Ultomiris Fails Phase 3 in HSCT-TMA: Second Alexion Setback This Month

AstraZeneca (AZN) announced on July 27, 2026, that Ultomiris (ravulizumab-cwvz) failed to achieve statistical significance on the primary endpoint of event-free survival through 26 weeks in the Phase 3 ALXN1210-TMA-313 trial. The trial tested the long-acting C5 complement inhibitor against placebo in adults and adolescents aged 12 and older with thrombotic microangiopathy after haematopoietic stem cell transplant (HSCT-TMA), a rare and potentially fatal complication affecting fewer than 6,000 people in the US.

The global, randomized, double-blind, placebo-controlled trial enrolled 146 patients across 18 countries. The primary endpoint measured time from randomization until TMA-related clinical worsening or death. While Ultomiris showed a trend toward treatment benefit at 26 weeks compared to placebo, it did not reach statistical significance. The safety profile was consistent with the known profile of Ultomiris and with complications seen in patients undergoing HSCT.

This is the second Phase 3 failure for AstraZeneca’s Alexion rare disease division in July 2026. On July 9, the company disclosed that eplontersen (Wainua), partnered with Ionis Pharmaceuticals (IONS), missed its primary endpoint in the CARDIO-TTRansform trial for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), the largest ATTR-CM trial ever conducted. The back-to-back misses put pressure on the Alexion pipeline, which AstraZeneca acquired for $39 billion in 2021.

The HSCT-TMA failure does not kill the entire program. A separate open-label Phase 3 trial in pediatric patients (ALXN1210-TMA-314) demonstrated clinically meaningful overall survival of 87.2% at 26 weeks and 73.4% at 52 weeks. Alexion is advancing regulatory filings for the pediatric population based on those results plus data from ALX-TMA-502, an external control study. The FDA granted Breakthrough Therapy designation for Ultomiris in pediatric HSCT-TMA, and the drug holds Orphan Drug designation in the US and Japan.

The broader Ultomiris franchise remains intact. The drug is already approved for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic ureaemic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). A separate IgA nephropathy (IgAN) filing based on the I CAN Phase 3 trial, which showed a 43.4% reduction in proteinuria versus placebo at 34 weeks, was granted FDA Priority Review in June 2026 with a PDUFA date anticipated in the fourth quarter. That filing uses a different endpoint (proteinuria reduction) and a different disease mechanism than the HSCT-TMA event-free survival endpoint, so the failure does not directly implicate the IgAN program.

Alexion CEO Marc Dunoyer said the company is “moving forward with regulatory filings” for the pediatric HSCT-TMA indication while continuing discussions with health authorities regarding potential next steps for the adult indication, including additional analyses in the context of real-world data.

AZN closed at $172.48 on July 28, up from $169.64 on July 25. The stock has shown limited reaction to the HSCT-TMA failure, consistent with the indication’s small patient population and the fact that Ultomiris’s commercial trajectory depends on its approved indications and the pending IgAN filing, not on HSCT-TMA.

What to watch next: The Ultomiris IgAN PDUFA in Q4 2026 is the next major Alexion catalyst. If approved, it would be the first C5 complement inhibitor for IgAN. Investors will also be watching for full ALXN1210-TMA-313 results at a forthcoming medical meeting, where secondary endpoint data (overall survival, non-relapse mortality) may clarify whether the adult indication has any regulatory path forward.

Sources: AstraZeneca press release, ClinicalTrials.gov NCT04543591