Belmosudil for treating chronic pulmonary allograft dysfunction

Abstract

The present disclosure relates generally to the treatment of patients with chronic pulmonary allograft dysfunction (CLAD) after lung transplantation, patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation, or patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation by administering belmosudil.

Description

[Technical field]

[0001] The present disclosure relates generally to the treatment of patients with pulmonary disorders, including chronic pulmonary allograft dysfunction (CLAD), restrictive allograft syndrome (RAS), and bronchiolitis obliterans syndrome (BOS), following lung transplantation or allogeneic hematopoietic stem cell transplantation. [Background technology]

[0002] Chronic pulmonary allograft dysfunction (CLAD) has two subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). CLAD is the leading cause of morbidity and mortality after lung transplantation. CLAD results from inflammatory and fibrotic changes in either the airways (BOS) or lung parenchyma (RAS). CLAD pathology is driven by a combination of immune dysfunction and profibrotic pathway activation, leading to tissue damage and fibrosis.

[0003] Treatment options include chemotherapy-induced pulmonary bypass (CNI) (such as tacrolimus or cyclosporine), antiproliferatives (cell cycle inhibitors such as mycophenolate or azathioprine), and low-dose steroids (such as prednisolone). Management of CLAD is center-specific and unfortunately, there is no currently approved treatment. Lung transplant centers typically increase or modify baseline immunosuppression protocols, introduce mTOR inhibitors (mTORi) instead of CNIs or antiproliferatives, increase steroid doses, introduce antithymocyte globulin, and occasionally extracorporeal photochemotherapy (ECP) or, less commonly, alemtuzumab (anti-CD52). The macrolide antibiotic, azithromycin, is frequently used based on studies showing that it can stabilize lung function in a subset of CLAD patients, typically those with bronchoalveolar lavage (BAL) neutrophilia. However, in most patients, CLAD does not respond, with a gradual decline in graft function. Collectively, this evidence highlights a significant unmet need and urgency to investigate novel therapies to stabilize lung function and potentially improve overall survival in patients with CLAD.

[0004] Bronchiolitis obliterans syndrome (BOS) is one of the most severe complications after lung or allogeneic hematopoietic stem cell transplantation (allo-HSCT), but is also observed in systemic autoimmune diseases and after exposure to environmental pollutants. BOS after lung transplantation is characterized by inflammation of subepithelial structures and dysregulated repair of small airways in the transplanted lung, which leads to fibroplasia and abnormal regeneration of the epithelium, resulting in scarring, which leads to airway narrowing, airflow restriction, and ultimately loss of lung function (KC Meyer, et al., An international ISHLT / ATS / ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome, Eur. Respir. J. 44(6)(2014)1479-1503; Krishna, Rachana, and Tony I. Oliver. “Bronchiolitis Obliterans (Obliterative Bronchiolitis, Constrictive Bronchiolitis).”(2017); Mini-Series, Lung Transplantation. “Bronchiolitis Obliterans Syndrome (BOS) following lung transplant.” Am J Respir Crit Care Med 193(2016):P19-P20). BOS is a major cause of late mortality and morbidity after lung transplantation or allo-HSCT.Approximately 40% to 50% of patients undergoing lung transplantation are diagnosed with BOS within 5 years after transplantation, and the median survival after this diagnosis is 3 to 5 years (KC Meyer, et al., An international ISHLT / ATS / ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome, Eur. Respir. J. 44(6)(2014)1479-1503; RDYusen, et al., The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report-2014; focus theme: retransplantation, J. Heart Lung Transplant. 33(10)(2014)1009-1024).

[0005] BOS after HSCT results from an immunological attack of the small airways by the donor immune system, resulting in fibrotic narrowing and subsequent obstruction of the respiratory bronchi. (Williams KM.How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.Blood 2017;129(4):448-455). Historically, treatment options for BOS after hematopoietic stem cell transplantation consisted of standard cGVHD therapy, including systemic corticosteroids and immunosuppressants, with the hope of intervening in the disease before irreversible damage occurs. In a small randomized double-blind study, inhaled budesonide / formoterol significantly improved FEV1 compared with placebo in patients with mild / severe BOS after hematopoietic stem cell transplantation. (Bergeron A,et alBudesonide / Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation.Am J Respir Crit Care Med 2015;191(11):1242-1249). A phase II study evaluating the combination of inhaled fluticasone, azithromycin, and montelukast (FAM) with short steroid pulses suggested that this treatment approach may limit the decline in lung function in new-onset BOS. (Williams KM,et al.Fluticasone,Azithromycin,and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant 2016;22(4):710-716). Similarly, other immunosuppressive or immunomodulatory therapies can halt disease progression but rarely improve either lung function or symptoms.(Brownback KR et al. Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation. J Clin Apher 2016;31(4):347-352; Brownback KR,et al. Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease. Lung 2017;195(6):781-788). Thus, novel therapeutic approaches for BOS after HSCT remain an unmet need. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides a method of treating a subject diagnosed with bronchiolitis obliterans syndrome following a lung transplant by administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (belmosudil), to a subject in need thereof.

[0007] The present disclosure provides a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) after lung transplantation by administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharma- ceutically acceptable salt thereof (belmosudil) to a subject in need thereof.

[0008] The present disclosure also provides a method of treating a subject diagnosed with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation by administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (belmosudil) to a subject in need thereof, wherein the subject has mild to moderate bronchiolitis obliterans syndrome, or early bronchiolitis obliterans syndrome.

[0009] The present disclosure further provides a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction after lung transplantation, the method comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (belmosudil), to a subject in need thereof.

[0010] In some embodiments, the chronic pulmonary allograft dysfunction comprises bronchiolitis obliterans syndrome. In some embodiments, the chronic pulmonary allograft dysfunction comprises restrictive allograft syndrome. In some embodiments, the subject has mild bronchiolitis obliterans syndrome. In some embodiments, the subject has moderate bronchiolitis obliterans syndrome.

[0011] In some embodiments, belmosudil can be administered to a subject at a dose selected from the group consisting of 200 mg per day, 200 mg twice per day, and 400 mg per day. In some embodiments, belmosudil can be administered to a subject at a dose selected from the group consisting of 200 mg per day, 200 mg twice per day, and 400 mg per day, and belmosudil is administered as a 28-day cycle, the number of cycles ranging from 3 to 15. In some embodiments, the number of cycles is more than 3, 4, 5, 10, 15, 20, 25, or 30, or until a desired response is achieved.

[0012] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to illustrate non-limiting embodiments. [Brief description of the drawings]

[0013] [Figure 1] 1 is a CONSORT flow diagram illustrating the Phase IIa, open-label, dose-finding study of belmosudil in Example 1. [Diagram 2] Forest plot for subgroup analysis of ORR in the safety population. Subgroups were defined based on baseline assessments. [Figure 3A] Best individual responses by organ system among responders are shown. n=number of responders in the global severity assessment and number of specific organs involved at baseline. Percentages are calculated based on the corresponding n. [Figure 3B] Response and progression heatmap for all patients in the safety population. Of the 11 patients with joint progression, 7 had a P-ROM loss of only 1 unit. [Figure 4] The time to response among belmozudil responders is shown. The percentage is calculated based on the number of responders. [Diagram 5] Time to response by selected organs among responders is shown. Percentages are calculated based on the number of responders in the population. [Figure 6A] Change in percentage of CD41 Tregs after treatment with belmosudil compared to baseline of Tregs (total regulatory T cells). Pre-dose peripheral blood samples were collected at C1D1 (Day 1 of Cycle 1), C2D1 (Day 1 of Cycle 2), C4D1 (Day 1 of Cycle 4), C7D1 (Day 1 of Cycle 7) and at the end of treatment visit. [Figure 6B]Change in percentage of CD41 Tregs after treatment with belmosudil compared to baseline Tregs (regulatory T cell responders). Pre-dose peripheral blood samples were collected at C1D1 (Day 1 of Cycle 1), C2D1 (Day 1 of Cycle 2), C4D1 (Day 1 of Cycle 4), C7D1 (Day 1 of Cycle 7) and at the end of treatment visit. [Figure 6C] Change in percentage of CD41 Tregs after treatment with belmosudil compared to baseline Tregs (regulatory T cell non-responders). Pre-dose peripheral blood samples were collected at C1D1 (Day 1 of Cycle 1), C2D1 (Day 1 of Cycle 2), C4D1 (Day 1 of Cycle 4), C7D1 (Day 1 of Cycle 7) and at the end of treatment visit. [Figure 7] 1 is a CONSORT flow diagram illustrating the Phase II randomized trial of belmosudil in Example 2. [Figure 8] Forest plot of subgroup analysis of ORR (mITT). High ORR was observed in all subgroups analyzed in the mITT population, with efficacy maintained regardless of prior therapy. The 50th percentile of duration of cGVHD prior to enrollment was 29 months. Response assessments performed at or after the initiation of new systemic therapy for cGVHD were excluded from the analysis. [Figure 9] ORR by organ system in the mITT population is shown. Organ-specific analysis in the mITT population demonstrated ORR in skin, eye, mouth, liver, lung, joint / fascia, upper GI tract, lower gastrointestinal tract, and esophagus. CRs were seen across all affected organs. [Figure 10A] Durability of response to belmosudil by dose. Kaplan-Meier plot of DOR in the responder population. DOR is defined as the time from response to documented progression or initiation of alternative cGVHD systemic therapy; durability data continue to mature. [Figure 10B] Durability of response to belmosudil by dose. Kaplan-Meier curves of estimated FFS in the mITT population, including reasons for failure. FFS was defined as the absence of cGVHD treatment change, NRM, and recurrent malignancy. [Figure 10C] Durability of response to belmosudil by dose. Kaplan-Meier curves of estimated OS in the mITT population. [Figure 11] The clinical trial design of Example 2 is described below. [Figure 12] Figure 1 shows the best change in percent predicted FEV1 from baseline in 59 subjects from Example 3. The dotted lines indicate absolute improvements of 5% and 10%, respectively. Baseline NIH Lung Score was 1, 2, or 3. Each bar represents an individual subject. [Figure 13] Figure 1 shows the best change in pulmonary Lee Symptom Scale (LSS) from baseline in the 59 subjects of Example 3. LSS lung scores (white) are grouped according to baseline NIH lung scores. A change of 10 points (half a standard deviation from the baseline score) was considered clinically meaningful. The corresponding best change in %FEV1 from baseline for each individual subject is shown in black. [Figure 14-1] Heatmap of best response metrics of disease and symptoms in BOS. Best improvement in baseline characteristics and multiple metrics of pulmonary response for all 59 subjects is shown. Detailed definition of metrics is provided in Table 35. Abbreviations used in Figure 14 are as follows: cGVHD: chronic graft-versus-host disease; F: female; FEV1: forced expiratory volume in 1 second; M: male; mod: moderate; NIH: National Institutes of Health; NR: no response; PD: progressive disease; PFT: pulmonary function tests; PR: partial response, SD: stable condition; Sev: severe; unk: unknown. [Figure 14-2] Continued from Figure 14-1. [Figure 14-3] Continued from Figure 14-2. [Figure 15-1] 15A-15G show correlations between multiple metrics of disease and symptoms in BOS. Analysis of 583 paired time points revealed no significant association between PFT assessments (%FEV1 or FEV1 at L) and symptom metrics (LSS pulmonary subscore or NIH pulmonary symptom score). [Figure 15-2] Continued from Figure 15-1. [Figure 16] The trajectory of all % predicted FEV1 measurements collected during belmosudil therapy is shown. The graphical representation shows the % predicted FEV1 measurements of subjects in Example 3 who were responders (PR or CR by NIH criteria, n=19) in black and non-responders (n=40) in white. The fit lines of responders and non-responders were generated using locally weighted smoothing (LOESS technique) to visually present the relationship between % predicted FEV1 and response over time. [Figure 17] 1 shows the best ORR for pulmonary cGVHD according to NIH response criteria for subjects of Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition "Bronchiolitis obliterans syndrome (BOS)" can occur after lung transplantation or hematopoietic stem cell transplantation (HSCT). BOS after HSCT is also known as pulmonary cGVHD, pulmonary cGVHD, or cGVHD with pulmonary involvement. 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. The diagnosis of BOS is based on the occurrence of obstruction (measured as a decrease in forced expiratory volume in 1 second (FEV1)), the absence of restriction (a decrease in forced vital capacity (FVC) or total lung capacity), and the absence of opacities seen on computed tomography scans (KC Meyer, G. Raghu, GM Verleden, et al., An international ISHLT / ATS / ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome, Eur. Respir. J. 44(6)(2014)1479-1503; GM Verleden, ARG Lanville, ED Lease, et al., Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT, J. Heart Lung Transplant 38(5)(2019)493-503). In particular, FEV1 has been identified as a prognostic marker in BOS after allo-HSCT or lung transplantation (JH Ahn, KW Jo, JW Song, et al., Prognostic role of FEV1 for survival in bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation, Clin. Transplant. 29(12)(2015)1133-1139).

[0015] BOS occurring after lung transplantation or HSCT can be diagnosed at various stages of progression. The NIH pulmonary symptom scoring system, which has been used to score BOS associated with cGVHD after HSCT, can be used to identify and / or monitor BOS status and progression, including mild BOS, moderate BOS, and severe BOS. The term "NIH pulmonary symptom score" or "NIH cGVHD pulmonary score" is a clinical symptom-based score ranging from 0 to 3. A score of 0 is used for no symptoms, a score of 1 is used for symptoms of shortness of breath when climbing stairs, a score of 2 is used for symptoms of shortness of breath on level ground, and a score of 3 is used for shortness of breath at rest or shortness of breath requiring oxygen. As used herein, the term "mild BOS" refers to subjects with an NIH pulmonary symptom score of 1, and the term "moderate BOS" refers to subjects with an NIH pulmonary symptom score of 2. The term "severe BOS" refers to subjects with an NIH symptom score of 3.

[0016] "Early stage" BOS includes both mild and moderate BOS, and may also be referred to as "early BOS." In some embodiments, the term "early BOS" refers to subjects with an NIH Pulmonary Symptom Score of 1 or 2. In some embodiments, "severe BOS" or "late BOS" refers to subjects with an NIH Pulmonary Symptom Score of 3.

[0017] The term "allo-HSCT", also called bone marrow or stem cell transplantation or "allo-HCT", refers to cell transplantation in which hematopoietic cells from a donor are transplanted 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 circumstances, umbilical cord blood can be used. Donors and recipients can be matched on human leukocyte antigen (HLA) genes, such as siblings. Donors and recipients can be half-matched (haploidentical) parents and children. Myeloablative transplantation uses very high doses of chemotherapy or radiation before transplantation with autologous or allogeneic hematopoietic stem cells. Non-myeloablative, or reduced-intensity, transplantation allows patients to receive less intense chemotherapy before transplantation with allogeneic hematopoietic stem cells.

