On December 15, 2021, the U.S. Food and Drug Administration (FDA) approved abatacept (Orencia®) for prophylaxis of acute graft-versus-host disease (aGVHD), in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), in adults and pediatric patients aged 2 and older who are undergoing hematopoietic stem cell transplantation (HSCT) from a matched or one allele-mismatched unrelated donor.

FDA Approves Abatacept for Prophylaxis of Acute Graft-Versus-Host Disease

This is the first drug approved to prevent aGVHD. The application included use of real-world data in the determination of clinical effectiveness. Real-world data is clinical data routinely collected from a variety of sources, including registry data, to generate real-world evidence.

Efficacy was evaluated in two studies in patients aged 6 and older who were undergoing HSCT from a matched or one allele-mismatched unrelated donor.

A randomized 1:1, double-blind, placebo-controlled clinical trial (GVHD-1; NCT 01743131) of patients who underwent an 8/8 human leukocyte antigen (HLA)-matched HSCT received abatacept or placebo in combination with a CNI and MTX. Although severe (grade 3–4) aGVHD-free-survival assessed at day 180 after transplantation was not significantly improved in patients who received abatacept compared to patients who received a placebo (HR = 0.55, 95% CI = 0.26, 1.18), the overall survival (OS) 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 a placebo (HR = 0.33, 95% CI = 0.12, 0.93). The moderate to severe (grade 2–4) aGVHD-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 a placebo (HR = 0.54, 95% CI = 0.35, 0.83).

Additional evidence of effectiveness was provided by a clinical study (GVHD-2) using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) in patients who underwent a 7/8 HLA-matched HSCT between 2011 and 2018. The registry-based study analyzed outcomes of 54 patients who were treated with abatacept for the prophylaxis of aGVHD, in combination with a CNI and MTX, versus 162 patients randomly selected from the CIBMTR registry treated with a CNI and MTX alone. The OS rate at day 180 after HSCT was 98% (95% CI = 78%, 100%) for patients who received abatacept in combination with CNI and MTX compared to 75% (95% CI = 67%, 82%) for patients who received CNI and MTX alone.

The most common adverse reactions reported in 10% or more of patients who received abatacept for the prophylaxis of aGVHD are anemia, hypertension, CMV reactivation/CMV 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 six months post-transplantation and be monitored for cytomegalovirus infection or reactivation for six months post-transplantation.

The recommended dose depends on patients’ age and is described in the full prescribing information for abatacept.

The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with Health Canada, Switzerland’s Swissmedic, and Israel’s Ministry of Health. The application reviews are ongoing at the other regulatory agencies.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.

FDA granted the application priority review, breakthrough designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for IndustryꟷExpedited Programs for Serious ConditionsꟷDrugs and Biologics. 

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088. 

For assistance with single-patient investigational new drug applications for oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.