Method of administering belumosudil for the treatment of chronic graft-versus-host disease in a patient subpopulation

Abstract

The present disclosure provides a method of administering belumosudil mesylate to a specific subpopulation of cGVHD patients.

Description

Technical Field

[0001] The present disclosure relates to a method of administering besremi mesylate (REZUROCK™) for the treatment of chronic graft-versus-host disease (cGVHD) in a specific subpopulation of patients.

Background Art

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

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

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

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

[0006] The management of cGVHD continues to evolve with the emergence of targeted therapies. cGVHD is characterized by the overproduction of the pro-inflammatory cytokines IL-21 and IL-17, and the overactivation of follicular helper T cells and B cells, which results in the overproduction of antibodies.

[0007] In 2017, the US Food and Drug Administration approved the Bruton tyrosine kinase inhibitor ibrutinib for the treatment of adults with cGVHD after failure of one or more prior systemic therapies. In patients with cGVHD who are required to have either erythematous rash of more than 25% total body surface area or NIH mouse score of more than 4, a trial using ibrutinib reported an overall response rate (ORR) of 67% and a discontinuation rate due to treatment-emergent adverse events (TEAE) of 43%. (Waller EK, et al: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b / 2 study. Biol Blood Marrow Transpl 25:2002-2007, 2019).

[0008] There remains an opportunity to study other treatment options for cGVHD patients, including female patients with reproductive potential and male patients with female partners with reproductive potential.

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0009] The present disclosure provides a method of administering belumosudil, in some embodiments belumosudil mesylate (REZUROCK™), to a subpopulation of patients at particular risk for the treatment of cGVHD.

[0010] In one embodiment, the present disclosure provides 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of cGVHD in male or female patients of reproductive potential, which includes the step of advising the patient to use effective contraception during treatment and for at least 1 week after the last administration of the compound.

[0011] In another embodiment, the present disclosure provides for the use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound), in the treatment of a fertile female patient having cGVHD, comprising the step of confirming the pregnancy status of the patient before initiating treatment with the compound. In some embodiments, the use of its mesylate (belumosudil) is provided.

[0012] In another embodiment, the present disclosure provides for the use of belumosudil in the treatment of chronic graft-versus-host disease (cGVHD) in a lactating patient, comprising advising the patient not to breastfeed during treatment with the compound and for at least 1 week after the last administration of the compound.

[0013] In other embodiments, the present disclosure provides for the use in the treatment of chronic graft-versus-host disease (cGVHD) in a pregnancy-risk patient, comprising the step of advising the patient about the reproductive risks associated with treatment with the compound.

[0014] In another embodiment, the present disclosure relates to a method of treating a patient having cGVHD, comprising, prior to treatment, the step of determining whether the patient is a pregnancy-risk patient. The present disclosure further provides for administering the compound to the patient if it is determined that the patient is not a pregnancy-risk patient, or, if it is determined that the patient is a pregnancy-risk patient, advising the patient about the potential reproductive risks when undergoing treatment with belumosudil, and / or using or recommending the use of effective contraception during treatment with belumosudil and for at least 1 week after the last administration thereof.

[0015] This embodiment can be more fully understood by reference to the detailed description and examples intended to illustrate, but not limit, the non-limiting embodiments.

Mode for Carrying Out the Invention

[0016] Overview Belmosulodzil is an orally selective rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 inhibition acts on the dysregulated adaptive immune system and fibrosis resulting from abnormal tissue repair. Belmosulodzil inhibits ROCK2 and ROCK1 at IC 50 values of approximately 100 nM and 3 μM, respectively.

[0017] In ex vivo or in vitro human T cell assays, belmosulodzil downregulated pro-inflammatory responses via regulation of STAT3 / STAT5 phosphorylation and a shift in the Th17 / Treg balance. Belmosulodzil also inhibited abnormal profibrotic signaling in vitro. By controlling ROCK2 activity, belmosulodzil mediates signaling in immune cell function and fibrosis pathways, thereby alleviating the effects caused by this wasting disease, such as inflammation and fibrotic changes in multiple tissues involving several organs including the lung, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0018] The mesylate salt of belmosulodzil is marketed as REZUROCK™ in the United States and other countries for the treatment of patients with chronic graft-versus-host disease (cGVHD), optionally after failure of at least two prior systemic therapy lines. The compound belmosulodzil has the chemical name: 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound belmosulodzil is also known as KD025. The active pharmaceutical ingredient of REZUROCK™ has the molecular formula C 27 H 28 N6O5S with a molecular weight of 548.62 g / mol and is belmosulodzil mesylate having the chemical name 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1).

[0019] The chemical structure of belmosulodzil mesylate is as follows.

Chemical Structure

[0020] The method for producing vermoxyl 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.

[0021] The applicant in this specification evaluated vermoxyl in multiple rat and rabbit embryo-fetal toxicology studies as described in the following Examples 1-5 (i.e., Example 1 entitled "A Pilot Prenatal Developmental Toxicity and Toxicokinetic Study in Sprague-Dawley Rats", Example 2 entitled "A Pilot Prenatal Developmental Toxicity and Toxicokinetic Study in New Zealand White Rabbits With Non-pregnant Dose Range Finding Phase", Example 3 entitled "An Embryo-Fetal Developmental Toxicity Study in Sprague-Dawley Rats With a Toxicokinetic Evaluation", Example 4 entitled "An Embryo-Fetal Developmental Toxicity Study in New Zealand White Rabbits With a Toxicokinetic Evaluation", and Example 5 entitled "A Combination Study of Fertility and Early Embryonic Development to Implantation in Sprague-Dawley Rats").

[0022] Based on the findings from the aforementioned tests, vermoxil may cause harm to the fetus when administered to pregnant women. In the aforementioned animal tests, pregnant rats during the organogenesis period were administered vermoxil at doses of 25, 50, 150, and 300 mg / kg / day in the pilot test (Example 1 of this specification) and at doses of 15, 50, and 150 mg / kg / day in the pivotal test (Example 3 of this specification). In the pilot test, maternal toxicity and embryo-fetal developmental effects were observed. Maternal toxicity (decrease in body weight gain) occurred at doses of 150 and 300 mg / kg / day. An increase in post-implantation loss occurred at 50 and 300 mg / kg / day. Fetal malformations were observed at 50 mg / kg / day and above, including anal and tail absence, umbilical cord tumors, and dome-shaped heads. The exposure (AUC) at 50 mg / kg / day in rats was approximately 3 times the human exposure at the recommended human dose of 200 mg.

[0023] In the rabbit embryo-fetal development test (Example 4 of this specification), pregnant animals were orally administered vermoxil at 50, 125, and 225 mg / kg / day during the organogenesis period, which resulted in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of 125 mg / kg / day and above. Embryo-fetal effects were observed at doses of 50 mg / kg / day and above, including spontaneous abortion, increased post-implantation death, decreased proportion of live fetuses, malformations, and decreased fetal body weight. Malformations included malformations of the tail (short), ribs (branched, fused, or deformed), sternal segmentation (fused), and neural arches (fused, displaced, deformed). The exposure (AUC) at 50 mg / kg / day in rabbits was approximately 0.07 times the human exposure at the recommended dose of 200 mg.

[0024] In the rat fertility test combining male and female (Example 5 of this specification), male animals treated with vemurafenib were mated with untreated ones, or untreated male animals were mated with vemurafenib-treated females. Vemurafenib was orally administered to male rats at doses of 50, 150, or 275 mg / kg / day for 70 days before and throughout the mating period, and to female rats for 14 days before mating and up to day 7 of pregnancy. At a dose of 275 mg / kg / day, adverse findings in female rats (treated with vemurafenib or untreated but mated with treated males) included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of vemurafenib to male rats at a dose of 275 mg / kg / day resulted in abnormal sperm findings (decreased motility, decreased count, and increased proportion of abnormal sperm) and changes in the testis / epididymis organs (weight loss and degeneration). Fertility was decreased in both males and females treated at a dose of 275 mg / kg / day, reaching statistical significance in males. Adverse changes in male and female genitalia also occurred in the general toxicity tests, and the findings included sperm degeneration at a vemurafenib dose of 35 mg / kg / day in dogs and decreased ovarian follicular development at 275 mg / kg / day in rats. During the recovery period, the changes were partially or completely reversed. The exposures (AUC) at doses of 35 mg / kg / day in dogs and 275 mg / kg / day in rats were 0.5-fold and 8 - 9-fold, respectively, of the clinical exposure at the recommended dose of 200 mg daily.

[0025] The present disclosure provides a method of administering vemurafenib, in some embodiments vemurafenib mesylate (REZUROCK™), to a specific subpopulation of patients including women of reproductive potential and pregnancy risk partners. This subpopulation includes lactating women due to the potential for adverse reactions in children breastfed by patients taking vemurafenib.

[0026] Definitions As used herein, "about" includes the exact amount modified by the term "about" and amounts expected to be within experimental error, such as within 15%, 10%, or 5%. For example, "about 200 mg" means "200 mg" and also means a range of mg within experimental error, such as ±15%, 10%, or 5% of 200 mg. As used herein, the term "about" can be used to modify ranges and specific values.

[0027] As used herein (e.g., with reference to the administration of an API, including a compound or vermoxnil, to a subject), "administer" or "administered" refers to the act of prescribing a medicament containing the API for the subject to take during treatment, the act of dispensing the medicament to the subject, and / or the act of physically receiving or ingesting the medicament. Thus, an API (e.g., a compound or vermoxnil) can be "administered" by a physician or other medical professional writing a prescription for the medicament, and / or by a pharmacist filling in the prescription, and / or by a pharmacist dispensing the medicament to the subject, and / or by a patient or subject taking the drug and / or their partner or caregiver.

[0028] "API" means "active pharmaceutical ingredient".

[0029] "Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" or "allogeneic hematopoietic cell transplantation (allo-HCT)", also called bone marrow transplantation or stem cell transplantation, refers to a technique of transplanting donor-derived hematopoietic cells into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some situations, cord blood can be used. The donor and recipient can be matched by the human leukocyte antigen (HLA) gene, such as siblings. The donor and recipient can be a parent and child who are half-matched (haplotype-matched).

[0030] Unless otherwise clearly indicated in context, the "belumosudil" used refers to any form of the compound belumosudil as well as its pharmaceutically acceptable salts. The term "belumosudil" refers to both the compound belumosudil (e.g., in free base form, amorphous form or crystalline form), the pharmaceutically acceptable salts of belumosudil, such as the mesylate form used as REZUROCK™, and any form of belumosudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0031] "Breastfeeding" means delivering breast milk produced by lactation to a child, including both administering breast milk to the child from the breast and / or collecting breast milk and delivering it to the child by other means, such as from a bottle or container.

[0032] "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 the clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) is the percentage of people in a test or treatment group who have a partial response (PR) or complete response (CR) to treatment within a certain period. Failure-free survival (FFS) means the time from the first dose of belumosudil to a failure event, or the interval from the start of belumosudil to the addition of a new cGVHD therapy, recurrence of the underlying disease, or time to non-relapse mortality (NRM). Overall survival (OS) means the length of time from the date of diagnosis of the disease or the start of treatment. Duration of response (DOR) means the time from the point of initial response (e.g., PR or CR) to documented progression from the best response of cGVHD, to the start of additional systemic cGVHD therapy from the initial response, or to death. Time to next therapy (TTNT) means the time to the start of subsequent systemic cGVHD therapy.

[0033] "Clinically recommended amount" or "clinically recommended dosage" refers to the amount or dosage of an API that has been recommended and / or approved for administration to a patient by a person of ordinary skill in the art of pharmaceutical chemistry for treating the disease state in question after clinical trials. In some embodiments, the clinically recommended amount of belumosudil is 200 mg once daily with food until chronic GVHD requiring new systemic therapy progresses.

[0034] As used in the claims and embodiments of this specification, "compound" is synonymous with the above - inclusive definition of belumosudil when the context of use is clear.

[0035] "CYP3A" refers to the CYP3A family of p - 450 isoenzymes, including CYP3A4.

[0036] "Effective contraception" is the use of artificial methods or other techniques to effectively prevent intercourse resulting in pregnancy. Examples of contraception include barrier methods such as condoms, hormonal methods (e.g., birth control pills), intrauterine devices such as coils, and male or female sterilization surgery. The simultaneous use of multiple forms of contraception is contemplated by the definition of effective contraception and enhances the effectiveness of contraception.

[0037] As used herein, "fetus" encompasses a fetus in the process of development, including a fertilized egg, embryo, or fetus at a later stage of development.

