Methods of treating chronic graft versus host disease with belumosudil after ceasing administration of ruxolitinib

Abstract

The present disclosure provides methods of administering belumosudil mesylate salt to patients with cGVHD. In some embodiments, the methods include administering belumosudil mesylate to patients after ceasing administration of ruxolitinib.

Description

[0001] METHODS OF TREATING CHRONIC GRAFT VERSUS HOST DISEASE WITH BELUMOSUDIL AFTER CEASING ADMINISTRATION OF RUXOLITINIB

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 559,600, filed February 29, 2024, the entire contents of which is incorporated by reference herein for all purposes.

[0004] TECHNICAL FIELD

[0005]

[0002] The present disclosure relates to methods of administering belumosudil mesylate (REZUROCK®) to patients for the treatment of chronic graft-versus-host disease (cGVHD) after ceasing administration of ruxolitinib (JAKAFI ®).

[0006] BACKGROUND

[0007]

[0003] Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potential, serious complication following solid organ transplant and allogeneic hematopoietic cell transplant (alloHCT). cGVHD affects up to 70% of all alloHCT recipients, with an incidence of 20%-50% in children. It is the leading cause of nonrelapse mortality beyond 2 years after alloHCT. It is a potential, serious complication following solid organ transplant. The estimated prevalence of cGVHD is 14,000 patients in the United States (as of 2016). (Bachier CR et ah. Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. Presented at ASH2019, Orlando, FL, December 7-10, 2019) (“Bachier etaEf

[0004] Patients with cGVHD have substantial impairment in quality of life (QOL) as assessed by the Lee Symptom Scale (LSS), which measures the effect of cGVHD on patients’ functioning and well-being. It is reported that only one third of patients who have cGVHD and start systemic treatment will be alive, in remission and off immunosuppressive therapy by 5 years. (Lee SJ et ah. Success of immunosuppressive treatments in patients with chronic graft- versus-host disease . Biol Blood Marrow Transpl 24:555-562, 2018) (“Lee etallf.

[0008]

[0005] The pathophysiology of cGVHD can be separated into three phases: early inflammation because of tissue injury, a dysregulated adaptive immune system, and chronic inflammation and aberrant tissue repair with fibrosis.

[0006] First-line therapy for National Institutes of Health (NIH)-defined moderate to severe chronic graft-versus-host disease (cGVHD) is corticosteroids alone or in combination with sirolimus or a calcineurin inhibitor. However, up to 70% of patients require additional lines of therapy (Bachier CR et al). Furthermore, the long-term use of corticosteroids is associated with significant side effects (Lee et aT).

[0009]

[0007] In 2021, the US Food and Drug Administration approved ruxolitinib (sold commercially as JAKAFI ®), a Janus kinase (JAK) inhibitor, for the treatment of adults and pediatric patients 12 years and older with cGVHD after failure of one or two lines of systemic therapy.

[0010]

[0008] There remains an opportunity to study other treatment options for patients with cGVHD, including those who have failed > 1 lines of therapy.

[0011] SUMMARY

[0012]

[0009] The present disclosure provides methods of administering belumosudil mesylate (REZUROCK®) to patients for treatment of cGVHD after ceasing administration of ruxolitinib (JAKAFI ®).

[0013]

[0010] In one embodiment, the present disclosure provides for methods of treating cGVHD in a subject in need thereof, wherein the subject is receiving ruxolitinib as a second line treatment, comprising ceasing the administration of ruxolitinib as a second line treatment and administering belumosudil as a third line treatment when the subject has a significant increase in the adverse events of cytopenia and anemia.

[0014] [OH] In another embodiment, the present disclosure provides for methods of treating cGVHD in a subject in need thereof, wherein the subject is receiving ruxolitinib, the method comprising the steps of monitoring the subject for adverse reactions comprising cytopenia and / or anemia; instructing the cessation of administration of ruxolitinib to the subject when the subject experiences a significant increase in at least one adverse reaction of cytopenia or anemia; and administering belumosudil to the subject.

