Methods of administering besudil in combination with CYP3A inducer and / or proton pump inhibitor

Abstract

The present application relates to co-administration of besudil with a CYP3A inducer and / or a proton pump inhibitor for use in the treatment of a subject suffering from chronic graft versus host disease (cGVHD).

Description

Technical Field

[0001] The present application relates to the use of belumosudil or a pharmaceutically acceptable salt thereof for treating a subject suffering from chronic graft-versus-host disease (cGVHD), wherein at least one CYP3A inducer or a 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-relapsed death more than 2 years after alloHCT. In the United States, the estimated prevalence of cGVHD is 14,000 patients (as of 2016). (Bachier CR et al.: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneichematopoietic cell transplantation: A US claims analysis. Published at ASH 2019 held in Orlando, FL from December 7 to 10, 2019) ("Bachier et al.").

[0003] As assessed by Lee Symptom Scale (Lee Symptom Scale, LSS) (which measures the impact of cGVHD on the function and health of patients), the quality of life (QOL) of cGVHD patients is seriously impaired. It is reported that only one-third of patients with cGVHD and starting systemic treatment survive, are in remission and stop immunosuppressive therapy within 5 years. (Lee SJ et al.: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease.Biol Blood Marrow Transpl24:555-562,2018) ("Lee et al.").

[0004] The pathophysiology of cGVHD can be divided into three stages: early inflammation caused by tissue damage, dysregulation of the adaptive immune system, and chronic inflammation and abnormal tissue repair with 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) is corticosteroids alone or in combination with sirolimus or calcineurin inhibitors. However, up to 70% of patients require additional lines of therapy. (Bachier CR et al.). In addition, long-term use of corticosteroids is associated with significant side effects. (Lee et al.).

[0006] The management of cGVHD has been developing with the emergence of targeted therapy. In 2017, the U.S. Food and Drug Administration approved ibrutinib (a Bruton's tyrosine kinase inhibitor) for the treatment of adults with cGVHD after failure of one or more systemic therapy lines. In patients with cGVHD requiring >25% body surface area erythema rash or NIH oral score>4, a study using ibrutinib reported an overall response rate (ORR) of 67% and a discontinuation rate of 43% due to adverse events (TEAEs) occurring during treatment. (Waller EK et al.: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of aphase 1b / 2study. Biol Blood Marrow Transpl 25: 2002-2007, 2019).

[0007] For patients who have failed ≥1 line of therapy, there is still an opportunity to investigate other treatment options. Summary of the invention

[0008] The present application relates to 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof ("compound" or "besudild") for use in treating 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 application also provides a method for treating a subject with cGVHD who is concurrently taking a CYP3A inducer and / or a PPI, the method comprising administering to the subject an adjusted dose of besudil to mediate the exposure reduction effect of the CYP3A inducer and / or the proton pump inhibitor in treating the cGVHD.

[0010] A more complete understanding of embodiments of the present invention may be obtained by referring to the detailed description and examples which are intended to illustrate non-limiting embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The design of the clinical study described in Example 1 is described.

[0012] Figure 2A Shown are the mean ± SD besudil pharmacokinetic profiles after administration of a single dose of 200 mg besudil alone (squares) and the mean ± SD besudil pharmacokinetic profiles after administration of a single dose of 200 mg besudil in combination with itraconazole (circles), rabeprazole (triangles) and rifampicin (diamonds).

[0013] Figure 2B Shown are mean±SD besudil pharmacokinetic profiles after dosing 200 mg besudil twice daily (BID) alone (squares) and after dosing 200 mg besudil BID in combination with omeprazole (circles). Figure 2A and Figure 2B The inset in shows the log-linear plot excluding the lower error bar.

[0014] Figure 3A Shown are the mean±SD KD025m2 pharmacokinetic profiles after a single dose of 200 mg besudil alone (squares) and the mean±SD KD025m2 pharmacokinetic profiles after a single dose of 200 mg besudil in combination with itraconazole (circles), rabeprazole (triangles) and rifampicin (diamonds).

[0015] Figure 3B Shown are the mean±SD KD025m2 pharmacokinetic curves after administration of 200 mg besudil BID alone (squares) and the mean±SD KD025m2 pharmacokinetic curves after administration of 200 mg besudil BID in combination with omeprazole (circles). Figure 3A and Figure 3B Insets in both show the log-linear plots excluding the lower error bar.

[0016] Figure 4A Shown are the mean±SD KD025m1 pharmacokinetic profiles after a single dose of 200 mg besudil alone (squares) and after a single dose of 200 mg besudil in combination with itraconazole (circles), rabeprazole (triangles) and rifampicin (diamonds).

[0017] Figure 4B Shown are the mean±SD KD025m1 pharmacokinetic curves after administration of 200 mg besudil BID alone (squares) and the mean±SD KD025m1 pharmacokinetic curves after administration of 200 mg besudil BID in combination with omeprazole (circles). Figure 4A and Figure 4B The upper inset shows the log-linear plot excluding the lower error bar.

[0018] Figure 5 The design of the clinical study described in Example 2 is shown.

[0019] Figure 6 Shown are mean ± SD besudil pharmacokinetic profiles following administration of 200 mg besudil under fasting (tablets) and fed (tablets / capsules) conditions. Figure 6 The insets show the data on a log-linear scale. DETAILED DESCRIPTION Overview

[0020] cGVHD is characterized by overproduction of the proinflammatory cytokines IL-21 and IL-17 and overactivation of T follicular helper cells and B cells, which in turn leads to overproduction of antibodies. By controlling ROCK2 activity, besudol mediates signaling in immune cell function and fibrotic pathways, thereby alleviating the effects caused by this debilitating disease, such as inflammation of multiple tissues and fibrotic changes that may involve multiple organs including the lungs, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0021] In vitro evaluations have shown that the metabolism of besudiil is primarily dependent on cytochrome P450 CYP3A4 activity and that the solubility of besudiil is pH dependent. Preclinical studies in mice, rats, rabbits, and dogs have shown that besudiil undergoes hepatic metabolism to form 2 major metabolites, termed KD025m1 (a ROCK2-active minor metabolite) and KD025m2 (a ROCK2-inactive major metabolite). These major metabolites were subsequently quantified in clinical trials throughout the besudiil development program; exposure values ​​for the major inactive metabolite, KD025m2, were 15% to 20% of the parent, while exposure values ​​for the minor active metabolite, KD025m1, were <5% of the parent.

[0022] In vitro evaluation identified cytochrome P450 CYP3A4 as the major CYP isoform responsible for the metabolism of besudild. Incubation of besudild with recombinant enzymes showed that CYP3A4 was responsible for the metabolism of besudild (41.9%), although CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 (<5%), CYP2C19 (<5%), and UDP-glucuronosyltransferase 1A1 may also contribute to a lesser extent.

[0023] Therefore, a two-part clinical drug-drug interaction study was conducted to evaluate the effects of itraconazole (a CYP3A4 inhibitor), rifampin (a CYP3A4 inducer), and rabeprazole and omeprazole (both proton pump inhibitors [PPIs]) on the pharmacokinetics of besudil described in Example 1.

[0024] No clinically relevant changes in besudil exposure were observed after a single 200 mg oral dose of besudil with itraconazole; however, exposure of the major inactive metabolite, KD025m2, was reduced. In contrast, the CYP3A4 inducer rifampin significantly reduced exposure of besudil and its inactive metabolite, KD025m2, and increased exposure of the active metabolite, KD025m1. In healthy subjects, co-administration of rifampin reduced the Cmax of besudil by 59% and the AUC of besudil by 72%. In healthy subjects, co-administration of efavirenz, a CYP3A inducer, reduced the Cmax of besudil by 32% and the AUC of besudil by 35%.

[0025] When a single 200 mg oral dose of besudil was co-administered with the PPIs rabeprazole and omeprazole, parent and metabolite exposures were greatly reduced. In healthy subjects, co-administration of rabeprazole decreased the Cmax of besudil by 87% and the AUC of besudil by 80%, and omeprazole decreased the Cmax of besudil by 68% and the AUC of besudil by 47%.

[0026] Besudil was safe when administered with or without a perpetrator compound, and no significant adverse events were reported.

[0027] Therefore, co-administration of besudil with CYP3A inducers will reduce besudil exposure. Therefore, when co-administered with CYP3A inducers, the dose of besudil should be increased. For example, in one embodiment, when co-administered with a strong CYP3A inducer, the dose of besudil can be increased to 200 mg twice a day or 400 mg per day.

[0028] Co-administration of besudil with a proton pump inhibitor (PPI) will also reduce besudil exposure. When co-administered with a proton pump inhibitor, the dose of besudil can be increased. For example, in one embodiment, when co-administered with a proton pump inhibitor, the dose of besudil can be increased to 200 mg twice a day or 400 mg per day. definition

[0029] As used herein, "about" includes the exact amount modified by the term about as well as the amount expected to be within experimental error (e.g., within 15%, 10%, or 5%). For example, "about 200 mg" means "200 mg" as well as the mg range within experimental error (e.g., within the range of 200 mg ± 15%, 10%, or 5%). As used herein, the term "about" can be used to modify ranges as well as specific values.

[0030] As used herein, "administering" or "administering to" (e.g., with respect to administration of an API, including "co-administering" one or more APIs (e.g., a compound, besudil, a PPI, and / or a CYP3A inducer) to a subject) refers to the act of prescribing one or more drugs containing the one or more APIs for a subject to take during a treatment period, the act of prescribing a regimen of drugs for a subject to take, the act of dispensing one or more drugs to a subject, and / or the act of physically receiving or ingesting one or more drugs. Thus, an API (e.g., a compound, besudil, a PPI, and / or a CYP3A inducer) can be "administered" by a physician or other medical professional who writes a prescription for any of one or more such drugs; and / or "administered" by a pharmacist who fills the prescription and / or dispenses the one or more drugs to a subject; and / or "administered" by a patient or subject who ingests the one or more drugs and / or his or her partner or caregiver who delivers the one or more drugs to the subject.

[0031] "API" means "active pharmaceutical ingredient."

[0032] "Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" (also called bone marrow transplantation or stem cell transplantation) or "allogeneic hematopoietic cell transplantation (allo-HCT)" refers to the process of transplanting hematopoietic cells from a donor 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 cases, umbilical cord blood can be used. The donor and recipient can match on human leukocyte antigen (HLA) genes, such as brothers and sisters. The donor and recipient can be parents and children who are only half-matched (haploid compatible).