[0038] "Pregnancy" means the period of intrauterine development from conception to parturition.

[0039] "Immunosuppressive therapy" (IST) refers to a therapy that is typically administered for at least 6 months after allogeneic HSCT in an attempt to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine.

[0040] "Lactating patient" means a patient who is capable of producing breast milk.

[0041] The Lee Symptom Scale (LSS) summary score measures the impact on a patient's function and health. The Lee Symptom Scale is a 30-item scale developed to measure the symptoms of cGVHD, as described in Lee SJ, et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease. Biol Blood Marrow Transplant 2002;8:444-452.

[0042] "Treatment line" or "therapy line" describes the order or sequence in which different treatments are given to a patient as their disease progresses. Initial treatment (first-choice treatment) may stop functioning or stop working after a certain period. After both first-choice treatments are discontinued, a second, different treatment (second-choice therapy) may be administered. Subsequent treatment lines may be administered if the second-choice therapy stops functioning or stops working. Some patients may receive multiple treatment lines over the course of their disease.

[0043] The first-choice therapy for National Institutes of Health (NIH)-defined moderate to severe chronic graft-versus-host disease (cGVHD) can be corticosteroids alone or corticosteroids in combination with sirolimus or a calcineurin inhibitor. (Carpenter PA, et al.: A phase II / III randomized, multicenter trial of prednisone / sirolimus versus prednisone / sirolimus / calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 103:1915-1924, 2018).

[0044] Examples of corticosteroid therapy for the treatment of cGVHD include, but are not limited to, prednisone, prednisolone, methylprednisolone, and budesonide. Examples of prior systemic therapy for treating cGVHD include, but are not limited to, prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib, and ofatumumab.

[0045] A "malformation" is usually an abnormal or significantly harmful permanent deviation that is not compatible with normal postnatal survival or development. "Malformation" means a structural abnormality that changes the general physical adaptability, interferes with or disrupts body functions, or is generally considered incompatible with life. Specific examples of processes that result in malformations include significant or severe irregularities, asymmetries, or irregularities of structures caused by fusion, fission, detachment, displacement, perforation, dilation, elongation, hypertrophy, thinning, or branching. The absence of a part or the whole structure is also considered a malformation.

[0046] "Myeloablative transplantation" refers to a transplantation process that uses very high doses of chemotherapy or radiation before transplantation with autologous or allogeneic hematopoietic stem cells. Non-myeloablative transplantation, or reduced-intensity transplantation, involves the patient receiving less intensive chemotherapy prior to transplantation with allogeneic hematopoietic stem cells.

[0047] The "NIH Lung Symptom Score" or "NIH cGVHD Lung Score" is a score based on clinical symptoms in the range of 0 to 3. Score 0 is used for no symptoms, score 1 is used for shortness of breath with stairs, score 2 is used for shortness of breath on flat ground, and score 3 is used for shortness of breath at rest or shortness of breath requiring oxygen.

[0048] "Or" is used in an inclusive sense (equivalent to "and / or") unless the context otherwise requires.

[0049] As used herein, "patient" includes animals or humans, and in one embodiment, includes humans in need of treatment with or being treated with vermox, or who are candidates for treatment.

[0050] As used herein, "pregnancy" or "being pregnant" means the state in which a female patient has a fertilized egg, embryo or fetus and is developing in the uterus, and encompasses all stages of fetal development from conception to birth.

[0051] As used herein, "pregnancy risk patient" means any patient whose age, gender, and / or life situation pose a risk of becoming pregnant themselves or causing pregnancy in another person. Thus, "pregnancy risk patients" include female patients who are capable of reproduction, as well as male patients who are sexually active with a female patient capable of reproduction. The term "pregnancy risk patient" does not include patients who are pregnant.

[0052] As used herein, "pregnancy risk partner" means any person who has a relationship with a pregnancy risk patient who can, by any means (e.g., natural means or via in vitro fertilization), pose a risk of pregnancy to the patient.

[0053] When used with respect to a female patient, "reproductive" means that the patient is physiologically capable of producing oocytes (eggs or oocytes) and / or of retaining a fetus in the uterus (e.g., after being implanted by artificial insemination). A "reproductive" female patient does not include a female in whom pregnancy has been confirmed or verified (e.g., by laboratory tests). When used with respect to a male patient, "reproductive" means a male who is capable of producing sperm to fertilize a female's oocytes.

[0054] "Reproductive risk" includes risks of adverse effects on the development of a fetus or embryo, including, for example, weight loss, injury, and / or deformities, as well as risks of pregnancy and risks to a breastfed child obtained from a patient during treatment.

[0055] "Patient at reproductive risk" means a patient who can pose or create a reproductive risk as defined herein, including female patients with reproductive capacity, male patients with reproductive capacity, lactating patients, or pregnant patients.

[0056] For example, "risk" as used herein in the definitions of "pregnancy risk patient" and "pregnancy risk partner" means that there is a possibility of pregnancy, even if slight or remote.

[0057] "Side effect" means a physiological response resulting from a treatment other than the desired effect. In certain embodiments, side effects can include embryo-fetal developmental effects and malformations. Side effects can be detected directly or indirectly.

[0058] "Steroid-refractory" (SR) cGVHD is defined as the progression of cGVHD during steroid or corticosteroid administration, in one embodiment, during prednisone administration.

[0059] "Subject" means an animal being treated with belumosudil, including an animal or human control.

[0060] A "therapeutically effective amount" of an API means an amount sufficient to effect treatment of a disease state (e.g., cGVHD) when administered to a human. When applied to cGVHD in humans, "treating" or "treatment" 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) alleviating cGVHD, i.e., causing regression, recovery, or improvement of cGVHD, or reducing the number, frequency, duration, or severity of its clinical symptoms.

[0061] The therapeutically effective amount of the API can vary depending on the health and condition of the subject being treated, the degree of disease progression, the evaluation of the medical situation, and other relevant factors. The therapeutically effective amount can be within the range that can be determined through testing, and by reference to clinical trial data and results, as described, for example, in Examples 1 and 2 of this specification and in the scientific literature.

[0062] As used herein with respect to the step of verifying the pregnancy status of a female subject, "verifying" includes any form or method of investigation for confirming the pregnancy status of the female subject, including physical examination, consultation, and / or diagnostic tests. It should be understood that one can "verify" the pregnancy status of a female subject by conducting a consultation, performing a physical examination, requesting a diagnostic test, instructing or prescribing a diagnostic test, performing a diagnostic pregnancy test, and / or receiving the results of any such test or tests for confirming the pregnancy status of the female subject.

[0063] Exemplary embodiments In one embodiment, the present disclosure provides 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) or its mesylate (Belmosudil) for use in the treatment of cGVHD in a specific subpopulation of patients who are reproductive risk patients.

[0064] In one embodiment, the reproductive risk (RR) patient is a female patient who is fertile, in other embodiments, the RR patient is a male patient who has a fertile female partner, in other embodiments, the RR patient is a lactating patient, and in other embodiments, the RR patient is a pregnant patient.

[0065] In some embodiments, the RR patient is a female patient of reproductive potential who is using effective contraception during treatment, and in some embodiments, the female patient is using effective contraception during treatment and for at least one week after the last administration of the compound. In some embodiments, the RR patient is a male patient of reproductive potential who is using effective contraception during treatment, and in some embodiments, the male patient is using effective contraception during treatment and for at least one week after the last administration of the compound.

[0066] In one embodiment, the present disclosure provides the use of a compound or its mesylate (belumosudil) in the treatment of cGVHD in RR patients, including the step of advising the patient about the reproductive risks to the fetus or embryo and / or a nursing child from treatment with the compound or belumosudil. In another embodiment, the present disclosure provides verifying the status of the RR patient (e.g., in the case of a female, whether she is pregnant) before administering the compound or belumosudil.

[0067] In another embodiment, the present disclosure provides the use of a compound or its mesylate (belumosudil) in the treatment of cGVHD in female patients of reproductive potential, including advising the patient to use effective contraception during treatment and for at least one week after the last administration of the compound.

[0068] In another embodiment, the present disclosure provides the use of a compound or its mesylate (belumosudil) in the treatment of cGVHD in a female patient who is pregnant or becomes pregnant while taking the compound, including advising the female patient about the potential risks to the fetus in undergoing treatment with the compound during pregnancy.

[0069] In some embodiments, a patient being treated for cGVHD may become pregnant while receiving treatment with the compound. In such embodiments, the present disclosure contemplates advising the female patient about the potential risks to the fetus in undergoing treatment with the compound during pregnancy.

[0070] In some embodiments, the present disclosure provides the use of a compound or a mesylate thereof (belumosudil) in the treatment of cGVHD in male patients having a fertile female partner, comprising advising the male patient to use effective contraception during the period of treatment with the compound and for at least 1 week after the last administration of the compound.

[0071] In another embodiment, the present disclosure provides the use of a compound or a mesylate thereof (belumosudil) in the treatment of cGVHD in lactating patients, comprising advising the patient not to breastfeed during the period of treatment with the compound and for at least 1 week after the last administration of the compound.

[0072] In another embodiment, the present disclosure provides the use of a compound or a mesylate thereof (belumosudil) in the treatment of cGVHD in pregnancy-risk patients using effective contraception during treatment with the compound or belumosudil. In some embodiments, the pregnancy-risk patient is female, and in other embodiments, the pregnancy-risk patient is male. In another embodiment, the pregnancy-risk patient uses effective contraception during treatment and for at least 1 week after the last administration of the compound.

[0073] In another embodiment, the present disclosure provides the use of a compound or a mesylate thereof (belumosudil) in the treatment of cGVHD in non-lactating patients.

[0074] In some embodiments, the compound or a mesylate thereof (belumosudil) is administered to the patient at a dose of 200 mg per day.

[0075] The present disclosure further provides a method of treating a patient with a compound or its mesylate (belumosudil) for cGVHD, comprising: (a) verifying whether the patient is a reproductive risk patient; (b) (i) if it is confirmed that the patient is not a reproductive risk patient, administering belumosudil to the patient, or (ii) if it is confirmed that the patient is a reproductive risk patient, advising on the potential reproductive risks associated with treatment with belumosudil, and / or advising to use effective contraception during the period of treatment with the compound and for at least one week after the last administration of the compound, and / or, in the case of a lactating patient, advising not to breastfeed during the treatment with the compound and for at least one week after the last administration of the compound.

[0076] In some embodiments, it can be verified that the patient is a lactating patient or a pregnant patient, or a male or female patient at risk of pregnancy. In such embodiments, the present disclosure contemplates advising the patient about the reproductive risks associated with belumosudil, and / or using effective contraception during the treatment with the compound and for at least one week after the last administration of the compound, and / or, where applicable, advising not to breastfeed during the treatment with belumosudil and for at least one week after receiving its last dose.

[0077] In some embodiments, the present disclosure provides a method of treating cGVHD in a patient, comprising: (a) verifying whether the patient is a reproductive risk patient; (b) (i) if it is confirmed that the patient is not a reproductive risk patient, administering belumosudil to the patient, or (ii) if it is confirmed that the patient is a reproductive risk patient, using effective contraception during treatment with belumosudil and for at least one week after receiving the last administration.

[0078] In some embodiments, the subject (or patient) has undergone an allogeneic hematopoietic stem cell transplantation that is a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplantation is a haploidentical HSCT.

[0079] In some embodiments, the belumosudil treatment is continued based on the patient's tolerance until the active cGVHD symptoms resolve or progress. The number of treatment cycles and duration depend on the patient. In some embodiments, belumosudil is administered to the patient in one or more 28-day cycles.

[0080] In some embodiments, the number of cycles ranges from 3 to 15. In some embodiments, the number of cycles ranges from 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments, the number of cycles is from 5 to 11. In some embodiments, the number of cycles is from 6 to 12. In some embodiments, the number of cycles ranges from 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the number of cycles is from 5 to 7. In some embodiments, the number of cycles is from 5 to 6. In some embodiments, the number of cycles is 5. In some embodiments, the number of cycles is 6. In some embodiments, the number of cycles is 7. In some embodiments, the number of cycles is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0081] In some embodiments, the subject has chronic graft-versus-host disease and has failed one to three prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed two to five prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has failed at least one, at least two, at least three, at least four, or at least five.

[0082] In some embodiments, the subject has experienced a complete response to the last treatment of graft-versus-host disease prior to belumosudil. In some embodiments, the subject has experienced a partial response to the last treatment of graft-versus-host disease prior to belumosudil. In some embodiments, prior to belumosudil, the subject is in a stable state with respect to the last treatment of graft-versus-host disease.