[0018] Belmosudil is an oral selective rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitor. ROCK2 inhibition acts on fibrosis that occurs as a result of a dysregulated adaptive immune system and abnormal tissue repair. (Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, Chen W, Scher JU, Mo R et alSelective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America 2014;111(47):16814-16819.Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A et al.Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism.Blood 2016;127(17):2144-2154).

[0019] As used herein, the term "belmosudil" is intended to include 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide and any pharma- ceutically acceptable salts thereof. Belmosudil is also known as KD025 and is marketed in the United States as REZUROCK® for the treatment of patients with chronic GVHD after failure of at least two prior lines of systemic therapy. The active pharmaceutical ingredient of REZUROCK® has the molecular formula C 27 H 28It is belmosudil mesylate of N6O5S and has a molecular weight of 548.62 g / mol. The chemical name of belmosudil mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1). The chemical structure of belmosudil mesylate is as follows: [ka]

[0020] Belmosudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF, and soluble in DMSO. Belmosudil tablets are for oral administration. Each tablet contains 200 mg of free base, which corresponds to 242.5 mg of belmosudil mesylate. The tablets 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.

[0021] Belmosudil is 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.

[0022] The first-line treatment for moderate-to-severe chronic graft-versus-host disease (cGVHD) as defined by the National Institutes of Health (NIH) is corticosteroids alone or in combination with sirolimus or calcineurin inhibitors. (Carpenter PA, Logan BR, Lee SJ, 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). However, up to 70% of patients require additional lines of therapy. (Bachier CR, Aggarwal SK, Hennegan K, et al: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. Presented at ASH 2019, Orlando, FL, December 7-10, 2019; Lee SJ, Nguyen TD, Onstad L, et al: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transpl 24: 555-562, 2018: Flowers MED, Martin PJ: How we treat chronic graft-versus-host disease. Blood 125: 606-615, 2015). Furthermore, long-term use of corticosteroids is associated with significant side effects.(Biol Blood Marrow Transpl 24:555-562,2018:Flowers MED,Martin PJ:How we treat chronic graft-versus-host disease.Blood 125:606-615,2015);MacDonald KPA,Hill GR,Blazar BR:Chronic graft-versus-host disease:Biological insights from preclinical and clinical studies.Blood 129:13-21,2017).Examples of corticosteroid therapy for the treatment of cGVHD include, but are not limited to, prednisone, prednisolone, methylprednisolone, and budesonide.

[0023] Pulmonary function tests (PFTs) measure lung volume, capacity, flow rate, and gas exchange. Spirometry or plethysmography may be used to obtain the results. Spirometry is a physiological test that measures the ability to inhale and exhale air over time. The main results of spirometry are the forced vital capacity (FVC) and the forced expiratory volume (FEV). The spirometry procedure has three phases: 1) maximum inspiration; 2) the "burst" of expiration; 3) continuing complete expiration until the end of the test. Vital capacity (VC) is the volume of gas expelled from a full inspiration to the residual volume. FVC includes patients exhaling at the maximum rate and effort. Forced expiratory volume in 1 second (FEV1) is the volume of air (in liters) exhaled in the first second during a forced expiration after a maximum inspiration. Usually, at least 80% of the forced vital capacity (FVC) is exhaled in the first second. Pulmonary plethysmography can be used to measure total lung volume, the amount of air left in the lungs when breathing out normally (called functional residual capacity (FRC)), and the amount of air left when breathing out as far as possible, i.e., residual capacity (RC). Pulmonary function can also be measured using radiology, such as inspiratory and expiratory chest CT scans, 18-fluorodeoxyglucose positron emission tomography, or MRI.

[0024] The Lee Symptom Scale (LSS) summary score measures the impact on patient function and health. The Lee Symptom Scale is a 30-item scale developed to measure symptoms of cGVHD and is described in Lee SJ, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002;8:444-452.

[0025] As used herein, the term "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. An initial treatment (first line therapy) may not work or stop working after a period of time. After such a first line therapy is discontinued, a second, different treatment (second line therapy) may be given. Subsequent lines of therapy may be given if the second therapy does not work or stops working. Some patients may receive multiple lines of therapy over the course of the disease. Examples of previous systemic therapy to treat cGVHD include, but are not limited to, prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0026] As used herein, the term "subject" or "patient" includes animals or humans.

[0027] Examples of clinical endpoints include: Overall response rate (ORR) is the percentage of people in a study or treatment group who have a partial response (PR) or complete response (CR) to treatment within a certain period of time. Treatment failure survival (FFS) means the time from the first dose of belmozudil to a failure event, or the interval from the start of belmozudil to the addition of a new cGVHD therapy, recurrence of the underlying disease, or non-recurrence death (NRM). Overall survival (OS) means the length of time from the date of diagnosis of disease or the start of treatment. Duration of response (DOR) means the time from the time of initial response (e.g., PR or CR), from best response to cGVHD to documented progression, from initial response to the start of additional systemic cGVHD therapy, or to death. Time to next therapy (TTNT) means the time to the start of a subsequent systemic cGVHD therapy.

[0028] Steroid-refractory (SR) cGVHD was defined as progressive cGVHD when prednisone was ≥ 1 mg / kg / day for ≥ 1-2 weeks, or stable cGVHD when prednisone was ≥ 0.5 mg / kg / day for ≥ 1-2 months.

[0029] Immunosuppressive therapy (IST) is typically administered for at least 6 months after allo-HSCT to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine. In some embodiments, standard of care immunosuppressants may include at least one of the following: calcineurin inhibitors, cell cycle inhibitors, and mTOR inhibitors.

[0030] BOS can occur after allogeneic HSCT and after lung transplantation. Although post-lung transplant and post-allogeneic HSCT bronchiolitis obliterans syndrome are distinct entities, the clinical, imaging, and functional features are similar in both settings and include progressive dyspnea associated with progressive airflow limitation that may ultimately lead to chronic cough, sputum production, nasal congestion, and respiratory failure.

[0031] Chronic pulmonary allograft dysfunction (CLAD) has two subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). CLAD is the leading cause of morbidity and mortality after lung transplantation. CLAD results from inflammatory and fibrotic changes in either the airways (BOS) or lung parenchyma (RAS). The pathology of CLAD is driven by immune dysregulation resulting in tissue injury and subsequent secretion of profibrotic mediators. The mechanisms underlying CLAD appear to be similar to those seen in chronic graft-versus-host disease (cGVHD) of the lung after allogeneic hematopoietic stem cell transplantation.

[0032] The nomenclature of CLADs is typically explained as follows:

[0033] [Table 1]

[0034] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) after lung transplantation, the method comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (bermosudil), to a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the CLAD comprises bronchiolitis obliterans syndrome (BOS). In some embodiments, the CLAD comprises restrictive allograft syndrome (RAS). In some embodiments, the CLAD is at stage 1 or stage 2. In some embodiments, the CLAD is at stage 1, stage 2, or stage 3. In some embodiments, the CLAD is at stage 1, stage 2, stage 3, or stage 4. In some embodiments, the CLAD is at stage 1. In some embodiments, the CLAD is at stage 2. In some embodiments, the subject has mild BOS. In some embodiments, the subject has moderate BOS. In some embodiments, the subject has early BOS. In some embodiments, the subject does not have severe BOS.

[0035] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD), where CLAD is BOS following lung transplantation, the method comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (belmosudil), to a subject in need thereof.

[0036] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD), where CLAD is RAS following lung transplantation, the method comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]-N-(propan-2-yl)acetamide, or a pharmacologic acceptable salt thereof (belmosudil), to a subject in need thereof.

[0037] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation, comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (Belmosudil), to a subject in need thereof. In some embodiments, the subject is a human.

[0038] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation, comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (Belmosudil), to a subject in need thereof. In some embodiments, the subject is a human.

[0039] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic stem cell transplantation, the method comprising administering a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof, wherein the subject has mild BOS or moderate BOS. In some embodiments, the subject is a human. In some embodiments, the subject has mild BOS. In some embodiments, the subject has moderate BOS. In some embodiments, the subject does not have severe BOS.

[0040] In some embodiments, there is provided a use of a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) following lung transplantation. In some embodiments, there is provided a compound comprising a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) following lung transplantation.

[0041] In some embodiments, there is provided a use of a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharma- tically acceptable salt thereof for the preparation of a medicament for the treatment of a subject diagnosed with bronchiolitis obliterans syndrome after lung transplantation. In some embodiments, there is provided a compound comprising a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharma- tically acceptable salt thereof for use in the treatment of a subject diagnosed with bronchiolitis obliterans syndrome after lung transplantation.

[0042] In some embodiments, there is provided a use of a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a subject diagnosed with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic stem cell transplantation, optionally wherein the subject has mild BOS or moderate BOS.

[0043] In some embodiments, there is provided a compound comprising a therapeutically effective amount of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof, for use in treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic stem cell transplantation, optionally wherein the subject has mild BOS or moderate BOS.

[0044] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) after lung transplantation, the method comprising administering 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (bermosudil), at a dose selected from 200 mg daily and 200 mg twice daily, to a subject in need thereof. In some embodiments, the subject is a human.

[0045] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation or allogeneic hematopoietic stem cell transplantation, the method comprising administering 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharma- ceutically acceptable salt thereof (bermosudil), at a dose selected from 200 mg daily, 200 mg twice daily, and 400 mg daily to a subject in need thereof. In some embodiments, the subject is a human.

[0046] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD) after lung transplantation, the method comprising administering belmosudil at a dose selected from 200 mg daily and 200 mg twice daily. In some embodiments, the subject is a human.

[0047] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD), wherein CLAD is BOS following lung transplantation, the method comprising administering belmosudil at a dose selected from 200 mg daily and 200 mg twice daily. In some embodiments, the subject is a human.

[0048] In some embodiments, provided herein is a method of treating a subject diagnosed with chronic pulmonary allograft dysfunction (CLAD), wherein CLAD is RAS following lung transplantation, the method comprising administering belmosudil at a dose selected from 200 mg daily and 200 mg twice daily. In some embodiments, the subject is a human.

[0049] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation or allogeneic hematopoietic stem cell transplantation, wherein belmosudil is administered to a subject in need thereof until a desired response is achieved. In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation or allogeneic hematopoietic stem cell transplantation, wherein belmosudil is administered at a dose selected from 200 mg per day, 200 mg twice per day, and 400 mg per day, wherein belmosudil is administered to a subject in need thereof until a desired response is achieved. In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation or allogeneic hematopoietic stem cell transplantation, the method comprising administering belmosudil to a subject in need thereof at a dose selected from the group consisting of 200 mg daily, 200 mg twice daily, and 400 mg daily, wherein belmosudil is administered as a 28-day cycle, the number of cycles ranging from 3 to 15. 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. In some embodiments, the desired response does not include further disease progression. In some embodiments, the desired response includes slowing disease progression. In some embodiments, the desired response does not include further decline in pulmonary function. In some embodiments, the desired response includes slowing decline in pulmonary function. In some embodiments, belmosudil is administered until there is no disease progression. In some embodiments, belmosudil is administered until there is no decline in pulmonary function. In some embodiments, administration of belmosudil is maintained to preserve the desired response achieved. In some embodiments, the subject is a human.

[0050] In some embodiments, provided herein is a method of treating a subject diagnosed with bronchiolitis obliterans syndrome (BOS) after lung transplantation, the method comprising administering belmosudil to a subject in need thereof at a dose selected from the group consisting of 200 mg daily and 200 mg twice daily.

[0051] 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.

[0052] In some embodiments, the allogeneic hematopoietic stem cell transplant is a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplant is a haploidentical HSCT.

[0053] In some embodiments, belmosudil is administered in 28 day cycles.

[0054] In some embodiments, the number of cycles is 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 5 to 11. In some embodiments, the number of cycles is 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 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.

[0055] In some embodiments, belmosudil is administered to a subject at a dose selected from the group consisting of 200 mg per day, 200 mg twice per day, and 400 mg per day. In some embodiments, the dose is 200 mg per day. In some embodiments, the dose is 200 mg twice per day. In some embodiments, the dose is 400 mg per day.

[0056] In some embodiments, the pulmonary therapeutic success is defined by at least one of an NIH pulmonary symptom score and a pulmonary function test. In some embodiments, the pulmonary therapeutic success is defined by a pulmonary function test alone. In some embodiments, the pulmonary therapeutic success is defined by an NIH pulmonary symptom score alone. In some embodiments, the pulmonary function test measurements are obtained by spirometry. In some embodiments, the pulmonary function test measurements are obtained by plethysmography.

[0057] In some embodiments, the therapeutic response in the lungs is defined by the measurement of %FEV1. In some embodiments, the subject experiences an improvement in %FEV1 from baseline during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of ≧5% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of ≧10% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of ≧20% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of ≥1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥11%, ≥12%, ≥13%, ≥14%, ≥15%, ≥16%, ≥17%, ≥18%, ≥19%, ≥20%, ≥21%, ≥22%, ≥23%, ≥24%, ≥25%, ≥26%, ≥27%, ≥28%, ≥29%, or ≥30% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of about 5% to about 30% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of about 10% to about 30% during treatment with belmosudil. In some embodiments, the subject experiences an absolute improvement in %FEV1 from baseline of about 20% to about 30% during treatment with belmosudil.

[0058] In some embodiments, the therapeutic response in the lung is defined by measuring FEV1 in mL. In some embodiments, the subject experiences at least 200mL improvement in FEV1 from baseline during treatment with belmosudil. In some embodiments, the subject experiences at least 100mL improvement in FEV1 from baseline during treatment with belmosudil. In some embodiments, the subject experiences at least 50mL, at least 100mL, at least 150mL, at least 200mL, at least 250mL, at least 300mL improvement in FEV1 from baseline during treatment with belmosudil.

[0059] In some embodiments, FEV1 is assessed at baseline and on day 1 of cycles 2 through 5. In some embodiments, FEV1 is assessed at baseline and on day 1 of each cycle starting on day 1 of cycle 2.

[0060] In some embodiments, the improvement is maintained for at least two consecutive FEV1 assessments. In some embodiments, the improvement is maintained for at least three consecutive FEV1 assessments. In some embodiments, the improvement is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive FEV1 assessments.

[0061] In some embodiments, the pulmonary therapeutic response is a complete response. In some embodiments, the pulmonary therapeutic response is a partial response. In some embodiments, the pulmonary therapeutic response is a stable condition. In some embodiments, the pulmonary therapeutic response is upgraded from a partial response as measured by %FEV1 alone to a complete response as measured by NIH pulmonary symptom score.

[0062] In some embodiments, the subject has a baseline NIH pulmonary symptom score of 1 before treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 2 before treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 3 before treatment with belmosudil.

[0063] In some embodiments, the subject experiences an improvement in NIH pulmonary symptom score during treatment with belmosudil. In some embodiments, the subject experiences an NIH pulmonary symptom score of 0 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 1 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 0 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 2 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 0 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 3 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 0 during treatment with belmosudil.

