REZUROCK Tablet Ref.[109441] Active ingredients: Belumosudil

Belumosudil exposure-response relationships and the time course of pharmacodynamic response are not established.

Cardiac Electrophysiology

At 2.4 times the maximum exposure for approved recommended dose, REZUROCK does not prolong the QT interval to any clinically relevant extent.

The following pharmacokinetic parameters are presented for chronic GVHD patients administered belumosudil 200 mg once daily, unless otherwise specified. The mean (% coefficient of variation, CV) steady-state AUC and C_max of belumosudil was 22,700 (48) h∙ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil C_max and AUC increased in an approximately proportional manner over a dosage range of 200 and 400 mg (1 to 2 times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4.

Absorption

Median T_max of belumosudil at steady state was 1.26 to 2.53 hours following administration of 200 mg once daily or twice daily in patients. The mean (CV) bioavailability was 64 (17%) following a single belumosudil dose in healthy subjects.

Effect of food

Belumosudil C_max and AUC increased 2.2 times and 2 times, respectively, following administration of a single belumosudil dose with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) compared to the fasted state in healthy subjects. Median T_max was delayed 0.5 hours.

Distribution

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

Belumosudil binding to human serum albumin and human α₁-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro.

Elimination

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

Metabolism

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

Excretion

Following a single oral dose of radiolabeled belumosudil in healthy subjects, 85% of radioactivity was recovered in feces (30% as unchanged) and less than 5% in urine.

Specific Populations

No clinically significant differences in belumosudil pharmacokinetics were observed with regard to age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥60 and <90 mL/min/1.72m² to eGFR ≥30 and <60 mL/min/1.72m²). The effect of severe renal impairment on the pharmacokinetics of belumosudil has not been studied.

Patients with Hepatic Impairment

Following a single 200 mg dose of belumosudil, changes in belumosudil exposure in subjects with varying degrees of hepatic impairment based on Child-Pugh score without liver GVHD relative to subjects with normal hepatic function is shown in Table 4.

Table 4. Effect of Varying Degrees of Hepatic Impairment on Belumosudil Exposure:

Drug Interaction Studies

Clinical studies and model-informed approaches

Effects of other drugs on Belumosudil:

Strong Cytochrome P450 (CYP) 3A Inhibitors: There was no clinically meaningful effect on belumosudil exposure when coadministered with itraconazole in healthy subjects.

Strong CYP3A Inducers: Coadministration of rifampin decreased belumosudil C_max by 59% and AUC by 72% in healthy subjects.

Moderate CYP3A Inducers: Coadministration of efavirenz is predicted to decrease belumosudil C_max by 19% and AUC by 35% in healthy subjects.

Proton Pump Inhibitors: Coadministration of rabeprazole decreased belumosudil C_max by 87% and AUC by 80%, and omeprazole decreased belumosudil C_max by 68% and AUC by 47% in healthy subjects.

Effects of Belumosudil on other drugs:

CYP3A Substrates: Coadministration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) C_max and AUC approximately 1.3- and 1.5-fold, respectively.

CYP2C9 Substrates: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

CYP2C8 Substrates: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.

In Vitro studies:

Transporter Systems: Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations.

Enzymes Systems: Belumosudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9.

Carcinogenesis

Carcinogenicity studies have not been conducted with belumosudil.

Mutagenesis

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

Impairment of Fertility

In a combined male and female rat fertility study, belumosudil-treated male animals were mated with untreated females, or untreated males were mated with belumosudil-treated females. Belumosudil was administered orally at doses of 50, 150 or 275 mg/kg/day to male rats 70 days prior to and throughout the mating period, and to female rats 14 days prior to mating and up to Gestation Day 7. At the dose of 275 mg/kg/day, adverse findings in female rats (treated with belumosudil or untreated but mated with treated males) included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of belumosudil to male rats at a dose of 275 mg/kg/day resulted in abnormal sperm findings (reduced motility, reduced count, and increased percentage of abnormal sperm), and testes/epididymis organ changes (reduced weight and degeneration). Fertility was reduced in both treated males or females at the 275 mg/kg/day dose and reached statistical significance in males. Adverse changes in male and female reproductive organs also occurred in general toxicology studies; findings included spermatozoa degeneration at a belumosudil dose of 35 mg/kg/day in dogs and decreased follicular development in ovaries at 275 mg/kg/day in rats. Changes were partially or fully reversed during the recovery period. The exposure (AUC) at the doses of 35 mg/kg/day in dogs, and 275 mg/kg/day in rats is 0.5 times and 8–9 times, respectively, the clinical exposure at the recommended dose of 200 mg daily.

14.1 Chronic Graft versus Host Disease

Study KD025-213 (NCT03640481) was a randomized, open-label, multicenter study of REZUROCK for treatment of patients with chronic GVHD who had received 2 to 5 prior lines of systemic therapy and required additional treatment. Patients were excluded from the studies if platelets were <50 × 10⁹/L; absolute neutrophil count <1.5 × 10⁹/L; AST or ALT >3 × ULN; total bilirubin >1.5 × ULN; QTc(F) >480 ms; eGFR <30 mL/min/1.73 m²; or FEV1 ≤39%. There were 66 patients treated with REZUROCK 200 mg taken orally once daily. Concomitant treatment with supportive care therapies for chronic GVHD was permitted. Concomitant treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapies was permitted as long as the subject has been on a stable dose for at least 2 weeks prior to study. Initiation of new systemic chronic GVHD therapy while on study was not permitted.

Demographics and baseline characteristics are summarized in Table 5.

Table 5. Demographics and Baseline Characteristics of Patients with Chronic GVHD:

^* Denominator excludes patients with unknown status.
^† Prednisone equivalents/kilogram.

The efficacy of REZUROCK was based on overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response or partial response according to the 2014 NIH Response Criteria. The ORR results are presented in Table 6. The ORR was 75% (95% CI: 63, 85). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12 months since response.

Table 6. Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in Study KD025-213:

^* Estimated using Clopper-Pearson method.

ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in the Lee Symptom Scale summary score through Cycle 7 Day 1 in 52% (95% CI: 40, 65) of patients.