Efzimfotase alfa has shown positive Phase 3 results in children with hypophosphatasia, while mixed outcomes were reported in adolescent and adult populations.

The global Phase 3 clinical programme for efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy, included three trials across 196 patients in 22 countries, spanning pediatric, adolescent and adult populations with hypophosphatasia (HPP).

In the MULBERRY Phase 3 trial, efzimfotase alfa met its primary endpoint in treatment-naïve children aged two to under 12 years. The study demonstrated statistically significant and clinically meaningful improvements in bone health compared to placebo, measured by Radiographic Global Impression of Change score at week 25. Secondary endpoints, including Rickets Severity Score, physical function and motor proficiency, also showed improvement.

The CHESTNUT Phase 3 trial evaluated patients switching from STRENSIQ (asfotase alfa) and showed that efzimfotase alfa was well tolerated, maintaining treatment benefit on bone health at week 25 based on secondary endpoint measures.

In contrast, the HICKORY Phase 3 trial in adolescents and adults did not meet its primary endpoint of improvement in the Six-Minute Walk Test at week 25. The company said this was influenced by stronger-than-expected performance in the placebo group among adult-onset patients.

However, efzimfotase alfa demonstrated improvements in fatigue, measured by Functional Assessment of Chronic Illness Therapy-Fatigue, and showed clinically meaningful benefits in prespecified subgroups of adolescents and adults with pediatric-onset disease. These included improvements in mobility, physical function and pain reduction compared to placebo.

Initial data from the ongoing open-label extension of the HICKORY trial indicated continued improvements at week 48, with patients switching from placebo also showing benefit after 24 weeks of treatment.

Efzimfotase alfa was reported to be well tolerated across all three trials, with an acceptable safety profile.

Hypophosphatasia is a rare genetic disorder affecting bone mineralisation, with symptoms ranging from skeletal abnormalities in childhood to progressive muscle weakness, pain and respiratory complications in later life.

Eric Rush, clinical geneticist and lead principal investigator in the MULBERRY trial, said: “The results from the global MULBERRY clinical trial demonstrate efzimfotase alfa’s potential to address the underlying pathophysiology of HPP and to prevent and reverse the substantial skeletal and functional impacts of this lifelong rare disease.”

He added: “I am encouraged by these results and the potential for this innovative, investigational therapy to redefine care in HPP with a convenient self-administered option taken every two weeks.”

Kathryn Dahir, director of the program for metabolic bone disorders at Vanderbilt Health and lead investigator in the HICKORY trial, said: “Findings from the broad HICKORY registrational trial, the first to include patients with adult-onset disease, highlight the heterogeneity of the disease and the value of assessing a range of clinically meaningful endpoints across diverse patient populations.”

She added: “The results indicate a clinically relevant impact on mobility, physical function, pain and fatigue, demonstrating the potential for efzimfotase alfa to improve outcomes for patients living with this disease.”

Marc Dunoyer, chief executive officer of Alexion, AstraZeneca Rare Disease, said: “The efzimfotase alfa clinical program, comprised of three global Phase 3 trials, was the first to include patients with both pediatric- and adult-onset HPP with heterogeneous manifestations beyond bone.”

He added: “We are encouraged by the improvements observed across this patient population who exhibit a wide range of severity and clinical characteristics.”

The data are expected to be presented at an upcoming medical meeting and shared with regulatory authorities, as the company evaluates next steps for the therapy across different patient populations.