TW202402294A - Methods of administering belumosudil for treatment of chronic graft versus host disease - Google Patents

Abstract

The present disclosure provides methods of administering belumosudil mesylate salt to patients with cGVHD.

Description

Methods of administering berusudil to treat chronic graft-versus-host disease

This article relates to the administration of belumosudil mesylate (REZUROCK™) to patients for the treatment of chronic graft-versus-host disease (cGVHD).

Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potentially serious complication after solid organ transplantation and allogeneic hematopoietic cell transplantation (alloHCT). Up to 70% of all alloHCT recipients are affected by cGVHD, with an incidence of 20%-50% in children. It is the leading cause of non-relapse death more than 2 years after alloHCT. In the United States, the estimated prevalence of cGVHD is 14,000 patients (as of 2016). (Bachier CR et al.: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. Published at ASH 2019, Orlando, FL, December 7-10, 2019 ) (“Bachier et al.”).

Patients with cGVHD have significantly impaired quality of life (QOL), as assessed by the Lee Symptom Scale (LSS), which measures the impact of cGVHD on a patient's functioning and well-being. It has been reported that only one-third of patients with cGVHD who initiate systemic therapy will survive, taking 5 years to achieve remission and wean off immunosuppressive therapy. (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.").

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

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

The management of cGVHD continues to evolve with the emergence of targeted therapies. cGVHD is characterized by overproduction of the proinflammatory cytokines IL-21 and IL-17 and overpriming of T follicular helper cells and B cells, which in turn leads to overproduction of antibodies.

In 2017, the US Food and Drug Administration approved ibrutinib (Bruton's tyrosine kinase inhibitor) for the treatment of patients with patients who have failed one or more first-line systemic therapies. Adults with cGVHD. In patients with cGVHD requiring an erythematous rash of >25% body surface area or an NIH oral score of >4, studies on ibrutinib reported an overall response rate (ORR) of 67% and a 43% Discontinuation rates due to treatment-emergent adverse events (TEAEs). (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).

There remain opportunities to investigate additional treatment options for patients with cGVHD, including those who have failed ≥1 line of therapy.

This article provides methods for administering berusudil mesylate (REZUROCK™) to patients for the treatment of cGVHD.

In one embodiment, provided herein is 2-{3-[4-(1H-indazol-5-ylamine)-2-quinazolinyl]phenoxy}-N-(propan-2-yl ) The use of acetamide or a pharmaceutically acceptable salt (compound) thereof and/or berusucidil mesylate in patients who experience one or more treatment-related adverse reactions while receiving clinically recommended doses of said compound , the uses include: discontinuing administration of the compound to the patient if the patient experiences at least one adverse reaction of grade 3 or higher; and if the at least one adverse reaction does not escalate to grade 4 level and the patient returns to a Grade 1 level or lower grade level after discontinuation of treatment, then administration of the compound is resumed at the clinically recommended dose for the patient.

In one embodiment, provided herein is the use of a compound or berusudil mesylate and/or a method of treating cGVHD in a subject, the method comprising the steps of: to target the patient administering the compound to the patient at a clinically recommended dose; monitoring the patient for adverse reactions; if the patient experiences at least one Grade 3 adverse reaction, discontinuing administration of the compound to the patient; and Administration of the compound to the patient is resumed when at least one adverse reaction in the patient has returned to grade 1 or less.

In another embodiment, provided herein is permanently discontinuing administration of the compound to the patient if the patient experiences at least one Grade 4 adverse reaction.

A more complete understanding of embodiments of the present invention may be obtained by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

Overview

Begrusudil is an oral, selective rho-associated coiled-coil–containing protein kinase-2 (ROCK2) inhibitor. ROCK2 inhibition acts on a dysregulated adaptive immune system and fibrosis that occurs due to abnormal tissue repair. Begrusudil inhibits ROCK2 and ROCK1 with _IC50 values of approximately 100 nM and 3 μM, respectively.

Berusudil downregulates pro-inflammatory responses by modulating STAT3/STAT5 phosphorylation and altering Th17/Treg balance in ex vivo or in vitro human T cell assays. Begrusudil also inhibits aberrant profibrotic signaling in vitro. By controlling ROCK2 activity, berusudil mediates immune cell function and signaling in fibrotic pathways, thereby alleviating the effects caused by this debilitating disease, such as inflammation in multiple tissues and skin, joints/fascia and fibrotic changes in the lungs.

In vivo, the activity of berusudil was demonstrated in animal models of chronic GVHD.

Begrusudil mesylate is marketed as REZUROCK ^™ in the United States and other countries for the treatment of patients with chronic GVHD (cGVHD), in some cases after failure of at least two prior lines of systemic therapy. The chemical name of the compound berusudil is: 2-{3-[4-(1 H -indazol-5-ylamine)-2-quinazolinyl]phenoxy}- N -(propan- 2-yl)acetamide. The compound berusudil is also known as KD025. The active pharmaceutical ingredient of REZUROCK ^TM is berusudil mesylate, its molecular formula is C ₂₇ H ₂₈ N ₆ O ₅ S, its molecular weight is 548.62 g/mol, and its chemical name is 2-{3-[4-( 1 H -indazol-5-ylamine)-2-quinazolinyl]phenoxy}- N -(propan-2-yl)acetamide methanesulfonate (1:1).

The chemical structure of berusudil mesylate is as follows:

Berusuudil and methods for preparing the compounds are described in the following US patents: US Patent No. 8,357,693, US Patent No. 9,815,820, US Patent No. 10,183,931, and US Patent No. 10,696,660.

This article provides methods for administering berusudil mesylate (REZUROCK™) to patients with risk management steps to address potential adverse effects. definition

As used herein, "about" includes the exact amounts modified by the term "about" as well as amounts expected to be within experimental error (eg, like within 15%, 10%, or 5%). For example, "about 200 mg" means "200 mg" and a range of mg within experimental error (e.g., 200 mg plus or minus 15%, 10%, or 5%). As used herein, the term "about" may be used to modify a range as well as a specific value.

As used herein, "administer" or "administer to" (e.g., includes reference to discontinuing administration to a subject and/or resuming administration of an API (including a compound or berusudil) to a subject) use of this term) refers to the act of prescribing one or more drug products containing an API for consumption by a subject during treatment, the act of dispensing said one or more drug products to a subject, and/or the act of physically receiving or ingesting The action of the one or more pharmaceuticals. Accordingly, an API (e.g., Compound or Begrusudil) may be "administered" by: a physician or other medical professional who writes a prescription for one or more drug products; and/or dispenses the prescription and/or The pharmacist who dispenses the drug(s) to the subject; and/or the patient or subject who ingests the drug(s) and/or his or her companion or caregiver who provides the drug(s) to the subject, each of which Personnel may also "stop" investing and/or "resume" investing in the API.

"Adverse reaction" means a physiological reaction resulting from treatment with an API that is undesirable, harmful or unpleasant to the patient or the treatment process. In certain embodiments, adverse reactions include, but are not limited to, infections, gastrointestinal disorders, respiratory disorders, thoracic or mediastinal disorders, vascular disorders, musculoskeletal or connective tissue disorders, neurological disorders, metabolic disorders and/or Cutaneous and subcutaneous disorders.

In other embodiments, more common adverse reactions may include, but are not limited to, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, gamma-glutaminyltransferase Elevated lymphocytes, lymphopenia, and hypertension. Adverse effects can be detected directly or indirectly.

"API" means "active pharmaceutical ingredient".

"Allogeneic hematopoietic stem cell transplantation (allo-HSCT)", also known as bone marrow transplantation or stem cell transplantation or "allogeneic hematopoietic cell transplantation (allo-HCT)", refers to a transplant from a donor The process of transplanting blood-forming cells into a recipient who is not an identical twin. The source of hematopoietic stem cells used for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some cases, umbilical cord blood may be used. The donor and recipient can be human leukocyte antigen (HLA) genetically identical, such as siblings. The donor and recipient can be only half-identical (haploidentical) parents and children.

When the term "belumosudil" is used herein, it will be understood that, unless the context clearly indicates otherwise, the term may encompass the compound belumosudil in any form as well as its pharmaceutically acceptable of salt. The term "berusudil" refers to both the compound berusudil (e.g., in the free base form, the amorphous form, or the crystalline form), the pharmaceutically acceptable salts of berusudil (e.g., in the form of REZUROCK mesylate form used in ^TM ) and any form of berusudil that may be used in a formulation or pharmaceutical composition for administering the compound to a patient.

"Ceasing" or "cessation" when referring to administration of an API means temporarily or permanently no longer administering the API to a patient. For example, it may be possible to temporarily "stop" administration of an API if the patient experiences a treatment-related Grade 3 adverse reaction (and resume administration if the patient recovers to Grade 0 or 1), or if the patient experiences a treatment-related Grade 4 adverse reaction. grade adverse reactions, administration of the API should be permanently discontinued or discontinued.

A "clinical endpoint" or "study 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 regimen as designed in the clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) refers to the percentage of people in a study or treatment group who have a partial response (PR) or a complete response (CR) to treatment within a certain time period. Failure-free survival (FFS) refers to the time from the first dose of berusudil to the failure event, or the start of berusudil and the addition of a new cGVHD therapy, recurrence of the underlying disease, or non- The interval between nonrelapse mortality (NRM). Overall survival (OS) refers to the length of time from the date of diagnosis of the disease or the date of initiation of treatment. Duration of response (DOR) means the time from initial response (eg, PR or CR) until documented progression of cGVHD from optimal response, from initial response to initiation of additional systemic cGVHD therapy, or death time. Time to next treatment (TTNT) refers to the time to start subsequent systemic cGVHD therapy.

A "clinically recommended amount" or "clinically recommended dose" means one recommended and/or approved by a person skilled in the art of medicinal chemistry following clinical trials (e.g., as described in Examples 1 and 2 herein) for administration to a patient to treat a condition. The amount or dosage of the API for the disease state discussed. In some embodiments, the clinically recommended dose of berusudil mesylate is 200 mg per day, in some embodiments 200 mg per day, administered orally with food.

“CYP3A” refers to the CYP3A family of p-450 isoenzymes, including CYP3A4.

When the term "grade" is used with respect to the graded level of an adverse reaction, the term is intended to be defined in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CTCAE presents grades 1 to 5 and a unique clinical description of the severity of each adverse reaction based on this general guidance: Grade 1 - Mild (asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated); Grade 2 - Moderate (minimal, local or non-invasive intervention indicated); Grade 3 - Severe (medically significant but not immediately life-threatening; indicating hospitalization or prolonged hospitalization; disabling; limiting self-care); Grade 4 - life-threatening (urgent intervention indicated); and Level 5 - AE-related death.

“Immunosuppressive therapy” (IST) refers to therapy typically administered for at least six months after allo-HSCT in an attempt to prevent GVHD. Examples of ISTs include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine.

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

"Line of treatment" or "line of therapy" describes the order or sequence in which different therapies are given to a patient as the patient's disease progresses. Initial treatment (first-line therapy) may not work or may stop working after a while. After first-line therapy has been discontinued, a second, different treatment may be given (second-line therapy). Subsequent lines of therapy may be given when second-line therapy does not work or stops working. Some patients may be given multiple lines of therapy over the course of the disease.

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

Examples of corticosteroid therapies used to treat cGVHD include, but are not limited to, prednisone, prednisolone, methylprednisolone, and budesonide. Examples of prior systemic therapies used to treat cGVHD include, but are not limited to, prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, motimax Cophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib, and ofatumumab.

Reference to "monitoring" with respect to the assessment of adverse reactions or side effects means observing, examining, and/or evaluating the progression of one or more adverse reactions over at least two points in time (in some embodiments, over a period of time). Monitoring can be done through consultation, patient self-report, visual observation, physical examination, use of equipment, and/or laboratory testing. Any person who may be involved in administering the API to a subject, as defined above, may also be involved in monitoring adverse reactions.

"Myeloablative transplantation" refers to a transplantation procedure that uses very high doses of chemotherapy or radiation before transplanting autologous or allogeneic hematopoietic stem cells. Non-myeloablative transplantation, or reduced-intensity transplantation, involves patients undergoing less intense chemotherapy before transplantation of allogeneic hematopoietic stem cells.

The "NIH Lung Symptom Score" or "NIH cGVHD Lung Score" is a clinical symptom-based score ranging from 0 to 3. A score of 0 is used for no symptoms, a score of 1 is used for symptoms of shortness of breath when going up stairs, a score of 2 is used for symptoms of shortness of breath on level ground, and a score of 3 is used for symptoms of shortness of breath at rest or when oxygen is required.

Unless the context otherwise requires, "or" is used inclusively (equivalent to "and/or").

As used herein, "patient" or "subject" includes animals or humans, in one embodiment a human.

"Pharmaceutical composition" means a mixture of substances, including pharmaceutical agents, suitable for administration to an individual. For example, pharmaceutical compositions may include sterile aqueous solutions or APIs formulated in oral dosage forms (eg, tablets or capsules).

"Pharmaceutically acceptable salts" means physiologically and pharmaceutically acceptable salts of the compounds provided herein. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by converting existing acid or base moieties into their salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues (such as amines); alkali or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts of the present invention include, for example, conventional nontoxic salts of the parent compound formed from nontoxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound containing a basic or acidic moiety. Generally, such salts can be obtained by preparing the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two (non-aqueous media such as diethyl ether, Prepared by reaction in ethyl acetate, ethanol, isopropyl alcohol or acetonitrile).

"Risk" as used herein (e.g., with respect to adverse events) means the possibility (even if remote or remote) that the adverse event will occur.

"Side Effect" means any physiological reaction attributable to treatment with an API other than the disease or disorder for which the API is being administered. Side effects can include "adverse events" (or AEs) or "adverse reactions", or they can be harmless or even beneficial side effects.

"Steroid-refractory" (SR) cGVHD is defined as cGVHD that progresses while on steroids or corticosteroids (in one embodiment, on prednisone). [0064] "Treatment-emergent" when used with respect to an adverse reaction or adverse event means that the adverse reaction or event, or symptoms thereof, is manifested during the time period during which the patient is exposed to the API (eg, occurs during a course of treatment). "Therapeutic related" when used with respect to an adverse reaction or adverse event means that occurs or worsens during the period of exposure to the API and is based on a clinical assessment of the patient's diagnosis, one or more conditions, and/or physiological profile. Adverse reactions that occur during treatment are more likely to be attributable to exposure to the API rather than other causes or preexisting conditions (rather than the disease state for which the treatment is being provided). For example, if the clinical evaluation of the patient informs that one or more adverse reactions are related to a preexisting disease or disorder and are unlikely to be related to the API, the adverse reactions will not be considered "therapy related."