[0083] In some embodiments, the prior line of systemic therapy for chronic graft-versus-host disease has been discontinued.

[0084] In some embodiments, the prior line of systemic therapy is selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0085] In some embodiments, the cGVHD is steroid-refractory (SR) cGVHD. In some embodiments, the subject is refractory to the last treatment line prior to belumosudil treatment.

[0086] In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from the group consisting of prednisone, prednisolone, methylprednisolone, and budesonide. In some embodiments, the concomitant corticosteroid therapy is prednisone. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased after at least one cycle of belumosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% after at least one cycle of belumosudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is decreased by about 10% to about 70%, about 15% to about 65%, about 20% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to about 60%, or about 45% to about 55% after at least one cycle of belumosudil treatment. In some embodiments, the concomitant corticosteroid therapy is discontinued after at least one cycle of belumosudil treatment.

[0087] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0088] Belumosudil tablets In one embodiment, vermostil is formulated into tablets for oral administration. Vermostil mesylate is a yellow powder that is substantially insoluble in water. Vermostil tablets can be prepared for oral administration. Each tablet contains 200 mg of the free base corresponding to 242.5 mg of vermostil mesylate. The tablets may also contain the following inert ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide. Each 200 mg tablet is a pale yellow film-coated oval tablet with "KDM" debossed on one side and "200" debossed on the other side. The tablets are stored at room temperature, 20°C to 25°C (68°F to 77°F), with a deviation of 15°C to 30°C (59°F to 86°F) allowed.

[0089] The following abbreviations may be useful in considering the description herein.

[0090]

Table 1

Examples

[0091] Example 1: Pilot prenatal developmental toxicity and toxicokinetics study in Sprague-Dawley rats Test objectives and design This pilot study was conducted to provide information on dose selection of vermostil for use in subsequent embryo-fetal developmental toxicity studies (Example 3) in Sprague-Dawley rats. The second part of the study was a pilot developmental toxicity test, i.e., a test to determine the toxicokinetics of vermostil and its two metabolites, KD025m1 and KD025m2, when vermostil was administered once daily to pregnant rats by oral gavage from gestation day (GD) 6 to 17. The design of the study is shown in Table 1.

[0092]

Table 2

[0093] A total of 52 Sprague-Dawley (SD) rats were used in this study. Vehicle, 0.4% (w / w) methylcellulose (400 cps) in distilled water, or vermostil was administered once daily by gavage to timed-pregnant female SD rats at various dose levels shown in Table 1 at a dose volume of 10 mL / kg from gestation day (GD) 6 to 17. The animals were assigned to the groups shown in Table 1.

[0094] Observation Animal observations included cage-side evaluations (twice daily), evaluations of clinical signs (daily from GD6 to 20), body weights (at arrival - GD2 or 3 - and GD6, 9, 12, 15, 18, and 20), food consumption (GD6 to 20 days), and anatomical pathology including uterine examinations. Toxicokinetic evaluations were performed for vermostil and metabolites. External examinations were performed on all fetuses.

[0095] Clinical signs were limited to 300 mg base / kg / day and had a low incidence but were considered possibly treatment-related. Clinical signs consisted of a disheveled and / or thin appearance and a hunched posture.

[0096] Mean body weight gain and food consumption at 25 and 50 mg base / kg / day decreased slightly (dose-related) from GD6 - 9, GD6 - 18, and GD6 - 20. At 150 mg base / kg / day, mean body weight decreased throughout pregnancy, with weight loss starting at GD6 - 9 and decreases in weight gain being prominent from GD12 - 15, GD6 - 18, and GD6 - 20. Food consumption at 150 mg base / kg / day decreased correspondingly during these same intervals. Weight gain and increased food consumption after treatment (GD18 - 20) at 25, 50, and 150 mg base / kg / day were considered rebound / recovery effects. Mean body weight values, mean body weight gain, and food consumption were adversely affected at each interval after the start of dosing at GD6 at 300 mg base / kg / day.

[0097] No adverse maternal autopsy findings were observed in any treatment group. The available littermates were numbered 5 each in the 0, 25, 50, 150, and 300 mg base / kg / day groups. At the dose levels of 25, 50, and 150 mg base / kg / day, all females maintained pregnancy until the scheduled autopsy date at GD20.

[0098] Although the dose-response was not clear in the intrauterine data at 25, 50, and 150 mg base / kg / day, the mean number of early resorptions increased significantly and the mean number of live fetuses decreased slightly in the 50 mg base / kg / day group. The mean post-implantation loss (% per littermate) was 4.41, 4.00, 11.62, 4.51, and 24.51 at 0, 25, 50, 150, and 300 mg base / kg / day, respectively. The mean surviving littermate sizes at these same dose levels were 12.8, 13.2, 11.6, 12.2, and 10.0, respectively.

[0099] The mean fetal weights (female fetuses) at 0, 25, 50, 150, and 300 mg base / kg / day were 1.36, 4.19, 4.39, 4.18, and 3.34 g, respectively. The combined mean fetal weights (male and female) at these same dose levels were 4.50, 4.37, 4.50, 4.22, and 3.42 g, respectively. As post-implantation loss (early resorption) increased (including females with total embryo loss), the mean fetal weight decreased significantly at 300 mg base / kg / day.

[0100] The historical incidence of external fetal malformations in the dose range finding study in rats is non-typical, but in this study, the incidence of littermates was significant, ranging from 40% and 20% of the affected littermates at 50 and 150 mg base / kg / day, respectively, to 25% of the affected littermates at 300 mg base / kg / day. In the 50 mg base / kg / day group, in this dose group, 1 fetus was edematous (generalized) and the other fetus / littermate had no anus and tail. In the 150 mg base / kg / day group, 1 number of fetuses had a umbilical cord tumor. 1 fetus at 300 mg base / kg / day had a domed head.

[0101] Results In this oral pilot prenatal developmental toxicity study using birmodzil, maternal toxicity was considered slight at 25 and 50 mg base / kg / day and moderate at 150 mg base / kg / day (moderate is defined as notable and there is a significant potential for increasing severity. Limited tissue or organ function is possible). Maternal toxicity, embryotoxicity, and fetotoxicity were considered excessive at 300 mg base / kg / day, and this dose level would be excluded for selection in subsequent developmental toxicity studies in rats.

[0102] For the parent compound birmodzil, the dose level of 25 mg base / kg / day corresponded to a maternal C of 1800 ng / mL at the end of the dosing regimen (GD17) and a maternal AUC of 20400 ng·hour / mL. For KD025m1, the maternal C was 176 ng / mL and the AUC was 2230 ng·hour / mL. For KD025m2, the maternal C was 127 ng / mL and the AUC was 1480 ng·hour / mL. max (GD17) and a maternal AUC of 20400 ng·hour / mL 0-24 corresponded to, for KD025m1, the maternal C max was 176 ng / mL and the AUC 0-24 was 2230 ng·hour / mL. For KD025m2, the maternal C max was 127 ng / mL and the AUC 0-24 was 1480 ng·hour / mL.

[0103] Example 2: Pilot Prenatal Developmental Toxicity and Toxicokinetics Study in New Zealand White Rabbits with a Non-Pregnant Dose Range Finding Phase Test Objectives and Design This study was conducted to provide information for dose selection of birmodzil for use in subsequent embryofetal developmental toxicity studies (Example 4) in New Zealand White (NZW) rabbits. The study was conducted in two phases: Phase A was a range-finding study using non-pregnant rabbits, and Phase B was a pilot developmental toxicity study. Vehicle, 0.4% (w / w) methylcellulose (400 cps) in distilled water, or birmodzil was administered once daily by oral gavage to non-pregnant or time-mated female NZW rabbits for two sets of 5 consecutive days (Phase A) or once daily by oral gavage from gestation day (GD) 6 to 18 (Phase B). The design of the study is further shown in Table 2 below.

[0104]

Table 3

[0105] Observation Animal observations included clinical signs, body weight, food consumption, and anatomical pathology including uterine examination. Toxicokinetic evaluations were performed for vermoxdil and two metabolites. All fetuses were given an appropriate external examination.

[0106] Survival was not affected at any of the dose levels administered in Phase A. All animals survived until the scheduled end date. The final treatment-related effects in Phase A appeared at dose levels of 300 and 400 mg base / kg / day and consisted of slight weight loss and decreased food consumption.

[0107] The potential treatment-related clinical findings seen at each of the dose levels of 100, 200, 300, and 400 mg base / kg / day administered from Day 15 to Day 19 of the study were fecal abnormalities (minor / absent) with brown discoloration of the anogenital area on the final day of the study (Day 20 of the study) for female number 108 at 400 mg base / kg / day.

[0108] Survival was not affected in Phase B at any of the doses administered. Dose-dependent maternal responses occurred at dose levels of 100 and 250 mg base / kg / day and consisted of decreased weight gain / loss, decreased food consumption, clinical signs (anorexia, fecal abnormalities, thin appearance), and a generally dose-related increase in the amount of veterinary intervention (food enrichment). No treatment-related maternal autopsy findings were observed and no treatment-related embryo or fetal toxicity was apparent at any of the dose levels.

[0109] Results When berzosertib was administered to pregnant rabbits at 25, 50, 100, and 250 mg base / kg / day from gestational day 6 to 18, no toxicologically relevant maternal toxicity was observed at 25 or 50 mg base / kg / day. Dose-dependent maternal responses at 100 and 250 mg base / kg / day were evident by decreases in weight gain / loss, decreases in food consumption, clinical signs (anorexia, fecal abnormalities, thin appearance), and a generally dose-related increase in the amount of veterinary intervention (food enrichment).

[0110] For the NOAEL for maternal toxicity (50 mg base / kg / day), for berzosertib, the dose level of 50 mg base / kg / day corresponded to a maternal C max (GD18) of 621 ng / mL and a maternal AUC 0-24 of 2480 ng·hour / mL at the end of the dosing regimen. For KD025m1, the maternal C max was 528 ng / mL and the AUC 0-24 was 1320 ng·hour / mL. For KD025m2, the maternal C max was 1090 ng / mL and the AUC 0-24 was 2990 ng·hour / mL. For the NOAEL for developmental toxicity (250 mg base / kg / day), for berzosertib, the dose level of 250 mg base / kg / day corresponded to a maternal C max (GD18) of 2100 ng / mL and a maternal AUC 0-24 of 15600 ng·hour / mL at the end of the dosing regimen. For KD025m1, the maternal C max was 1040 ng / mL and the AUC 0-24 was 4760 ng·hour / mL. For KD025m2, the maternal C max was 3080 ng / mL and the AUC 0-24 was 19700 ng·hour / mL.

[0111] Based on the results of this study, dose levels of 0, 50, 125, and 225 mg base / kg / day were selected for the embryo-fetal developmental toxicity study (Example 4) in New Zealand white rabbits.

[0112] Example 3: Embryo-Fetal Developmental Toxicity Study in Sprague-Dawley Rats with Toxicokinetics Evaluation Test Objectives and Design This study was conducted to determine the embryo-fetal developmental toxicity, including the potential for teratogenicity, of vemurafenib in Sprague-Dawley rats. This study also included a toxicokinetics (TK) evaluation to determine the exposure / toxicity relationship of vemurafenib and its metabolites (KD025m1 and KD025m2). A vehicle, 0.4% (w / w) methylcellulose (400 cps) in distilled water, or vemurafenib was administered once daily by oral gavage to time-mated SD rats from gestation day (GD) 6 to 17.

[0113] For this study, a total of 140 time-mated female rats (approximately 8 to 10 weeks of age) were obtained from Charles River Laboratories, Raleigh, North Carolina and acclimated from arrival until dosing on GD6. During the acclimation period, the animals were observed twice daily for any signs of general health and disease. A detailed clinical examination was performed on all animals and body weights were recorded prior to selection. Animals assigned to the study had body weights within ±20% of the mean body weight. Food consumption was collected during the acclimation period.

[0114] Using a standard body weight-based randomization procedure, 133 female animals (body weight at randomization 162 - 226 g) were assigned to the control, treatment, and TK groups as shown in Table 3.