[0033] Besudiol is an oral selective inhibitor of rho-associated coiled-coil-containing protein kinase 2 (ROCK2). ROCK2 inhibition plays a role in adaptive immune system disorders and fibrosis due to abnormal tissue repair. Besudiol has an IC of approximately 100 nM and 3 μM, respectively. 50 The value inhibits ROCK2 and ROCK1. Besudild downregulates proinflammatory responses in ex vivo or in vitro human T cell assays by regulating STAT3 / STAT5 phosphorylation and changing the Th17 / Treg balance. In vitro, besudild also inhibits abnormal profibrotic signaling. In vivo, besudild exhibits activity in animal models of chronic GVHD.

[0034] The chemical name of the compound besudiol is as follows: 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound besudiol is also known as KD025. The mesylate salt of besudiol is marketed in the United States as REZUROCK TM Marketed for the treatment of patients with chronic GVHD who have failed at least two prior lines of systemic therapy. TM The active pharmaceutical ingredient is besudeli methanesulfonate, which has the molecular formula C 27 H 28 N6O5S, molecular weight 548.62 g / mol, and chemical name 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1).

[0035] The chemical structure of besudil mesylate is as follows:

[0036] Besudil and methods for making the compound are described in the following U.S. Patents: U.S. Patent No. 8,357,693, U.S. Patent No. 9,815,820, U.S. Patent No. 10,183,931, and U.S. Patent No. 10,696,660.

[0037] When the term "besudiil" is used in this application, it should be understood that unless the context clearly indicates otherwise, the term can cover any form of the compound besudiil and its pharmaceutically acceptable salts. The term "besudiil" refers to both the compound besudiil (e.g., free base form, amorphous form or crystalline form) and the pharmaceutically acceptable salts of besudiil (e.g., as REZUROCK TM The term "besudil" refers to any form of besudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0038] "Clinical endpoint" or "study endpoint" refers to an event or result in a clinical trial, which can be objectively measured to determine the results and potential beneficial effects of a drug or dosage regimen designed in a clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) is the percentage of people with partial response (PR) or complete response (CR) to treatment in a certain period of time in a study or treatment group. Failure-free survival (FFS) refers to the time from the first dose of besudiil to the failure event, or the interval between the beginning of besudiil and the addition of a new cGVHD therapy, the recurrence of the underlying disease or non-recurrent death (NRM). Overall survival (OS) refers to the length of time from the diagnosis date of the disease or the treatment of the disease. Duration of response (DOR) refers to the time from the initial response (e.g., PR or CR) until the best response progress from cGVHD recorded, from the initial response to the start of another systemic cGVHD therapy or death. The time of the next treatment (TTNT) refers to the time to the start of subsequent systemic cGVHD therapy.

[0039] "Clinically recommended amount" or "clinically recommended dose" refers to the amount or dose of the API recommended and / or approved by a person skilled in the art of medicinal chemistry for administration to a subject to treat the disease state in question after clinical trials, for example, as stated in publications, clinical trial results, and on approved drug labels. In one embodiment, the clinically recommended dose of besudil is 200 mg once daily as indicated on the drug label of besudil in the absence of administration of a CYP3A inducer or PPI.

[0040] With respect to the administration of besudil with CYP3A inducers and / or PPIs, "co-administration", "combined with", and / or "co-administered" as used herein means that during the course of treatment of the patient with besudil, the patient is also receiving one or more doses of one or more CYP3A inducers and / or PPIs (also referred to herein as "mutagenic compounds"). The mutagenic compound need not be administered concomitantly with or on the same day as besudil for it to be considered "co-administered" according to this definition. The mutagenic compound may be administered simultaneously with besudil, several days prior to administration of besudil, and / or during the course of treatment to be "co-administered". As described in Example 1, a mutagenic compound will not be considered "co-administered" or "combined with" besudil if there is a sufficient washout period between administrations to take into account at least 5 half-lives of the active portion of the administered dose.

[0041] As used in the claims and embodiments of this application, and when apparent from the context when used, "compound" is synonymous with all of the above definitions of besudil.

[0042] "Concurrent administration," "simultaneous" and / or "concurrent administration" herein with respect to administration of an API (eg, as administered to a CYP3A inducer and / or PPI that is administered "concurrently" with besudil) is synonymous with "co-administration" as defined above.

[0043] "CYP3A" refers to the CYP3A family of p-450 isozymes, including CYP3A4. Examples of CYP3A inducers may include glucocorticoids, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampicin (rifamycin), fosphenytoin, lumacato, lumacato-ivacato, mitotane and St. John's wort. CYP3A inducers may include phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cynobamate, dabrafenib, dexamethasone, analgin, elagolix, estradiol, eslicarbazepine, lorlatinib, mitrapivaval, modafinil, nafcillin, pegidatinib, rifabutin, rifapentine and sotolacib. Additional CYP3A inducers may include armodafinil, modafinil and rufinamide. In some embodiments of the present application, the CYP3A inducer is considered to be a strong CYP3A inducer. Examples of strong CYP3A inducers include rifampicin and phenytoin.

[0044] As used herein, "exposure reduction effect" or "exposure reduction effects" refers to the effect of CYP3A and PPI compounds on the pharmacokinetics of besudil (e.g., the exposure levels (total and peak) of besudil and its metabolites and the elimination rates of besudil and its major metabolites KD025m1 and KD025m2). Further reference is made to Example 1 and the present application. Figure 2A-Figure 4B As an illustration of the term "exposure reduction effect".

[0045] As used herein, a high-fat, high-calorie meal refers to a meal containing about 800 to 1,000 calories, wherein about 50% of the total caloric content of the meal comes from fat 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.

[0046] The Lee Symptom Scale (LSS) total score measures the impact on patient function and health status. The Lee Symptom Scale is a 30-item scale developed to measure symptoms of cGVHD and is described in Lee SJ et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease. Biol Blood Marrow Transplant 2002; 8: 444-452.

[0047] "Line of treatment" or "line of therapy" describes the order or sequence in which different therapies are given to a patient as his or her disease progresses. The initial treatment (first-line therapy) may not work or may stop working after a period of time. After the first-line therapy is discontinued, a second, different treatment (second-line therapy) may be given. When the second-line therapy does not work or stops working, a subsequent line of therapy may be given. Some patients may be given multiple lines of therapy during the course of their disease.

[0048] The first-line therapy for moderate to severe chronic graft-versus-host disease (cGVHD) defined by the National Institutes of Health (NIH) can be a single corticosteroid or a combination of corticosteroids and 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).

[0049] The example of corticosteroid therapy for the treatment of cGVHD includes but is not limited to prednisone, prednisolone, methylprednisolone and budesonide. The example of previous systemic therapy for the treatment of cGVHD includes but is not limited to prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib and ofatumumab.

[0050] "Immunosuppressive therapy" (IST) refers to therapy that is usually administered for at least six months after allo-HSCT in an attempt to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors (e.g., tacrolimus and cyclosporine).

[0051] A "myeloablative transplant" is a transplant procedure that uses very high doses of chemotherapy or radiation therapy before transplanting autologous or allogeneic hematopoietic stem cells. A nonmyeloablative transplant or reduced-intensity transplant involves the patient receiving less intensive chemotherapy before transplanting allogeneic hematopoietic stem cells.

[0052] The “NIH Pulmonary Symptom Score” or “NIH cGVHD Pulmonary Score” is a score based on clinical symptoms ranging from 0 to 3. A score of 0 is used for no symptoms, 1 for symptoms of shortness of breath when going up and down stairs, 2 for symptoms of shortness of breath on level ground, and 3 for shortness of breath at rest or requiring oxygen.

[0053] Unless the context requires otherwise, "or" is used in its inclusive sense (equivalent to "and / or").

[0054] As used herein, "patient" or "subject" includes animals or humans; in one embodiment, the term "patient" refers to a human subject.

[0055] As used herein, "mutagenic compound" refers to a compound whose co-administration effects are studied, such as CYP3A inducers and PPIs.

[0056] As used in this application, "protocol" refers to a method or plan for administering one or more APIs to a subject in need of treatment. The term "protocol" is intended to cover the patient's overall detailed care plan and the individual or partial steps that are part of the overall plan. For example, a regimen may include the dosage of each API that the patient will (or is) receiving, the combination of APIs that the patient receives, the timing and method of administration of each API (e.g., considering the effects that DDI, food effects, and different formulations or delivery methods may have on absorption and bioavailability) and the management of side effects, as well as an overall plan covering the dosage, combination, timing and method of administration and side effects considered together.

[0057] "Proton pump inhibitors" or "PPIs" are drugs that inhibit the production of H + / K + Drugs that activate the ATPase proton pump and cause a decrease in gastric acid production. Because PPIs reduce gastric acid production, they can increase gastric pH, which can affect the solubility and potential bioavailability of orally delivered drugs. Examples of PPIs include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.

[0058] "Steroid-resistant" (SR) cGVHD is defined as cGVHD that progresses on the use of steroids or corticosteroids (in one embodiment, on the use of prednisone).

[0059] "Standard treatment conditions" refers to the treatment and / or dosage regimen used to administer besudil to a patient for the treatment of cGVHD, wherein the patient is also not co-administered a CYP3A inducer or PPI during the course of treatment, per the above definition of "co-administration."

[0060] A "therapeutically effective amount" of an API refers to an amount sufficient to achieve treatment of the disease state being treated when administered to a human to treat a disease (e.g., cGVHD). As applied to human cGVHD, "treating" or "treatment" includes (1) reducing the risk of cGVHD and / or inhibiting cGVHD, i.e., preventing or reducing the occurrence of cGVHD or its clinical symptoms; and (2) alleviating cGVHD, i.e., causing regression, reversal or improvement of cGVHD or reducing the number, frequency, duration or severity of its clinical symptoms.

[0061] The therapeutically effective amount of the API may vary depending on the health and physical condition of the subject to be treated, the degree of disease progression, the assessment of the medical condition, and other relevant factors. It is expected that the therapeutically effective amount may fall within the range that can be determined by experimentation and by reference to clinical trial data and results described, for example, in Examples 1 and 2 of the present application and in the scientific literature. Exemplary Embodiments

[0062] In some embodiments, besudil or a pharmaceutically acceptable salt thereof (compound) for use in treating chronic graft-versus-host disease (cGVHD) in a subject is provided, wherein at least one CYP3A inducer or a proton pump inhibitor (PPI) is co-administered to the subject.