A "therapeutically effective amount" of an API means an amount that when administered to a human for the treatment of a disease (eg, cGVHD) is sufficient to effect treatment of the disease state being treated. When applied to cGVHD in humans, "treating" or "treatment" includes (1) reducing the risk of developing cGVHD and/or inhibiting cGVHD, that is, preventing or reducing the development of cGVHD or its clinical symptoms; and (2) Alleviating cGVHD, that is, causing the regression, reversal or alleviation of cGVHD or reducing the number, frequency, duration or severity of its clinical symptoms.

The therapeutically effective amount of the API may vary depending on the health and physical condition of the subject to be treated, the extent of disease progression, assessment of the medical condition, and other relevant factors. It is expected that the therapeutically effective amount may fall within a range that can be determined experimentally and by reference to clinical trial data and results (eg, as described in Examples 1 and 2 herein and in the scientific literature). Exemplary embodiments

In one embodiment, provided herein is 2-{3-[4-(1H-indazol-5-ylamine)-2-quinazolinyl]phenoxy}-N-(propan-2-yl ) The use of acetamide or a pharmaceutically acceptable salt thereof (compound) in patients who experience one or more treatment-related adverse reactions when receiving clinically recommended doses of said compound, including: if the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 and the patient returns to Grade 1 or less after discontinuation of treatment, administration of the compound is resumed at the clinically recommended dose for the patient.

In one embodiment, provided herein is a use of the compound or berusudil mesylate, the use comprising the steps of: administering said compound to said patient at a dose clinically recommended for said patient; monitoring said patient for adverse reactions; If the patient experiences at least one Grade 3 adverse reaction, discontinue administration of the compound to the patient; and Administration of the compound to the patient is resumed when at least one adverse reaction in the patient has returned to grade 1 or less.

In some embodiments, the patient's at least one adverse reaction has returned to Grade 0 after discontinuation of compound administration, and administration is resumed.

In some embodiments, at least one adverse reaction in the patient is Grade 4, wherein administration of the compound to the patient is permanently discontinued.

In some embodiments, the patient is monitored for adverse effects over a period of time; in some embodiments, the monitoring occurs at least monthly.

In some embodiments, provided herein is a clinically recommended dose of 200 mg per day for a patient before and after the patient experiences one or more treatment-related adverse effects.

In some embodiments, provided herein is a clinically recommended dose of 200 mg once daily with food for use in patients before and/or after one or more adverse effects.

In some embodiments, provided herein is a clinically recommended dose of 400 mg per day for use in a patient before and after the patient experiences one or more treatment-related adverse effects; in some embodiments, if the patient is also administered One or more PPIs or CYP3A inducers, the patient is administered this dose.

In some embodiments, provided herein are the use of a reduced (e.g., compared to when at least one adverse reaction occurs) in a patient after the patient has returned to a Grade 1 level or lower and administration of the compound is resumed. doses previously administered to patients) clinically recommended doses.

In some embodiments, provided herein are clinically recommended dosages for use in patients in the range of 200 mg per day to 400 mg per day.

In some embodiments, the patient is being treated for chronic graft-versus-host disease (cGVHD); in some embodiments, the patient has failed at least two lines of prior systemic therapy for cGVHD.

In some embodiments, provided herein is the assessment or grading of the severity of a patient's adverse effects using the Common Terminology Criteria for Adverse Events (CTCAE) (in some embodiments, CTCAE version 5.0).

In some embodiments, the at least one adverse reaction experienced by the patient is infection, weakness, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, gamma-glutamine Elevated transferases, lymphopenia, or hypertension.

In some embodiments, the at least one adverse reaction experienced by the patient is a viral infection, a bacterial infection, or an infection with an unknown pathogen.

In some embodiments, the at least one adverse reaction experienced by the patient is an infection by an unidentified pathogen, the infection by an unidentified pathogen being acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, meibomian gland infection inflammation, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory infection, bronchitis, sepsis or septic shock.

In some embodiments, the at least one adverse reaction experienced by the patient is weakness, edema, or fever.

In some embodiments, the at least one adverse reaction experienced by the patient is a gastrointestinal disorder; in some embodiments, the gastrointestinal disorder is nausea, diarrhea, abdominal pain, or dysphagia.

In some embodiments, the at least one adverse reaction experienced by the patient is a respiratory disorder, a thoracic disorder, or a mediastinal disorder; in some embodiments it is dyspnea, cough, or nasal congestion.

In some embodiments, the at least one adverse effect experienced by the patient is a vascular disorder; in some embodiments, bleeding or hypertension.

In some embodiments, the at least one adverse effect experienced by the patient is a musculoskeletal disorder or connective tissue disorder; in some embodiments, the musculoskeletal disorder or connective tissue disorder is musculoskeletal pain, muscle spasm, or joint pain.

In some embodiments, the at least one adverse effect experienced by the patient is a neurological disorder; in some embodiments, headache or migraine.

In some embodiments, the at least one adverse effect experienced by the patient is a metabolic disorder; in some embodiments, the metabolic disorder is decreased appetite, rash, or scrapie.

In some embodiments, the at least one adverse effect experienced by the patient is a metabolic disorder; in some embodiments, the metabolic disorder is decreased appetite; and in some embodiments, the patient experiences a cutaneous or subcutaneous disorder, such as Rash or scrapie.

In other embodiments, provided herein is a method for treating patients receiving a clinically recommended dose of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(prop-2-yl)acetamide or a pharmaceutically acceptable salt (compound) thereof for use in patients who experience one or more treatment-related adverse reactions, the method comprising: if the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 and the patient returns to Grade 1 or less after discontinuation of treatment, administration of the compound is resumed at the clinically recommended dose for the patient.

In some embodiments, methods provided herein include the patient experiencing at least one grade 3 adverse reaction, and when the patient's at least one adverse reaction has reverted to grade 1 or less, reverting to said The patient is administered the compound.

In some embodiments, methods provided herein include the patient experiencing at least one Grade 4 adverse reaction, and permanently discontinuing administration of the compound to the patient.

In the embodiments disclosed herein, including the uses and treatment methods provided herein, the clinically recommended dosage for the patient may range from 200 mg per day to 400 mg per day; in some embodiments, for the The clinically recommended dose for such a patient is 200 mg per day; in some embodiments, after the patient has returned to Level 1 or less and administration of the compound is resumed, the clinically recommended dose for the patient is ( a reduced dose compared to before the patient experienced adverse effects.

In some embodiments, the subject has undergone an allogeneic hematopoietic stem cell transplant, which is a congruent HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplant is haploidentical HSCT.

In some embodiments, berusudil treatment is continued based on patient tolerance until active cGVHD symptoms resolve or progress. The number and duration of treatment cycles are patient dependent. In some embodiments, berusudil is administered to the patient over one or more 28-day periods.

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

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

In some embodiments, the subject experiences improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences a decrease in LSS score of at least 7 points. In some embodiments, the subject experiences a decrease in LSS score of at least 10 points. In some embodiments, the improvement is maintained over at least two consecutive evaluations. In some embodiments, LSS scores are assessed at baseline and on Day 1 of each cycle starting on Day 1 of Cycle 2.

In some embodiments, the subject has chronic graft-versus-host disease and has failed one to three lines of systemic treatment for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed at least two lines of prior systemic treatment for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed two to five lines of prior systemic treatment for chronic graft-versus-host disease. In some embodiments, the subject has responded to at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten Three lines of prior systemic therapy for chronic graft-versus-host disease had failed.

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

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

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.

In some embodiments, the cGVHD is steroid refractory (SR) cGVHD. In some embodiments, the subject is refractory to the last line of treatment prior to berusudil treatment.

In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from the group consisting of prednisone, prednisolone, methylprednisolone, and budesonide. In some embodiments, the concomitant corticosteroid therapy is prednisone. In some embodiments, the dose of the concomitant corticosteroid therapy is reduced after at least 1 cycle of berusudil treatment. In some embodiments, after at least 1 cycle of berusudil treatment, the dose of the concomitant corticosteroid therapy is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, At least about 50%, at least about 60%, or at least about 70%. In some embodiments, after at least 1 cycle of berusudil treatment, the dose of concomitant corticosteroid therapy is reduced from about 10% to about 70%, from about 15% to about 65%, from about 20 % to about 60%, from about 30% to about 60%, from about 35% to about 60%, from about 40% to about 60%, or from about 45% to about 55%. In some embodiments, the concomitant corticosteroid therapy is discontinued after at least 1 cycle of berusudil treatment.

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

In some embodiments, the subject has at least 4 organs affected. In some embodiments, the subject has at least 3 organs affected. In some embodiments, the subject has at least 2 organs affected. berusudil tablets

In one embodiment, berusudil is formulated as a lozenge for oral administration. Begrusudil mesylate is a yellow powder that is nearly insoluble in water. Berusuudil tablets can be prepared for oral administration. Each lozenge contains 200 mg free base, equivalent to 242.5 mg berusudil mesylate. The tablets may also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silica, and magnesium stearate. The tablet film is composed of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and iron oxide yellow. Each 200 mg tablet is a light yellow, film-coated rectangular tablet debossed with "KDM" on one side and "200" on the other side. Store tablets at room temperature 20ºC to 25ºC (68°F to 77°F); excursions allowed from 15ºC to 30ºC (59°F to 86°F).   Overview

The following abbreviations may be helpful in considering the examples and descriptions in this article. Abbreviation AE adverse events AR adverse reactions AMS accelerator mass spectrometry alloHCT allogeneic hematopoietic cell transplantation BID twice daily (twice daily) BM marrow ikB chronic graft versus host disease CMV cytomegalovirus CR full response CTCAE Common Terminology Standards for Adverse Events DDI drug-drug interactions DOR reaction duration EOI end of infusion FFS No expiry time HLA human leukocyte antigen IST immunosuppressive therapy IV intravenously LSC liquid scintillation counting LSS Lee Symptom Scale NMT no more than ORR overall response rate OS overall survival PBSC peripheral blood stem cells PPI proton pump inhibitor PR partial reaction QOL quality of life SD standard deviation SR Steroid refractory TEAE Adverse events occurring during treatment TTNT Time until next treatment QD daily; every day Example Example 1 : Subject Eligibility for a Phase IIa Labeled Open-Label Dose-Finding Study of Berusudil

Eligible patients are allogeneic bone marrow transplantation or allogeneic hematopoietic cell transplantation (alloHCT) recipients, age ≥18 years, persistent cGVHD after one to three lines of prior systemic therapy, and the patient is receiving Corticosteroid treatment with or without calcineurin inhibitors and/or concurrent extracorporeal photopheresis. Continue berusudil until progression of cGVHD or unacceptable toxicity. Study design and treatment

Patients were enrolled into three sequential cohorts: Cohort One received berusudil 200 mg once daily; Cohort Two received berusudil 200 mg twice daily (twice a day); and Cohort Two Three received berusudil 400 mg once daily. (Figure 1) Prior to enrollment in subsequent cohorts, the safety profile for each prior cohort was analyzed after eight patients reached two months of treatment to ensure there were no safety signals. The 2-month time frame was chosen because all clinically significant berusudil-related adverse events (AEs) to date have occurred within ≤36 days of starting berusudil. No safety concerns were identified, allowing planned dose escalation.

Begrusudil was administered orally in 28-day cycles until disease progression or unacceptable toxicity. Progression was defined according to the 2014 NIH cGVHD consensus criteria. Long-term follow-up will be conducted every 8 weeks until the end of the study. After 4 weeks of berusudil therapy, corticosteroid therapy could be tapered at the discretion of the investigator. Screening occurs within 28 days of the first study dose. Response was initially assessed after two cycles; however, this was modified to assess response on Day 1 of each cycle beginning with Day 1 of Cycle 2. study endpoint

The primary efficacy endpoint was ORR at any time point, defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) per 2014 NIH cGVHD consensus criteria. Only response assessments after berusudil but before the subsequent line of therapy were included in the ORR. All responses were assessed by the researchers. Secondary endpoints include PR or CR, duration of response (DOR), organ system response rate, LSS score, corticosteroid dose reduction, time to next treatment (TTNT), failure-free survival (FFS), and overall survival. Number and percentage of patients with steroid-dependent cGVHD with optimal response in terms of OS (OS). The safety and tolerability of berusudil was evaluated through AE assessment, physical examination, vital sign measurements, laboratory tests, and electrocardiograms throughout the study. Pre-dose samples were collected for pharmacodynamic (PD) evaluation, which included assessment of immune cell subtypes in peripheral blood. Statistical analysis

With a sample size of 16 patients per cohort, there was a >90% probability that ≥1 study participant would experience an AE with a potential rate of ≥14% in the study, as derived from probability calculations for the assumed sample size. Assuming an optimal ORR of 25% (which was determined to be clinically meaningful), the study would be expected to have approximately a 90% probability of showing a response in ≥ 2 patients per cohort. This study was unable to show significant differences in efficacy, AE or PD analysis between groups. The primary analysis was performed using the safety population, defined as enrolled patients who received ≥ 1 dose of study drug. The Clopper-Pearson (exact) method was used to construct two-sided 95% CIs for ORR. Estimates of FFS and OS were calculated using the Kaplan-Meier (KM) method.   Result subjects

A total of fifty-four patients were enrolled in the sequential cohorts: 17 patients in cohort 1, 16 patients in cohort 2, and 21 patients in cohort 3 (Fig. 1). As of the data cutoff date for this analysis, the median duration of follow-up was as follows: 36 months for Cohort 1, 32 months for Cohort 2, and 24 months for Cohort 3. The overall median duration of follow-up was 29 months (range: 1-39 months).

Demographic and baseline characteristics were generally comparable between groups (Tables 1, 2). Median age at baseline was 52 years (range: 20-75 years). Cohort 1 had the longest median time from cGVHD diagnosis to treatment, at 26 months (compared with 18 months in cohort 2 and 16 months in cohort 3, respectively). According to the researchers' assessment, 78% of the patients had severe cGVHD. Half of the patients had ≥ 4 organ involvement, and compared with patients with pulmonary involvement in cohort 1 (24%) and cohort 2 (19%), patients with pulmonary involvement in cohort 3 (48%) )More. The median baseline corticosteroid dose (mg/kg/d, prednisone equivalent) in each group was 0.22, 0.19, and 0.17, respectively. Patients in Cohort 1 had received a median of three lines of prior therapy, whereas patients in Cohorts 2 and 3 had received a median of two lines of prior therapy. Seventy-three percent (35 of 48, data for six patients were unavailable) of patients were refractory to their last line of therapy before study enrollment. The CONSORT diagram (Fig. 1) shows the patient arrangement. Median duration of treatment was as follows: 8.5 months for Cohort 1 (range: 2-39 months), 7.5 months for Cohort 2 (range: 1-35 months), and 9 months for Cohort 3 (Range: 1-29 months). 28% of patients had received berusudil for >18 months. Reasons for discontinuation of berusudil included: progression of cGVHD (n = 22), patient voluntary withdrawal (n = 8), recurrence of underlying disease (n = 7), investigator decision (n = 3), AE considered potentially related treatment-related (n = 3) and death (n = 2). LTFU means long-term follow-up.

