FDA Postpones Approval Decision on Belumosudil for Chronic Graft-Versus-Host Disease

The FDA has extended the review period for the new drug application (NDA) for belumosudil (KD025), which is being considered as a potential treatment option for patients with chronic graft-versus-host disease (cGVHD), announced Kadmon Holdings, Inc, in a press release. The new Prescription User Fee Act target action date for the application decision is August 30, 2021, according to a notice issued to the developer by the FDA.¹

Additional information is needed for the FDA to review the NDA, and the agency has determined that the receipt of this information would make a significant change to the application as a whole. The FDA letter noted that 3 additional months are therefore needed in order for the FDA to review the application for belumosudil.

"We remain confident in the data supporting our application for belumosudil in cGVHD and look forward to continuing to work closely with the FDA during the remainder of the review process," said Harlan W. Waksal, MD, president, and chief executive officer, Kadmon Holdings, Inc, in a statement.

The NDA for belumosudil as treatment of cGVHD was granted priority review by the FDA in November 2020. The application is supported by findings from the phase 2 KD025-213 clinical trial (ROCKstar; NCT03640481), which is exploring treatment with the agent in patients with cGVHD following 2 prior lines of systemic therapy.

In the 2-arm, open-label, randomized, multicenter study, approximately 166 patients are being assigned 1:1 to either belumosudil 200 mg once daily (QD) or belumosudil 200 mg twice daily (BID). Treatment will continue through 28 cycles for all patients until clinically significant progression of cGVHD. According to the study protocol, any patient who does not respond to treatment after 12 cycles should be withdrawn from the study.

The primary end point of the study is the objective response rate (ORR) defined by the 2014 National Institute of Health Consensus Development Project on clinical trials in chronic GVHD. The secondary end points included duration of response, Lee Symptom Scale score, corticosteroid reductions, failure-free survival, and overall survival.

Topline results from the ROCKstar study presented during the 2021 Transplantation and Cellular Therapy Meetings showed that belumosudil has clinical benefit for patients with cGVHD, a finding that is consistent with prior research on the drug. High ORRs were observed in the overall population and across all the subgroups of patients assessed in the study and the primary end point was met. Responses to belumosudil were also durable and clinically meaningful regardless of each patient’s cGVHD characteristics and prior treatment. The agent was also well tolerated in the study subjects with manageable adverse events (AEs).²

Patients in the study are stratified based on whether or not they previously received ibrutinib (Imbruvica) as well as whether they present with severe cGVHD at baseline. The median age of the overall patient population [n = 132] at baseline was 56 years (range, 21-77). The group was 57% male. Patients had received a median of 4 prior lines of therapy and notably, 34% had received prior ibrutinib. Patients had a 28-month median time to chronic GVHD diagnosis. In 66% of the patients enrolled, cGVHD was considered severe. Four or more organs were involved in the cGVHD for 52% of the study population. The patients also had a median prednisone dose of 0.2 mg and 73% were refractory to their prior therapy.

In the 132 patients evaluated for the top-line analysis, treatment with belumosudil QD led to an ORR of 73% (95% CI, 60%-83%), and the BID dose achieved an ORR of 74% (95% CI, 62%-84%). The median time to response was 4 weeks. At 6 weeks, patients in the study showed an failure-free survival rate of 77% (95% CI, 69%-84%).

The most common AEs in both treatment arms, occurring in greater than 20% of patients, included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%) upper respiratory tract infections (23%), peripheral edema (21%), and headache (20%). Notably, at least 1 liver-related investigation occurred in 23% of patients. The most common liver-related AE was increased gamma-glutamyltransferase, which occurred in 11% of patients. Thirty-four percent of the population experienced at least 1 serious AE. There were also 8 deaths in the study related to AEs. Notably, no cases of cytomegalovirus reactivation or cytomegalovirus infection were reported.

Belumosudil is a selective oral inhibitor of Rho-associated coiled-coil kinase 2. The NDA for the agent as treatment of cGVHD is undergoing review through the FDA's Real-Time Oncology Review (RTOR) and Project Orbis pilot programs. Previously, the FDA granted a breakthrough therapy designation to the agent for the treatment of patients with cGVHD after failure of 2 or more lines of systemic therapy, and an orphan drug designation for the treatment of cGVHD.¹

"We are committed to bringing belumosudil to market, once approved, to help meet the needs of patients living with cGVHD," Waksal added.

References:

1. Kadmon announces U.S. FDA has extended the review period for belumosudil in chronic graft-versus-host disease. News release. Kadmon Holding, Inc. March 10, 2021. Accessed March 12, 2021. https://bit.ly/3cq8eg7

2. Cutler C, Arai S, Zoghi B, et al. Belumosudil for Chronic Graft-Versus-Host Disease (cGVHD) after 2 or More Prior Lines of Therapy: The Rockstar Study (KD025-213). Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 9.