[0063] In another embodiment, at least one CYP3A inducer is co-administered to the subject simultaneously with besudil; in another embodiment, the CYP3A inducer is a glucocorticoid, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampicin (rifamycin), fosphenytoin, lumacato, lumacato-ivacator, mitotane, St. John's wort, phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cynomolgus, dabrafenib, dexamethasone, metamizole, elagolix, estradiol, eslicarbazepine, lorlatinib, mirapival, modafinil, nafcillin, pegidatinib, rifabutin, rifapentine, sotolacib, armodafinil, modafinil, and rufinamide.

[0064] In another embodiment, the CYP3A inducer is a CYP3A4 inducer.

[0065] In another embodiment, the CYP3A inducer is a strong CYP3A inducer; in one embodiment, the strong CYP3A inducer is rifampicin or phenytoin.

[0066] In another embodiment, the CYP3A4 inducer is phenobarbital, phenytoin, rifampin, St. John's wort, or a glucocorticoid.

[0067] In another embodiment, the CYP3A4 inducer is rifampicin.

[0068] In another embodiment, the PPI is co-administered to the subject simultaneously with besudil.

[0069] In another embodiment, the PPI is omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, or ilaprazole.

[0070] In another embodiment, the PPI is rabeprazole or omeprazole.

[0071] In another embodiment, the dose of besudil co-administered according to the present application is about 400 mg per day; in other embodiments, the dose of the compound (besudil) is about 200 mg administered twice a day, with a total daily dose of about 400 mg; in other embodiments, the dose of the compound (besudil) is in the range of about 400 mg to 800 mg per day; in other embodiments, the dose of the compound (besudil) is 400 mg per day, 400 mg twice a day, or 800 mg per day.

[0072] In some embodiments, the dose of the compound is increased compared to the clinically recommended dose of the compound for use in said subject under standard treatment conditions to mediate the exposure reducing effect of the co-administered CYP3A inducer and / or PPI.

[0073] In another embodiment, a method of co-administering the CYP3A inducer rifampicin with besudil is provided, wherein the exposure reducing effect of rifampicin is characterized by a decrease in Cmax of about 59% and / or a decrease in AUC of besudil of about 72%.

[0074] In another embodiment, a method of co-administering the CYP3A inducer efavirenz with besudil is provided, and the exposure reducing effect of efavirenz is characterized by a decrease in Cmax of about 32% and / or a decrease in AUC of besudil of about 35%.

[0075] In another embodiment, a method of co-administering a PPI (eg, omeprazole, rabeprazole) with besudil is provided, wherein there is an exposure reducing effect characterized by a decrease in the Cmax and / or AUC of besudil, substantially as shown in Table 4 herein.

[0076] In another embodiment, a method of co-administering a PPI and / or a CYP3A inducer with besudil is provided, wherein the CYP3A inducer is rifampicin administered at a daily dose depending on the subject's body weight and in the range of about 10 to 20 mg / kg; and / or wherein the CYP3A inducer is rifampicin administered at a dose of about 600 mg per day for about 5 to 9 days; or wherein the PPI is omeprazole administered at a dose of about 20 mg to 120 mg per day; or wherein the PPI is omeprazole administered at a dose of 20 mg per day; or wherein the PPI is rabeprazole administered at a dose of about 5 to 40 mg per day; or wherein the PPI is rabeprazole administered at a daily dose of 20 mg twice a day.

[0077] In some embodiments, the use or method comprises a treatment cycle wherein a CYP3A inducer or PPI is administered sequentially on days when the subject does not receive a dose of the compound (besudil); in some embodiments, the CYP3A inducer or PPI is administered prior to administration of the compound.

[0078] In some embodiments, the use or method comprises a treatment cycle wherein the CYP3A inducer or PPI is administered substantially simultaneously with the dose of the compound (besudil).

[0079] In some embodiments, a method of administering a compound (or besudil) to a subject is provided, the method comprising administering a high-fat, high-calorie meal about one hour or less (in some embodiments, within thirty minutes or less; in some embodiments, within a range of thirty minutes to one hour before administering the compound) prior to administering the compound.

[0080] In some embodiments, a method of treating chronic graft-versus-host disease (cGVHD) in a subject who is concurrently taking a CYP3A inducer or a proton pump inhibitor (PPI) is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of besudil mesylate.

[0081] In some embodiments, a method for treating a subject having cGVHD is provided, the method comprising the steps of: a) determining whether the subject requires treatment with at least one CYP3A inducer or PPI and, if so, determining the dosage thereof; b) 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 (compound) for a subject under standard conditions; and c) determining an upward adjusted dose of a compound to be administered to said subject to mediate an exposure reducing effect of said CYP3A inducer and / or proton pump inhibitor in treating said cGVHD.

[0082] In some embodiments, a method of administering an adjusted dose of besudil to account for an exposure reducing effect of a PPI and / or CYP3A inducer is provided, wherein the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 30% to 90%; in some embodiments, the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 30% to 80%; in some embodiments, the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 35% to 75%; in some embodiments, the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 55% to 90%; in some embodiments, the exposure reducing effect is characterized by a decrease in the AUC of besudil by about 60% to 90%; in some embodiments, the exposure reducing effect is characterized by a decrease in the AUC of besudil by about 55% to 85%; in some embodiments, the exposure reducing effect is characterized by a decrease in the AUC of besudil by about 40% to 60%.

[0083] In some embodiments, a method of treating chronic graft-versus-host disease (cGVHD) in a subject who is concomitantly taking a CYP3A inducer or a proton pump inhibitor (PPI) is provided, the method comprising administering to a subject in need thereof a regimen to mediate the exposure-reducing effect of the CYP3A inducer or the PPI and to take into account the food effect.

[0084] In some embodiments, the subject receiving the treatment has undergone an allogeneic hematopoietic stem cell transplant as a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplant is a haploidentical HSCT.

[0085] In some embodiments, besudil treatment is continued based on the patient's tolerance until active cGVHD symptoms subside or progress. The number of cycles and duration of treatment depend on the patient. In some embodiments, besudil is administered to the patient in one or more 28-day cycles.

[0086] In some embodiments, the range of cycle number is 3 to 15. In some embodiments, the range of cycle number is 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 range of cycle number is 5 to 11. In some embodiments, the range of cycle number is 6 to 12. In some embodiments, the range of cycle number is 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the range of cycle number is 5 to 7. In some embodiments, the range of cycle number is 5 to 6. In some embodiments, the cycle number is 5. In some embodiments, the cycle number is 6. In some embodiments, the cycle number is 7. In some embodiments, the cycle number is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0087] In some embodiments, the number of cycles ranges from 3 cycles to loss of response. In some embodiments, the number of cycles ranges from 4 cycles to loss of response. In some embodiments, the number of cycles ranges from 5 cycles to loss of response. In some embodiments, the number of cycles ranges from 6 cycles to loss of response. In some embodiments, the number of cycles ranges from 7 cycles to loss of response. In some embodiments, the number of cycles ranges from 8 cycles to loss of response. In some embodiments, the number of cycles is greater than 3, 4, 5, 10, 15, 20, 25, or 30, or until a desired response is achieved.

[0088] In some embodiments, the subject experiences an improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences a reduction in LSS score of at least 7 points. In some embodiments, the subject experiences a reduction in LSS score of at least 10 points. In some embodiments, the improvement is maintained in at least two consecutive assessments. In some embodiments, the LSS score is assessed at baseline and on Day 1 of each cycle starting from Day 1 of Cycle 2.

[0089] 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.

[0090] In some embodiments, the subject experienced a complete response to the last treatment for graft-versus-host disease prior to besudiil. In some embodiments, the subject experienced a partial response to the last treatment for graft-versus-host disease prior to besudiil. In some embodiments, the subject experienced stable disease during the last graft-versus-host disease treatment prior to besudiil.

[0091] In some embodiments, the prior line of systemic therapy for chronic graft-versus-host disease has been discontinued.

[0092] In some embodiments, the prior line of systemic therapy is selected from prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0093] In some embodiments, the cGVHD is steroid-resistant (SR) cGVHD.In some embodiments, the subject is resistant to the last line of treatment prior to besudil treatment.

[0094] In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from 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 1 cycle of besudil 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 1 cycle of besudil treatment. In some embodiments, the dose of 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 1 cycle of besudiil treatment. In some embodiments, concomitant corticosteroid therapy is discontinued after at least 1 cycle of besudiil treatment.

[0095] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0096] In some embodiments, the subject has at least 4 organs affected. In some embodiments, the subject has at least 3 organs affected. In some embodiments, the subject has at least 2 organs affected. tablet

[0097] Besudil mesylate is a yellow powder that is virtually insoluble in water. Besudil tablets can be prepared for oral administration. Each tablet contains 200 mg of the free base, equivalent to 242.5 mg of besudil 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 oval tablet with a debossed pattern "KDM" on one side and a debossed pattern "200" on the other side. Tablets are stored at room temperature 20°C to 25°C (68°F to 77°F); excursions are permitted at 15°C to 30°C (59°F to 86°F). Clinical Approval and Pharmacokinetics

[0098] Based on the efficacy and safety observed in clinical studies, 200 mg per day was selected as the preferred dose for the treatment of SR cGVHD when besudelin was administered without co-administration of CYP3A inducers and / or proton pump inhibitors. TM ) states that the recommended dose is 200 mg taken orally once daily with food.

[0099] The dose of 200 mg twice daily was well tolerated and showed higher responses in certain organs (e.g., skin). However, the difference compared to the 200 mg daily dose was not considered significant in those settings used for labeling purposes.

[0100] Unless otherwise specified, the following pharmacokinetic parameters are presented below for chronic GVHD patients dosed with 200 mg of besudiil once daily. The mean (coefficient of variation, CV%) steady-state AUC and Cmax of besudiil were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of besudiil increased in a roughly proportional manner over the dose range of 200 and 400 mg (1 to 2 times daily recommended doses). The accumulation ratio of besudiil was 1.4.