Table 1. Baseline Demographic and Clinical Characteristics Features Cohort 1 KD025 200 mg once daily ( n = 17 ) Cohort 2 KD025 200 mg twice daily ( n = 16 ) Cohort 3 KD025 400 mg once daily ( n = 21 ) Total ( N=54 ) age, median, years (range) 50 (20-63) 55 (30-75) 46 (25-75) 52 (20-75) Male, n (%) 13 (77) 9 (56) 12 (57) 34 (63) Indications for transplantation, n ( % ) AML 3 (18) 8 (50) 9 (43) 20 (37) ALL 3 (18) 2 (13) 3 (14) 8 (15) MDS 2 (12) 2 (13) 2 (10) 6 (11) non-hodgkin lymphoma 3 (18) 0 2 (10) 5 (9) Other non-Hodgkin lymphomas 0 2 (13) 1 (5) 3 (6) other 6 (35) 2 (13) 4 (19) 12 (22) Treatment intensity, n ( % ) ^a Myeloablative 9 (53) 5 (31) 10 (48) 24 (44) nonmyeloablative 7 (41) 8 (50) 10 (48) 25 (46) unknown 1 (6) 3 (19) 1 (5) 5 (9) Stem cell source, n (%) ^a peripheral blood 15 (88) 15 (94) 18 (86) 48 (89) marrow 0 0 1 (5) 1 (2) cord blood 1 (6) 0 0 1 (2) unknown 1 (6) 1 (6) 2 (10) 4 (7) HLA match of donor or recipient , n ( % ) ^a Congruent 14 (82) 13 (81) 18 (86) 45 (83) Partially consistent 3 (18) 3 (19) 2 (10) 8 (15) unknown 0 0 1 (5) 1 (2) CMV- positive serology status (donor / recipient), n ( % ) +/+ 4 (24) 4 (25) 6 (29) 14 (26) +/- 1 (6) 3 (19) 0 4 (7) -/+ 6 (35) 4 (25) 6 (29) 16 (30) -/- 3 (18) 4 (25) 6 (29) 13 (24) At least 1 unknown 3 (18) 1 (6) 3 (14) 7 (13) Median time from cGVHD diagnosis to enrollment, months (range) 26.4 (0.0-130.7) 18.0 (1.0-69.9) 16.0 (1.0-161.9) 20.0 (0.0-161.9) cGVHD severity, n (%) ^b Severe 12 (71) 14 (88) 16 (76) 42 (78) Moderate 5 (29) 2 (13) 4 (19) 11 (20) Mild 0 0 1 (5) 1 (2) organ involvement Median number of organs involved, n (range) 3 (2-6) 4 (1-7) 3 (2-7) 3 (2-7) ≥ 4 organs involved, n (%) 8 (47) 10 (63) 9 (43) 27 (50) Eye, n (%) 14 (82) 11 (69) 17 (81) 42 (78) Skin, n (%) 13 (77) 12 (75) 15 (71) 40 (74) Mouth, n (%) 13 (77) 11 (69) 11 (69) 35 (65) Joints and/or fascia, n (%) 11 (65) 11 (69) 12 (57) 34 (63) Lung, n (%) 4 (24) 3 (19) 10 (48) 17 (32) Upper gastrointestinal tract, n (%) 2 (12) 4 (25) 2 (10) 8 (15) Esophagus, n (%) 2 (12) 0 4 (19) 6 (11) Lower gastrointestinal tract, n (%) 1 (6) 2 (13) 1 (5) 4 (7) Liver, n (%) 0 2 (13) 0 twenty four) Karnofsky median performance status, n ( % ) ≤ 50 0 0 1 (5) 1 (2) 60-70 4 (24) 4 (25) 6 (29) 14 (26) 80-90 13 (77) 12 (75) 14 (67) 39 (72) 100 0 0 0 0 Prior therapy characteristics Median previous LOT, n 3 2 2 3 ≥ 2 previous LOTs, n (%) 15 (88) 9 (56) 14 (67) 38 (70) Refractory to previous LOT, n (%) ^a 11/15 (73) 9/13 (69) 15/20 (75) 35/48 (73) Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; cGVHD, chronic graft-versus-host disease; CMV, cytomegalovirus; LOT, line of therapy; MDS, myelodysplastic syndrome syndrome. The denominator of ^a excludes patients with unknown status (six patients in total). ^bDisease severity was determined using the Physician-Reported Global cGVHD Activity Assessment Form.

Table 2. Additional Baseline Demographics Features Cohort 1 KD025 200 mg once daily ( n = 17 ) Cohort 2 KD025 200 mg twice daily ( n = 16 ) Cohort 3 KD025 400 mg once daily ( n = 21 ) Total ( N=54 ) Type of prior systemic cGVHD therapy, number ( % ) CS 17 (100) 16 (100) 21 (100) 54 (100) tacrolimus 8 (47) 7 (44) 11 (52) 26 (48) Sirolimus 10 (59) 8 (50) 6 (29) 24 (44) Rituximab 8 (47) 3 (19) 5 (24) 16 (30) ECP 5 (29) 4 (25) 6 (29) 15 (28) MMF 4 (24) 4 (25) 4 (19) 12 (22) cyclosporine 3 (18) 0 2 (10) 5 (9) ibrutinib 1 (6) 0 3 (14) 4 (7) MTX 1 (6) 2 (13) 0 3 (6) Isazomi 1 (6) 1 (6) 0 twenty four) ATG 1 (6) 0 0 1 (2) Ofatumumab 0 0 1 (5) 1 (2) imatinib 1 (6) 0 0 1 (2) ruxolitinib 0 0 1 (5) 1 (2) Types of systemic cGVHD therapy continued CS, quantity (%) 17 (100) 16 (100) 21 (100) 54 (100) Mean prednisone equivalent dose at enrollment, mg/kg/d 0.22 0.24 0.28 0.25 CNI, quantity (%) 7 (41) 6 (38) 12 (57) 25 (46) ECP, quantity (%) 4 (24) 4 (25) 4 (19) 12 (22) Abbreviations: ATG, antithymocyte globulin; cGVHD, chronic graft-versus-host disease; CNI, calcineurin inhibitor; CS, corticosteroid; ECP, extracorporeal photopheresis; MMF, mycophenolate mofetil; MTX, methotrexate. effect

Overall response rate. In the safety population (N = 54), the ORR (95% CI) was 65% (51% to 77%). The ORR (95% CI) was similar across cohorts: 65% (38% to 86%) for cohort 1, 69% (41% to 89%) for cohort 2, and 62% for cohort 3 ( 38% to 82%) (Table 3). Efficacy data for subgroups and secondary endpoints are presented as pooled data for each group. Table 3. Efficacy and CS reduction Features Cohort 1 KD025 200 mg once daily (n = 17) Cohort 2 KD025 200 mg twice daily (n = 16) Cohort 3 KD025 400 mg once daily (n = 21) Total (N = 54) ORR, % (95% CI) 65 (38 to 86) 69 (41 to 89) 62 (38 to 82) 65 (51 to 77) Subgroup analysis, n/N(% , 95% CI) ≤ 2 previous LOTs 10/15(67,38 to 88) 5/8(63,25 to 92) 8/12 (67, 35 to 90) 23/35(66,48 to 81) Refractory to previous LOT 7/11 (64, 31 to 89) 6/9 (67, 30 to 93) 9/15 (60, 32 to 94) 22/35(63,45 to 79) ≤ 4 organs involved 4/8(50,16 to 84) 8/10(80,44 to 98) 7/9 (78, 40 to 97) 19/27(70,50 to 86) Severe cGVHD ^a 8/12 (67, 35 to 90) 9/14 (64, 35 to 87) 8/16(50,25 to 75) 25/42(60,43 to 74) Clinically significant improvement (LSS) ^b Overall, n(%, 95% CI) 9(53,28 to 77) 7 (44, 20 to 70) 11(52,30 to 74) 27 (50, 36 to 64) Responders, n/N (%, 95% CI) 8/11 (73, 39 to 94) 3/11 (27, 6 to 61) 9/13 (69, 39 to 91) 20/35(57,39 to 74) Non-responders, n/N (%, 95% CI) 1/6 (17, 0.4 to 64) 4/5(80,28 to 99) 2/8(25,3 to 65) 7/19(37,16 to 62) Proportional to CS reduction, n (%, 95% CI) 13 (76, 50 to 93) 9 (56, 30 to 80) 14 (67, 43 to 85) 36 (67, 53 to 79) Mean percent change in CS dose from baseline, % Overall -50 -36 -47 -45 responder -63 -36 -63 -55 non-responder -26 -37 -19 -26 CS discontinued, n (%, 95% CI) 4 (24, 7 to 50) 2(13,2 to 38) 4 (19, 5 to 42) 10 (19, 9 to 31) Abbreviations: cGVHD, chronic graft-versus-host disease; CS, corticosteroids; LOT, line of therapy; LSS, Lee Symptom Scale; ORR, overall response rate. ^aDisease severity was determined using the Physician-Reported Global cGVHD Activity Assessment Form. ^b Changes in cGVHD symptom burden were measured by LSS. Clinically meaningful improvement in symptom burden was defined as a reduction in the LSS summary score of at least seven points.

Responses were achieved across key subgroups, including an ORR of 60% (25 of 42) in patients with severe cGVHD and an ORR of 66% in patients who had received ≥ 2 prior lines of systemic therapy (23 of 35), the ORR was 63% (22 of 35) in patients whose last line of therapy before enrollment was refractory, and ≥4 organ involvement The ORR was 70% (19 of 27) (Figure 2). All responses at the patient level were PR; however, organ-specific analysis showed CR in all affected organs except lung, where the best response was PR (Figure 3A and Figure 3B). Figure 3B shows the best organ response, with three partial responses in the lung at a dose of 400 mg once daily.

Responses were generally rapid, with >75% of all responses obtained at the first response assessment at week 8 (Figure 4A). Four of 35 reactions occurred after 24 weeks of berusudil treatment, with late organ reactions observed in the lungs, joints and/or fascia, and eyes (Figure 4B).

Among responders, the median K-MDOR across cohorts was 35 weeks (Fig. 5A). For patients who had received ≥ 2 prior lines of systemic therapy, the median K-MDOR was 38 weeks.

Time until next treatment. The median duration of K-MTTNT was 14 months (Figure 5B). Subsequent systemic cGVHD therapies include tacrolimus, sirolimus, ibrutinib, ruxolitinib, extracorporeal photopheresis, and mycophenolate mofetil.

FFS and OS . FFS rates (95% CI) at 6, 12, and 24 months were 76% (62% to 85%), 47% (33% to 60%), and 33% (21% to 46%), respectively (Figure 5C). FFS was defined as the time from the first dose of berusudil to the failure event. Reasons for failure included initiation of new systemic therapy (n = 27), recurrence of underlying disease (n = 7), and death (n = 2). The important endpoint was the percentage of patients who achieved FFS with a response (CR/PR) at 12 months, which was 24% in this study. The OS rates (95% CI) at 12 and 24 months were 91% (79% to 96%) and 82% (69% to 90%), respectively (Fig. 5D).

QOL assessment. Clinically meaningful improvement in LSS scores during berusudil treatment, defined as a ≥7-point reduction in LSS summary score, was observed in 50% of patients. Thirty-five percent of all patients (37% of responders and 32% of non-responders) reported clinically meaningful improvements in LSS scores at consecutive assessments.

Corticosteroid moderation. During berusudil treatment, 67% of patients had their corticosteroid dose reduced, and 19% discontinued corticosteroid therapy entirely. The average corticosteroid dose was reduced by 45%. The median time to discontinuation of corticosteroid therapy was 29 weeks (range: 8-77 weeks). Responders had a mean corticosteroid dose reduction of 55%, whereas non-responders had a 26% reduction in corticosteroid dose (Table 3). safety

Berusudil was well tolerated and berusudil-exposed patients were >56 years of age. The median relative dose intensity was 98% overall. The percentages of patients with relative dose intensity >95% for each cohort were 77%, 63%, and 71%, respectively. Dose reductions were performed in 9% of patients and the median duration of reductions was 97 days (range: 21-859 days). Dose interruptions occurred in 41% of patients, and the median duration of interruption was 10 days (range: 2-39 days).

AEs were consistent with those expected in a population of patients with advanced cGVHD receiving corticosteroid therapy. AEs reported in ≥ 20% of patients were: upper respiratory tract infection (46%), diarrhea (33%), fatigue (33%), nausea (33%), elevated liver function tests (33%), dyspnea (30%), headache (24%), peripheral edema (24%), cough (22%), and hypertension (20%) (Table 4). Serious AEs were reported in 43% of patients, and AEs reported in >1% of patients were: dyspnea (7%), pulmonary infection (6%), hypoxia (4%), and influenza-like illness (4 %). AEs were grade ≥ 3 in 61% of patients, with the most common being dyspnea (13%), elevated liver function tests (7%), hyperglycemia (7%), and hypoxia (7%) (Table 4) . Cytopenia of grade ≥ 3 was reported in two patients (4%). These occurred when the underlying malignancy recurred in patients who had maintained normal blood counts during their berusudil treatment.

Table 4. Security overview AE , quantity ( % ) Cohort 1 KD025 200 mg once daily ( n = 17 ) Cohort 2 KD025 200 mg twice daily ( n = 16 ) Cohort 3 KD025 400 mg once daily ( n = 21 ) Total ( N=54 ) Any AE 17 (100) 16 (100) 16 (100) 53 (98) ≥ Grade 3 AE 9 (53) 10 (63) 14 (67) 33 (61) Drug-related AEs 8 (47) 8 (50) 14 (67) 30 (56) SAE 5 (29) 6 (38) 12 (57) 23 (43) die 0 0 2 (10) twenty four) Drug-Related SAEs 0 0 0 0 All grades in ≥ 20% URI 9 (53) 9 (56) 7 (33) 25 (46) Diarrhea 6 (35) 5 (31) 7 (33) 18 (33) Nausea 6 (35) 4 (25) 8 (38) 18 (33) fatigue 6 (35) 3 (19) 9 (43) 18 (33) Elevated ALT/AST 11 (65) 5 (31) 2 (10) 18 (33) difficulty breathing 3 (18) 6 (38) 7 (33) 16 (30) peripheral edema 3 (18) 4 (25) 6 (29) 13 (24) headache 4 (24) 3 (19) 6 (29) 13 (24) cough 1 (6) 4 (25) 7 (33) 12 (22) high blood pressure 5 (29) 2 (13) 4 (19) 11 (20) ≥Level 3 in ≥5% difficulty breathing 1 (6) 2 (13) 4 (19) 7 (13) lung infection or pneumonia 1 (6) 2 (13) 2 (10) 5 (9) Elevated ALT/AST 2 (12) 2 (13) 0 4 (7) hyperglycemia 2 (12) 0 2 (10) 4 (7) hypoxia 1 (6) 1 (6) 2 (10) 4 (7) anemia 2 (12) 1 (6) 0 3 (6) Abbreviations: AE, adverse event; SAE, serious adverse event; URI, upper respiratory tract infection.

