AstraZeneca's Efzimfotase Alfa Shows Promise in Phase III Hypophosphatasia Trials with Mixed Results
Key Insights
Efzimfotase alfa met its primary endpoint in pediatric patients with hypophosphatasia (search), demonstrating statistically significant bone health improvements in the MULBERRY trial.
The investigational therapy failed to achieve statistical significance in its primary endpoint for adolescents and adults in the HICKORY trial, though it showed benefits in specific subgroups.
The drug offers potential advantages over current treatment with less frequent dosing every two weeks and maintained efficacy when patients switched from existing therapy.
AstraZeneca's Alexion division announced positive results from its comprehensive Phase III clinical program evaluating efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy for hypophosphatasia (search) (HPP (search)). The global program enrolled 196 patients across three trials spanning children, adolescents and adults with the rare metabolic disease across 22 countries.
Pediatric Trials Demonstrate Clear Efficacy
The MULBERRY Phase III trial achieved its primary endpoint in treatment-naïve children aged 2 to 12 years with HPP (search). Efzimfotase alfa demonstrated statistically significant and clinically meaningful improvement in bone health compared to placebo, as measured by Radiographic Global Impression of Change (RGI-C) Score at week 25. The trial also showed statistically significant improvement in the key secondary endpoint of Rickets Severity Score (RSS) at week 25.
"The results from the global MULBERRY clinical trial demonstrate efzimfotase alfa's potential to address the underlying pathophysiology of HPP (search) and to prevent and reverse the substantial skeletal and functional impacts of this lifelong rare disease," said Eric Rush, MD, Clinical Geneticist at Children's Mercy Hospital Kansas and lead principal investigator in the MULBERRY trial.
The companion CHESTNUT Phase III trial evaluated safety and tolerability in pediatric patients switching from STRENSIQ (asfotase alfa) to efzimfotase alfa. Results showed the investigational therapy was well-tolerated with a favorable safety profile and maintained treatment benefits on bone health at week 25.
Mixed Results in Adolescent and Adult Population
The HICKORY Phase III trial in adolescents and adults presented more complex results. While efzimfotase alfa showed numerical improvement, it did not achieve statistical significance in the primary endpoint of Six-Minute Walk Test (6MWT) at week 25 compared to placebo. This outcome was largely attributed to better-than-expected results in the adult-onset HPP (search) placebo group.
However, the therapy demonstrated nominally significant improvements in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in the overall study population. More importantly, in prespecified subgroups of adolescents and adults with pediatric-onset HPP (search), efzimfotase alfa showed nominally statistically significant and clinically meaningful benefits in mobility as measured by 6MWT, along with improvements in physical function and pain reduction.
"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," noted Kathryn Dahir, MD, Director of the Program for Metabolic Bone Disorders at Vanderbilt Health and lead investigator in the HICKORY trial.
Addressing Unmet Medical Needs
Efzimfotase alfa is designed to offer advantages over the current standard of care, STRENSIQ, including lower injection volume and less frequent dosing administered every two weeks via subcutaneous injection. The investigational therapy aims to replace deficient alkaline phosphatase enzyme activity, the underlying cause of HPP (search).
HPP (search) affects an estimated 11,500 people diagnosed across the US, Germany, France, UK, Italy, Spain, Japan and China, with approximately 80% being adults. A recent US study estimated diagnosed prevalence at 2.8 per 100,000 people. The rare disease is characterized by defective bone and teeth mineralization, impaired calcium and phosphate regulation, and functional impairments including muscle weakness, neurologic symptoms, fatigue and debilitating pain.
Safety Profile and Next Steps
Efzimfotase alfa demonstrated an acceptable safety profile across all three Phase III trials. Initial findings from ongoing long-term, open-label extensions show continued improvement in primary and key secondary endpoints at week 48. Participants who switched from placebo to efzimfotase alfa showed clinically meaningful improvements across multiple efficacy outcomes after 24 weeks of treatment.
"The efzimfotase alfa clinical programme, comprised of three global Phase III trials, was the first to include patients with both paediatric- and adult-onset HPP (search) with heterogeneous manifestations beyond bone," said Marc Dunoyer, Chief Executive Officer of Alexion, AstraZeneca Rare Disease. "Collectively, these results support the potential for efzimfotase alfa to transform the treatment paradigm for people living with this rare disease."
The company plans to present the data at an upcoming medical meeting and share results with global regulatory authorities.