[0015]

[0012] The present disclosure and further embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify nonlimiting embodiments. DETAILED DESCRIPTION

[0016] Overview

[0017]

[0013] 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 the fibrosis that occurs because of aberrant tissue repair. Belumosudil inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 pM, respectively.

[0018]

[0014] Belumosudil down-regulated proinflammatory responses via regulation of STAT3 / STAT5 phosphorylation and shifting Thl7 / Treg balance in ex-vivo or in vitro-human T cell assays. Belumosudil also inhibited aberrant pro-fibrotic signaling, in vitro. By controlling ROCK2 activity, belumosudil mediates signaling in immune cellular function and fibrotic pathways, thereby alleviating the effects caused by cGVHD, such as inflammation of multiple tissues and fibrotic changes that may involve several organs including the lungs, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0019]

[0015] In vivo, belumosudil demonstrated activity in animal models of chronic GVHD.

[0020]

[0016] 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), in some instances after failure of at least two prior lines of systemic therapy. The compound belumosudil has the chemical name: 2-{3-[4-(U / -indazol-5-ylamino)-2- quinazolinyl]phenoxy}-7V-(propan-2-yl) acetamide, which is also referred to herein as belumosudil free base. The compound belumosudil is also known as KD025. The active pharmaceutical ingredient of REZUROCK® is belumosudil mesylate salt with the molecular formula C27H28N6O5S, a molecular weight of 548.62 g / mol, and having the chemical name 2- {3-[4-(U7-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-7V-(propan-2-yl) acetamide methanesulfonate (1 : 1).

[0021]

[0017] The chemical structure of belumosudil mesylate is as follows:

[0022]

[0018] Belumosudil and processes for making the compound are described in the following US patents: US Patent No. 8,357,693, US Patent No. 9,815,820, US Patent No. 10,183,931, and US Patent No. 10,696,660.

[0023]

[0019] In 2021, the US Food and Drug Administration approved belumosudil (sold commercially as REZUROCK®), for the treatment of adults and pediatric patients 12 years and older with cGVHD after failure of at least two prior lines of systemic therapy.

[0024]

[0020] The phosphate of ruxolitinib is marketed under the tradename JAKAFI®. The compound ruxolitinib has the chemical name (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile. The ruxolitinib phosphate salt has a molecular weight of 404.36 g / mol, and the chemical name (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate.

[0025]

[0021] The present disclosure provides methods of administering belumosudil mesylate (REZUROCK®) to patients that are receiving ruxolitinib as a second line treatment when the patients exhibit adverse reactions resulting from the ruxolitinib treatment. The adverse reactions resulting from the ruxolitinib treatment can include cytopenia and anemia.

[0026] Definitions

[0027]

[0022] “About” as used herein includes the exact amount modified by the term, about, as well as an amount that would be expected to be within experimental error, such as for example, within 15%, 10%, or 5%. For example, “about 200 mg” means “200 mg” and also a range of mgs that is within experimental error, e.g., plus or minus 15%, 10%, or 5% of200 mg. As used herein, the term “about” may be used to modify a range and also, a particular value.

[0028]

[0023] “Administering” or “administered to” as used herein (for example, including use of this term with reference to cease administration of an API, including ruxolitinib, to a subject), refers to the act of prescribing medicine(s) containing the API for the subject to take during treatment, the act of dispensing the medicine(s) to the subject, and / or the act of physically receiving or ingesting the medicine(s). Thus, an API (e.g., belumosudil or ruxolitinib), can be “administered” by a physician or other medical professional who writes prescriptions for medicine(s); and / or by a pharmacist who fills said prescriptions and / or dispenses the medicine(s) to the subject; and / or by the patient or subject who ingests the medicine and / or his or her partner or caretaker who provides the medicine to a subject, each of whom also may “cease” administration of the API.

