Method of administering velmosdil in combination with a CYP3A inducer and / or a proton pump inhibitor

Abstract

The present disclosure relates to the co - administration of belumosudil with a CYP3A inducer and / or a proton pump inhibitor for use in the treatment of subjects having chronic graft - versus - host disease (cGVHD).

Description

Technical Field

[0001] The present disclosure relates to the use of belumosudil or a pharmaceutically acceptable salt thereof for treating a subject having chronic graft-versus-host disease (cGVHD), wherein at least one CYP3A inducer or proton pump inhibitor is co-administered to the subject.

Background Art

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

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

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

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

[0006] The management of cGVHD has continued to evolve with the emergence of targeted therapies. In 2017, the US Food and Drug Administration approved the Bruton's tyrosine kinase inhibitor ibrutinib for the treatment of adults with cGVHD after failure of one or more prior systemic therapies. In studies of patients with cGVHD who were required to have either an erythematous rash covering more than 25% of the body surface area or an NIH mouse score of more than 4, an overall response rate (ORR) of 67% and a discontinuation rate due to treatment-emergent adverse events (TEAE) of 43% were reported with ibrutinib. (Waller EK, et al: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b / 2 study. Biol Blood Marrow Transpl 25:2002-2007, 2019).

[0007] There remains an opportunity to study other treatment options for patients who have failed one or more lines of therapy.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure relates to 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the "compound" or "belumosudil") for use in the treatment of chronic graft-versus-host disease (cGVHD) in a subject, wherein at least one CYP3A inducer or proton pump inhibitor (PPI) is co-administered to the subject.

[0009] The present disclosure also provides a method for treating a subject having cGVHD who is concurrently taking a CYP3A inducer and / or a PPI, the method comprising administering to the subject a dose of belumosudil that has been adjusted to mediate the exposure-reducing effect of the CYP3A inducer and / or the proton pump inhibitor when treating cGVHD.

[0010] This embodiment can be more fully understood by referring to the detailed description and examples intended to illustrate non-limiting embodiments.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0012] Overview cGVHD is characterized by the overproduction of the pro-inflammatory cytokines IL-21 and IL-17, and the overactivation of follicular helper T cells and B cells, which in turn leads to the overproduction of antibodies. By controlling ROCK2 activity, belumosudil mediates signal transduction in immune cell function and the fibrotic pathway, thereby alleviating the effects caused by this wasting disease, such as inflammation and fibrotic changes in multiple tissues involving several organs including the lungs, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0013] In vitro evaluation suggested that the metabolism of belumosudil mainly depends on cytochrome P450 CYP3A4 activity and the solubility of belumosudil is pH-dependent. Preclinical studies in mice, rats, rabbits, and dogs showed that belumosudil undergoes liver metabolism to form two major metabolites called KD025m1 (ROCK2-active minor metabolite) and KD025m2 (ROCK2-inactive major metabolite). These major metabolites were then quantified in clinical trials throughout the belumosudil development program. The exposure of the major inactive metabolite KD025m2 was 15% - 20% of the parent, while the exposure value of the minor active metabolite KD025m1 was less than 5% of the parent.

[0014] In vitro evaluation determined that cytochrome P450 CYP3A4 is the major CYP isoform involved in the metabolism of vemurafenib. Incubation of vemurafenib with the recombinant enzyme showed that CYP3A4 is responsible for the metabolism of vemurafenib (41.9%), while CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 (<5%), CYP2C19 (<5%), and uridine diphosphate glucuronosyltransferase 1A1 may not contribute much.

[0015] Thus, to evaluate the effects of itraconazole (a CYP3A4 inhibitor), rifampicin (a CYP3A4 inducer), and rabeprazole and omeprazole (both proton pump inhibitors [PPI]) on the pharmacokinetics of vemurafenib described in Example 1, a two-part clinical drug-drug interaction study was conducted.

[0016] After a single oral dose of 200 mg of vemurafenib with itraconazole, no clinically relevant changes in vemurafenib exposure were observed; however, the exposure of the main inactive metabolite KD025m2 decreased. Conversely, the CYP3A4 inducer rifampicin significantly decreased the exposure of vemurafenib and its inactive metabolite KD025m2 and increased the exposure to the active metabolite KD025m1. Co-administration of rifampin can decrease vemurafenib Cmax by 59% and AUC by 72% in healthy subjects. Co-administration of efavirenz (a CYP3A inducer) can decrease vemurafenib Cmax by 32% and AUC by 35% in healthy subjects.

[0017] Co-administration of a single oral dose of 200 mg of vemurafenib with the PPIs rabeprazole and omeprazole significantly decreased the exposure of the parent and metabolites. In healthy subjects, co-administration of rabeprazole can decrease vemurafenib Cmax by 87% and AUC by 80%, and omeprazole can decrease vemurafenib Cmax by 68% and AUC by 47%.

[0018] The administration of both with and without the harmful compound of birmodzil was safe and no significant adverse events were reported.

[0019] Therefore, the co - administration of birmodzil and CYP3A inducers reduces birmodzil exposure. Therefore, the dosage of birmodzil should be increased when co - administered with CYP3A inducers. For example, in one embodiment, the dosage of birmodzil is increased to 200 mg twice a day or 400 mg per day when co - administered with a strong CYP3A inducer.

[0020] The co - administration of birmodzil and proton pump inhibitors (PPIs) also reduces birmodzil exposure. The dosage of birmodzil can be increased when co - administered with proton pump inhibitors. For example, in one embodiment, the dosage of birmodzil is increased to 200 mg twice a day or 400 mg per day when co - administered with proton pump inhibitors.

[0021] Definitions As used herein, "about" includes the exact amount modified by the term "about" and amounts expected to be within experimental error, such as within 15%, 10%, or 5%. For example, "about 200 mg" means "200 mg" and also means the range of mg within experimental error, such as ± 15%, 10%, or 5% of 200 mg. As used herein, the term "about" can be used to modify ranges and specific values.

[0022] As used herein (e.g., with reference to the administration of an API, including the "co - administration" of one or more APIs, such as a compound, vermox, PPI, and / or a CYP3A inducer, to a subject), "administer" or "administered" refers to the act of prescribing a medicament containing one or more APIs for a subject to ingest during treatment, the act of prescribing a protocol for a medicament for a subject to ingest, the act of dispensing a medicament to a subject, and / or the act of physically receiving or ingesting a medicament. Thus, an API (e.g., a compound, vermox, PPI, and / or a CYP3A inducer) can be "administered" by a physician or other healthcare professional who writes a prescription for any one of such medicaments. And / or by a pharmacist who dispenses said prescription, and / or by dispensing one or more medicaments to a subject; and / or by a patient or subject who ingests the medicament and / or by their partner or caregiver who delivers the medicament to the subject.

[0023] "API" means "active pharmaceutical ingredient".

[0024] "Allogeneic hematopoietic stem cell transplantation (allo - HSCT)" and "allogeneic hematopoietic cell transplantation (allo - HCT)", also called bone marrow transplantation and stem cell transplantation, refer to the procedure of transplanting donor - derived hematopoietic cells into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some situations, cord blood can be used. The donor and recipient can be matched by the human leukocyte antigen (HLA) gene, such as siblings. The donor and recipient can be a parent and child who are half - matched (haplotype - matched).

[0025] Belmosulodzil is an orally 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. Belmosulodzil inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 μM, respectively. Belmosulodzil downregulated pro-inflammatory responses via the regulation of STAT3 / STAT5 phosphorylation and the shift of the Th17 / Treg balance in ex vivo or in vitro human T cell assays. Belmosulodzil also inhibited abnormal profibrotic signaling in vitro. In vivo, belmosulodzil showed activity in an animal model of chronic GVHD.

[0026] The compound belmosulodzil has the chemical name: 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound belmosulodzil is also known as KD025. The mesylate salt of belmosulodzil is marketed in the United States as REZUROCK™ for the treatment of patients with chronic GVHD after the failure of at least two prior lines of systemic therapy. The active pharmaceutical ingredient of REZUROCK™ has the molecular formula C 27 H 28 N6O5S and is the mesylate salt of belmosulodzil having the chemical name 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1).

[0027] The chemical structure of belmosulodzil mesylate is as follows.

Chemical formula

[0028] The method for producing belmosulodzil and the compound is described in the following US patents. US Patent No. 8,357,693, US Patent No. 9,815,820, US Patent No. 10,183,931, and US Patent No. 10,696,660.

[0029] When the term "belumosudil" is used in this specification, it should be understood that this term may include any form of the compound belumosudil as well as its pharmaceutically acceptable salts, unless the context clearly indicates otherwise. The term "belumosudil" refers to both the compound belumosudil (e.g., in free base form, amorphous form or crystalline form), the pharmaceutically acceptable salts of belumosudil, such as the mesylate form used as REZUROCK™, and any form of belumosudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

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

[0031] "Clinically recommended amount" or "clinically recommended dosage" refers to the amount or dosage of the API that has been recommended and / or approved for administration to a subject by a person of ordinary skill in the art of pharmaceutical chemistry for treating the disease state in question after clinical trials, and is described, for example, in publications, clinical trial results, and approved drug labels. In one embodiment, as shown in the drug label of velmosdil, the clinically recommended dosage of velmosdil without the administration of a CYP3A inducer or PPI is 200 mg once a day.

[0032] As used herein with respect to the administration of velmosdil with a CYP3A inducer and / or PPI, "co-administration", "in combination with", and / or "co-administered" means that during the course of treating a patient with velmosdil, the patient has also received one or more dosages of one or more CYP3A inducers and / or PPIs (also referred to herein as "executing compounds"). The offending compound need not be administered simultaneously or on the same day as velmosdil, which should be considered "co-administered" under this definition. The offending compound can be "co-administered" with velmosdil simultaneously, during the several days prior to the administration of velmosdil, and / or during the course of treatment. As described in Example 1, if there is a washout period sufficient to account for at least five half-lives of the active moiety administered between doses, the offending compound is not considered to have been "co-administered" or "administered in combination" with velmosdil.

[0033] As used in the claims and embodiments herein, "compound" is synonymous with the above inclusive definition of velmosdil where the context of use is clear.