[0101] Absorption: Following once-daily or twice-daily dosing of 200 mg in patients, the median Tmax of besudil at steady state was 1.26 to 2.53 hours. Following a single dose of besudil in healthy subjects, the mean (CV%) bioavailability was 64% (17%).

[0102] Food Effect: In healthy subjects, the Cmax and AUC of besudil increased 2.2-fold and 2-fold, respectively, following administration of a single besudil dose with a high-fat, high-calorie meal (800 to 1,000 calories, with approximately 50% of the total caloric content of the meal coming from fat), compared to the fasting state. The median Tmax was delayed by 0.5 hours.

[0103] Distribution: After a single dose of besudil in healthy subjects, the geometric mean volume of distribution was 184 L (geo CV% 67.7%). In vitro, the binding rates of besudil to human serum albumin and human α1-acid glycoprotein were 99.9% and 98.6%, respectively.

[0104] Elimination, Metabolism, and Excretion: In patients, the mean (CV%) elimination half-life of besudil was 19 hours (39%) and the clearance was 9.83 L / hour (46%). In vitro, besudil is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9. Following a single oral dose of radiolabeled besudil in healthy subjects, 85% of the radioactivity was recovered in the feces (30% unchanged) and less than 5% of the radioactivity was recovered in the urine.

[0105] The following abbreviations may aid in considering the embodiments and description of the present application. abbreviation Example Example 1: Phase I Two-Part Open-Label Study to Evaluate the Effects of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the Pharmacokinetics of Besudinil

[0106] A clinical drug-drug interaction (DDI) study was conducted to investigate the effects of CYP3A4 inhibitors and CYP3A4 inducers on the pharmacokinetics (PK) of besudiil. Itraconazole and rifampicin (CYP3A4 inhibitors and inducers, respectively) were selected as exemplary DDI candidates for this evaluation. In addition, since the solubility of besudiil 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 besudiil was also evaluated in this DDI study.

[0107] The primary objectives of this DDI study were to (1) determine the effects of itraconazole, rifampin, and rabeprazole on the PK of besudil following a single oral 200 mg dose and (2) determine the effects of omeprazole on the PK of besudil following a 200 mg twice daily (BID) dose in healthy male subjects. Secondary objectives were to provide additional information on the safety and tolerability of this dosing regimen in healthy men. Study Design

[0108] This was a single-center, non-randomized DDI study conducted in 35 (Part 1) and 38 (Part 2) healthy men. The key inclusion criterion was men aged 18 to 55 years (inclusive). The study was conducted in 2 parts: In Part 1 (Periods 1 to 4), besudil was investigated when co-administered with itraconazole, rabeprazole, and rifampicin. In Part 2, co-administration with omeprazole was investigated. The study design is presented in Figure 1 middle.

[0109] On the first day of each period (1st to 4th period) in Part 1, 35 subjects received a single dose of 200mg besudiil tablets. In the 2nd to 4th period, repeated doses of 200mg itraconazole QD, 20mg rabeprazole BID or 600mg rifampicin QD were also administered for several days before besudiil administration, and the above drugs (only itraconazole and rabeprazole) were administered concomitantly with besudiil on the first day. At least 2 to 8 days of washout occurred between each period to take into account at least 5 half-lives of the active part of the previous period medication. On the first day of each period (1st and 2nd period) in Part 2, 38 independent subjects received 200mg besudiil tablets BID (12 hours apart). During the 2nd period, repeated doses of 20mg omeprazole QD were administered for 3 days before besudiil administration, and administered together with besudiil doses on the 1st day.

[0110] In both study parts, subjects were fasted overnight before besudil administration. Before receiving besudil, a standard breakfast consisting of 1 bowl of cereal, 200 mL of semi-skimmed milk, and 1 croissant or roll with pre-filled jam was provided. All besudil doses were administered 30 minutes after the start of the meal, because besudil administered with food reduces the rate of absorption and increases the extent of absorption, as described in Example 2.

[0111] Sample collection and analysis

[0112] In each period of Part 1 and Part 2, blood was collected at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 hours before and after administration of Besudiil to analyze Besudiil, KD025m1 and KD025m2. In Part 2, additional blood samples were collected at 12.5, 13, 13.5, 14, 15, 16, 17, 18, 20 and 22 hours after administration of Besudiil. Blood samples were collected in 6mL K3EDTA tubes and processed within 30 minutes after collection. Then within 90 minutes after collection, the resulting plasma was frozen and stored at 70°C until transported to the bioanalysis laboratory.

[0113] Besudiol and its two metabolites (KD025m1 and KD025m2) were prepared for sample analysis using a protein precipitation method and quantified by a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method in a validation range of 10 to 5000 ng / mL. Although the concentration of promutagenic compounds was not quantified, co-administration studies were performed to demonstrate that the presence of itraconazole, rabeprazole, rifampicin, and omeprazole did not affect the quantification of besudiol in human plasma.

[0114] Statistical data analysis

[0115] The sample size calculation was based on the following assumptions: 1) Based on the food effect, C max The within-subject variability is 50% and the AUC last The intra-subject variability of C max and AUC last 90% confidence interval (CI) with a type 1 error of 0.05; 3) an acceptance interval of 70.00 to 143.00%; and 4) 80% powder, assuming the true ratio is between 95.00 and 105.00. Based on these assumptions, it is estimated that 34 participants are needed to evaluate C max (PK parameter with the highest variability).

[0116] The PK population was defined as subjects who received at least 1 dose of besudil and had at least 1 valid post-dose concentration for PK parameter estimation. In addition, subjects had to meet the following criteria for at least 1 analyte characteristic: 1) max The PK analysis data set was a subset of the relevant PK population and included subjects with sufficient valid PK characteristics who had completed both the test (besudilar + mutator compound) and reference (besudilar alone) treatment periods to allow relevant treatment comparisons to be made.

[0117] The PK parameters of plasma besudiol, KD025m1 and KD025m2 were calculated using the standard non-compartmental model approach in Phoenix WinNonlin (v8.0). The main PK parameters of besudiol and its main metabolites were C max , AUC last and AUC inf .

[0118] To evaluate the effect of each mutagenic compound on besudil PK (the primary endpoint of the study), C max , AUC last and AUC inf Formal statistical analyses were performed. Paired treatment comparisons were performed with besudiil 200 mg QD alone as reference and besudiil 200 mg QD + a mutagenic compound (itraconazole, rifampicin, rabeprazole, or omeprazole) as test. For each comparison, the PK parameters were natural log transformed and analyzed using a mixed effects model that included treatment as a fixed effect and subject as a random effect. Adjusted geometric mean ratios (GMRs) and corresponding 90% CIs were calculated. last and AUC inf If the 90% CI of the results was within the acceptance interval of 70.00% to 143.00%, it was concluded that there was no effect of the pro-mutagenic compound on the PK of besudil. Security

[0119] The safety and tolerability of besudild were secondary endpoints of the study and were evaluated by AEs, vital signs, physical examination, electrocardiogram (ECG), and clinical laboratory tests. All subjects who received at least one dose of besudild or a mutagenic compound were included in the safety population. result Subject disposition and demographics

[0120] A total of 35 healthy men were enrolled and received medication in Part 1 of the study. Five subjects were discontinued early due to withdrawal of consent or investigator's discretion (poor protocol compliance / positive drug test) and did not receive all 4 treatments. In Part 2 of the study, a total of 38 healthy men were enrolled and completed two treatment periods. Table 1 further shows the subject disposition of the study.

[0121] Table 1: Subject disposition for the study of Example 1

[0122] The age range of subjects was 20 to 55 years in Part 1 and 18 to 52 years in Part 2, with median ages of approximately 34 and 30 years, respectively. All subjects were within the protocol-defined body mass index (BMI) range, spanning from 21.1 to 32.2 kg / m 2 Most subjects were white. According to the study exclusion criteria, no study participants were current smokers, and all drank between 0 and 20 units of alcohol per week. The subject demographics of the study are further presented in Table 2. Table 2: Subject Demographics by Treatment SD = Standard Deviation Drug-drug interactions

[0123] The PK parameters of the analytes besudil (Table 3A), KD025m2 (Table 3B) and KD025m1 (Table 3C) when besudil was administered alone and in combination with itraconazole, rabeprazole, rifampicin and omeprazole are shown in Tables 3A-3C. The results of the statistical analysis performed to evaluate the drug interactions between besudil and each combination drug are presented in Table 4.

[0124] Table 3A-3C: PK parameters of besudil after administration with or without CYP3A compounds and PPIs Table 3A: Analyte = Besudil Table 3B: Analyte = KD025m2 Table 3C: Analyte = KD025m1 In Tables 3A-3C, except for T max In addition, all parameters are presented as geometric mean (geometric CV%) and arithmetic mean (standard deviation). max Presented as median (range). N = number of subjects in the PK analysis dataset; n = number of subjects with observations; NC = not calculated; NR = not reported a n = 34; b n = 33; c n = 29; d n = 28;e n = 27; f n = 11; g n = 31; h n = 23; i n = 13; j n = 19; k n = 37; l n = 35; m n = 32; n n = 36; o n = 12; p n = 14; q n = 15; r n = 17; s n = 20; t n = 2; u n = 3; v n = 21; w n=7

[0125] Table 4: Statistical analysis of besudil Pk parameters after administration of besudil alone and with itraconazole, rifampicin, rabeprazole or omeprazole CI = confidence interval; GMR = adjusted geometric mean ratio; N = number of subjects in the PK analysis data set; n = number of subjects with observations; N / A = not applicable; NC = not calculated Test: single dose of 200 mg besudil QD + 200 mg itraconazole QD × 9 days, 20 mg rabeprazole QD × 4 days, or 600 mg rifampin QD × 9 days (Part 1); 200 mg besudil BID + 20 mg omeprazole QD × 3 days on day 1 (Part 2) Reference: single dose of 200 mg besudil QD alone (Part 1) or 200 mg besudil BID alone (Part 2) Effects of itraconazole