[0115] [Table 4]

[0116] Administration The vehicle and vermostil were administered once daily from GD6 to GD17 at approximately the same time each day (±2 hours from GD6 dosing) via orogastric gavage. The dose levels for the treatment groups were 15, 50, and 150 mg base / kg / day at a dose volume of 10 mL / kg. The control group received the vehicle in the same manner as the treatment groups. Additionally, the TK animals were administered the vehicle or vermostil at the same dose levels and volumes in the same manner as the main test groups. The vehicle and vermostil formulations were continuously stirred at room temperature for at least 30 minutes before dosing and during the dosing period. The individual doses were based on the most recent body weight.

[0117] Observation The animals were subjected to in-life and postmortem evaluations. In-life evaluations included cage-side observations (for morbidity, mortality, injuries), detailed clinical signs, body weight, food consumption, and anatomical pathology including uterine examinations. Toxicokinetic evaluations were performed for vermostil and metabolites (KD025m1 and KD025m2). External and visceral or skeletal examinations were performed on all fetuses.

[0118] Cage-side and clinical observations No treatment-related deaths were observed at any dose level. Five females at 150 mg base / kg / day had persistent injuries suspected to be related to gavage feeding. For clarity in discussing the test results, these five females were not included in the tabulation of the summary data.

[0119] Detailed clinical observations were performed daily from GD6 to GD20 (±1 hour at 4 hours after dosing on the dosing day). The observations included, but were not limited to, evaluation of the skin, hair, eyes, ears, nose, mouth, thorax, abdomen, external genitalia, extremities, and feet, as well as evaluation of respiration. The clinical findings are summarized in Table 4.

[0120]

Table 5

[0121] Body weight The body weights of the entire animals were measured and recorded at GD6, 9, 12, 15, 18, and 20. The individual weight changes were calculated for the following GD intervals: 6 - 9, 9 - 12, 12 - 15, 15 - 18, 18 - 20, 6 - 18, and 6 - 20. The adjusted body weight (GD20 body weight - pregnant uterine weight) and the adjusted body weight change (GD6 - 20) were also calculated.

[0122] The maternal body weights and weight changes are summarized in Tables 5 and 6 below.

[0123]

Table 6

[0124]

Table 7

[0125] The mean maternal body weight decreased with statistical significance in a dose - related manner at 50 and 150 mg base / kg / day throughout the treatment and post - treatment periods (GD9, 12, 15, 18, and 20). The mean weight gain also decreased in a dose - related manner at 50 and 150 mg base / kg / day, and the decrease in weight gain was statistically significant at 50 and 150 mg base / kg / day from GD6 - 9 and 9 - 12. From GD12 - 15, the weight gain at 50 mg base / kg / day was comparable to the control group, but remained significantly decreased at 150 mg base / kg / day during this same period. The weight gain decreased somewhat (statistically significant) at both dose levels during the last few days of the treatment period (GD15 - 18), and after the treatment period (GD18 - 20), the mean weight gain showed a recovery response, being similar to (50 mg base / kg / day) or greater than (150 mg base / kg / day, statistically significant) the control group. Evaluation of the inclusive intervals (GD6 - 18 and 6 - 20) revealed a consistent dose - related decrease in the mean maternal weight gain at 50 and 150 mg base / kg / day (statistically significant at both dose levels).

[0126] Food consumption The food consumption of the primary test animals was measured, recorded on the corresponding body weight days, and calculated at the same intervals. Mean maternal food consumption decreased with statistical significance in relation to the dose at 50 and 150 mg base / kg / day throughout the treatment period (GD6-9, 9-12, 12-15, 15-18, 6-18, and 6-20). After the treatment period (GD18-20), food consumption was similar to that of the control group, showing a recovery response.

[0127] The maternal food consumption is summarized in Table 7 below.

[0128]

Table 8

[0129] All animals in the test were pregnant, and the pregnancy index was 100% in each test group. The available littermates were numbered 25, 25, 25, and 20 in the control, 15, 50, and 150 mg base / kg / day groups, respectively.

[0130] At GD20, after euthanizing each surviving primary test female by carbon dioxide inhalation, the abdominal vena cava was exsanguinated and immediately subjected to cesarean section. The skin was reflected from the ventral midline incision, the mammary tissue was examined, and the location of any subcutaneous masses was determined. Subsequently, the abdominal cavity was opened to expose the uterus. The uterus was removed and the pregnant uterine weight was recorded. Starting from the distal end of the left uterine horn, the positions of the surviving and non-surviving fetuses, early and late absorptions in each uterine horn, and the total number of implants were recorded. The number of corpora lutea in each ovary was also recorded.

[0131] The fetuses were removed by making a longitudinal dorsal incision along both uterine horns. The fetal membranes of each fetus were gently removed, each fetus was separated from the placenta, and the umbilical cord was fully extended. The placenta was examined in its entirety.

[0132] The uteri of the females that were thought to be non-pregnant were opened and placed in 10% ammonium sulfide solution to detect the implantation sites. If lesions were detected, they were considered early absorptions and the data of this female were included in the mean calculation.

[0133] The average pregnant uterine weight decreased slightly at 150 mg base / kg / day. However, the average final body weight, adjusted final body weight, and adjusted final body weight change at 150 mg base / kg / day were decreased with statistical significance when compared to the corresponding control values and were considered treatment-related.

[0134] The average pregnant uterine weight at 50 mg base / kg / day was similar to the control value. However, the average final body weight, adjusted final body weight, and adjusted final body weight change at 50 mg base / kg / day were decreased with statistical significance when compared to the corresponding control values and were considered treatment-related.

[0135] The pregnant uterine weight and adjusted body weight / weight change are summarized in Table 8. The fetal weights are summarized in Table 9.

[0136]

Table 9

[0137]

Table 10

[0138] For subjects treated at 15 and 50 mg base / kg / day, when compared to the values of their respective control groups, none of the fetal weight values were statistically significant. All average fetal weight values, combined for male, female, and both genders, decreased with statistical significance at 150 mg base / kg / day, and the values decreased between -7 and -8% compared to the corresponding control values.

[0139] Toxicokinetics analysis Exposure to vermoxdil, KD025m1, and KD025m2 increased with an increase in the vermoxdil dosage level to 15 - 150 mg base / kg. The vermoxdil C in pregnant rats max value increase was generally smaller than the dosage proportional to GD6 and GD17, and generally, it was the dosage proportional to GD6 and GD17 for AUC 0-24 The KD025m1 C in pregnant rats maxThe increase in value was generally proportional to GD6 and GD17 in terms of dosage, and for AUC 0-24 it was greater than the dosage proportional to GD6 and GD17. For KD025m2 C in pregnant rats max and AUC 0-24 the increase in value was generally proportional to GD6 in terms of dosage and greater than the dosage proportional to GD17. After multiple administrations of vermostil to pregnant rats, no obvious accumulation of vermostil, KD025m1, and KD025m2 was observed. For AUC 0-24 The metabolite-to-parent ratio indicates that vermostil is converted to KD025m1 and KD025m2 in pregnant rats after forced oral administration of vermostil. The metabolite-to-parent substance ratios were in the ranges of 0.0799 to 0.188 and 0.0482 to 0.125 for KD025m1 and KD025m2, respectively.

[0140] These TK results are summarized in Table 10 below.

[0141]

Table 11

[0142] Results When vermostil was administered to pregnant rats from gestational day 6 to 17 at 15, 50, and 150 mg base / kg / day, developmental toxicity in the mother and fetus occurred at 150 mg base / kg / day, with significant decreases in mean maternal body weight, weight gain, and food consumption. The mean fetal body weight also decreased significantly and was considered harmful. The dosage level of 50 mg base / kg / day resulted in a harmful dosage-related decrease in mean maternal body weight, weight gain, and food consumption. The dosage level of 15 mg base / kg / day did not cause any harmful maternal or fetal developmental effects. The dosage level of 50 mg base / kg / day was considered the NOAEL for fetal developmental toxicity.

[0143] In the case of the parent compound vermostil, the dosage level of 50 mg base / kg / day resulted in a maternal C of 4360 ng / mL at the end of the dosing regimen max(GD17) and maternal AUC of 33300 ng·h / mL 0-24 Corresponding to this, for KD025m1, maternal C max was 434 ng / mL, and the AUC 0-24 was 4780 ng·h / mL. For KD025m2, maternal C max was 350 ng / mL, and the AUC 0-24 was 3580 ng·h / mL. The dose level of 15 mg base / kg / day was regarded as the NOAEL for maternal toxicity. In the case of the parent compound, vermoxdyl, the dose level of 15 mg base / kg / day corresponded to a maternal C max (GD17) and maternal AUC of 11900 ng·h / mL 0-24 Corresponding to this, for KD025m1, maternal C max was 93.3 ng / mL, and the AUC 0-24 was 948 ng·h / mL. For KD025m2, maternal C max was 55.6 ng / mL, and the AUC 0-24 was 572 ng·h / mL.

[0144] Example 4: Embryo-fetal developmental toxicity study in New Zealand White rabbits with pharmacokinetic evaluation The purpose of this study was to determine the embryo-fetal developmental toxicity of vermoxdyl in New Zealand White (NZW) rabbits, including the potential for teratogenicity. This study also included a pharmacokinetic evaluation to determine the exposure / toxicity relationship of vermoxdyl and its metabolites (KD025m1 and KD025m2). Vehicle, 0.4% (w / w) methylcellulose (400 cps) in distilled water or vermoxdyl was administered once daily by oral gavage to female New Zealand White (NZW) rabbits from gestation day (GD) 6 to 18. Using a standard weight-based randomization procedure, 111 female animals (weight at randomization 2.64 kg to 3.56 kg) were assigned to the control, treatment, and TK groups specified in Table 11 below.

[0145]

Table 12

[0146] The animals assigned to the study had body weights within ±20% of the average weight. The animals were individually housed in suspended stainless steel cages in an environmentally controlled room. The animals were acclimated according to SOP. Fluorescent lighting was provided for approximately 12 hours per day. The dark cycle was intermittently interrupted for study-related activities. Temperature and humidity were monitored and recorded and maintained as close as possible to a maximum within the ranges of 61–72°F and 30–70%, respectively. Food was provided daily from 8:00 to 12:00 a.m., starting on the second day of acclimation and continuing throughout the study. During the dosing period, food was provided 1.5 hours ± 30 minutes prior to dosing and left available as needed until the next food offering.

[0147] Dosing Vehicle and vermostil were administered once daily from GD6 to GD18 at approximately the same time (±2 hours from the first dose on GD6) via orogastric gavage. The dose levels for the treatment groups were 50, 125, 225 mg base / kg / day at a dose volume of 10 mL / kg. The control group received vehicle in the same manner as the treatment groups. Additionally, TK animals were dosed with vehicle or vermostil at the same dose levels and volumes and in the same manner as the main study groups. Vehicle and vermostil formulations were continuously stirred at room temperature for at least 30 minutes before dosing and during the dosing period. Individual doses were based on the most recent body weight.

[0148] Observation Animal observations included clinical signs, body weight, food consumption, and anatomical pathology including uterine examination. Toxicokinetic evaluations were performed for vermostil and metabolites (KD025m1 and KD025m2). External, visceral, and skeletal examinations were performed on all fetuses.

[0149] Cage-side and clinical observations All animals were observed twice daily at the cage side (for morbidity, mortality, and injuries). From GD6 to 29 daily (4 hours ± 1 hour after dosing on the dosing day), each main study test was removed from the cage and a detailed clinical examination was performed. In some cases, clinical findings were recorded at unscheduled intervals. Observation included, but was not limited to, evaluation of the skin, hair, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, extremities, and feet, as well as evaluation of respiration. Two animals aborted at GD19 at 125 and 225 mg base / kg / day, respectively (animal numbers 251 and 282). It was found that additional animals at 225 mg base / kg / day died at GD9. These events were considered adverse and treatment-related.

[0150] In the 225 mg base / kg / day group, clinical findings of poor body condition were seen and could be correlated with the decreased weight gain and food consumption data considered treatment-related and adverse. Red substances in the cage pans were seen in two animals that aborted at 125 and 225 mg base / kg / day, respectively, and the abortions were considered treatment-related and adverse (see previous section). Maternal survival and pregnancy status are summarized in Table 12 below. Clinical findings are summarized in Table 13 below.

[0151]

Table 13

[0152]

Table 14

[0153]

Table 15

[0154] Body weight The weights of all animals were measured and recorded at GD0, 6, 10, 13, 16, 19, 21, 25, and 29. Individual weight changes were calculated for the following GD intervals: 0 - 6, 6 - 10, 10 - 13, 13 - 16, 16 - 19, 19 - 21, 21 - 25, 25 - 29, 6 - 19, 19 - 29, and 0 - 29. Adjusted body weight (GD29 weight - pregnant uterine weight) and adjusted body weight change (GD0 - 29) were also calculated. Individual weight values were recorded for TK animals.

