The FDA has granted a priority review designation to a supplemental biologics license application seeking the approval of abatacept for the prevention of moderate to severe acute graft-versus-host disease in patients aged 6 years and older who are receiving unrelated donor hematopoietic stem cell transplantation.
The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) seeking the approval of abatacept (Orencia) for the prevention of moderate to severe acute graft-versus-host disease (aGVHD) in patients aged 6 years and older who are receiving unrelated donor hematopoietic stem cell transplantation.1
The application is supported by data from the phase 2 ABA2 trial (NCT01743131), as well as a registry trial based on real-world evidence. Data from ABA2 showed that abatacept, when added to a standard GVHD prophylactic regimen given to patients with hematologic malignancies receiving a stem cell transplant from an unrelated, human leukocyte antigen (HLA)–matched or mismatched donor, led to a significant reduction in severe aGVHD and associated morbidity without increasing disease relapse.
Data from the real-world analysis proved to be consistent with those findings.
Under the Prescription Drug User Fee Act, the FDA will decide on the sBLA by December 23, 2021.
“While stem cell transplants are an effective treatment for aggressive leukemias and other hematologic malignancies, patients who receive stem cell transplants from unrelated and HLA-mismatched donors are at high risk for developing aGVHD,” lead study investigator Leslie Kean, MD, PhD, director of the Pediatric Stem Cell Transplantation Program at Boston Children’s Hospital and Dana-Farber Cancer Institute, stated in a press release. “There is a tremendous need to expand the stem cell donor pool by lowering the risk of aGVHD in both adults and children receiving unrelated donor stem cell transplants.”
The multicenter, phase 2 trial, was comprised of 2 cohorts: a single-arm cohort that enrolled patients receiving transplants from mismatched unrelated donors (MMUD; 7/8 cohort) and a randomized, double-blind, placebo-controlled cohort that enrolled patients receiving transplants from 8/8 matched unrelated donors (MUD; 8/8 cohort).
All participants were given a calcineurin inhibitor, either cyclosporin or tacrolimus, and dosing was initiated on day -2 and continued through at least day 100, as tolerated. Patients also received methotrexate on days 1, 3, 6, and 11; they underwent transplant on day 0. Participants given abatacept received the agent at a dose of 10 mg/kg on days -1, 5, 14, and 28.
The primary end point of the trial was cumulative incidence of severe grade 3/4 aGVHD at day +100, and a key secondary end point was severe aGVHD–free survival (SGFS) at day +180.2 Other end points comprised grade 3/4 aGVHD at day +180, grade 2-4 aGVHD at days +100 and +180, chronic GVHD at 1 year, non-relapse mortality, relapse, relapse-free survival, overall survival, cytomegalovirus reactivation and disease, Epstein-Barr virus reactivation and post-transplant lymphoproliferative disease, hematologic recovery, and donor engraftment.
In the 8/8 cohort, the 2 arms were balanced with respect to all parameters evaluated. The 7/8 was also noted to be well matched with Center for International Blood and Marrow Transplant Research (CIBMTR) calcineurin inhibitor/methotrexate controls for all variables except overall disease type. According to the investigators, the apparent mismatch in overall disease type resulted from a nonuniform case:control matching ratio for the abatacept cohort in that some patients who received the agent were matched 1:2 vs 1:3 or 1:4. Despite this imbalance, the analysis of time-dependent outcomes accounted for the matching-pair design and eliminated the effect of this imbalance on parameter estimation.
Results showed that in the 7/8 cohort, patients who received abatacept had a substantial decrease in the day +100 cumulative incidence of severe aGVHD. Those who received abatacept plus a calcineurin inhibitor/methotrexate, the incidence was 2.3% in the intent-to-treat population vs 30.2% in the calcineurin inhibitor/methotrexate CIBMTR controls (P < .001; HR, 0.0).
Results from a post-hoc analysis demonstrated similarly superior outcomes in those in this cohort who received abatacept plus calcineurin inhibitor/methotrexate vs the CIBMTR controls who received calcineurin inhibitor/methotrexate plus anti-thymocyte globulin.
In the 8/8 cohort, a decrease in severe aGVHD was also observed with abatacept vs placebo, at 6.8% vs 14.8%, respectively (P = .13; HR, 0.45; 80% CI, 0.22-0.9). As the sample size for ABA2 was designed with an alpha error of 0.2, the cohort reached the protocol-specified statistical end point.
Notably, other end points were examined as exploratory analyses, and they all demonstrated significant improvement over the controls.
Additionally, in the 7/8 cohort, the SGFS rates with abatacept plus calcineurin inhibitor/methotrexate vs calcineurin inhibitor/methotrexate were 97.7% and 58.7%, respectively (P < .001; HR, 0.0). In the 8/8 cohort, these rates were 93.2% and 82.0% with abatacept vs placebo, respectively (P = .05; HR, 0.37; 80% CI, 0.19-0.73).
Regarding chronic GVHD, the abatacept regimen did not improve the condition. In the 7/8 and 8/8 cohorts, patients who received the agent experienced a 1-year mild-severe chronic GVHD cumulative incidence of 62.0% vs 51.9%, respectively, vs 45.9% and 45.3%, respectively, with CIBMTR and placebo controls (P = .74; HR, 1.26; 80% CI, 0.97-1.64 and P = .55; HR, 1.17; 80% CI, 0.85-1.61, respectively).
Notably, the addition of abatacept to the regimen did not result in increased relapse in either the 7/8 cohort (HR, 0.45; 80% CI, 0.22-0.91; P = .21) or the 8/8 cohort (HR, 0.86; 80% CI, 0.54-1.35; P = .66). The relapse point estimate at 2 years in the 7/8 cohort for abatacept and the calcineurin inhibitor/methotrexate CIBMTR controls were 9.3% and 21.4%, respectively. In the 8/8 cohort, the 2-year relapse rates with abatacept vs placebo were 21.5% and 23.6%, respectively.
“For patients who receive unrelated donor stem cell transplants, in particular for racial and ethnic minority patient populations, there is a heightened risk of developing aGVHD, a potentially life-threatening medical complication for which there are no approved preventive therapies,” Mary Beth Harler, MD, head of Immunology and Fibrosis Development at Bristol Myers Squibb, stated in a press release. “We look forward to working with the the FDA to bring [abatacept] to this new population and employ pathbreaking science in an effort to address unmet needs of underserved patients.”