[0034] As used herein with respect to the administration of an API (e.g., when applied to a CYP3A inducer and / or PPI administered "simultaneously" with velmosdil), "co-administration", "simultaneously", and / or "take simultaneously" are synonymous with "co-administered" as defined above.

[0035] "CYP3A" refers to the CYP3A family of p-450 isoenzymes, including CYP3A4. Examples of CYP3A inducers may include glucocorticoids, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampin (rifamycin), fosphenytoin, lumacaftor, lumacaftor-ivacaftor, mitotane, and St. John's wort. CYP3A inducers may include phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, estradiol, eslicarbazepine, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, rifapentine, and sotorasib. Further CYP3A inducers may include armodafinil, modafinil, and rufinamide. In some embodiments herein, the CYP3A inducer is considered a strong CYP3A inducer. Examples of strong CYP3A inducers include rifampicin and phenytoin.

[0036] As used herein, the "exposure reduction effect" or "exposure reduction effect" refers to the effects of CYP3A and PPI compounds on vemurafenib PK, e.g., the exposure levels (overall and peak) of vemurafenib and its metabolites, and the elimination rates of vemurafenib and its major metabolites, KD025m1 and KD025m2. For an exemplification of the term "exposure reduction effect", further refer to Example 1 and Figures 2A-4B herein.

[0037] As used herein, a high-fat, high-calorie diet means a diet in which about 50% of the total calorie content of the diet contains about 800 to 1,000 calories from fatty foods. For example, in one embodiment, a high-fat breakfast may consist of hash browns, bacon, fried eggs, white bread, and 240 mL of whole milk.

[0038] The Lee Symptom Scale (LSS) summary score measures the impact on a patient's function and health. The Lee Symptom Scale is a 30-item scale developed to measure the symptoms of cGVHD, as described in Lee SJ et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease. Biol Blood Marrow Transplant 2002;8:444-452.

[0039] "Line of treatment" or "treatment line" describes the order or sequence in which different treatments are given to a patient as their disease progresses. The first treatment (primary treatment) may not work or may stop functioning after a certain period. After the first-choice treatment is discontinued, a second, different treatment (second-choice treatment) may be administered. Subsequent treatment lines may be administered if the second treatment does not work or stops functioning. Some patients may receive multiple treatment lines over the course of their disease.

[0040] The first-choice treatment for moderate to severe chronic graft-versus-host disease (cGVHD) as defined by the National Institutes of Health (NIH) in the United States can be corticosteroids alone, or in combination with sirolimus or a calcineurin inhibitor. (Carpenter PA, et al.: A phase II / III randomized, multicenter trial of prednisone / sirolimus versus prednisone / sirolimus / calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 103:1915-1924, 2018).

[0041] Examples of corticosteroid therapy for the treatment of cGVHD include, but are not limited to, prednisone, prednisolone, methylprednisolone, and budesonide. Examples of prior systemic therapy for treating cGVHD include, but are not limited to, prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib, and ofatumumab.

[0042] "Immunosuppressive therapy" (IST) refers to a therapy typically administered for at least 6 months after allogeneic - HSCT in an attempt to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine.

[0043] "Myeloablative transplantation" refers to a transplantation process that uses very high - dose chemotherapy or radiation prior to transplantation with autologous or allogeneic hematopoietic stem cells. Myeloablative - free transplantation or reduced - intensity transplantation includes patients having less - potent chemotherapy prior to transplantation with allogeneic hematopoietic stem cells.

[0044] The "NIH Lung Symptom Score" or "NIH cGVHD Lung Score" is a clinical - symptom - based score in the range of 0 - 3. Score 0 is used for no symptoms, score 1 is used for shortness of breath on stairs, score 2 is used for shortness of breath on flat ground, and score 3 is used for shortness of breath at rest or shortness of breath requiring oxygen.

[0045] "Or" is used in an inclusive sense (equivalent to "and / or") unless the context requires otherwise.

[0046] As used herein, "patient" or "subject" includes animals or humans. In one embodiment, the term "patient" refers to a human subject.

[0047] As used herein, the term "pepetitor compound" refers to a compound investigated for its co - administration effect, such as a CYP3A inducer and a PPI.

[0048] As used herein, "protocol" refers to a method or plan used to administer one or more APIs to a subject in need of treatment. The term "protocol" is intended to encompass the overall and detailed plan for a patient's care, as well as the individual or partial steps that are part of the overall plan. For example, a protocol may include the dosage used for each API that a patient receives (or will receive), the combination of APIs that a patient receives, the timing and method of administration of each API (e.g., taking into account DDI, the effect of food, and the effect that different formulations or delivery modes may have on absorption and bioavailability), as well as the management of side effects, and the overall plan that includes the dosage, combination, timing and method of administration, and side effects considered together.

[0049] "Proton pump inhibitor" or "PPI" refers to a drug that inhibits the gastric H + / K + ATPase proton pump and causes a decrease in gastric acid production. Since PPIs decrease gastric acid production, they can increase the gastric pH that affects the solubility and potentially the bioavailability of orally delivered pharmaceuticals. Examples of PPIs include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and silaprazole.

[0050] "Steroid - resistant" (SR) cGVHD is defined as the progression of cGVHD during steroid or corticosteroid administration. In one embodiment, prednisone is being administered.

[0051] "Standard treatment conditions" refers to the treatment and / or dosing plan for administering belumosudil to a patient for the treatment of cGVHD, and a CYP3A inducer or PPI is also not co - administered to the patient during the course of treatment according to the above definition of "co - administered".

[0052] The "therapeutically effective amount" of the API means an amount sufficient to effect treatment of the disease state being treated when administered to a human for treating a disease (e.g., cGVHD). When applied to cGVHD in humans, "treating" or "treatment" includes (1) reducing the risk of developing cGVHD and / or inhibiting cGVHD, i.e., arresting or reducing the development of cGVHD or its clinical symptoms. (2) reducing cGVHD, i.e., causing regression, remission or improvement of cGVHD, or reducing the number, frequency, duration or severity of its clinical symptoms.

[0053] The therapeutically effective amount of the API can vary depending on the health and condition of the subject being treated, the degree of disease progression, the assessment of the medical situation, and other relevant factors. It is expected that the therapeutically effective amount can be within the range that can be determined through testing and with reference to clinical trial data and results, as described, for example, in Examples 1 and 3 of this specification and in the scientific literature.

[0054] Exemplary embodiments In some embodiments, provided is belumosudil or a pharmaceutically acceptable salt (compound) thereof for use in the treatment of chronic graft-versus-host disease (cGVHD) in a subject, wherein at least one CYP3A inducer or proton pump inhibitor (PPI) is co-administered to the subject.

[0055] In another embodiment, at least one CYP3A inducer is co-administered to a subject simultaneously with velmosimil. In another embodiment, the CYP3A inducer is a glucocorticoid, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampin (rifampicin), fosphenytoin, lumacaftor, lumacaftor, lumacaftor-ivacaftor, mitotane, St. John's wort, phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, estradiol, eslicarbazepine, lorlatinib, mitapivat, modafinil, nafcillin, peqidartinib, rifabutin, rifapentine, sotorasib, armodafinil, or rufinamide.

[0056] In another embodiment, the CYP3A inducer is a CYP3A4 inducer.

[0057] In another embodiment, the CYP3A inducer is a potent CYP3A inducer. In one embodiment, the potent CYP3A inducer is rifampicin or phenytoin.

[0058] In another embodiment, the CYP3A4 inducer is phenobarbital, phenytoin, rifampicin, St. John's wort or a glucocorticoid.

[0059] In another embodiment, the CYP3A4 inducer is rifampicin.

[0060] In another embodiment, the PPI is co-administered to a subject simultaneously with velmosimil.

[0061] In another embodiment, the PPI is omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole or silaprazole.

[0062] In another embodiment, the PPI is rabeprazole or omeprazole.

[0063] In another embodiment, the dose of velmosimil by co - administration disclosed herein is about 400 mg per day. In other embodiments, the dose of the compound (velmosimil) is administered twice a day at about 200 mg each time for a total daily dose of about 400 mg. In other embodiments, the dose of the compound (velmosimil) ranges from about 400 mg to 800 mg per day. In other embodiments, the dose of the compound (velmosimil) is 400 mg per day, 400 mg twice a day, or 800 mg per day.

[0064] In some embodiments, the dose of the compound is increased beyond the clinically recommended dose of the compound for a subject under standard treatment conditions in order to mediate the exposure - reducing effect of a co - administered CYP3A inducer and / or PPI.

[0065] In another embodiment, a method of co - administering the CYP3A inducer rifampicin with velmosimil is provided, wherein the exposure - reducing effect of rifampicin is characterized by a decrease of about 59% of the Cmax of velmosimil and / or about 72% of the AUC of velmosimil.

[0066] In another embodiment, a method of co - administering the CYP3A inducer efavirenz with velmosimil is provided, wherein the exposure - reducing effect of efavirenz is characterized by a decrease of about 32% of the Cmax of velmosimil and / or about 35% of the AUC of velmosimil.

[0067] In another embodiment, a method of co - administering a PPI (e.g., omeprazole, rabeprazole) with velmosimil is provided, which has an exposure - reducing effect characterized by a decrease in the Cmax and / or AUC of velmosimil substantially as shown in Table 4 herein.

[0068] In another embodiment, a method of co-administering a PPI and / or a CYP3A inducer with vemurustat, wherein the CYP3A inducer is rifampicin administered at a daily dose in the range of about 10 to 20 mg / kg depending on the weight of the subject is provided. And / or the CYP3A inducer is rifampicin administered at a dose of about 600 mg per day for about 5 to 9 days; or the PPI is omeprazole administered at a dose of about 20 mg to 120 mg per day; or the PPI is omeprazole administered at a dose of 20 mg per day; or the PPI is rabeprazole administered at a dose of about 5 to 40 mg per day; or the PPI is rabeprazole administered at a daily dose of 20 mg administered twice a day.

[0069] In some embodiments, the use or method includes a treatment cycle of sequentially administering a CYP3A inducer or a PPI on days when the subject does not receive a dose of the compound (vemurustat). In some embodiments, the CYP3A inducer or PPI is administered prior to administration of the compound.

