Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Sanofi Winthrop Industrie, 82 Avenue Raspail, 94250 Gentilly, France
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA48
Belumosudil is a selective Rho-associated, coiled-coil containing protein kinase-2 (ROCK2) inhibitor that mediates signalling in immune cellular function and fibrotic pathways.
At 2.2 times the maximum exposure of the approved recommended dose, belumosudil does not prolong the QT interval to any clinically relevant extent.
Study KD025-213 was a phase 2, open-label, multicentre study of belumosudil for the treatment of patients with cGVHD. The intent-to-treat (ITT) adult population included 156 patients. Patients 12 years of age or older were eligible for the study if they had received 2 to 5 prior lines of systemic therapy and required additional therapy. Eligible patients received a stable dose of corticosteroids for two weeks prior to entry into the study. Patients were randomised 1:1 to receive belumosudil dosed orally at 200 mg once daily or 200 mg twice daily. Patients were excluded from the study 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%.
Belumosudil was added to continued use of standard cGVHD therapies such as corticosteroids, calcineurin inhibitors (CNIs, cyclosporine or tacrolimus), sirolimus, ECP and/or topical or inhaled therapies per institutional guidelines if a stable dose/schedule was in place at study entry. Transient increases in corticosteroids dosing (up to 1 mg/kg/day prednisone equivalent) for up to 6 weeks were permitted for cGVHD flare. An elevated corticosteroids dose for > 6 weeks, or more than 2 cGVHD flare episodes during the first 6 months of belumosudil treatment were considered as treatment failures, as was the initiation of a new systemic therapy for cGVHD.
Of adult patients enrolled in the 200 mg once daily arm (N=78), the median age was 53 years (range 21 to 77 years), 63% were male, and 85% were white. The majority (73%) of patients had severe cGVHD disease with 81% of patients were refractory to their last systemic therapy prior to study enrollment. The organs involved at baseline were skin (82%), joints/fascia (77%), eyes (73%), lung (35%), mouth (53%), oesophagus (30%), upper gastrointestinal tract (GI) (18%), lower GI (9%) and liver (13%). Fifty-one percent of patients had four or more organs involved. The most frequently used systemic concomitant treatments that the patients taking on Cycle 1 Day 1 in study KD025-213 were corticosteroids, CNIs (tacrolimus or cyclosporin), sirolimus, MMF, and ECP. The median number of prior lines of systemic cGVHD therapy was 3.0. The study also enrolled 2 adolescent patients, ages 12 and 13 years, to the 200 mg once daily arm.
The primary efficacy endpoint of overall response rate (ORR) was defined as the proportion of subjects who achieved either a complete response (CR [resolution of all manifestations in each organ or site]) or a partial response (PR [improvement in at least one organ or site without progression in any other organ or site]) at any post-baseline response assessment according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD. Secondary endpoints included duration of response and time to response. Responses, including complete responses, were achieved across all organs involved (skin, eyes, mouth, oesophagus, upper GI, lower GI, liver, lungs, and joints/fascia). ORR and key secondary endpoints results are presented in Table 3.
Table 3. Best overall response rate and other efficacy results, ITT adult population:
| Variable | Belumosudil 200 mg once daily (N=78) |
| Overall response rate (%) | 73.1 |
| 95% CI of ORR (%) | 61.8, 82.5 |
| Complete response (%) | 5.1 |
| Partial response (%) | 67.9 |
| ORR at 6 months (%) | 43.6 |
| 95% CI of ORR at 6 months | 32.4, 55.3 |
| #K-M duration of response (primary), median, weeks (95% CI) | 23.9 (11.43, 50.43) |
| Time to response, median, weeks (range) | 4.43 (3.7, 80.1) |
Abbreviations: CI = confidence interval; ORR = overall response rate; KM = Kaplan-Meier; NR = not reached; ITT = intent-to-treat
Note: Data cut-off: 02 September 2022
Note: 2-sided, exact CI of ORR was calculated using the Clopper Pearson method.
Note: Responder population was used for duration of response and time to response. The percentages are calculated based on the number of ITT population.
# Duration of response (primary) is defined as the time from first response to deterioration from best response (e.g., CR to PR, or PR-LR), the initiation of new systemic treatment or death.
ORR-defined as the proportion of subjects who achieved a complete response (CR) or a partial response (PR) at any time in the absence of new systemic treatment for cGVHD according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD, and as assessed by investigators.
A total of 3 adolescent patients were treated with belumosudil 200 mg once daily in the interventional clinical studies and belumosudil responses were observed in these patients. The safety and efficacy of belumosudil in adolescents aged 12 to 18 years are supported by evidence from study KD025-213.
In study KD025-213, two adolescent patients were treated with belumosudil 200 mg once daily. One of them achieved a PR. The responder showed a time to response (TTR) of 53 days and duration of response (DOR) of 820 days.
Based on PK model predictions, the efficacy and safety are expected to be similar in adolescents and adult patients.