No cases of cytomegalovirus (CMV) infection or reactivation have been reported with begrusudil. Three patients discontinued berusudil due to potential drug-related AEs (Cohort 1: diarrhea and headache; Cohort 3: fatigue). Four patients (all in Cohort 3) died during the study (secondary to leukemia relapse, pneumonia (unknown pathogen), cardiac arrest, and progression of cGVHD), and none of the deaths were attributable to berusudil. Regarding observed AEs, there was no dose response. PD analysis

In an exploratory PD analysis of peripheral blood mononuclear cells in each cohort, the percentage of CD41 Tregs showed an increasing trend at the early end of cycle 2 day 1 of berusudil treatment. A concurrent decrease in Th17 cells was also observed. Th17 cells continue to decrease until C4D1 to C6D25. The percentage of CD41 Tregs continued to increase up to C4D1 and C7D1, as shown in (Figure 6). Due to the small sample size, limited information on steroid dosage was available, precluding any statistical analysis.

This study is the first to evaluate berusudil treatment in human patients with cGVHD. All phenotypes of cGVHD are included, with no requirement for inflammatory or fibrotic manifestations. Patients with advanced multiorgan cGVHD treated with berusudil achieved a 65% ORR with improved QOL, reduced corticosteroid doses, and limited toxicity. In the case of relatively small sample size, there was no difference in ORR between groups.

The response rates achieved with berusudil were meaningful and consistent across subgroups, including patients with severe cGVHD, those who had received ≥ 2 prior lines of systemic therapy, those who had The last line of therapy before enrollment was for refractory patients and patients with ≥ 4 organ involvement. In patients with non-severe cGVHD, the ORR was 83%, indicating the need for further research into how berusudil may benefit patients earlier in their disease. All responses at the patient level were PRs; no CRs were achieved. However, given the severity and extent of fibrotic cGVHD manifestations in this patient population, CR is not expected in all organs, as some advanced fibrotic changes in the eyes, mouth, lungs, or joints and/or fascia may be irreversible. . CR was observed in all organs except the lungs, where PR was obtained.

Berusudil response kinetics indicate that most responders respond rapidly within 8 weeks of receiving berusudil. Berusudil was well tolerated, and the median DOR among all responders was 35 weeks. Adherence to therapy depends on the safety and long-term tolerability profile of the intervention. The median duration of treatment was 8 months (range: 1-39 months). 28% of patients remained on berusudil for >18 months. No CMV infections or reactivations were reported, although 57% of patients were CMV seropositive. The incidence of TEAEs and grade ≥3 TEAEs was similar between groups. The combination of well-tolerated therapy and efficacy in inducing response translated into a 2-year OS rate of 82%, a median TTNT of 14 months, and 76% and 47% at 6 and 12 months, respectively. FFS rate.

In prospective studies conducted by the cGVHD Consortium, the 12-month FFS for response (CR/PR) after first-line therapy was 12% to 15%. (Martin PJ, Storer BE, Inamoto Y, et al: An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease. Blood 130:360-367, 2017) In this study (1-3 prior therapies line), the 12-month FFS rate with response was 24%.

In the present study, berusuudil therapy was associated with corticosteroid moderation. Current treatment paradigms rely on corticosteroids as the mainstay of therapy; however, associated long-term toxicities force the use of the lowest possible doses or discontinuation whenever possible. The use of corticosteroid therapy is closely related to quality of life because the side effect profile of corticosteroid therapy contributes to patient symptom burden. Reductions in corticosteroid dose were observed in both responders and non-responders to begrusudil. Approximately 20% of patients are able to discontinue corticosteroid therapy during berusudil treatment. Even in the absence of an NIH-defined response, patients experienced clinical benefit, as demonstrated by LSS score improvement or corticosteroid dose reduction.

In this study, responses were obtained in patients with signs of fibrosis in the lungs, joints and/or fascia, and eyes. In some cases, these responses were observed after 24 weeks of treatment, further emphasizing the benefit of maintaining effective therapy to achieve clinical benefit, particularly in patients with difficult-to-treat disease. Because the lower berusudil dose of 200-mg once daily was equally safe and effective, this dose was further compared to the 200-mg twice-daily dose to evaluate dosage recommendations in the study described in Example 2 . Example 2 : A Phase II Randomized Study of Berusudil This Example 2 study was a study of berusudil mesylate in patients who had received 2 to 5 prior lines of systemic therapy and required additional therapy. Randomized, labeled, open-label, multicenter study in patients with chronic GVHD. If the patient's platelets are < 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 FEV1 ≤ 39%, the patients were excluded from the study. Sixty-six patients were treated with 200 mg of REZUROCK taken orally once daily. Concomitant treatment with supportive care therapy for chronic GVHD is allowed. Concomitant treatment with GVHD prophylaxis and standard-of-care systemic chronic GVHD therapy was allowed as long as subjects were taking stable doses for at least 2 weeks prior to the study. Initiation of new systemic chronic GVHD therapies while on study was not permitted. Subject eligibility

Eligible subjects were allogeneic hematopoietic cell transplant recipients, age ≥12 years, with persistent cGVHD after 2 to 5 prior lines of systemic therapy. Subjects were required to be on stable corticosteroid therapy 2 weeks before screening and to have a Karnofsky or Lansky performance status scale score ≥ 60. Some concurrent immunosuppressive drug therapy is allowed because drug-drug interactions are not expected. If the subject has recurrence of their underlying malignancy; forced expiratory volume in 1 second (FEV1) ≤ 39% or NIH lung symptom score of 3; suffers from post-transplant lymphoproliferative disorder; hepatic transaminase (aspartate Transaminase [AST] or alanine aminotransferase [ALT]) > 3 times the upper limit of normal; total bilirubin > 1.5 times the upper limit of normal for any reason; or currently receiving ibrutinib will They exclude. Study design and treatment

Eligibility screening takes place within 14 days of Day 1 of Cycle 1. Treatment consisting of berusudil 200 mg once daily (Group A) or 200 mg twice daily (Group B) was administered orally to subjects with cGVHD (Figure 7). Randomization was stratified (1:1) by cGVHD severity and prior ibrutinib exposure. Berusuudil was administered continuously during 28-day treatment cycles until clinically significant progression of cGVHD or unacceptable toxicity. Progression was defined using organ-specific cGVHD response assessment, as defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD (referred to as the 2014 NIH cGVHD Consensus Criteria) . After taking berusudil for ≥ 2 weeks, corticosteroid therapy may be tapered at the discretion of the investigator. If in the investigator's judgment there is no evidence of clinical benefit, subjects who do not achieve a response after 12 cycles of berusudil treatment should be withdrawn. study endpoint

The primary endpoint was optimal ORR at any time, defined as the proportion of subjects achieving a complete response (CR) or partial response (PR) according to 2014 NIH consensus criteria. All responses were assessed by study site researchers. Secondary endpoints included duration of response (DOR), time to response, change in LSS summary score, failure-free survival (FFS), corticosteroid dose reduction, and overall survival (OS). DOR is the time from initial PR or CR until documented progression of cGVHD from best response, time from initial response to initiation of additional systemic cGVHD therapy, or death. The 7-day LSS summary score was calculated based on the developers' recommendations and compared to the score from baseline; an improvement of ≥7 points was considered clinically meaningful. FFS was defined as the interval between initiation of berusudil and the addition of new cGVHD therapy, relapse, or NRM. The safety of berusudil was evaluated by adverse event (AE) and serious AE (SAE) assessment. Relative dose intensity (RDI) is used as a surrogate measure of drug tolerance and is defined as actual dose intensity/planned dose intensity, where dose intensity is defined as the cumulative dose (mg/d) over the duration of exposure. Actual dose intensity is the sum of the actual doses received over the duration of exposure and includes dose reductions and/or interruptions. Statistical analysis

The sample size is based on the primary efficacy endpoint (best ORR), an interim analysis is planned, and the target ORR is 55%. With a target sample size of 63 subjects per treatment arm and an estimated dropout rate of 10%, each treatment arm is estimated to have approximately 90% power to produce a 95% confidence interval (CI) for the ORR, excluding 30 % as the lower boundary. Based on consultation with key opinion leaders, an ORR of 30% is considered clinically meaningful in this heavily pre-treated population with cGVHD and unmet medical need. For the primary endpoint of optimal ORR, multiplicity adjustment was performed using the Hochberg procedure. The primary analysis was conducted using a modified intention-to-treat (mITT) population (defined as randomized subjects who received ≥ 1 dose of berusudil). After enrolling 126 subjects in the mITT population, interim analyses, primary analyses, and follow-up analyzes are planned at approximately 2, 6, and 12 months. Here, we report data from the 12-month analysis. CI was calculated using the Clopper-Pearson interval (exact) method.   Results Subject Characteristics

A total of 132 subjects were enrolled in the clinical study. Overall, baseline demographic and clinical characteristics were comparable across treatment groups (Table 5). At the time of enrollment, the median subject age was 56 years (range: 21-77). The median time from cGVHD diagnosis to enrollment was 28 months (range: 2-162). At screening, 31% of subjects had moderate cGVHD and 67% had severe cGVHD based on 2014 NIH consensus criteria; 52% had ≥ 4 organ involvement. At baseline, 36% of subjects had lung involvement, and 38% of these subjects had an NIH lung symptom score of 2. Subjects had been previously treated with a median of 3 lines of systemic therapy. 72% of subjects (n = 79) had cGVHD refractory to their last line of systemic therapy, 34% (n = 45) had previously received ibrutinib, and 29% (n = 38) had previously received ruxolitinib, and 72% (n = 95) had received ≥ 3 prior lines of therapy. The median baseline corticosteroid dose was 0.2 mg/kg (range 0.03-1.07) prednisone equivalent per day. The mean baseline corticosteroid dose was 0.25 mg/kg (range 0.03-1.07) prednisone equivalent per day.

Table 5. Baseline Demographic and Clinical Characteristics Features Berusudil 200 mg once daily ( n = 66 ) ** Begrusudil 200 mg twice daily ( n = 66 ) Total ( N=132 ) age, median (range), y 53 (21-77) 57 (21-77) 56 (21-77) male 42 (64) 33 (50) 75 (57) Indications for transplantation AML 28 (42) 25 (38) 53 (40) ALL 7 (11) 12 (18) 19 (14) MDS 8 (12) 5 (8) 13 (10) CML 5 (8) 3 (5) 8 (6) myelofibrosis 3 (5) twenty three) 5 (4) CLL twenty three) twenty three) 4 (3) Non-Hodgkin lymphoma and DLBCL 3 (5) 4 (7) 7 (5) other 7 (11) 11 (17) 18 (14) Processing intensity Myeloablative 41 (62) 42 (64) 83 (63) nonmyeloablative 22 (33) 22 (33) 44 (33) unknown 3 (5) twenty three) 5 (4) stem cell source peripheral blood 57 (86) 63 (96) 120 (91) marrow 6 (9) 3 (5) 9 (7) cord blood 0 0 0 unknown 3 (5) 0 3 (2) Donor/recipient HLA match Congruent 57 (86) 62 (94) 119 (90) Partially consistent 8 (12) 3 (5) 11 (8) unknown 0 1 (2) 1 (1) Missing 1 (2) 0 1 (1) CMV positive serological status (donor/recipient) + / + 23 (35) 16 (24) 39 (30) i) + / - 3 (5) 8 (12) 11 (8) ii) - /+- 18 (27) 17 (26) 35 (27) iii) - / - 13 (20) 16 (24) 29 (22) 1 unknown 3 (5) 3 (5) 6 (5) unknown/unknown 5 (8) 6 (9) 11 (8) Missing 1 (2) 0 1 (1) iv) Time from cGVHD diagnosis to enrollment, median (range), months 25 (2-162) 30 (4-144) 29 (2-162) NIH cGVHD Severity* Severe 46 (70) 43 (65) 89 (67) Moderate 18 (27) 23 (35) 41 (31) Mild twenty three) 0 twenty two) organ involvement Number of organs involved, median (range) 4 (0-7) 4 (2-7) 4 (0-7) ≥ 4 organs involved 33 (50) 35 (53) 68 (52) skin 55 (83) 55 (83) 110 (83) joints/fascia 51 (77) 49 (74) 100 (76) Eye 48 (73) 49 (74) 97 (74) Mouth 30 (46) 42 (64) 42 (64) lung 24 (36) 23 (35) 47 (36) esophagus 19 (29) 12 (18) 31 (24) upper gastrointestinal tract 13 (20) 10 (15) 23 (17) lower gastrointestinal tract 6 (9) 7 (11) 13 (10) liver 9 (14) 4 (6) 13 (10) Baseline overall severity rating 0 1 (2) 0 1 (1) 1 0 0 0 2 twenty three) 1 (2) 3 (2) 3 3 (5) twenty three) 5 (4) 4 8 (12) 3 (5) 11 (8) 5 6 (9) 8 (12) 14 (11) 6 12 (18) 14 (21) 26 (20) 7 11 (17) 20 (30) 31 (24) 8 19 (29) 14 (21) 33 (25) 9 4 (6) 3 (5) 7 (5) 10 0 1 (2) 1 (1) Karnofsky median physical status 60-70 10 (15) 19 (29) 29 (22) 80-90 52 (79) 43 (65) 95 (72) 100 4 (6) 4 (6) 8 (6) Prior therapy characteristics Median previous LOT, n 3 4 3 2 previous LOTs 23 (35) 14 (21) 37 (28) 3 previous LOTs 13 (20) 17 (26) 30 (23) 4 previous LOTs 15 (23) 14 (21) 29 (22) 5 previous LOTs 14 (21) 19 (29) 33 (25) ≥ 6 previous LOTs 1 (2) twenty three) 3 (2) Refractory to previous LOT 44 (79) 35 (65) 79 (72) Type of previous systemic cGVHD therapy CS (prednisone) 65 (99) 65 (99) 130 (99) tacrolimus 40 (61) 42 (64) 82 (62) ECP 31 (47) 32 (49) 63 (48) Sirolimus 29 (44) 33 (50) 62 (47) ibrutinib 22 (33) 23 (35) 45 (34) ruxolitinib 20 (30) 18 (27) 38 (29) MMF 18 (27) 15 (23) 33 (25) Rituximab 15 (23) 13 (20) 28 (21) MTX 3 (5) 3 (5) 6 (5) cyclosporine 4 (6) 3 (5) 5 (4) imatinib 3 (5) 1 (2) 4 (3) Isazomi 0 1 (2) 1 (1) Ofatumumab 0 1 (2) 1 (1) Type of concomitant systemic cGVHD therapy † CS 65 (99) 66 (100) 131 (99) CNI 24 (36) 25 (38) 49 (37) ECP 17 (26) 22 (33) 39 (30) Sirolimus 17 (26) 18 (27) 35 (27) MMF 11 (17) twenty three) 13 (10) imatinib 1 (2) 1 (2) twenty two) Rituximab 1 (2) 0 1 (1) ruxolitinib 1 (2) 0 1 (1) Other systemic cGVHD therapies 9 (14) 13 (20) 22 (17) Prednisone equivalent dose at entry, median (range), mg/kg/d 0.20 (0.03-0.95) 0.20 (0.03-1.07) 0.20 (0.03-1.07) Unless otherwise noted, data are n (%). Due to rounding, percentages may not add to 100%. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; DLBCL, diffuse large B-cell lymphoma; GI, gastrointestinal; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; MTX, methotrexate. *Disease severity was determined using the NIH Global cGVHD Severity Score. †Classified as concomitant systemic cGVHD medication on Cycle 1 Day 1. ** One subject was determined to be unevaluable due to the absence of qualifying symptoms of cGVHD at baseline; therefore, the plot in Table 5 can be adjusted accordingly.