[0029]

[0024] An “Adverse Reaction” means a physiological response attributable to treatment with an API that is undesired and detrimental or discomforting to the patient or course of treatment. In certain embodiments, adverse reactions include, without limitation, cytopenia and anemia. Adverse reactions may be detected directly or indirectly.

[0030]

[0025] “API” means “active pharmaceutical ingredient.”

[0031]

[0026] “Allogeneic hematopoietic stem cell transplantation (allo-HSCT)” also called bone marrow transplantation or stem cell transplantation, or “allogeneic hematopoietic cell transplantation (allo-HCT)” refers to a procedure where hematopoietic cells from a donor are grafted into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation may be peripheral blood stem cells (PBSC) or bone marrow (BM). In some circumstances umbilical cord blood may be used. The donor and recipient may be matched at the human leukocyte antigen (HLA) genes, such as siblings. The donor and recipient may be a parent and a child who are only half-matched (haploidentical).

[0032]

[0027] When the term “belumosudil” is used herein, it should be understood that, unless the context clearly indicates otherwise, the term may cover the compound belumosudil in any form as well as pharmaceutically acceptable salts thereof. The term “belumosudil” refers both to the compound belumosudil (for example, in the free base form, amorphous form, or crystalline form), to pharmaceutically acceptable salts of belumosudil, for example, the mesylate salt form as used in as REZUROCK®, and to any form of belumosudil that may be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0033]

[0028] When the term “ruxolitinib” is used herein, it should be understood that, unless the context clearly indicates otherwise, the term may cover the compound ruxolitinib in any form as well as pharmaceutically acceptable salts thereof. The term “ruxolitinib” refers both to the compound ruxolitinib (for example, in the free base form, amorphous form, or crystalline form), to pharmaceutically acceptable salts of ruxolitinib, for example, the phosphate salt form as used in as JAKAFI® and to any form of ruxolitinib that may be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0034]

[0029] “Ceasing” or “cessation” when used regarding administration of an API means that the API is no longer being administered to the patient on either a temporary or permanent basis. For example, if the patient experiences a treatment-related adverse reaction that is cytopenia and / or anemia during treatment with ruxolitinib, administration of the ruxolitinib may be “ceased.”

[0035]

[0030] “Clinically recommended amount” or “clinically recommended dose” refers to the amount or dosage of API that has been recommended and / or approved for administration to a patient by those skilled in the field of medicinal chemistry to treat the disease state in question following clinical trials. In some embodiments, the clinically recommended dose of belumosudil mesylate is 200 mg a day; in some embodiments, 200 mg a day orally administered with food.

[0036]

[0031] The clinically recommended amount or dosage of API may be expressed as an amount equivalent to a salt form (such as a mesylate or phosphate salt) of the API, or it may be expressed as an amount equivalent to the free base of the API. For example, in some embodiments, belumosudil and / or ruxolitinib is provided as the free base compound (z.e., not as a pharmaceutically acceptable salt). In some embodiments, belumosudil is provided in a dose of about 200 mg belumosudil measured as the equivalent amount of free base. In an embodiment, belumosudil is provided in a dose equivalent to about 200 mg of free base. In an embodiment, belumosudil is provided in a dose equivalent to about 200 mg of free base daily. In an embodiment, belumosudil is provided in a dose equivalent to about 200 mg of free base twice daily. In an embodiment, belumosudil is provided in a dose equivalent to about 200-400 mg of free base. In an embodiment, belumosudil is provided in a dose equivalent to about 200- 400 mg of free base a day.

[0037]

[0032] “Immunosuppressive therapy” (1ST) refers to therapy that is typically administered for at least six months after allo-HSCT to try to prevent GVHD. Examples of IST’s include sirolimus, prednisone and calcineurin inhibitors such as tacrolimus and cyclosporine.