[0155] For the body weight data (mean body weight and mean body weight change) at 50 mg base / kg / day, no treatment-related adverse effects were seen. At 125 mg base / kg / day, there was no statistically significant difference when comparing the mean body weight values to the control group, and the maximum percentage difference occurred at GD19 (-5.1%).

[0156] However, there was a tendency for the mean body weight gain to decrease during the treatment period at 125 mg base / kg / day. The following differences were statistically significant, with a mean body weight decrease occurring from GD6 - 10, a decrease in mean body weight gain from GD13 - 16, contributing to the overall decrease in mean body weight gain during the treatment period (GD6 - 19). After the treatment period at 125 mg base / kg / day, the mean body weight gain increased significantly from GD25 - 29, contributing to the overall mean body weight gain after treatment from GD19 - 29.

[0157] Over the entire test period (GD0 - 29), the weight gain at 125 mg base / kg / day remained decreased compared to the respective control values, and the difference from the control group was -8.6%. At 225 mg base / kg / day, the mean body weight decreased with statistical significance throughout the treatment period and initially after the first treatment period (GD10, 13, 16, 19, and 21), and the difference from the control group ranged from -6.3% to -9.2%. When evaluating the mean body weight change at 225 mg base / kg / day, the following differences were statistically significant. A mean body weight decrease occurred from GD6 - 10, the mean body weight increase decreased from GD10 - 13 and GD13 - 16, contributing to the overall mean body weight decrease during the treatment period (GD6 - 19). However, there was a tendency for an increased mean body weight gain after treatment at 225 mg base / kg / day compared to the control group. The increase in mean body weight gain was statistically significant from GD19 - 21 and GD21 - 25 when compared to the control group, contributing to the overall increase in mean body weight during the post-treatment period (GD19 - 29). Over the entire test period (GD0 - 29), the weight gain at 225 mg base / kg / day remained decreased (statistically significant), and the difference from the control group was -24.2%.

[0158] The tendency for weight gain to decrease at 125 and 225 mg base / kg / day over the entire treatment period, correlating with a decrease in food intake, was considered a dose-related adverse reaction to vermoxdil. The tendency for an increase in mean body weight gain and food consumption after treatment at 125 and 225 mg base / kg / day was considered to indicate a rebound / recovery effect.

[0159] The body weight and body weight changes of the mother are summarized in Tables 14 and 15 below.

[0160]

Table 16

[0161]

Table 17

[0162] Food consumption When food consumption at 50 mg base / kg / day was compared with the control group for the entire treatment period, GD6 - 19, the percentage was -8.8%. At 125 mg base / kg / day, food consumption decreased throughout the treatment period, the following differences were statistically significant, food consumption decreased from GD6 - 10, 10 - 13, 13 - 16 and 16 - 19, and contributed to the decrease in food consumption during the entire treatment period (GD6 - 19).

[0163] For the entire treatment period (GD6 - 19) at 125 mg base / kg / day, the percentage difference from the control group was -34.1%. After the treatment period at 125 mg base / kg / day, food consumption increased significantly from GD21 - 25 and GD25 - 29, and contributed to the overall increase in food after treatment from GD19 - 29. Throughout the entire test period (GD0 - 29), food consumption remained decreased (statistically significant) at 125 mg base / kg / day, and the difference from the control group was -11.6%.

[0164] At 225 mg base / kg / day, food consumption decreased throughout the treatment period, the following differences were statistically significant, food consumption decreased from GD6 - 10, 10 - 13, 13 - 16 and 16 - 19, and contributed to the decrease in food consumption during the entire treatment period (GD6 - 19). For the entire treatment period (GD6 - 19) at 225 mg base / kg / day, the percentage difference from the control group was -49.7%. After the treatment period at 225 mg base / kg / day, food consumption increased significantly from GD21 - 25 and GD25 - 29, and contributed to the overall increase in food after treatment from GD19 - 29. Throughout the entire test period (GD0 - 29), food consumption remained decreased (statistically significant) at 225 mg base / kg / day, and the difference from the control group was -17.8%.

[0165] The tendency towards a decrease in food consumption throughout the treatment period, correlated with the decrease in weight gain at 125 and 225 mg base / kg / day, was considered a harmful dose - related response to vermostil treatment. The tendency of increased food consumption and average weight gain after treatment at 125 and 225 mg base / kg / day was considered to indicate a rebound / recovery effect.

[0166] Summarize the maternal food consumption in Table 16 below.

[0167] [Table 18]

[0168] Examination of the Postmortem Uterus, Ovaries, and Fetuses At GD29, each surviving major study female was euthanized by intravenous injection of pentobarbital sodium / euthanasia solution, and then a method approved by the SOP was performed to ensure death and immediately subjected to laparotomy for hysterectomy. The skin was reflected from the ventral midline incision, the mammary tissue was examined, and the location of any subcutaneous masses was determined. The abdomen was then opened to expose the uterus. The uterus was removed and the pregnant uterine weight was recorded. Starting from the distal end of the left uterine horn, the location of live and non-live fetuses, early and late resorptions in each uterine horn, and the total number of implants were recorded. The number of corpora lutea in each ovary was also recorded.

[0169] The fetuses were removed by making a longitudinal dorsal incision along both uterine horns. The fetal membranes of each fetus were gently removed, each fetus was separated from the placenta, and the umbilical cord was fully extended. The placenta was examined in its entirety.

[0170] The uteri of females that were not thought to be pregnant were opened and placed in 10% ammonium sulfide solution to detect implantation sites. If no lesions were detected, the females were considered not to be pregnant.

[0171] When uterine values were compared to those of the control group, no treatment-related adverse effects were apparent at 50 mg base / kg / day.

[0172] Post-implantation losses (% / littermate) at 125 and 225 mg base / kg / day were 7.42% and 17.72%, respectively, compared to 4.07% / littermate in the control group. The dose-related increase in post-implantation losses (% / littermate) at 125 and 225 mg base / kg / day, the corresponding increase in the average number of resorptions (combination of early and late), and the decrease in the average number of live fetuses / littermate size were considered treatment-related and adverse.

[0173] At 225 mg base / kg / day, the mean fetal weight of male fetuses decreased (statistically significant), contributing to the decrease in mean fetal weight for combined genders. The body weight value (litter incidence) of male fetuses was 38.92 g compared to the control value of 42.05 g, and the difference from the control group was -7.44%. The mean fetal weight for combined genders at 225 mg base / kg / day was 38.60 g compared to the control value of 40.96 g, and the difference from the concurrent control group was -5.76%. The mean fetal weight for combined genders according to past data was 41.426 g. The effect on mean fetal weight at 225 mg base / kg / day was considered treatment-related and adverse.

[0174] Intrauterine data are summarized in Table 17 below. Fetal weight data are reported in Table 18 below.

[0175]

Table 19

[0176]

Table 20

[0177] Short tails (overall) of fetuses with malformations occurred only at 225 mg base / kg / day and were considered an adverse treatment-related response. At 225 mg base / kg / day, there were 5 fetuses with this abnormality from 2 litters. The litter / fetus incidence was 10.5% / 3.2% compared to the incidence in historical data of 5.0% / 0.6%.

[0178] External fetal malformations are summarized in Tables 19 and 20 below.

[0179]

Table 21

[0180]

Table 22

[0181] In addition to the caudal vertebral abnormalities seen during skeletal examination, in two fetuses from a twin pregnancy showing the above-mentioned short tail anomaly, fetal mutant tail flexion (overall) was observed at 225 mg base / kg / day. The incidence of this variation in the same litter (fetus) was 5.3% (1.3%) in this study and 4.3% (0.5%) in the historical data, respectively. The incidence was considered treatment-related and harmful considering the correlation with short tail anomaly.

[0182] The overall incidence of fetal visceral mutations increased at 125 and 225 mg base / kg / day compared to the control, but there was no dose-related trend, and their occurrence was generally limited and typical of that seen in historical data. This included fetal ureteral abnormalities, which increased with statistical significance (litter-based) at 125 mg base / kg / day (litter incidence 21.1%) and 225 mg base / kg / day (litter incidence 26.3%). However, in past data, the incidence of ureteral abnormalities in the litter (fetus) was 42.1% (7.7%), and thus this variation was not considered a harmful treatment-related effect.

[0183] The results of fetal visceral observations are summarized in Table 21, and fetal skeletal abnormalities are reported in Table 22.

[0184]

Table 23

[0185]

Table 24

[0186] The overall incidence of fetal skeletal malformations increased at 50, 125, and 225 mg base / kg / day, but there was no clear dose-related trend at 50 and 125 mg base / kg / day. However, there was a trend in the fetal skeletal data at 225 mg base / kg / day, with an increase in the overall incidence of fetal skeletal malformations, an increase in specific skeletal malformations, which not only increased compared to the concurrent control group typically, but was outside the range seen in past control data. Fetal skeletal findings that mainly contributed to the overall increase in abnormalities at 225 mg base / kg / day consisted of thoracic and thoracic vertebral malformations, including bifurcated (statistically significant), fused, or deformed ribs, fused sternum, fused neural arches, and fused, displaced, and deformed (statistically significant) findings. The finding of bifurcated ribs occurred at a litter / fetal incidence of 21.2% (2.6%), and the incidence in past data was 5.0% (0.5%). The finding of fused ribs occurred at a litter / fetal incidence of 15.8% (2.6%), and the incidence in past data was 14.3% (1.7%). The finding of rib deformities occurred at a litter / fetal incidence of 15.8% (1.9%), and the incidence in past data was 5.9% (0.7%). The finding of fused sternal segments occurred at a litter / fetal incidence of 31.6% (4.5%), and the incidence in past data was 26.1% (3.9%).

[0187] The finding of fused neural arches (thoracic) occurred at a litter / fetal incidence of 10.5% (1.9%), and the incidence in past data was 9.5% (1.1%). The finding of misalignment of neural arches (thoracic) occurred at a litter / fetal incidence of 10.5% (1.3%), and the incidence in past data was 5.3% (0.6%). The finding of deformation of neural arches (thoracic) occurred at a litter / fetal incidence of 21.1% (2.6%), and the incidence in past data was 9.5% (1.1%). These skeletal malformations observed at 225 mg base / kg / day were considered to be related to and harmful to vermostil.

[0188] Furthermore, two fetal skeletal variations were increased (statistically significant) at 225 mg base / kg / day and were considered likely to be adverse and treatment-related. One of these findings was seen in the cervical vertebrae, classified as central or semi-central, which occurred at an incidence of 21.1% (2.6%) in littermates / fetuses, compared with an incidence of 5.3% (0.6%) in past data. The other fetal skeletal variation increased at 225 mg base / kg / day was the finding of excessive sternal segmentation (e), which occurred at an incidence of 21.1% (4.5%) in littermates / fetuses, compared with an incidence of 5.3% (1.5%) in past data.

[0189] Maternal macroscopic observations The maternal autopsy findings of three animals that did not survive until the scheduled autopsy examination at GD29 revealed the following. Two animals aborted at GD19, at 125 and 225 mg base / kg / day respectively (animal numbers 251 and 282). The bladder and uterus of one subject (dosed at 125 mg base / kg / day) contained a small / low amount of red fluid, and another animal at 225 mg base / kg / day was found to have died at GD9. The cause of death was not determined at autopsy. The adipose tissue of this animal was yellowed (moderate, jaundice), and there were multiple red lesions (mild) on the thymus. The death was considered to be an adverse treatment-related effect.

[0190] Toxicokinetic analysis Exposure to vermostil, KD025m1 and KD025m2 increased with increasing vermostil dose levels from 50 to 225 mg base / kg. The mean C max values of vermostil, KD025m1 and KD025m2 in pregnant rabbits generally increased proportionally to the dose at GD6 and GD18, and the increase in AUC 0-24 was greater than the increase proportionally to the dose at GD6 and GD18. However, there was greater variability in AUC 0-24 at the 225 mg base / kg dose level. The AUC 0-24 values were approximately the same as or lower than those at GD6 at GD18, and no obvious accumulation of vermostil, KD025m1 and KD025m2 was observed after multiple administrations of vermostil to pregnant rabbits.

[0191] Average AUC 0-24 The metabolite-to-parent ratio indicates that vermoxir is converted to KD025m1 and KD025m2 in pregnant rabbits after forced oral administration of vermoxir. The metabolite-to-parent substance ratios were in the ranges of 0.344 - 0.820 and 0.652 - 1.98 for KD025m1 and KD025m2, respectively. The results of the TK analysis are reported in Table 23 below.