[0126] After administration of 200 mg of besudil (QD × 9 days) with or without 200 mg of itraconazole, besudil was rapidly absorbed. max It appeared 3 hours after taking the drug with or without itraconazole (Figure 2). Co-administration of itraconazole and besudil resulted in a geometric mean C max , AUC last and AUC infThe value was 1.2 times that of besudil alone, with the 90% CI of GMR within the relative bioavailability limit of 70.00% to 143.00% (Table 4). Concomitant administration of itraconazole did not appear to reduce or prolong the elimination half-life of besudil. After co-administration of besudil and itraconazole, the concentration of the metabolite KD025m1 in all subjects except one decreased to unquantifiable levels. Similarly, for C max , AUC last and AUC inf , KD025m2 exposure decreased by 35%, 33% and 33%, respectively (Table 3A-Table 3C). Effects of Rifampin

[0127] Administration of 200 mg besudil with or without 600 mg rifampin (QD x 9 days) resulted in rapid absorption of besudil, with a median T observed at 3 hours post-dose. max (Figure 2). In the presence of rifampicin, peak and total besudil exposure levels were reduced because C max , AUC last and AUC inf The results were about 59%, 72% and 72% lower than when besudil was used alone, respectively. The concomitant administration of rifampicin also reduced the elimination half-life of besudil from a geometric mean of 7.89 hours without rifampicin to 2.17 hours with rifampicin. Compared with besudil alone, rifampicin increased the exposure of the metabolite KD025m1 (C max and AUC last ) increased by 129% and 150%, respectively, and decreased the exposure of the metabolite KD025m2 by 55% to 67%, respectively. Effects of the PPIs rabeprazole and omeprazole

[0128] After concomitant administration of a single 200 mg dose of besudol and 20 mg of rabeprazole (a PPI), the median T max The delay was 2 hours (Figure 2), and the mean besudil exposure was approximately 87% lower than that of besudil alone (C max ), 82% (AUC last ) and 80% (AUC inf )(Table 3A). For all parameters, the 90% CIs did not fall within the limits of relative bioavailability in this study. Rabeprazole appeared to have no effect on the elimination half-life of besudil. As with besudil, exposure to the metabolites KD025m1 and KD025m2 was reduced following coadministration of besudil with rabeprazole. KD025m1 levels were not quantifiable in all but one subject, and the C of KD025m2 was negative in the presence of rabeprazole. maxand AUC last A decrease of 93% and 94% respectively.

[0129] Similarly, treatment with 200 mg besudil BID and 20 mg omeprazole (a slightly weaker PPI than rabeprazole) resulted in a delay of 1 to 2 hours in the absorption of besudil. In the presence of omeprazole, the C of the first dose of besudil was significantly higher than that of besudil alone. max 68% lower; AUC of besudil at first dose 0-24 The 90% CIs for all primary endpoints did not fall within the relative bioavailability acceptance limits of 70.00% to 143.00%. Concentrations of KD025m1 were sparse and sporadic following administration of besudiil with omeprazole, with several subjects having unquantifiable characteristics after two dosing occasions. Concentrations of KD025m2 were also reduced when besudiil was administered concomitantly with omeprazole, with C max，第一剂量 , C max，第二剂量 and AUC 0-24 Reductions of approximately 73%, 57% and 63% respectively. Security

[0130] There were no deaths or AEs leading to subject withdrawal from the study. A total of 33 treatment-emergent AEs (TEAEs) were reported in Periods 1, 2, and 4, most of which were mild in severity (Table 3). Three AEs (all mild in severity) were considered possibly related to besudild: abdominal distension, hot flashes, and fatigue. One serious AE (SAE) of ankle fracture was reported 11 days after dosing with besudild plus itraconazole. This SAE was serious and was considered unrelated to besudild. Gastrointestinal disorders were the most commonly reported system organ class, reported by 3 subjects after taking besudild alone and 5 subjects after taking besudild plus itraconazole. There were no clinically significant laboratory findings, except for 1 moderate AE of neutropenia (common in healthy subjects of African origin). analyze

[0131] This was a single-center, nonrandomized, DDI study conducted in healthy male subjects. The PK objectives of this study were to determine the effects of CYP3A4 inhibitors and inducers (itraconazole and rifampicin, respectively) and PPIs (rabeprazole and omeprazole) on the PK of besudild and its metabolites after oral administration in healthy male subjects. Itraconazole, an index CYP3A4 inhibitor, and rifampicin, an index CYP3A4 inducer, were selected as mutagenic compounds. Rabeprazole and omeprazole PPIs were selected to evaluate pH-dependent changes in besudild PK based on the ability of rabeprazole to increase pH levels and the widespread use of omeprazole in the treatment of gastroesophageal reflux disease (GERD) and management of gastrointestinal involvement in patients with cGVHD.

[0132] Although itraconazole is classified as a strong CYP3A inhibitor, it does not induce maximal CYP3A inhibition compared to ketoconazole. However, itraconazole has been shown in the literature to achieve clinically relevant inhibition of CYP3A4 at a dose regimen of 200 mg QD for 4 days. 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 andmethylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol. 2001; 51(5): 443-450.

[0133] In this study, a 9-day regimen of 200 mg QD was utilized (from day -7 to 1 day after besudilar administration [day 2]). This 9-day duration was considered short enough to avoid the time-dependent half-life increase 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.

[0134] The 200 mg dose level is further supported based on the itraconazole prescribing information as it is the clinically recommended dose for the treatment of various fungal infections. While no meaningful changes in besudild exposure were noted when co-administered with itraconazole, a CYP3A4 inhibitor, reduced exposure of KD025m2 was observed. Additionally, KD025m1 concentrations were reduced to almost unquantifiable levels. This supports preclinical data suggesting that CYP3A4 may play a role in metabolizing besudild to the ROCK2-active minor metabolite, KD025m1, and the ROCK2-inactive major metabolite, KD025m2.

[0135] With respect to rifampin, a 5- to 9-day dosing regimen of 600 mg QD has been modeled by others and shown to produce steady-state induction of CYP3A4 activity. Since this was also the labeled dosing regimen, the 9-day dosing prior to besudil administration was considered appropriate for this drug interaction study. Additionally, since rifampin is also an organic ion transporter (OAT) inhibitor, besudil and rifampin were not administered concomitantly on Day 1 to avoid confounding effects in the event that besudil was later identified as an OAT substrate. Coadministration with rifampin, a CYP3A4 inducer, resulted in a significant decrease in besudil exposure (C max , AUC inf and AUC last 59%, 72%, and 72%, respectively). Combined with the increase in KD025m1 exposure, these results suggest a higher degree of metabolism of besudil by induction of CYP3A4 activity. The geometric mean half-life value decreased from 7.89 (besudil alone) to 2.17 hours (with rifampicin); however, the reduction in half-life may be attributed to the distribution phase of besudil rather than a true elimination phase feature, as besudil concentrations in the presence of rifampicin reached unquantifiable levels earlier.

[0136] The effect of CYP3A4 induction on besudiidil metabolism is further supported by in vitro assessments that determined that metabolism of besudiidil to KD025m1 is CYP3A4 and CYP2C8 dependent, while metabolism to KD025m2 is CYP3A4 dependent, with further metabolism 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 increased exposure of KD025m1 observed with co-administration of rifampicin is consistent with the metabolic pathway of besudiidil. Additionally, while the generation of KD025m1 may be increased by induction of both CYP3A4 and CYP2C8, induction of the UGT1A1 enzyme may increase the elimination rate of KD025m2 even with increased generation via CYP3A4, explaining the reduced exposure of KD025m2 with rifampicin administration.

[0137] Rabeprazole, a strong PPI, inhibits gastric acid secretion by noncompetitively blocking H+ / K+-ATPase at the secretory surface of gastric parietal cells, thereby raising the intragastric pH to above 3.0. The recommended starting dose of rabeprazole sodium is 20 mg per day for subjects with GI ulcers and GERD and 60 mg per day for subjects with hypersecretion syndrome (Accord-UK Ltd. Summary of Product Characteristics: Rabeprazole 20 mg Gastro-resistant Tablets, available at: www.medicines.org.uk / emc / medicine / 27143 / SPC / Rabeprazole+20mg+Gastro-resistant+Tablets / . Updated April 16, 2020, accessed August 12, 2021). A dosing regimen of 20 mg BID followed by QD dosing for 3 days prior to besudol administration was selected for this short-term study. Omeprazole doses were administered at the lowest labeled dose (20 mg) in part 2 of the study to investigate weaker interactions of PPIs with besudil.

[0138] Exposure to besudild and its metabolites was reduced following coadministration with rabeprazole, a strong PPI, suggesting that increased gastric pH results in decreased solubility of besudild, which in turn reduces besudild absorption. Similar trends in the PK of besudild and metabolites were observed following coadministration with the weaker PPI omeprazole. These findings are consistent with previously performed solubility studies demonstrating that besudild solubility decreased 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 besudild and PPIs is possible; therefore, the prescribing information states that the besudild dosage should be increased when coadministered with a PPI.

[0139] It is important to note that although omeprazole has the potential to induce CYP3A4, it is a relatively weak CYP3A4 inducer and was only administered for a total of 4 days in this study. Therefore, any DDI is not thought to be due to CYP induction but rather likely to be due to the pH-restricted solubility of besudil.

[0140] The safety profile of besudild in this study was not evident for a single oral dose of 200 mg besudild alone and in combination with 200 mg itraconazole or 600 mg rifampin. Most TEAEs were mild in severity and all resolved by the end of the study. One SAE was reported; this event was not related to besudild.

[0141] Potential drug-drug interactions between besudil and itraconazole, a CYP3A4 inhibitor, and rifampin, a CYP3A4 inducer, were explored. No clinically meaningful changes in besudil PK were observed in the presence of itraconazole; however, concentrations of both besudil metabolites were reduced relative to besudil alone. Rifampin was found to have a significant effect on besudil PK, as observed by decreased exposures of besudil and KD025m2 and increased exposures of KD025m1 in the presence of rifampin. Coadministration of both the PPI rabeprazole and the weaker PPI omeprazole with besudil resulted in significant decreases in besudil and metabolite exposures; therefore, it is recommended that besudil be administered at higher levels when coadministered with a PPI. No safety or tolerability risk has been established for single doses of besudil alone or in combination with repeated doses of itraconazole, rifampin, omeprazole, or rabeprazole. Example 2: Two Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Besudil in Healthy Adult Subjects

[0142] The interaction between food and the pharmacokinetic profile of orally administered drugs is influenced by many factors. The mechanisms driving pharmacokinetic food-drug interactions depend largely on the drug substance and formulation, effects on gastrointestinal physiology (e.g., pH, environment, emptying rate), and meal composition (caloric and fat content). Food effects represent a complex challenge in oral drug administration.