The CONSORT plot (Fig. 7) shows the allocation of subjects. The median duration of treatment was 10 months (range: 0.4-22.0), and the median follow-up was 14 months (range: 1-22). 44% of subjects had received treatment for ≥ 12 months. At the time of data analysis, 37% of subjects continued to receive berusudil. Reasons for discontinuation included: cGVHD progression (n = 21), voluntary withdrawal (n = 13), AE (n = 16), physician decision (n = 11), underlying malignancy progression (n = 5), due to underlying malignancy or death due to disease progression (n = 4), other (n = 7), and nonadherence to study medication (n = 3). effect

The best ORRs for berusudil 200 mg once daily and 200 mg twice daily were 74% (95% CI, 62-84) and 77% (95% CI, 65-87), respectively (Table 6). High ORR (61%-85%) was observed in all subgroups (Figure 8). Reactions from each group were pooled unless otherwise stated. The efficacy of berusudil was maintained regardless of prior ibrutinib therapy (n = 46) or ruxolitinib therapy (n = 38). The ORR in the subcohort with prior ruxolitinib therapy was 68% (95% CI, 51-83). The ORR (95% CI) in the subcohort with prior ibrutinib therapy was 74% (95% CI, 59-86).

Table 6. Efficacy Endpoints for Two Groups Within the mITT Population Efficacy endpoint: Begrusudil, 200 mg once daily ( n = 66 ) ** Begrusudil, 200 mg twice daily ( n = 66 ) Total ( N=132 ) ORR 49 (74) 51 (77) 100 (76) 95%Cl 62-84 65-87 68-83 ORR of response within 6 months of treatment 47 (71) 48 (73) 95 (72) 95%Cl 59-82 60-83 64-80 CR twenty three) 1 (2) 3 (2) PR 45 (68) 47 (71) 92 (70) ORR of response within 12 months of treatment 49 (74) 50 (76) 99 (75) 95%Cl 62-84 64-86 67-82 CR 4 (6) twenty three) 6 (5) PR 45 (68) 48 (73) 93 (71) Clinically significant improvement from baseline ( LSS ) * Overall 39 (59) 41 (62) 80 (61) Responders, n/N (%) 34/49 (69) 36/51 (71) 70/100 (70) Non-responders, n/N (%) 5/17 (29) 5/15 (33) 10/32 (31) FFS at 6 months (95% CI), % 73 (61-83) 76 (63-84) 75 (66-81) FFS at 12 months (95% CI), % 57 (44-68) 56 (43-67) 56 (47-64) Proportional to CS reduction 42 (64) 44 (67) 86 (65) Median CS reduction from baseline to maximum reduction, % 38 50 50 Mean change in CS dose from baseline, % Overall -43 -48 -45 responder -49 -58 -54 non-responder -twenty two -10 -16 CS abort 13 (20) 15 (23) 28 21) Unless otherwise noted, data are n (%). *Changes in cGVHD symptom burden were measured using LSS. Clinically meaningful improvement in symptom burden was defined as a ≥7-point reduction in LSS score. ** One subject was determined to be unevaluable due to the absence of qualifying symptoms of cGVHD at baseline; therefore, the plot in Table 6 can be adjusted accordingly.

The best ORR (including CR) of all involved organs was evaluated. In the mITT population, organ-specific analyzes demonstrated optimal ORRs of 37% for skin, 42% for eyes, 55% for mouth, 39% for liver, and 39% for lungs. The best ORR was 26%, the best ORR was 71% in joints/fascia, 52% in the upper gastrointestinal (GI) tract, 69% in the lower GI tract, and the best ORR in the esophagus is 45% (Figure 9; Table 7). Overall, seven patients achieved CR in all affected organs. Of the 12 subjects with pulmonary responses, 3 subjects were scored as CR based on normalization to FEV1 (median increase 23%; range: 18-25), and 3 subjects were scored as CR based on the absence of Pulmonary function testing cases in which the NIH Pulmonary Symptom Score decreases from 1 to 0 are scored as CR. An additional six subjects had PR with a ≥10% increase in FEV1 (median increase of 10% for all subjects with PR; range: 0-15) or NIH Pulmonary Symptom Score when pulmonary function testing was not available Lowered by 1 point. Of the 41 subjects with skin reactions, 11 subjects had a reduction in sclerotic features, 15 subjects had a reduction in body surface area involvement, and 13 subjects had an improvement in both body surface area involvement and sclerotic features. Two subjects had skin reactions based on the investigators' clinical assessment and not according to 2014 NIH consensus criteria.

Table 7. Summary of ORR by dose and organ system Organ system, n ( % ) Begrusudil, 200 mg QD ( n = 66 ) ** Begrusudil, 200 mg BID ( n = 66 ) Total ( N=132 ) joints and fascia 51 (77) 49 (74) 100 (76) CR 10 (20) 10 (20) 20 (20) PR 28 (55) 23 (47) 51 (51) ORR 38 (75) 33 (67) 71 (71) lower gastrointestinal tract 6 (9) 7 (11) 13 (10) CR 4 (67) 4 (57) 8 (62) PR 0 1 (14) 1 (8) ORR 4 (67) 5 (71) 9 (69) Mouth 30 (45) 42 (64) 72 (55) CR 15 (50) 17 (41) 32 (44) PR 1 (3) 7 (17) 8 (11) ORR 16 (53) 24 (57) 40 (56) upper gastrointestinal tract 13 (20) 10 (15) 23 (17) CR 7 (54) 4 (40) 11 (48) PR 1 (8) 0 1 (4) ORR 8 (62) 4 (40) 12 (52) esophagus 19 (29) 12 (18) 31 (23) CR 9 (47) 5 (42) 14 (45) PR 0 0 0 ORR 9 (47) 5 (42) 14 (45) Eye 48 (73) 49 (74) 97 (73) CR 8 (17) 6 (12) 14 (14) PR 8 (17) 19 (39) 27 (28) ORR 16 (33) 25 (51) 41 (42) liver 9 (14) 4 (6) 13 (10) CR 2 (22) 2 (50) 4 (31) PR 1 (11) 0 1 (8) ORR 3 (33) 2 (50) 5 (39) skin 55 (83) 55 (83) 110 (83) CR 8 (15) 10 (18) 18 (16) PR 10 (18) 13 (24) 23 (21) ORR 18 (33) 23 (42) 41 (37) lung 24 (36) 23 (35) 47 (36) CR 4 (17) 2 (9) 6 (13) PR 3 (13) 3 (13) 6 (13) ORR 7 (29) 5 (22) 12 (26) BID, twice daily; CR, complete response; GI, gastrointestinal; ORR, overall response rate; PR, partial response; QD, daily. ** One subject was determined to be unevaluable due to the absence of qualifying symptoms of cGVHD at baseline; therefore, the plot in Table 6 can be adjusted accordingly.

The overall median time to response was 5 weeks (range: 4-66) (Figure 10A). 91% of responses occurred within 6 months of treatment, and the remaining 9% of responses were seen after 6 to 12 months of treatment. 59% of responders maintained response for ≥ 20 weeks. In the responder population, the median DOR was 54 weeks. Overall FFS rates at 6 and 12 months were 75% (95% CI, 66-81) and 56% (95% CI, 47-64), respectively (Figure 10B). Overall, low non-relapse mortality (NRM) (7%) and relapse rates (3%) were observed. The most common failure event was initiation of new systemic cGVHD therapy (38%). The 2-year OS rate was 89% (95% CI, 82-93) (Figure 10C).

During treatment with berusudil, 65% of subjects reduced their corticosteroid dose. In the mITT group, the mean corticosteroid dose was reduced by 45%, and among responders, the mean corticosteroid dose was reduced by 54%. Corticosteroid therapy was discontinued in 21% of subjects. Additionally, 22% of those subjects successfully discontinued calcineurin inhibitor (CNI) therapy, and 20% and 21% discontinued sirolimus and mycophenolate mofetil, respectively.

Clinically meaningful improvements in 7-day LSS summary scores (≥ 7-point reduction) from baseline were observed in 59% and 62% of the ITT population with berusuudil 200 mg once daily and 200 mg twice daily, respectively. ). This improvement was observed in 69% and 71% of responders and in 29% and 33% of non-responders in the berusudil 200 mg once daily and 200 mg twice daily groups, respectively. This improvement occurs. safety

Berusudil was well tolerated, and the median RDI was 99.7%. 81% of subjects received RDI >95%. AEs were consistent with those expected in patients with cGVHD receiving corticosteroid therapy and other immunosuppressive therapies (IST) (Table 8). 38% of subjects had ≥ 1 SAE; the most common was pneumonia (7%). The most common (≥5%) grade 3 or 4 AEs were pneumonitis (8%), hypertension (6%), and hyperglycemia (5%). Liver function tests (LFT) were elevated in 24% of subjects; at baseline, g-glutaminyltransferase (GGT) was elevated in 5% of subjects and AST was elevated in 5% of subjects , 3% of subjects had elevated ALT, 3% had elevated LFT, and 1% had elevated bilirubin. The most common liver-related AE was increased GGT (12%). Of the 83 subjects who discontinued treatment, 28 (21%) discontinued due to overall AEs, 16 (12%) due to possible drug-related AEs, and 5 (4%) due to progression of underlying malignant disease. discontinued, and 21 (16%) discontinued due to cGVHD progression. Fourteen subjects died during the study, 2 due to multiorgan failure and infection possibly related to berusuudil, 2 due to cardiac arrest, 2 due to respiratory failure, and 1 Deaths occurred due to pleural hemorrhage due to lung biopsy, 1 died due to relapse of acute myeloid leukemia, and 6 died during long-term follow-up (LTFU) (>28 days after last dose). Anemia grade ≥ 3 was reported in 3% of subjects, neutropenia was reported in 2% of subjects, and thrombocytopenia was reported in 2% of subjects. There was 1 case of Epstein-Barr viremia requiring treatment and 1 case of cytomegalovirus (CMV) reactivation; neither case was related to berusudil treatment.

Table 8. Security overview AE Begrusudil, 200 mg once daily ( n = 66 ) ** Begrusudil, 200 mg twice daily ( n = 66 ) Total ( N=132 ) Any AE 65 (99) 66 (100) 131 (99) ≥ Grade 3 AE 37 (56) 34 (52) 71 (54) Drug-related AEs 49 (74) 40 (61) 89 (67) SAE 27 (41) 23 (35) 50 (38) die* 8 (12) 6 (9) 14 (11) Drug-Related SAEs 5 (8) twenty three) 7 (5) All grades in ≥ 20% of subjects (overall) fatigue 30 (46) 20 (30) 50 (38) Diarrhea 23 (35) 21 (32) 44 (33) Nausea 23 (35) 18 (27) 41 (31) cough 20 (30) 17 (26) 37 (28) upper respiratory tract infection 17 (26) 18 (27) 35 (27) difficulty breathing 21 (32) 12 (18) 33 (25) headache 13 (20) 18 (27) 31 (24) peripheral edema 17 (26) 13 (20) 30 (23) Vomiting 18 (27) 10 (15) 28 (21) muscle spasms 13 (20) 13 (20) 26 (20) ≥ Grade 3 in ≥ 5% of any group pneumonia 6 (9) 4 (6) 10 (8) high blood pressure 4 (6) 4 (6) 8 (6) hyperglycemia 3 (5) 3 (5) 6 (5) Liver related AEs 12 (18) 19 (29) 31 (24) Elevated GGT 6 (9) 10 (15) 16 (12) Elevated AST 5 (8) 8 (12) 13 (10) Elevated ALT 4 (6) 7 (11) 11 (8) Elevated blood alkaline phosphatase 4 (6) 6 (9) 10 (8) Hypoalbuminemia twenty three) twenty three) 4 (3) Elevated transaminases 1 (2) 1 (2) twenty two) Increased conjugated bilirubin 1 (2) 0 1 (1) Elevated LFT 1 (2) 0 1 (1) All data are n (%). *Six subjects died during long-term follow-up (LTFU) (>28 days after last dose). ** One subject was determined to be unevaluable due to the absence of qualifying symptoms of cGVHD at baseline; therefore, the plot in Table 8 can be adjusted accordingly.

This Example 2 study demonstrates the promising efficacy and favorable safety profile of berusudil therapy in patients with steroid-refractory (SR) cGVHD. Patients with severe disease with multiorgan involvement and fibrotic manifestations who were treated after a median of 3 lines of prior systemic therapy were included in the 200-mg once-daily and 200-mg twice-daily treatment groups, respectively. The study population consisting of subjects with cGVHD achieved the best ORR of 74% and 77%.

