Ultomiris Phase III Trial Misses Primary Endpoint in Adults with HSCT-TMA, But Paediatric Data Show Clinically Meaningful Survival Benefit
核心洞察
Ultomiris (ravulizumab) failed to achieve statistical significance for event-free survival at 26 weeks versus placebo in the ALXN1210-TMA-313 Phase III trial in adults and adolescents with HSCT-TMA (搜索).
In the paediatric ALXN1210-TMA-314 open-label trial, Ultomiris demonstrated clinically meaningful overall survival of 87.2% at 26 weeks and 73.4% at 52 weeks.
Alexion is advancing regulatory filings for Ultomiris in paediatric HSCT-TMA (搜索), supported by real-world evidence from the ALX-TMA-502 external control study.
Alexion, AstraZeneca Rare Disease, announced on 27 July 2026 that the Phase III ALXN1210-TMA-313 trial of Ultomiris (ravulizumab) did not meet its primary endpoint of event-free survival through 26 weeks compared to placebo in adults and adolescents aged 12 years or older with thrombotic microangiopathy (搜索) after haematopoietic stem cell transplant (HSCT-TMA (搜索)). The primary endpoint was defined as the time from randomisation until TMA-related clinical worsening or death, whichever occurred first.
Despite the miss on the primary endpoint, Ultomiris showed a trend toward treatment benefit in the adult and adolescent population at 26 weeks. Discussions with health authorities are ongoing regarding the interpretation of these data, including in the context of real-world evidence from the ALX-TMA-502 external control study.
Paediatric trial demonstrates clinically meaningful survival
In contrast, the ALXN1210-TMA-314 open-label Phase III trial in paediatric patients with HSCT-TMA (搜索) produced clinically meaningful overall survival results. Ultomiris treatment was associated with overall survival of 87.2% at 26 weeks and 73.4% at 52 weeks. These findings stand in stark contrast to historical one-year survival rates in paediatric HSCT-TMA patients, which are estimated between 17% and 44% based on scientific literature.
Christopher Dvorak, MD, Professor and Chief of the Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation at UCSF Benioff Children's Hospitals, commented: "Children who develop HSCT-TMA (搜索) 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."
Based on the paediatric results and supporting data from ALX-TMA-502, Alexion is advancing regulatory filings for Ultomiris in paediatric patients with HSCT-TMA (搜索). Ultomiris has already been granted Orphan Drug Designation in the US and Japan for HSCT-TMA, as well as Breakthrough Therapy designation by the US FDA specifically for paediatric patients with HSCT-TMA.
The challenge of conducting trials in HSCT-TMA (搜索)
Vincent Ho, MD, Director of Clinical Operations, Adult Hematopoietic Stem Cell Transplantation at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, acknowledged the difficulty of the undertaking: "HSCT-TMA (搜索) 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."
Marc Dunoyer, Chief Executive Officer of Alexion, emphasised the significance of the programme: "As the largest, global registrational programme conducted across a broad population of patients with HSCT-TMA (搜索) 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."
Trial designs and patient populations
The ALXN1210-TMA-313 trial was a global, Phase III, randomised, double-blind, placebo-controlled, multicentre study that enrolled 146 patients from 18 countries across North America, South America, Europe, Asia, and Australia. Participants were randomised 1:1 to receive either Ultomiris or placebo intravenously for 26 weeks, in addition to best supportive care. The dosing regimen included a loading dose on Days 1, 5, and 10, followed by weight-based maintenance dosing every eight weeks.
The ALXN1210-TMA-314 paediatric trial enrolled 41 patients from seven countries across North America, Europe, and Asia. This open-label, single-arm study evaluated Ultomiris in patients aged 28 days to less than 18 years. The primary endpoint was complete TMA response at 26 weeks, defined as a composite measure of haematologic and renal parameters. Dosing was weight-based, with maintenance infusions every four weeks for patients under 20 kg and every eight weeks for those 20 kg and above.
The ALX-TMA-502 real-world study provided historical control data from 307 patients across 10 countries, assessing overall survival in both complement inhibitor treatment-naïve participants and those treated with eculizumab.
Safety and next steps
The safety profile observed across both the ALXN1210-TMA-313 and ALXN1210-TMA-314 trials was consistent with the known safety profile of Ultomiris and with that seen in patients undergoing HSCT. Alexion plans to present the full data at a forthcoming medical meeting.
HSCT-TMA (搜索) is estimated to affect fewer than 6,000 people in the US. The condition is thought to arise from overactivation and/or dysregulation of the complement system triggered by factors associated with HSCT, including conditioning regimens and other transplant-related complications. One-year overall survival rates in adults range from approximately 17% to 58%, underscoring the significant unmet need in this population.
Dunoyer concluded: "We are moving forward with regulatory filings, with the goal of bringing a new treatment option to paediatric patients with HSCT-TMA (搜索) 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."