Alexion Advances Paediatric HSCT-TMA Regulatory Filings Despite Ultomiris Misses Primary Endpoint in Phase III Adult HSCT-TMA Trial

High-level results from the Phase III ALXN1210-TMA-313 trial showed that Ultomiris (ravulizumab) did not achieve statistical significance for its primary endpoint of event-free survival at 26 weeks compared with placebo in adults and adolescents aged 12 years and older with thrombotic microangiopathy following haematopoietic stem cell transplantation (HSCT-TMA). The primary endpoint measured the time from randomisation to either TMA-related clinical worsening or death.

Christopher Dvorak, MD, Professor and Chief of the Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation at UCSF Benioff Children’s Hospitals, said: “Children who develop HSCT-TMA have an extremely poor prognosis without targeted treatment. While the scientific understanding of this condition continues to evolve, survival remains a critical measure of clinical benefit. The overall survival results observed in this Phase III paediatric trial are clinically meaningful for this young patient population with significant unmet need and may lead to a targeted treatment option for children facing this serious, post-transplant complication.”

In paediatric patients with HSCT-TMA, results from the open-label Phase III ALXN1210-TMA-314 trial showed clinically meaningful overall survival rates of 87.2% at 26 weeks and 73.4% at 52 weeks. Based on these findings, along with supporting data from the ALX-TMA-502 external control study, Alexion, AstraZeneca Rare Disease is moving forward with regulatory submissions for Ultomiris in paediatric HSCT-TMA. The company said the additional data further support a clinically meaningful survival benefit in this patient population.

Vincent Ho, MD, Director of Clinical Operations, Adult Hematopoietic Stem Cell Transplantation and Institute Physician at Dana-Farber Cancer Institute, Professor of Medicine at Harvard Medical School, said: “HSCT-TMA is a serious complication after stem cell transplant with high rates of associated morbidity and mortality and for which effective therapy remains an area of great unmet need. Conducting a global, randomised trial in this complex, life-threatening, post-transplant condition is exceedingly difficult. While the Phase III trial in adults and adolescents did not meet the primary endpoint, the results add new, important insights to advance the field. Continued evaluation of these data together with results collected from recent, real-world experience, will further advance clinical understanding and treatment of this complex transplant complication.”

Although the adult and adolescent study did not meet its primary endpoint, Ultomiris demonstrated a trend towards treatment benefit at 26 weeks compared with placebo. Alexion is continuing discussions with health authorities regarding the interpretation of the results, including how the findings align with available real-world evidence. The safety results across both Phase III studies were consistent with the established safety profile of Ultomiris and the safety profile generally observed in patients undergoing HSCT.

Marc Dunoyer, Chief Executive Officer, Alexion, said: “As the largest, global registrational programme conducted across a broad population of patients with HSCT-TMA and the only placebo-controlled trial in this adult population, these trials have demonstrated the potential of Ultomiris to improve survival in paediatric patients with this complex condition. We are moving forward with regulatory filings, with the goal of bringing a new treatment option to paediatric patients with HSCT-TMA and their families as quickly as possible. At the same time, we will continue engagement with global health authorities on potential next steps for the adult indication, as we advance additional analyses in the context of real-world data.”

HSCT-TMA is a serious and potentially life-threatening complication that can develop following haematopoietic stem cell transplantation, a procedure increasingly used to treat certain cancers and other diseases. The condition can cause blood clots and damage to small blood vessels, potentially leading to organ failure and death. It is estimated to affect fewer than 6,000 people in the US. Alexion plans to present the latest findings at an upcoming medical meeting. Ultomiris has received Orphan Drug Designation in the US and Japan for HSCT-TMA and Breakthrough Therapy designation from the US FDA for paediatric patients with the condition.