Method of administering vermosdil in combination with a transport protein substrate

Abstract

This disclosure relates to the simultaneous administration of belmosdil and transport protein substrates, such as organic anion transport polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp), for use in the treatment of subjects with chronic graft-versus-host disease (cGVHD).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Patent Application No. 63 / 588,359, filed on 6 October 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to a method for treating chronic graft-versus-host disease (cGVHD) by co-administration of an organic anion transporting polypeptide 1B1 (OATP1B1), a substrate of breast cancer resistance protein (BCRP) and / or P-glycoprotein (P-gp), and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof, wherein the dose of the substrate is reduced compared to the clinically recommended dose when the substrate is administered without bermosdil. [Background technology]

[0003] Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potential serious complication following 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 leading cause of non-relapse mortality beyond two years post-alloHCT. The estimated prevalence of cGVHD in the United States is 14,000 patients (as of 2016). (Bachier CR et al: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. ASH 2019, Orlando, FL, presented December 7–10, 2019) ("Bachier et al.").

[0004] Patients with cGVHD have substantial impairments in their quality of life (QOL), as assessed by the Lee Symptom Scale (LSS), which measures the impact of cGVHD on patient function and well-being. Only one-third of patients with cGVHD who initiated systemic treatment have been reported to survive, achieve remission, and discontinue immunosuppressive therapy at 5 years. (Lee SJ et al: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transpl 24:555-562, 2018) ("Lee et al.").

[0005] The pathophysiology of cGVHD can be divided into three phases: early inflammation due to tissue damage, dysregulation of the adaptive immune system, and abnormal tissue repair accompanied by chronic inflammation and fibrosis. The management of cGVHD continues to evolve with the emergence of targeted therapies.

[0006] In addition to one or more drug therapies used to treat cGVHD, patients with cGVHD may receive further medications to address side effects of cGVHD medication and / or to treat non-cGVHD-related disorders or conditions. These further drug therapies may affect and be affected by the drugs used to treat cGVHD. Drug-drug interactions may depend on the individual patient's metabolic profile, the mechanism of action of the drugs, the biological targets of the drugs, and the patient's nutritional intake. Drug metabolism further complicates these interactions because drug metabolites may be active therapeutic agents of certain drugs.

[0007] Drug-drug interactions can lead to increased or decreased patient exposure to the drugs involved, including toxic or ineffective levels, and are difficult to predict and resolve. Drug dose adjustments may be necessary to mediate these interactions, which can result in a difficult trial-and-error period for cGVHD patients. In some cases, discontinuation of drug treatment may be a consequence.

[0008] Opportunities to investigate exposure to and administration of concurrently administered drugs still exist. [Overview of the project] [Means for solving the problem]

[0009] This disclosure relates to treating chronic graft-versus-host disease (cGVHD) in a target population, comprising the co-administration of at least one substrate of organic anion transporting polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), or P-glycoprotein (P-gp), and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof ("the Compound"), wherein the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without the Compound.

[0010] The Disclosure also provides a method for treating a subject having cGVHD, comprising: (a) determining whether the subject requires co-administration of at least one substrate of OATP1B1, BCRP, or P-gp; (b) determining a clinically recommended dose of at least one substrate of OATP1B1, BCRP, or P-gp for the subject, given that the substrate is administered without co-administration of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound); (c) determining at least one substrate of OATP1B1, BCRP, or P-gp to be administered to the subject at a lower dose that mediates the increase in substrate exposure due to the administration of the compound; and (d) co-administering at least one substrate of OATP1B1, BCRP, or P-gp and the compound.

[0011] This embodiment can be better understood by referring to the detailed description and examples intended to illustrate non-limiting embodiments. [Modes for carrying out the invention]

[0012] Overview cGVHD is characterized by the overproduction of pro-inflammatory cytokines IL-21 and IL-17, as well as the overactivation of follicular helper T and B cells, which subsequently lead to the overproduction of antibodies. By regulating ROCK2 activity, vermosdil mediates signaling in immune cell function and fibrotic pathways, thereby mitigating the effects caused by this wasting disease, such as inflammation and fibrotic changes in multiple tissues, including several organs, including the lungs, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0013] In vitro evaluations suggested that belmosdil metabolism is primarily dependent on cytochrome P450 CYP3A4 activity and that belmosdil solubility is pH-dependent. Preclinical studies in mice, rats, rabbits, and dogs showed that belmosdil undergoes hepatic metabolism to form two major metabolites called KD025m1 (ROCK2 active minor metabolite) and KD025m2 (ROCK2 inactive major metabolite). These major metabolites were subsequently quantified in clinical trials throughout the belmosdil development program. Exposure to the major inactive metabolite KD025m2 was 15%–20% of parents, while exposure to the minor active metabolite KD025m1 was less than 5% of parents.

[0014] It has been determined that vermosdil may affect exposure to co-administered drugs, including drugs that are substrates of transport proteins. Transport proteins can move materials across biological membranes, including facilitating the pumping of drugs into or out of cells against their concentration gradients. Examples of transport proteins include the ATP-binding cassette (ABC) transporter family, of which breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are members. Solute carrier proteins (SLCs) are uptake transporters, including organic anion transport polypeptide 1B1 (OATP1B1) (OATP). OATP1B1 is highly expressed in the human liver and can extract its substrate from the circulating blood into, for example, hepatocytes. Once inside the cell, the transport protein substrate may undergo further transport or be metabolized, and the metabolites may also function as transport protein substrates. Therefore, drugs that are substrates or inhibitors of transport proteins may affect drug-drug interactions in patients, for example, patients taking multiple drugs to manage chronic diseases.

[0015] Therefore, to evaluate the effects of oral belmosdil on the inhibition of the two-phase drug-metabolizing enzyme UGT1A1 and the transporters P-gp, BCRP, and OATP1B1, as described in Example 3, a three-part, non-randomized, open-label trial was conducted in healthy volunteers. This trial consisted of three parts: Part 1 was conducted to evaluate the effects of multiple doses of belmosdil on a single dose pharmacokinetic drug (PK) of raltegravir (UGT1A1-sensitive substrate); Part 2 was conducted to evaluate the effects of multiple doses of belmosdil on a single dose PK of dabigatran etexilate (P-gp-sensitive substrate); and Part 3 was conducted to evaluate the effects of multiple doses of belmosdil on a single dose PK of rosuvastatin (BCRP / OATP1B1-sensitive substrate).

[0016] Vermosdil was safe to administer with each of the concurrently administered drugs, and no significant adverse events were reported.

[0017] Co-administration of velmoszil and a drug that is a substrate for these transport proteins can increase the exposure of the substrate. Accordingly, the dosage of the substrate can be reduced when co-administered with velmoszil. In one embodiment, the dosage of the transport protein substrate is reduced when co-administered with velmoszil. For example, in one embodiment, the dosage of rosuvastatin is reduced from the clinically recommended dosage when co-administered with a clinically recommended dosage of velmoszil. In one embodiment, the dosage of rosuvastatin is reduced to about 5 mg per day when co-administered with about 200 mg of velmoszil.

[0018] Definitions As used herein, "about" includes the exact quantity modified by the term "about", as well as quantities expected to be within experimental error, such as within 15%, 10%, or 5%. For example, "about 200 mg" means "200 mg", and also means a range of mg within experimental error, for example ±15%, 10%, or 5% of 200 mg. As used herein, the term "about" may also be used to modify ranges and specific values.

[0019] As used herein (for example, with respect to administration of APIs including "co-administration" of one or more APIs such as a compound, velmoszil and / or a substrate of OATP1B1, BCRP or P-gp to a subject), "administer" or "administered" refers to the act of prescribing a medicament comprising one or more APIs for the subject to ingest during treatment, the act of prescribing a protocol for the medicament to be ingested by the subject, the act of dispensing the medicament to the subject, and / or the act of physically receiving or ingesting the medicament. Accordingly, an API (for example, a compound, velmoszil and / or a substrate of OATP1B1, BCRP or P-gp) can be "administered" by a physician or other healthcare professional who writes a prescription for any one of such medicaments, and / or by a pharmacist who dispenses the prescription, and / or dispenses to one or more pharmaceutical subjects, and / or is administered by the patient or subject taking the medicament and / or their partner or caregiver who delivers the medicament to the subject.

[0020] "API" means "active pharmaceutical ingredient".

[0021] "Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" and "allogeneic hematopoietic cell transplantation (allo-HCT)", also referred to as bone marrow transplantation or stem cell transplantation, refer to the procedure of transplanting donor-derived hematopoietic cells into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some circumstances, umbilical cord blood may be used. Donors and recipients may be matched at the human leukocyte antigen (HLA) genes, such as siblings. Donors and recipients may be half-matched (haplotype-matched) parent and child.

[0022] Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 inhibition acts on fibrosis that occurs as a result of a dysregulated adaptive immune system and abnormal tissue repair. Belumosudil inhibits ROCK2 and ROCK1 with IC50 values of about 100 nM and 3 μM, respectively. Belumosudil downregulated pro-inflammatory responses by modulating STAT3 / STAT5 phosphorylation and shifting the Th17 / Treg balance in ex vivo or in vitro human T cell assays.

[0023] The compound belumosudil has the chemical name 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound belumosudil is also known as KD025. The mesylate salt of belumosudil is marketed in the United States as REZUROCK™ for the treatment of patients with chronic GVHD after failure of at least two prior lines of systemic therapy. The active pharmaceutical ingredient of REZUROCK™ has the molecular formula C with a molecular weight of 548.62 g / mol 27 H 28It is a belmosdyl mesylate containing N6O5S and having the chemical name 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamidomethanesulfonate (1:1).

[0024] The chemical structure of belmosdylmesylate is as follows: [ka]

[0025] Methods for producing belmosdil and the compound are described in the following U.S. Patents: U.S. Patent No. 8,357,693, U.S. Patent No. 9,815,820, U.S. Patent No. 10,183,931, and U.S. Patent No. 10,696,660.

[0026] Where the term “belmosdil” is used herein, unless the context clearly indicates otherwise, it should be understood that the term may encompass any form of the compound belmosdil and any pharmaceutically acceptable salt thereof. The term “belmosdil” refers to all forms of belmosdil, including the compound belmosdil (e.g., in free base form, amorphous form or crystalline form), any pharmaceutically acceptable salts of belmosdil, such as the mesylate form used in REZUROCK®, and any form of belmosdil that may be used in formulations or pharmaceutical compositions for administering the compound to a patient.

[0027] BCRP refers to a breast cancer resistance protein, a membrane transport protein encoded by the ABCG2 gene, and a member of the ATP-binding cassette (ABC) transporter family. BCRP is also known as ATP-binding cassette superfamily G member 2 (ABCG2) and CDw338. Substrates of BCRP include 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17-β-glucuronide, estrone-3-sulfate, methotrexate, rosuvastatin, prazosin, and sulfasalazine.

[0028] A "clinical endpoint" or "trial endpoint" refers to an event or outcome in a clinical trial that can be objectively measured to determine the outcome and potential beneficial effects of a drug or administration protocol designed in that clinical trial.