[0064] In some embodiments, the subject experiences an improvement in NIH pulmonary symptom score during treatment with belmosudil. In some embodiments, the subject experiences an NIH pulmonary symptom score of 1 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 2 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 1 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 3 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 1 during treatment with belmosudil.

[0065] In some embodiments, the subject experiences an improvement in NIH pulmonary symptom score during treatment with belmosudil. In some embodiments, the subject experiences an NIH pulmonary symptom score of 2 during treatment with belmosudil. In some embodiments, the subject has a baseline NIH pulmonary symptom score of 3 before treatment with belmosudil, and the subject experiences an improvement in NIH pulmonary symptom score of 2 during treatment with belmosudil.

[0066] In some embodiments, the therapeutic effect in lung is measured according to Lee symptom scale lung score.In some embodiments, the subject experiences at least 10 points of Lee symptom scale lung subscore reduction from baseline during treatment with belmosudil.In some embodiments, the subject experiences at least 5 points of Lee symptom scale lung subscore reduction from baseline during treatment with belmosudil.In some embodiments, the subject experiences at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points of Lee symptom scale lung subscore reduction from baseline during treatment with belmosudil.

[0067] 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.

[0068] In some embodiments, the subject experienced a complete response to the last graft-versus-host disease treatment prior to belmosudil. In some embodiments, the subject experienced a partial response to the last graft-versus-host disease treatment prior to belmosudil. In some embodiments, the subject experienced stable disease to the last graft-versus-host disease treatment prior to belmosudil.

[0069] In some embodiments, the previous line of systemic therapy for chronic graft-versus-host disease has been discontinued.

[0070] In some embodiments, the prior line of systemic therapy is selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0071] In some embodiments, the cGVHD is steroid-refractory (SR) cGVHD.

[0072] 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 reduced after at least one cycle of belmosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is reduced 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 belmosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is reduced 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 belmosudil treatment. In some embodiments, the concomitant corticosteroid therapy is discontinued after at least one cycle of belmosudil treatment.

[0073] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0074] In some embodiments, the subject has undergone an allogeneic bone marrow transplant or hematopoietic stem cell transplant. In some embodiments, the subject is undergoing glucocorticoid therapy and calcineurin therapy. In some embodiments, the subject is undergoing glucocorticoid therapy. In some embodiments, the subject is undergoing one or more combination therapies that are not generally considered to be immunosuppressive. In some embodiments, the subject is undergoing combined extracorporeal photochemotherapy (ECP). In some embodiments, the subject has persistent active cGVHD symptoms as defined by the 2014 NIH Consensus Development Project on Clinical Trial Criteria in cGVHD after at least two months of corticosteroid therapy. In some embodiments, the subject has undergone three or fewer previous lines of treatment for cGVHD. In some embodiments, the subject has a Karnofsky performance scale of >40. In some embodiments, the subject has a score of >1.5×10 9 / L absolute neutrophil count (without myeloid growth factor in the previous week) and ≥ 50 × 10 9 / L (without transfusions or thrombopoietin or thrombopoietin analogs within the previous 2 weeks). In some embodiments, the subject has a total bilirubin ≦1.5×upper limit of normal (ULN), ALT and AST ≦3×ULN, a glomerular filtration rate (GFR) ≧30 mL / min / 1.73 m using the 4-variable Modification of Diet in Renal Disease (MDRD-4) formula. 2 In some embodiments, the subject is at least 18 years of age, and in some embodiments, the subject is not pregnant.

[0075] In some embodiments, the subject has at least one of the following characteristics: has undergone an allogeneic bone marrow transplant; has undergone a hematopoietic stem cell transplant; is receiving glucocorticoid therapy and calcineurin therapy; is receiving glucocorticoid therapy; is receiving one or more concomitant therapies not generally considered immunosuppressive; is receiving concomitant extracorporeal photochemotherapy [ECP]; has persistent active cGVHD symptoms as defined by the 2014 NIH Consensus Development Project on Clinical Trial Criteria in cGVHD after at least 2 months of corticosteroid therapy; has received 3 or fewer previous lines of treatment for cGVHD; has a Karnofsky performance scale of >40; has an absolute neutrophil count of ≥ 1.5 x 109 / L (without myeloid growth factor in the previous week) and ≥ 50 x 10 9 / L (without transfusions or thrombopoietin or thrombopoietin analogs within the previous 2 weeks); total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT and AST ≤ 3 × ULN, glomerular filtration rate (GFR) ≥ 30 mL / min / 1.73 m using the 4-variable Modification of Diet in Renal Disease (MDRD-4) formula 2 are at least 18 years of age; and are not pregnant.

[0076] In some embodiments, the subject is not concurrently undergoing an investigational GVHD treatment. In some embodiments, the subject does not have acute GVHD. In some embodiments, the subject is not pregnant or breastfeeding. In some embodiments, the subject is not taking drugs that are generally known to be moderate or strong inhibitors of CYP3A4 isoenzymes or moderate or strong CYP3A4 inducers. In some embodiments, the subject has no history of poorly controlled psychiatric disorders. In some embodiments, the subject has no history of coronary artery disease. In some embodiments, the subject has no regular and excessive alcohol use in the previous 6 months, defined as >14 drinks per week for men or >7 drinks per week for women (where approximately 10 g of alcohol is equivalent to 1 "drink" unit, where 1 unit is equivalent to 1 ounce of distilled spirits, 12 ounces of beer, or 4 ounces of wine). In some embodiments, the subject has no history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV). In some embodiments, the subject has not been diagnosed with another malignancy (other than the malignancy for which the transplant was performed) within the past three years, except for completely excised basal cell or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, excised ductal carcinoma in situ, or low-risk prostate cancer after curative resection. In some embodiments, the subject has no recurrence of the underlying cancer or post-transplant lymphoproliferative disease. In some embodiments, the subject has no previous exposure to belmosudil or known allergy / sensitivity to belmosudil or other ROCK2 inhibitors. In some embodiments, the subject is not taking other immunosuppressive drugs for GVHD, including mTOR (mammalian target of rapamycin) inhibitors. In some embodiments, the subject does not have a QTcF>450msec.

[0077] In some embodiments, the subject has at least one of the following characteristics: not receiving concurrent investigational GVHD treatment; not having acute GVHD; not being pregnant or breastfeeding; not taking medications commonly known to be moderate or strong inhibitors of the CYP3A4 isoenzyme or that are moderate or strong CYP3A4 inducers; not having a history of poorly controlled psychiatric illness; not having a history of coronary artery disease; not having regular and excessive use of alcohol in the previous 6 months, defined as >14 drinks of alcohol per week for men or >7 drinks of alcohol per week for women (where approximately 10 grams of alcohol is equivalent to 1 "drink" unit, where 1 unit is 1 ounce of distilled liquor, 12 ounces of beer, or 4 ounces of wine). equal to); no history of human immunodeficiency virus (HIV); no history of active hepatitis C virus (HCV); no history of hepatitis B virus (HBV); no diagnosis of another malignancy (other than the malignancy for which the transplant was performed) within the past 3 years, except for completely excised basal cell or squamous cell carcinoma of the skin, excised cervical intraepithelial neoplasia, or low-risk prostate cancer after curative resection; no recurrence of underlying cancer or post-transplant lymphoproliferative disorder; no previous exposure to belmosudil; no known allergy / sensitivity to belmosudil or other ROCK2 inhibitors; not taking other immunosuppressants for GVHD, including mTOR (mammalian target of rapamycin) inhibitors; and no QTcF>450msec.

[0078] In some embodiments, the subject has at least one of the following characteristics: has undergone an allogeneic bone marrow transplant; has undergone a hematopoietic stem cell transplant; is receiving glucocorticoid and calcineurin therapy; is receiving glucocorticoid therapy; is receiving one or more concomitant therapies not generally considered immunosuppressive; is receiving concomitant extracorporeal photochemotherapy [ECP]; has persistent active cGVHD symptoms as defined by the 2014 NIH Consensus Development Project on Clinical Trial Criteria in cGVHD after at least 2 months of corticosteroid therapy; has received 3 or fewer previous lines of treatment for cGVHD; has a Karnofsky performance scale of >40; is >= 1.5 x 10 9 / L absolute neutrophil count (without myeloid growth factor in the previous week) and ≥ 50 × 10 9 / L (without transfusions or thrombopoietin or thrombopoietin analogs within the previous 2 weeks); total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT and AST ≤ 3 × ULN, glomerular filtration rate (GFR) ≥ 30 mL / min / 1.73 m using the 4-variable Modification of Diet in Renal Disease (MDRD-4) formula 2have a history of chronic obstructive pulmonary disease; are at least 18 years of age; are not pregnant or breastfeeding; are not receiving concurrent investigational GVHD treatment; do not have acute GVHD; are not taking medications commonly known to be moderate or strong inhibitors of the CYP3A4 isoenzyme or that are moderate or strong CYP3A4 inducers; have no history of poorly controlled psychiatric disorders; have no history of coronary artery disease; have no regular and excessive use of alcohol in the previous 6 months, defined as >14 drinks per week for men or >7 drinks per week for women (where approximately 10 grams of alcohol equals 1 "drink" unit, where 1 unit equals 1 ounce of distilled liquor, 12 ounces of beer, or 4 ounces of wine); are not a member of the human immune system; No history of immunodeficiency virus (HIV); no history of active hepatitis C virus (HCV); no history of hepatitis B virus (HBV); no diagnosis of another malignancy (other than the malignancy for which the transplant was performed) within the past 3 years, except for completely excised basal cell or squamous cell carcinoma of the skin, excised cervical intraepithelial neoplasia, or low-risk prostate cancer after curative resection; no recurrence of underlying cancer or post-transplant lymphoproliferative disorder; no previous exposure to belmosudil; no known allergy / sensitivity to belmosudil or other ROCK2 inhibitors; not taking other immunosuppressants for GVHD, including mTOR (mammalian target of rapamycin) inhibitors; and no QTcF>450msec.

[0079] In some embodiments, the subject has undergone an allogeneic hematopoietic cell transplant. In some embodiments, the subject has previously received at least 2 lines, but no more than 5 lines, of systemic therapy for cGVHD. In some embodiments, the subject has received glucocorticoid therapy at a stable dose over the previous 2 weeks. In some embodiments, the subject has persistent cGVHD symptoms. In some embodiments, the subject has a Karnofsky (if ≥ 16 years old) / Lansky (if < 16 years old) performance score of ≥ 60. In some embodiments, the subject has a ≥ 1.5 x 10 9 / L absolute neutrophil count and ≥ 50 × 10 9In some embodiments, the subject has an ALT and AST ≦3×ULN, total bilirubin ≦1.5×ULN, and a glomerular filtration rate (GFR) ≧30 mL / min / 1.73 m using the MDRD-4 parameter formula. 2 In some embodiments, the subject has a body weight of > 40 kg. In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy. In some embodiments, the subject is receiving one or more of sirolimus, MMF, methotrexate, rituximab, and extracorporeal photochemical circulation (ECP) therapy concomitantly.

[0080] In some embodiments, the subject has at least one of the following characteristics: has undergone an allogeneic hematopoietic cell transplant; has previously received at least two, but not more than five, lines of systemic therapy for cGVHD; has been receiving glucocorticoid therapy at a stable dose for the previous two weeks; has persistent cGVHD symptoms; has a Karnofsky (if ≥ 16 years old) / Lansky (if < 16 years old) performance score of ≥ 60; 9 / L absolute neutrophil count and ≥ 50 × 10 9 / L; ALT and AST ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN, and glomerular filtration rate (GFR) ≥ 30 mL / min / 1.73 m using the MDRD-4 parameter formula. 2 have a weight of ≥ 40 kg; are at least 18 years old; are receiving concomitant corticosteroid therapy; are receiving concomitant calcineurin inhibitor therapy; and are concurrently receiving one or more of the following: sirolimus, MMF, methotrexate, rituximab, and extracorporeal photocytolysis (ECP) therapy.

[0081] In some embodiments, the subject has not undergone systemic cGVHD treatment. In some embodiments, the subject has no histological recurrence of the underlying cancer or post-transplant lymphoproliferative disease. In some embodiments, the subject has not undergone combination treatment with ibrutinib. In some embodiments, the subject has no history of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or history of hepatitis B virus (HBV). In some embodiments, the subject has not been diagnosed with another malignancy (other than the malignancy for which the transplant was performed) within the past 3 years, except for completely excised basal cell or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, excised ductal carcinoma in situ, or prostate cancer with a Gleason score <6 and a stable PSA for 12 months. In some embodiments, the subject has no previous exposure to belmosudil. In some embodiments, the subject has no known allergy / sensitivity to belmosudil or any other ROCK2 inhibitor. In some embodiments, the subject does not have a QTc(F)>480msec. In some embodiments, the subject does not have an FEV1≦39% or a pulmonary score of 3.

[0082] In some embodiments, the subject has at least one of the following characteristics: not receiving systemic cGVHD treatment; not having histological recurrence of the underlying cancer or post-transplant lymphoproliferative disease; not receiving concomitant treatment with ibrutinib; not having a history of human immunodeficiency virus (HIV); not having hepatitis C virus (HCV); not having a history of hepatitis B virus (HBV); not having been diagnosed with another malignancy (other than the malignancy for which the transplant was performed) within the past 3 years, except for completely excised basal cell or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, resected ductal carcinoma in situ, or prostate cancer with a Gleason score of <6 and a stable PSA for 12 months; not having previous exposure to belmosudil; not having a known allergy / sensitivity to belmosudil or any other ROCK2 inhibitor; not having a QTc(F)>480msec; and not having an FEV1≦39% or a pulmonary score of 3.

[0083] In some embodiments, the subject has at least one of the following characteristics: has undergone an allogeneic hematopoietic cell transplant; has previously received at least two, but not more than five, lines of systemic therapy for cGVHD; has been receiving glucocorticoid therapy at a stable dose for the previous two weeks; has persistent cGVHD symptoms; has a Karnofsky (if ≥ 16 years old) / Lansky (if < 16 years old) performance score of ≥ 60; 9 / L absolute neutrophil count and ≥ 50 × 10 9 / L; ALT and AST ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN, and glomerular filtration rate (GFR) ≥ 30 mL / min / 1.73 m using the MDRD-4 parameter formula. 2 have a body weight of ≥ 40 kg; are at least 18 years old; are receiving concomitant corticosteroid therapy; are receiving concomitant calcineurin inhibitor therapy; are receiving concomitant one or more of the following: sirolimus, MMF, methotrexate, rituximab, and extracorporeal photochemotherapy; are not receiving systemic cGVHD treatment; are not receiving histologic recurrence of the underlying cancer or post-transplant lymphoproliferative disease; are not receiving concomitant treatment with ibrutinib; are not receiving a history of human immunodeficiency virus (HIV); are not receiving a history of active hepatitis C virus (HCV); are not receiving hepatitis B virus (HBV) therapy. have no history of hepatitis B virus (HBV); have not been diagnosed with another malignancy (other than the malignancy for which a transplant was performed) within the past 3 years, except for completely excised basal cell or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, excised ductal carcinoma in situ, or prostate cancer with a Gleason score <6 and a stable PSA for 12 months; have no previous exposure to belmosudil; have no known allergy / sensitivity to belmosudil or other ROCK2 inhibitors; have no QTc(F)>480msec; and have no FEV1≦39% or a lung score of 3.

