Ultomiris indication expands into kidney disease

Adult trial misses primary endpoint…pediatric regulatory efforts continue

IgA nephropathy application receives priority review…expands the company’s renal portfolio

With the company continuing to expand Ultomiris’s indication into additional rare disease indications, a Phase III trial in adults with hematopoietic stem cell transplant-associated thrombotic microangiopathy failed to meet its primary endpoint. In contrast, its indication for IgA nephropathy has been granted priority review by the US Food and Drug Administration, allowing AstraZeneca to continue broadening the drug’s rare disease portfolio.

According to industry sources on the 30th, AstraZeneca recently disclosed results from the global Phase 3 ALXN1210-TMA-313 trial of Ultomiris (ravulizumab) in patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Hematopoietic stem cell transplant-associated thrombotic microangiopathy is a severe complication in which overactivation of the complement system after transplantation causes vascular endothelial injury and thrombosis. It can lead to damage to major organs, including the kidneys, and death, and remains a rare disease with limited treatment options.

Adult transplant complication trial fails to meet endpoint…pediatric approval in progress

C5 complement inhibitor ‘Ultromiris’

The ALXN1210-TMA-313 trial enrolled 146 adolescents and adults aged 12 years or older diagnosed with hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Patients received Ultomiris or placebo plus best supportive care for 26 weeks. The primary endpoint was event-free survival, defined by the time to disease worsening or death.

In the trial, Ultomiris failed to demonstrate a statistically significant improvement in EFS versus placebo. However, the company explained that a trend toward treatment benefit was observed and that it plans to continue discussions with regulatory authorities based on additional analyses, including real-world evidence.

By contrast, the global Phase III ALXN1210-TMA-314 trial in pediatric patients produced positive results.

Overall survival was 87.2% at Week 26 and 73.4% at Week 52. Alexion is pursuing regulatory approval for the pediatric indication using these results together with data from an external control study (ALX-TMA-502). In the US, the pediatric indication has received both breakthrough therapy and orphan drug designations.

Competition is also intensifying in the hematopoietic stem cell transplant-associated thrombotic microangiopathy market.

In the US, Omeros’ MASP-2 inhibitor Yartemlea (narsoplimab) was approved last year as the first treatment for the condition.

Yartemlea blocks the lectin complement pathway, giving it a different target from Ultomiris, which inhibits terminal complement protein C5. Their development strategies also differed. Yartemlea obtained approval based on a single-arm trial, while Ultomiris sought an indication expansion through a global placebo-controlled Phase III trial.

Expansion beyond hematologic diseases into neurologic and renal diseases…expands rare disease indications

Ultomiris is a monoclonal antibody targeting complement protein C5. It was developed as a successor to ‘Soliris (eculizumab)’ with an extended half-life, allowing adult patients to administer maintenance dosing once every eight weeks.

Its first indication was paroxysmal nocturnal hemoglobinuria. It was subsequently approved for atypical hemolytic uremic syndrome, generalized myasthenia gravis and neuromyelitis optica spectrum disorder, expanding its use from primarily hematologic diseases into neuroimmunologic conditions.

AstraZeneca is now broadening the development focus of Ultomiris into kidney disease.

Last month, the US FDA granted Priority Review to a supplemental application for Ultomiris to treat adults with IgA nephropathy. The filing was based on an interim analysis of the global Phase III I CAN trial. If approved, Ultomiris would become the first C5 complement inhibitor for IgA nephropathy.

In the I CAN study, the 24-hour urinary protein-to-creatinine ratio was reduced by 43.4% versus placebo at Week 34, meeting statistical significance. Follow-up is ongoing to determine whether the treatment provides long-term preservation of kidney function.

Other ongoing studies include the global Phase III AWAKE trial evaluating delayed graft function after kidney transplantation and a trial in pediatric generalized myasthenia gravis.