[0029] The “clinically recommended dose” or “clinically recommended dosage” refers to the amount or dosage of an API recommended and / or approved for administration to a subject by those skilled in the art of the field of medicinal chemistry to treat the disease condition in question, as described, for example, in publications, clinical trial results, and approved drug labels. In one embodiment, the clinically recommended dosage is expressed for the API in free base form. In one embodiment, the clinically recommended dosage is expressed for the API in free acid, i.e., protonated form. In one embodiment, the clinically recommended dosage for belmosdil is approximately 200 mg once daily. In one embodiment, the clinically recommended dosage for belmosdil is approximately 200 mg twice daily. In one embodiment, the clinically recommended dosage for raltegravir is approximately 400 mg once daily. In one embodiment, the clinically recommended dosage for raltegravir is approximately 400 mg twice daily. In one embodiment, the clinically recommended dosage of dabigatran is approximately 150 mg twice daily. In another embodiment, the clinically recommended dosage of dabigatran is approximately 75 mg twice daily. In yet another embodiment, the clinically recommended dosage of dabigatran is approximately 75 mg once daily. In yet another embodiment, the clinically recommended dosage of rosuvastatin is approximately 5-40 mg once daily. In yet another embodiment, the clinically recommended dosage of rosuvastatin is approximately 5-20 mg once daily.

[0030] As used herein with respect to the administration of at least one transport protein substrate with belmosdil, “concurrent administration,” “in combination with,” and / or “concurrently administered” means that during the course of treatment of the patient with belmosdil (also referred herein as “interacting compound”), the patient also receives one or more doses of one or more transport protein substrates (also referred herein as “interacted compound”). To be considered “concurrently administered” under this definition, the transport protein substrate does not need to be administered simultaneously with or on the same day as belmosdil. A transport protein substrate may be “concurrently administered” with belmosdil, in the days prior to the administration of belmosdil, and / or during the course of treatment. A transport protein substrate is not considered “concurrently administered” or “in combination with” belmosdil if there is a sufficient washout period to account for at least five half-lives of the active portion administered between doses.

[0031] In one embodiment, the transport protein substrate administered simultaneously includes a substrate of a member of the ATP-binding cassette (ABC) transporter family or a member of the solute carrier (SLC) family.

[0032] As used in the claims and embodiments herein, “compound” is synonymous with the above comprehensive definition of belmosdil, where evident from the context of use.

[0033] In relation to the administration of APIs as used herein (for example, when applied to transport protein substrates administered "simultaneously" with belmosdil), "simultaneous administration," "simultaneously," and / or "simultaneous intake" are synonymous with "administered simultaneously" as defined above.

[0034] "CYP3A" refers to the CYP3A family of P450 isoenzymes, including CYP3A4.

[0035] Where the term “dabigatran” is used herein, unless the context clearly indicates otherwise, it should be understood that the term may encompass any form of the compound dabigatran etexilate and any pharmaceutically acceptable salt thereof. The term “dabigatran” refers to the compound dabigatran, any pharmaceutically acceptable salt of dabigatran, such as mesylates used in PRADAXA®, and any form of dabigatran that may be used in formulations or pharmaceutical compositions for administering the compound to a patient.

[0036] As used herein, “exposure effect” or “exposure” refers to the effect of belmosdil on the pharmacokinetics (PK) of transport protein substrates, e.g., exposure levels (overall and peak) for substrates and their metabolites. Exposure may also refer to the effect of transport protein substrates, inhibitors, and / or co-substrates on the PK of belmosdil and its metabolites, as well as the elimination rates of belmosdil and its major metabolites, KD025m1 and KD025m2, as is evident from the context of use. For example, co-administration of belmosdil can increase exposure to transport protein substrates, as determined by the increase in the Cmax and / or AUC of the substrates. Excessive exposure may result in toxic levels of belmosdil, or transport protein substrates, or their metabolites. For illustrative purposes of the term “exposure effect,” see further Example 3 herein.

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

[0038] The Lee Symptom Scale (LSS) summary score measures the impact on a patient's function and health. The Lee Symptom Scale is a 30-item scale developed to measure the symptoms of cGVHD 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.

[0039] As used herein, “mediate” means modulating or compensating for changes in pharmacological exposure to an API based on the effect of a co-administered drug. For example, co-administration of belmosdil can increase exposure to a transport protein substrate. In one embodiment, mediating the increase in exposure to a transport protein substrate when co-administered with belmosdil includes reducing the dose of the substrate.

[0040] "OATP1B1" refers to a membrane transport protein belonging to the organic anion transport polypeptide 1B1, solute carrier family (SLC), and encoded by the SLCO1B1 gene. Substrates of OATP1B1 include estradiol-17β-glucuronide, pitavastatin, pravastatin, and rosuvastatin.

[0041] "Or" is used in an inclusive sense unless the context requires otherwise (equivalent to "and / or").

[0042] As used herein, “patient” or “subject” includes animals or humans. In one embodiment, the term “patient” refers to a human subject.

[0043] "P-glycoprotein" and "P-gp" refer to permeable glycoprotein 1, a membrane transport protein encoded by the ABCB1 gene and a member of the ATP-binding cassette (ABC) transporter family. P-gp is also known as ATP-binding cassette subfamily B member 1 (ABCB1), multidrug resistance protein 1 (MDR1), and CD243. Substrates of P-gp include digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, thalinolol, vinblastine, and dabigatran etexilate.

[0044] A "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, is suitable for administration to a subject, without excessive toxicity, irritation, allergic response, or other undesirable effects, and is commensurate with a reasonable benefit / risk ratio. Pharmacologically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Such salts include those formed from inorganic acids, salts formed from organic acids such as methanesulfonic acid, and salts formed when acidic protons present in the parent compound are substituted with metal ions, such as alkali metal ions or alkaline earth ions (including those having potassium or calcium cations).

[0045] As used herein, “protocol” refers to a method or plan used to administer one or more APIs to a subject requiring treatment. The term “protocol” is intended to encompass an overall, detailed plan of patient care, as well as individual or partial steps that are part of the overall plan. For example, a protocol may include the dosage used for each API the patient will receive (or is receiving), the combination of APIs the patient will receive, the timing and method of administration of each API (e.g., taking into account DDIs, the effects of food, and the effects that different formulations or modes of delivery may have on absorption and bioavailability), as well as the management of side effects, and an overall plan encompassing the dosages, combinations, timing and method of administration, and side effects that are considered together.

[0046] Where the term “raltegravir” is used herein, unless the context clearly indicates otherwise, it should be understood that the term may encompass any form of the compound raltegravir and any pharmaceutically acceptable salt thereof. The term “raltegravir” refers to the compound raltegravir, any pharmaceutically acceptable salt of raltegravir, such as the potassium salt used in ISENTRESS, and any form of raltegravir that may be used in formulations or pharmaceutical compositions for administering the compound to a patient.

[0047] Where the term “rosuvastatin” is used herein, unless the context clearly indicates otherwise, it should be understood that the term may encompass any form of the compound rosuvastatin and any pharmaceutically acceptable salt thereof. The term “rosuvastatin” refers to the compound rosuvastatin, any pharmaceutically acceptable salt of rosuvastatin, such as the calcium salt used in CRESTOR, and any form of rosuvastatin that may be used in formulations or pharmaceutical compositions for administering the compound to a patient.

[0048] "Standard treatment conditions" refers to the treatment and / or drug regimen for the administration of belmosdil to a patient for the treatment of cGVHD, and also refers to the treatment and / or drug regimen for the administration of transport protein substrates to a patient, in accordance with the above definition of "concurrently administered".

[0049] A "substrate" or "transport protein substrate" refers to a substrate of a transport protein that is selectively transported by that protein. Transport proteins induce the movement of substances, such as small molecule APIs, across biological membranes. As transport proteins traverse membranes, they can alter the concentration of substances on either side of the membrane, including their effect on the pharmacokinetics and pharmacodynamics of orally delivered drugs, and on their concentration gradients. A transport protein substrate is a compound that is selectively transported by the protein. Examples of transport proteins include organic anion transport polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Transport proteins can share substrates; for example, rosuvastatin is a substrate of both OATP1B1 and BCRP.

[0050] The substrate of the transport protein may be a drug or a drug metabolite. In one embodiment, the drug administered co-administered with belmosdil is transported by OATP1B1, BCRP, or P-gp. In one embodiment, the drug administered co-administered with belmosdil is transported by OATP1B1 or BCRP. In one embodiment, the drug administered co-administered with belmosdil is transported by P-gp. In one embodiment, the drug administered co-administered with belmosdil is transported by OATP1B1 and BCRP. In one embodiment, rosuvastatin administered co-administered with belmosdil is transported by OATP1B1 and BCRP.

[0051] In one embodiment, the transport protein substrate is at least one substrate of OATP1B1, BCRP, or P-gp. In one embodiment, the transport protein substrate is at least one substrate of OATP1B1, BCRP, and P-gp. In one embodiment, the transport protein substrate is one or more substrates of OATP1B1, BCRP, and P-gp. In one embodiment, the transport protein substrate is a substrate of P-gp. In one embodiment, the transport protein substrate is a substrate of OATP1B1 and BCRP. In one embodiment, the transport protein substrate is a substrate of OATP1B1, a substrate of BCRP, or a substrate of P-gp.

[0052] In some embodiments, the transport protein substrate is selected from estradiol-17β-glucuronide, pitavastatin, pravastatin, rosuvastatin, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17β-glucuronide, estrone-3-sulfate, methotrexate, prazosin, sulfasalazine, digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, talinolol, vinblastine, and dabigatran etexilate. In one embodiment, the transport protein substrate is rosuvastatin or dabigatran etexilate.

[0053] The "therapeutic dose" of the API means an amount sufficient to treat the disease condition being treated when administered to a human to treat a disease (e.g., cGVHD). When applied to cGVHD in humans, "treating" or "treating" includes (1) reducing the risk of developing cGVHD and / or inhibiting cGVHD, i.e., stopping or reducing the development of cGVHD or its clinical symptoms, and (2) mitigating cGVHD, i.e., causing regression, recovery or improvement of cGVHD, or reducing the number, frequency, duration or severity of its clinical symptoms.

[0054] The therapeutically effective dose of the API may vary depending on the health and physical condition of the patient being treated, the stage of disease progression, the assessment of the medical condition, and other relevant factors. The therapeutically effective dose is expected to be within a range that can be determined through trials, as described, for example, in Example 3 of this specification and in the scientific literature, and by referring to clinical trial data and results.

[0055] Exemplary Embodiments In some embodiments, 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) is provided for use in the treatment of chronic graft-versus-host disease (cGVHD) in subjects, wherein at least one substrate of OATP1B1, BCRP, or P-gp is administered co-administered to the subject, and the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0056] In some embodiments, 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) is provided for use in the treatment of chronic graft-versus-host disease (cGVHD) in subjects, wherein at least one substrate of UGT1A1 is administered co-administered to the subject, and the dose of at least one substrate of UGT1A1 is reduced compared to the clinically recommended dose when the substrate is administered without the compound. In one embodiment, the drug administered co-administered with the compound includes raltegravir.

[0057] In another embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of at least one substrate of OATP1B1, BCRP, or P-gp and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0058] In another embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of at least one substrate of the enzyme UGT1A1 and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of at least one substrate of UGT1A1 is reduced compared to the clinically recommended dose when the substrate is administered without the compound. In one embodiment, the substrate of UGT1A1 is raltegravir.

[0059] In another embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of a drug comprising a substrate of OATP1B1, a substrate of BCRP, or a substrate of P-gp, along with 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of the drug is reduced compared to the clinically recommended dose when the drug is administered without the compound.

[0060] For example, the drug therapy administered concurrently with the compound may include transport protein substrates selected from estradiol-17β-glucuronide, pitavastatin, pravastatin, rosuvastatin, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17β-glucuronide, estrone-3-sulfate, methotrexate, prazosin, sulfasalazine, digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, talinolol, vinblastine, and dabigatran etexilate. In one embodiment, the drug administered concurrently with the compound includes rosuvastatin or dabigatran etexilate.