[0084] In some embodiments, the subject is at least 18 years old. In some embodiments, the subject underwent a bilateral lung transplant at least 1 year ago. In some embodiments, the subject received a diagnosis of CLAD within the previous 9 months. In some embodiments, the subject has CLAD stage 1 or 2 and has an FEV1 of >50%-80% of PTBL. In some embodiments, the subject has progressive CLAD. In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the subject is receiving concomitant therapy with one or more of a calcineurin inhibitor, a cell cycle inhibitor, and an mTORi. In some embodiments, the subject received concomitant azithromycin therapy at least 6 weeks ago. In some embodiments, the subject has a body mass index >= 18 kg / m 2 has.

[0085] In some embodiments, the subject has at least one of the following characteristics: is at least 18 years old; has undergone a bilateral lung transplant at least 1 year ago; has received a diagnosis of CLAD within the previous 9 months; has CLAD stage 1 or 2 and has an FEV1 of >50%-80% of PTBL; has advanced CLAD; is receiving concomitant corticosteroid therapy; is receiving concomitant therapy with one or more of a calcineurin inhibitor, a cell cycle inhibitor, and an mTORi; has previously received at least 6 weeks of concomitant azithromycin therapy; and has a body mass index of > 18 kg / m 2 has.

[0086] In some embodiments, the subject does not have an FEV1 of ≦50% of the baseline value after transplant (CLAD 3 and 4). In some embodiments, the subject is not intolerant to belmosudil or any of its components. In some embodiments, the subject does not have any condition that may affect the ability to perform pulmonary function tests. In some embodiments, the subject does not have pulmonary function decline that may be explained by a non-CLAD cause. In some embodiments, the subject has not been diagnosed or treated for malignancies within the past 3 years, except for complete resection of basal cell or squamous cell carcinoma of the skin, intraepithelial malignancy, or low-risk prostate cancer after curative therapy. In some embodiments, the subject does not have untreated symptomatic gastroesophageal reflux disease (GERD). In some embodiments, the subject does not have a baseline resting oxygen saturation of <88% on room air or the use of supplemental oxygen at rest. In some embodiments, the subject does not have a known prolongation of the QT interval (>480 msec). In some embodiments, the subject has not received prior therapy for CLAD other than azithromycin and a standard of care immunosuppressant. In some embodiments, the subject has not previously received belmosudil. In some embodiments, the subject has no known hypersensitivity to azithromycin, erythromycin, any macrolide, or any ketolide drug. In some embodiments, the standard of care immunosuppressant may include at least one of the following: a calcineurin inhibitor, a cell cycle inhibitor, and an mTOR inhibitor.

[0087] In some embodiments, the subject has at least one of the following characteristics: no FEV1 of ≦50% of baseline value after transplant (CLAD 3 and 4); no intolerance to belmosudil or any of its components; no condition that may affect the ability to perform pulmonary function tests; no pulmonary function decline that may be explained by non-CLAD causes; no diagnosis or treatment of malignancy within the past 3 years, except for complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, intraepithelial malignancy, or low-risk prostate cancer after curative therapy; no untreated symptomatic gastroesophageal reflux disease (GERD); no baseline resting oxygen saturation of <88% on room air or use of supplemental oxygen at rest; no known prolongation of the QT interval (>480 msec); no previous therapy for CLAD other than azithromycin and standard of care immunosuppressants; no previous belmosudil; and no known hypersensitivity to azithromycin, erythromycin, any macrolide, or any ketolide drug. In some embodiments, the standard of care immunosuppressants may include at least one of the following: calcineurin inhibitors, cell cycle inhibitors, and mTOR inhibitors.

[0088] In some embodiments, the subject has at least one of the following characteristics: is at least 18 years old; has undergone a bilateral lung transplant at least 1 year ago; has received a diagnosis of CLAD within the past 9 months; has CLAD stage 1 or 2 and has an FEV1 of >50%-80% of PTBL; is receiving concomitant corticosteroid therapy; is receiving concomitant therapy with one or more of a calcineurin inhibitor, a cell cycle inhibitor, and an mTORi; has previously received at least 6 weeks of concomitant azithromycin therapy; and has a body mass index of >18 kg / m 2have no FEV1 of ≦50% of baseline value after transplant (CLAD 3 and 4); are not intolerant to belmosudil or any of its components; have no condition that may affect the ability to perform pulmonary function tests; have no pulmonary function decline that can be explained by non-CLAD causes; have not been diagnosed or treated for malignancy within the past 3 years, except for complete resection of basal cell or squamous cell carcinoma of the skin, intraepithelial malignancy, or low-risk prostate cancer after curative therapy; have no untreated symptomatic gastroesophageal reflux disease (GERD); have no baseline resting oxygen saturation of <88% on room air or use of supplemental oxygen at rest; have no known prolongation of the QT interval (>480 msec); have not received previous therapy for CLAD other than azithromycin and standard of care immunosuppressants; have not previously received belmosudil; and have no known hypersensitivity to azithromycin, erythromycin, any macrolide, or any ketolide drug. In some embodiments, the standard of care immunosuppressants may include at least one of the following: calcineurin inhibitors, cell cycle inhibitors, and mTOR inhibitors. EXAMPLES

[0089] Example 1: A Phase IIa, open-label, dose-finding study of belmozudil Eligibility Eligible patients were allogeneic bone marrow transplant or allogeneic hematopoietic cell transplant (alloHCT) recipients aged ≥18 years with persistent cGVHD symptoms after 1-3 prior lines of systemic therapy and had received corticosteroid treatment with or without calcineurin inhibitors and / or concomitant extracorporeal photochemotherapy. Belmosudil was continued until cGVHD progression or unacceptable toxicity.

[0090] Inclusion Criteria. Adult male and female subjects, at least 18 years of age, who had an allogeneic bone marrow or hematopoietic stem cell transplant. At the time of study entry, they received glucocorticoid and calcineurin therapy or glucocorticoid therapy alone for cGVHD. Participants on calcineurin therapy alone without glucocorticoid therapy were not eligible. Participants also received other treatments that were not considered immunosuppressive (extracorporeal photochemotherapy; ECP) ​​and were considered for enrollment in the study on a case-by-case basis. They had persistent active cGVHD symptoms after at least 2 months of steroid therapy as defined by the 2014 National Institutes of Health Consensus Development Project on Clinical Trial Criteria in cGVHD. ≤3 prior lines of treatment for cGVHD. Karnofsky performance scale greater than (>) 40. Adequate organ and bone marrow function assessed during the 14 days prior to enrollment as follows: 1.5 × 10 9 Absolute neutrophil count ≥ 50 × 10 / L (without myeloid growth factor within 1 week of study entry); 9 platelet count of ≥ 30 milliliters per minute per 1.73 square meters (mL / min / 1.73 m ) using the four-variable modification of diet in renal disease formula; platelet count of ≥ 30 milliliters per minute per 1.73 square meters (mL / min / 1.73 m ) using the four-variable modification of diet in renal disease formula; 2 ).

[0091] Exclusion Criteria: Pregnant or breastfeeding female participants. Received investigational GVHD treatment within 28 days of study entry. Had acute GVHD. Taken any medication known to be a moderate or strong inhibitor of cytochrome (CY) P3A4 isoenzyme or any medication that is a moderate or strong CYP3A4 inducer. History or other evidence of severe illness or any other condition (such as poorly controlled psychiatric illness or coronary artery disease) that, in the opinion of the investigator, would make the participant unsuitable for the study. Regular and excessive use of alcohol within 6 months prior to study entry, defined as alcohol intake >14 drinks per week for men and >7 drinks per week for women. Approximately 10 grams of alcohol equals 1 "drink" unit. One unit is equivalent to 1 ounce of distilled spirits, 12 ounces of beer, or 4 ounces of wine. Known history of human immunodeficiency virus or active hepatitis C virus or hepatitis B virus. Diagnosed with another malignancy (other than the malignancy for which the transplant was performed) within 3 years of enrollment, except for completely excised basal or squamous cell carcinoma of the skin, excised cervical intraepithelial carcinoma, excised ductal carcinoma in situ, or low-risk prostate cancer after curative resection. Recurrence of underlying cancer at screening or lymphoproliferative disorder after transplant. Previous exposure to belmosudil or known allergy / sensitivity to belmosudil or other Rho-associated protein kinase 2 inhibitors. Taking other immunosuppressive medications for GVHD, including mammalian target of rapamycin inhibitors (Note: only steroids, calcineurin inhibitors, and ECP are permitted). Corrected QT interval >450 ms using the Fridericia formula.

[0092] Study Design and Treatment Patients were enrolled in three successive cohorts: Cohort 1 received belmosudil 200 mg once daily, Cohort 2 received belmosudil 200 mg twice daily, and Cohort 3 received belmosudil 400 mg once daily (Figure 1). Prior to enrollment of the subsequent cohorts, safety data from each previous cohort was analyzed after 8 patients had reached 2 months of treatment to confirm the absence of safety signals. The 2-month time frame was chosen because all clinically significant belmosudil-related adverse events (AES) to date had occurred ≤36 days from the initiation of belmosudil. No safety concerns were identified, allowing for planned dose escalation.

[0093] Belmosudil was administered orally in 28-day cycles until disease progression or unacceptable toxicity. Progression was defined according to the 2014 NIH cGVHD consensus criteria. Long-term follow-up was every 8 weeks until study termination. After 4 weeks of belmosudil therapy, corticosteroid therapy could be tapered at the investigator's discretion. Screening was performed within 28 days of the first study dose. Response was initially assessed after 2 cycles, but this was modified to assess response on day 1 of each cycle, starting on day 1 of cycle 2.

[0094] Study Endpoints The primary efficacy endpoint was ORR, defined as the proportion of patients who achieved either a complete response (CR) or partial response (PR) according to the 2014 NIH cGVHD consensus criteria at any time point. Only response assessments before the next line of therapy after belmosudil were counted in the ORR. All responses were assessed by the investigator. Secondary endpoints included the number and percentage of patients with steroid-dependent cGVHD who had a 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), progression-free survival (FFS), and overall survival (OS). Safety and tolerability of belmosudil were assessed throughout the study by AE assessment, physical examination, vital sign measurements, laboratory tests, and electrocardiograms. Predose samples were collected for pharmacodynamic (PD) evaluation, including evaluation of immune cell subtypes in peripheral blood.

[0095] statistical analysis With a sample size of 16 patients per cohort, this study participant had a >90% probability of ≥1 study participant experiencing an AE with a baseline rate of ≥14%, derived from a probability calculation for the assumed sample size. Assuming a best ORR of 25%, determined to be clinically meaningful, the study was expected to have an approximately 90% probability of showing a response in ≥2 patients per cohort. The study was not powered to show significant differences between cohorts for efficacy, AE, or PD analyses. Primary analyses were performed using the safety population, defined as enrolled patients receiving ≥1 dose of study drug. Two-sided 95% CIs for ORR were constructed using the Clopper-Pearson (exact) method. Kaplan-Meier (KM) methods were used to calculate estimates of FFS and OS.

[0096] Results. Target A total of 54 patients were enrolled in consecutive cohorts: 17 patients in cohort 1, 16 patients in cohort 2, and 21 patients in cohort 3 ( Fig. 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 overall median follow-up period was 29 months (range, 1–39 months).

[0097] Demographic and baseline characteristics were comparable across cohorts (Table 1, Table 2). Median age at baseline was 52 years (range, 20-75 years). Median time from cGVHD diagnosis to treatment was longest in cohort 1 at 26 months (compared to 18 and 16 months in cohorts 2 and 3, respectively). Seventy-eight percent of patients had severe cGVHD as assessed by the investigator. Half of patients had ≥4 organ involvement, and more patients in cohort 3 had pulmonary involvement (48%) compared to patients in cohorts 1 (24%) and 2 (19%). Median baseline corticosteroid doses (mg / kg / d prednisone equivalents) were 0.22, 0.19, and 0.17 across cohorts, respectively. Patients in cohort 1 had received a median of three prior lines of therapy, whereas patients in cohorts 2 and 3 had received a median of two prior lines of therapy. Seventy-three percent of patients (35 of 48; data unavailable for 6 patients) were refractory to their last line of therapy before study enrollment. A CONSORT diagram (Figure 1) shows patient disposition. Median duration of treatment 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. Twenty-eight percent of patients received belmozudil for >18 months. Reasons for discontinuing belmozudil included cGVHD progression (n=22), patient-initiated withdrawal (n=8), recurrence of underlying disease (n=7), investigator decision (n=3), AEs considered possibly treatment-related (n=3), and death (n=2). LTFU means long-term follow-up.

[0098] [Table 2]

[0099] [Table 3]

[0100] [Table 4]

[0101] Effectiveness Overall response rate. In the safety population (N=54), the ORR (95% CI) was 65% (51%-77%). ORR (95% CI) was similar between cohorts: 65% (38%-86%) in cohort 1, 69% (41%-89%) in cohort 2, and 57% (34%-78%) in cohort 3 (Table 3). Efficacy data for subgroups and secondary endpoints are presented as pooled data across cohorts.

[0102] [Table 5]

[0103] Responses were achieved across important subgroups, with ORRs of 60% (25 of 42) in patients with severe cGVHD, 66% (23 of 35) in patients who had received ≥2 prior lines of systemic therapy prior to enrollment, 63% (22 of 35) in patients who were refractory to their last line of therapy prior to enrollment, and 70% (19 of 27) in patients with ≥4 involved organs (Figure 2). All responses at the patient level were PRs, but organ-specific analysis showed that CRs were achieved across all affected organs except the lung, with PR being 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 the 400 mg dose once daily.

[0104] Responses were generally rapid, with >75% of all responses achieved by first response assessment at week 8 (Figure 4). Four of 35 responses occurred after 24 weeks of belmosudil treatment, with late organ responses observed in the lungs, joints and / or fascia, and eyes (Figure 5).

[0105] Proportion of participants with overall response (OR): OR was defined as the percentage of participants with complete response (CR) or partial response (PR). OR determination for chronic graft-versus-host disease (cGVHD) was based on cGVHD response assessment performed by clinicians according to the 2014 National Institutes of Health (NIH) Consensus Development Project for Clinical Trials on cGVHD criteria. CR was defined as resolution of all symptoms in each organ or site. PR was defined as improvement of at least one organ or site without progression in other organs or sites, and cGVHD progression was defined as clinically meaningful worsening in one or more organs regardless of improvement in other organs. Time frame: from first response to documented disease progression or death from any cause or data cutoff, whichever occurred first (maximum duration: up to 64.2 months).