[0070] In some embodiments, the use or method includes a treatment cycle in which a CYP3A inducer or a PPI is administered substantially simultaneously with a dose of the compound (vemurustat).

[0071] In some embodiments, a method of administering a compound (or vemurustat) to a subject is provided, which includes administering a high-fat and high-calorie diet within about 1 hour before administration of the compound. In some embodiments, within about 30 minutes or less; in some embodiments, 30 minutes to 1 hour before compound administration.

[0072] In some embodiments, a method of treating chronic graft-versus-host disease (cGVHD) in a subject taking a CYP3A inducer or a proton pump inhibitor (PPI) simultaneously is provided, which includes administering a therapeutically effective amount of besimostat mesylate salt to a subject in need thereof.

[0073] In some embodiments, a method for treating a subject having cGVHD is provided, a) determining whether the subject requires treatment with at least one CYP3A inducer or PPI, and if so, determining the dosage thereof; b) calculating a therapeutically effective dosage of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof for the subject under standard conditions; and c) determining an up - adjusted dosage of the compound to be administered to the subject to mediate the exposure - reducing effect of the CYP3A inducer and / or proton pump inhibitor when treating cGVHD.

[0074] In some embodiments, provided is a method of administering vemurafenib at a dosage adjusted to account for the exposure - reducing effect of a PPI and / or CYP3A inducer, wherein the exposure - reducing effect is characterized by a decrease of about 30% to 90% in vemurafenib Cmax. In some embodiments, the exposure - reducing effect is characterized by a decrease of about 30% to 80% in vemurafenib Cmax; in some embodiments, the exposure - reducing effect is characterized by a decrease of about 35% to 75% in vemurafenib Cmax; in some embodiments, the exposure - reducing effect is characterized by a decrease of about 55% to 90% in vemurafenib Cmax; in some embodiments, the exposure - reducing effect is characterized by a decrease of about 60% to 90% in AUC; in some embodiments, the exposure - reducing effect is characterized by a decrease of about 55% to 85% in vemurafenib AUC; in some embodiments, the exposure - reducing effect is characterized by a decrease of about 40% to 60% in vemurafenib AUC.

[0075] In some embodiments, provided is a method of treating chronic graft - versus - host disease (cGVHD) in a subject taking a CYP3A inducer or a proton pump inhibitor (PPI) concomitantly, the method comprising administering to the subject in need thereof a protocol that mediates the exposure - reducing effect of the CYP3A inducer or PPI, and taking into account the food effect.

[0076] In some embodiments, the subject being treated has undergone allogeneic hematopoietic stem cell transplantation (HSCT) that is matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplantation is haploidentical HSCT.

[0077] In some embodiments, the belumosudil treatment is continued based on the patient's tolerance until the active cGVHD symptoms resolve or progress. The number of treatment cycles and duration depend on the patient. In some embodiments, belumosudil is administered to the patient in one or more 28-day cycles. In some embodiments, the number of cycles is from 3 to 15. In some embodiments, the number of cycles ranges from 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 ranges from 5 to 11. In some embodiments, the number of cycles ranges from 6 to 12. In some embodiments, the number of cycles ranges from 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the number of cycles is from 5 to 7. In some embodiments, the number of cycles ranges from 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.

[0078] In some embodiments, the number of cycles ranges from 3 cycles until loss of response. In some embodiments, the number of cycles ranges from 4 cycles until loss of response. In some embodiments, the number of cycles ranges from 5 cycles until loss of response. In some embodiments, the number of cycles ranges from 6 cycles until loss of response. In some embodiments, the number of cycles ranges from 7 cycles until loss of response. In some embodiments, the number of cycles ranges from 8 cycles until loss of response. In some embodiments, the number of cycles is more than 3, 4, 5, 10, 15, 20, 25, or 30, or until the desired response is achieved.

[0079] In some embodiments, the subject experiences improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences at least a 7-point decrease in the LSS score. In some embodiments, the subject experiences at least a 10-point decrease in the LSS score. In some embodiments, the improvement is maintained over at least two consecutive evaluations. In some embodiments, the LSS score is evaluated on the first day of each cycle starting from the baseline and the first day of cycle 2.

[0080] 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, or at least five prior lines of systemic therapy for chronic graft-versus-host disease.

[0081] In some embodiments, the subject experienced a complete response to the last treatment for graft-versus-host disease prior to belumosudil. In some embodiments, the subject experienced a partial response to the last treatment for graft-versus-host disease prior to belumosudil. In some embodiments, stable disease during the last treatment for graft-versus-host disease prior to belumosudil.

[0082] In some embodiments, prior lines of systemic therapy for chronic graft-versus-host disease have been discontinued.

[0083] 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.

[0084] In some embodiments, the cGVHD is steroid-refractory (SR) cGVHD. In some embodiments, the subject is refractory to the last line of therapy prior to belumosudil treatment.

[0085] 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 belumosudil 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 belumosudil 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 belumosudil treatment. In some embodiments, the concomitant corticosteroid therapy is discontinued after at least one cycle of belumosudil treatment.

[0086] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0087] In some embodiments, the subject has involvement of at least 4 organs. In some embodiments, the subject has involvement of at least 3 organs. In some embodiments, the subject has involvement of at least 2 organs.

[0088] Tablet Belmosodecil mesylate is a yellow powder that is substantially insoluble in water. Belmosodecil tablets can be prepared for oral administration. Each tablet contains 200 mg of the free base corresponding to 242.5 mg of belmosodecil mesylate. The tablets may also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide. Each 200 mg tablet is a light yellow film-coated rectangular tablet debossed with "KDM" on one side and "200" on the other side. Store the tablets at room temperature, 20°C to 25°C (68°F to 77°F); excursions are permitted at 15°C and 30°C (59°F to 86°F).

[0089] Clinical Approval and Pharmacokinetics Based on the efficacy and safety observed in clinical trials, when belmosodecil is administered without concomitant administration of CYP3A inducers and / or proton pump inhibitors, 200 mg daily was selected as the preferred dose for the treatment of SR cGVHD. The approved drug label for belmosodecil mesylate (REZUROCK™) states that the recommended dose is 200 mg orally once daily with food.

[0090] The use of a twice-daily dose of 200 mg was well tolerated and showed a higher response in certain organs such as the skin. However, the differences compared to the 200 mg once-daily dose were not considered significant in these settings for labeling purposes.

[0091] Unless otherwise specified, the following pharmacokinetic parameters for chronic GVHD patients administered 200 mg of belumosudil once daily are shown below. The mean (coefficient of variation %, CV%) steady-state AUC and Cmax of belumosudil were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of belumosudil increased almost proportionally over the dose range of 200 and 400 mg (1 to 2 times the recommended once-daily dose). The accumulation ratio of belumosudil was 1.4.

[0092] Absorption: The median T of belumosudil at steady state max was between 1.26 and 2.53 hours after administering 200 mg of the drug once or twice daily to patients. The mean (%CV) bioavailability was 64% (17%) after a single dose of belumosudil in healthy subjects.

[0093] Dietary effect: Compared to fasting in healthy subjects, after administration of a single dose of belumosudil with a high-fat and high-calorie diet (about 50% of the total calorie content of the diet from fat, 800 to 1,000 calories), the C max and AUC of belumosudil increased 2.2-fold and 2-fold, respectively. The median of T max was delayed by 0.5 hours.

[0094] Distribution: The geometric mean volume of distribution of belumosudil after a single dose in healthy subjects was 184 L (geo CV% 67.7%). The binding of belumosudil to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6% in vitro, respectively.

[0095] Elimination, Metabolism, and Excretion: The mean (%CV) elimination half-life of vemurafenib in patients was 19 hours (39%), and the clearance was 9.83 L / hour (46%). Vemurafenib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9 in vitro. After single oral administration of radiolabeled vemurafenib to healthy subjects, 85% of the radioactivity was recovered in feces (30% unchanged), and less than 5% was recovered in urine.

[0096] The following abbreviations may be useful in considering the examples and descriptions herein.

[0097] [Table 1] Examples

[0098] Example 1: A Phase I, two-part, open-label study to evaluate the effects of itraconazole, rifampicin, rabeprazole, and omeprazole on the pharmacokinetics of vemurafenib To investigate the effects of CYP3A4 inhibitors and inducers on the pharmacokinetics (PK) of vemurafenib, a clinical drug-drug interaction (DDI) study was conducted. Itraconazole and rifampicin (CYP3A4 inhibitor and inducer, respectively) were selected as exemplary DDI candidates for this evaluation. Additionally, since the solubility of vemurafenib is pH-dependent (i.e., 0.011, 1.644, 1.433, 0.003, and 0.000 mg / mL at pH levels of 1.08, 1.6, 2.0, 6.5, and 6.8, respectively), the interaction between proton pump inhibitors (PPIs) and vemurafenib was also evaluated in this DDI study.

[0099] The primary objectives of this DDI study were as follows: (1) to determine the effects of itraconazole, rifampicin, and rabeprazole on the PK of vermoxdazole following a single oral dose of 200 mg in healthy male subjects, and (2) to determine the effect of omeprazole on the PK of vermoxdazole following administration of 200 mg twice daily (BID). The secondary objective was to provide additional information regarding the safety and tolerability of this dosing regimen in healthy males.

[0100] Study Design This was a single-site, non-randomized DDI study in 35 (Part 1) and 38 (Part 2) healthy males. The important inclusion criteria were males aged 18 to 55 years. The study was conducted in two parts: In Part 1 (Periods 1 - 4), vermoxdazole was investigated when co-administered with itraconazole, rabeprazole, and rifampicin. In Part 2, co-administration with omeprazole was studied. The study design is shown in Figure 1.

[0101] On Day 1 of each period in Part 1 (Periods 1 - 4), a single dose of 200 mg of vermoxdazole tablets was administered to 35 subjects. In Periods 2 - 4, repeated doses of 200 mg of itraconazole QD, 20 mg of rabeprazole BID, or 600 mg of rifampicin QD were also administered for several days prior to vermoxdazole administration and co-administered with vermoxdazole on Day 1 (for itraconazole and rabeprazole only). At least a 2 - 8 day washout occurred between each period to account for at least 5 half-lives of the active moiety administered in the previous period. On Day 1 of each period in Part 2 (Periods 1 and 2), 200 mg of vermoxdazole tablets BID (12-hour intervals) were administered to 38 separate subjects. During Period 2, repeated doses of 20 mg of omeprazole QD were given for 3 days prior to vermoxdazole administration and with the Day 1 vermoxdazole dose.