[0143] In order to evaluate the pharmacokinetic (PK) differences between the two formulations and determine the presence of a potential food effect of besudil, two Phase 1 studies were conducted. The first study was an initial preliminary food effect study that evaluated the administration of besudil capsules with food. The following study was a relative bioavailability and food effect study that compared commercially available tablets with capsule formulations in addition to characterizing the food effect of besudil tablets. This example reports the PK and safety results from the two studies. Study Design

[0144] Both studies were single-center, open-label, randomized, single-dose crossover studies conducted in healthy men. Key inclusion criteria included subjects aged 18 to 55 years (inclusive) and using a highly effective birth control method during the study and 1 to 3 months after the study. For both studies, the API was besudil mesylate, equivalent to 100 mg (capsules) or 200 mg (tablets) free base.

[0145] In the first food effect study, a dose of 500 mg besudil (5×100 mg capsules) was chosen because there was no drug-related toxicity at this dose in previous single and multiple ascending dose (SAD / MAD) studies. Twelve healthy men were enrolled in the study and randomized in a crossover manner to receive a single dose of 5×100 mg besudil capsules under fed and fasted conditions. The study design is shown in the Figure 5 middle.

[0146] For the fed condition, subjects were given a high-fat meal consisting of fried eggs, bacon, buttered toast, hash browns, and 8 ounces of whole milk 30 minutes before receiving besudil. For the fasted condition, subjects fasted overnight for ≥10 hours before receiving besudil and fasted for an additional 4 hours after dosing. Water was allowed ad libitum except for 1 hour before and after dosing. A 7-day washout period separated each dose of besudil administered under fed or fasted conditions.

[0147] In the second relative bioavailability / food effect study, commercially available tablets and early formulation capsules were studied. The 200 mg tablet dose was selected because it was well tolerated in healthy subjects and produced quantifiable concentrations throughout the PK curve. In addition, since besudiil tablets and capsules are manufactured in 200 mg and 100 mg dosage units, respectively, the 200 mg dose allows for accurate comparative variability assessments between the two formulations. A total of 23 healthy men were enrolled in the study and randomly received 3 single doses of 200 mg besudiil according to their designated treatment order. These demographic data are shown in Table 5 below. Table 5: Demographic data of clinical study Example 2 (second study) BA = bioavailability; BMI = body mass index; PK = pharmacokinetics; SD = standard deviation

[0148] For treatment A, subjects took 200 mg besudiil tablets after fasting overnight, and then continued to fast for 4 hours after taking the medicine. For treatments B and C, before taking the medicine, the subjects ate a high-fat breakfast consisting of hash browns, bacon, fried eggs, white bread and 240 mL whole milk within 25 minutes. Thirty minutes after the start of breakfast, the subjects received a single dose of 200 mg besudiil tablets (treatment B) or 2 × 100 mg besudiil capsules (treatment C). All subjects will receive each treatment, and the washout period between each period is at least 6 days. In addition to 1 hour before and after taking the medicine, free drinking water is allowed in all research periods. Pharmacokinetic sample collection

[0149] In both studies, serial blood samples were collected for PK analysis before dosing and 1, 2, 4, 6, 8, 12, 16, 24, and 36 hours after dosing. Additional samples were collected 30 hours after dosing in the first study; 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 in K3EDTA tubes on ice and processed within 30 minutes of collection and then frozen at approximately -70°C to -80°C immediately after collection.

[0150] Sample preparation was performed by protein precipitation. Besudil 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. Pharmacokinetic and statistical analysis methods

[0151] The primary endpoint of the first initial preliminary food effect study was safety and tolerability, and the secondary endpoints were the PK of besudil and its metabolites (KD025m1 and KD025m2). For the second relative bioavailability / food effect study, the primary endpoint was the comparison of the PK parameters of besudil administered as a tablet in the fed state compared to the fasted state. Secondary endpoints included the PK comparison of besudil administered as a tablet compared to a capsule formulation and safety and tolerability assessments.

[0152] Statistical analysis was performed in SAS using the PROC MIXED procedure and restricted maximum likelihood estimation methods. In both studies, the presence of food effects was evaluated by formal statistical analysis of natural log-transformed AUC and Cmax using mixed effects modeling techniques. The model included treatment, period, and sequence as fixed effects, and subjects nested within the sequence as random effects. The adjusted geometric mean ratio (GMR) and its 90% confidence interval (CI) for fed (test) versus fasted (reference) treatment were calculated. If the 90% CI was within the bioequivalence limits of 80.00% to 125.00%, it was inferred that there was no food effect.

[0153] To evaluate the relative bioavailability between formulations in the second study, the same analysis was performed for both tablets (test) vs. capsules (reference) in the fed state. For both studies, all subjects who received at least one dose of study drug and had available post-dose PK data were included in the PK population. result Pharmacokinetic results

[0154] In the initial preliminary food effect study, after administration of a single oral dose of besudil 500 mg (capsules) under both fed and fasting conditions, besudil was rapidly absorbed with no observed lag time. Cmax was reached 2 hours earlier under fasting conditions compared to fed conditions. After reaching peak concentrations, mean plasma concentrations of besudil declined in a similar manner between the two treatments.

[0155] Both Cmax and AUC of besudil were higher in the fed state compared to the fasted state, with GMRs above 125% for all PK parameters included in the statistical analysis. The inter-subject variability of Cmax and AUC in the fasted state was slightly lower compared to the fed state. Similar trends were observed for the metabolite data.

[0156] In a second relative bioavailability / food effect study, administration of 200 mg tablets with a high-fat breakfast reduced variability and increased besudil exposure to 225% (Cmax) and 180% (AUCinf) of that observed under fasting conditions. A 0.5 h delay in Tmax was observed with fed dosing. Statistical analysis of GMR further supports the existence of a food effect. Circulating metabolite levels were low regardless of formulation and fed state.

[0157] These results from the first and second studies are summarized in Table 6 below, which shows the pharmacokinetic parameters of besudil from the two food effect studies and the relative bioavailability data from the second study. Table 6: Pharmacokinetic parameters of besudil in two food-effect studies

[0158] As this application Figure 6 As shown, after a single dose of 200 mg besudil in the fed state, besudil exposure was slightly higher for tablets compared to capsules. The exposure variability between subjects was moderate for tablets and capsules, but slightly higher for tablets. Besudil exposure (Cmax and AUC) was approximately 17%-19% higher for tablets compared to capsules.

[0159] These results suggest that administration with food reduces the rate of absorption of besudild and increases its extent of absorption. This was first demonstrated in the initial food effect study, in which a high-fat meal given 30 minutes before besudild administration significantly increased systemic exposure (Cmax, AUC0-t, and AUCinf) to 2.5- to 3-fold that of besudild administered in the fasted state. Tmax was reached 2 hours later under fed conditions.

[0160] Comparable findings of increased rate and extent of absorption were noted in a second food effect study, in which administration of a 200 mg tablet under fed conditions delayed Tmax by 0.5 hours and increased besudil exposure to approximately 2-fold that of the tablet under fasting conditions. In addition, inter-subject exposure variability was reduced by approximately 60% when the tablet was administered with food. These results suggest that the besudil tablet formulation slightly minimizes the effect of food on PK compared with the capsule formulation and that food improves the consistency of exposure between subjects.

[0161] In addition to the food effect, the relative bioavailability of the two formulations was also evaluated under fed conditions. For both tablets and capsules, besudil was rapidly absorbed and eliminated, as evidenced by the rapid appearance of metabolites KD025m1 and KD025m2. The variability assessed by CV% of the exposure parameters was similar, indicating that there was no significant difference in the inter-subject variability of PK between the two formulations. Example 3: US REZUROCK TM (Besudil) FDA label

[0162] ---------------------------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)

[0163] -----------------------Dosage and administration---------------------- Recommended dose: 200 mg, taken orally once daily with food. (2.1) ---------------------Dosage form and strength-------------------- Tablet: 200 mg. (3)

[0164] ------------------------------Contraindications---------------------------- none. (4)

[0165] ------------------------------------Warnings and precautions---------------------- Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.1、8.1、8.3)

[0166] ----------------------------Drug Interactions----------------------------- Strong CYP3A inducers: Increase REZUROCK dose to 200 mg twice daily.(7.1) Proton Pump Inhibitors: Increase REZUROCK dose to 200 mg twice daily. (7.1)

[0167] ------------------------------Adverse Reactions----------------------------- The most common (≥20%) adverse reactions (including laboratory abnormalities) were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, lymphocytopenia, and hypertension. (6.1)

[0168] -----------------------Use in special populations----------------------- Lactation: Breastfeeding is not recommended. (8.2) See 17 for patient counseling information and FDA-approved patient labeling. Full Prescribing Information 1 Indications and Usage

[0169] 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. 2 Dosage and administration 2.1 Recommended Dosage

[0170] The recommended dose of REZUROCK is 200 mg, administered orally once daily until chronic GVHD progresses to the point where new systemic therapy is required. Instruct patients as follows: Swallow REZUROCK tablets whole. Do not cut, crush, or chew the tablets. Take REZUROCK with food at approximately the same time each day [see CLINICAL PHARMACOLOGY ( 12.3 )]. If a dose of REZUROCK is missed, instruct patients not to take an additional dose to make up for the missed dose.

[0171] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. Consider the risks and potential benefits of REZUROCK before initiating treatment with REZUROCK in patients with pre-existing severe renal or hepatic impairment [see CLINICAL PHARMACOLOGY ( 12.3 )]. 2.2 Dose adjustment for adverse reactions

[0172] Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly. Table 7 Adjust the dose of REZUROCK for adverse reactions. Table 7: Recommended Dose Modifications of REZUROCK for Adverse Reactions *Based on CTCAE v 4.03 2.3 Dose Modifications Due to Drug Interactions

[0173] Strong CYP3A inducers When coadministered with strong CYP3A inducers, increase the dose of REZUROCK to 200 mg twice daily [See Drug Interactions ( 7.1 )]. Proton pump inhibitors When coadministered with a proton pump inhibitor, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions ( 7.1 )]. 3 Dosage forms and specifications

[0174] Each 200 mg tablet is a light yellow film-coated oval tablet with a debossed design of "KDM" on one side and a debossed design of "200" on the other side. 4 Contraindications

[0175] none. 5 Warnings and Precautions 5.1. Embryo-fetal toxicity

[0176] Based on findings in animals and its mechanism of action, REZUROCK may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of besudil to pregnant rats and rabbits during the period of organogenesis produced adverse developmental outcomes, including embryo-fetal mortality and malformations at maternal exposures (AUC) lower than these parameters in patients at the recommended dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations ( 8.1、8.3 ), nonclinical toxicology ( 13.1 )]. 6 Adverse Reactions 6.1 Clinical Trial Experience

[0177] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic graft-versus-host disease

[0178] 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 Studies ( 14.1 )]. The median duration of treatment was 9.2 months (range, 0.5 to 44.7 months).