[0106] Analysis was performed on the mITT population. Participants received belmosudil orally on days 1, 8, 15, and 22 of each 28-day treatment cycle until disease progression, unacceptable toxicity, or death, whichever occurred first (maximum duration: 64.2 months). The data are shown in the table below.

[0107] [Table 6]

[0108] Duration of response (DOR). DOR was defined as the time (in weeks) from the first documentation of a response to the first documentation of a worsening from the best response (e.g., CR to PR, or PR to LR). LOR included response status of unchanged (LOR-U), mixed (LOR-M), or progressive (LOR-P). According to the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria, CR was defined as resolution of all symptoms in each organ or site, PR was defined as improvement in at least one organ or site without progression in other organs or sites, LOR-M was defined as CR or PR in at least one organ with progression in another organ, LOR-U was defined as an outcome that did not meet the criteria for CR, PR, progression, or mixed response, and LOR-P was defined as progression in at least one organ or site without response in other organs or sites. Kaplan-Meier was used for analysis. Timeframe: From first response to documented disease progression or death from any cause or data cutoff, whichever occurs first (maximum duration: up to 64.2 months.

[0109] Analyses were performed on the responder population, which included participants who received at least one dose of study drug and achieved a PR or CR response on post-baseline response assessments. Participants received belmosudil orally on days 1, 8, 15, and 22 of each 28-day treatment cycle (maximum duration: 64.2 months) until disease progression, unacceptable toxicity, or death, whichever occurred first. Data are shown in the table below.

[0110] [Table 7]

[0111] Time to next treatment (TTNT). TTNT was defined as the time (in months) from first treatment to new systemic cGVHD treatment. TTNT was censored by the last response assessment or long-term follow-up assessment, whichever came first. Kaplan-Meier survival methods were used for analysis. Time frame: from the time of first treatment to the time of new systemic cGVHD treatment or long-term follow-up assessment, whichever came first (maximum duration: up to 64.2 months). Analysis was performed on the mITT population. Data are shown in the table below.

[0112] [Table 8]

[0113] Subsequent systemic cGVHD therapy includes tacrolimus, sirolimus, ibrutinib, ruxolitinib, extracorporeal photochemotherapy, and mycophenolate mofetil.

[0114] FFS and OS. Progression-free survival (FFS) and overall survival (OS) Progression-free survival was defined as the time (in months) from the first dose of study drug to the initiation of another new systemic treatment for cGVHD, recurrence of underlying disease, or death. If no such event occurred, FFS was censored at either the last response assessment or the most recent and available long-term follow-up assessment. Kaplan-Meier survival methods were used for the analysis. The analysis was performed on the mITT population. Time frame: from the first dose of study drug to the initiation of another new systemic treatment for cGVHD, recurrence of underlying disease, or death, or data cutoff, whichever occurred first (maximum duration: up to 64.2 months). Participants received belmosudil orally on days 1, 8, 15, and 22 of each 28-day treatment cycle until disease progression, unacceptable toxicity, or death, whichever occurred first (maximum duration: 64.2 months). The data are shown in the table below.

[0115] [Table 9]

[0116] Overall survival was defined as the time (in months) from the first dose of study drug to death from any cause. If there was no death, OS was censored by the last visit, last long-term follow-up, or study cut-off date, whichever was later. Kaplan-Meier survival methods were used for analysis. Time frame: from the first dose of study drug to the date of death from any cause or data cut-off, whichever came first (maximum duration: up to 64.2 months). Participants received belmosudil orally on days 1, 8, 15, and 22 of each 28-day treatment cycle until disease progression, unacceptable toxicity, or death, whichever came first (maximum duration: 64.2 months). The data are shown in the table below.

[0117] [Table 10]

[0118] Quality of life assessments. During belmosudil treatment, a clinically meaningful improvement in LSS score, defined as a decrease of ≥ 7 points in the LSS summary score, was observed in 50% of patients. Thirty-five percent of all patients (37% of responders and 32% of non-responders) reported clinically significant improvements in LSS score at successive assessments.

[0119] Corticosteroid sparing. During belmosudil treatment, 67% of patients had their corticosteroid dose reduced, and 19% discontinued corticosteroid therapy completely. The mean corticosteroid dose was reduced by 45%. The median time to discontinuation of corticosteroid therapy was 29 weeks (range, 8-77 weeks). The mean corticosteroid dose reduction was 55% in responders and 26% in nonresponders (Table 3).

[0120] Best overall response (BOR). BOR was defined as participants with either CR or PR or lack of response (LOR), where LOR included response status of unchanged (LOR-U), mixed (LOR-M) or progressive (LOR-P). BOR was assessed according to the 2014 NIH Consensus Development Project for Clinical Trials on cGVHD criteria. CR was defined as resolution of all symptoms in each organ or site, PR was defined as improvement in at least one organ or site without progression in other organs or sites, LOR-M was defined as CR or PR in at least one organ with progression in another organ, LOR-U was defined as an outcome that did not meet the criteria for CR, PR, progression or mixed response, and LOR-P was defined as progression in at least one organ or site without response in other organs or sites. Time frame: from date of randomization to date of first documentation of progression or death from any cause or data cutoff, whichever occurs first (maximum duration: up to 64.2 months). Analysis was performed on the mITT population. Data are shown in the table below.

[0121] [Table 11]

[0122] The greatest improvement from baseline in the Global Severity Rating (GSR) from clinician-reported cGVHD assessment. GSR assessment was performed by asking participants to rate the disease severity of their cGVHD symptoms on a 0-10 point numerical scale, with a score of 0 indicating "not at all severe cGVHD symptoms" and a score of 10 indicating "the most severe cGVHD symptoms imaginable." Response was defined using scores from 9 organs: skin, eyes, mouth, esophagus, upper gastrointestinal (GI) tract, lower GI tract, liver, lungs, and joints and fascia + GSR. End of treatment (EOT) visits were conducted within 3 days after the participant's last dose of study drug. Baseline values ​​were defined as the last valid, non-missing value obtained within 28 days before the participant received their first study drug. Time frame: from baseline to end of treatment (i.e., up to 64.2 months). Analyses were performed on the mITT population. Participants received belmosudil 200 mg orally QD on days 1, 8, 15, and 22 of each 28-day treatment cycle until disease progression, unacceptable toxicity, or death, whichever occurred first (maximum duration: 64.2 months). The data are shown in the table below.

[0123] [Table 12]

[0124] Number of participants with greatest improvement from baseline in participant self-report of cGVHD activity assessment. cGVHD symptom severity was self-reported by participants. Participants were asked to rate disease symptom severity over the past week for the following questions: worst skin itchiness, worst dry mouth, worst sore mouth, worst mouth sensitivity, major adherence to eyes, and severity of eye symptoms. Severity assessment was done with a 0-10 point numeric rating score (scare), with a score of 0 indicating "not severe cGVHD symptoms at all" and a score of 10 indicating "most severe cGVHD symptoms imaginable." EOT visits were conducted within 3 days after the participant's last dose of study medication. Baseline values ​​were defined as the last valid, non-missing value obtained within 28 days before the participant received their first study medication. Time frame: from baseline to end of treatment (i.e., up to 64.2 months). Analyses were performed on the mITT population. Data are shown in the table below.

[0125] [Table 13]

[0126] Best response in each of the individual organs. Best response was defined as the percentage of participants with CR or PR. Response was assessed according to the 2014 NIH Consensus Development Project for Clinical Trials on cGVHD criteria; CR was defined as resolution of all symptoms in each organ or site, and PR was defined as improvement in at least one organ or site without progression in other organs or sites. Organ response assessments were performed for nine individual organs: skin, eye, mouth, esophagus, upper GI, lower GI, liver, lung, and joints and fascia. Time frame: from date of randomization to disease progression or data cutoff, whichever came first (maximum duration: up to 64.2 months). Analysis was performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0127] [Table 14]

[0128] safety Belmosudil was well tolerated, with >56 patient-years of belmosudil exposure. Median relative dose intensity was 98% overall. The percentages of patients with relative dose intensity >95% were 77%, 63%, and 71%, respectively, across cohorts. Dose reductions occurred in 9% of patients, with a median duration of reduction of 97 days (range, 21-859 days). Dose interruptions occurred in 41% of patients, with a median duration of interruption of 10 days (range, 2-39 days).

[0129] 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%), increased liver function tests (33%), dyspnea (30%), headache (24%), peripheral edema (24%), cough (22%), and hypertension (20%) (Table 13). Serious AEs were reported in 43% of patients, with serious AEs reported in >1 patient being dyspnea (7%), pulmonary infection (6%), hypoxia (4%), and influenza-like illness (4%). Sixty-one percent of patients had grade ≥3 AEs, the most common of which were dyspnea (13%), increased liver function tests (7%), hyperglycemia (7%), and hypoxia (7%) (Table 13). Grade ≥3 cytopenias were reported in two patients (4%). These occurred at the time of recurrence of the underlying malignancy in patients who had otherwise maintained normal blood counts during belmosudil treatment.

[0130] [Table 15]

[0131] No cases of cytomegalovirus (CMV) infection or reactivation were reported with belmosudil. Three patients discontinued belmosudil due to possibly drug-related AEs (cohort 1: diarrhea and headache; cohort 3: fatigue). Four patients, all in cohort 3, died during the study (secondary to leukemia recurrence, pneumonia (unknown pathogen), cardiac arrest, and cGVHD progression), but these deaths were not attributable to belmosudil. There was no dose response with respect to the observed AEs.

[0132] Adverse events reported. Time frame: from the first dose of study drug to 28 days after the last dose of study drug (maximum duration: up to 64.2 months). Reported AEs and deaths were treatment-emergent AEs that occurred, worsened, or became severe between the first dose of study drug and 28 days after the last dose of study drug. All-cause mortality data collected during the study were evaluated for all enrolled participants. Deaths related to disease progression were not reported as AEs. Participants received belmosudil 200 mg orally QD on days 1, 8, 15, and 22 of each 28-day treatment cycle until disease progression, unacceptable toxicity, or death, whichever occurred first (maximum duration: 64.2 months). Data are presented in the following three tables.

[0133] [Table 16]

[0134] [Table 17]

[0135] [Table 18]

[0136] [Table 19]

[0137]

Table 20

[0138]

Table 21

[0139]

Table 22

[0140]

Table 23

[0141]

Table 24

[0142]

Table 25

[0143]

Table 26

[0144]

Table 27

[0145] Number of participants with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and not necessarily causally related to treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: results in death, is life-threatening, requires hospitalization or requires extension of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect, is a medically significant event. A TEAE was defined as an AE that developed, worsened, or became serious during the TEAE period (defined as the time from the first dose of study treatment to 28 days after the last dose of study drug). TEAEs included both SAEs and non-SAEs. Time frame: from the first dose of study treatment to 28 days after the last dose of study drug (maximum duration: up to 64.2 months). Analysis was performed on the safety population, which included all participants who received at least one dose of study drug. Data are shown in the table below.

[0146] [Table 28]

[0147] PD analysis In an exploratory PD analysis of peripheral blood mononuclear cells across the cohort, the percentage of CD41 Tregs showed an early trend of increase by day 1 of cycle 2 of belmosudil treatment. A concomitant decrease in Th17 cells was also observed. Th17 cells continued to decrease through C4D1 and C6D25. The percentage of CD41 Tregs continued to increase through C4D1 and C7D1, as shown in (Figure 6). Due to the small sample size, correlation data with steroid dose was limited in statistical analysis.

[0148] This study was the first to evaluate belmosudil treatment in human patients with cGVHD. All phenotypes of cGVHD were included, without the need for inflammatory or fibrotic manifestations. Patients with advanced multiorgan cGVHD treated with belmosudil achieved an overall response rate (ORR) of 65%, with improved quality of life, corticosteroid dose reduction, and limited toxicity. With a relatively small sample size, there was no difference in ORR between cohorts.

[0149] Belmosudil achieved meaningful and consistent response rates across subgroups, including patients with severe cGVHD, those who had received ≥2 prior lines of systemic therapy, those who were refractory to their last line of therapy prior to enrollment, and those with ≥4 involved organs. The ORR for patients with non-severe cGVHD was 83%, suggesting that further studies of how belmosudil may benefit patients earlier in the disease are indicated. All responses at the patient level were PRs, and no CRs were achieved. However, given the severity and extent of fibrotic cGVHD symptoms in this patient population, achieving CR in all organs was not expected, as some advanced fibrotic changes in the eyes, mouth, lungs, or joints and / or fascia may be irreversible. CRs were observed in all organs except the lungs, where PRs were achieved.

[0150] Belmosudil response kinetics suggest that most responders achieved a rapid response within 8 weeks after receiving belmosudil. Belmosudil was well tolerated, with a median DOR of 35 weeks across all responders. Ability to continue therapy will depend on the safety and long-term tolerability profile of the intervention. Median duration of treatment was 8 months (range, 1-39 months). 28% of patients remained on belmosudil for >18 months. No CMV infections or reactivations were reported, despite 57% of patients being CMV seropositive. Incidence of TEAEs and grade ≥3 TEAEs was similar between cohorts. The combination of a well-tolerated treatment and efficacy in response induction translated into a 2-year OS rate of 82%, a median TTNT of 14 months, and FFS rates of 76% and 47% at 6 and 12 months, respectively.

[0151] In a prospective study 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 study (after 1-3 prior lines of therapy), the 12-month FFS rate with response was 24%.

[0152] In this study, belmosudil therapy was associated with a corticosteroid-sparing effect. Current treatment paradigms rely on corticosteroids as the mainstay of treatment, but the associated long-term toxicity requires the use of the lowest possible dose or possible discontinuation. The use of corticosteroid therapy is linked to quality of life, as the side effect profile of corticosteroid therapy contributes to the patient's symptom burden. Corticosteroid dose reduction was observed across both responders and non-responders to belmosudil. Approximately 20% of patients were able to discontinue corticosteroid therapy during belmosudil treatment. Even in the absence of NIH-defined response, patients experienced clinical benefit, as evidenced by improvement in LSS score or reduction in corticosteroid dose.

[0153] Change from baseline in corticosteroid dose. EOT visits were conducted within 3 days after the participant's last dose of study medication. Baseline value was defined as the last valid non-missing value obtained within 28 days before the participant received their first study medication. The mITT population was analyzed using "Overall number of participants analyzed" = participants with available data for this outcome measure. Time frame: from baseline to end of treatment (i.e., up to 64.2 months). Data are presented in the table below.