[0038]

[0033] “Line of treatment” or “line of therapy” describes the sequence or order in which different therapies are given to a patient as the patient’s disease progresses. Initial treatment (first-line therapy) may not work or may stop working after a period. After first-line therapy is discontinued, a second different treatment (second-line therapy) may be given. After second- line therapy is discontinued, a third different treatment (third-line therapy) may be given. Subsequent lines of therapy may be given when a third-line therapy does not work or stops working. Some patients may be administered multiple lines of therapy over the course of a disease.

[0039]

[0034] First-line therapy for National Institutes of Health (NIH)-defined moderate to severe chronic graft-versus-host disease (cGVHD) may 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. Haematol ogica 103:1915- 1924, 2018).

[0040]

[0035] “Monitoring” with reference to assessment of adverse reactions means observing, checking, and / or assessing the progression of one or more adverse reaction(s) over at least two points in time; in some embodiments, over a period of time; in some embodiments, monthly; in some embodiments, at least monthly. The monitoring can be performed via consultation, patient self-reporting, visual observation, physical examination, use of devices, laboratory testing, and / or any other means for detecting the adverse reactions, directly or indirectly. Any person who may be involved with administration of the API to a subject, as defined above, may also be involved with monitoring adverse reactions.

[0041]

[0036] “ Or” is used in the inclusive sense (equivalent to “and / or”) unless the context requires otherwise.

[0042]

[0037] “Patient” or “subject” as used herein includes an animal or a human, in one embodiment, a human.

[0043]

[0038] Steroid-refractory” (SR) cGVHD is defined as cGVHD progression while on steroids or corticosteroids; in one embodiment, while on prednisone.

[0044]

[0039] Treatment emergent” when used with reference to an adverse reaction or adverse event means that the adverse reaction or event, or symptoms thereof, manifested during a time period when the patient was exposed to the API (e.g., emerged during the course of treatment).

[0040] Treatment-related” when used with reference to an adverse reaction or adverse event means that a treatment-emergent adverse reaction arose or worsened during a period of exposure to the API and based on clinical assessment of a patient’s diagnosis, condition(s) and / or physiological profile, was more likely attributable to exposure to the API than other causes or pre-existing conditions (other than the disease-state for which treatment is being provided). For example, if clinical assessment of the patient informs that the adverse reaction(s) were related to pre-existing diseases or disorders and unlikely related to the API, then the adverse reaction will not be considered “treatment related.”

[0041] A “therapeutically effective amount” of an API means an amount which, when administered to a human for treating a disease (for example, cGVHD), is sufficient to effect treatment for the disease state being treated. As applied to cGVHD in a human, “treating” or “treatment” includes (1) reducing the risk of developing cGVHD and / or inhibiting cGVHD, i.e., arresting or reducing the development of cGVHD or its clinical symptoms; and (2) relieving cGVHD, i.e., causing regression, reversal, or amelioration of the cGVHD or reducing the number, frequency, duration or severity of its clinical symptoms.

[0045]

[0042] The therapeutically effective amount of an API may vary depending upon the health and physical condition of the subject to be treated, the extent of disease progression, the assessment of the medical situation, and other relevant factors. It is expected that the therapeutically effective amount may fall within a range that can be determined through trial and through reference to clinical trial data and results, for example, as described in scientific literature.

[0046] Exemplary Embodiments

[0047]

[0043] In one embodiment, the present disclosure provides for methods of treating cGVHD is a subject in need thereof, wherein the subject is receiving ruxolitinib as a second line treatment, comprising ceasing the administration of ruxolitinib as a second line treatment and administering belumosudil as a third line treatment when the subject has a significant increase in the adverse events of cytopenia and anemia.

[0048]

[0044] In one embodiment, the present disclosure provides for methods of treating cGVHD in a subject in need thereof, wherein the subject is receiving ruxolitinib, the method comprising the steps of: (a) monitoring the subject for adverse reactions comprising cytopenia and / or anemia; (b) ceasing or instructing the cessation of administration of ruxolitinib to the subject when the subject experiences a significant increase in at least one adverse reaction of cytopenia or anemia; and (c) administering belumosudil to the subject.