[0061] In one embodiment, the compound comprises a pharmaceutically acceptable salt of belmosdil. In another embodiment, the compound comprises belmosdil mesylate.

[0062] In one embodiment, the dose of the compound is approximately 200 mg.

[0063] In some embodiments, the compound is administered once daily.

[0064] In some embodiments, the compound is administered twice daily.

[0065] In some embodiments, the compound is administered orally.

[0066] In one embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of an OATP1B1 substrate selected from estradiol-17β-glucuronide, pitavastatin, pravastatin, and rosuvastatin, and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of the OATP1B1 substrate is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0067] In one embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of rosuvastatin and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of rosuvastatin is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0068] In one embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of a BCRP substrate selected from 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17-β-glucuronide, estrone-3-sulfate, methotrexate, rosuvastatin, prazosin, and sulfasalazine, and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of the BCRP substrate is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0069] In one embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of a P-gp substrate selected from digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, talinolol, vinblastine, or dabigatran etexilate, and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of the P-gp substrate is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0070] In another embodiment, a method is provided for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising co-administration of at least one substrate of OATP1B1, BCRP, or P-gp with approximately 200 mg of belmosdil mesylate, wherein the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without belmosdil mesylate.

[0071] In some embodiments, the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced by about half compared to the clinically recommended dose when the substrate is administered without the compound. In some embodiments, the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced by only about 50% compared to the clinically recommended dose when the substrate is administered without the compound. In some embodiments, the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced by only about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to the clinically recommended dose when the substrate is administered without the compound.

[0072] In some embodiments, the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to the clinically recommended dose when the substrate is administered without the compound.

[0073] In another embodiment, the substrate of OATP1B1 is administered to the subject simultaneously with the compound.

[0074] In another embodiment, the substrate of OATP1B1 is at least one of estradiol-17β-glucuronide, pitavastatin, pravastatin, or rosuvastatin. In another embodiment, the substrate of OATP1B1 is at least one of estradiol-17β-glucuronide, pitavastatin, pravastatin, rosuvastatin, atorvastatin, lovastatin, or symvastatin. In another embodiment, the substrate of OATP1B1 is a statin. In another embodiment, the substrate of OATP1B1 is at least one of atorvastatin, lovastatin, pitavastatin, rosuvastatin, or symvastatin. In one embodiment, the substrate of OATP1B1 is atorvastatin. In one embodiment, the substrate of OATP1B1 is lovastatin. In one embodiment, the substrate of OATP1B1 is pitavastatin. In one embodiment, the substrate of OATP1B1 is symvastatin.

[0075] In another embodiment, the substrate of OATP1B1 is rosuvastatin. In some embodiments, the co-administered dose of rosuvastatin does not exceed 5 mg per day. In another embodiment, the co-administered dose of rosuvastatin is approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 5–40 mg, approximately 10–40 mg, approximately 10–20 mg, approximately 10–15 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or approximately 40 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 10 mg, and the co-administered dose is reduced to approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 20 mg, and the co-administered dose is reduced to approximately 10 mg or approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 30 mg, and the co-administered dose is reduced to approximately 20 mg, approximately 10 mg, or approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 5 mg, while the co-administered dose is reduced to less than approximately 5 mg, approximately 4 mg, approximately 3 mg, approximately 2.5 mg, approximately 2 mg, or approximately 1 mg.

[0076] In some embodiments, the BCRP substrate is administered to the subject simultaneously with the compound.

[0077] In another embodiment, the substrate of BCRP is at least one of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17-β-glucuronide, estrone-3-sulfate, methotrexate, rosuvastatin, prazosin, or sulfasalazine. In some embodiments, the substrate of BCRP is a statin.

[0078] In another embodiment, the substrate of BCRP is rosuvastatin. In some embodiments, the co-administered dose of rosuvastatin does not exceed 5 mg per day. In another embodiment, the co-administered dose of rosuvastatin is approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 5–40 mg per day, and the co-administered dose does not exceed 5 mg per day. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 10 mg, and the co-administered dose is reduced to approximately 5 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 5–40 mg, approximately 10–40 mg, approximately 10–20 mg or 10–15 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg or approximately 20 mg. In another embodiment, the clinically recommended dose of rosuvastatin is approximately 5 mg, and the co-administered dose is less than approximately 5 mg, approximately 4 mg, approximately 3 mg, approximately 2.5 mg, approximately 2 mg or approximately 1 mg, etc.

[0079] In some embodiments, the substrates of OATP1B1 and BCRP are administered simultaneously to the subject along with the compound. In one embodiment, the substrates of OATP1B1 and BCRP are statins. In another embodiment, the substrates of OATP1B1 and BCRP are rosuvastatin.

[0080] In some embodiments, the P-gp substrate is administered to the subject simultaneously with the compound.

[0081] In another embodiment, the substrate of P-gp is at least one of digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, thalinolol, vinblastine, or dabigatran etexilate.

[0082] In another embodiment, the substrate of P-gp is dabigatran etexilate. In some embodiments, the co-administered dose of dabigatran etexilate is less than approximately 300 mg, less than approximately 150 mg, or less than approximately 75 mg. In one embodiment, the co-administered dose of dabigatran etexilate does not exceed approximately 75 mg per day. In one embodiment, the co-administered dose of dabigatran etexilate does not exceed approximately 150 mg per day. In another embodiment, the co-administered dose of dabigatran etexilate is approximately 75 mg. In another embodiment, the clinically recommended dose of dabigatran etexilate is between approximately 75 mg and 300 mg, and the co-administered dose is reduced to approximately 75 mg.

[0083] In another embodiment, two or more substrates of OATP1B1, BCRP, or P-gp are administered to the patient simultaneously.

[0084] In one embodiment, the substrate of UGT1A1 is administered to the subject simultaneously with the compound. In one embodiment, the substrate of UGT1A1 is raltegravir.

[0085] In some embodiments, the compound is administered once daily.

[0086] In some embodiments, the compound is administered twice daily.

[0087] In some embodiments, the compound is administered orally.

[0088] In another embodiment, the compound contains about 200 mg of belmosdil mesylate, and the dose of at least one substrate of OATP1B1, BRCP, or P-gp is reduced to about half compared to the clinically recommended dose when the substrate is administered without the compound. In some embodiments, at least one substrate of OATP1B1, BRCP, or P-gp is rosuvastatin, the dose of rosuvastatin does not exceed 5 mg per day, and about 200 mg of belmosdil mesylate is administered once daily. In some embodiments, at least one substrate of OATP1B1, BRCP, or P-gp is rosuvastatin, the dose of rosuvastatin does not exceed 5 mg per day, and about 200 mg of belmosdil mesylate is administered twice daily. In some embodiments, about 200 mg of belmosdil mesylate is expressed as free base equivalent.

[0089] In some embodiments, the co-administered dose of rosuvastatin is approximately 10 mg. In some embodiments, the co-administered dose of rosuvastatin is approximately 5 mg. In some embodiments, the co-administered dose of rosuvastatin is less than approximately 5 mg, approximately 4 mg, approximately 3 mg, approximately 2.5 mg, approximately 2 mg, or approximately 1 mg, etc.

[0090] In one embodiment, the dose of the compound administered concurrently as described herein is about 200 mg per day; in another embodiment, the dose of the compound is about 400 mg per day; in another embodiment, the dose of the compound is administered in two doses of about 200 mg per day for a total daily dose of about 400 mg; in another embodiment, the dose of the compound is 400 mg per day or 400 mg twice per day. In some embodiments, vermosdil mesylate is expressed as free base equivalent.

[0091] In one embodiment, approximately 200 mg of belmosdil mesylate, expressed as free base equivalent, is administered once daily.

[0092] In one embodiment, approximately 200 mg of belmosdil mesylate, expressed as free base equivalent, is administered twice daily.

[0093] In some embodiments, the use or method comprises a treatment cycle in which at least one substrate of OATP1B1, BCRP, or P-gp is administered concurrently on a day in which the subject does not receive the compound; in some embodiments, at least one substrate of OATP1B1, BCRP, or P-gp is administered before administration of the compound; in some embodiments, at least one substrate of OATP1B1, BCRP, or P-gp is administered substantially concurrently with the compound; and in some embodiments, at least one substrate of OATP1B1, BCRP, or P-gp is administered on the same day as the compound.

[0094] In some embodiments, the use or method includes a treatment cycle in which at least one substrate and compound of OATP1B1, BCRP, or P-gp is administered daily.

[0095] In some embodiments, the use or method includes a treatment cycle in which at least one substrate and compound of OATP1B1, BCRP, or P-gp is administered together with food.

[0096] In another embodiment, the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced to mediate an increase in exposure to the concurrently administered substrate due to the co-administration of the compound. In some embodiments, the substrates of OATP1B1 and BCRP are administered concurrently with the compound, and the doses of the substrates of OATP1B1 and BCRP are reduced to mediate an increase in exposure to the substrate due to the co-administration of the compound. In some embodiments, the dose of rosuvastatin is reduced to mediate an increase in exposure to the substrate due to the co-administration of the compound. In some embodiments, the dose of dabigatran etexilate is reduced to mediate an increase in exposure to the substrate due to the co-administration of the compound.

[0097] In some embodiments, a method is provided for treating chronic graft-versus-host disease (cGVHD) in subjects who co-ingest at least one substrate of OATP1B1, BCRP, or P-gp, comprising administering a therapeutically effective amount of belmosdil mesylate to the subject in question.

[0098] In some embodiments, a method is provided for treating a subject having cGVHD, and the method is (a) A step of determining whether the subject requires simultaneous administration of at least one substrate of OATP1B1, BCRP, or P-gp, (b) A step of determining the clinically recommended dose of at least one substrate of OATP1B1, BCRP, or P-gp for a subject when the substrate is administered without co-administration of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof. (c) A step of determining at least one substrate of OATP1B1, BCRP, or P-gp administered to a lower dose subject that mediates the increase in substrate exposure by administration of the compound, and (d) A step of simultaneously administering at least one substrate and compound of OATP1B1, BCRP, or P-gp. Includes.

[0099] In one embodiment, a method for treating a subject having cGVHD includes the step of monitoring the subject for signs and symptoms of excessive exposure to substrates of OATP1B1 and BCRP. In one embodiment, signs and symptoms of excessive exposure include elevated levels of rosuvastatin exposure. In one embodiment, signs and symptoms of excessive exposure include elevated levels of vermosdil exposure.

[0100] In some embodiments, the subject involves at least four organs. In some embodiments, the subject involves at least three organs. In some embodiments, the subject involves at least two organs.

[0101] In some embodiments, the subjects had chronic graft-versus-host disease and had not responded to 1 to 3 prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subjects had chronic graft-versus-host disease and had not responded to at least 2 prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subjects had chronic graft-versus-host disease and had not responded to 2 to 5 prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subjects had not responded to at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 prior lines of systemic therapy for chronic graft-versus-host disease.

[0102] In some embodiments, the subjects experienced a complete response to the last treatment for graft-versus-host disease prior to belmosdil. In some embodiments, the subjects experienced a partial response to the last treatment for graft-versus-host disease prior to belmosdil. In some embodiments, the disease was stable during the last treatment for graft-versus-host disease prior to belmosdil. In some embodiments, the preceding line of systemic therapy for chronic graft-versus-host disease was discontinued.

