The method according to any one of claims 31 to 34, wherein the clinically recommended dose for the patient is 200 mg per day.

37. The method according to any one of claims 31 to 32 or 34 to 36, wherein the clinically recommended dose is reduced after the patient recovers to grade 1 or lower and administration of the compound is restarted, as compared to the clinically recommended dose administered to the patient before the at least one adverse reaction appears.

38. The method according to any one of claims 31 to 37, wherein the compound is the besmosdil mesylate salt.

39. The method according to any one of claims 31 to 38, or the use according to any one of claims 1 to 11, wherein the patient has chronic graft-versus-host disease (cGVHD).

40. The method according to claim 39, wherein the patient has failed at least two prior lines of systemic therapy for the cGVHD.

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