[0102] In both study parts, the subjects were fasted overnight before belsomra administration. Before administering belsomra, a standard breakfast consisting of 1 bowl of cereal, 200 mL of semi-skimmed milk, and 1 croissant or roll containing pre-packaged jam was prepared. Since administration with food results in a decreased rate and increased extent of absorption as described in Example 2, all belsomra doses were administered 30 minutes after the start of the meal.

[0103] Sample collection and analysis In each period of Part 1 and Part 2, blood samples were taken for the analysis of belsomra, KD025m1, and KD025m2 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing. Additional blood samples were collected in Part 2 at 12.5, 13, 13.5, 14, 15, 16, 17, 18, 20, and 22 hours after belsomra administration. Blood samples were collected into 6 mL K3EDTA tubes and processed within 30 minutes of collection. The resulting plasma was then frozen within 90 minutes of collection and stored at 70 °C until shipment to the bioanalytical laboratory.

[0104] Belsomra and its two metabolites (KD025m1 and KD025m2) were prepared for sample analysis using the protein precipitation method and quantified by liquid chromatography using tandem mass spectrometry (LC-MS / MS) methods that were validated from 10 to 5000 ng / mL. A co-administration study was conducted to demonstrate that the presence of itraconazole, rabeprazole, rifampicin, and omeprazole did not affect the quantification of belsomra in human plasma, although the concentrations of the offending compounds were not quantified.

[0105] Statistical data analysis The sample size calculation was based on the following assumptions. 1) Intra-subject variability of 50% for C max and 40% for AUC las t based on the food effect; 2) A type 1 error of 0.05 for C max and AUC last90% confidence interval (CI) for; 3) Acceptance interval 70.00 - 143.00%; 4) Assuming the true ratio is between 95.00 and 105.00, 80% of the powder. Based on these assumptions, C, the PK parameter with the highest variability max It was estimated that 34 subjects evaluable for were required.

[0106] The PK population was defined as subjects who had received at least one dose of vermoxdyl and had at least one valid post - dose concentration for PK parameter estimation. Furthermore, subjects had to meet the following criteria for at least one analyte profile: 1) No missing samples at critical time points (e.g., near C max ), 2) No protocol deviations that would affect the study objectives regarding PK endpoints, and 3) No related AEs suggesting that not all doses were absorbed, such as vomiting. The PK analysis dataset was a subset of the relevant PK population and included subjects with a sufficiently valid PK profile that completed both the test (vermoxdyl + investigational compound) and reference (vermoxdyl alone) treatment periods to enable relevant treatment comparisons.

[0107] The PK parameters of plasma vermoxdyl, KD025m1, and KD025m2 were calculated using the standard non - compartmental method in Phoenix WinNonlin (v8.0). The primary PK parameters were C max , AUC last and AUC inf for vermoxdyl and its major metabolite.

[0108] To evaluate the effect of each investigational compound on vermoxdyl PK (the primary evaluation item of this study), C max , AUC last and AUC infA formal statistical analysis was performed. Using berberine 200 mg QD alone as the reference and berberine 200 mg QD + the incriminated compound (itraconazole, rifampicin, rabeprazole or omeprazole) as the test, pairwise treatment comparisons were made. For each comparison, the PK parameters were natural logarithm-transformed and analyzed using mixed-effect modeling that included treatment as a fixed effect and subject as a random effect. The adjusted geometric mean ratio (GMR) and the corresponding 90% CI were calculated. For berberine C max , AUC las t and AUC inf , if the 90% CIs were within the acceptance interval of 70.00 - 143.00%, it was concluded that there was no effect of the incriminated compound on berberine PK.

[0109] Safety The safety and tolerability of berberine were secondary evaluation items of this study and were evaluated by AE, vital signs, physical examination, electrocardiogram (ECG) and clinical tests. All subjects who received at least one dose of berberine or the vehicle compound were included in the safety population.

[0110] Results Subject disposition and demographics A total of 35 healthy males were enrolled and administered in Part 1 of the study. Five subjects were prematurely discontinued due to the consent or discretion withdrawal of the principal investigator (non-compliance with the protocol / positive drug test) and did not receive all four treatments. In Part 2 of the study, a total of 38 healthy males were enrolled and completed both treatment periods. Table 1 further shows the subject disposition of the study.

[0111]

Table 2

[0112] The age range of the subjects was 20 to 55 years old in Part 1 and 18 to 52 years old in Part 2, and the median ages were approximately 34 years old and 30 years old, respectively. All subjects were within the protocol-specified body mass index (BMI) range of 21.1 kg / m to 32.2 kg / m. The majority of the 2 subjects were white. For each test exclusion criterion, the study participants were not current smokers, and all had an alcohol intake of 0 to 20 units per week. The demographic statistics of the study are further shown in Table 2.

[0113]

Table 3

[0114] Drug-drug interaction The PK parameters when administering vemurafenib alone and in combination with itraconazole, rabeprazole, rifampicin, and omeprazole are shown in Tables 3A to 3C for the analyte vemurafenib (Table 3A), KD025m2 (Table 3B), and KD025m1 (Table 3C). The results of the statistical analysis conducted to evaluate the drug interaction between vemurafenib and each formulation are shown in Table 4.

[0115] Tables 3A - 3C: PK parameters of vemurafenib after administration with and without CYP3A compounds and PPIs

[0116]

Table 4

[0117]

Table 5

[0118]

Table 6

[0119]

Table 7

[0120]

Table 8

[0121] Effect of Itraconazole After administration of 200 mg of vermoxdyl (QD × 9 days) with or without 200 mg of itraconazole, vermoxdyl was rapidly absorbed. T max The median of was observed 3 hours after dosing for both with and without itraconazole (Figure 2A). Co - administration of itraconazole and vermoxdyl resulted in 1.2 - fold of the geometric mean C max , AUC last and AUC inf values, and the 90% CI of the GMR was within the relative bioavailability limit of 70.00 - 143.00% (Table 4). Co - administration of itraconazole did not appear to shorten or prolong the elimination half - life of vermoxdyl. The concentration of metabolite KD025m1 decreased to levels below quantitation in all subjects except one after co - administration of vermoxdyl and itraconazole. Similarly, KD025m2 exposure decreased by 35%, 33% and 33% for C max , AUC last and AUC inf respectively (Tables 3A - 3C).

[0122] Effect of Rifampicin Administration of 200 mg of vermoxdyl (QD × 9 days) with or without 600 mg of rifampicin resulted in rapid absorption of vermoxdyl, and the median of T max was observed 3 hours after dosing (Figure 2A). In the presence of rifampicin, C max , AUC last and AUC infwere approximately 59%, 72%, and 72% lower, respectively, than those of single - dosed velmosdil, resulting in reduced peak and overall velmosdil exposure levels. Co - administration of rifampicin also decreased the elimination half - life of velmosdil from a geometric mean of 7.89 hours without rifampicin to 2.17 hours with rifampicin. Compared to velmosdil alone, rifampicin increased the exposure of metabolite KD025m1 (C max and AUC last ) by 129% and 150%, respectively, and decreased the exposure of metabolite KD025m2 from 55 to 67%.

[0123] Effect of PPI rabeprazole and omeprazole After co - administration of a single 200 - mg dose of velmosdil and 20 mg of rabeprazole, a PPI, the median Tmax was delayed by 2 hours (Figures 2A and 2B), and the mean velmosdil exposure was approximately 87% (C max ), 82% (AUC last ), and 80% (AUC inf ) lower than when velmosdil was administered alone (Table 3A). For all parameters, the 90% CI did not fall within the limits of relative bioavailability in this study. Rabeprazole did not appear to affect the elimination half - life of velmosdil. Similar to velmosdil, the exposure of metabolites KD025m1 and KD025m2 decreased after co - administration of velmosdil and rabeprazole. KD025m1 levels were below the limit of quantification in all subjects except one, and KD025m2 C max and AUC last decreased by 93% and 94%, respectively, in the presence of rabeprazole.

[0124] Similarly, treatment with 20 mg of omeprazole, a PPI slightly weaker than rabeprazole, and velmosdil BID 200 mg resulted in a 1 - to 2 - hour delay in velmosdil absorption. In the presence of omeprazole, the C max of the first dose of velmosdil was 68% lower than the Cmax of velmosdil alone. AUC 0-24was 53% lower. For all primary endpoints, the 90% CI did not fall within the relative bioavailability tolerance limits of 70.00 - 143.00%. After co - administration of velmosnil with omeprazole, the concentration of KD025m1 was sparse and sporadic, and some subjects had a non - quantifiable profile after both dosing opportunities. When velmosnil was co - administered with omeprazole, the concentration of KD025m2 also decreased, and C max , 第1の用量 , C max , 第2の用量 , and AUC 0-24 decreased by approximately 73%, 57%, and 63% respectively.

[0125] Safety In the trial, there were no deaths or AEs leading to subject withdrawal. A total of 33 treatment - emergent AEs (TEAEs) were reported in periods 1, 2, and 4, and most of them were of mild severity (Table 3). Three AEs (all of mild severity) were considered possibly related to velmosnil: abdominal distension, facial flushing, and fatigue. One serious AE (SAE) of ankle fracture was reported 11 days after velmosnil + itraconazole administration. This SAE was severe and considered unrelated to velmosnil. Gastrointestinal disorders were the most commonly reported system organ class, reported by 3 subjects after administration of velmosnil alone and 5 subjects after administration of velmosnil + itraconazole. Except for one moderate AE of neutropenia that commonly occurs in healthy subjects of African origin, there were no clinically significant clinical laboratory findings.