[0103] In some embodiments, the lead line of systemic therapy is selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0104] This specification also provides the use of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) in the manufacture of a pharmaceutical useful for treating the pathological conditions described herein, particularly chronic graft-versus-host disease (cGVHD), by co-administration with at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1) or a pharmaceutically acceptable salt thereof, breast cancer resistance protein (BCRP) or a pharmaceutically acceptable salt thereof. In some embodiments, the use of the compound is for the manufacture of a pharmaceutical for treating cGVHD by co-administration with at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is used to manufacture a pharmaceutical for treating cGVHD by co-administering it with at least one substrate of breast cancer resistance protein (BCRP) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is used to manufacture a pharmaceutical for treating cGVHD by co-administering it with at least one substrate of P-glycoprotein (P-gp) or a pharmaceutically acceptable salt thereof.

[0105] This specification also provides the use of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) in the manufacture of a medicament for treating chronic graft-versus-host disease (cGVHD), the compound being used in combination with at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1) or a pharmaceutically acceptable salt thereof, breast cancer resistance protein (BCRP) or a pharmaceutically acceptable salt thereof, or P-glycoprotein (P-gp) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is used in combination with at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is used in combination with at least one substrate of breast cancer resistance protein (BCRP) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is used in combination with at least one substrate of P-glycoprotein (P-gp) or a pharmaceutically acceptable salt thereof.

[0106] This embodiment can be better understood by referring to the detailed description and examples intended to illustrate non-limiting embodiments.

[0107] Embodiment 1. A method for treating chronic graft-versus-host disease (cGVHD) in a subject of interest, comprising the co-administration of at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), and / or P-glycoprotein (P-gp), and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

[0108] Embodiment 2. The method according to Embodiment 1, wherein the compound comprises a mesylate of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide.

[0109] Embodiment 3. The method according to Embodiment 1 or 2, wherein the dose of the compound is about 200 mg.

[0110] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the substrate of OATP1B1 is administered simultaneously to the subject.

[0111] Embodiment 5. The method according to Embodiment 4, wherein the substrate of OATP1B1 is at least one of estradiol-17β-glucuronide, pitavastatin, pravastatin, rosuvastatin, atorvastatin, lovastatin, or simvastatin.

[0112] Embodiment 6. The method according to Embodiment 4, wherein the substrate of OATP1B1 is a statin.

[0113] Embodiment 7. The method according to Embodiment 6, wherein the substrate of OATP1B1 is rosuvastatin.

[0114] Embodiment 8. The method according to Embodiment 7, wherein the concurrent dose of rosuvastatin does not exceed 5 mg per day.

[0115] Embodiment 9. The method according to Embodiment 7, wherein the concurrent dose of rosuvastatin is approximately 5 mg.

[0116] Embodiment 10. The method according to Embodiment 7, wherein the clinically recommended dose of rosuvastatin is approximately 5 to 40 mg per day, and the co-administered dose does not exceed approximately 5 mg per day.

[0117] Embodiment 11. The method according to Embodiment 7, wherein the clinically recommended dose of rosuvastatin is about 10 mg, and the concurrently administered dose does not exceed about 5 mg.

[0118] Embodiment 12. A method according to any one of Embodiments 1 to 3, wherein the BCRP substrate is administered simultaneously to the subject.

[0119] Embodiment 13. The method according to Embodiment 12, wherein the substrate of BCRP is at least one of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), estradiol-17-β-glucuronide, estrone-3-sulfate, methotrexate, rosuvastatin, prazosin, or sulfasalazine.

[0120] Embodiment 14. The method according to Embodiment 12, wherein the substrate of BCRP is a statin.

[0121] Embodiment 15. The method according to Embodiment 12, wherein the substrate of BCRP is rosuvastatin.

[0122] Embodiment 16. The method according to Embodiment 12, wherein the substrate of BCRP is rosuvastatin calcium salt.

[0123] Embodiment 17. The method according to Embodiment 15 or 16, wherein the co-administered dose of rosuvastatin does not exceed 5 mg per day.

[0124] Embodiment 18. The method according to Embodiment 15 or 16, wherein the concurrent dose of rosuvastatin is approximately 5 mg.

[0125] Embodiment 19. The method according to Embodiment 15 or 16, wherein the clinically recommended dose of rosuvastatin is approximately 5 to 40 mg per day, and the co-administered dose does not exceed approximately 5 mg per day.

[0126] Embodiment 20. The method according to Embodiment 15 or 16, wherein the clinically recommended dose of rosuvastatin is about 10 mg, and the concurrent dose does not exceed about 5 mg.

[0127] Embodiment 21. The method according to any one of Embodiments 1 to 3, wherein the P-gp substrate is administered simultaneously to the subject.

[0128] Embodiment 22. The method according to Embodiment 21, wherein the substrate of P-gp is at least one of digoxin, fexofenadine, loperamide, N-methylquinidine (NMQ), quinidine, talinolol, vinblastine, or dabigatran.

[0129] Embodiment 23. The method according to Embodiment 21, wherein the substrate of P-gp is dabigatran.

[0130] Embodiment 24. The method according to Embodiment 21, wherein the substrate of P-gp is dabigatran etexilate.

[0131] Embodiment 25. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate is less than approximately 300 mg.

[0132] Embodiment 26. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate is less than approximately 150 mg.

[0133] Embodiment 27. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate is less than approximately 75 mg.

[0134] Embodiment 28. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate does not exceed 75 mg per day.

[0135] Embodiment 29. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate does not exceed 150 mg per day.

[0136] Embodiment 30. The method according to Embodiment 24, wherein the co-administered dose of dabigatran etexilate is approximately 75 mg.

[0137] Embodiment 31. The method according to Embodiment 24, wherein the clinically recommended dose of dabigatran etexilate is approximately 75 mg to 300 mg.

[0138] Embodiment 32. The method according to Embodiment 24, wherein the clinically recommended dose of dabigatran etexilate is approximately 150 mg to 300 mg, and the concurrently administered dose does not exceed approximately 75 mg.

[0139] Embodiment 33. The method according to Embodiment 1, wherein two or more substrates of OATP1B1, BCRP, or P-gp are administered simultaneously to the patient.

[0140] Embodiment 34. The method according to any one of Embodiments 1 to 33, wherein the compound is administered once daily.

[0141] Embodiment 35. The method according to any one of Embodiments 1 to 33, wherein the compound is administered twice daily.

[0142] Embodiment 36. The method according to Embodiment 1, wherein the dose of the compound is about 200 mg, and the dose of at least one substrate, OATP1B1, BRCP, or P-gp, is reduced to about half compared to the clinically recommended dose when the substrate is administered without the compound.

[0143] Embodiment 37. The method according to Embodiment 36, wherein at least one substrate of OATP1B1, BCRP, or P-gp is rosuvastatin.

[0144] Embodiment 38. The method according to Embodiment 37, wherein the daily dose of rosuvastatin does not exceed 5 mg per day in free base form.

[0145] Embodiment 39. The method according to Embodiment 37, wherein the dose of rosuvastatin does not exceed 5 mg per day, and the compound is administered once daily.

[0146] Embodiment 40. The method according to Embodiment 37, wherein the dose of rosuvastatin does not exceed 5 mg per day, and the compound is administered twice daily.

[0147] Embodiment 41. The method according to Embodiment 37, wherein the co-administered dose of rosuvastatin is approximately 10 mg.

[0148] Embodiment 42. The method according to any one of Embodiments 36 to 41, wherein the compound comprises bellosdil mesylate.

[0149] Embodiment 43. A method according to any one of Embodiments 1 to 42, comprising a treatment cycle in which at least one substrate of OATP1B1, BCRP, or P-gp is administered concurrently on a day in which the subject does not receive the compound.

[0150] Embodiment 44. A method according to any one of Embodiments 1 to 42, comprising a treatment cycle in which at least one substrate of OATP1B1, BCRP, or P-gp is administered substantially concurrently with the compound.

[0151] Embodiment 45. A method according to any one of Embodiments 1 to 42, comprising a treatment cycle in which at least one substrate of OATP1B1, BCRP, or P-gp is administered on the same day as the compound.

[0152] Embodiment 46. A method according to any one of Embodiments 1 to 42, comprising a treatment cycle in which at least one substrate and compound of OATP1B1, BCRP, or P-gp is administered daily.

[0153] Embodiment 47. A method according to any one of Embodiments 1 to 42, comprising a treatment cycle in which at least one substrate and compound of OATP1B1, BCRP, or P-gp is administered together with food.

[0154] Embodiment 48. A method according to any one of Embodiments 1 to 47, wherein the subject has chronic graft-versus-host disease and has not responded to at least two prior lines of systemic therapy for chronic graft-versus-host disease.

[0155] Embodiment 49. The method according to Embodiment 1, wherein the dose of at least one substrate of OATP1B1, BCRP, or P-gp is reduced in order to mediate the increase in exposure to the concurrently administered substrate by the concurrent administration of the compound.

[0156] Embodiment 50. The method according to Embodiment 1, wherein at least one substrate of OATP1B1, BCRP, or P-gp is a substrate of OATP1B1 and BCRP, and the doses of the substrates of OATP1B1 and BCRP are reduced in order to mediate their increase in substrate exposure by co-administration of the compounds.

[0157] Embodiment 51. A method for treating a subject having cGVHD, comprising: (a) determining whether the subject requires co-administration of at least one substrate of OATP1B1, BCRP, or P-gp; (b) determining a clinically recommended dose of at least one substrate of OATP1B1, BCRP, or P-gp for the subject, given that the substrate is administered without co-administration of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound); (c) determining at least one substrate of OATP1B1, BCRP, or P-gp to be administered to the subject at a lower dose that mediates the increase in substrate exposure due to the administration of the compound; and (d) co-administering at least one substrate of OATP1B1, BCRP, or P-gp and the compound.

[0158] Embodiment 52. The method according to Embodiment 51, wherein at least one substrate of OATP1B1, BCRP, or P-gp is a substrate of OATP1B1 and BCRP.

[0159] Embodiment 53. The method according to Embodiment 52, further comprising the step of monitoring the subject for signs and symptoms of excessive exposure to substrates of OATP1B1 and BCRP.

[0160] Embodiment 54. The method according to any one of Embodiments 51 to 53, wherein the compound is administered simultaneously at a dose of approximately 200 mg per day.

[0161] Embodiment 55. The method according to any one of Embodiments 51 to 53, wherein the compound is administered simultaneously at a dose of approximately 400 mg per day.

[0162] Embodiment 56. A method according to any one of Embodiments 51 to 55, wherein the compound comprises bellosdil mesylate.

[0163] Embodiment 57. The method according to Embodiment 51, wherein at least one substrate of OATP1B1, BCRP, or P-gp is rosuvastatin.

[0164] Embodiment 58. The method according to Embodiment 51, wherein at least one substrate of OATP1B1, BCRP, or P-gp is rosuvastatin calcium salt.

[0165] Embodiment 59. The method according to Embodiment 57 or 58, wherein rosuvastatin is administered concurrently at a dose of approximately 5 mg per day.

[0166] Embodiment 60. The method according to Embodiment 57 or 58, wherein rosuvastatin is administered concurrently in a dose not exceeding approximately 5 mg per day.

[0167] The following abbreviations may be helpful when considering the examples and descriptions herein.