[0192]

Table 25

[0193] Results When vermoxir was administered to pregnant rabbits at 50, 125, and 225 mg base / kg / day from day 6 to day 18 of pregnancy, maternal and developmental toxicities occurred at 125 and 225 mg base / kg / day. It was found that one animal aborted at 125 and 225 mg base / kg / day, respectively, and another animal died at 225 mg base / kg / day.

[0194] The effects on body weight and food consumption during the treatment periods at 125 and 225 mg base / kg / day were adverse and considered related to vermoxir treatment. The dose-related increase in post-implantation losses (composed of early and late resorptions) and the decrease in viable fetus / litter size at 125 and 225 mg base / kg / day were considered treatment-related and adverse. The effect on fetal weight occurred only at 225 mg base / kg / day, and the fetal examination data (external and skeletal) revealed fetal developmental effects only at 225 mg base / kg / day. As a conclusion, the dose level of 50 mg base / kg / day was considered the NOAEL for maternal and developmental toxicities.

[0195] In the case of the parent compound, vermoxdyl, a dose level of 50 mg base / kg / day corresponded to a maternal Cmax (GD18) of 437 ng / mL and a maternal AUC0-24 of 1590 ng·hour / mL at the end of the dosing regimen. For KD025m1, the maternal Cmax was 569 ng / mL and the AUC0-24 was 1220 ng·hour / mL. For KD025m2, the maternal Cmax was 1120 ng / mL and the AUC0-24 was 2470 ng·hour / mL.

[0196] Example 5: Combined test of fertilizing ability and early embryo development for implantation in Sprague-Dawley rats Test objectives and design This test was conducted to determine the effects of vermoxdyl on the female estrous cycle, tubal transport, embryo implantation and development, as well as the functional effects on male fertilizing ability. This test design used naive animals of both sexes, incorporated treatments for both sexes, and provided a recovery period for the treated males based on the test results. This test also included a toxicokinetic evaluation to determine the exposure / toxicity relationship.

[0197] Male and female Sprague-Dawley (SD) rats were obtained from Charles River Laboratories, Raleigh, North Carolina (approximately 7 to 10 weeks old). Using a standard randomization procedure by body weight, 273 male and 273 female animals (weights at randomization were 229 - 497 g and 169 - 242 g, respectively) were assigned to control, treatment, and toxicokinetic (TK) groups. The group design for this test is shown in Table 24. The dose volume for each group was 10 mL / kg, providing a dose concentration that was 1 / 10 of the dose level in mg / base / mL units. (In Table 24, T = treated; U = untreated).

[0198]

Table 26

[0199] All animals underwent a detailed clinical examination before selection, and their body weights were recorded at receipt and before selection. Furthermore, male animals assigned to groups 5 - 8 were given a detailed clinical examination once a week, and their body weights were recorded once a week during the acclimation period.

[0200] Except during pair formation, animals were individually housed in solid-bottom cages with a non-aromatic floor in an environmentally controlled room. During pair formation, rats were co-housed in the male's cage (one male and one female from the corresponding group). During the acclimation period, the animals were observed twice a day for any signs of general health and disease.

[0201] Administration Vehicles and vermostil were administered once daily in the morning at approximately the same time each day (±2 hours from the dose on day 1) to all treated animals by oral gavage at dose levels of 0, 50, 150, and 275 mg base / kg / day and a dose volume of 10 mL / kg. The high dose level (275 mg base / kg / day) provided an opportunity to have some mild toxicity and enabled the evaluation of reproductive performance and early embryo developmental toxicity at an exposure level approximately 4-fold higher than the expected highest steady-state clinical exposure. The selected low (50 mg base / kg / day) and medium (150 mg base / kg / day) dose levels were intended to show a dose-dependent response and were expected to be clinically relevant (approximately 0.5 - 1-fold and 2-fold of the expected maximum steady-state clinical exposure, respectively).

[0202] Administration was started at 11 weeks of age, 70 days before pair formation (with untreated females) for treated males, and 14 days before pair formation (with untreated males) for treated females. Administration in males continued through the mating and post-mating periods until euthanasia, and administration in females continued through the mating period until GD7. Females without evidence of mating were administered for 7 days after the end of the mating period. Males designated for the recovery period were dosed for 70 days and then given a 77-day recovery period.

[0203] Furthermore, the TK animals were administered the vehicle or vermoxil in the same manner as the main test groups at the same dose levels and volumes. The TK animals were administered for 70 days and 14 days to males and females, respectively. The administration to male and female TK was started simultaneously and euthanasia was continued. The refrigerated 1-day aliquots of the administration formulations were brought to room temperature with continuous stirring for at least 30 minutes before administration. The vehicle and vermoxil formulations were continuously stirred before and during dose administration. The individual doses were based on the most recent body weight.

[0204] Observation and Analysis The animals were observed for anatomical pathology including detailed clinical changes, body weight, food consumption, determination of the sexual cycle, plasma analysis, sperm analysis, toxicokinetic analysis, and examination of the uterus and ovaries.

[0205] Cage-side observations were made at least twice a day. All animals were observed for morbidity, mortality, injury, and availability of food and water.

[0206] Detailed clinical observations were made during the treatment phase: twice a week (4 hours + / − 1 hour on the dosing day) for males and daily (4 hours + / − 1 hour on the dosing day) for females during treatment. During the non-treatment phase (males and females), detailed clinical observations were made weekly and before the scheduled uterine examination (females) on GD13. The observations included, but were not limited to, the evaluation of the skin, hair, eyes, ears, nose, mouth, thorax, abdomen, external genitalia, extremities and feet, and the evaluation of respiration.

[0207] For each endpoint, the treatment groups were compared to the control group using the analysis outlined in Table 25. As shown, the data for some endpoints were transformed by arcsine square root transformation before performing the specified analysis.

[0208]

Table 27

[0209] Toxicokinetic Analysis A total of 402 bermudagrass, 402 KD025m1, and 402 KD025m2 samples were analyzed using protein precipitation, followed by high-performance liquid chromatography and subsequently tandem mass spectrometry detection (LC-MS / MS). Exposure to bermudagrass increased with increasing dose levels from 50 to 275 mg base / kg / day.

[0210] C max and AUC 0-24 The increases in values were generally smaller than the dose-proportional values on day 1 for females, approximately dose-proportional on day 1 for males, and approximately dose-proportional on days 14 and 70 for females and males, respectively. Bermudagrass C max and AUC 0-24 The gender differences in values were less than 2-fold, except for group 14 on day 1 (50 mg base / kg / day) where females were approximately 2.10-fold and 2.44-fold higher than males, respectively. The cumulative ratio values of AUC 0-24 were in the range of 0.533 - 1.72 for females on day 14 and 0.859 - 1.98 for males on day 70. The data are summarized in Table 26.

[0211]

Table 28

[0212] Exposure to KD025m1 increased with increasing bermudagrass dose levels from 50 to 275 mg base / kg / day. C in males max and AUC 0-24 The increases in values were less than dose-proportional between dose levels of 50 - 150 mg base / kg / day and approximately dose-proportional to the dose between dose levels of 150 - 275 mg base / kg / day.

[0213] C in females max and AUC 0-24 The increases in values were approximately dose-proportional. Except for group 14 (50 mg base / kg / day) where males were approximately 2.10 - 2.62-fold higher than females, the gender differences in KD025m1 C max and AUC 0-24 were less than 2-fold. The AUC 0-24The cumulative ratio values were in the range of 0.738 to 1.49 for females on the 14th day and 0.634 to 1.24 for males on the 70th day. The metabolite-to-parent ratio was in the range of 0.102 to 0.520 for AUC 0-24 and was summarized in Table 27.

[0214]

Table 29

[0215] Exposure to KD025m2 increased with an increase in the dosage level of vermoxil to 50 - 275 mg base / kg / day. The increase in C max and AUC 0-24 values in males was less than proportional between dosage levels of 50 - 150 mg base / kg / day and was approximately proportional to the dosage between dosage levels of 150 - 275 mg base / kg / day.

[0216] The increase in C max and AUC 0-24 values in females was approximately proportional to the dosage on the 1st day and was greater than the dosage-proportional value on the 14th day. Except for the 14th group (50 mg base / kg / day) where males were approximately 2.58 - 3.70 times higher than females, the gender difference in KD025m2 C max and AUC 0-24 values was generally less than 2-fold. After multiple administrations of vermoxil to rats, no significant accumulation (<2-fold) of KD025m2 was observed. The cumulative ratio values of AUC 0-24 were in the range of 0.657 to 1.80 for females on the 14th day and 0.701 to 1.35 for males on the 70th day. The metabolite-to-parent ratio was in the range of 0.0429 to 0.270 for AUC 0-24 and was summarized in Table 28.

[0217]

Table 30

[0218] In this fertility and early embryonic development toxicity study using birmosdil, effects were observed in males and females treated at 150 and 275 mg base / kg / day.

[0219] In treated females, at 275 mg base / kg / day, adverse clinical findings of abnormal feces (few / absent or discolored) and emaciation were observed.

[0220] Furthermore, females at 150 and 275 mg base / kg / day had lower mean body weights, a mean body weight change, and decreased mean food consumption throughout the treatment period, which were considered to be related to birmosdil and adverse. In females, at 50 mg base / kg / day, lower mean body weights and / or body weight changes and decreased food consumption were also observed. These differences at 50 mg base / kg / day were potentially related to birmosdil but were essentially sporadic, small in magnitude, and not considered adverse.

[0221] At 275 mg base / kg / day, in treated females, a birmosdil-related increase in mean post-implantation deaths and mean resorptions was observed, which correlated with a decrease in the mean number of viable embryos. Ovarian and uterine parameters (number of corpora lutea, number of implantations, viable embryos, and resorptions, and pre- and post-implantation losses) at 50 and 150 mg base / kg / day were not affected by treatment with birmosdil. The reproductive index and fertility index were not affected in females treated at all dose levels evaluated. No macroscopic findings or organ weight differences related to birmosdil were observed in treated females.

[0222] In treated males, at 275 mg base / kg / day, adverse clinical findings of abnormal feces (few / absent) and emaciation were observed. In males, salivation was observed at 275 mg base / kg / day and 150 mg base / kg / day, which was potentially related to birmosdil but this finding was not dose-responsive and was essentially sporadic and thus not considered adverse. Furthermore, males at 150 and 275 mg base / kg / day had lower mean body weights, a mean body weight change, and decreased mean food consumption throughout the treatment period, which were considered to be related to birmosdil and adverse.

[0223] Most of these findings at 150 and 275 mg base / kg / day decreased in frequency during the recovery period, indicating the reversibility of the toxicity. In males, at 50 mg base / kg / day, lower mean body weight and / or body weight change and decreased food consumption were also observed. These differences at 50 mg base / kg / day were potentially related to vermoxdyl but were essentially sporadic, small in magnitude, and not considered harmful.

[0224] At 275 mg base / kg / day, the fertility indices of treated males were low (72% and 75% respectively) and were considered related to and harmful due to vermoxdyl. During the recovery period, no effect on the reproductive index and fertility index (mating, fertility, and fecundity parameters) was seen at 275 mg base / kg / day. The reproductive index and fertility index at 50 and 150 mg base / kg / day were not affected by treatment with vermoxdyl.

[0225] At 275 mg base / kg / day, in untreated females (25 untreated females mated with treated males), there were 6 non-pregnant untreated females, and the mean implantation number and mean viable embryo number decreased. These differences in pregnancy outcomes and uterine parameters at 275 mg base / kg / day were considered related to the abnormal sperm evaluations (low motility, low mean number of sperm, and increased proportion of abnormal sperm) observed in treated males, were related to vermoxdyl, and were considered harmful. In males treated at 275 mg / kg / day, during the recovery period, reproductive, fertility, and sperm parameters were not affected. Male reproductive and fertilization ability parameters were not affected at 50 and 150 mg base / kg / day.

[0226] At necropsy during the terminal and recovery periods, vermoxdyl-related gross observations of small testes (bilateral) and epididymides (left, right, right tail) were observed at the 275 mg / kg dose, which correlated with a decrease in mean organ weight (absolute). Furthermore, at 275 mg / kg / day, microscopic observations of the testes (minimal to severe degeneration / atrophy) and epididymides (minimal to mild luminal cell debris) were noted in approximately 64% and 68%, respectively, of the terminal males, and at recovery necropsy, the percentage of treated males with these findings was approximately 30% and 40%, respectively. Gross findings, organ weights, and microscopic findings were not affected by treatment at 50 and 150 mg base / kg / day.