[0126] Analysis This was a single-site, non-randomized DDI study in healthy male subjects. The PK objectives of this trial were to determine the effects of CYP3A4 inhibitors and inducers (itraconazole and rifampicin, respectively) and PPIs (rabeprazole and omeprazole) on the PK of vemurafenib and its metabolites after oral administration to healthy male subjects. Itraconazole, a CYP3A4 index inhibitor, and rifampicin, a CYP3A4 index inducer, were selected as the investigational compounds. Rabeprazole and omeprazole PPIs were selected to evaluate the pH-dependent changes in vemurafenib PK based on the ability of rabeprazole to increase the pH level and the widespread use of omeprazole in the treatment of gastroesophageal reflux disease (GERD) and the management of gastrointestinal involvement in cGVHD patients.

[0127] Itraconazole is classified as a potent CYP3A inhibitor but does not induce maximal CYP3A inhibition compared to ketoconazole. However, in a 4-day dosing regimen of 200 mg QD, itraconazole has been demonstrated in the literature to achieve clinically relevant inhibition of CYP3A4. Kantola T,et al.,Effect of itraconazole on the pharmacokinetics of atorvastatin.Clin Pharmacol Ther.1998;64(1):58-65; Lebrun-Vignes B,et al.,Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects.Br J Clin Pharmacol.2001;51(5):443-450.

[0128] In this study, a 9-day regimen of 200 mg QD was utilized (from day - 7 to day 1 [day 2] after belumosudil administration). This 9-day period was considered short enough to avoid the time-dependent prolongation of the half-life that occurs after approximately 15 days of itraconazole administration. Hardin TC et al., Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother. 1988;32(9):1310 - 1313.

[0129] The 200 mg dose level is further supported as it is the clinically recommended dose for the treatment of various fungal infections according to itraconazole prescribing information. No significant change in belumosudil exposure was observed with the administration of itraconazole (a CYP3A4 inhibitor), but a decrease in KD025m2 exposure was observed. Furthermore, the KD025m1 concentration decreased to levels that were mostly unquantifiable. This supports preclinical data suggesting that CYP3A4 is likely to play a role in the metabolism of belumosudil to the minor metabolite KD025m1 of ROCK2 activity and the major metabolite KD025m2 of ROCK2 inactivity.

[0130] Regarding rifampicin, a dosing schedule of 600 mg QD over 5 - 9 days has been modeled by others and has been shown to result in steady-state induction of CYP3A4 activity. Since this is also the labeled dosing regimen, a 9-day administration before belumosudil administration was considered appropriate for this drug interaction study. Also, since rifampicin is also an organic ion transporter (OAT) inhibitor, co-administration of belumosudil and rifampicin was not done on day 1 to avoid potential interactions in case belumosudil is later identified as an OAT substrate. Co-administration with rifampicin (a CYP3A4 inducer) resulted in a significant decrease in belumosudil exposure (C max , AUC inf , AUC lastThey decreased by 59%, 72%, and 72% respectively). In combination with the increased exposure to KD025m1, these results indicate a higher degree of metabolism of vermoxdyl accompanied by induction of CYP3A4 activity. The geometric mean half-life value decreased from 7.89 (vermodil alone) to 2.17 hours (with rifampicin); however, the decrease in half-life may be due to the characterization of the distribution phase rather than the true elimination phase of vermodil because the vermodil concentration reached undetectable levels more quickly in the presence of rifampicin.

[0131] The effect of CYP3A4 induction on vermodil metabolism was further confirmed by in vitro evaluation which determined that the metabolism of vermodil to KD025m1 is CYP3A4- and CYP2C8-dependent, the metabolism to KD025m2 is CYP3A4-dependent, and the metabolism is further regulated by UGT1A1. Since rifampicin is known to induce CYP3A4, CYP2C8, and UGT1A1 (Chen J, et al., Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;5:3), the observed increase in KD025m1 exposure with co-administration of rifampicin is consistent with the metabolic pathway of vermodil. In addition, the production of KD025m1 can increase from the induction of both CYP3A4 and CYP2C8, but the induction of the UGT1A1 enzyme can increase the excretion rate of KD025m2 even if the production via CYP3A4 increases, explaining the decrease in KD025m2 exposure with rifampicin administration.

[0132] Rabeprazole, a strong PPI, suppresses gastric acid secretion by non-competitive blockade of H+ / K+-adenosine triphosphatase at the secretory surface of gastric parietal cells, thereby raising intragastric pH above 3.0. The recommended starting dose of sodium rabeprazole for subjects with GI ulcers and GERD is 20 mg / day, and the recommended starting dose for subjects with hypersecretory syndromes is 60 mg / day (Summary of Product Characteristics by Accord-UK Ltd: Rabeprazole 20mg Gastro-resistant Tablets available at www.medicines.org.uk / emc / medicine / 27143 / SPC / Rabeprazole+20mg+Gastro-resistant+Tablets / . Updated 16 April 2020 Accessed 12 August 2021). For this short-term study, a 3-day dosing regimen of 20 mg BID and then a QD dose before administration of velmosdil were selected. To investigate the weaker PPI interaction with velmosdil, the omeprazole dose was administered at the lowest labeled dose (20 mg) in part 2 of the study.

[0133] The decrease in the exposure of velmosdil and its metabolites after co-administration with rabeprazole, a strong PPI, suggests that the increase in intragastric pH results in a decrease in the solubility of velmosdil and a reduction in its absorption. A similar trend in velmosdil and metabolite PK was observed with co-administration of omeprazole, a weaker PPI. These findings are consistent with previously conducted solubility studies, showing a decrease in velmosdil solubility from >100 μg / mL at pH 2.7 to approximately 4 μg / mL at pH 6.5 and approximately 3 μg / mL at pH 7.4. Based on the results of this study, a clinically meaningful interaction between velmosdil and PPI is possible. Thus, the prescribing information indicates that the dose of velmosdil should be increased when co-administered with PPI.

[0134] Omeprazole may induce CYP3A4, but it is a relatively weak CYP3A4 inducer, and it should be noted that it was administered for only a total of 4 days in this study. Therefore, no DDI is considered to be caused by CYP induction. Instead, it is highly likely to be caused by the pH-limited solubility of velmosdil.

[0135] The safety profile of velmosdil in this study was not remarkable at a single oral dose of 200 mg of velmosdil alone and in combination with 200 mg of itraconazole or 600 mg of rifampicin. Most of the TEAE were of mild severity and all recovered by the end of the study. One SAE was reported; this event was unrelated to velmosdil.

[0136] The potential drug-drug interactions between velmosdil and itraconazole (a CYP3A4 inhibitor) and rifampicin (a CYP3A4 inducer) were investigated. No clinically meaningful changes in velmosdil PK were observed in the presence of itraconazole. However, the concentrations of both velmosdil metabolites decreased compared to when velmosdil was administered alone. Rifampicin was found to have a significant effect on velmosdil PK, as observed by a decrease in velmosdil and KD025m2 exposure and an increase in KD025m1 exposure by rifampicin. Co-administration of both the PPI rabeprazole and the weaker PPI omeprazole with velmosdil resulted in a significant decrease in velmosdil and metabolite exposure. Therefore, velmosdil is recommended to be administered at a higher level when co-administered with a PPI. No risks of safety or tolerability were identified for single doses of velmosdil administered alone or in combination with repeated doses of itraconazole, rifampicin, omeprazole, or rabeprazole.

[0137] Example 2: Two Phase 1 trials to evaluate the food effect and relative bioavailability of tablet and capsule formulations of velmosdil in healthy adult subjects The interaction between the pharmacokinetic profile of food and orally administered drugs is affected by many factors. The mechanisms driving pharmacokinetic food-drug interactions mainly depend on the active ingredient and formulation, the impact on gastrointestinal physiology (e.g., pH, environment, excretion rate), and the diet composition (calorie and fat content). The diet effect is a complex issue in oral drug administration.

[0138] Two Phase 1 studies were conducted to evaluate the pharmacokinetic (PK) differences between two formulations and to determine the presence of a potential diet effect of velmosdil. The first study was an initial preliminary food effect study evaluating the administration of velmosdil capsules with food. The following study was a relative bioavailability and food effect study comparing commercially available tablet and capsule formulations in addition to characterizing the food effect of velmosdil tablets. This example reports the PK and safety results from both studies.

[0139] Study Design Both studies were single-site, open-label, randomized, single-dose crossover studies in healthy males. Important inclusion criteria included subjects aged 18 to 55 years (inclusive) who were using a highly effective contraceptive method both during the study period and for 1 to 3 months after the study. For both studies, the API was velmosdil mesylate corresponding to 100 mg (capsule) or 200 mg (tablet) of the free base.

[0140] In the first food effect study, a dose of 500 mg of velmosdil (5 × 100 mg capsules) was selected because there was no drug-related toxicity at that dose in previous single and multiple ascending dose (SAD / MAD) studies. Twelve healthy males were enrolled in the study and randomized to receive a single dose of 5 × 100 mg velmosdil capsules under both fed and fasted conditions in a crossover fashion. This study design is shown in Figure 5 of this specification.

[0141] For the fed state, the subjects were given a high-fat diet consisting of omelets, bacon-topped toast, hash browns, and 8 ounces of whole milk 30 minutes before receiving belumosudil. In the fasting state, the subjects were fasted overnight for 10 hours or more before belumosudil administration and then fasted for an additional 4 hours after administration. Water was freely available except for 1 hour before and 1 hour after dosing. A 7-day washout period was provided, and each dose of belumosudil was administered either under fed conditions or fasting conditions.

[0142] In the second relative bioavailability / food effect study, both commercially available tablets and a previous formulation capsule were investigated. A 200 mg tablet dose was selected because it had good tolerability in healthy subjects and quantifiable concentrations were obtained across the entire PK profile. Additionally, since belumosudil tablets and capsules were manufactured in 200 mg and 100 mg dose units, respectively, the 200 mg dose enabled an accurate comparison variability assessment between the two formulations. A total of 23 healthy males were enrolled in the study and randomized to receive three single doses of 200 mg belumosudil according to the assigned treatment sequence. These demographics are shown in Table 5.