[0168] Abbreviation Adverse events (AEs) alloHCT allogeneic hematopoietic cell transplantation BID twice a day (bi-daily) BM bone marrow cGVHD (Chronic Graft-Vs-Host Disease) CMV (Cytomegalovirus) Complete Response (CR) DDI drug-drug interaction Duration of response to DOR FFS failure-free survival rate HLA Human Leukocyte Antigen IST immunosuppressive therapy LSS Lee Symptom Scale ORR Total Playback Efficiency OS overall survival PBSC peripheral blood stem cells PPIs (Proton Pump Inhibitors) PR (Partial response) QOL (Quality of Life) SD standard deviation SR (Steroid-resistant) Adverse events that occurred under TEAE treatment TTNT: Time until the next treatment QD Daily [Examples]

[0169] Example 1: REZUROCK (trademark) (Belmosdil) FDA label, USA ----------------Indications and Use--------------- REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients aged 12 years or older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. (1) ----------------Dosage and Administration--------------- Recommended dosage: Administer 200 mg orally once daily with food. (2.1) ----------------Dosage Form and Strength---------------- Tablets: 200mg. (3) ------------------Contraindications------------------- None. (4) ----------------Warnings and Cautions---------------- Embryo-fetal toxicity: May harm the fetus. Advise women about the potential risks to the fetus and their reproductive capacity, and use effective contraception. (5.1, 8.1, 8.3) ----------------Drug Interactions---------------- Increase the dosage of the potent CYP3A inducer REZUROCK to 200 mg twice daily. (7.1) Proton pump inhibitor: Increase the dosage of REZUROCK up to 200 mg twice daily. (7.1) -----------------Adverse Reactions----------------- The most common (≥20%) adverse reactions, including abnormal clinical laboratory findings, were infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension. (6.1) ---------------Use in specific groups------------- Breastfeeding: Advise against breastfeeding. (8.2) Patient counseling information and FDA For information on labeling approved patients, see section 17.

[0170] Complete prescription information 1. Indications and Use REZUROCK is indicated for the treatment of adult and pediatric patients aged 12 years or older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0171] 2. Dosage and Administration 2.1 Recommended Dosage The recommended dose of REZUROCK is 200 mg orally once daily until chronic GVHD progresses to the point where new systemic therapy is required. The patient will be instructed to do the following: Swallow the entire REZUROCK tablet. Do not cut, crush, or chew the tablet. Take REZUROCK with meals at approximately the same time each day [see Clinical Pharmacology (12.3)]. If the REZUROCK dosage is insufficient, instruct the patient not to administer additional doses to compensate for the deficiency.

[0172] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, the risks and potential benefits should be considered before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)].

[0173] 2.2 Dose changes due to adverse reactions Total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) should be monitored at least monthly. The REZUROCK dosage should be adjusted for adverse reactions according to Table 1.

[0174] [Table 1]

[0175] 2.3 Dosage changes due to drug interactions A powerful CYP3A inducer When administered concurrently with a potent CYP3A inducer, increase the REZUROCK dosage to 200 mg twice daily. [See Drug Interactions (7.1)].

[0176] Proton pump inhibitors When administered concurrently with a proton pump inhibitor, increase the REZUROCK dosage to 200 mg twice daily [see Drug Interactions (7.1)].

[0177] 3. Dosage Form and Strength Each 200mg tablet is a pale yellow, film-coated rectangular tablet with "KDM" debossed on one side and "200" on the other.

[0178] 4 Contraindications none.

[0179] 5. Warnings and Precautions 5.1 Embryo-fetal toxicity Based on animal studies and its mechanism of action, REZUROCK may harm the fetus if administered to pregnant women. In animal reproductive studies, administration of belmosdil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and malformations, at lower maternal exposure (AUC) than in patients receiving the recommended dose. Instruct pregnant women about the potential risks to the fetus. Instruct women of reproductive potential and men 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), Non-clinical Toxicology (13.1)].

[0180] 6. Adverse reactions 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in a clinical trial of one drug cannot be directly compared to rates in a clinical trial of another drug and may not reflect the actual observed rates.

[0181] Chronic graft-versus-host disease In two clinical trials (Trial KD025-213 and Trial KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Trial (14.1)]. The median treatment duration was 9.2 months (ranging from 0.5 to 44.7 months).

[0182] A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure.

[0183] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Nausea (4%) was the most common adverse reaction leading to permanent discontinuation of REZUROCK in more than 3% of patients. Adverse reactions leading to treatment discontinuation occurred in 29% of patients. Adverse reactions leading to treatment discontinuation in more than 2% of patients included infection (11%), diarrhea (4%), asthenia, dyspnea, bleeding, hypotension, abnormal liver function tests, nausea, fever, edema, and renal failure (2% each).

[0184] The most common (≧20%) adverse reactions, including abnormal clinical laboratory findings, were infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension.

[0185] Table 2 summarizes non-laboratory adverse reactions.

[0186] [Table 2]

[0187] [Table 3]

[0188] Table 3 summarizes the abnormalities observed in the REZUROCK test.

[0189] [Table 4]

[0190] 7. Drug Interactions 7.1 Effects of other drugs on REZUROCK A powerful CYP3A inducer Co-administration of REZUROCK with potent CYP3A inducers reduces vermosdil exposure [see Clinical Pharmacology (12.3)], which may decrease the efficacy of REZUROCK. When co-administered with potent CYP3A inducers, the dosage of REZUROCK should be increased [see Dosage and Administration (2.3)].

[0191] Proton pump inhibitors Co-administration of REZUROCK with a proton pump inhibitor reduces bermosdil exposure [see Clinical Pharmacology (12.3)], which may decrease the efficacy of REZUROCK. When co-administered with a proton pump inhibitor, the dosage of REZUROCK should be increased [see Dosage and Administration (2.3)].

[0192] 8. Use in specific populations 8.1 Pregnancy Risk Overview Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], REZUROCK may be harmful to the fetus if administered to pregnant women. There is no available human data on the use of REZUROCK in pregnant women to assess drug-related risks. In animal reproductive studies, administration of belmosdil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including growth, embryo-fetal mortality, and embryo-fetal malformations, at maternal exposure (AUC) that was more than 3 times (rats) and more than 0.07 times (rabbits) compared to human exposure (AUC) at the recommended dose (see animal data). Inform pregnant women and women of the potential risks to their fetuses and their reproductive capabilities.

[0193] In the general U.S. population, the estimated background risks for major birth defects and miscarriages in clinically recognized pregnancies are 2–4% and 15–20%, respectively.

[0194] data Animal data Embryofetal development studies were conducted in pregnant animals during organogenesis by administering belmosdil orally at doses of 25 mg, 50 mg, 150 mg, and 300 mg / kg / day in pilot studies, and 15 mg, 50 mg, and 150 mg / kg / day in pivotal studies. Maternal toxicity and embryofetal developmental effects were observed in the pilot studies. Maternal toxicity (decreased weight gain) occurred at doses of 150 mg and 300 mg / kg / day. Increased post-implantation loss occurred at doses of 50 mg and 300 mg / kg / day. Fetal malformations were observed at ≥50 mg / kg / day and included absence of anus and tail, umbilical cord protuberance, and dome-shaped head. The exposure (AUC) in rats at 50 mg / kg / day was approximately three times that of human exposure at the recommended dose of 200 mg.

[0195] In a rabbit embryo-fetal development study, pregnant animals were orally administered bermosdil at 50 mg, 125 mg, and 225 mg / kg / day during organogenesis, resulting in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of 125 mg / kg / day or higher. Embryo-fetal effects were observed at doses ≥50 mg / kg / day and included spontaneous abortion, increased post-implantation mortality, decreased fetal survival rate, malformations, and decreased fetal weight. Malformations included tail (shortening), rib (fragmentation, adhesion, or deformity), sternal segment (adhesion), and neural arch (fusion, misalignment, deformity). The exposure (AUC) in rabbits at 50 mg / kg / day was approximately 0.07 times that of human exposure at the recommended dose of 200 mg.

[0196] 8.2 Breastfeeding Risk Overview There is no available data on the presence of belmosdil or its metabolites in human breast milk, its effects on breastfed children, or milk production. Due to the potential for serious adverse reactions from belmosdil in breastfed children, breastfeeding women should be advised not to breastfeed during treatment with REZUROCK and for at least one week after the last dose.

[0197] 8.3 Females and men of reproductive capacity REZUROCK may harm the fetus if administered to pregnant women [see Use in specific populations (8.1)].

[0198] Pregnancy test Confirm the pregnancy status of women of reproductive age before initiating treatment with REZUROCK.

[0199] contraception woman Women of reproductive age should be instructed 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 a patient becomes pregnant while taking this drug, the patient should be informed of the potential risks to the fetus.

[0200] male Men with fertile female partners should be instructed to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK.

[0201] infertility woman Based on findings from rats, REZUROCK may impair the fertility of female rats. The effects on fertility are reversible [see Nonclinical Toxicity (13.1)].

[0202] male Based on findings from rats and dogs, REZUROCK may impair male fertility. The effects on fertility are reversible [see Nonclinical Toxicity (13.1)].

[0203] 8.4 Use in children The safety and efficacy of REZUROCK have been established in pediatric patients aged 12 years and older. The use of REZUROCK in this age group is supported by evidence from well-controlled studies of REZUROCK in adults, which demonstrate that age and weight did not have a clinically significant effect on the pharmacokinetics of the active pharmaceutical ingredient (API), that API exposure is expected to be similar between adults and pediatric patients aged 12 years and older, and that the disease course is sufficiently similar in adults and pediatric patients to allow extrapolation of adult data to pediatric patients.

[0204] The safety and efficacy of REZUROCK in pediatric patients under 12 years of age have not been established.

[0205] 8.5 Use by the elderly Of the 186 patients with chronic GVHD in the REZUROCK clinical trial, 26% were 65 years of age or older. No clinically significant differences in the safety or efficacy of REZUROCK were observed compared to younger patients.

[0206] 11. Explanation Belmosdil is a kinase inhibitor. The active pharmaceutical ingredient is belmosdil mesylate, with the molecular formula C27H28N6O5S and a molecular weight of 548.62 g / mol. The chemical name of belmosdil mesylate is 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamidomethanesulfonate (1:1). Its chemical structure is as follows: [ka]

[0207] Belmosdil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0208] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of free base equivalent, which is equivalent to 242.5 mg of bellosdil mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0209] The tablet film is made of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide.

[0210] 12. Clinical Pharmacology 12.1 Mechanism of Action Belmosdil is an inhibitor of Rho-related coiled-coil protein kinase (ROCK), inhibiting ROCK2 and ROCK1 with IC50 values ​​of approximately 100 nM and 3 μM, respectively. Belmosdil downregulated pro-inflammatory responses in ex vivo and in vitro human T-cell assays by modulating STAT3 / STAT5 phosphorylation and shifting the Th17 / Treg balance. Belmosdil also inhibited abnormal pro-fibrotic signaling in vitro. In vivo, belmosdil showed activity in an animal model of chronic GVHD.

[0211] 12.2 Pharmacodynamics The exposure-response relationship and the time course of pharmacodynamic responses to belmosdil have not been established.

[0212] 12.3 Pharmacokinetics Unless otherwise specified, the following pharmacokinetic parameters are given for patients with chronic GVHD who received belmosdil 200 mg once daily. The mean steady-state AUC and Cmax of belmosdil were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of belmosdil increased almost proportionally across the dosing range of 200 mg and 400 mg (1 to 2 times the recommended once-daily dose). The cumulative ratio of belmosdil was 1.4.

