Kadmon Holdings recently announced that the U.S. Food and Drug Administration (FDA) has approved Rezurock (belumosudil) 200 mg once daily (QD) for the treatment of pediatric patients (≥12 years old) and adult patients with chronic graft-versus-host disease (cGVHD) who have failed at least two prior systemic therapies.
Notably, Rezurock is the first and only ROCK2 small molecule inhibitor approved by the FDA. Previously, the FDA granted belumosudil Breakthrough Therapy Designation (BTD) and Priority Review, and reviewed its New Drug Application (NDA) under the Real-Time Oncology Review (RTOR) pilot program.
Chronic Graft-versus-Host Disease (cGVHD)
cGVHD is a common and fatal complication following hematopoietic stem cell transplantation. In cGVHD, transplanted immune cells (grafts) attack the patient's cells (host), leading to inflammation and fibrosis in multiple tissues, including the skin, mouth, eyes, joints, liver, lungs, esophagus, and gastrointestinal tract. There are approximately 14,000 patients with cGVHD in the United States.
Rezurock Mechanism of Action: The active pharmaceutical ingredient in Rezurock is belumosudil (KD025), an orally selective Rho-associated coiled-coil protein kinase 2 (ROCK2) inhibitor. ROCK2 is a signaling pathway that regulates inflammatory responses and fibrosis. By inhibiting the ROCK2 signaling pathway, belumosudil downregulates pro-inflammatory Th17 cells, increases regulatory T (Treg) cells, rebalances the immune response, and treats immune dysfunction. In addition to cGVHD, belumosudil is also being evaluated in a phase 2 clinical trial (KD025-209) for the treatment of adult patients with systemic sclerosis (SSc). In 2020, the FDA granted belumosudil Orphan Drug Designation (ODD) for the treatment of SSC.
Safety and Efficacy of Rezurock in Clinical Studies
The FDA approved Rezurock based on the safety and efficacy results of the pivotal clinical trial ROCKstar (KD025-213, NCT03640481). This was a randomized, multicenter, open-label phase 2 study conducted in adult and adolescent patients (≥12 years of age) with cGVHD who had previously received 2 to 5 prior systemic therapies. In this study, 65 patients received Rezurock 200 mg once daily (QD). The median time to cGVHD diagnosis was 25.3 months, 48% of patients had 4 or more organ involvements, the median number of prior systemic therapies was 3, and 78% of patients were refractory to their last treatment. Patients received 200 mg of Rezurock once daily until clinically significant disease progression or unacceptable toxicity.
Results showed that on day 1 of the 7th treatment cycle, the overall response rate (ORR) was 75% (n=49/65; 95% CI: 63, 85), with a complete response rate (CR) of 6% (n=4/65) and a partial response rate (PR) of 69% (n=45/65). The median time from treatment initiation to first remission was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved remission, 62% remained free of death or new systemic therapy for at least 12 months after achieving remission. The median duration of remission (calculated as cGVHD from first remission to disease progression, death, or need for new systemic therapy) was 1.9 months (95% CI: 1.2, 2.9). The ORR results were supported by an exploratory analysis of patient-reported symptom distress: on day 1 of the 7th cycle of treatment, 52% of patients showed a clinically meaningful improvement in their Lee Symptom Scale (LSS) score (a tool for measuring cGVHD symptoms and their distress to patients) from baseline (a reduction of ≥7 points).
In this study, patients receiving Rezurock reported significant improvements in cGVHD symptoms. This suggests that Rezurock treatment not only leads to organ remission but also improves patient well-being, which is crucial for a chronic disease with a high symptom burden. Rezurock was well-tolerated in the study, and adverse events were consistent with those expected in patients with advanced cGVHD receiving corticosteroids and/or other immunosuppressants.