[0179] One patient reported fatal adverse reactions, including severe nausea, vomiting, diarrhea, and multi-organ failure.

[0180] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Adverse reactions leading to permanent discontinuation of REZUROCK in >3% of patients included nausea (4%). Adverse reactions leading to dose interruptions occurred in 29% of patients. Adverse reactions leading to dose interruptions in ≥2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, abnormal liver function tests, nausea, pyrexia, edema, and renal failure (2% each).

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

[0182] Table 8 summarizes the non-laboratory adverse reactions. Table 8: Treatment with REZUROCK > Non-laboratory adverse reactions in 10% of patients with chronic GVHD aInfection by unspecified pathogens, including acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, and septic shock. bIncluding influenza, rhinovirus infection, viral gastroenteritis, viral upper respiratory tract infection, viral bronchitis, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenza virus infection, varicella-zoster virus infection, and viral infection. c Includes cellulitis, Helicobacter infection, staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia coli urinary tract infection, Escherichia coli gastroenteritis, Pseudomonas infection, and bacterial urinary tract infection. dIncludes fatigue, weakness, and asthenia. eIncludes peripheral edema, systemic edema, facial edema, local edema, and edema. fIncluding nausea and vomiting. gIncludes abdominal pain, upper abdominal pain, and lower abdominal pain. hIncludes dyspnea, dyspnea on exertion, apnea, orthopnea, and sleep apnea syndrome. iIncludes cough and productive cough. jIncludes contusions, hematomas, epistaxis, increasing tendency to bruising, conjunctival hemorrhage, hematochezia, oral hemorrhage, catheter site hemorrhage, hematuria, hemothorax, and purpura. kIncludes extremity pain, back pain, flank pain, extremity discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. lIncluding headaches and migraines. mIncludes rash, maculopapular rash, erythematous rash, systemic rash, and exfoliative dermatitis. nIncluding itching and itching all over the body. Table 9 summarizes the laboratory abnormalities with REZUROCK. Table 9: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK 7. Drug Interactions 7.1 Effects of Other Drugs on REZUROCK

[0183] Strong CYP3A inducers

[0184] Coadministration of REZUROCK with strong CYP3A inducers decreased besudil exposure [see CLINICAL PHARMACOLOGY ( 12.3 )], which may reduce the efficacy of REZUROCK. When coadministered with strong CYP3A inducers, increase the dose of REZUROCK [see DOSAGE AND ADMINISTRATION ( 2.3 )].

[0185] Proton pump inhibitors

[0186] Coadministration of REZUROCK with proton pump inhibitors decreased besudil exposure [see CLINICAL PHARMACOLOGY ( 12.3 )], which may reduce the efficacy of REZUROCK. When coadministered with proton pump inhibitors, increase the dose of REZUROCK [see DOSAGE AND ADMINISTRATION ( 2.3 )]. 8 Use in special populations 8.1 Pregnancy

[0187] Risk Overview

[0188] Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology ( 12.1 )], REZUROCK may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of REZUROCK in pregnant women to evaluate the drug-associated risk. In animal reproduction studies, administration of besudil to pregnant rats and rabbits during the period of organogenesis produced adverse developmental outcomes, including altered growth, embryo-fetal mortality, and embryo-fetal malformations at maternal exposures (AUC) that were approximately ≥3 times (rats) and ≥0.07 times (rabbits) those at human exposures (AUC) at the recommended dose (see Number of animals according to ). Inform pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

[0189] data

[0190] Animal data

[0191] Embryo-fetal development studies were conducted in rats, where besudil was administered to pregnant animals at oral doses of 25, 50, 150 and 300 mg / kg / day during the organogenesis period in a pilot study, and at doses of 15, 50 and 150 mg / kg / day in a pivotal study. In the pilot study, maternal toxicity and embryo-fetal development effects were observed. Maternal toxicity (reduced 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, including the absence of anus and tail, umbilicus protrusion and dome-shaped head. The exposure (AUC) of rats at 50 mg / kg / day was approximately 3 times that of humans at the recommended dose of 200 mg.

[0192] In the embryo-fetal development study of rabbits, oral doses of besudil were administered to pregnant animals during the organogenesis period at 50, 125 and 225 mg / kg / day, resulting in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of ≥125 mg / kg / day. Embryo-fetal effects, including spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, malformations and reduced fetal weight, were observed at doses of >50 mg / kg / day. Malformations included the following malformations: tail (short), ribs (branched, fused or deformed), sternum (fused) and neural arches (fused, dislocated and deformed). The exposure (AUC) of rabbits at a dose of 50 mg / kg / day was approximately 0.07 times that of humans at the recommended dose of 200 mg. 8.2 Lactation Risk Overview

[0193] There are no available data regarding the presence of besudil or its metabolites in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions from besudil in the breastfed child, advise lactating women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose. 8.3 Females and Males of Reproductive Potential

[0194] REZUROCK may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy test

[0195] Verify the pregnancy status of females of reproductive potential prior to initiating treatment with REZUROCK. contraception measure female

[0196] Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one 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 apprised of the potential hazard to a fetus. male

[0197] Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. Infertility female

[0198] Based on findings in rats, REZUROCK may impair female fertility. Effects on fertility were reversible [see Nonclinical Toxicology ( 13.1 )]. male

[0199] Based on findings in rats and dogs, REZUROCK may impair male fertility. Effects on fertility were reversible [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use

[0200] The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years of age and older. The use of REZUROCK in this age group is supported by evidence from adequate and rigorously controlled studies of REZUROCK in adults, in which additional population pharmacokinetic data demonstrated that age and body weight have no clinically meaningful effects on the pharmacokinetics of the drug substance, that exposure to the drug substance is expected to be similar between adult patients and pediatric patients 12 years of age and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data from adult patients to pediatric patients.

[0201] The safety and effectiveness of REZUROCK have not been established in pediatric patients less than 12 years of age. 8.5 Elderly Use

[0202] Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years and older. No clinically meaningful differences in the safety or effectiveness of REZUROCK were observed compared to younger patients. 11 Drug instructions

[0203] Besudiol is a kinase inhibitor. The active pharmaceutical ingredient is besudiol mesylate, with a molecular formula of C27H28N6O5S and a molecular weight of 548.62 g / mol. The chemical name of besudiol mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide mesylate (1:1). The chemical structure is as follows:

[0204] Besudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0205] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base, equivalent to 242.5 mg of besudeli mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0206] The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide. 12 Clinical Pharmacology 12.1 Mechanism of Action

[0207] Besudild 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. Besudild downregulates proinflammatory responses in ex vivo or in vitro human T cell assays by modulating STAT3 / STAT5 phosphorylation and altering the Th17 / Treg balance. In vitro, besudild also inhibits aberrant profibrotic signaling. In vivo, besudild exhibits activity in animal models of chronic GVHD. 12.2 Pharmacodynamics

[0208] The exposure-response relationship and time course of the pharmacodynamic response to besudil have not been determined. 12.3 Pharmacokinetics

[0209] Unless otherwise specified, the following pharmacokinetic parameters are presented for chronic GVHD patients dosed with 200 mg of besudiil once daily. The mean (coefficient of variation, CV%) steady-state AUC and Cmax of besudiil were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of besudiil increased in a roughly proportional manner over the dose range of 200 and 400 mg (1 to 2 times, once daily, the recommended dose). The accumulation ratio of besudiil was 1.4. absorb

[0210] Following once-daily or twice-daily dosing of 200 mg besudil in patients, the median Tmax of besudil at steady state ranged from 1.26 to 2.53 hours. Following a single besudil dose in healthy subjects, the mean (CV%) bioavailability was 64% (17%). Effects of food

[0211] In healthy subjects, the Cmax and AUC of besudil increased 2.2-fold and 2-fold, respectively, following administration of a single besudil dose with a high-fat, high-calorie meal (800 to 1,000 calories, approximately 50% of total caloric content from fat) compared to the fasting state. The median Tmax was delayed by 0.5 hours. distributed

[0212] Following a single dose of besudil in healthy subjects, the geometric mean volume of distribution was 184 L (geoCV% 67.7%).

[0213] In vitro, the binding rates of besudil to human serum albumin and human α1-acid glycoprotein were 99.9% and 98.6%, respectively. eliminate

[0214] In patients, the mean (CV%) elimination half-life of besudil was 19 hours (39%) and the clearance was 9.83 L / hour (46%). metabolism

[0215] In vitro, besudil is metabolized primarily by CYP3A4 and, to a lesser extent, by CYP2C8, CYP2D6, and UGT1A9. excretion

[0216] Following a single oral dose of radiolabeled besudil in healthy subjects, 85% of the radioactivity was recovered in the feces (30% unchanged) and less than 5% of the radioactivity was recovered in the urine. Special Populations

[0217] The age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥ 60 and < 90 mL / min / 1.72 m 2 To eGFR ≥ 30 and < 60 mL / min / 1.72 m 2 ), no clinically significant differences in the pharmacokinetics of besudild were observed. The effect of severe renal impairment on the pharmacokinetics of besudild has not been studied. Drug interaction studies The impact of other drugs on clinical studies of besudil and model-guided approaches

[0218] Strong Cytochrome P450 (CYP) 3A Inhibitors: There were no clinically meaningful effects on besudil exposure when co-administered with itraconazole in healthy subjects.

[0219] Strong CYP3A inducers: In healthy subjects, co-administration of rifampin decreased the Cmax of besudil by 59% and the AUC of besudil by 72%.

[0220] Moderate CYP3A Inducers: In healthy subjects, co-administration of efavirenz is predicted to decrease the Cmax of besudil by 32% and the AUC of besudil by 35%.