[0154] [Table 29]

[0155] Change from baseline in calcineurin inhibitors (CNIs). Calcineurin inhibitors included systemic tacrolimus and cyclosporine. This outcome measure reports the number of participants who were taking a CNI at baseline and had a reduction and discontinuation of CNI use during the study compared to baseline. EOT visits were conducted within 3 days after the participant's last dose of study medication. Baseline values ​​were defined as the last valid, non-missing value obtained within 28 days before the participant received their first study medication. Time frame: from baseline to end of treatment (i.e., up to 64.2 months). Data are presented in the table below.

[0156] [Table 30]

[0157] Time to response (TTR). Time to response was measured as the time (in weeks) from the first administration of study drug to the first documentation of response. Response was defined as subjects achieving PR or CR on post-baseline response assessment. According to the 2014 NIH Consensus Development Project for Clinical Trials on cGVHD criteria, CR was defined as the resolution of all symptoms in each organ or site, and PR was defined as improvement of at least one organ or site without progression in other organs or sites. Time frame: from first treatment to the time of first documentation of response or data cutoff, whichever came first (maximum duration: up to 64.2 months). Analysis was performed on the responder population. Data are shown in the table below.

[0158] [Table 31]

[0159] In this study, responses were achieved in patients with fibrotic symptoms in the lungs, joints and / or fascia, and eyes. These responses were observed in some cases after 24 weeks of treatment, further highlighting the need to maintain effective therapy to achieve clinical benefit, especially in patients with difficult-to-treat disease. The lower dose of 200 mg once daily of belmosudil was equally safe and effective, and is therefore being further compared with the dose of 200 mg twice daily in the study described in Example 2 for final dose recommendation.

[0160] Change from baseline in the Lee cGvHD Symptom Scale global score at a particular time point. The Lee cGVHD Symptom Scale is a patient-reported symptom scale used to measure symptom burden, with 7 subscales (skin, eyes and mouth, breathing, feeding and digestion, muscles and joints, energy, and mental and emotional) rated as follows: 0-not at all, 1-slightly, 2-moderately, 3-quite a bit, 4-extremely, with lower values ​​representing better outcomes. Scores on each subscale were normalized to a score ranging from 0 to 100, with higher scores indicating worse symptoms. The global score was calculated as the mean of these 7 subscales. The EOT visit was conducted within 3 days after the participant's last dose of study medication. The baseline value was defined as the last valid, non-missing value obtained within 28 days before the participant received their first study medication. Timeframe: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 67, and EOT (i.e., any time up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, a "0" in the Number of Analyses field means that none of the participants were available for analysis at the specified time point. The data are presented in the table below.

[0161]

Table 32

[0162]

Table 33

[0163]

Table 34

[0164]

Table 35

[0165]

Table 36

[0166]

Table 37

[0167]

Table 38

[0168]

Table 39

[0169] Change from baseline in percent predicted forced expiratory volume in 1 second (FEV1) at each specified time point. FEV1 was the volume of air exhaled from the lungs in the first second of forced expiration as measured by spirometry. Baseline values ​​were defined as the last valid, nonmissing value obtained within 28 days before the participant received their first study medication. EOT visits were conducted within 3 days after the participant's last dose of study medication. Time frames: baseline, Day 1 of cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 67, EOT (i.e., any time point up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0170] [Table 40]

[0171] [Table 41]

[0172] [Table 42]

[0173] [Table 43]

[0174] [Table 44]

[0175] [Table 45]

[0176] [Table 46]

[0177] [Table 47]

[0178] [Table 48]

[0179] Change from baseline in percent predicted forced vital capacity (FVC) at each specified time point. FVC was the total volume of air (in liters) exhaled from the lungs during a pulmonary function test measured by spirometry, which assesses changes in lung function related to disease state. Baseline values ​​were defined as the last valid, non-missing value obtained within 28 days before the participant received their first study medication. EOT visits were conducted within 3 days after the participant's last dose of study medication. Time frames: baseline, Day 1 of cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 67, EOT (i.e., any time point up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0180]

Table 49

[0181]

Table 50

[0182]

Table 51

[0183]

Table 52

[0184]

Table 53

[0185]

Table 54

[0186]

Table 55

[0187]

Table 56

[0188] Change from baseline in percent predicted hemoglobin (HGB) corrected diffusing capacity of the lung for carbon monoxide (DLco) at each specified time point. DLco is a measure of the lung's ability to transfer gas from the air to the blood. Change from baseline in diffusing capacity of the lung for carbon monoxide (corrected percent predicted hemoglobin level) was reported for this measure. Baseline value was defined as the last valid non-missing value obtained within 28 days before the participant received their first study medication. EOT visits were conducted within 3 days after the participant's last dose of study medication. Time frames: baseline, Day 1 of cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 67, EOT (i.e., any time point up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0189] [Table 57]

[0190] [Table 58]

[0191] [Table 59]

[0192] [Table 60]

[0193] [Table 61]

[0194] [Table 62]

[0195] [Table 63]

[0196] Change from baseline in percent predicted total lung capacity (TLC) at each specified time point. TLC is the volume of air in the lungs during maximal inspiratory effort. Baseline values ​​were defined as the last valid nonmissing value obtained within 28 days before the participant received their first study medication. EOT visits were conducted within 3 days after the participant's last dose of study medication. Time frames: baseline, Day 1 of cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 67, EOT (i.e., any time point up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0197] [Table 64]

[0198] [Table 65]

[0199] [Table 66]

[0200] [Table 67]

[0201] [Table 68]

[0202] [Table 69]

[0203] [Table 70]

[0204] Change from baseline in percent predicted residual volume (RV) at each specified time point. RV is the amount of air remaining in the lungs after maximal forced expiration. Baseline values ​​were defined as the last valid, nonmissing value obtained within 28 days before the participant received their first study medication. EOT visits were conducted within 3 days after the participant's last dose of study medication. Time frames: baseline, Day 1 of cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 67, EOT (i.e., any time point up to 64.2 months). Analyses were performed on the mITT population, where "number analyzed" = participants with data available for each category specified. Here, "0" in the number analyzed field means that none of the participants were available for analysis at the specified time point. Data are shown in the table below.

[0205]

Table 71

[0206]

Table 72

[0207]

Table 73

[0208]

Table 74

[0209]

Table 75

[0210]

Table 76

[0211]

Table 77

[0212]

Table 78

[0213] Pharmacokinetics (PK): Pharmacokinetic (PK) Maximum plasma concentration (Cmax): Maximum plasma concentration (Cmax) of belmosudil and its metabolites (KD025m1 and KD025m2). Cmax was the maximum plasma concentration obtained by non-compartmental analysis. Cmax data for belmosudil and its metabolites KD025m1 and KD025m2 are reported for this outcome measure. Time frame: Cycle 1 and 2: Pre-dose (0 hours), 1, 2, 3, 4, 5 and 6 hours post-dose on Day 1. Analysis was performed on the PK population including all participants who received at least one dose of study drug and had at least one post-dose PK sample taken, where "number analyzed" = participants with data available for each category specified. Data are presented in the table below.

[0214] [Table 79]

[0215] [Table 80]

[0216] Pharmacokinetics (PK): Time of maximum plasma concentration (Tmax) of belmosudil and its metabolites (KD025m1 and KD025m2). Tmax was defined as the time to reach maximum plasma concentration obtained by non-compartmental analysis. Tmax data for belmosudil and its metabolites KD025m1 and KD025m2 are reported in this outcome measure. Time frames: Cycle 1 and 2: pre-dose (0 hours), 1, 2, 3, 4, 5 and 6 hours post-dose on Day 1. Analysis was performed on the PK population, where "number analyzed" = participants with data available for each category specified. Data are shown in the table below.

[0217] [Table 81]

[0218] [Table 82]

[0219] Pharmacokinetics (PK): Area under the plasma concentration vs. time curve for belmosudil and its metabolites (KD025m1 and KD025m2) from 0 to 6 hours post-dose (AUC0-6h). AUC0-6h was defined as the area under the plasma concentration vs. time curve from time 0 to 6 hours post-dose obtained by non-compartmental analysis from concentration-time data. AUC0-6h data for belmosudil and its metabolites KD025m1 and KD025m2 are reported in this outcome measure. Time frames: Cycle 1 and 2: pre-dose (0h), 1, 2, 3, 4, 5 and 6h post-dose on day 1. Analysis was performed on the PK population, where "number analyzed" = participants with available data for each category specified. Data are shown in the table below.

[0220] [Table 83]

[0221] [Table 84]

[0222] Example 2: Phase II randomized trial of Belmosudil Eligibility Eligible subjects were allogeneic hematopoietic cell transplant recipients ≥12 years of age with persistent cGVHD symptoms after receiving 2–5 previous lines of systemic therapy. Subjects were required to have received 2 weeks of stable corticosteroid therapy and had a Karnofsky or Lansky Performance Status Scale score ≥60 prior to screening. Specific concomitant immunosuppressive medications were permitted as no drug-drug interactions were anticipated. Subjects were excluded if they had recurrence of underlying malignancy, had a forced expiratory volume in 1 second (FEV1) of ≤39% or an NIH pulmonary symptom score of 3, developed post-transplant lymphoproliferative disease, had hepatic transaminases (aspartate aminotransferase [AST] or alanine transaminase [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.

[0223] Study Design and Treatment Screening for eligibility was performed within 14 days of day 1 of cycle 1. Treatment consisted of belmosudil 200 mg daily (arm A) or 200 mg twice daily (arm B) administered orally to subjects with cGVHD (Figure 7). Randomization was stratified (1:1) by cGVHD severity and prior exposure to ibrutinib. Belmosudil was administered continuously in 28-day treatment cycles until progression of clinically significant cGVHD or progression of unacceptable 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, referred to as the 2014 NIH Consensus Criteria. After ≥ 2 weeks on belmosudil, corticosteroid therapy may be tapered at the investigator's discretion. Subjects who have not achieved a response after 12 cycles of belmosudil treatment should be discontinued in the absence of evidence of clinical benefit in the investigator's judgment.

[0224] Study Endpoints The primary endpoint was best ORR at any time, defined as the proportion of subjects achieving a complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria. All responses were assessed by the study site investigator. Secondary endpoints included duration of response (DOR), time to response, change in LSS summary score, progression-free survival (FFS), corticosteroid dose reduction, and overall survival (OS). DOR was measured from the time of initial PR or CR, from best cGVHD response to documented progression, from initial response to initiation of additional systemic cGVHD therapy, or to death. Seven-day LSS summary scores were calculated based on the developer's recommendations and compared with scores from baseline. An improvement of ≥7 pts was considered clinically meaningful. FFS was defined as the interval between initiation of belmosudil and addition of new cGVHD therapy, relapse, or NRM. The safety of Belmosudil was evaluated by adverse event (AE) and serious AE (SAE) assessments. Relative dose intensity (RDI) was used as a surrogate measure of drug tolerability and was defined as actual dose intensity / planned dose intensity, where dose intensity was defined as the cumulative dose (mg / d) over the exposure period. Actual dose intensity captured the sum of the actual doses received during the exposure period and incorporated dose reductions and / or interruptions.

[0225] statistical analysis Sample size was based on the primary efficacy endpoint (best ORR), with one planned interim analysis and a target ORR of 55%. With 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 yield a 95% confidence interval (CI) for the ORR excluding 30% as a lower bound. Based on discussion with key opinion leaders, an ORR of 30% was considered clinically meaningful in this heavily pretreated population with cGVHD and unmet medical need. The Hochberg procedure was used for multiplicity adjustment of the primary endpoint of best ORR. The primary analysis was performed using the modified intention-to-treat (mITT) population, defined as randomized subjects who received ≥1 dose of belmosudil. After enrolling 126 subjects in the mITT population, interim, primary, and follow-up analyses were planned at approximately 2, 6, and 12 months, respectively. Here, we report the results of the 12-month analysis. CIs were calculated using the Clopper-Pearson interval (exact) method.

[0226] result Subject characteristics A total of 132 subjects were enrolled in the clinical trial. Overall, baseline demographic and clinical characteristics were comparable across treatment arms (Table 30). At enrollment, the median subject age 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 subjects had moderate cGVHD at screening, 67% had severe cGVHD, and 52% had ≥4 organ involvement. Thirty-six percent of subjects had pulmonary involvement at baseline, and 38% of these subjects had an NIH pulmonary symptom score of 2. Subjects had been previously treated with a median of 3 lines of systemic therapy. Seventy-two percent (n=79) of subjects had cGVHD refractory to their 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 equivalents (range, 0.03-1.07). The mean baseline corticosteroid dose was 0.25 mg / kg / day of prednisone equivalents (range, 0.03-1.07).

[0227] [Table 85]

[0228] [Table 86]

[0229] [Table 87]

[0230] A CONSORT diagram (Figure 7) shows subject disposition. Median treatment duration was 10 months (range, 0.4-22.0), and median follow-up was 14 months (range, 1-22). Forty-four percent of subjects were on treatment for ≥12 months. At the time of data analysis, 37% of subjects continued to receive belmosudil. Reasons for discontinuation included progression of cGVHD (n=21), voluntary withdrawal (n=13), AE (n=16), physician decision (n=11), progression of underlying malignancy (n=5), death due to underlying malignancy or disease progression (n=4), other (n=7), and nonadherence to study drug (n=3).

[0231] Effectiveness The best ORR for belmosudil 200 mg daily and 200 mg twice daily was 74% (95% CI, 62–84) and 77% (95% CI, 65–87), respectively (Table 6). High ORR (61–85%) was observed in all subgroups (Figure 8). Pooled responses across arms unless otherwise stated. Efficacy of belmosudil was maintained regardless of prior ibrutinib (n=46) or ruxolitinib (n=38) therapy. The ORR in the subgroup with prior ruxolitinib therapy was 68% (95% CI, 51–83). The ORR (95% CI) in the subgroup with prior ibrutinib therapy was 74% (95% CI, 59–86).

[0232] [Table 88]

[0233] Best ORR, including CR, was evaluated across all affected organs. In the mITT population, organ-specific analysis demonstrated best ORR of 37% for skin, 42% for eye, 55% for mouth, 39% for liver, 26% for lung, 71% for joint / fascia, 52% for upper gastrointestinal (GI) tract, 69% for lower GI tract, and 45% for esophagus (Figure 9; Table 32). Overall, 7 subjects achieved CR in all affected organs. Among the 12 subjects with pulmonary response, 3 were scored as CR based on normalization of FEV1 (median increase, 23%; range, 18-25), with an additional 3 CRs based on reduction in NIH pulmonary symptom score of 1-0 in the absence of pulmonary function tests. Six additional subjects had a PR and either an increase in FEV1 of ≥10% (median increase for all subjects who achieved a PR, 10%; range, 0-15) or, if pulmonary function testing was unavailable, a decrease in the NIH pulmonary symptom score of 1 point. Among the 41 subjects with a cutaneous response, 11 had a decrease in sclerotic features, 15 had a decrease in body surface area involvement, and 13 had improvement in body surface area involvement and sclerotic features. Two subjects had a cutaneous response according to investigator clinical assessment, not according to the 2014 NIH consensus criteria.