[0213] absorption The median Tmax of belmosdil at steady state was 1.26–2.53 hours after administering 200 mg once or twice daily to patients. The mean (%CV) bioavailability was 64% (17%) after a single dose of belmosdil in healthy subjects.

[0214] The influence of food Compared to a fasted state in healthy subjects, a single dose of belmosdil administered with a high-fat and high-calorie diet (800-1,000 calories, with approximately 50% of the total calorie content from fat) increased the Cmax and AUC of belmosdil by 2.2 times and 2 times, respectively. The median Tmax was delayed by 0.5 hours.

[0215] distribution The geometric mean volume of distribution after a single dose of belmosdil in healthy subjects was 184 L. (Geometric CV% 67.7%).

[0216] The binding of belmosdil to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro.

[0217] Removal The mean (%CV) elimination half-life of belmosdil in patients was 19 hours (39%), and the clearance was 9.83 L / hour (46%).

[0218] metabolism Belmosdil is primarily metabolized by CYP3A4, and to a lesser extent in vitro by CYP2C8, CYP2D6, and UGT1A9.

[0219] discharge After a single oral administration of radiolabeled belmosdil to healthy subjects, 85% of the radioactivity was recovered in the feces (30% remained unchanged), and less than 5% was recovered in the urine.

[0220] Specific group Age (18-77 years), sex, weight (38.6kg-143kg), or mild to moderate renal impairment (eGFR ≥ 60 and < 90 mL / min / 1.72m²). 2 eGFR ≥ 30 and < 60 mL / min / 1.72 m³ 2 Regarding this, no clinically significant difference in the pharmacokinetics of belmosdil was observed. The effect of severe renal impairment on the pharmacokinetics of belmosdil has not been studied.

[0221] Drug interaction testing Clinical research and model studies – Informed approaches to the effects of other drugs on belmosdil Potent cytochrome P450 (CYP) 3A inhibitor: When administered concurrently with itraconazole to healthy subjects, belmosdil exposure had no clinically significant effect.

[0222] Co-administration of the potent CYP3A inducer, rifampin, reduced belmosdil Cmax by 59% and AUC by 72% in healthy subjects.

[0223] Co-administration of the moderate CYP3A inducer efavirenz is predicted to reduce the Cmax of belmosdil by 32% and the AUC by 35% in healthy subjects.

[0224] Proton pump inhibitors: In healthy subjects, co-administration of rabeprazole reduced belmosdil Cmax by 87% and AUC by 80%, while omeprazole reduced belmosdil Cmax by 68% and AUC by 47%.

[0225] The effects of belmosdil on other drugs CYP3A substrate: Concurrent administration of belmosdil is predicted to increase the Cmax and AUC of midazolam (sensitive CYP3A substrate) by approximately 1.3 times and 1.5 times, respectively.

[0226] CYP2C9 substrate: Concurrent administration of belmosdil is not expected to have a clinically meaningful effect on exposure to CYP2C9 substrates (such as warfarin).

[0227] CYP2C8 substrates: Concurrent administration of belmosdil is not expected to have a clinically meaningful effect on exposure to CYP2C8 substrates other than OATP1B1 substrates.

[0228] In vitro testing Transporter system: Belmosdil is a substrate of P-gp. Belmosdil inhibits BCRP, P-gp, and OATP1B1 at clinically appropriate concentrations. Enzyme system: Belmosdil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9.

[0229] 13 Non-clinical toxicity 13.1 Carcinogenicity, mutagenicity, and fertility impairment No carcinogenicity studies have been conducted using belmosdil.

[0230] Belmosdil was not genotoxic in in vitro bacterial mutagenicity (Ames) assays, in vitro chromosomal aberration assays in human peripheral blood lymphocytes (HPBLs), or in vivo rat bone marrow micronucleus assays.

[0231] In rat reproductive studies combining males and females, belmosdil-treated males were mated with untreated females, or untreated males were mated with belmosdil-treated females. Belmosdil was administered orally to male rats at doses of 50, 150, or 275 mg / kg / day, 70 days prior to mating and throughout the mating period, and to female rats 14 days prior to mating and up to day 7 of gestation. At a dose of 275 mg / kg / day, adverse findings in female rats (either belmosdil-treated or untreated but mated with treated males) included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of belmosdil at a dose of 275 mg / kg / day to male rats resulted in abnormal sperm characteristics (decreased motility, decreased count, and increased percentage of abnormal sperm) and changes in testicular / epididal organs (weight loss and degeneration).

[0232] Fertility was reduced in both males and females treated with a dose of 275 mg / kg / day, reaching statistical significance in males. Adverse changes in the male and female genitalia also occurred in general toxicity studies, with findings including spermatogenesis in dogs at a dose of 35 mg / kg / day of belmosdil and decreased ovarian follicular development in rats at 275 mg / kg / day. During the recovery period, the changes were partially or completely reversed. The exposure (AUC) at doses of 35 mg / kg / day in dogs and 275 mg / kg / day in rats was 0.5 times and 8-9 times, respectively, the clinical exposure at the recommended daily dose of 200 mg.

[0233] 14 Clinical Trials 14.1 Chronic graft-versus-host disease The KD025-213 trial (NCT03640481) was a randomized, open-label, multicenter trial of REZUROCK for the treatment of chronic GVHD patients who had received 2-5 prior lines of systemic therapy and required further treatment. The patient had platelet counts <50 × 10⁶ 9 / L; Absolute neutrophil count < 1.5 × 10 9 / L;AST or ALT > 3 × ULN;Total bilirubin > 1.5 × ULN;QTc(F) > 480 ms;eGFR < 30 mL / min / 1.73 m 2 Patients were excluded from the study if their FEV1 was ≤39%. Sixty-six patients were treated with REZUROCK 200 mg orally once daily. Concomitant use with supportive care for chronic GVHD was permitted. Concomitant use with GVHD prophylaxis and standard care systemic chronic GVHD therapy was permitted as long as the patient was at a stable dose for at least two weeks prior to the study. Initiation of new systemic chronic GVHD treatments during the study was not permitted.

[0234] Demographics and baseline characteristics are outlined in Table 4.

[0235] [Table 5]

[0236] The efficacy of REZUROCK is based on the overall response rate (ORR) by Day 1 of Cycle 7, where overall response included complete response or partial response per the 2014 NIH Response Criteria. The ORR results are shown in Table 5. The ORR was 75% (95% CI: 63, 85). The median duration of response, calculated from the initial 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 initial response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, 62% (95% CI: 46, 74) of patients did not experience death or initiation of new systemic therapy for at least 12 months after response.

[0237]

Table 6

[0238] The ORR results were supported by an exploratory analysis of patient-reported symptom bother that showed at least a 7-point reduction in the Lee Symptom Scale summary score by Day 1 of Cycle 7 in 52% (95% CI: 40, 65) of patients.

[0239] 16 Supply / Storage and Handling Instructions REZUROCK 200 mg tablets are supplied as pale yellow, film-coated, oblong tablets containing 200 mg of belumosudil (equivalent to 242.5 mg of belumosudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other, and is packaged as follows: 200 mg tablets in 30-count bottle: NDC79802-200-30

[0240] Store at room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0241] Dispense to patients only in the original container. Store in the original container to protect from moisture. Ensure the cap is replaced securely each time after opening. Do not discard the desiccant.

[0242] 17. Patient counseling information Advise patients to read FDA-approved patient labeling (Patient Information).

[0243] Embryo-fetal toxicity: • Instruct pregnant women and women about the potential risks to the fetus in their reproductive capacity. • Instruct healthcare providers about known or suspected pregnancies in women of reproductive capacity. [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Advise women of reproductive age to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Warnings and Precautions (5.1)]. Men with female partners of reproductive capacity should be instructed 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)].

[0244] breastfeeding Women should be instructed not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [see Use in specific populations (8.2)].

[0245] infertility Inform fertile men and women that REZUROCK may impair their fertility [see Use in Specific Populations (8.3)].

[0246] Administration Instruct patients to take REZUROCK orally once daily with food, as directed by their physician, and that the oral dose (tablet) should be swallowed completely 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)].

[0247] If a patient misses a daily dose of REZUROCK, instruct the patient to return to the normal schedule the next day and take the missed dose as soon as possible on the same day. The patient should not take an additional dose to make up for the missed dose [see Dosage and Administration (2.1)].

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

[0249] [Table 7]

[0250] [Table 8]

[0251] [Table 9]

[0252] Example 2: Interaction between Velsumosil and transporter substrates Interactions Effects of other drugs on Velmosil Strong CYP3A4 inducers Co-administration of Velmosil with a strong CYP3A inducer reduces Velmosil exposure, which may decrease the efficacy of Velmosil. When co-administered with a strong CYP3A inducer, increase the dosage of Velmosil.

[0253] Proton pump inhibitors Co-administration of Velmosil with a proton pump inhibitor reduces Velmosil exposure, which may decrease the efficacy of Velmosil. When co-administered with a proton pump inhibitor, increase the dosage of Velmosil.

[0254] Effects of Velmosil on other drugs OATP1B1 / BCRP substrate: Concomitant administration of belmosdil with drugs transported by OATP1B1 and BCRP may result in increased exposure to these concomitant drugs (e.g., rosuvastatin), which may increase the risk of substrate-related toxicity. If possible, consider switching to drugs less sensitive to OATP1B1 and BCRP inhibition. When used together, the dose of rosuvastatin should not exceed 5 mg once daily. Closely monitor patients for signs and symptoms of excessive exposure to drugs that are substrates of OATP1B1 and BCRP.

[0255] Drug interaction testing The effects of belmosdil on other drugs Transporter system Co-administration of the OATP1B1 / BCRP substrate belmosdil increases rosuvastatin Cmax and AUC by 3.6-fold and 4.6-fold, respectively.

[0256] P-glycoprotein (P-gp) substrate: Co-administration of belmosdil doubled exposure to dabigatran, suggesting a moderate possibility of inhibiting P-gp substrate transport.

[0257] Example 3: A three-part, non-randomized, open-label study designed to evaluate the effects of oral belmosdil on UGT1A1, P-gp, BCRP, and OATP1B1 inhibition in healthy male subjects under dietary conditions. Objective: Primary outcome measures: Part 1: To determine the effect of multiple doses of REZUROCK® (belmosdil) tablets on single-dose oral pharmacokinetics (PK) of ISENTRESS® (raltegravir), a drug that interacts with UGT1A1. Part 2: To determine the effect of multiple doses of REZUROCK (belmosdil) tablets on single-dose oral pharmacokinetics (PK) of PRADAXA® (dabigatran etexilate), a P-gp interacting drug. Part 3: To determine the effect of multiple doses of REZUROCK (belmosdil) tablets on single-dose oral pharmacokinetics (PK) of CRESTOR® (rosuvastatin calcium), an OATP1B1 / BCRP-interacting drug.

[0258] Secondary evaluation criteria: Part 1: To provide single-dose pharmacokinetic (PK) data for raltegravir as an interacting drug and its metabolite, raltegravir glucuronide, after administration of raltegravir alone and in combination with REZUROCK (belmosdil) tablets. Part 2: To provide single-dose PK data for the interacting drug dabigatran etexilate, both alone and in combination with REZUROCK (belmosdil) tablets. Part 3: To provide single-dose PK data for the interacting drug rosuvastatin, both alone and in combination with REZUROCK (belmosdil) tablets. Parts 1, 2, and 3: Determine the pharmacokinetics (PKs) of belmosdil and known metabolites (KD025m1, KD025m2) after single and multiple oral administrations of REZUROCK (belmosdil) tablets in healthy participants under food intake. Parts 1, 2, and 3: Provide further safety and tolerability information for REZUROCK (belmosdil) tablets when administered concurrently with raltegravir (Part 1), a UGT1A1 interacting drug; dabigatran etexilate (Part 2), a P-gp interacting drug; and rosuvastatin (Part 3), an OATP1B1 / BCRP interacting drug.

