FDA Rejects Iomab-B BLA Application, Requests New Randomized Study
The FDA has rejected the SIERRA study data for Iomab-B’s biologics license application filing due to insufficient evidence of overall survival improvement.
- Data from the SIERRA study (NCT02665065) are not sufficient to support a biologics license application (BLA) filing for Iomab-B as a treatment for patients with relapsed/refractory acute myeloid leukemia (AML), according to the FDA.
- The SIERRA trial previously met its primary end point of durable complete remission (CR).
- The FDA has requested an additional head-to-head randomized trial demonstrating an improvement in overall survival (OS) in order to support the BLA filing of Iomab-B.
Despite the phase 3 SIERRA trial meeting its primary end point of 6-month durable CR rate, the FDA has decided that data from the study are not sufficient to support a BLA filing for Iomab-B as a treatment for patients with relapsed/refractory AML.1
This announcement from the FDA was made following clinical and chemistry, manufacturing, and controls discussions between the FDA and Actinium Pharmaceuticals concluded and the BLA pathway for Iomab-B was set. However, the FDA now recommends that Actinium conduct a study to evaluate allogeneic bone marrow transplant (BMT) using Iomab-B plus a reduced-intensity conditioning (RIC) regimen consisting of fludarabine and total-body irradiation vs allogeneic BMT using RIC, including cyclophosphamide plus fludarabine and total-body irradiation.
Unlike the previous SIERRA trial, this new proposed study design will not allow crossover. In SIERRA, approximately 60% of patients crossed over from the control arm to the investigational arm, confounding OS results in the intention-to-treat (ITT) population.
“While this is not the outcome we expected, we will work with the FDA to further discuss specifics of the proposed randomized head-to-head clinical study to determine its strategic feasibility. The 12 oral presentations of the SIERRA results at prestigious BMT, hematology, and nuclear medicine medical conferences in the US and [European Union] are an attestation of the strong interest from the transplant community for better conditioning regimens due to the high unmet need,” Avinash Desai, MD, chief medical officer of Actinium, said in a press release.
Iomab-B is an induction and conditioning targeted radiotherapy agent made of an anti-CD45 monoclonal antibody and iodine-131 radioisotope payload.
Red blood cells: © vipman4 - stock.adobe.com
About the SIERRA Trial
A total of 153 patients aged 55 years or older with relapsed/refractory AML were enrolled in the SIERRA trial. The study was designed based on guidance set forth from an end of phase 2 meeting with the FDA. In this meeting, the FDA stated that durable CR would be an acceptable end point to support a filing of the BLA for Iomab-B.2
Results from the SIERRA trial were previously presented during the 2023 Transplantation & Cellular Therapy Meetings.2,3 Here, a significant improvement in durable CR was seen, and the study met its prespecified primary end point with 22% (n = 13/76) of patients on Iomab-B maintaining a durable CR for 180 days or more compared with none in the control arm (95% CI, 12.29%-34.73%; P <.0001).
Additional findings showed that long-term OS was seen in 13 patients with a durable CR. All patients survived at 6 months, 92.3% at 12 months, 71.9% at 18 months, and 59.9% at 24 months. For event-free survival (EFS), rates were also significantly improved in the Iomab-B arm with 28% of patients experiencing EFS at 180 days vs 0.2% in the conventional chemotherapy arm (HR, 0.22; 95% CI, 0.15-0.34, P <.0001).
Among the 59 evaluable patients in the Iomab-B arm, 74.6% (n = 44) achieved a CR with complete platelet recovery (CRp) vs 6.3% in the control arm. For the 44 patients who crossed over from the control arm to receive Iomab-B, 91% received transplant, and 52.3% of these patients achieved a CR/CRp. Additionally, 6 of the crossover patients had a durable CR of 180 days or more at the time of follow-up (95% CI, 5.17%-27.35%).
“We are grateful to the patients, their families, as well as the study investigators and their staff who participated in the SIERRA trial. As a first-of-its-kind study, SIERRA broadened the investigation of Iomab-B as a targeted induction and conditioning agent from a single center to 24 leading BMT centers in North America, demonstrating its potential for the first time in a randomized, controlled study. Through the conduct of SIERRA, Actinium also built strong relationships with key thought leaders. This track record will provide a solid foundation to work with a partner on a subsequent Iomab-B trial, and we look forward to finalizing the path forward for Iomab-B in the US with the FDA,” Desai added in the press release.1
“We are disappointed that the positive results from the SIERRA trial are not deemed adequate by the FDA to support a BLA filing despite meeting the primary end point with statistical significance and producing positive efficacy and safety outcomes on several measures,” said Sandesh Seth, chief executive officer and chairman of Actinium, in the press release. “SIERRA represented a first-of-its-kind radiotherapeutic trial and demonstrated Actinium’s ability to execute seamlessly across manufacturing, supply chain, clinical development, and operations. We intend to leverage these capabilities as we continue to advance our highly differentiated antibody-radiation conjugate pipeline for cell and gene therapy conditioning, hematology therapeutics, and solid tumor candidates. We are committed to establishing the best development path forward for Iomab-B in the US and finding a partner while keeping internal resources and strategic priorities in focus.”