[0049]

[0045] In some embodiments, the increase in the adverse events of cytopenia and anemia is compared to the occurrence of cytopenia and anemia in the subject receiving belumosudil.

[0050]

[0046] In some embodiments, the subject has a decrease in the adverse events of cytopenia and anemia after administration of belumosudil.

[0051]

[0047] In some embodiments, the ruxolitinib is administered as a second line treatment.

[0052]

[0048] In some embodiments, the belumosudil is administered as a third line treatment.

[0053]

[0049] In some embodiments, the belumosudil is belumosudil mesylate salt.

[0050] In some embodiments, the disclosure provides for methods of treating cGVHD by administering belumosudil at a dose that is in the range of 200 mg a day to 400 mg a day.

[0054]

[0051] In some embodiments, the disclosure provides for methods of treating cGVHD by administering belumosudil at a dose that is 200 mg taken once daily with food.

[0055]

[0052] In some embodiments, the subject has chronic graft-versus-host disease.

[0056]

[0053] In some embodiments, the cGVHD is steroid-refractory (SR) cGVHD.

[0057]

[0054] In some embodiments, the disclosure provides for methods of treating cGVHD by administering belumosudil at a dose that is equivalent to 200-400 mg of the free base a day.

[0058] Belumosudil Tablets

[0059]

[0055] In one embodiment, the belumosudil is formulated for oral administration. In one embodiment, the belumosudil is formulated into a tablet for oral administration. Belumosudil mesylate is a yellow powder that is practically insoluble in water. Belumosudil tablets may be prepared for oral administration. Each tablet contains 200 mg of the free base equivalent to 242.5 mg of belumosudil mesylate. The tablet also may 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 oblong tablet debossed with "KDM" on one side and "200" on the other side. Tablets are stored at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C and 30°C (59°F to 86°F).

[0060] Ruxolitinib Tablets

[0061]

[0056] In one embodiment, the ruxolitinib is formulated for oral administration, such as a tablet. For example, in some embodiments, each tablet contains 6.6 mg, 13.2 mg, 19.8 mg, 26.4 mg, or 33 mg of ruxolitinib phosphate that is equivalent to 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg of ruxolitinib free base.

[0062] Examples

[0063] Example 1: A study to examine the use of ruxolitinib and belumosudil in patients with cGVHD.

[0064]

[0057] Background

[0065]

[0058] Chronic Graft- Versus-Host Disease (cGVHD) impacts up to 50% of patients receiving allogenic hematopoietic stem cell transplants. Historically, treatment options for patients with steroid refractory cGVHD have been limited, but in 2021, the United States Food and Drug Administration (FDA) approved ruxolitinib and belumosudil for the treatment of patients with cGVHD who have received at least 1 or 2 prior lines of systemic treatment, respectively.

[0066]

[0059] Aim

[0067]

[0060] To examine the real-world use of ruxolitinib and belumosudil in patients with cGVHD.

[0068]

[0061] Methods

[0069]

[0062] An institutional review board-exempted, retrospective medical chart audit of patients with cGVHD was conducted from July to September 2023. Respondents included medical oncologists, hematology oncologists, or hematologists with at least 3 years of specialty-focused clinical practice. Inclusion criteria for patient charts were a formal diagnosis of cGVHD maintained for at least 12 months, exposure to at least 2 lines of therapy, and treatment of ruxolitinib and / or belumosudil in second-line (2L) or third-line (3L). A web-enabled case report form was provided for the abstraction of patient charts. Patients receiving ruxolitinib or belumosudil in 2L who switched to the other medication could be considered for the 3L sample. Key information captured included patient and disease characteristics, prior and future lines of therapy for cGVHD, efficacy (partial (PR) or complete response (CR)), symptoms, and adverse events. Respondents also reported treatment goals, rationale for therapy selection, and overall perceptions of therapies. Descriptive statistical analyses were conducted.