Response to berusudil was sustained and clinically meaningful regardless of response to prior therapy, severity of cGVHD, and number of organ involvements. Responses were observed in all organs, which is clinically meaningful, as CR and PR were achieved in difficult-to-treat organs such as the lung and liver, as well as in organs with fibrotic manifestations such as the skin. cGVHD severely impairs quality of life, especially in patients with fibrotic multiorgan involvement, and treating these patients can be challenging. The observation of CR and PR as well as improved LSS, limited interactions, and lack of drug toxicity are promising results that demonstrate the potential that berusudil treatment may have to improve overall patient well-being. Seven patients achieved CR in all affected organs. In cGVHD, it may be difficult to achieve CR in all affected organs because irreversible changes occur in several organs (most notably the eye and lungs). The clinical benefit and tolerability of berusudil therapy demonstrates the potential to halt the anticipated cycle of therapies targeting cGVHD seen in clinical practice. At the 12-month analysis, 59% of responders had an ongoing response for ≥ 20 weeks. At the 12-month analysis, among responders, the median DOR was 54 weeks.

In a patient population susceptible to AEs and infections due to immunosuppressive therapy (IST), berusudil was well tolerated, allowing the majority of subjects to remain adherent to therapy to achieve clinically meaningful results. Results and improvements in quality of life, which can be maintained with continued treatment. Only 12% of subjects discontinued berusudil due to possible drug-related AEs. The median duration of treatment was 10 months (range: 0.4-22.0), and 37% of subjects continued to receive berusudil after this time point. AEs were manageable, and few grade ≥ 3 SAEs were attributable to berusudil. SAE rates were comparable between the two treatment groups. Many current cGVHD treatment options are immunosuppressive and therefore increase the risk of infection and may cause hematological toxicities, including leukopenia, anemia, and thrombocytopenia. Grade ≥ 3 cytopenias occurred in <4% of subjects, and there was only one reported case of cytomegalovirus (CMV) reactivation unrelated to berusudil treatment. Cytopenia and CMV infection present as serious complications of cGVHD and cGVHD treatment; therefore, the low rate of ≥ grade 3 cytopenias and CMV infection are promising features of berusudil's safety profile.

In this study, all subjects received berusudil. Requiring randomization to best available therapy was not considered appropriate because the subject had previously progressed after ≥ 2 lines of systemic therapy, in which response rates were historically low. Indeed, subjects in this study had tried a median of three lines of the best available treatment for cGVHD before enrollment, which used, among other agents, ECP (48%), ibrutinib nib (34%), ruxolitinib (29%), and rituximab (21%). Among subjects who were refractory to their last line of therapy, the best ORR was 75%. Example 3 : Risk management of side effects

In the previous clinical studies in Examples 1 and 2, 83 adult patients with chronic GVHD were treated with berusudil 200 mg once daily. The median duration of treatment was 9.2 months (range: 0.5 to 44.7 months). A fatal adverse reaction was reported in a patient with severe nausea, vomiting, diarrhea, and multiorgan failure.

A fatal adverse reaction was reported in a patient with severe nausea, vomiting, diarrhea, and multiorgan failure.

Permanent discontinuation of berusudil due to adverse reactions occurred in 18% of patients. Adverse reactions leading to permanent discontinuation of berusudil included nausea (4%) in >3% of patients. Adverse reactions leading to dose interruption occurred in 29% of patients. Adverse reactions leading to dose interruption in ≥ 2% were infection (11%), diarrhea (4%), and (2% each) asthenia, dyspnea, bleeding, hypertension, abnormal liver function tests, nausea, pyrexia , edema and renal failure.

The most common (≥20%) adverse reactions (including laboratory abnormalities) are infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, gamma-glutamine Elevated chelate transferase, lymphopenia, and hypertension.

Table 9 summarizes non-laboratory adverse reactions. Table 9. Nonlaboratory adverse reactions in ≥ 10% of patients with chronic GVHD treated with berusudil adverse reactions Berusudil 200 mg once daily ( N=83 ) All ratings ( % ) Level 3-4 ( % ) Infections and infestations Infection (pathogen not specified) ^a 53 16 Viral ^infectionb 19 4 Bacterial ^infectionc 16 4 General disorders and administration site conditions ^Powerless 46 4 ^Edemae 27 1 Fever 18 1 Gastrointestinal Disgusting ^f 42 4 Diarrhea 35 5 Abdominal ^paing twenty two 1 difficulty swallowing 16 0 Respiratory system, chest and mediastinum ^Difficulty breathingh 33 5 ^coughi 30 0 nasal congestion 12 0 Blood vessel Bleeding ^j twenty three 5 high blood pressure twenty one 7 Musculoskeletal and connective tissue Musculoskeletal ^paink twenty two 4 muscle spasms 17 0 joint pain 15 2 nervous system headache ^l twenty one 0 metabolism and nutrition decreased appetite 17 1 skin and subcutaneous rash ^m 12 0 ^scrapien 11 0 ^aInfections with unspecified pathogen include acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolumitis, infectious colitis, pulmonary infection, skin infection, dental infection, urinary tract infection Infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis or septic shock. ^bIncludes influenza, rhinovirus infection, gastroenteritis virus infection, viral upper respiratory tract infection, bronchitis virus infection, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenza virus infection, varicella zoster Rash virus infection, viral infection. ^C includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastrointestinal infection Escherichia coli, Pseudomonas infections, bacterial urinary tract infections. ^d includes fatigue, weakness, and discomfort. ^e includes peripheral edema, generalized edema, facial edema, localized edema, and edema. ^f includes nausea and vomiting. ^g Including abdominal pain, upper abdominal pain, and lower abdominal pain. ^h includes dyspnea, exertional dyspnea, apnea, orthopnea, and sleep apnea syndrome. ^iIncludes cough and expectorant cough. ^jIncludes contusions, hematomas, epistaxis, increased bruising, conjunctival hemorrhage, bloody stools, mouth bleeding, catheter site bleeding, hematuria, hemopleural effusion, and purpura. ^k includes limb pain, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, and musculoskeletal pain. ^lIncludes headaches and migraines. ^m includes rash, maculopapular rash, erythematous rash, generalized rash, and exfoliative dermatitis. ^nIncludes scrapie and generalized pruritus.

Table 10 summarizes laboratory abnormalities associated with berusudil. Table 10. Selected laboratory abnormalities in patients with chronic GVHD treated with berusudil. Berusudil 200 mg once daily Level 0-1 Baseline Maximum value after level 2-4 ( Max Post ) Maximum value after level 3-4 parameters ( N ) ( % ) ( % ) Chemistry Phosphate reduction 76 28 7 Elevated gamma-glutaminyltransferase 47 twenty one 11 Decreased calcium 82 12 1 Elevated alkaline phosphatase 80 9 0 Increased potassium 82 7 1 Elevated alanine aminotransferase 83 7 2 Elevated creatinine 83 4 0 Hematology lymphopenia 62 29 13 Decreased hemoglobin 79 11 1 Thrombocytopenia 82 10 5 Decreased neutrophil count 83 8 4

Table 11 summarizes recommended berusudil dose modifications for adverse effects.

adverse reactions Severity * REZUROCK dosage modification Hepatotoxicity [ see Adverse Reactions (6.1)] Grade 3 AST or ALT (5x to 20x ULN) or Grade 2 bilirubin (1.5x to 3x ULN) Maintain REZUROCK until bilirubin, AST, and ALT return to Grade 0-1, then resume REZUROCK at the recommended dose. Grade 4 AST or ALT (more than 20x ULN) or ≥ grade 3 bilirubin (more than 3x ULN) Permanently abort REZUROCK. Other adverse reactions [ see Adverse Reactions (6.1)] Level 3 Maintain REZUROCK until recovery to Level 0-1, then resume REZUROCK at recommended dosage levels. Level 4 Permanently abort REZUROCK. *Based on CTCAE v 4.03 Example 4 : US REZUROCK™ (Berusudil) FDA Instructions---------------------------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 lines of prior systemic therapy. (1) -----------------------Dosage and Administration----------------------

Recommended dose: 200 mg taken orally once daily with food. (2.1) --------------------------Dosage Forms and Specifications--------------------------

Tablet: 200 mg. (3) ----------------------------------Contraindications------------------ ----------

without. (4) -----------------------Warnings and Precautions----------------------

Embryotoxicity: May cause harm to the fetus. Women of reproductive potential are advised to be aware of potential risks to the fetus and to use effective contraception. (5.1, 8.1, 8.3) ----------------------------------Drug Interactions---------------- -------------

Strong CYP3A Inducers: Increase REZUROCK dose to 200 mg twice daily. (7.1) Proton Pump Inhibitors: Increase REZUROCK dose to 200 mg twice daily. (7.1) ----------------------------------Adverse reactions------------------ ----------

The most common (≥20%) adverse reactions (including laboratory abnormalities) are infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, gamma-glutamine Elevated chelate transferase, lymphopenia, and hypertension. (6.1) -----------------------Used by special groups-----------------------

Breastfeeding: Breastfeeding is not recommended. (8.2) See Patient Counseling Information and FDA-approved patient labeling in 17. Full Prescribing Information1Indications and Uses

REZUROCK is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. 2 Dosage and Administration 2.1 Recommended Dosage

The recommended dose of REZUROCK is 200 mg administered orally once daily until progression of chronic GVHD requires new systemic therapy.

Instruct patients to: • Swallow REZUROCK tablets whole. Do not chop, crush, or chew lozenges. • Take REZUROCK with a meal 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 additional doses to make up the missed dose.

Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. In 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)] . 2.2 Dose modification for adverse reactions

Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly. Modify REZUROCK dosage for adverse reactions according to Table 12 . Table 12 : REZUROCK Recommended Dose Modifications for Adverse Reactions adverse reactions Severity * REZUROCK dosage modification Hepatotoxicity [ see Adverse Reactions (6.1)] Grade 3 AST or ALT (5x to 20x ULN) or Grade 2 bilirubin (1.5x to 3x ULN) Maintain REZUROCK until bilirubin, AST, and ALT return to Grade 0-1, then resume REZUROCK at the recommended dose. Grade 4 AST or ALT (more than 20x ULN) or ≥ grade 3 bilirubin (more than 3x ULN) Permanently abort REZUROCK. Other adverse reactions [ see Adverse Reactions Level 3 Maintain REZUROCK until recovery to Level 0-1, then resume REZUROCK at recommended dosage levels. (6.1)] Level 4 Permanently abort REZUROCK. * Dose modification due to drug interactions based on CTCAE v 4.03 2.3 Strong CYP3A Inducers

When coadministered with strong CYP3A inducers, increase the dose of REZUROCK to 200 mg twice daily [ see Drug Interactions (7.1)] .

proton pump inhibitor

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

Each 200 mg tablet is a light yellow, film-coated rectangular tablet debossed with "KDM" on one side and "200" on the other side. 4 Contraindications

without. 5 Warnings and Precautions 5.1 Embryotoxicity

Based on findings in animals and its mechanism of action, REZUROCK may cause fetal harm when administered to pregnant women. In animal reproduction studies, administration of berusudil to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes (including embryonic mortality and malformations) at maternal exposures (AUC) less than recommended maternal exposure in patients at the dose. Pregnant women are advised to be aware of potential risks to the fetus. Advise females of reproductive potential and males who are partners of a female of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [ see Use in Specific Groups (8.1 , 8.3) , Nonclinical Toxicology ( 13.1 )] . 6 Adverse reactions 6.1 Clinical trial experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of one drug cannot be directly compared to adverse reaction rates in clinical trials of another drug and may not reflect what is actually observed rate of adverse reactions. 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 duration of treatment was 9.2 months (range: 0.5 to 44.7 months).

A fatal adverse reaction was reported in a patient with severe nausea, vomiting, diarrhea, and multiorgan failure.

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

The most common (≥ 20%) adverse reactions (including laboratory abnormalities) are infection, asthenia, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, gamma-glutamine Elevated chelate transferase, lymphopenia, and hypertension. Table 13 summarizes non-laboratory adverse reactions. Table 13 : Non-laboratory adverse reactions in ≥ 10% of patients with chronic GVHD treated with REZUROCK adverse reactions REZUROCK 200 mg once daily ( N=83 ) All ratings ( % ) Level 3-4 ( % ) Infections and infestations Infection (pathogen not specified) ^a 53 16 Viral ^infectionb 19 4 Bacterial ^infectionc 16 4 General disorders and administration site conditions ^Powerless 46 4 ^Edemae 27 1 Fever 18 1 Gastrointestinal Disgusting ^f 42 4 Diarrhea 35 5 Abdominal ^paing twenty two 1 difficulty swallowing 16 0 Respiratory system, chest and mediastinum ^Difficulty breathingh 33 5 ^coughi 30 0 nasal congestion 12 0 Blood vessel Bleeding ^j twenty three 5 high blood pressure twenty one 7 Musculoskeletal and connective tissue Musculoskeletal ^paink twenty two 4 adverse reactions REZUROCK 200 mg once daily ( N=83 ) All ratings ( % ) Level 3-4 ( % ) muscle spasms 17 0 joint pain 15 2 nervous system headache ^l twenty one 0 metabolism and nutrition decreased appetite 17 1 skin and subcutaneous ^rashm 12 0 scrapie ⁿ 11 0 a Infections with unspecified pathogen include acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolumitis, infectious colitis, pulmonary infection, skin infection, dental infection, urinary tract infection Infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis or septic shock. bIncludes influenza, rhinovirus infection, gastroenteritis virus infection, viral upper respiratory tract infection, bronchitis virus infection, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenza virus infection, varicella zoster Rash virus infection, viral infection. c Cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis E. coli, Pseudomonas infection, bacterial urinary tract Infect. d includes fatigue, weakness, and discomfort. e Including peripheral edema, generalized edema, facial edema, localized edema, and edema. f Including nausea and vomiting. g Including abdominal pain, upper abdominal pain, and lower abdominal pain. h Including dyspnea, exertional dyspnea, apnea, orthopnea, and sleep apnea syndrome. i Including cough, productive cough. j Including contusions, hematomas, epistaxis, increased bruising, conjunctival hemorrhage, bloody stools, mouth bleeding, catheter site bleeding, hematuria, hemopleural effusion, and purpura. k Including limb pain, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, and musculoskeletal pain. l Including headaches and migraines. m Including rash, maculopapular rash, erythematous rash, generalized rash, and exfoliative dermatitis. n Including scrapie and generalized pruritus. Table 14 summarizes laboratory abnormalities for REZUROCK. Table 14 : Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK REZUROCK 200 mg once daily Level 0-1 Baseline Maximum value after level 2-4 Maximum value after level 3-4 parameters ( N ) ( % ) ( % ) Chemistry Phosphate reduction 76 28 7 Elevated gamma-glutaminyltransferase 47 twenty one 11 Decreased calcium 82 12 1 Elevated alkaline phosphatase 80 9 0 Increased potassium 82 7 1 Elevated alanine aminotransferase 83 7 2 Elevated creatinine 83 4 0 Hematology lymphopenia 62 29 13 Decreased hemoglobin 79 11 1 Thrombocytopenia 82 10 5 Decreased neutrophil count 83 8 4 7 Drug Interactions 7.1 Effects of Other Drugs on REZUROCK Strong CYP3A Inducers

Coadministration of REZUROCK with strong CYP3A inducers reduces berusudil exposure [ see Clinical Pharmacology (12.3)] , which may reduce the efficacy of REZUROCK. Increase the dose of REZUROCK when coadministered with strong CYP3A inducers [ see Dosage and Administration (2.3)] . proton pump inhibitor

Coadministration of REZUROCK with proton pump inhibitors decreases berusudil exposure [ see Clinical Pharmacology (12.3)] , which may reduce the efficacy of REZUROCK. Increase the dose of REZUROCK when coadministered with a proton pump inhibitor [ see Dosage and Administration (2.3)] . 8 Use in Special Groups 8.1 Summary of Pregnancy Risks

Based on findings from animal studies and its mechanism of action [ see Clinical Pharmacology (12.1)] , REZUROCK may cause fetal harm when administered to pregnant women. There are no available human data on the use of REZUROCK in pregnant women and the risks associated with the drug cannot be evaluated. In animal reproduction studies, administration of berusudil to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes (including altered growth, embryonic death, and embryonic malformations) at maternal exposures of ( AUC) is approximately ≥ 3 times (rat) and ≥ 0.07 times (rabbit) the human exposure (AUC) at the recommended dose (see Animal Data). Pregnant women and women of reproductive potential are advised to be aware of the potential risk to the fetus.