[0143]

Table 9

[0144] In Treatment A, the subjects were given a 200 mg belumosudil tablet after an overnight fast and then continued fasting for an additional 4 hours after dosing. In the case of Treatments B and C, before dosing, the subjects consumed a high-fat breakfast consisting of hash browns, bacon, omelets, white bread, and 240 mL of whole milk over 25 minutes. Thirty minutes after the start of breakfast, the subjects received a single dose of either 200 mg belumosudil tablets (Treatment B) or 2 x 100 mg belumosudil capsules (Treatment C). All subjects received each treatment, and a washout of at least 6 days was conducted between each period. Water was freely available during all study periods except for 1 hour before and 1 hour after dosing.

[0145] Pharmacokinetic Sample Collection In both studies, serial blood samples for PK analysis were collected before dosing and at 1, 2, 4, 6, 8, 12, 16, 24, and 36 hours after dosing. In the first study, additional samples were collected at 30 hours after dosing. In the second study, additional samples were collected at 3, 5, and 48 hours after dosing. Blood samples (5 - 6 mL per sample) were collected into K3EDTA tubes on ice, processed within 30 minutes of collection, and then frozen at approximately -70 to -80 °C immediately after collection.

[0146] Sample preparation was performed by protein precipitation. Vermostil and its two metabolites (KD025m1 and KD025m2) were quantified using a liquid chromatography tandem mass spectrometry (LC-MS / MS) method validated from 10.0 to 5000 ng / mL.

[0147] Pharmacokinetic and Statistical Analysis Methods The primary endpoints of the first preliminary food effect study were safety and tolerability, and the secondary endpoints were PK for vermostil and its metabolites (KD025m1 and KD025m2). For the second relative bioavailability / food effect study, the primary endpoint was the comparison of PK parameters of vermostil administered as tablets in the fed state versus the fasted state. Secondary endpoints included the PK comparison of vermostil administered as tablet formulations versus capsule formulations, as well as the evaluation of safety and tolerability.

[0148] Statistical analysis was performed in SAS using the PROC MIXED procedure and restricted maximum likelihood estimation. In both studies, mixed - effect modeling techniques were used to evaluate the presence of a diet effect by formal statistical analysis of the natural logarithm - transformed AUC and Cmax. The model included treatment, period, and sequence as fixed effects and subjects nested within sequence as random effects. For the fed treatment (test) versus fasted treatment (reference), adjusted geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were calculated. If the 90% CI was within the bioequivalence limits of 80.00 to 125.00%, it was to be concluded that there was no diet effect.

[0149] To evaluate the relative bioavailability between formulations in the second study, the same analysis was performed on both fed tablets (test) versus capsules (reference). For both studies, all subjects who received at least one dose of the test drug and for whom post-dose PK data were available were included in the PK population.

[0150] Results Pharmacokinetic Results In the initial preliminary diet effect study, after single oral administration of 500 mg of vermoxdil (capsule) both during feeding and fasting, vermoxdil was rapidly absorbed without a lag time. Cmax was achieved 2 hours earlier under fasting conditions compared to during feeding. After reaching the peak concentration, the mean plasma concentration of vermoxdil decreased in a similar manner between the two treatments.

[0151] Both Cmax and AUC of vermoxdil were higher during feeding than in the fasting state, and the GMR exceeded 125% for all PK parameters included in the statistical analysis. The inter-subject variability between Cmax and AUC was slightly lower in the fasting state than during feeding. A similar trend was also observed for metabolite data.

[0152] In the second relative bioavailability / food effect study, administration of a 200 mg tablet with a high-fat breakfast decreased variability and increased vermoxdil exposure to 225% (Cmax) and 180% (AUCinf) of that observed under fasting conditions. A 0.5-hour delay in Tmax was observed with fed administration. Statistical analysis of the GMR further confirmed the presence of a food effect. Circulating metabolite levels were low regardless of formulation and feeding state.

[0153] These results from both the first and second studies are summarized in Table 6 below, which shows the pharmacokinetic parameters of vermoxdil in the two diet effect studies and the relative bioavailability data in the second study.

[0154]

Table 10

[0155] As shown in Figure 6 of this specification, after a single administration of 200 mg of vemurustil in the fed state, vemurustil exposure was slightly higher for tablets compared to capsules. The variability in exposure among subjects was moderate for both tablets and capsules, but slightly higher for tablets. Vemurustil exposure (Cmax and AUC) was approximately 17 - 19% higher for tablets compared to capsule formulations.

[0156] These results demonstrate that fed administration reduces the rate and increases the extent of vemurustil absorption. This was first demonstrated in an initial diet effect study, in which administration of a high - fat meal 30 minutes prior to vemurustil administration significantly increased systemic exposure (Cmax, AUC0 - t, and AUCinf) by 2.5×3 - fold for vemurustil compared to administration in the fasting state. Tmax was achieved 2 hours after dosing under fed conditions.

[0157] In a second diet effect study, administration of 200 mg tablets under fed conditions delayed Tmax by 0.5 hours and increased vemurustil exposure to approximately 2 - fold that of tablet exposure under fasting conditions, and similar findings of increased absorption rate and extent were observed. Additionally, when food was administered with the tablets, the variability in exposure among subjects decreased by approximately 60%. These results demonstrate that vemurustil tablet formulations minimize the effect of food on PK slightly compared to capsule formulations and that food improves the consistency of exposure across the subject population.

[0158] In addition to the food effect, the relative bioavailability of the two formulations was evaluated under fed conditions. For both tablets and capsules, vemurustil was rapidly absorbed and eliminated, as demonstrated by the rapid appearance of metabolites KD025m1 and KD025m2. The variability evaluated by CV% of exposure parameters was similar, suggesting no significant difference in inter - subject variability in PK between the two formulations.

[0159] Example 3: US REZUROCK (trademark) (vemurustil) FDA label -------Indications and Usage---------------------- REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. (1)

[0160] -------Dosage and Administration----------------------- Recommended Dosage: 200 mg orally once daily with food. (2.1)

[0161] -------Dosage Form and Strength----------------------- Tablets: 200 mg (3)

[0162] -------Contraindications--------------------------- None (4)

[0163] --------Warnings and Precautions---------------------- Embryo-Fetal Toxicity: May cause fetal harm. Advise females of the potential risk to the fetus and use effective contraception. (5.1, 8.1, 8.3)

[0164] --------Drug Interactions---------------------- Strong CYP3A Inducers: Increase the REZUROCK dosage up to 200 mg twice daily. (7.1) Proton Pump Inhibitors: Increase the REZUROCK dosage up to 200 mg twice daily. (7.1)

[0165] --------Adverse Reactions----------------------- The most common (≥20%) adverse reactions including clinical laboratory abnormalities were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension. (6.1)

[0166] --------Use in Specific Populations------------------ Lactation: Advise not to breastfeed. (8.2) For patient count information and FDA-approved patient labeling, see 17.

[0167] Full Prescribing Information 1 Indications and Usage REZUROCK is indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0168] 2 Dosage and Administration 2.1 Recommended Dosage The recommended dose of REZUROCK is 200 mg administered orally once daily until the progression of chronic GVHD requires a new systemic therapy. Instruct the patient as follows. Swallow the REZUROCK tablets whole. Do not cut, crush, or chew the tablets. Take REZUROCK at approximately the same time each day with food [see Clinical Pharmacology (12.3)]. If the dose of REZUROCK is missed, instruct the patient not to take an additional dose to make up for the missed dose.

[0169] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)].

[0170] 2.2 Dose Modification for Adverse Reactions Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly. Modify the REZUROCK dosage according to Table 7 for adverse reactions.

[0171] [Table 11]

[0172] 2.3 Dose Modification Due to Drug Interactions Potent CYP3A Inducers When co-administered with a strong CYP3A inducer, increase the dose of REZUROCK to 200 mg twice daily. [See Drug Interactions (7.1).]

[0173] Proton Pump Inhibitors When co-administered with a proton pump inhibitor, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0174] 3 Dosage Forms and Strengths Each 200 mg tablet is a light yellow film-coated rectangular tablet debossed with "KDM" on one side and "200" on the other side.

[0175] 4 Contraindications None

[0176] 5 Warnings and Precautions 5.1 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, REZUROCK can cause harm to the fetus when administered to pregnant women. In animal reproductive studies, administration of belumosudil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and malformations, at maternal exposures (AUC) lower than those in patients at the recommended dose. Inform pregnant women of the potential risk to the fetus. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

[0177] 6 Adverse Reactions 6.1 Clinical Trial Experience Clinical trials are conducted under widely varying conditions, and the rates of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates actually observed.

[0178] Chronic graft-versus-host disease In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Trials (14.1)]. The median treatment duration was 9.2 months (range 0.5 to 44.7 months).

[0179] A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure.

[0180] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Adverse reactions that led to permanent discontinuation of REZUROCK in more than 3% of patients included nausea (4%). Adverse reactions that led to dose interruption occurred in 29% of patients. Adverse reactions that led to discontinuation of dosing in 2% or more were infections (11%), diarrhea (4%), asthenia, dyspnea, hemorrhage, hypotension, abnormal liver function tests, nausea, fever, edema, and renal insufficiency (each 2%).

[0181] The most common (≥20%) adverse reactions including clinical laboratory abnormalities were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension.

[0182] Table 8 summarizes the non-laboratory adverse reactions.

[0183]

Table 12

[0184]

Table 13

[0185] Table 9 summarizes the laboratory abnormalities of REZUROCK.

[0186]

Table 14

[0187] 7 Drug Interactions 7.1 Effects of Other Drugs on REZUROCK Strong CYP3A Inducers Concomitant administration of REZUROCK with strong CYP3A inducers decreases vemurafenib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. If coadministered with a strong CYP3A inducer, increase the dose of REZUROCK [see Dosage and Administration (2.3)].

[0188] Proton Pump Inhibitors Concomitant administration of REZUROCK and a proton pump inhibitor decreases vemurafenib exposure [see Clinical Pharmacology (12.3)], which may decrease the efficacy of REZUROCK. Increase the dose of REZUROCK when administered concomitantly with a proton pump inhibitor [see Dosage and Administration (2.3)].