[0070]

[0063] Results

[0071]

[0064] In total, 155 unique patient charts were abstracted with 88 patients providing data on 3L treatments (Table 1). Patients receiving 3L belumosudil commonly received ruxolitinib in 2L (86%). Over 75% of respondents expressed willingness to prescribe ruxolitinib in 2L or 3L, and belumosudil in 3L, with slightly fewer respondents willing to prescribe belumosudil in 2L (60%). Patients receiving belumosudil in 2L showed a greater degree of fibrotic manifestations than patients receiving ruxolitinib in 2L (60% versus 35%; p<0.05); however, in 3L, patients receiving ruxolitinib had a greater degree of fibrotic disease than patients receiving belumosudil (38% versus 50%; p-value, not significant). Rates of PR and CR were similar for ruxolitinib and belumosudil in 2L (PR: 33% versus 23%; CR: 29% versus 47%) and 3L (PR: 38% versus 46%; CR: 20% versus 11%). Fatigue was the most common adverse event across all patient charts regardless of lines of therapy. Overall rates of adverse events were similar across ruxolitinib and belumosudil, with a significantly increased incidence of cytopenia and anemia in patients receiving 2L ruxolitinib versus belumosudil (cytopenia 18% versus 2%; anemia 15% versus 0%). Among patients receiving belumosudil in 3L who received ruxolitinib in 2L, reported rates of cytopenia and anemia decreased from the beginning to end of 3L therapy by 22% and 19%, respectively.

[0072]

[0065] Summary / Conclusion

[0073]

[0066] The similar observed efficacy for ruxolitinib and belumosudil and potential resolution of cytopenia and anemia with 3L belumosudil may recommend more rapid transition from 2L ruxolitinib to 3L belumosudil.

[0074]

[0067] Table 1. Distribution of Patient Charts for Second- and Third-Line cGVHD

[0075] Treatment

[0076] * Patients could receive belumosudil or ruxolitinib monotherapy in either category or with other non-belumosudil / non-ruxolitinib treatments. Other can be defined as any treatment received other than monotherapy use of belumosudil or ruxolitinib.

[0077] ** Not all patient charts reported 3L treatment. Patients who received belumosudil and / or ruxolitinib in 2L but did not receive 3L treatment were still eligible for inclusion.

[0078]

[0068] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

Claims

CLAIMS1. A method of treating cGVHD in a subject in need thereof, wherein the subject is receiving ruxolitinib as a second line treatment, comprising ceasing or instructing the cessation of the administration of ruxolitinib as a second line treatment and administering belumosudil as a third line treatment when the subject has a significant increase in the adverse events of cytopenia and anemia.

2. The method of claim 1, wherein the increase in the adverse events of cytopenia and anemia is compared to the occurrence of cytopenia and anemia in the subject receiving belumosudil.

3. The method of any one of the previous claims, wherein the subject has a decrease in the adverse events of cytopenia and anemia after administration of belumosudil.

4. A method of treating cGVHD in a subject in need thereof, wherein the subject is receiving ruxolitinib, the method comprising the steps of:(a) monitoring the subject for adverse reactions comprising cytopenia and / or anemia;(b) ceasing or instructing the cessation of administration of ruxolitinib to the subject when the subject experiences a significant increase in at least one adverse reaction of cytopenia or anemia; and(c) administering belumosudil to the subject.

5. The method of claim 4, wherein the ruxolitinib is administered as a second line treatment.

6. The method of claim 4, wherein the belumosudil is administered as a third line treatment.

7. The method of any of the preceding claims, wherein the belumosudil is belumosudil mesylate salt.

8. The method of any of the preceding claims, wherein the dose of belumosudil for the subject is in the range of 200 mg a day to 400 mg a day.

9. The method of claim 8, wherein the dose of belumosudil for the subject is 200 mg taken once daily with food.

10. The method of any of the preceding claims, wherein the dose of belumosudil for the subject is equivalent to 200-400 mg of the free base a day.

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