Regulatory Decision Summary for Rholistiq

The evaluation of efficacy and safety for this submission was supported by a phase 2, single-arm study in patients with cGVHD after at least 2 prior lines of systemic therapy and a phase 2A dose-escalation study in patients with cGVHD after at least one prior line of systemic therapy.

The pivotal phase 2 study KD025-213 supports the market authorization of Rholistiq for the treatment of adults and pediatric patients 12 years and older with cGVHD, who have failed at least 2 prior lines of therapy. KD025-213 was a randomized two-cohort, single-arm, dose-ranging study that included 65 patients treated with belumosudil 200 mg daily. The primary efficacy endpoint, objective response rate (ORR) according to the 2014 National Institute of Health (NIH) consensus criteria, was 75% through Cycle 7 Day 1, with a partial response rate of 69% and a complete response rate of 6%. The responses were consistent across subgroups and were seen across all organ systems. The median duration of response (DOR), calculated from first response to progression from best response in any organ, death, or new systemic therapy for chronic GVHD, was 1.9 months (95% Confidence Interval [CI]: 1.2, 2.9). Median DOR, calculated from first response to deterioration from best overall response, death, or new systemic therapies was 3.7 months (95% CI: 1.9, 8.3). 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.

The ORR was supported by exploratory analyses of patient reported symptoms in the Lee Symptom Scale Score (LSS). 34 patients (52%) reported a 7-point reduction in symptoms from baseline. Efficacy was additionally supported by study KD025-208, a phase 2A exploratory dose-escalation trial in patients with steroid-dependant cGHVD who had failed 1-3 previous lines of treatment. 17 patients were treated with belumosudil 200 mg daily. At cycle 7 day 1, ORR was 58.8% (95% CI 32.9, 81.6).

Overall, Rholistiq appeared to be generally tolerable in the intended population. The overall pooled safety data included 186 patients that assessed all doses of belumosudil in cGVHD. The pivotal safety analysis included 83 patients who took the recommended dose of 200 mg daily. The median duration of treatment was 9.2 months (range 0.5 to 44.7 months). Treatment emergent adverse events (TEAEs) occurred in 99% of patients, with grade 3-5 TEAE seen in 55%. SAEs were reported in 37.3% of patients in the 200 mg daily group and in 36% of all belumosudil-treated patients. A total of 7 (3.8%) patients with cGVHD experienced SAEs that were considered treatment-related. The most common (≥10%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain and distension, musculoskeletal pain and weakness, headache, phosphate decreased, gamma glutamyl transferase increased, alkaline phosphatase increased, lymphocytes decreased, hypertension, rash, falls, pruritus, renal failure, constipation, dehydration and dry mouth. A fatal adverse reaction related to belumosudil was reported in one patient with severe nausea, vomiting, diarrhea and multi-organ failure. Important safety signals for belumosudil include infection, GI toxicity, hepatotoxicity and cytopenia. There are no human data available regarding the potential effect of belumosudil on pregnancy or development of the embryo or fetus. Based on findings from non-clinical studies and its mechanism of action, belumosudil can cause fetal harm. This is addressed through labeling.

No clinical data on the safety or efficacy of belumosudil in pediatric patients 12 years of age and older were available. There is a clear unmet medical need for effective and tolerable therapies in this population. The pharmacometrics analysis shows no clinically significant differences in belumosudil pharmacokinetics with regard to weight over the range of 38.6 to 143 kilograms (kg). Given the biology of treatment-refractory cGVHD and mechanism of action of belumosudil, the use of belumosudil for treatment-refractory cGVHD can be extrapolated to postpubertal pediatric patients weighing at least 40 kg.

Rholistiq demonstrated an acceptable safety and efficacy profile in patients with cGVHD, a serious and life-threatening disease with limited therapeutic options. There are considerable limitations of study design in a complex heterogeneous, waxing and waning disease such as cGVHD. Despite the limitations of study design including small sample size and use of a single-arm trial, the study did attempt to control for heterogeneity where possible. Although the pivotal study population was small (n = 65), the study was powered appropriately. It is recognized that enrollment of sufficient sample size poses the most difficult challenge in conducting trials for treatment of cGVHD. Notwithstanding the small study population, significance in the ORR was substantial and reproducible across the two clinical trials and in patients who had failed multiple other treatments. Additionally, there were limitations to the determination of the most appropriate measure of DOR. Regardless of definition, there were a substantial number of patients who did not require new treatment at 12 months and responses were seen in patients who had previously failed prior treatment with ibrutinib (33.3%) and ruxolitinib (30.3%).

A bioavailability study supported the recommendation that Rholistiq be given orally once daily, with food, at approximately the same time each day. Strong CYP3A inducers and proton-pump-inhibitors (PPIs) reduced the C_max and AUC by over 50% in drug-drug interaction studies. Belumosudil should be administered at 200 mg twice daily in the presence of strong CYP3A inducers and PPIs.

A Risk Management Plan (RMP) for Rholistiq was submitted by Kadmon Pharmaceuticals to Health Canada. Upon review, the RMP was considered to be acceptable.

Taken together, the observed ORR and DOR are considered substantial evidence to support clinical benefit in patients with cGHVD. On the basis of the information reviewed, Rholistiq presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-harm-uncertainty profile of the product, it was recommended that Rholistiq be granted authorization.