[0259] method. Part 1 was a single-center, non-randomized, open-label, single-period design to evaluate the effect of multiple doses of belmosdil on single-dose pharmacokinetics (PK) of raltegravir (UGT1A1-sensitive substrate), and was to enroll 19 healthy male participants. Part 2 was a single-center, non-randomized, open-label, single-period design to evaluate the effect of multiple doses of belmosdil on single-dose pharmacokinetics (PK) of dabigatran etexilate (a P-gp-sensitive substrate), and was to enroll 19 healthy male participants. Part 3 was a single-center, non-randomized, open-label, single-period design to evaluate the effect of multiple doses of belmosdil on single-dose rosuvastatin (BCRP / OATP1B1-sensitive substrate) pharmacokinetics, and was to enroll 15 healthy male participants.

[0260] Throughout this clinical trial report, the term “trial intervention” refers to the following: • Investigative medicinal product (IMP) for drug interactions: REZUROCK (belmosdil) tablets, 200 mg • Drugs that may interact with IMPs: ISENTRESS (raltegravir) film-coated tablets (400 mg), PRADAXA (dabigatran etexilate) capsules (75 mg), and CRESTOR (rosuvastatin calcium) tablets (10 mg).

[0261] Examination designs for Parts 1, 2, and 3 In each trial part, participants underwent preliminary screening procedures upon their screening visit (from day -28 to day -2 of each trial part). Participants were admitted to the clinical unit on the morning before the first dose of the trial intervention (i.e., day -1).

[0262] Registered participants were administered interacting IMPs and uninteracted IMPs as follows: • Part 1 (Regimen A [Raltegravir + Belmosdil]): Participants received a single dose of the interacting IMP raltegravir on the mornings of days 1 and 7. In addition, participants received a single dose of the interacting belmosdil tablet on the mornings of days 3 through 8 (once daily [QD]). On day 7, the interacting IMP and the interacting IMP were administered simultaneously. • Part 2 (Regimen B [dabigatran etexilate + belmosdil]): Participants received a single dose of the interacting IMP dabigatran etexilate on the mornings of days 1 and 9. In addition, participants received a single dose of the interacting belmosdil tablets on the mornings of days 5 through 12 (QD). On day 9, the interacting IMP and the interacting IMP were administered simultaneously. • Part 3 (Regimen C [Rosuvastatin Calcium + Belmosdil]): Participants received a single dose of the interacting IMP rosuvastatin on the mornings of days 1 and 10. In addition, participants received a single dose of the interacting belmosdil tablets on the mornings of days 6 through 13 (QD). On day 10, the interacting IMP and the interacting IMP were administered simultaneously.

[0263] Participants were given a light snack in the evening before each dose and were required to fast for at least 10 hours until the following morning, without consuming any food or drink (except water). All study interventions were administered while eating, after a standard breakfast (administration was planned to take place 30 minutes after the start of breakfast).

[0264] In each part of the study, blood samples were periodically collected for PK analysis of plasma concentrations of the following analytes: raltegravir and raltegravir glucuronide (Part 1), unconjugated dabigatran (Part 2), rosuvastatin (Part 3), vermosdil and known metabolites (KD025m1, KD025m2) (Parts 1, 2, and 3). The following safety evaluations were also performed in Parts 1, 2, and 3: incidence of adverse events (AEs), vital signs, electrocardiogram (ECG), physical examination, and laboratory safety testing.

[0265] All participants remained on-site for 48 hours after the final dose for safety and PK assessment, and follow-up phone calls were made 3 to 7 days after the final dose to check on the participants' ongoing health status.

[0266] Number of participants. Part 1 (Regimen A): In Part 1, we planned to enroll 19 participants. All 19 participants were enrolled, administered Regimen A (raltegravir + vermosdil), and completed the study. All 19 enrolled participants were included in the safety and PK population and analysis set. Part 2 (Regimen B): In Part 2, we planned to enroll 19 participants. All 19 participants were enrolled, administered Regimen B (dabigatran etexilate + belmosdil), and all enrolled participants completed the study. All 19 enrolled participants were included in the safety and PK population and analysis set. Part 3 (Regimen C): In Part 3, we planned to enroll 15 participants, but one participant was determined to be ineligible for administration on day 1. Therefore, 14 participants were enrolled and administered Regimen C (rosuvastatin calcium + vermosdil), and all enrolled participants completed the study. All 14 enrolled participants were included in the safety and PK population and analysis set.

[0267] Diagnostic and inclusion criteria. This study involved healthy male participants aged 18-55 years at the time of signing informed consent, with a body mass index (BMI) of 18.0-32.0 kg / m² as measured at the time of screening. 2 Participants were enrolled with a body weight of ≥50 kg. Participants identified as having low metabolism for UGT1A1 in Part 1, and participants identified as having a reduced-function gene or predicted reduced-function gene for SLCO1B1 (OATP1B1) in Part 3, were excluded from the study.

[0268] Test product Part 1 (Regimen A): Interactions IMP: ISENTRESS (raltegravir) film-coated tablets for oral use, 400 mg (expressed as free phenol equivalent) Part 2 (Regimen B): Interactions IMP: PRADAXA (dabigatran etexilate) capsules for oral use, 75 mg (expressed as free drug equivalent) Part 3 (Regimen C): Interacting IMP: CRESTOR (rosuvastatin calcium) tablets, 10 mg (expressed as free drug equivalent) Parts 1, 2, and 3 (regimen A, B, and C, respectively): Interactions IMP: REZUROCK (belmosdil) tablets, 200 mg (expressed as free base equivalent)

[0269] All experimental interventions were administered orally while the patient was eating.

[0270] Trial intervention period. In Part 1, participants received raltegravir on two separate occasions (mornings of day 1 and day 7) and a single dose of belmosdil QD for six consecutive days (mornings of days 3-8). In Part 2, participants received dabigatran etexilate on two separate occasions (mornings of day 1 and day 9) and a single dose of belmosdil QD for eight consecutive days (mornings of days 5-12). In Part 3, participants received rosuvastatin on two separate occasions (mornings of day 1 and day 10) and a single dose of belmosdil QD for eight consecutive days (mornings of days 6-13).

[0271] Evaluation criteria. Primary evaluation criteria. Part 1: PK Parameters: AUC(0-last) and AUC(0-inf) for raltegravir after the trial treatment (raltegravir + belmosdil) and reference treatment (raltegravir alone), as needed. Where possible and appropriate, the results of statistical analysis of the PK parameters AUC(0-last) and AUC(0-inf) for raltegravir in the trial treatment (raltegravir + belmosdil) compared with the reference treatment (raltegravir alone). Part 2: PK parameters: After receiving the test (dabigatran etexilate + belumosil) treatment and the reference (dabigatran etexilate alone) treatment, AUC(0-last) and AUC(0-inf) for unconjugated dabigatran as needed. Where possible and appropriate, results of statistical analysis of the PK parameters AUC(0-last) and AUC(0-inf) for unconjugated dabigatran in the test treatment (dabigatran etexilate + belumosil) compared to the reference treatment (dabigatran etexilate alone). Part 3: PK parameters: After receiving the test (rosuvastatin + belumosil) treatment and the reference (rosuvastatin alone) treatment, AUC(0-last) and AUC(0-inf) for rosuvastatin as needed. Where possible and appropriate, results of statistical analysis of the PK parameters AUC(0-last) and AUC(0-inf) for rosuvastatin in the test treatment (rosuvastatin + belumosil) compared to the reference treatment (rosuvastatin alone).

[0272] Secondary endpoints. Part 1: PK parameters: After receiving the test (raltegravir + belumosil) treatment and the reference (raltegravir alone) treatment, Tmax, Cmax and T for raltegravir as needed 1 / 2 . PK parameters: After receiving the test (raltegravir + belumosil) treatment and the reference (raltegravir alone) treatment, AUC(0-last), AUC(0-inf), Tmax, Cmax and T for raltegravir glucuronide as needed 1 / 2 . Where possible and appropriate, results of statistical analysis of the PK parameter Cmax for raltegravir in the test treatment (raltegravir + belumosil) compared to the reference treatment (raltegravir alone). Where possible and appropriate, results of statistical analysis of the PK parameters Cmax, AUC(0-last) and AUC(0-inf) for raltegravir glucuronide in the test treatment (raltegravir + belumosil) compared to the reference treatment (raltegravir alone). Part 2: PK Parameters: After trial (dabigatran etexilate + belmosdil) treatment and reference (dabigatran etexilate monotherapy) treatment, Tmax, Cmax, and Tmax for unconjugated dabigatran as needed. 1 / 2 Where possible and appropriate, the results of a statistical analysis of Cmax, a PK parameter for unconjugate dabigatran, in the test treatment (dabigatran etexilate + belmosdil) compared with the reference treatment (dabigatran etexilate alone). Part 3: PK Parameters: After trial (rosuvastatin + vermosdil) treatment and reference (rosuvastatin monotherapy) treatment, Tmax, Cmax, and Tmax for rosuvastatin as needed. 1 / 2 Where possible and appropriate, the results of a statistical analysis of Cmax, a pharmacokinetic parameter for rosuvastatin, in the test treatment (rosuvastatin + vermosdil) compared with the reference treatment (rosuvastatin alone). Parts 1, 2 and 3: PK parameters: Tmax, Cmax, AUC(0-last), AUC(0-tau) and Tmax for Belmosdil, KD025m1 and KD025m2 as needed. 1 / 2 . Parts 1, 2, and 3: To provide further safety and tolerability information for belmosdil by evaluating adverse events, vital signs, ECG, physical examination, and laboratory safety assessments after administration of three interacting drugs (raltegravir [Part 1], dabigatran etexilate [Part 2], and rosuvastatin [Part 3]) alone and in combination with belmosdil.

[0273] statistical methods. For regimens A, B, and C (parts 1, 2, and 3), the PK parameters were calculated as maximum blood concentration (Cmax) and area under the curve (AUC(0-last)) from time 0 to the time of the last measurable concentration, and for regimen B (part 2) only, the area under the curve from time 0 extrapolated to infinity (AUC(0-inf)). For each regimen / part, formal statistical analysis was performed separately, and these were compared in the following pairwise treatment comparisons (test pair reference, i.e., interacted + interacting IMP vs. interacted IMP alone): Regimen A (part 1): For parent raltegravir and its metabolite raltegravir glucuronide, raltegravir + belmosdil (day 7) vs. raltegravir alone (day 1). Regimen B (part 2): For unconjugated dabigatran, dabigatran + belmosdil (day 9) vs. dabigatran alone (day 1). Regimen C (Part 3): For rosuvastatin, rosuvastatin + belmosdil (day 10) vs. rosuvastatin alone (day 1). PK parameters underwent natural logarithmic transformation and were analyzed using mixed-effects modeling techniques. For each comparison, adjusted geometric mean ratios and 90% confidence intervals (CIs) of the ratios were obtained. Ratios were defined as trial / reference. In addition, within-subject variability was presented. Where possible and appropriate, further PK parameters were estimated for plasma raltegravir, raltegravir glucuronide, unconjugate dabigatran, and rosuvastatin, belmosdil, and known metabolites (KD025m1 and KD025m2). Formal statistical analysis was not performed on PK data for plasma belmosdil and known metabolites (KD025m1 and KD025m2), or on safety data during this trial. No formal interim analysis was performed for this trial.