[0189] 8 Use in Specific Populations 8.1 Pregnancy Summary of Risks Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], REZUROCK can cause fetal harm when administered to a pregnant woman. There are no available human data regarding the use of REZUROCK in pregnant women to evaluate drug-related risks. In animal reproductive studies, administration of vemurafenib to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including growth, embryo-fetal mortality, and embryo-fetal malformations, at maternal exposures (AUC) approximately 3-fold greater than human exposure (AUC) at the recommended dose (rats) and 0.07-fold greater than human exposure (AUC) at the recommended dose (rabbits) [see Animal Data]. Inform pregnant women and females of reproductive potential of the potential risk to the fetus. In the general population in the United States, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

[0190] Data Animal Data During animal organogenesis, vemurafenib was administered to rats at doses of 25, 50, 150, and 300 mg / kg / day in pilot studies and 15, 50, and 150 mg / kg / day in pivotal studies to conduct embryo-fetal development studies. Maternal toxicity and embryo-fetal developmental effects were observed in pilot studies. Maternal toxicity (decreased weight gain) occurred at doses of 150 and 300 mg / kg / day. Increased post-implantation loss occurred at 50 and 300 mg / kg / day. Fetal malformations were observed at ≥50 mg / kg / day and included anal and tail absence, umbilical cord tumor, and dome-shaped head. Exposure (AUC) at 50 mg / kg / day in rats was approximately 3-fold that of human exposure at the recommended dose of 200 mg.

[0191] In the embryofetal development study in rabbits, pregnant animals orally administered with belumosudil at 50, 125, and 225 mg / kg / day during the organogenesis period resulted in maternal toxicity and embryofetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of 125 mg / kg / day and above. Embryo-fetal effects were observed at doses of ≥50 mg / kg / day and included spontaneous abortions, increased post-implantation deaths, decreased proportion of live fetuses, malformations, and decreased fetal weights. Malformations included malformations of the tail (short), ribs (bifurcation, fusion, or deformation), sternal segmentation (fusion), and neural arches (fusion, displacement, deformation). The exposure (AUC) at 50 mg / kg / day in rabbits was approximately 0.07-fold of the human exposure at the recommended dose of 200 mg.

[0192] 8.2 Lactation Summary of Risks There is no available data on the presence of belumosudil or its metabolites in human breast milk, or the effects on children who were breastfed, or on lactation. Due to the potential for serious adverse reactions from belumosudil in children who are breastfed, advise women who are breastfeeding not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose.

[0193] 8.3 Reproductive Potential Women and Men REZUROCK can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

[0194] Pregnancy Testing Confirm the pregnancy status of women of reproductive potential before initiating treatment with REZUROCK.

[0195] Contraception Women Instruct women of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus.

[0196] Male Male patients with a potentially fertile female partner should be instructed to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK.

[0197] Infertility Female Based on findings in rats, REZUROCK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0198] Male Based on findings in rats and dogs, REZUROCK may impair male fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0199] 8.4 Use in Pediatric Patients The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years of age and older. Use of REZUROCK in this age group is supported by evidence from well-controlled studies in adults with additional population pharmacokinetic data demonstrating that age and weight do not have a clinically meaningful impact on the pharmacokinetics of the parent drug, that exposure to the parent drug is expected to be similar between adults and pediatric patients 12 years of age and older, and that the disease course is sufficiently similar between adults and pediatric patients to allow extrapolation of data from adults to pediatric patients.

[0200] The safety and effectiveness of REZUROCK have not been established in pediatric patients less than 12 years of age.

[0201] 8.5 Use in Elderly Patients Of the 186 patients with chronic GVHD in the clinical trials of REZUROCK, 26% were 65 years of age or older. No clinically significant differences in the safety or effectiveness of REZUROCK were observed compared to younger patients.

[0202] 11 Description Belmosulodzil is a kinase inhibitor. The drug substance is belmosulodzil mesylate, which has a molecular formula of C27H28N6O5S and a molecular weight of 548.62 g / mol. The chemical name of belmosulodzil mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1). The chemical structure is as follows: [Chemical formula]

[0203] Belmosulodzil mesylate is a yellow powder that is poorly soluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0204] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base equivalent to 242.5 mg of belmosulodzil mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0205] The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide.

[0206] 12 Clinical Pharmacology 12.1 Mechanism of Action Belmosulodzil is an inhibitor of rho-associated coiled-coil containing protein kinase (ROCK), which inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 μM, respectively. Belmosulodzil downregulated the inflammatory response through the regulation of STAT3 / STAT5 phosphorylation and the shift of the Th17 / Treg balance in ex vivo or in vitro human T cell assays. Belmosulodzil also inhibited abnormal fibrotic signaling in vitro. In vivo, belmosulodzil showed activity in an animal model of chronic GVHD.

[0207] 12.2 Pharmacodynamics The exposure-response relationship of belumosudil and the time course of pharmacodynamic responses have not been established.

[0208] 12.3 Pharmacokinetics Unless otherwise specified, the following pharmacokinetic parameters are shown for chronic GVHD patients administered 200 mg of belumosudil once daily. The mean (coefficient of variation %, CV%) steady-state AUC and Cmax of belumosudil were 22,700 (48%) h·ng / mL and 2,390 (44%) ng / mL, respectively. The Cmax and AUC of belumosudil increased almost proportionally over the dose range of 200 and 400 mg (1 to 2 times the recommended daily dose). The accumulation ratio of belumosudil was 1.4.

[0209] Absorption The median Tmax of belumosudil at steady state was 1.26 to 2.53 hours after administering 200 mg to patients once or twice daily. The mean (%CV) bioavailability was 64% (17%) after a single dose of belumosudil in healthy subjects.

[0210] Dietary Effect Compared to fasting in healthy subjects, after administration of a single dose of belumosudil with a high-fat and high-calorie diet (about 50% of the total calorie content of the diet from fat, 800 to 1,000 calories), the Cmax and AUC of belumosudil increased 2.2-fold and 2-fold, respectively. The median Tmax was delayed by 0.5 hours.

[0211] Distribution The geometric mean of the volume of distribution after a single dose of belumosudil in healthy subjects was 184 L. (Geometric CV% 67.7%).

[0212] The binding of belumosudil to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6% in vitro, respectively.

[0213] Elimination The mean (%CV) elimination half-life of vemurafenib in patients was 19 hours (39%), and the clearance was 9.83 L / hour (46%).

[0214] Metabolism Vemurafenib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9 in vitro.

[0215] Excretion After single oral administration of radiolabeled vemurafenib to healthy subjects, 85% of the radioactivity was recovered in feces (30% unchanged), and less than 5% was recovered in urine.

[0216] Specific Populations No clinically significant differences in the pharmacokinetics of vemurafenib were observed with respect to age (18 to 77 years), sex, weight (38.6 kg to 143 kg), or mild to moderate renal impairment (eGFR ≥60 and <90 mL / min / 1.72 m 2 ~eGFR ≥30 and <60 mL / min / 1.72 m 2 ). The effect of severe renal impairment on the pharmacokinetics of vemurafenib has not been studied.

[0217] Drug Interaction Studies Clinical studies and an informed approach regarding the effects of other drugs on vemurafenib Potent cytochrome P450 (CYP) 3A inhibitor: When co-administered with itraconazole to healthy subjects, there was no clinically meaningful effect on vemurafenib exposure.

[0218] Potent CYP3A inducer: Co-administration of rifampin decreased vemurafenib Cmax by 59% and AUC by 72% in healthy subjects.

[0219] Moderate CYP3A inducer: Co-administration of efavirenz is predicted to decrease vemurafenib Cmax by 32% and AUC by 35% in healthy subjects.

[0220] Proton pump inhibitor: In healthy subjects, co - administration of rabeprazole decreased the Cmax of velmosimil by 87% and the AUC by 80%, and omeprazole decreased the Cmax of velmosimil by 68% and the AUC by 47%.

[0221] Effect of velmosimil on other drugs CYP3A substrate: Co - administration of velmosimil is predicted to increase the Cmax and AUC of midazolam (a sensitive CYP3A substrate) by about 1.3 - fold and 1.5 - fold, respectively.

[0222] CYP2C9 substrate: Co - administration of velmosimil is not expected to have a clinically significant effect on the exposure of CYP2C9 substrates (such as warfarin).

[0223] [[ID=1�]]CYP2C8 substrate: Co - administration of velmosimil is not expected to have a clinically significant effect on the exposure of CYP2C8 substrates that are not OATP1B1 substrates.

[0224] In vitro tests Transporter system: Velmosimil is a substrate of P - gp. Velmosimil inhibits BCRP, P - gp and OATP1B1 at clinically relevant concentrations.

[0225] Enzyme system: Velmosimil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9.

[0226] 13 Non - clinical toxicity 13.1 Carcinogenesis, mutagenesis, obesity disorders Carcinogenicity tests with velmosimil have not been conducted.

[0227] Velmosimil was not genotoxic in in vitro bacterial mutagenicity (Ames) assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes (HPBL), or in vivo rat bone marrow micronucleus assay.

[0228] In the rat fertility study with combined male and female, untreated females were mated with male animals treated with vemurafenib, or untreated males were mated with female animals treated with vemurafenib. Vemurafenib was orally administered to male rats at doses of 50, 150, or 275 mg / kg / day for 70 days prior to and throughout the mating period, and to female rats for 14 days prior to mating and up to day 7 of pregnancy. At a dose of 275 mg / kg / day, adverse findings in female rats (treated with vemurafenib or untreated but mated with treated males) included increased pre- or post-implantation losses and decreased numbers of viable embryos. Administration of vemurafenib to male rats at a dose of 275 mg / kg / day resulted in abnormal sperm findings (decreased motility, decreased count, and increased percentage of abnormal sperm) and changes in the testis / epididymis organs (weight loss and degeneration).

[0229] Fertility was decreased in both males and females treated at a dose of 275 mg / kg / day, reaching statistical significance in males. Adverse changes in male and female genitalia also occurred in the general toxicity studies. Findings included sperm degeneration at a vemurafenib dose of 35 mg / kg / day in dogs and decreased ovarian follicular development at 275 mg / kg / day in rats. During the recovery period, the changes were partially or completely reversed. The exposures (AUC) at doses of 35 mg / kg / day in dogs and 275 mg / kg / day in rats were 0.5-fold and 8 - 9-fold, respectively, of the clinical exposure at the recommended dose of 200 mg daily.