[0227] Exposures, C, evaluated by vermoxdil and its metabolites, KD025m1 and KD025m2 max and AUC 0-24 values increased with increasing vermoxdil dose levels from 50 to 275 mg base / kg / day. The C max and AUC 0-24 value increases were generally less than dose-proportional on Day 1 for females, dose-proportional on Day 1 for males, and approximately dose-proportional on Days 14 and 70 for males and females.

[0228] The increases in C max and AUC 0-24 values for KD025m1 and KD025m2 in males were less than dose-proportional between dose levels of 50 and 150 mg base / kg / day and less than approximately dose-proportional between dose levels of 150 and 275 mg base / kg / day. The increases in C max and AUC 0-24 values for KD025m1 and KD025m2 in females were approximately dose-proportional, except for KD025m2 on Day 14 where the increase was greater than dose-proportional.

[0229] Vermoxdil C max and AUC 0-24 gender differences in values were less than 2-fold, except for Group 14 (50 mg base / kg / day) on Day 1 where females were approximately 2.10- and 2.44-fold higher than males, respectively.

[0230] Except for Group 14 (50 mg base / kg / day) where males were approximately 2.10 - 3.70-fold higher than females, the C maxand AUC 0-24 The gender difference in values was generally less than 2-fold.

[0231] In the case of KD025 m1, the metabolite-to-parent ratio was in the range of 0.102 - 0.520 for AUC 0-24 and in the range of 0.0429 - 0.270 for AUC in the case of KD025 m2. 0-24

[0232] Based on these results, the NOAEL for general toxicity evaluation items was considered to be 50 mg base / kg / day for male and female rats [AUC of 21600 ng·hour / mL (male) and 26200 ng·hour / mL (female) 0-24 and C of 2480 ng / mL (male) and 3200 ng / mL (female) max .

[0233] The NOAEL for male and female reproductive ability and fertility was considered to be 150 mg base / kg / day and 275 mg base / kg / day, respectively [AUC of 70100 ng·hour / mL 0-24 and C of 10100 ng / mL max (male) and AUC of 209000 ng·hour / mL 0-24 and C of 14900 ng / mL max (female)].

[0234] In treated females, the NOAEL for ovarian and uterine parameters was considered to be 150 mg base / kg / day (AUC of 99500 ng·hour / mL 0-24 and C of 9860 ng / mL max ).

[0235] Example 6: US REZUROCK (trademark) (belumosudil) FDA label Indications and Usage REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. (1)

[0236] Dosage and Administration Recommended Dosage: Orally administer 200 mg once daily with food. (2.1)

[0237] Dosage Form and Strength Tablet: 200 mg (3)

[0238] Contraindications None (4)

[0239] Warnings and Precautions Embryo-Fetal Toxicity: May cause harm to the fetus. Advise women of the potential risk to the fetus with respect to fertility and use effective contraception. (5.1, 8.1, 8.3)

[0240] Drug Interactions Strong CYP3A Inducers: Increase the REZUROCK dosage to 200 mg twice daily. (7.1)

[0241] Proton Pump Inhibitors: Increase the REZUROCK dosage to 200 mg twice daily. (7.1)

[0242] Adverse Reactions The most common (≥20%) adverse reactions including clinical laboratory abnormalities were infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia and hypertension. (6.1)

[0243] Use in Specific Populations Lactation: Advise not to breastfeed. (8.2)

[0244] For patient counseling information and FDA-approved patient labeling, see 17.

[0245] Full Prescribing Information 1 Indications and Usage REZUROCK is indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0246] 2 Dosage and Administration 2.1 Recommended Dosage The recommended dose of REZUROCK is 200 mg administered orally once daily until progression of chronic GVHD requires a new line of systemic therapy.

[0247] Instruct the patient to: · Swallow the REZUROCK tablets whole. Do not cut, crush, or chew the tablets. · Take REZUROCK with food at approximately the same time each day [see Clinical Pharmacology (12.3)]. · If a dose of REZUROCK is missed, instruct the patient not to take an additional dose to make up for the missed dose.

[0248] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)].

[0249] 2.2 Dose Modification for Adverse Reactions Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly. Modify the REZUROCK dosage for adverse reactions according to Table 29.

[0250] Table 29: Recommended Dosage Modifications of REZUROCK for Adverse Reactions

[0251]

Table 31

[0252] 2.3 Dose Modification Due to Drug Interaction Strong CYP3A Inducers If co-administered with a strong CYP3A inducer, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0253] Proton Pump Inhibitors If co-administered with a proton pump inhibitor, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0254] 3 Dosage Forms and Strengths Each 200 mg tablet is a light yellow film-coated oval tablet debossed with "KDM" on one side and "200" on the other side.

[0255] 4 Contraindications None

[0256] 5 Warnings and Precautions 5.1 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, REZUROCK may cause fetal harm if administered to a pregnant woman. In animal reproductive studies, administration of belumosudil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality and malformations at maternal exposures (AUC) less than those in patients at the recommended dose. Advise pregnant women of the potential risk 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 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

[0257] 6 Adverse Reactions 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates actually observed.

[0258] Chronic graft-versus-host disease In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1)]. The median treatment duration was 9.2 months (range 0.5 to 44.7 months).

[0259] A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multiple organ failure.

[0260] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Adverse reactions that led to permanent discontinuation of REZUROCK in more than 3% of patients included nausea (4%). Adverse reactions leading to interruption of dosing occurred in 29% of patients. Side effects resulting in discontinuation of dosing in 2% or more were infections (11%), diarrhea (4%), asthenia, dyspnea, hemorrhage, hypotension, abnormal liver function tests, nausea, fever, edema, and renal failure (2% each).

[0261] The most common (≥20%) adverse reactions, including clinical laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyltransferase, lymphopenia, and hypertension.

[0262] Table 30 summarizes the non-laboratory adverse reactions.

[0263] [Table 32]

[0264] [Table 33]

[0265] Table 31 summarizes the laboratory abnormalities of REZUROCK.

[0266]

Table 34

[0267] 7 Drug Interactions 7.1 Effects of Other Drugs on REZUROCK Potent CYP3A Inducers Concomitant administration of REZUROCK with potent CYP3A inducers decreases belumosudil exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. If coadministered with a potent CYP3A inducer, increase the dose of REZUROCK [see Dosage and Administration (2.3)].

[0268] Proton Pump Inhibitors Concomitant administration of REZUROCK with proton pump inhibitors decreases belumosudil exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. If coadministered with a proton pump inhibitor, increase the dose of REZUROCK [see Dosage and Administration (2.3)].

[0269] 8 Use in Specific Populations 8.1 Pregnancy Summary of Risk Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], REZUROCK may cause fetal harm if administered to a pregnant woman. There are no available human data on the use of REZUROCK in pregnant women to evaluate drug-related risks. In animal reproductive studies, administration of belumosudil to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including growth, embryo-fetal mortality, and embryo-fetal malformations, at maternal exposures (AUC) approximately 3-fold higher (rats) and 0.07-fold higher (rabbits) than the human exposure (AUC) at the recommended dose (see Animal Data). Advise pregnant women and women of reproductive potential about the potential risk to the fetus.

[0270] In the general population of the United States, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are approximately 2 - 4% and 15 - 20%, respectively.

[0271] Data Animal Data During the animal organogenesis period, vermostil was administered to rats at doses of 25, 50, 150, and 300 mg / kg / day in the pilot study and 15, 50, and 150 mg / kg / day in the pivotal study for embryo - fetal development studies. Maternal toxicity and embryo - fetal developmental effects were observed in the pilot study. Maternal toxicity (decrease in body weight gain) occurred at doses of 150 and 300 mg / kg / day. An increase in post - implantation loss occurred at 50 and 300 mg / kg / day. Fetal malformations were observed at 50 mg / kg / day and above, including anal and tail absence, umbilical cord tumor, and dome - shaped head. The exposure (AUC) at 50 mg / kg / day in rats was approximately 3 times that of human exposure at the recommended dose of 200 mg.

[0272] In the rabbit embryo - fetal development study, pregnant animals were orally administered vermostil at 50, 125, and 225 mg / kg / day during the organogenesis period, which resulted in maternal toxicity and embryo - fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of 125 mg / kg / day and above. Embryo - fetal effects were observed at doses of 50 mg / kg / day and above, including spontaneous abortion, increased post - implantation death, decreased proportion of live fetuses, malformations, and decreased fetal weight. Malformations included malformations of the tail (short), ribs (branching, fusion, or deformation), sternal segmentation (fusion), and neural arches (fusion, displacement, deformation). The exposure (AUC) at 50 mg / kg / day in rabbits was approximately 0.07 times that of human exposure at the recommended dose of 200 mg.

[0273] 8.2 Lactation Summary of Risks There is no available data on the presence of belumosudil or its metabolites in human breast milk, or on the effects on children who have been breastfed, or on breast milk production. Due to the potential for serious adverse reactions from belumosudil in children who are being breastfed, advise lactating women not to breastfeed during treatment with REZUROCK and for at least 1 week after the last dose.

[0274] 8.3 Reproductive Potential Women and Men REZUROCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

[0275] Pregnancy Testing Confirm the pregnancy status of women of reproductive potential before initiating treatment with REZUROCK.

[0276] Contraception Women Advise women of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.

[0277] Men Advise men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose of REZUROCK.

[0278] Infertility Women Based on findings in rats, REZUROCK can impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0279] Men Based on findings in rats and dogs, REZUROCK can impair male fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

[0280] 8.4 Use in Pediatric Patients The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years of age and older. Use of REZUROCK in this age group is supported by evidence from well-controlled studies in adults with additional population pharmacokinetic data demonstrating that age and weight did not clinically meaningfully affect the pharmacokinetics of the active drug substance, that exposure to the active drug substance was expected to be similar between adults and pediatric patients 12 years of age and older, and that the disease course was sufficiently similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients.

[0281] The safety and effectiveness of REZUROCK have not been established in pediatric patients less than 12 years of age.

[0282] 8.5 Use in Elderly Patients Of the 186 patients with chronic GVHD in the clinical trials of REZUROCK, 26% were 65 years of age or older. No clinically significant differences in the safety or effectiveness of REZUROCK were observed compared to younger patients.

[0283] 11 Description Belmosulodex is a kinase inhibitor. The active pharmaceutical ingredient is belmosulodex mesylate, which has the molecular formula C 27 H 28 N6O5S and a molecular weight of 548.62 g / mol. The chemical name of belmosulodex mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1). The chemical structure is as follows. [Chemical Structure Diagram]

[0284] Belmosulodex mesylate is a yellow powder that is poorly soluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0285] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base, equivalent to 242.5 mg of besremi mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0286] The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide.

[0287] 12 Clinical Pharmacology 12.1 Mechanism of Action Besremi is an inhibitor of rho-associated coiled-coil containing protein kinase (ROCK), which inhibits ROCK 2 and ROCK 1 at IC 100 values of approximately 3 nM and 50 μM, respectively. Besremi downregulated the pro-inflammatory response via the regulation of STAT3 / STAT5 phosphorylation and the shift of the Th17 / Treg balance in ex vivo or in vitro human T cell assays. Besremi also inhibited abnormal profibrotic signaling in vitro. In vivo, besremi showed activity in an animal model of chronic GVHD.

[0288] 12.2 Pharmacodynamics The exposure-response relationship and the time course of the pharmacodynamic response of besremi have not been established.

[0289] 12.3 Pharmacokinetics Unless otherwise specified, the following pharmacokinetic parameters are shown for patients with chronic GVHD who received 200 mg of besremi once daily. The mean (coefficient of variation %, CV%) steady-state AUC and C max of besremi were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The C maxAnd the AUC increased almost proportionally over the dose range of 200 and 400 mg (1 to 2 times the recommended once-daily dose). The accumulation ratio of vemotogrel was 1.4.

[0290] Absorption The T of vemotogrel at steady state max The median was 1.26 to 2.53 hours after patients were administered 200 mg once or twice daily. The mean (%CV) bioavailability was 64% (17%) after a single dose of vemotogrel in healthy subjects.

[0291] Effect of food Compared with fasting in healthy subjects, after administration of a single dose of vemotogrel with a high-fat and high-calorie diet (about 50% of the total calorie content of the diet from fat, 800 to 1,000 calories), the C of vemotogrel max and AUC increased 2.2-fold and 2-fold, respectively. The median of T max was delayed by 0.5 hour.