The European Medicines Agency has deferred the obligation to submit the results of studies with belumosudil in one or more subsets of the paediatric population in treatment of chronic graft versus host disease (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Median Tmax of belumosudil across studies was approximately 3 hours. Following a single oral dose of belumosudil 200 mg, mean absolute bioavailability (% coefficient of variation) was 64% (17%).
In healthy subjects, the administration of a single 200 mg dose of belumosudil with a high-fat and high-calorie meal (800 to 1 000 kilocalories with approximately 50% of total caloric content of the meal from fat) increased belumosudil Cmax to 2.25 times that following fasted administration and AUC to 2 times that following fasted administration. Median Tmax was delayed 0.5 hour.
Based on population PK modelling, the mean steady-state AUC (% coefficient of variation) in patients with cGVHD receiving 200 mg once daily administered with food was 18 800 (33%) h•ng/mL; mean steady-state Cmax was 2 230 (31%) ng/mL. With once daily administration, steady-state concentrations of belumosudil were achieved with an accumulation ratio of 1.2.
Based on population PK modelling, pharmacokinetics were described by a two compartmental model with a mean distribution half-life of 1.57 h (78%). Belumosudil mean (% coefficient of variation, CV) apparent volume of distribution of the central compartment was 35.8 L (93%). In in vitro preparations, binding to human serum albumin was 99.9% and binding to human α1-acid glycoprotein was 98.6%.
Based on in vitro assessment, CYP3A4 was the predominant CYP isoform responsible for the metabolism of belumosudil, although CYP2C8, CYP2D6 and UGT1A9 contributed to a lesser extent.
Population PK modelling results in cGVHD patients showed that belumosudil elimination mean (% coefficient of variation, CV) elimination half-life was 32.9 h (15%). Belumosudil mean (% CV) apparent clearance in patients (%CV) was 12.5 L/h (38%).
The Human Mass Balance study results indicated that faecal excretion is the major route of excretion (85% of the dose). Of the dose recovered in faeces, 30% was parent belumosudil. Less than 5% of the dose was recovered in urine.
Exposure to belumosudil (Cmax and AUC) appears to be slightly greater than dose proportional over the 20 to 500 mg once daily dose range, but less than dose-proportional for doses above 500 mg in healthy subjects. In subjects with cGVHD, the exposure increase between 200 and 400 mg is approximately proportional.
Based on population PK analysis no clinically relevant differences in belumosudil pharmacokinetics were observed with regard to age (20 to 77 years), race, gender, or weight (38.6 to 143 kg).
Based on population PK analysis, no clinically relevant differences in belumosudil pharmacokinetics were observed in patients with mild or moderate renal impairment. Severe renal impairment has not been studied.
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:
| Hepatic impairment category | Changes in belumosudil exposure in subjects with hepatic impairment compared to subjects with normal hepatic function | |||
| Total (Free + Bound) concentrations | Free concentrations | |||
|---|---|---|---|---|
| Cmax | AUC | Cmax | AUC | |
| Mild (Child-Pugh A) | 1.2-fold increase | 1.4-fold increase | 14% decrease | 19% decrease |
| Moderate (Child-Pugh B) | 6% decrease | 1.5-fold increase | 12% decrease | 1.4-fold increase |
| Severe (Child-Pugh C) | 1.3-fold increase | 4.2-fold increase | 5.4-fold increase | 16-fold increase |
No signs of PK dissimilarity were observed in three adolescent patients from whom sparse PK data were available.
In repeated dose studies, toxicity was observed at belumosudil average plasma concentration levels below or similar to the expected human exposure and in the studies of toxicity to reproduction, the toxicity was observed below the expected human exposure.
No evidence of special hazard for humans on safety pharmacology or genotoxicity was identified in vitro and in vivo studies.
In repeated oral dose studies in rats and dogs the adverse effects observed in one or both species included toxicities in the gastrointestinal tract (emesis, loose stools, and/or abnormal black contents, increase in salivation), liver (elevated liver enzymes, hypertrophy/increased organ weight, and cholestasis/inflammation), kidney (increased blood urea nitrogen, tubular changes, pigmentation, intracellular protein droplets in the epithelium), hemolymphoid system (regenerative anaemia, lymphocyte depletion in spleen and thymus), and reproductive system.
In male rats and dogs, toxicities included lower epididymis and testes weights associated with abnormal sperm findings such as multifocal bilateral spermatozoan degeneration in the epididymis and testes, and multinucleated spermatids in the testes, reduced motility and count of sperm; in the repeat dose studies the changes were reversible in dogs but not fully reversible in rats.
In female rats, lower uterine weights that correlated with uterine/cervical hypoplasia and decreased follicular development in ovaries related to adverse body weight reduction was observed. These changes were reversible.
Adverse effects in female rats (treated with belumosudil or untreated but mated with treated males) included increased pre- or post-implantation loss, decreased number of viable embryos and foetal malformations including absence of anus and tail, omphalocele, and dome shaped head.
In rabbits, maternal toxicity and embryo-foetal developmental effects (including spontaneous abortion, increased post-implantation loss, decreased percentage of live foetuses, and decreased foetal body weight and skeletal/external malformations) were observed.
No carcinogenic effects were reported in transgenic mice.
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