[0230] 14 Clinical Trials 14.1 Chronic Graft-versus-Host Disease The KD025-213 study (NCT03640481) was a randomized, open-label, multi-center study of REZUROCK for the treatment of patients with chronic GVHD who had received 2 - 5 prior lines of systemic therapy and required further treatment. Patients were excluded from the study if platelets were <50×10 9 / L; absolute neutrophil count <1.5×10 9 / L; AST or ALT >3×ULN; total bilirubin >1.5×ULN. Patients were excluded from the study if QTc(F) >480 ms; eGFR <30 mL / min / 1.73 m 2; or FEV1 ≤ 39%. Sixty-six patients were treated with oral administration of REZUROCK 200 mg once daily. Concurrent treatment with supportive therapy for chronic GVHD was permitted. Concurrent treatment with GVHD prophylaxis and standard care for systemic chronic GVHD therapy was permitted as long as the subject had been on a stable dose for at least two weeks prior to the study. Initiation of new systemic chronic GVHD treatment during the study was not permitted.

[0231] Demographics and baseline characteristics are summarized in Table 10.

[0232]

Table 15

[0233]

Table 16

[0234] The efficacy of REZUROCK was based on the overall response rate (ORR) up to day 1 of cycle 7, where overall response included complete or partial response according to the 2014 NIH response criteria. The results are shown in Table 11. The ORR was 75% (95% CI: 63, 85). The median duration of response calculated from the first response to progression, death, or new systemic therapy for chronic GVHD was 1.9 months (95% CI: 1.2, 2.9). 1. The median time to first response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, death or initiation of new systemic therapy did not occur in 62% (95% CI: 46, 74) of patients for at least 12 months after response.

[0235]

Table 17

[0236] The results of the ORR were supported by an exploratory analysis of patient-reported symptom bother that showed at least a 7-point decrease in the total symptom score of the Leeds Symptom Scale by day 1 of cycle 7 in 52% (95% CI: 40, 65) of patients.

[0237] 16 Supply / Storage and Handling REZUROCK 200 mg tablets are supplied as pale yellow, film-coated, rectangular tablets containing 200 mg of belumosudil (equivalent to 242.5 mg of belumosudil mesylate). Each tablet is debossed with “KDM” on one side and “200” on the other side and is packaged as follows: 200 mg tablets in a 30-count bottle: NDC 79802-200-30

[0238] Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0239] Dispense to patients only in the original container. Store in the original container to protect from moisture. Always replace the cap securely after opening. Do not discard the desiccant.

[0240] 17 Patient Counseling Information Advise patients to read the FDA-approved Patient Information.

[0241] Embryo-Fetal Toxicity: · Inform pregnant women and females of the potential risk to the fetus of reproductive potential. Inform healthcare providers of known or suspected pregnancy in females of reproductive potential. [See Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3).]. · Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Warnings and Precautions (5.1)]. · Instruct male patients with a potentially fertile female partner to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.3)].

[0242] Lactation Instruct females not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.2)].

[0243] Contraception Inform males and females that REZUROCK may impair fertility [see Use in Specific Populations (8.3)].

[0244] Administration Instruct the patient to take REZUROCK orally once daily with food, as directed by a physician, and that the oral dosage (tablet) should be swallowed whole with a glass of water without cutting, crushing, or chewing the tablet at approximately the same time each day [see Dosage and Administration (2.1)].

[0245] Advise the patient that if a dose of REZUROCK is missed, the patient should return to the normal schedule the next day and take the missed dose as soon as possible on the same day. The patient should not take an additional dose to make up for a missed dose [see Dosage and Administration (2.1)].

[0246] Drug Interactions Advise the patient to inform their healthcare provider of all concomitant medications, including prescription, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

[0247]

Table 18

[0248]

Table 19

[0249]

Table 20

[0250] The present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, but the description and examples should not be construed as limiting the scope of the present invention. The disclosures of all patents and scientific documents cited herein are hereby expressly incorporated by reference in their entirety into this specification.

Claims

1. 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (compound), for use in the treatment of chronic graft-versus-host disease (cGVHD) in a subject, wherein at least one CYP3A inducer or proton pump inhibitor (PPI) is co-administered to the subject.

2. Use according to claim 1, wherein a CYP3A inducer is co-administered to the subject.

3. Use according to claim 1 or 2, wherein the CYP3A inducer is glucocorticoid, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampin (rifampicin), fosphenytoin, lumacaftor, lumacaftor-ivacaftor, mitotane, St. John's wort, phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, estradiol, eslicarbazepine, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, sotorasib, armodafinil, modafinil, or rufinamide.

4. Use according to claim 1 or 2, wherein the CYP3A inducer is a CYP3A4 inducer.

5. Use according to claim 4, wherein the CYP3A4 inducer is phenobarbital, phenytoin, rifampicin, St. John's wort or glucocorticoid.

6. Use according to claim 5, wherein the CYP3A4 inducer is rifampicin.

7. Use according to claim 1, wherein a PPI is co-administered to the subject.

8. Use according to claim 7, wherein the PPI is omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole or ilaprazole.

9. Use according to claim 7 or 8, wherein the PPI is rabeprazole or omeprazole.

10. Use according to claim 1, wherein a CYP3A inducer and a PPI are co-administered to the subject.

11. Use according to any one of claims 1 to 10, wherein the dosage of the compound is about 400 mg per day.

12. The use according to claim 11, wherein the dosage of the compound is about 200 mg administered twice a day relative to a total daily dosage of about 400 mg.

13. The use according to any one of claims 1 to 10, wherein the dosage of the compound is in the range of about 400 mg to 800 mg per day.

14. The use according to claim 13, wherein the dosage of the compound is 400 mg per day, 400 mg twice a day, or 800 mg per day.

15. The use according to any one of claims 2 to 6, wherein the dosage of the compound is increased beyond the clinically recommended dosage of the compound for the subject under standard treatment conditions in order to mediate the exposure reduction effect of a co-administered CYP3A inducer.

16. The use according to claim 15, wherein the CYP3A inducer is rifampicin, and the exposure reduction effect of rifampicin is characterized in that the Cmax of veremodzil is reduced by about 59% and / or the AUC is reduced by about 72%.

17. The use according to claim 15, wherein the CYP3A inducer is efavirenz, and the exposure reduction effect of efavirenz is characterized in that the Cmax of veremodzil is reduced by about 32% and / or the AUC is reduced by about 35%.

18. The use according to any one of claims 7 to 9, wherein the dosage of the compound is increased beyond the clinically recommended dosage of the compound for the subject under standard treatment conditions in order to mediate the exposure reduction effect of a co-administered PPI.

19. The use according to claim 18, wherein the PPI is omeprazole, and the exposure reduction effect of omeprazole is characterized by a reduction in veremodzil Cmax and / or AUC substantially as shown in Table 4.

20. The use according to claim 18, wherein the PPI is rabeprazole, and the exposure reduction effect of rabeprazole is characterized by a reduction in veremodzil Cmax and / or AUC substantially as shown in Table 4.

21. The use according to any one of claims 1 to 6 or 15 to 16, wherein the CYP3A inducer is rifampicin administered at a daily dosage in the range of about 10 to 20 mg / kg depending on the weight of the subject.

22. The use according to any one of claims 1 to 6 or 15 to 16, wherein the CYP3A inducer is rifampicin administered at a dosage of about 600 mg per day for about 5 to 9 days.

23. The use according to any one of claims 1, 7 to 9 or 18, wherein the PPI is omeprazole administered at a dose of about 20 mg to 120 mg per day.

24. The use according to any one of claims 1, 7 to 9 or 18, wherein the PPI is omeprazole administered at a dose of 20 mg per day.

25. The use according to any one of claims 1, 7 to 9 or 18, wherein the PPI is rabeprazole administered at a dose of about 5 to 40 mg per day.

26. The use according to any one of claims 1, 7 to 9 or 18, wherein the PPI is rabeprazole administered at a daily dose of 20 mg administered twice a day.

27. The use according to any one of claims 1 to 26, wherein the CYP3A inducer or PPI comprises a treatment cycle administered on a day when the subject does not receive the dose of the compound.

28. The use according to any one of claims 1 to 25, comprising a treatment cycle of administering the CYP3A inducer or PPI substantially simultaneously with the dose of the compound.

29. The use according to any one of claims 1 to 27, further comprising administering a high-fat, high-calorie diet within about 1 hour before administration of the compound.

30. The use according to any one of claims 1 to 29, wherein the subject has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for the chronic graft-versus-host disease.

31. A method of treating chronic graft-versus-host disease (cGVHD) in a subject taking a CYP3A inducer or a proton pump inhibitor (PPI) simultaneously, the method comprising administering to the subject in need thereof a therapeutically effective amount of besremi mesylate salt.

32. The method according to claim 31, wherein the dose of besremi mesylate salt administered to the subject is adjusted to mediate the exposure reduction effect of the CYP3A inducer and / or PPI.

33. A method for treating a subject having cGVHD, 1) determining whether the subject requires treatment with at least one CYP3A inducer or PPI and, if necessary, determining its dose, 2) calculating the therapeutically effective dose of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for the subject under standard conditions, and 3) determining an adjusted upward dose of the compound to be administered to the subject to mediate the exposure reduction effect of the CYP3A inducer and / or PPI when treating the cGVHD, the method comprising: **Claim 34** The method according to claim 33, wherein the exposure reduction effect is characterized by a decrease of about 30% to 90% in veremoside Cmax. **Claim 35** The method according to claim 33, wherein the exposure reduction effect is characterized by a decrease of about 50% to 90% in veremoside Cmax. **Claim 36** The method according to claim 33, wherein the exposure reduction effect is characterized by a decrease of about 70% to 85% in veremoside AUC. **Claim 37** The method according to any one of claims 33 to 36, wherein the compound is veremoside mesylate salt. **Claim 38** The method according to any one of claims 31 to 37, wherein the compound is administered to the subject within about 30 minutes after ingestion of a high-fat meal. **Claim 39** A method of treating chronic graft-versus-host disease (cGVHD) in a subject taking a CYP3A inducer or a proton pump inhibitor (PPI) concurrently, the method comprising administering to the subject in need thereof a protocol that mediates the food effect in combination with the exposure reduction effect of the CYP3A inducer or PPI.

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