[0274] Summary results. Demographic and other baseline characteristics. In total, 52 healthy male participants, ranging in age from 19 to 54 years, were enrolled in the study; all weighed at least 50 kg and met the BMI requirements of the protocol (18.0–32.0 kg / m²). 2) was within the normal range. All participants were not currently smokers and consumed 0-2 units of alcohol per week.

[0275] exposure. For regimen A, all 19 participants received a total of two planned oral doses of raltegravir and six oral doses of belmosdil over an 8-day period: a single dose of 400 mg of raltegravir on days 1 and 7, and 200 mg of belmosdil in quick dose (QD) doses on days 3 through 8. The cumulative dose of belmosdil received by each participant was 1200 mg, and the exposure period was 6 days.

[0276] For regimen B, all 19 participants received a total of two planned oral doses of dabigatran etexilate and eight oral doses of belmosdil over 12 days: a single dose of 75 mg of dabigatran etexilate on days 1 and 9, and a QD dose of 200 mg of belmosdil on days 5 through 12. The cumulative dose of belmosdil received by each participant was 1600 mg, and the exposure period was 8 days.

[0277] Fifteen participants were scheduled to receive regimen C, but one participant was deemed ineligible for administration on day 1 of Part 3. All 14 participants received the planned two oral doses of rosuvastatin calcium and eight oral doses of belmosdil over 13 days: a single dose of 10 mg of rosuvastatin calcium on days 1 and 10, and a 200 mg belmosdil QD dose on days 6-13. The cumulative dose of belmosdil received by each participant was 1600 mg, and the exposure period was 8 days.

[0278] Pharmacokinetic results. Table 7 below shows the results of a statistical analysis of the effects of multiple doses of belmosdil on the single-dose oral PK endpoints AUC(0-last), AUC(0-inf) (regime B [dabigatran etexilate + belmosdil, part 2] only), and Cmax for raltegravir, raltegravir glucuronide, non-conjugate dabigatran, and rosuvastatin.

[0279] [Table 10]

[0280] Table 8 below shows the geometric mean (geometric coefficient of variation [CV%]) values ​​for plasma PK parameters for raltegravir and raltegravir glucuronide for Regimen A (Part 1).

[0281] [Table 11]

[0282] For Part 1 (Regimen A), peak and overall raltegravir exposure levels were comparable when raltegravir was administered with belmosdil tablets compared to administration alone. However, a significant decrease in peak and overall raltegravir glucuronide exposure levels was observed when raltegravir was administered with belmosdil compared to administration alone. Belmosdil co-administration did not alter the median time to peak blood concentration (Tmax) for either raltegravir or raltegravir glucuronide. The geometric mean final elimination half-life (T1 / 2) increased from approximately 1.4 hours (raltegravir) or 1.5 hours (raltegravir glucuronide) on day 1 to approximately 3.9 hours (both analytes) on day 7 after co-administration of belmosdil.

[0283] For Regimen B (Part 2), the geometric mean (geometric CV%) values ​​for plasma PK parameters for non-conjugate dabigatran are shown in Table 9 below.

[0284] [Table 12]

[0285] For Part 2 (Regimen B), the peak and overall exposure levels of non-conjugate dabigatran (after administration of dabigatran etexilate) increased 2.36 and 2.06 times, respectively, when administered with bermosdil compared to administration alone. Median Tmax and geometric mean T 1 / 2 The results were similar after administration of dabigatran etexilate alone or with belmosdil.

[0286] For Regimen C (Part 3), the geometric mean (geometric CV%) values ​​of plasma PK parameters for rosuvastatin are shown in Table 10 below.

[0287] [Table 13]

[0288] For Part 3 (Regimen C), the peak and overall exposure levels of rosuvastatin (after administration of rosuvastatin calcium) increased 3.59 times and 4.62 times, respectively, when administered with bermosdil compared to administration alone. Furthermore, co-administration of bermosdil resulted in a faster median Tmax (approximately 6 hours after administration on day 1 to approximately 2.5 hours after administration on day 10), and the geometric mean T 1 / 2 The time decreased from 4.1 hours to 2.7 hours, but this change should be interpreted cautiously given the smaller number of reliable estimates (n=5) on day 1 compared to day 10 (n=13).

[0289] For Regimen A (Part 1), the geometric mean (geometric CV%) values ​​of the PK parameters for belmosdil, KD025m1, and KD025m2 after oral administration of 200 mg of belmosdil alone and after co-administration of 400 mg of raltegravir (prototype UGT1A1 substrate) are shown in Table 11 below.

[0290] [Table 14]

[0291] In Part 1, after single and repeated doses of belmosdil, the median Tmax for belmosdil, KD025m1, and KD025m2 was achieved approximately 1.5–3 hours after administration, and exposure to belmosdil (Cmax and AUC) and KD025m2 increased 1.30–1.49 times after multiple doses.

[0292] Geometric mean T for belmoszil 1 / 2 From approximately 6 hours on day 3 to approximately 8 hours on day 8, the geometric mean T for KD025m1 increased after repeated administrations of belmosdil compared to a single dose, and the geometric mean T for KD025m1 increased. 1 / 2 This is approximately 1.6-2 hours on the 3rd and 8th days, and the geometric mean T for KD025m2. 1 / 2 This increased slightly from approximately 4 hours on the third day to approximately 5 hours on the eighth day.

[0293] For Regimen B (Part 2), the geometric mean (geometric CV%) values ​​of the PK parameters for belmosdil, KD025m1, and KD025m2 after oral administration of 200 mg of belmosdil alone, and after co-administration of 75 mg of dabigatran etexilate (prototype P-gp substrate) orally, are shown in Table 12 below.

[0294] [Table 15]

[0295] In Part 2, after single and repeated doses of belmosdil, the median Tmax for belmosdil, KD025m1, and KD025m2 was achieved approximately 1.5–2 hours after administration, and exposure to belmosdil (Cmax and AUC) and KD025m2 increased 1.27–1.42 times after single administration.

[0296] If sufficient estimates are available, the geometric mean T for belmoszil 1 / 2 From approximately 6 hours on day 5 to approximately 10 hours on day 12, the geometric mean T for KD025m2 increased after repeated administrations of belmosdil compared to a single dose, and the geometric mean T for KD025m2 increased. 1 / 2 This increased slightly from approximately 3 hours on day 5 to approximately 4 hours on day 12.

[0297] For Regimen C (Part 3), the geometric mean (geometric CV%) values ​​of the PK parameters for belmosudil, KD025m1, and KD025m2 after oral administration of 200 mg of belmosudil alone, and after co-administration of 10 mg of rosuvastatin calcium (prototype BCRP / OATP1B1 substrate) orally, are shown in Table 13 below.

[0298] [Table 16]

[0299] In Part 3, after single and repeated doses of belmosdil, the median Tmax for belmosdil, KD025m1, and KD025m2 was achieved approximately 1.5–2 hours after administration, and exposure to belmosdil (Cmax and AUC) and KD025m2 increased 1.21–1.57 times after multiple doses.

[0300] If sufficient estimates are available, the geometric mean T for belmoszil 1 / 2 Compared to a single dose, the geometric mean T for KD025m2 increased after repeated administrations of belmosdil up to approximately 5-9 hours. 1 / 2 The duration increased from approximately 2 hours to approximately 6 hours.

[0301] Safety-related results. Overall, the interacting IMP, belmosdil, was well-tolerated when administered co-administered with the uninteracted IMPs, raltegravir, dabigatran etexilate, and rosuvastatin calcium. No serious adverse events (TEAEs) leading to withdrawal or death were reported, and the total number of TEAEs and the number of participants reporting TEAEs were low. Only two participants (3.8%) reported one TEAE each during the study, both of which were grade 1 (mild) and resolved without drug or intervention. The investigator determined that only one event (headache) was related to the interacting IMP (belmosdil), and no TEAEs were determined to be related to the uninteracted IMP. No clinically significant findings were observed in laboratory assessments, vital sign measurements, ECG, or physical examination assessments for any of the regimens, and no trends were observed in these data. No new potential safety signals were observed after reviewing the data generated in this study.

[0302] Although the present invention is described in some detail by examples and illustrations for the purpose of clarity and understanding, the description and examples should not be construed as limiting the scope of the invention. All patent and scientific literature disclosures cited herein are expressly incorporated herein in their entirety by reference.

Claims

1. A method for treating chronic graft-versus-host disease (cGVHD) in a subject of need, the method comprising the co-administration of at least one substrate of organic anion transport polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), or P-glycoprotein (P-gp), and 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), wherein the dose of the at least one substrate of OATP1B1, BCRP, or P-gp is reduced compared to the clinically recommended dose when the substrate is administered without the compound.

2. The method according to claim 1, wherein the compound comprises a mesylate of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide.

3. The method according to claim 1 or 2, wherein the dose of the compound is about 200 mg.

4. The method according to any one of claims 1 to 3, wherein a substrate of OATP1B1 is administered simultaneously to the subject.

5. The method according to claim 4, wherein the substrate of OATP1B1 is at least one of estradiol-17β-glucuronide, pitavastatin, pravastatin, rosuvastatin, atorvastatin, lovastatin, or simvastatin.

6. The method according to claim 5, wherein the substrate of OATP1B1 is rosuvastatin.

7. The method according to any one of claims 1 to 3, wherein a substrate of BCRP is administered simultaneously to the subject.

8. The method according to claim 7, wherein the substrate of BCRP is rosuvastatin.

9. The method according to claim 8, wherein the concurrent dose of rosuvastatin does not exceed 5 mg per day.

10. The method according to any one of claims 1 to 3, wherein a substrate of P-gp is administered simultaneously to the subject.

11. The method according to claim 10, wherein the substrate of P-gp is dabigatran etexilate.

12. The method according to claim 11, wherein the simultaneous dose of dabigatran etexilate is less than approximately 300 mg.

13. The method according to claim 1, wherein the dose of the compound is about 200 mg, and the dose of the at least one substrate of OATP1B1, BRCP, or P-gp is reduced to about half the clinically recommended dose when the substrate is administered without the compound.

14. The method according to claim 13, wherein the at least one substrate of OATP1B1, BCRP, or P-gp is rosuvastatin.

15. The method according to claim 13 or claim 14, wherein the compound comprises belmosdyl mesylate.

16. The method according to any one of claims 1 to 15, wherein the subject has chronic graft-versus-host disease and has not responded to at least two prior lines of systemic therapy for the chronic graft-versus-host disease.

17. A method for treating a subject having cGVHD, (a) A step of determining whether the subject requires simultaneous administration of at least one substrate of OATP1B1, BCRP, or P-gp, (b) A step of determining a clinically recommended dose of at least one of the substrates of OATP1B1, BCRP, or P-gp for a subject when the substrate is administered without co-administration of 2-{3-[4-(1H-indazole-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof. (c) A step of determining a smaller dose of at least one substrate of OATP1B1, BCRP, or P-gp administered to a subject in order to mediate the increase of exposure to the substrate by the administration of the compound. (d) A step of simultaneously administering at least one substrate of OATP1B1, BCRP, or P-gp and the compound, Methods that include...

18. The method according to claim 17, wherein the compound comprises belmosdylmesylate.

19. The method according to claim 17, wherein the at least one substrate of OATP1B1, BCRP, or P-gp is rosuvastatin.

Images