On December 15, the U.S. Food and Drug Administration (FDA) approved abatacept (Orencia) for the prophylaxis of acute graft-vs-host disease (GVHD), in combination with a calcineurin inhibitor and methotrexate, in adults and pediatric patients aged 2 years and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or one allele-mismatched unrelated donor. This is the first drug approved to prevent acute GVHD.
The application included use of real-world data in the determination of clinical effectiveness. Efficacy was evaluated in two studies including patients aged 6 years and older undergoing HSCT from a matched or one allele–mismatched unrelated donor.
GVHD-1 was a randomized (1:1), double-blind, placebo-controlled clinical trial of patients who underwent an 8 of 8 human leukocyte antigen (HLA)-matched HSCT and received abatacept or placebo in combination with a calcineurin inhibitor and methotrexate. While severe (grade III–IV) acute GVHD–free survival assessed at day 180 after transplantation was not significantly improved in patients who received abatacept compared to patients who received a placebo (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.26–1.18), the overall survival rate at day 180 after HSCT was 97% (95% CI = 89%–99%) for patients who received abatacept compared to 84% (95% CI = 73%–91%) for patients who received placebo (HR = 0.33, 95% CI = 0.12–0.93). The moderate-severe (grade II–IV) acute GVHD–free survival rate at day 180 after HSCT was 50% (95% CI = 38%–61%) for patients who received abatacept compared to 32% (95% CI = 21%–43%) for patients who received placebo (HR = 0.54, 95% CI = 0.35–0.83).
Additional evidence of effectiveness was provided by GVHD-2, a clinical study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) in patients who underwent a 7 of 8 HLA-matched HSCT between 2011 and 2018. This registry-based study analyzed outcomes of 54 patients treated with abatacept for the prophylaxis of acute GVHD, in combination with a calcineurin inhibitor and methotrexate, vs 162 patients randomly selected from the CIBMTR registry treated with a calcineurin inhibitor and methotrexate alone. The overall survival rate at day 180 after HSCT was 98% (95% CI = 78%–100%) for patients who received abatacept in combination with a calcineurin inhibitor and methotrexate compared to 75% (95% CI = 67%–82%) for patients who received a calcineurin inhibitor and methotrexate alone.
The most common adverse reactions (≥ 10%) associated with abatacept for the prophylaxis of acute GVHD were anemia, hypertension, cytomegalovirus reactivation or infection, pyrexia, pneumonia, epistaxis, decreased CD4 lymphocytes, hypermagnesemia, and acute kidney injury. Patients who receive abatacept should receive antiviral prophylaxis for Epstein-Barr virus infection before starting treatment and for 6 months posttransplantation, and should also be monitored for cytomegalovirus infection/reactivation for 6 months posttransplant.
The recommended abatacept dose depends upon the age of the patient and is described in the prescribing information.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada, Switzerland’s Swissmedic, and Israel’s Ministry of Health. The application reviews are ongoing at the other regulatory agencies.
This review also used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.