In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. data animal data

Embryonic development studies were conducted in rats at oral doses of 25, 50, 150 and 300 mg/kg/day in the pilot study and at oral doses of 15, 50 and 150 mg/kg/day in the pivotal study. Berusudil was administered to pregnant animals during the period of organogenesis. In preliminary studies, maternal toxicity and embryonic development effects were observed. Maternal toxicity (reduced weight gain) occurred at doses of 150 and 300 mg/kg/day. Increased post-implantation losses occurred at 50 and 300 mg/kg/day. Fetal malformations including absence of anus and tail, protruding umbilicus, and dome-shaped head were observed at ≥ 50 mg/kg/day. The exposure (AUC) in rats at 50 mg/kg/day was approximately 3 times the human exposure at the recommended dose of 200 mg.

In an embryonic development study in rabbits, administration of berusudil to pregnant animals at oral doses of 50, 125, and 225 mg/kg/day during the period of organogenesis resulted in maternal toxicity and embryonic developmental effects. Maternal toxicity (weight loss and death) was observed at doses ≥ 125 mg/kg/day. Embryonic effects, including spontaneous abortion, increased postimplantation loss, decreased percentage of viable fetuses, malformations, and decreased fetal weight, were observed at doses ≥ 50 mg/kg/day. Deformities include tail deformity (shortness), rib deformity (bifurcation, fusion, or deformation), sternum deformity (fusion), and neural arch deformity (fusion, dislocation, and deformation). The rabbit exposure (AUC) at 50 mg/kg/day is approximately 0.07 times the human exposure at the recommended dose of 200 mg. 8.2 Summary of Breastfeeding Risks

There are no available data on the presence of berusudil or its metabolites in human milk or on the effects on breast-fed children or milk production. Because of the potential for serious adverse reactions caused by berusudil in breastfed children, advise nursing women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose. 8.3 Women and men of reproductive potential

REZUROCK may cause fetal harm when administered to pregnant women [ see Use in Specific Groups (8.1)] . pregnancy test

Verify the pregnancy status of females of reproductive potential before initiating treatment with REZUROCK. Contraception for women

Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential harm to the fetus. male

Advise men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. infertile women

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

Based on findings in rats and dogs, REZUROCK may harm male fertility. Effects on fertility are reversible [ see Nonclinical Toxicology (13.1)] . 8.4 Pediatric use

The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. The use of REZUROCK in this age group is supported by evidence from the adequate and well-controlled adult REZUROCK study and additional population pharmacokinetic data demonstrating that age and body weight do not have a clinically meaningful effect on the pharmacokinetics of the drug substance. Effects, exposure to the drug substance is expected to be similar between adults and pediatric patients aged 12 years and older, and the course of disease in adult and pediatric patients is similar enough to allow extrapolation of adult data to pediatric patients.

The safety and effectiveness of REZUROCK in pediatric patients younger than 12 years of age have not been established. 8.5 Use by the elderly

Of the 186 patients with chronic GVHD in the REZUROCK clinical study, 26% were 65 years and older. No clinically meaningful differences were observed in the safety or efficacy of REZUROCK compared with younger patients. 11 instructions

Begrusudil is a kinase inhibitor. The active pharmaceutical ingredient is berusudil mesylate, which has the molecular formula C27H28N6O5S and a molecular weight of 548.62 g/mol. The chemical name of berusudil mesylate is: 2-{3-[4-(1 H -indazol-5-ylamine)-2-quinazolinyl]phenoxy}- N - (Prop-2-yl)acetamide methanesulfonate (1:1). The chemical structure is as follows:

Berusudil mesylate is a yellow powder that is almost insoluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

REZUROCK lozenges are for oral administration. Each tablet contains 200 mg free base equivalent to

242.5 mg berusudil mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silica, and magnesium stearate.

The tablet film is composed of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and iron oxide yellow. 12 Clinical Pharmacology 12.1 Mechanism of Action

Begrusudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK). It inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 µM, respectively. Berusudil downregulates pro-inflammatory responses by modulating STAT3/STAT5 phosphorylation and altering Th17/Treg balance in ex vivo or in vitro human T cell assays. Begrusudil also inhibits aberrant profibrotic signaling in vitro. In vivo, the activity of berusudil was demonstrated in animal models of chronic GVHD. 12.2 Pharmacodynamics

The exposure-response relationship and time course of the pharmacodynamic response to berusudil have not been established. 12.3 Pharmacokinetics

Unless otherwise stated, the pharmacokinetic parameters presented below are for patients with chronic GVHD administered berusudil 200 mg once daily. The mean (coefficient of variation %, CV%) steady-state AUC and Cmax of berusudil were 22700 (48%) h·ng/mL and 2390 (44%) ng/mL, respectively. Berusudil Cmax and AUC increased in an approximately proportional manner (1 to 2 times the recommended once daily dose) over the dose range of 200 mg to 400 mg. The accumulation rate of Belusudil is 1.4. absorb

The median Tmax of berusudil at steady state after administration to patients at 200 mg once daily or twice daily was 1.26 to 2.53 hours. The mean (CV%) bioavailability of berusudil in healthy subjects after a single dose was 64% (17%). Food effect

Berusudil Cmax and AUC at a single berusudil dose compared to the fasting state in healthy subjects with a high-fat and high-calorie meal (800 to 1,000 calories, where approximately 50% of the total meal calorie content % from fat) increased by 2.2-fold and 2-fold respectively when administered together. Median Tmax delay is 0.5 hours. Distribution

The geometric mean volume of distribution in healthy subjects after a single dose of berusumidil was 184 L (geo CV% 67.7%).

The in vitro binding of berusudil to human serum albumin and human α1-acid glycoprotein was 99.9% and 98.6%, respectively. eliminate

The mean (CV%) elimination half-life of berusudil was 19 hours (39%), and clearance in patients was 9.83 L/hour (46%). Metabolism

Berusudil is metabolized in vitro primarily by CYP3A4 and, to a lesser extent, CYP2C8, CYP2D6, and UGT1A9. excretion

After a single oral dose of radiolabeled begrusudil was administered to healthy subjects, 85% of the radioactivity was recovered in the feces (30% unchanged) and less than 5% in the urine. special groups

In age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥ 60 and < 90 mL/min/1.72 ^m to eGFR ≥ 30 and < 60 mL/ min/1.72 m ² ), no clinically significant differences in the pharmacokinetics of berusudil were observed. The effect of severe renal impairment on the pharmacokinetics of berusudil has not been studied. Clinical Studies and Model - Informed Approaches Effects of Other Drugs on Belumosudil ( Clinical Studies and Model-Informed Approaches Effects of Other Drugs on Belumosudil )

Strong Cytochrome P450 (CYP) 3A Inhibitor: No clinically meaningful effect on berusudil exposure when coadministered with itraconazole in healthy subjects.

Strong CYP3A Inducer: In healthy subjects, coadministration with rifampicin decreased the Cmax of berusudil by 59% and the AUC by 72%.

Moderate CYP3A Inducers: In healthy subjects, coadministration with efavirenz is predicted to decrease the Cmax of berusudil by 32% and the AUC by 35%.

Proton Pump Inhibitors: In healthy subjects, coadministration of rabeprazole decreased the Cmax of begrusudil by 87% and the AUC of begrusudil by 80%, and coadministration of omeprazole decreased the berusudil Er's Cmax decreased by 68% and AUC decreased by 47%. Effects of berusudil on other drugs

CYP3A Substrates: Coadministration of berusudil is predicted to increase the Cmax and AUC of midazolam, a sensitive CYP3A substrate, by approximately 1.3-fold and 1.5-fold, respectively.

CYP2C9 Substrates: Coadministration of berusudil is not expected to have a clinically meaningful effect on exposure to CYP2C9 substrates such as warfarin.

CYP2C8 Substrates: Coadministration of berusudil is not expected to have a clinically meaningful effect on exposure to CYP2C8 substrates (non-OATP1B1 substrates). In vitro study of the transport system : berusudil is a P-gp acceptor. Begrusudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations. Enzyme systems : Berusuudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9. 13 Non-clinical toxicology 13.1 Carcinogenesis, mutagenesis, damage to fertility

Carcinogenicity studies have not been conducted with berusudil.

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

In fertility studies of combined male and female rats, berusudil-treated male animals were mated with untreated female animals, or untreated male animals were bred with berusudil-treated Female animals mate. Berusudil was administered orally to male rats at doses of 50, 150, or 275 mg/kg/day for 70 days before mating and throughout the mating period, and orally for 14 days before mating and until day 7 of gestation. administered to female rats. At the 275 mg/kg/day dose, adverse findings in female rats (berusudil-treated or untreated but mated with treated male rats) included pre- or post-implantation Increased losses and reduced number of viable embryos. Administration of berusudil to male rats at a dose of 275 mg/kg/day resulted in abnormal sperm findings (decreased motility, decreased counts, and increased percentage of abnormal sperm) and changes in the testicular/epididymal organs (decreased weight and degeneration) .

At a dose of 275 mg/kg/day, fertility was reduced in either treated males or females, with the reduction in male fertility reaching statistical significance. In general toxicology studies, adverse changes also occurred in male and female reproductive organs; findings included sperm degeneration in dogs at a berusudil dose of 35 mg/kg/day and in rats at 275 mg/kg/day. Reduced follicle development in the ovaries. These changes are partially or completely reversed during the recovery period. The exposure (AUC) in dogs at a dose of 35 mg/kg/day and in rats at a dose of 275 mg/kg/day was 0.5 times the clinical exposure at the recommended dose of 200 mg/day, respectively. 8-9 times. 14 Clinical Studies 14.1 Chronic Graft-versus-Host Disease

Study KD025-213 (NCT03640481) is a randomized, labeled, open-label, multicenter study of REZUROCK in patients with chronic GVHD who have received 2 to 5 prior lines of systemic therapy and require additional therapy. If the patient's platelets are < 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 FEV1 ≤ 39%, the patients were excluded from the study. Sixty-six patients were treated with 200 mg of REZUROCK taken orally once daily. Concomitant treatment with supportive care therapy for chronic GVHD is allowed. Concomitant treatment with GVHD prophylaxis and standard-of-care systemic chronic GVHD therapy was allowed as long as subjects were taking stable doses for at least 2 weeks prior to the study. Initiation of new systemic chronic GVHD therapies while on study was not permitted.

Demographic and baseline characteristics are summarized in Table 15 .

Table 15 : Demographic and Baseline Characteristics of Patients with Chronic GVHD REZUROCK 200 mg once daily ( N=65 ) Age, median, years (min, max) 53 (21, 77) Age ≥ 65 years old, n (%) 17 (26) Male, n (%) 42 (65) Race, n (%) white people 54 (83) Black person 6 (9) Other or not reported 5 (8) Median time (months) since chronic GVHD diagnosis (range) 25.3 (1.9, 162.4) ≥ 4 organs involved, n (%) 31 (48) Median number of prior lines of therapy (range) 3 (2, 6) Number of previous lines of therapy, n (%) 2 23 (35) 3 12 (19) 4 15 (23) ≥ 5 15 (23) Previous chronic GVHD treatment with ibrutinib, n (%) 21 (32) Previous chronic GVHD treatment with ruxolitinib, n (%) 20 (31) Refractory to last therapy, n (% ^a ) 43/55 (78) Severe chronic GVHD, n (%) 46 (71) REZUROCK 200 mg once daily ( N=65 ) Overall severity rating median (range) 7 (2, 9) Median Lee Symptom Scale score at baseline (range) 27 (7, 56) Corticosteroid dose at baseline (PE/kg) ^bMedian (range) 0.19 (0.03, 0.95) ^a Denominator excludes patients with unknown status ^b Prednisone equivalents/kg

REZUROCK's efficacy is based on overall response rate (ORR) through Day 1 of Cycle 7, where ORR includes complete response or partial response according to 2014 NIH response criteria. ORR results are presented in Table 16 . The ORR was 75% (95% CI: 63, 85). The median duration of response (calculated from first response in chronic GVHD to progression, death, or new systemic therapy) 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) were free of death or initiation of new systemic therapy for at least 12 months from response. Table 16 : Overall Response Rates Through Day 1 of Cycle 7 in Study KD025-213 in Patients with Chronic GVHD REZUROCK 200 mg once daily ( N=65 ) Overall response rate ( ORR ) 49 (75%) 95% confidence ^intervala (63%, 85%) full response 4 (6%) partial reaction 45 (69%) ^aEstimated using the Clopper-Pearson method

The ORR results were supported by an exploratory analysis of patient-reported symptom distress, which showed that 52% (95% CI: 40, 65) of patients had a Lee Symptom Scale summary score that decreased by at least 10% by Cycle 7 Day 1. 7 points. 16How to supply / store and handle

REZUROCK 200 mg tablets are supplied as pale yellow, film-coated rectangular tablets containing 200 mg of berusudil (equivalent to 242.5 mg of berusudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other side, and is packaged as follows:

200 mg tablet, in 30 count vial: NDC 79802-200-30

Store at room temperature 20ºC to 25ºC (68°F to 77°F); excursions from 15ºC to 30ºC (59°F to 86°F) allowed [see USP Controlled Room Temperature].