[0234] [Table 89]

[0235] The overall median time to response was 5 weeks (range, 4–66) (Figure 10A). 91% of responses occurred within 6 months of treatment, with the remaining 9% of responses 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. 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 nonrelapse mortality (NRM) (7%) and relapse (3%) were observed. The most common failure event was initiation of new systemic cGVHD therapy (38%). The 2-year OS rate was 89% (95% CI, 82–93) (Figure 10C).

[0236] During treatment with belmosudil, 65% of subjects had a corticosteroid dose reduction. The mean corticosteroid dose was reduced by 45% in the mITT population, with a mean corticosteroid dose reduction of 54% in responders. 21% of subjects discontinued corticosteroid therapy. In addition, 22% of these subjects successfully discontinued calcineurin inhibitor (CNI) therapy, and 20% and 21% of subjects discontinued sirolimus and mycophenolate mofetil, respectively.

[0237] Clinically meaningful improvements (≥7-point reductions) from baseline in 7-day LSS summary scores with belmosudil 200 mg daily and 200 mg twice daily were observed in 59% and 62% of the ITT populations, respectively. Improvements were observed in 69% and 71% of responders and 29% and 33% of non-responders in the belmosudil 200 mg daily and 200 mg twice daily arms, respectively.

[0238] safety Belmosudil was well tolerated, with a median RDI of 99.7%. 81% of subjects received an RDI >95%. AEs were consistent with those expected in cGVHD patients receiving corticosteroid therapy and other immunosuppressive therapy (IST) (Table 8). Thirty-eight percent of subjects had ≥1 SAE, the most common being pneumonia (7%). The most common (≥5%) grade 3 or 4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%). Twenty-four percent of subjects had increases in liver function tests (LFTs), with 5% of subjects having increases in g-glutamyltransferase (GGT), 5% of subjects having increases in AST, 3% of subjects having increases in ALT, 3% of subjects having increases in LFTs, and 1% of subjects having increases in bilirubin at baseline. The most common liver-related AE was increases in GGT (12%). Of 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 underlying malignant disease, and 21 (16%) discontinued due to progression of cGVHD. Fourteen subjects died during the study; 2 due to multiple organ failure and infection possibly related to belmosudil, 2 due to cardiac arrest, 2 due to respiratory failure, 1 due to hemothorax resulting from lung biopsy, 1 due to acute myeloid leukemia relapse, and 6 during long-term follow-up (LTFU) (>28 days after last dose). Grade ≥3 anemia was reported in 3% of subjects, neutropenia was reported in 2% of subjects, and thrombocytopenia was reported in 2% of subjects. There was one case of Epstein-Barr viremia requiring treatment and one case of cytomegalovirus (CMV) reactivation; both were unrelated to belmosudil treatment.

[0239] [Table 90]

[0240] This study in Example 2 demonstrated promising efficacy and a favorable safety profile of belmosudil therapy in patients with steroid-refractory (SR) cGVHD. The study population, consisting of subjects with severe cGVHD with multiorgan involvement and fibrotic manifestations treated with a median of 3 prior lines of systemic therapy, achieved best ORR of 74% and 77% in the 200 mg daily and 200 mg twice daily treatment arms, respectively.

[0241] Responses to belmosudil were sustained and clinically significant, regardless of response to previous therapy, severity of cGVHD, and number of involved organs. Responses were observed in all organs, which was clinically significant because CR and PR were achieved in difficult-to-treat organs, such as the lungs and liver, as well as in organs with fibrotic manifestations, such as the skin. cGVHD significantly reduces quality of life, especially in patients with fibrotic multiorgan involvement, which can be difficult to treat. The observed CR and PR, along with improvements in LSS, limited interactions, and lack of drug toxicity, are encouraging results that demonstrate that belmosudil treatment may have the potential to improve overall patient well-being. 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, especially the eyes and lungs. The clinical benefit and tolerability of belmosudil therapy demonstrate the potential to stop the expected cycle of treatment of cGVHD seen in clinical practice. Responses lasted ≥20 weeks in 59% of responders at the 12-month analysis. Median DOR was 54 weeks in responders at the 12-month analysis.

[0242] In a patient population vulnerable to AEs and infections due to immunosuppressive therapy (IST), belmosudil was well tolerated and most subjects continued therapy to achieve clinically meaningful outcomes and improved quality of life, which could be maintained with continued treatment. Only 12% of subjects discontinued belmosudil due to possible drug-related AEs. Median duration of treatment was 10 months (range, 0.4-22.0), with 37% of subjects continuing to receive belmosudil after this time point. AEs were manageable, with few grade ≥3 SAEs attributable to belmosudil. SAE rates were comparable between the two treatment arms. Many of the current cGVHD treatment options are immunosuppressive, which may increase the risk of infection and cause hematologic toxicities, including leukopenia, anemia, and thrombocytopenia. Grade ≥3 cytopenias were present in <4% of subjects, with only one report of cytomegalovirus (CMV) reactivation unrelated to belmosudil treatment. Cytopenias and CMV infections exist 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 belmosudil.

[0243] In this study, all subjects received belmosudil. Requiring randomization to best available therapy was not appropriate because subjects had previously progressed after ≥2 lines of systemic therapy, where response rates have historically been low. Indeed, subjects in this study had already attempted a median of 3 previous lines of best available therapy for cGVHD prior to enrollment, using agents such as ECP (48%), ibrutinib (34%), ruxolitinib (29%), and rituximab (21%). The best ORR was 75% in subjects who were refractory to the last line of therapy.

[0244] Based on the similar efficacy and safety observed in this study, 200 mg daily is the preferred dose for the treatment of SR cGVHD. The 200 mg twice daily dose showed better responses in certain organs, such as the skin, and slightly fewer AEs, but the differences did not appear to be significant compared to the 200 mg daily dose.

[0245] Example 3: Combined analysis of lung-specific responses in subjects treated with Belmosudil Methods. Subjects and study design Subjects enrolled in the clinical trials described in Examples 1 and 2 served as the population for the combined analysis.

[0246] Patients with BOS were identified as follows: 1) % predicted forced expiratory volume in 1 second (%FEV1) ≦79% at enrollment, and 2) clinician attribution of pulmonary disease due to cGVHD. Subjects were excluded from the study of Example 2 if they had a %FEV1<40% or an NIH pulmonary symptom score of 3.

[0247] In Example 1, patients with known suspected pulmonary involvement had pulmonary function assessments performed at baseline and on day 1 of each cycle. In Example 2, pulmonary function assessments were performed at baseline and at the time of response assessment, on day 1 of cycles 2-5, then on day 1 of every other cycle thereafter.

[0248] The severity of cGVHD was graded according to the 2014 NIH consensus criteria. (Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015;21(3):389-401 e381). Treatment response was defined using organ-specific cGVHD response assessments as defined by the 2014 NIH consensus criteria. (Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant 2015;21(6):984-999). According to these criteria, a complete pulmonary response (CR) is defined as a normal %FEV1 after previous involvement or, in the absence of PFTs, an NIH pulmonary symptom score of 0 after previous involvement. A partial pulmonary response (PR) is defined as a 10% increase in absolute predicted %FEV1 or, in the absence of PFTs, a decrease of ≥1 point in the NIH pulmonary symptom score. Pulmonary disease progression is defined as a 10% decline in absolute predicted %FEV1 or, in the absence of PFTs, a 1-point increase (excluding 0-1) in the NIH Pulmonary Symptom Score.

[0249] The present analysis evaluated the therapeutic effect of belmosudil in subjects with BOS, taking into account the unique mechanism of ROCK2 inhibition, which may address both the inflammatory and fibrotic physiology of BOS. (Kitko CL, White ES, Baird K. Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2012;18(1 Suppl):S46-52). In addition, multiple lung-specific metrics were analyzed to better characterize the long-term changes in lung function and patient symptoms.

[0250] statistical analysis Baseline characteristics were reported descriptively. Univariate and multivariate logistic regression analyses were performed to investigate clinical factors associated with NIH pulmonary response (listed in Table 1). Correlation analyses were performed to evaluate correlations between pulmonary response metrics. All tests were two-sided with a significance level of 0.05. All analyses were performed using SAS 9.3 (SAS Institute Inc., Cary, NC) and Rv3.5.2 (CRAN Project).

[0251] Results. Subject characteristics A total of 66 subjects with BOS were identified from the clinical trials described in Examples 1 and 2. Six subjects were excluded from this analysis because they did not have subsequent pulmonary function test evaluations beyond baseline, and one subject was reclassified as not having BOS. Of the 59 evaluable subjects, 17 (29%) were enrolled in the study described in Example 1, and 42 (71%) were enrolled in the study described in Example 2. The dose of belmosudil was either 200 mg daily (n=27, 46%), 200 mg twice daily (n=23, 39%), or 400 mg daily (n=9, 15%).

[0252] Baseline demographic and clinical characteristics are shown in Table 34. Median age at enrollment was 42.5 years (range, 26-77). Allogeneic HCT was performed primarily with myeloablative conditioning (n=44, 75%) and peripheral blood stem cells (n=54, 92%) from HLA-matched donors (n=53, 90%). Median time from cGVHD diagnosis to enrollment was 22 months (range, 1-161). NIH cGVHD Global Severity Score at enrollment was moderate (n=11, 19%) or severe (n=48, 81%). Most subjects (n=39, 66%) had at least 4 organ involvement at enrollment. Median number of prior lines of systemic therapy was 3 (range, 1-6). Overall cGVHD response to lines of systemic therapy prior to enrollment was partial response (n=12, 20%), stable disease (n=25, 42%), progressive disease (n=12, 20%), or unknown (n=10, 17%). The median number of cycles of belmosudil therapy received on study was 14 (range, 1-57). At the time of analysis, 16 subjects remained on treatment. Reasons for discontinuation of belmosudil included: progressive cGVHD (n=18), adverse events (n=8), underlying disease recurrence (n=6), subject withdrawal (n=4), physician discretion (n=4), nonadherence (n=2), and death (n=1). Thirty-one subjects (53%) experienced at least one respiratory infection (any grade) during treatment, with 11 subjects experiencing ≥2 episodes. These infections were classified as upper respiratory tract infection (n=33) or pneumonia (n=13). Eleven subjects experienced grade ≥3 respiratory infections, in which case belmosudil treatment was interrupted or discontinued in six cases. With a median follow-up among survivors of 27 months (range, 1.8-55), the 2-year overall survival was 82% (95% CI: 70, 90).

[0253] [Table 91]

[0254] BOS response according to NIH criteria

[0255] [Table 92]

[0256] Patients with BOS had a % predicted forced expiratory volume in 1 second (%FEV1) of ≤79% at enrollment and clinician attribution of pulmonary disease attributable to cGVHD. The NIH cGVHD pulmonary score at enrollment was 1 (n=30, 59%), 2 (n=23, 39%), or 3 (n=6, 10%). According to NIH response criteria, the best ORR for pulmonary cGVHD was 32% (PR 17%, CR 15%), as shown in Figure 17. The median time to first NIH pulmonary response was 5 cycles (range, 3-39), while the median time to best NIH pulmonary response was 7 cycles (range, 3-41). In 3 of 19 responders, subjects met the NIH criteria for pulmonary progression (median 4 cycles: range, 3-7) before meeting a later response criterion (median 11 cycles: range, 4-21). The clinical trial described in Example 2 was designed to allow subjects to continue therapy until clinically meaningful progression occurred, thus allowing for continued administration of belmosudil.

[0257] NIH response criteria were based on %FEV1 or, in the absence of PFTs, on NIH pulmonary symptom score. NIH pulmonary response was defined by measurement of %FEV1 alone for 12 subjects (63%). In the absence of %FEV1, NIH symptom score was used to define NIH response in 5 subjects (26%). In 2 subjects, NIH response was upgraded from PR (according to %FEV1) to CR based on NIH symptom score. When assessing NIH response alone with PFTs, the best ORR for pulmonary cGVHD was 24% (PR 14%, CR 10%).

[0258] BOS response according to FEV1 assessment Trajectories of all %FEV1 assessments collected in the study are shown in Figure 16. The best change in %FEV1 from baseline is shown in Figure 12. Twenty-three subjects (39%) experienced an absolute improvement in %FEV1 from baseline of ≥ 5% during treatment with belmosudil, and 13 subjects (22%) experienced an absolute improvement in %FEV1 of ≥ 10%. A best absolute improvement in %FEV1 of ≥ 5% from baseline was observed in subjects regardless of baseline NIH pulmonary score (score 1 (n=17, 57%), score 2 (n=3, 13%), score 3 (n=3, 50%). An absolute improvement in %FEV1 of ≥ 5% from baseline was observed in 84% of responders and 18% of non-responders by NIH criteria, respectively. All 13 subjects with an absolute improvement in %FEV1 of ≥ 10% were responders by NIH criteria (as defined). For subjects with a best improvement in %FEV1 of ≥ 5%, 14 of 23 responses were maintained across two consecutive FEV1 assessments. For subjects with a best improvement in %FEV1 of ≥ 10%, 9 of 13 responses were maintained across two consecutive FEV1 assessments.

[0259] Absolute FEV1 measurements were recorded only for subjects enrolled in the study of Example 2. Fifteen subjects (36%) experienced at least a 200mL improvement in FEV1 from baseline during treatment with belmosudil. This improvement was observed only in subjects with a baseline pulmonary score of 1 (n=10, 41%) or 2 (n=5, 31%). A 200mL improvement in FEV1 from baseline was observed in 66% of responders and 19% of non-responders by NIH criteria, respectively. Nine of these 15 responses were maintained over two consecutive FEV1 assessments.

[0260] Lung Lee Symptom Scale Score The best change in pulmonary LSS score from baseline is shown in Figure 13. Following the methodology used for LSS, we identified a 10-point difference (half a standard deviation from the baseline score) as a clinically meaningful organ-specific change in this dataset. (Lee S et al. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8(8): 444-452; Teh C et al. Reliability and Validity of the Modified 7-Day Lee Chronic Graft-versus-Host Disease Symptom Scale. Biol Blood Marrow Transplant 2020; 26(3): 562-567). Forty subjects (68%) experienced a clinically significant improvement (a 10-point reduction) in LSS pulmonary score. Clinically meaningful improvements were observed in subjects regardless of baseline NIH lung score (score 1 (n=20, 66%), score 2 (n=14, 61%), score 3 (n=6, 100%). Clinically meaningful improvements were observed in 68% of responders and 68% of non-responders by NIH criteria, respectively.

[0261] Analysis of subgroups and predictors of response There was a correlation between response and baseline NIH lung score. The best ORR was 50% (PR 23%, CR 27%) with baseline NIH lung score 1, 17% (PR 13%, CR 4%) with baseline NIH lung score 2, and 0% with NIH lung score 3 (Table 36).