[0292] Distribution The geometric mean volume of distribution after a single dose of vemotogrel in healthy subjects was 184 L (geo CV% 67.7%).

[0293] The binding of vemotogrel to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6% in vitro, respectively.

[0294] Elimination The mean (%CV) elimination half-life of vemotogrel in patients was 19 hours (39%), and the clearance was 9.83 L / hour (46%).

[0295] Metabolism Vemotogrel is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9 in vitro.

[0296] Excretion After a single oral administration of radiolabeled vermoxdile to healthy subjects, 85% of the radioactivity was recovered in feces (30% remained unchanged), and less than 5% was recovered in urine.

[0297] Specific population No clinically significant differences in the pharmacokinetics of vermoxdile were observed with respect to age (18 to 77 years), gender, body weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥ 60 and < 90 mL / min / 1.72 m 2 ~eGFR ≥ 30 and < 60 mL / min / 1.72 m 2 ). The effect of severe renal impairment on the pharmacokinetics of vermoxdile has not been tested.

[0298] Drug interaction study Clinical trials and model-informed approaches regarding the effects of other drugs on vermoxdile Potent cytochrome P450 (CYP) 3A inhibitor: When co-administered with itraconazole to healthy subjects, there was no clinically meaningful effect on vermoxdile exposure.

[0299] Potent CYP3A inducer: Co-administration of rifampin decreased vermoxdile C max by 59% and AUC by 72% in healthy subjects.

[0300] Moderate CYP3A inducer: Co-administration of efavirenz is predicted to decrease vermoxdile C max by 32% and AUC by 35% in healthy subjects.

[0301] Proton pump inhibitor: In healthy subjects, co-administration of rabeprazole decreased vermoxdile C max by 87% and AUC by 80%, and omeprazole decreased vermoxdile C max by 68% and AUC by 47%.

[0302] Effect of vermoxdile on other drugs CYP3A Substrate: Co-administration of vemurafenib is predicted to increase the C max and AUC of midazolam (a sensitive CYP3A substrate) by approximately 1.3-fold and 1.5-fold, respectively.

[0303] CYP2C9 Substrate: Co-administration of vemurafenib is not expected to have a clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

[0304] CYP2C8 Substrate: Co-administration of vemurafenib is not expected to have a clinically meaningful effect on the exposure of CYP2C8 substrates that are not OATP1B1 substrates.

[0305] In Vitro Tests Transport Systems: Vemurafenib is a substrate of P-gp. Vemurafenib inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations.

[0306] Enzyme Systems: Vemurafenib is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9.

[0307] 13 Nonclinical Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with vemurafenib have not been conducted.

[0308] Vemurafenib was not genotoxic in in vitro bacterial mutagenicity (Ames) assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes (HPBL), or in vivo rat bone marrow micronucleus assay.

[0309] In the rat fertility test with combined male and female, male animals treated with vemurafenib were mated with untreated females, or untreated male animals were mated with vemurafenib-treated females. Vemurafenib was orally administered to male rats at doses of 50, 150 or 275 mg / kg / day for 70 days prior to and throughout the mating period, and to female rats for 14 days prior to mating and up to day 7 of pregnancy. At the dose of 275 mg / kg / day, adverse findings in female rats (either treated with vemurafenib or untreated but mated with treated males) included increased pre- or post-implantation losses and decreased numbers of viable embryos. Administration of vemurafenib to male rats at the dose of 275 mg / kg / day resulted in abnormal sperm findings (decreased motility, decreased count, and increased proportion of abnormal sperm) and changes in the testis / epididymis organs (weight loss and degeneration).

[0310] Fertility was decreased in both males and females treated at the dose of 275 mg / kg / day, reaching statistical significance in males. Adverse changes in male and female genitalia also occurred in the general toxicity studies and findings included sperm degeneration at a vemurafenib dose of 35 mg / kg / day in dogs and decreased ovarian follicular development at 275 mg / kg / day in rats. During the recovery period, the changes were partially or completely reversed. The exposures (AUC) at doses of 35 mg / kg / day in dogs and 275 mg / kg / day in rats were 0.5-fold and 8 - 9-fold, respectively, of the clinical exposure at the recommended dose of 200 mg daily.

[0311] 14 Clinical Trials 14.1 Chronic Graft-versus-Host Disease The KD025-213 trial (NCT03640481) was a randomized, open-label, multi-center trial of REZUROCK for the treatment of patients with chronic GVHD who had received 2 - 5 prior lines of systemic therapy and required further treatment. Platelets < 50 × 10 9 / L; absolute neutrophil count < 1.5 × 10 9 / L; AST or ALT > 3 × ULN; total bilirubin > 1.5 × ULN; QTc(F) > 480 ms; eGFR < 30 mL / min / 1.73 m 2; or, if FEV1 ≤ 39%, the patient was excluded from the study. Sixty-six patients were treated with oral REZUROCK 200 mg once daily. Concurrent treatment with supportive therapy for chronic GVHD was permitted. Concurrent treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapy was permitted as long as the subject had been on a stable dose for at least 2 weeks prior to the study. Initiation of new systemic chronic GVHD treatment during the study was not permitted.

[0312] Demographics and baseline characteristics are summarized in Table 32.

[0313]

Table 35

[0314] The efficacy of REZUROCK was based on the overall response rate (ORR) through Day 1 of Cycle 7, where overall response included complete or partial response per the 2014 NIH response criteria. The results for ORR are shown in Table 33. The ORR was 75% (95% CI: 63, 85). The median duration of response calculated from the first response to progression, death, or new systemic therapy for chronic GVHD was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, 62% (95% CI: 46, 74) did not experience death or initiation of new systemic therapy for at least 12 months after response.

[0315]

Table 36

[0316] The results for ORR were supported by an exploratory analysis of bothersomeness of reported symptoms showing a decrease of at least 7 points in the Lee Symptom Scale summary score through Day 1 of Cycle 7 in 52% (95% CI: 40, 65) of patients.

[0317] 16 Supply / Storage Method and Handling Method REZUROCK 200 mg tablets are supplied as light yellow film-coated rectangular tablets containing 200 mg of belumosudil (equivalent to 242.5 mg of belumosudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other side and is packaged as follows:

[0318] 200 mg tablets in a 30-count bottle: NDC 79802-200-30

[0319] Store at room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0320] Dispense to patients only in the original container. Store in the original container to protect from moisture. Always replace the cap securely after each opening. Do not discard the desiccant.

[0321] 17 Patient Counseling Information Advise patients to read the FDA-approved Patient Information.

[0322] Embryo-Fetal Toxicity: Advise pregnant women and women of reproductive potential about the potential risk to the fetus of reproductive potential. Advise women of reproductive potential and inform the healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].

[0323] Advise women of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Warnings and Precautions (5.1)].

[0324] Advise men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose [see Use in Specific Populations (8.3)].

[0325] Breastfeeding Advise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.2)].

[0326] Infertility Advise men and women that REZUROCK may impair fertility [see Use in Specific Populations (8.3)].

[0327] Administration Instruct the patient to take REZUROCK orally once daily with food, as directed by a physician, and that the oral dosage (tablet) should be swallowed whole with a glass of water at approximately the same time each day without cutting, crushing, or chewing the tablet [see Dosage and Administration (2.1)].

[0328] Advise the patient that if a dose of REZUROCK is missed, the patient should return to the normal schedule the next day and take the missed dose as soon as possible on the same day. The patient should not take an additional dose to make up for the missed dose [see Dosage and Administration (2.1)].

[0329] Drug Interactions Advise 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)].

[0330] [Table 37]

[0331] [Table 38]

[0332] [Table 39]

[0333] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific documents cited herein are hereby expressly incorporated by reference in their entirety.

Claims

1. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in female patients capable of reproduction, comprising the step of advising said patient to use effective contraception during treatment and for at least 1 week after the last administration of the compound.

2. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in female patients who are pregnant or become pregnant while taking the compound, comprising advising said female patient about the potential risks to the fetus when undergoing treatment with the compound during pregnancy.

3. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in female patients capable of reproduction, comprising the step of verifying the pregnancy status of said patient before initiating treatment with the compound.

4. The use according to claim 1 or 2, further comprising the step of confirming the pregnancy status of said patient before initiating treatment with the compound.

5. The use according to claim 2, wherein the patient becomes pregnant while receiving treatment with the compound.

6. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in male patients having a female partner capable of reproduction, comprising the step of advising said male patient to use effective contraception during treatment with the compound and for at least 1 week after the last administration of the compound.

7. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound), for use in the treatment of chronic graft-versus-host disease (cGVHD) in fertile patients, using effective contraception during treatment with the compound.

8. The use according to claim 7, wherein the patient is using effective contraception during treatment with the compound and for at least 1 week after the last administration of the compound.

9. The use according to claim 7, wherein the patient is a fertile female.

10. The use according to claim 7, wherein the patient is a fertile male.

11. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in lactating patients, comprising the step of advising the patient not to breastfeed during treatment with the compound and for at least 1 week after the last administration of the compound.

12. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) for use in the treatment of chronic graft-versus-host disease (cGVHD) in non-lactating patients.

13. The use according to any one of claims 1 to 11, wherein the compound is the mesylate salt of 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide.

14. The use according to any one of claims 1 to 12, wherein the compound is administered to the patient at a dose of 200 mg per day.

15. The use according to any one of claims 1 to 13, wherein the patient has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for the chronic graft-versus-host disease.

16. The use according to claim 14, wherein the prior lines of systemic therapy are selected from prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

17. 2-{3-[4-(1H-Indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof (the compound), which comprises the step of advising the patient about the reproductive risks associated with treatment with the compound, for use in the treatment of chronic graft-versus-host disease (cGVHD) in patients at risk of pregnancy.

18. The use according to claim 16, wherein the patient is a female patient capable of reproduction.

19. The use according to claim 17, further comprising the step of confirming the pregnancy status of the patient before initiating treatment.

20. The use according to claim 16, wherein the patient is a male patient.

21. The use according to any one of claims 16 to 19, which comprises the step of advising the patient to use effective contraception during treatment with the compound and for at least one week after the last administration of the compound.

22. The use according to any one of claims 16 to 19, which comprises the step of advising the patient about the fertility risks associated with treatment with the compound.

23. The use according to any one of claims 16 to 21, wherein the compound is the mesylate salt of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide.

24. The use according to any one of claims 16 to 22, wherein the compound is administered to the patient at a dose of 200 mg per day.

25. The use according to any one of claims 16 to 23, wherein the patient has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for the chronic graft-versus-host disease.

26. Use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (the compound) in the treatment of graft-versus-host disease in female patients, comprising: (a) the step of confirming the pregnancy status of the patient before initiating treatment with the compound; (b) the step of advising the patient about the potential risks to the fetus if the patient is treated with the compound during pregnancy; and (c) the step of advising the patient to use contraception during treatment with the compound and for at least 1 week after the last administration of the compound. The use.

27. Use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) in the treatment of graft-versus-host disease in male patients having a potentially fertile female partner, (a) advising the patient about the potential risk to the fetus if the partner becomes pregnant while the patient is being treated with the compound, and (b) advising the patient to use contraception during treatment with the compound and for at least 1 week after the last administration of the compound comprising the use.

28. A method of treating a patient for chronic graft-versus-host disease (cGVHD) using the mesylate salt (belumosudil) of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, comprising (a) verifying whether the patient is a reproductive risk patient, and (b) (i) if it is verified that the patient is not a reproductive risk patient, administering belumosudil to the patient, or (ii) if it is verified that the patient is a reproductive risk patient, advising the patient about the potential reproductive risks when being treated with belumosudil comprising the method.

29. The method according to claim 27, further comprising, in step (a), if it is verified that the patient is a potentially fertile patient, advising the patient to use effective contraception during and for at least one week after the last administration of belumosudil.

30. The method according to claim 27, further comprising, in step (a), if it is verified that the patient is a lactating patient, advising the patient not to breastfeed the child during and for at least one week after the last administration of belumosudil.

31. A method of treating chronic graft-versus-host disease (cGVHD) in a patient, comprising (a) verifying whether the patient is a reproductive risk patient, and (b) (i) if it is verified that the patient is not a reproductive risk patient, administering belumosudil to the patient, or (ii) if it is verified that the patient is a reproductive risk patient, using effective contraception during treatment with belumosudil and for at least 1 week after the last administration, comprising the method.

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