AstraZeneca (LSE/STO/NYSE: AZN) reported that ravulizumab (Ultomiris) failed to meet the primary endpoint in a Phase III placebo-controlled trial in adults and adolescents with thrombotic microangiopathy following hematopoietic stem cell transplant, narrowing the drug's near-term approval prospects in HSCT-TMA to the pediatric population, where separate single-arm data are supporting a regulatory filing.
The ALXN1210-TMA-313 trial enrolled 146 patients aged 12 years or older across 18 countries and measured event-free survival over 26 weeks, defined as time from randomization to TMA-related clinical worsening or death. Ravulizumab did not achieve statistical significance versus placebo on that endpoint, though AstraZeneca's Alexion unit described a trend toward treatment benefit at 26 weeks and said discussions with health authorities are ongoing, including in the context of real-world evidence.
The pediatric arm tells a different story. The ALXN1210-TMA-314 open-label Phase III trial in 41 patients aged 28 days to under 18 years reported overall survival of 87.2% at 26 weeks and 73.4% at 52 weeks — figures that compare favourably against published one-year survival estimates of 17% to 44% for untreated paediatric HSCT-TMA. Alexion is advancing regulatory filings for the pediatric indication, supported by those results and data from ALX-TMA-502, a retrospective real-world study of 307 patients that provides historical control context. Ravulizumab holds Breakthrough Therapy designation from the US FDA and Orphan Drug Designation in the US and Japan specifically for pediatric HSCT-TMA.
Ravulizumab inhibits complement protein C5, blocking its cleavage into the anaphylatoxin C5a and the membrane attack complex C5b-9; in HSCT-TMA, uncontrolled complement activation triggered by conditioning regimens and transplant-related complications is thought to drive endothelial injury, microvascular thrombosis, and organ damage. The drug is already approved in the US, EU, Japan, and other markets for paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.
The adult trial failure has direct competitive implications. Omeros' Yartemlea (narsoplimab), a MASP-2 inhibitor targeting the lectin complement pathway, received FDA approval in December 2025 for HSCT-TMA in patients aged two years and older — making it the only approved therapy specifically for this indication in the US. The European Medicines Agency's CHMP issued a negative opinion on narsoplimab for HSCT-TMA, citing concerns about the reliability of external comparator survival data, meaning no approved therapy exists in Europe. A ravulizumab approval in the paediatric population would not directly compete with narsoplimab's adult label, but the two drugs would overlap in the paediatric segment and represent mechanistically distinct options — terminal C5 inhibition versus lectin pathway blockade — in a disease where the relative contribution of different complement pathways remains incompletely understood.