[0221] Proton Pump Inhibitors: In healthy subjects, co-administration of rabeprazole decreased the Cmax of besudil by 87% and the AUC of besudil by 80%, and omeprazole decreased the Cmax of besudil by 68% and the AUC of besudil by 47%. Effects of Besudil on other drugs

[0222] CYP3A Substrates: Co-administration of besudil is expected to increase the Cmax and AUC of midazolam, a sensitive CYP3A substrate, by approximately 1.3-fold and 1.5-fold, respectively.

[0223] CYP2C9 Substrates: Co-administration of besudil is not expected to have a clinically meaningful effect on the exposure of CYP2C9 substrates (e.g., warfarin).

[0224] CYP2C8 Substrates: Coadministration of besudil is not expected to have a clinically meaningful effect on the exposure of CYP2C8 substrates that are not OATP1B1 substrates. In vitro studies Transporter systems: Besudild is a substrate of P-gp. Besudild inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations. Enzyme systems: Besudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9. 13 Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0225] Carcinogenicity studies have not been conducted with besudil.

[0226] Besudil was not genotoxic in the in vitro bacterial mutagenicity (Ames) assay, the in vitro chromosome aberration assay in human peripheral blood lymphocytes (HPBL), or the in vivo rat bone marrow micronucleus assay.

[0227] In a combined male and female rat fertility study, male animals treated with besudil were mated with untreated female animals, or untreated male animals were mated with female animals treated with besudil. Besudil was orally administered to male rats at a dose of 50, 150 or 275 mg / kg / day 70 days before mating and throughout the mating period, and was orally administered to female rats 14 days before mating and until the 7th day of gestation. At a dose of 275 mg / kg / day, adverse findings in female rats (treated with besudil or untreated but mated with treated male rats) included increased pre-implantation or post-implantation losses and reduced numbers of viable embryos. Administration of besudil to male rats at a dose of 275 mg / kg / day resulted in the discovery of sperm abnormalities (reduced motility, decreased counts, and increased percentages of abnormal sperm) and testicular / epididymal organ changes (weight loss and degeneration). At a dose of 275 mg / kg / day, fertility was reduced in both treated males and females and reached statistical significance in males. Adverse changes in male and female reproductive organs also occurred in general toxicology studies; findings included sperm degeneration in dogs at a dose of 35 mg / kg / day of besudol and reduced follicular development in the ovaries of rats at a dose of 275 mg / kg / day. Changes were partially or completely reversed during recovery. The exposure (AUC) in dogs at a dose of 35 mg / kg / day and in rats at a dose of 275 mg / kg / day were 0.5 times and 8-9 times the clinical exposure at the recommended dose of 200 mg per day, respectively. 14 Clinical Research 14.1 Chronic Graft-Versus-Host Disease

[0228] Study KD025-213 (NCT03640481) is a randomized, open-label, multicenter study investigating REZUROCK for the treatment of patients with chronic GVHD who have received 2 to 5 prior lines of systemic therapy and require additional therapy. Patients were excluded from the study if they had: platelets <50×10 9 / L; absolute neutrophil count <1.5×10 9 / L; AST or ALT>3×ULN; total bilirubin>1.5×ULN; QTc(F)>480ms; eGFR<30mL / min / 1.73m 2; or FEV1 ≤ 39%. 66 patients were treated with REZUROCK 200 mg orally once daily. Concomitant treatment with supportive care therapy for chronic GVHD was allowed. Concomitant treatment with GVHD prophylaxis and standard of care systemic chronic GVHD therapy was allowed as long as the subject had been taking a stable dose for at least 2 weeks prior to the study. No new systemic chronic GVHD therapy was allowed to be started during the study. The demographic data and baseline characteristics are summarized in Table 10 . Table 10: Demographics and baseline characteristics of patients with chronic GVHD a The denominator excludes patients whose status is unknown b Prednisone equivalent / kg

[0229] The efficacy of REZUROCK was based on overall response rate (ORR) by Day 1 of Cycle 7, where an overall response included either a complete response or a partial response according to the 2014 NIH response criteria. ORR results were Table 11 The ORR was 75% (95% CI: 63, 85). The median duration of response, calculated from first response to progression, death, or new systemic therapy for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, 62% (95% CI: 46, 74) had no death or initiation of new systemic therapy for at least 12 months from the start of the response. Table 11: Overall Response Rates by Cycle 7 Day 1 in Patients with Chronic GVHD in Study KD025-213 a Estimate using the Clopper-Pearson method The ORR results were supported by an exploratory analysis of patient-reported symptom bother, which showed that 52% (95% CI: 40, 65) of patients had a reduction of at least 7 points in the Lee Symptom Scale total score by Day 1 of Cycle 7. 16 How to supply / Storage and handling

[0230] REZUROCK 200 mg tablets are supplied as light yellow film-coated oval tablets containing 200 mg of besudil (equivalent to 242.5 mg of besudil mesylate). Each tablet has a debossed pattern "KDM" on one side and a debossed pattern "200" on the other side and is packaged as follows: 30 200 mg tablets per bottle: NDC 79802-200-30

[0231] Store at room temperature 20°C to 25°C (68°F to 77°F); short-term travel permitted at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0232] Dispense to patients only in the original container. Store in the original container to protect from moisture. Close cap tightly after each opening. Do not discard desiccant. 17 Patient Counseling Information

[0233] Advise patients to read the FDA-approved patient labeling (Patient Information). Embryo-fetal toxicity : Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. [See WARNINGS AND PRECAUTIONS ( 5.1 ), medication for special populations ( 8.1、8.3 )]. Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see WARNINGS AND PRECAUTIONS ( 5.1 )]. Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations ( 8.3 )]. Lactation

[0234] Advise women not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility

[0235] Inform males and females of reproductive potential that REZUROCK may impair fertility [see Use in Specific Populations ( 8.3 )]. Drug administration

[0236] Inform patients to take REZUROCK orally once daily with food as directed by their physician and to swallow the oral dose (tablet) whole with a glass of water at approximately the same time each day without cutting, crushing, or chewing the tablet [see DOSAGE AND ADMINISTRATION ( 2.1 )].

[0237] Advise patients that if they miss a daily dose of REZUROCK, they should take it as soon as possible on the same day and resume their normal schedule the next day. Patients should not take an additional dose to make up for the missed dose [see DOSAGE AND ADMINISTRATION ( 2.1 )]. Drug interactions

[0238] Advise patients to inform their healthcare provider of all concomitant medications, including prescription, over-the-counter medicines, vitamins, and herbal products [see Drug Interactions ( 7 )].

[0239] Although the present invention has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, the description and example should not be construed as limiting the scope of the present invention. The disclosures of all patents and scientific literature cited in this application are expressly incorporated into this application in their entirety by reference.

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 treating 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. The use according to claim 1, wherein a CYP3A inducer is co-administered to the subject.

3. The method of claim 1 or 2, wherein the CYP3A inducer is a glucocorticoid, carbamazepine, apalutamide, enzalutamide, mitotane, phenytoin, rifampicin (rifamycin), fosphenytoin, lumacato, lumacato-ivacator, mitotane, St. John's wort, phenobarbital, bosentan, efavirenz, etravirine, primidone, bexarotene, cynomolgus, dabrafenib, dexamethasone, analgin, elagolix, estradiol, eslicarbazepine, lorlatinib, mirapival, modafinil, nafcillin, pegidatinib, rifabutin, rifapentine, sotolacib, armodafinil, modafinil or rufinamide. The use according to claim 1 or 2, wherein the CYP3A inducer is a CYP3A4 inducer.

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

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

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

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

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

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

11. The 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, and the total daily dose is 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 per day or 800 mg per day.

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

16. The use according to claim 15, wherein the CYP3A inducer is rifampicin and the exposure reducing effect of rifampicin is characterized by a decrease in Cmax of about 59% and / or a decrease in AUC of about 72% of besudil.

17. The use according to claim 15, wherein the CYP3A inducer is efavirenz, and the exposure-reducing effect of efavirenz is characterized by a decrease in Cmax of about 32% and / or a decrease in AUC of about 35% of besudil.

18. The use according to any one of claims 7 to 9, wherein the dose of the compound is increased compared to the clinically recommended dose of the compound for subjects under standard treatment conditions to mediate the exposure-reducing effect of the co-administered PPI.

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

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

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

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 dose 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 of 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 in a daily dose of 20 mg twice a day.

27. The use according to any one of claims 1 to 26, comprising a treatment cycle in which the CYP3A inducer or PPI is administered on days when the subject does not receive a dose of the compound.

28. The use according to any one of claims 1 to 25, comprising a treatment cycle in which the CYP3A inducer or PPI is administered 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 meal about one hour or less prior to administering the compound.

30. The use of any one of claims 1-29, 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 who is concurrently taking a CYP3A inducer or a proton pump inhibitor (PPI), the method comprising administering to the subject in need thereof a therapeutically effective amount of besudil mesylate.

32. The method of claim 31 , wherein the amount of besudinil mesylate administered to the subject is adjusted to mediate the exposure reducing effect of the CYP3A inducer and / or PPI.

33. A method for treating a subject suffering from cGVHD, the method comprising the steps of: 1) determining whether the subject requires treatment with at least one CYP3A inducer or PPI and, if so, determining the dosage; 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 (compound) for subjects under standard conditions; as well as 3) determining an up-adjusted dose of a compound to be administered to the subject to mediate an exposure-reducing effect of the CYP3A inducer and / or PPI in treating the cGVHD.

34. The method of claim 33, wherein the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 30% to 90%.

35. The method of claim 33, wherein the exposure reducing effect is characterized by a decrease in the Cmax of besudil by about 50% to 90%.

36. The method of claim 33, wherein the exposure reducing effect is characterized by a decrease in the AUC of besudil by about 70% to 85%.

37. The method according to any one of claims 33 to 36, wherein the compound is besudil mesylate.

38. The method of any one of claims 31 to 37, wherein the compound is administered to the subject within about thirty minutes of ingesting a high fat meal.

39. A method of treating chronic graft-versus-host disease (cGVHD) in a subject who is concomitantly taking a CYP3A inducer or a proton pump inhibitor (PPI), the method comprising administering to a subject in need thereof a regimen to mediate a combination of a food effect and an exposure-reducing effect of the CYP3A inducer or PPI.

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