Treatment with the selective ROCK2 inhibitor KD025 led to statistically significant overall response rates in patients with chronic graft-versus-host disease who have received ≥2 prior lines of systemic therapy.
Corey Cutler, MD, MPH, FRCPC
Treatment with the selective ROCK2 inhibitor KD025 led to statistically significant overall response rates (ORRs) in patients with chronic graft-versus-host disease (cGVHD) who have received ≥2 prior lines of systemic therapy, meeting the primary endpoint at an interim analysis of the phase II ROCKstar trial (KD025-213; NCT03640481).1
At the 200-mg once-daily dose, KD025 elicited an ORR of 64% (95% CI, 51%-75%; P <.0001), and the 200-mg twice-daily schedule led to a 67% ORR (95% CI, 54%-78%; P <.0001) in this patient population. Statistical significance was achieved if the lower bound of the 95% confidence interval of ORR was >30%.
Additionally, the therapy has been well tolerated and adverse events (AEs) were found to be consistent with what is expected in this patient population, Kadmon Holdings, the manufacturer of KD025, stated in a press release.
“KD025 was shown to be a highly active and well-tolerated therapy across the spectrum of this complex, multiorgan disease,” study investigator Corey Cutler, MD, MPH, FRCPC, associate professor of medicine, Harvard Medical School, and medical director of the Adult Stem Cell Transplantation Program, Dana-Farber Cancer Institute stated in the press release. “The response rates observed are particularly impressive since this study is being conducted in a real-world population with severe disease, supporting the potential role of KD025 in cGVHD patients who are in need of effective and well-tolerated therapies.”
The company added in the press release that it will be sharing the ORR findings at a pre—new drug application (NDA) meeting with the FDA.
Additionally, Kadmon Holdings noted that while the ORR endpoint was met at the interim analysis, the primary analysis of the trial will occur in the first quarter of 2020, which will be 6 months after completion of enrollment. The primary analysis will include updated safety and efficacy findings, including ORRs, duration of response (DOR), changes in corticosteroid dose, and changes in quality of life. These data will be presented at an upcoming scientific meeting.
In the ongoing, multicenter, open-label, phase II ROCKstar trial, KD025 is being tested in adults and adolescents with cGVHD who have received ≥2 prior lines of systemic therapy. Patients were randomized 1:1 to receive KD025 at either 200 mg daily (n = 66) or 200 mg twice daily (n = 66).
To be eligible for enrollment, patients must be ≥12 years old and have undergone allogenic hematopoietic stem cell transplant, previously received ≥2 lines of systemic therapy, receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to screening, have persistent cGVHD manifestations, a Karnofsky performance score ≥60 (if aged ≤16 years) or a Lansky performance score of ≥60 (if aged <16 years), and weigh ≥40 kg.
Those who are not on a stable dose or regimen of systemic cGVHD therapy for ≥2 weeks prior to screening, have histological relapse of the underlying disease or posttransplant lymphoproliferative disease at time of screening, and are currently being treated with ibrutinib (Imbruvica) are excluded from enrolling on the trial.
The primary endpoint is ORR; key secondary endpoints are DOR, change in Lee Chronic GVHD Symptom Scale Score, response rate by organ system, partial or complete response rate, failure-free survival, overall survival, time to response, and time to next treatment.
“We are extremely pleased with the outcomes of the interim analysis, which showed that KD025 has already greatly exceeded the threshold for success in this pivotal trial,” Harlan W. Waksal, MD, president and CEO of Kadmon, stated in a press release. “We look forward to sharing these results with the FDA at a pre-NDA meeting, where we will also discuss the timing for a regulatory filing for KD025 in cGVHD, which we expect to occur in 2020, subject to FDA input.”
In October 2018, the FDA previously granted a breakthrough therapy designation to KD025 for the treatment of patients with cGVHD who have received ≥2 prior lines of systemic therapy. The agency granted the drug an orphan drug designation in October 2017 for the same indication.
Prior data showed that the ROCK2 inhibitor achieved responses in patients with steroid-dependent GVHD.2 In an open-label, phase IIa trial of 17 patients, treatment with KD025 led to a 71% partial response rate (n = 12). Additionally, no treatment-related AEs were reported.
Cytokines (IL-21, IL-17) regulated by the ROCK2 signaling pathway play an integral role in the pathogenesis of cGVHD. Clinical research has demonstrated that inhibiting the ROCK2 pathway reduces the pathogenesis of cGVHD.