Dispense to patients only in original container. Store in original container to protect from moisture. Replace the lid securely after each opening. Do not discard the desiccant.        17Patient consultation information

Patients are advised to read the FDA-approved patient labeling (Patient Information). Embryotoxicity: • Advise pregnant women and females of reproductive potential to be aware of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider about known or suspected pregnancy [ see Warnings and Precautions (5.1) , Use in Specific Groups (8.1 , 8.3)] . • Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [ see Warnings and Precautions (5.1)] . • Advise men with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [ see Use in Specific Groups (8.3)] . Breastfeeding • Advise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [ see Use in Specific Groups (8.2)] . Infertility • Advise men and women of reproductive potential that REZUROCK may impair fertility [ see Use in Specific Groups (8.3)] . Administration • Inform patients to take REZUROCK orally once daily with food according to their physician's instructions and that the oral dose (lozenge) should be swallowed whole with a glass of water at approximately the same time each day and not to cut, crush, or chew the lozenge [ See Dosage and Administration (2.1)] . • Advise patients that if a daily dose of REZUROCK is missed, it should be taken as soon as possible that day and resume the normal schedule the next day. Patients should not take additional doses to make up for a missed dose [ see Dosage and Administration (2.1)] . Drug Interactions • Advise patients to inform their health care provider about all concomitant drug therapies, including prescription drugs, over-the-counter drugs, vitamins, and herbal products [ see Drug Interactions (7)] . Patient Information Form REZUROCK ( REZ-ur-ok ) ( Berusudil ) Lozenges What is REZUROCK ? REZUROCK is used to treat adults and children aged 12 years and older with chronic graft-versus-host disease (chronic GVHD) after you have had at least 2 prior treatments (systemic therapies) and they have not worked. Prescription drugs. It is not known whether REZUROCK is safe and effective in children younger than 12 years old. Before taking REZUROCK , tell your healthcare provider about all of your medical conditions, including whether you: •       Have kidney or liver problems. •       Pregnant or planning to become pregnant. REZUROCK may cause harm to your unborn child. If you are unable to get pregnant, your healthcare provider will perform a pregnancy test before starting treatment with REZUROCK. Tell your healthcare provider if you are pregnant or think you may become pregnant during treatment with REZUROCK.             Women who may become pregnant should use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose.             Men with a female partner who may become pregnant should use effective contraception during treatment with REZUROCK and for at least 1 week after the last dose. •       Breastfeeding or planning to breastfeed. It is not known whether REZUROCK is passed into breast milk. Do not breastfeed during treatment with REZUROCK and for at least 1 week after the last dose. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. REZUROCK may affect the way other medicines work, and other medicines may affect the way REZUROCK works. Know the medicines you take. Keep a list of them to show to your health care provider and pharmacist when you get new medicines. HOW SHOULD I TAKE REZUROCK ? •       Take REZUROCK exactly as your healthcare provider tells you to take it. •       Do not change your dose or stop taking REZUROCK without first talking with your healthcare provider. •       Take REZUROCK once a day with a meal. •       Take REZUROCK at about the same time every day. •       Swallow REZUROCK tablets whole with a glass of water. •       Do not chop, crush, or chew REZUROCK tablets. •       During treatment with REZUROCK, your healthcare provider will perform a blood test to check your liver at least 1 time per month. •       If you miss a dose of REZUROCK, take it as soon as you remember it that day. The next day, take your next dose of REZUROCK at your regular time. Do not take extra doses of REZUROCK to make up a missed dose. •       If you take too much REZUROCK, call your healthcare provider or go to the nearest hospital emergency room right away. WHAT ARE THE POSSIBLE SIDE EFFECTS OF REZUROCK ? The most common side effects of REZUROCK include: •       Infect •       swelling •       fatigue or weakness •       bleeding •       Nausea •       Stomach (abdominal) pain •       Diarrhea •       muscle or bone pain •       shortness of breath •       headache •       cough •       high blood pressure If you experience certain side effects, your healthcare provider can change your REZUROCK dose, temporarily stop, or permanently stop treatment with REZUROCK . REZUROCK may affect male and female reproduction. If you have concerns about this, tell your healthcare provider. These are not all possible side effects of REZUROCK. Call your doctor for medical advice about side effects. You can report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Kadmon Pharmaceuticals, LLC at 1-877-377-7865 How should I store REZUROCK ? •       Store REZUROCK at room temperature between 68ºF and 77ºF (20ºC and 25ºC). •       Save REZUROCK in its original container. The REZUROCK bottle contains a desiccant packet to help your tablets stay dry (free from moisture). Keep the dryer in a bottle. • Close the REZUROCK bottle tightly after you have taken your dose. Keep REZUROCK and all medicines out of the reach of children. General information about the safe and effective use of REZUROCK . Sometimes medicines are prescribed for purposes other than those listed in the Patient Information Leaflet. Do not use REZUROCK for conditions for which it is not prescribed. Do not give REZUROCK to other people, even if they are having the same symptoms that you are having. This may cause harm to them. You can ask your pharmacist or healthcare provider for information about REZUROCK written for health professionals. What are the ingredients of REZUROCK ? Active Ingredients: Berusudil Mesylate, Inactive Ingredients: Lozenge Core: Microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silica, and stearic acid Magnesium. Tablet coating: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and iron oxide yellow.

While the invention has been described in 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 patent and scientific documents cited herein are incorporated by reference in their entirety.

without

Figure 1 is a CONSORT flow chart depicting Example 1 of the Phase IIa labeled open-label dose finding study of berusuudil.

Figure 2 is a forest plot of ORR subgroup analysis within the safety population. Subgroups were defined based on baseline assessments.

Figure 3A depicts the best individual responses of organ systems in responders. n = number of responder groups for overall severity rating and number of specific organs involved at baseline. Percentages are calculated based on the corresponding n.

Figure 3B is a heat map of response and progression for all patients in the safety population. (A) Optimal response of the organ. (B) Organ response at progression or end of study. Of the 11 patients who had progression in the joint, seven had a decrease in P-ROM of only one unit.

Figure 4A depicts the time to response in berusudil responders. Percentages are calculated based on the number of responder groups.

Figure 4B depicts time to response in selected organs in responders. Percentages are calculated based on the number of responder groups.

Figure 5A depicts the persistence of response to berusudil in patients with cGVHD. Kaplan-Meier curve of estimated DOR for responders

Figure 5B depicts the persistence of response to berusudil in patients with cGVHD. Kaplan-Meier curves of estimated time to next systemic therapy for cGVHD (TTNT) in the safety population.

Figure 5C depicts the persistence of response to berusudil in patients with cGVHD. Kaplan-Meier curves for estimated FFS (including failure causes) in the safety population.

Figure 5D depicts the persistence of response to berusudil in patients with cGVHD. Kaplan-Meier curves for estimated overall survival in the safety population.

Figure 6A depicts changes in CD41 Treg percentage compared to Treg baseline (regulatory T cells, total) following treatment with berusuudil. Pre-dose collection at C1D1 (Cycle 1, Day 1), C2D1 (Cycle 2, Day 1), C4D1 (Cycle 4, Day 1), C7D1 (Cycle 7, Day 1), and end-of-treatment visits Peripheral blood samples.

Figure 6B depicts changes in CD41 Treg percentage compared to Treg baseline (regulatory T cell responders) following treatment with berusuudil. Pre-dose collection at C1D1 (Cycle 1, Day 1), C2D1 (Cycle 2, Day 1), C4D1 (Cycle 4, Day 1), C7D1 (Cycle 7, Day 1), and end-of-treatment visits Peripheral blood samples.

Figure 6C depicts changes in CD41 Treg percentage compared to Treg baseline (regulatory T cell non-responders) following treatment with berusuudil. Pre-dose collection at C1D1 (Cycle 1, Day 1), C2D1 (Cycle 2, Day 1), C4D1 (Cycle 4, Day 1), C7D1 (Cycle 7, Day 1), and end-of-treatment visits Peripheral blood samples.

Figure 7 is a CONSORT flow diagram depicting the Phase II randomized study of berusuudil for Example 2.

Figure 8 is a forest plot of ORR subgroup analysis (mITT). High ORR was observed in all subgroups analyzed in the mITT population, and efficacy was maintained regardless of prior treatment. The 50th percentile for cGVHD duration before enrollment was 29 months. Response assessments performed at or after initiation of new systemic therapy for cGVHD were excluded from the analysis.

Figure 9 depicts the ORR of organ systems in the mITT population. Organ-specific analysis in the mITT population demonstrated ORR in skin, eyes, mouth, liver, lungs, joints/fascia, upper gastrointestinal tract, lower gastrointestinal tract, and esophagus. CR was seen in all affected organs.

Figure 10A depicts the persistence of response to different doses of berusudil. Kaplan-Meier plot of DOR in responder population. DOR was defined as the time from response until documented progression or initiation of another systemic therapy for cGVHD; ongoing data are maturing.

Figure 10B depicts the persistence of response to different doses of berusudil. Kaplan-Meier curves for estimated FFS (including failure causes) in the mITT population. FFS was defined as the absence of cGVHD treatment changes, NRM, and malignancy recurrence.

Figure 10C depicts the persistence of response to different doses of berusudil. Kaplan-Meier curves for estimated OS in the mITT population.

Figure 11 depicts the clinical study design of Example 2.

without

without.

Claims (40)

A kind of 2-{3-[4-(1H-indazol-5-ylamine)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or its pharmaceutical The use of an acceptable salt (compound) in patients who experience one or more treatment-related adverse reactions when receiving clinically recommended doses of the compound includes: if the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 and the patient returns to Grade 1 or less after discontinuation of treatment, administration of the compound is resumed at the clinically recommended dose for the patient. The use as described in request item 1 includes the following steps: (a) administering the compound to the patient at a dose clinically recommended for the patient; (b) Monitor said patient for adverse reactions; (c) discontinue administration of the compound to the patient if the patient experiences at least one Grade 3 adverse reaction; and (d) Resume administration of the compound to the patient when at least one adverse reaction in the patient has returned to Grade 1 or less. The use of claim 1 or 2, wherein at least one adverse reaction of the patient has returned to grade 0 after discontinuation of compound administration. The use of Claim 1, comprising the step of permanently discontinuing administration of the compound to the patient if the patient experiences at least one Grade 4 adverse reaction. The use according to any one of claims 2 to 3, wherein the patient is monitored for adverse reactions at least once a month. The use according to any one of claims 1 to 5, wherein the compound is berusudil mesylate. The use of any one of claims 1 to 6, wherein the clinically recommended dose for the patient is 200 mg per day before and after the patient experiences one or more treatment-related adverse reactions. The use as claimed in any one of claims 1 to 7, wherein the clinically recommended dose for said patient is 200 mg once daily with food. The use of any one of claims 1 to 6, wherein the clinically recommended dose for the patient is 400 mg per day before and after the patient experiences one or more treatment-related adverse reactions. The use of any one of claims 1 to 3 or claims 5 to 9, wherein after the patient recovers to a grade 1 level or lower and administration of the compound is resumed, for the patient Clinically recommended dose reduction. The use according to any one of claims 1 to 10, wherein the clinically recommended dose for the patient is in the range of 200 mg per day to 400 mg per day. The use according to any one of claims 1 to 11, wherein the patient suffers from chronic graft-versus-host disease (cGVHD). The use of claim 12, wherein the patient has failed at least two prior lines of systemic treatment for the cGVHD. The use of any one of claims 1 to 13, wherein at least one adverse reaction in the patient is graded according to the Common Terminology Criteria for Adverse Events (CTCAE). The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is infection, weakness, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, phosphate Decreased, elevated gamma-glutaminyltransferase, lymphopenia, and hypertension. The use as described in claim 14, wherein the at least one adverse reaction is viral infection, bacterial infection or unknown pathogen infection. Use as claimed in claim 16, wherein the unknown pathogenic infection is acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolumitis, infectious colitis, pulmonary infection , skin infection, tooth infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory infection, bronchitis, sepsis or septic shock. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is weakness, edema or fever. The use according to any one of claims 1 to 14, wherein said at least one adverse reaction is gastrointestinal disorder. The use as claimed in claim 19, wherein the gastrointestinal disorder is nausea, diarrhea, abdominal pain or dysphagia. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is respiratory system disorder, chest disorder or mediastinal disorder. The use as claimed in claim 21, wherein the respiratory system disorder, chest disorder or mediastinal disorder is dyspnea, cough or nasal congestion. The use according to any one of claims 1 to 14, wherein said at least one adverse reaction is vascular disorder. The use as claimed in claim 23, wherein the vascular disorder is hemorrhage or hypertension. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a musculoskeletal disorder or a connective tissue disorder. The use as claimed in claim 25, wherein the musculoskeletal disorder or connective tissue disorder is musculoskeletal pain, muscle spasm or joint pain. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a neurological disorder. The use as claimed in claim 27, wherein the neurological disorder is headache or migraine. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a metabolic disorder. The use as claimed in claim 29, wherein the metabolic disorder is loss of appetite, rash or scrapie. One treatment was treated with 2-{3-[4-(1H-indazol-5-ylamine)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) at clinically recommended doses. Methods for treating patients who experience one or more treatment-related adverse reactions with acetamide or a pharmaceutically acceptable salt (compound) thereof, including: if the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 and the patient returns to Grade 1 or less after discontinuation of treatment, administration of the compound is resumed at the clinically recommended dose for the patient. The method of claim 31, wherein the patient experiences at least one grade 3 adverse reaction, the method comprising reverting to the grade 1 or lower when the patient's at least one adverse reaction has returned to grade 1 or lower. The compound is administered to the patient. The method of claim 31, wherein the patient experiences at least one Grade 4 adverse reaction, the method comprising permanently discontinuing administration of the compound to the patient. The method of claim 31 or 32, wherein the clinically recommended dose for the patient is in the range of 200 mg per day to 400 mg per day. The method of any one of claims 31 to 34, wherein the clinically recommended dose for the patient is in the range of 200 mg per day to 400 mg per day. The method of any one of claims 31 to 34, wherein the clinically recommended dose for the patient is 200 mg per day. The method of any one of claims 31 to 32 and 34 to 36, wherein the reduction occurs after the patient recovers to a Grade 1 level or less and administration of the compound is resumed. The method of any one of claims 31 to 37, wherein the compound is berusudil mesylate. The method according to any one of claims 31 to 38, the use according to any one of claims 1 to 11, wherein the patient suffers from chronic graft-versus-host disease (cGVHD). The method of claim 39, wherein said patient has failed at least two prior lines of systemic therapy for said cGVHD.