AstraZeneca's Ultomiris Misses Primary Endpoint in Adult HSCT-TMA Phase III Trial but Shows Promising Pediatric Survival Rates

Adult Phase III Trial Fails to Meet Primary Endpoint Despite Positive Trend

AstraZeneca announced that the ALXN1210-TMA-313 Phase III trial of Ultomiris in adults and adolescents aged 12 years or older with HSCT-TMA did not achieve statistical significance for its primary endpoint of event-free survival through 26 weeks. This endpoint measured the time from randomisation to TMA-related clinical worsening or death. The trial enrolled 146 patients across 18 countries spanning North America, South America, Europe, Asia, and Australia, representing a comprehensive global registrational program for this rare disease.

Despite not meeting the primary endpoint, Ultomiris exhibited a trend toward clinical benefit compared to placebo at 26 weeks in the adult and adolescent population. AstraZeneca emphasized ongoing engagement with global health authorities to interpret these findings, including the integration of real-world evidence. The safety profile observed was consistent with known Ultomiris data and typical HSCT patient experiences, with no unexpected safety concerns. Discussions with regulators continue as AstraZeneca explores alternative pathways for adult indication approval based on further analyses.

Paediatric Trial Shows Robust Overall Survival Supporting Regulatory Progress

Contrasting the adult results, the ALXN1210-TMA-314 open-label Phase III trial in paediatric HSCT-TMA patients demonstrated significant overall survival benefits. The trial reported survival rates of 87.2% at 26 weeks and 73.4% at 52 weeks, substantially exceeding historical one-year survival estimates of 17% to 44% in untreated paediatric patients, underscoring the severe prognosis of HSCT-TMA in children.

Enrolling 41 patients from seven countries across North America, Europe, and Asia, the ALXN1210-TMA-314 trial’s positive outcomes, along with supportive data from ALX-TMA-502, an external control study, have led Alexion, AstraZeneca Rare Disease, to advance regulatory filings for paediatric HSCT-TMA treatment. Marc Dunoyer, Alexion CEO, expressed the company’s commitment to delivering a new therapeutic option to affected children and their families promptly. The trial’s primary endpoint was complete TMA response at 26 weeks, with secondary endpoints including overall survival, non-relapse mortality, and TMA response criteria.

Real-World Evidence from External Control Study Reinforces Paediatric Benefit

AstraZeneca detailed ALX-TMA-502, a global observational retrospective study providing historical control and real-world context for HSCT-TMA treatment. This study evaluated overall survival in adults and paediatric patients aged 28 days and older diagnosed with HSCT-TMA within 52 weeks post-transplant. It included cohorts of complement inhibitor-naïve patients and those treated with eculizumab, encompassing 307 patients from 10 countries across North America, South America, Europe, and Asia.

The external control data further support Ultomiris’s clinically meaningful overall survival benefit in paediatric patients, bolstering AstraZeneca’s regulatory submission case. The primary endpoint was overall survival through 52 weeks post-diagnosis, with secondary endpoints including survival at 100 days and 26 weeks, and non-relapse mortality at multiple time points. Combining this real-world evidence with clinical trial data provides a comprehensive package for regulatory discussions worldwide.

HSCT-TMA: A Rare, Severe Post-Transplant Complication with Limited Therapies

HSCT-TMA is a rare, severe thrombotic microangiopathy occurring after haematopoietic stem cell transplantation, a procedure increasingly used for certain cancers and diseases. Affecting fewer than 6,000 individuals in the US, HSCT-TMA involves complement system overactivation triggered by transplant-related factors, leading to microvascular damage.

Clinical manifestations include blood clots and damage to small blood vessels, potentially causing organ failure and death. Historical data indicate one-year survival rates of 17% to 44% in paediatric patients and approximately 17% to 58% in adults, highlighting the critical unmet need. Symptoms overlap with other conditions, often causing diagnostic delays. Common signs include kidney damage, low platelet counts, anaemia, fragmented red blood cells, thrombosis, and hypertension.

Ultomiris: Long-Acting Complement Inhibitor with Multiple Approved Indications

Ultomiris (ravulizumab) is the longest-acting C5 complement inhibitor, delivering immediate and sustained complement blockade by targeting the C5 protein in the terminal complement cascade. After a loading dose, Ultomiris is administered intravenously every eight weeks in adults or every four to eight weeks in paediatric patients based on weight, offering dosing convenience.

Ultomiris is approved in the US, EU, Japan, and other regions for paroxysmal nocturnal haemoglobinuria (PNH) in adults and children, atypical haemolytic uraemic syndrome (aHUS) in adults and children, generalised myasthenia gravis in adults, and neuromyelitis optica spectrum disorder in adults. AstraZeneca continues to explore additional indications within a broad development program.

Regulatory Designations Facilitate Accelerated Development

Ultomiris has received Orphan Drug Designation in the US and Japan for HSCT-TMA, granting development incentives and market exclusivity benefits. Notably, the US FDA granted Breakthrough Therapy designation for paediatric HSCT-TMA treatment, enabling expedited development and review due to the drug’s potential to address a serious condition with unmet needs.

These designations highlight recognition of HSCT-TMA’s unmet medical need and the promising paediatric trial outcomes. AstraZeneca plans to present detailed trial data at an upcoming medical conference to advance clinical understanding of HSCT-TMA and complement inhibition’s role.

Expert Insights on Trial Outcomes and Unmet Needs

Christopher Dvorak, MD, Professor and Chief of Pediatric Allergy, Immunology and Bone Marrow Transplantation at UCSF Benioff Children's Hospitals, emphasized the poor prognosis for children with HSCT-TMA without targeted therapies. He noted that the paediatric trial’s overall survival results are clinically meaningful and may offer a new treatment option for this vulnerable population.

Vincent Ho, MD, Director of Clinical Operations for Adult Hematopoietic Stem Cell Transplantation at Dana-Farber Cancer Institute and Harvard Medical School Professor, acknowledged the adult trial’s challenges and the high unmet need for effective therapies. He highlighted the value of the trial’s insights and the importance of integrating real-world data to enhance understanding and treatment of HSCT-TMA.

AstraZeneca’s Strategic Path Forward for Adult and Paediatric Indications

Marc Dunoyer, Alexion CEO, described the trials as the largest global registrational program for HSCT-TMA and the only placebo-controlled study in adults. He affirmed the potential of Ultomiris to improve paediatric survival and confirmed ongoing regulatory filings aimed at rapidly delivering new treatment options for children.

For adults, AstraZeneca will maintain dialogue with global regulators while pursuing additional analyses incorporating real-world evidence. This dual approach prioritizes paediatric regulatory progress while exploring alternative adult efficacy measures or patient subsets to demonstrate clinical benefit.

Alexion Rare Disease Division and AstraZeneca’s Commitment

Alexion, AstraZeneca Rare Disease, leads Ultomiris development, focusing on rare diseases and transformative medicines based on complement biology. With over 30 years of leadership, Alexion continues expanding its pipeline and global reach to serve rare disease patients worldwide, headquartered in Boston, US.

AstraZeneca, headquartered in Cambridge, UK, is a global science-driven biopharmaceutical company specializing in Oncology, Rare Disease, and BioPharmaceuticals. Its medicines are marketed in over 125 countries, underscoring its commitment to rare disease innovation and patient access, which supports potential paediatric HSCT-TMA treatment availability.