[0262] [Table 93]

[0263] Logistic regression analysis was performed to identify clinical factors associated with lung-specific response according to NIH criteria (Table 37). Univariate analysis identified male gender, low baseline NIH cGVHD lung score, and overall cGvHD PR to last treatment before belmozudil as predictors of response. These variables remained significant in multivariate analysis (male gender, OR 14.07, p=0.0037; NIH lung score 1, OR 5.65, p=0.028; PR to previous line of therapy, OR 7.89, p=0.024).

[0264] [Table 94]

[0265] Correlation between lung-specific response metrics Correlations between multiple metrics of BOS response were investigated (NIH criteria, NIH PFT response criteria, NIH pulmonary symptom score, absolute improvement in FEV1, pulmonary LSS score; definitions are provided in Table 35). A heat map showing the best change in pulmonary response metrics in 59 patients is shown in Figure 14. When considering the association between NIH pulmonary score (score 0-3) and NIH pulmonary symptom score (score 0-3), 24 pairs (41%) are concordant and 35 pairs (59%) are discordant. The NIH pulmonary symptom score is lower than the NIH pulmonary score in 32 of the 35 discordant pairs. In addition, the LSS pulmonary score does not correlate with other metrics. For best pulmonary response by NIH criteria, 12 (63.2%) of 19 responders and 27 (67.5%) of 40 non-responders (p=0.77) had at least a 10-point reduction in LSS pulmonary score. For best improvement in %FEV1, 14 of 23 (61%) with ≥ 5% %FEV1 and 25 of 36 (69%) with < 5% %FEV1 showed a clinically significant improvement in LSS pulmonary score (p = 0.58) (Figure 13).

[0266] To further evaluate the correlation between metrics, measurements from all time points captured during treatment were aggregated. Of 583 paired samples between NIH lung score (based on FEV1%) and NIH symptom score, 285 pairs (49%) were concordant and 295 pairs (51%) were discordant. Among discordant pairs, 266 pairs had lower NIH lung symptom scores and 29 pairs had higher NIH lung symptom scores (Figure 15A). This indicates that NIH lung symptom scores largely overestimate response in subjects with primarily less progressive disease. As expected, FEV1 in liters correlates better with %FEV1 and NIH lung score than with NIH lung symptom score (Figures 15G, 15B, and 15D). For example, no paired samples with NIH lung score 0 had FEV1<2L, whereas 31 of 99 paired samples with NIH lung symptom score 0 had FEV1<2L. LSS Lung Score generally showed a large dissociation with NIH Lung Score > 1 and NIH Lung Symptom Score (Figure 15E and Figure 15F). Most of the paired samples between %FEV1 and LSS Lung Score fell below the diagonal (Figure 15D), and there was a dissociation between FEV1 in liters and LSS Lung Score (Figure 15F).

[0267] The observed discordance between the NIH lung score (based on %FEV1) and the NIH symptom score suggests that the symptom score generally overestimates PFT response, primarily in subjects with less progressive disease. In addition, the LSS lung score generally dissociates significantly from the NIH lung score > 1 and the NIH lung symptom score.

[0268] In this combined analysis of the studies of Examples 1 and 2, in a population with primarily less progressive disease, belmosudil was associated with a best ORR of 32% for BOS according to the 2014 NIH response criteria. Response rates were inversely proportional to NIH cGVHD lung score, with the highest response rates in subjects with a baseline lung score of 1. No responses were observed for subjects with a baseline lung score of 3. Furthermore, both low baseline NIH cGVHD lung score and overall cGVHD partial response to previous lines of systemic therapy before enrollment were associated with higher rates of organ-specific responses in multivariable analysis. This highlights the importance of initiating treatment of patients at an early stage of disease, whereas more advanced disease may have irreversible fibrotic changes and lung destruction. In subjects with responses, the median time to best response was 7 cycles (range, 3-41), suggesting that BOS may require a longer treatment period to achieve a response compared to the inflammatory-like symptoms of cGVHD. During treatment, the trajectory of FEV1 measurements is rarely linear. As noted in this analysis, only 60-70% of 5% or 10% improvements in absolute %FEV1 are achieved with successive assessments. Nevertheless, responses in FEV1 suggest clinically meaningful improvements in lung function in a subset of subjects with early forms of BOS.

[0269] In this analysis, no significant correlation was identified between measurements of FEV1 (%FEV1 or FEV1(L)) and symptom measurements (NIH symptom score or LSS lung score) in predominantly mild or moderate disease, raising the question of how such metrics might best be integrated when assessing treatment response. The first symptoms are usually late signs of BOS and may not appear until a more significant decline in lung function has occurred. Thus, the use of the NIH response criteria of the NIH symptom score in the absence of FEV1 measurements may result in an overestimation of response, especially in patients with less progressive disease. In this dataset, the NIH symptom score was used to define or improve clinical response in 7 of the 19 subjects (37%) who achieved an NIH response. In addition, the clinical meaning of the symptom score may be dependent on the clinical context. For example, in BOS, symptom measurements may carry more weight in patients with more advanced disease, in which case a significant FEV1 response may be lower. Given the limited size and lack of standardized follow-up in many cGVHD datasets, it remains unclear how individual metrics (PFTs, symptoms) and other measurements (functional assessments, biological markers) can be integrated to refine response criteria for BOS.

[0270] The data in this example demonstrate that belmosudil is associated with lung-specific clinical responses in subjects with mild to moderate BOS, including but not limited to early stage BOS.

[0271] Example 4: This example describes a Phase III study to evaluate the efficacy of oral belmosudil in adult participants with chronic pulmonary allograft dysfunction (CLAD) after bilateral lung transplantation The study will evaluate the efficacy and safety of belmosudil treatment in male or female participants aged ≥18 years with CLAD stage 1 or 2 at least one year after bilateral lung transplantation.

[0272] Eligibility Eligible patients were participants at least 18 years of age who were bilateral lung transplant recipients and had evidence of advanced CLAD stages 1 and 2 (forced expiratory volume in 1 second (FEV1) >50%-80% of peak post-transplant) with concomitant azithromycin therapy and a standard treatment regimen of immunosuppression.

[0273] Inclusion Criteria. Participants are eligible for inclusion in the study only if all of the following criteria apply: Participants must be at least 18 years old at the time of signing the informed consent. Participant types and disease characteristics: Participants ≥1 year after bilateral lung transplant at screening. Participants diagnosed with CLAD within 9 months prior to screening. Participants presenting with CLAD stage 1 or 2; FEV1 >50%-80% of PTBL at screening and randomization. Participants presenting with progressive CLAD. Participants willing to continue all standard treatments according to center protocols. Participants who have received at least 6 weeks of azithromycin after diagnosis of CLAD. Participants' body mass index ≥18 kg / m 2 .

[0274] Exclusion Criteria. Participants will be excluded from the study if any of the following criteria apply: Medical conditions: Post-transplant baseline value of FEV1 ≤ 50% (CLAD 3 and 4). Participants enrolled in other clinical trials. Participants with intolerance to belmosudil or any of its components. Any condition that may affect the ability to perform pulmonary function tests. Reduced pulmonary function that can be explained by non-CLAD causes. Diagnosed or treated for malignancy within 3 years prior to randomization, except for complete resection of basal or squamous cell carcinoma of the skin, intraepithelial malignancy, or low-risk prostate cancer after curative therapy. Untreated symptomatic gastroesophageal reflux disease (GERD). Baseline resting oxygen saturation < 88% on room air or use of supplemental oxygen at rest. Known prolongation of the QT interval (> 480 msec).

[0275] Prior / Concomitant Therapy: Participants who received treatment for CLAD other than azithromycin and standard of care immunosuppressants.

[0276] Participants were not allowed to receive any investigational drug, or any investigational device or procedure, or any prohibited treatment for this study. Participants had previous exposure to bemosudil.

[0277] Other Exclusion Criteria: Sensitivity to any of the study interventions, or components thereof, or to any drug or other allergy that in the opinion of the investigator contraindicates participation in the study. Participants with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drugs will be excluded from the study.

[0278] Study Design and Treatment Patients will receive either belmosudil or placebo during a 26-week double-blind treatment period. Participants will be treated with azithromycin and will receive continued azithromycin treatment in addition to standard of care immunosuppressive therapy. The study will evaluate the effect of belmosudil 200 mg orally QD (or 200 mg BID if participants take a strong CYP3A inducer or proton pump inhibitor) or placebo on lung function decline as assessed by the percentage of participants with lung function decline. For example, lung function decline can be assessed by the change in FEV1 over the study period.

[0279] The study consists of a 4-week screening period followed by a 26-week double-blind treatment period. After completion of the 26-week double-blind treatment period, all study participants will be offered to enroll in the OLE period of 26 weeks of belmozudil 200 mg orally (QD or BID if the participant is taking a strong CYP3A inducer or proton pump inhibitor).

[0280] Study Endpoints Endpoint Objectives: To demonstrate the efficacy of belmosudil compared to placebo in stage 1 and 2 CLAD progression after bilateral lung transplantation and to evaluate how belmosudil affects lung function in participants with CLAD; To demonstrate the efficacy of belmosudil compared to placebo on lung function as measured by FEV1 in participants with CLAD after bilateral lung transplantation, other measures of lung function such as forced vital capacity (FVC), total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO) can be used; To evaluate the effect of belmosudil on CLAD progression (time to CLAD progression during the double-blind treatment period); To evaluate the effect of belmosudil on patient-reported outcomes (PROs), such as change from baseline to week 26 in patient-reported outcomes; To evaluate the safety of belmosudil in participants with CLAD after bilateral lung transplantation (treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and laboratory results).

[0281] The present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, but the illustrations 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 by reference in their entireties.

Claims

1. A pharmaceutical composition, (a) Treatment of patients with chronic allograft lung failure (CLAD) after lung transplantation, (b) Treatment of patients with bronchiolitis obliterans (BOS) after lung transplantation, (c) A pharmaceutical composition comprising 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof, for use in the treatment of subjects having bronchiolitis obliterans (BOS) after allogeneic hematopoietic stem cell transplantation.

2. (a) The CLAD includes mild or moderate bronchiolitis obliterans (BOS), or (b) The CLAD includes restrictive allograft syndrome (RAS), The pharmaceutical composition according to claim 1 for the treatment of subjects having CLAD after lung transplantation.

3. The pharmaceutical composition according to claim 1 or 2, wherein the CLAD is stage 1 or 2.

4. The pharmaceutical composition according to claim 2 or 3, wherein the compound is administered in a dose selected from a dose equivalent to 200 mg of free base per day and 200 mg of free base twice per day.

5. The pharmaceutical composition according to claim 1, for the treatment of subjects having BOS after lung transplantation, wherein the subject has mild or moderate BOS.

6. The pharmaceutical composition according to claim 1, for the treatment of subjects having BOS after allogeneic hematopoietic stem cell transplantation, wherein the subject has mild or moderate BOS.

7. The pharmaceutical composition according to claim 5 or 6, wherein the compound is administered in a 28-day cycle.

8. Claims 5 to 7, wherein the compound is administered in doses selected from doses corresponding to 200 mg of free base per day, 200 mg of free base twice per day, and 400 mg of free base per day. A pharmaceutical composition as described in any one of the items.

9. The pharmaceutical composition according to any one of claims 5 to 8, wherein the subject has a therapeutic response in the lungs as defined by at least one of the NIH pulmonary symptom score and pulmonary function tests.

10. (a) The therapeutic response in the lung is defined by the measured value of %FEV1, and / or (b) The subject has an improvement in %FEV1 from baseline during treatment with the compound, and / or (c) The subject has an absolute improvement of ≥5% of %FEV1 from baseline during treatment with the compound, and / or (d) The subject has an absolute improvement of ≥10% of %FEV1 from baseline during treatment with the compound, and / or (e) The subject experiences an improvement of at least 200 mL of FEV1 from baseline during treatment with the compound, and / or (f) FEV1 is assessed at baseline and on day 1 of each cycle starting from day 1 of cycle 2, and / or (g) The subject has an improvement in %FEV1 from baseline during treatment with the compound, and the improvement is maintained across at least two consecutive FEV1 assessments. A pharmaceutical composition according to any one of claims 1 to 9.

11. The pharmaceutical composition according to claim 9, wherein the subject has a therapeutic response in the lung, defined by an upgrade from a partial response based on the measurement of %FEV1 alone to a complete response based on the measurement of the NIH pulmonary symptom score.

12. (a) The subject has a baseline NIH pulmonary symptom score of 1 prior to treatment with the compound, or (b) The subject has a baseline NIH pulmonary symptom score of 2 prior to treatment with the compound, or (c) The subject has a baseline NIH pulmonary symptom score of 3 prior to treatment with the compound, The pharmaceutical composition according to claim 9.

13. (a) The subject has an improvement in the NIH pulmonary symptom score during treatment with the compound, or (b) The subject has an NIH pulmonary symptom score of 0 during treatment with the compound, or (c) The subject has an NIH pulmonary symptom score of 1 during treatment with the compound, or (d) The pharmaceutical composition according to claim 9 or 12, wherein the subject has an NIH pulmonary symptom score of 2 during treatment with the compound.

14. (a) The subject has a therapeutic response in the lung as defined by the Lee Symptom Scale lung score, or (b) The subject has a reduction of at least 10 points in the Lee Symptom Scale lung subscore from baseline during treatment with the compound, A pharmaceutical composition according to any one of claims 6 to 9 and 11 to 13.

15. The subject has chronic graft-versus-host disease, and (a) At least two previous lines of systemic therapy have failed for the chronic graft-versus-host disease, or (b) Having failed two to five previous lines of systemic therapy for the chronic graft-versus-host disease, (c) Having experienced a partial response to the last treatment for graft-versus-host disease prior to the compound, or (d) The previous line of systemic therapy for chronic graft-versus-host disease has been discontinued. A pharmaceutical composition according to any one of claims 6 to 9 and 11 to 14.

16. The aforementioned prior line of systemic therapy is selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibruitinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab, and / or (a) The cGVHD is steroid-refractory (SR) cGVHD, and / or (b) The pharmaceutical composition according to claim 15, wherein the subject is receiving concomitant corticosteroid therapy, and the dose of the concomitant corticosteroid therapy is reduced after at least one cycle of the belmosdil treatment.

17. (a) The compound is administered in a 28-day cycle, and the number of cycles is in the range of 3 to 15, or (b) The number of cycles is in the range of 5 to 11, or (c) The number of cycles is in the range of 5 to 7, and / or The compound is administered in a dose selected from a dose equivalent to 200 mg of free base per day and 200 mg of free base twice per day. A pharmaceutical composition according to any one of claims 5 to 9 and 11 to 16.

18. The pharmaceutical composition according to any one of claims 6 to 8, wherein the allogeneic hematopoietic stem cell transplantation is performed using myeloablative prior treatment and peripheral blood stem cells from an HLA-matched donor.

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