AstraZeneca’s Efzimfotase Alfa Misses Endpoint in Hypophosphatasia Trial

AstraZeneca, through Alexion, AstraZeneca Rare Disease, has reported detailed results from the HICKORY Phase III trial of efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy for hypophosphatasia (HPP). The trial did not meet its primary endpoint, although results favoured treatment across several functional and symptom-related measures. The findings, presented at the 2026 American Society for Bone and Mineral Research (ASBMR) Annual Meeting, highlight differences in observed treatment responses between disease-onset subgroups.

Primary Endpoint Not Met Despite Numerical Improvement

HICKORY enrolled 124 treatment-naïve adolescents and adults aged 12 years and older with HPP, randomised in a 2:1 ratio to receive subcutaneous efzimfotase alfa or placebo every two weeks for 24 weeks. The primary endpoint was change from baseline in the Six-Minute Walk Test (6MWT), assessed at week 25.

Efzimfotase alfa achieved a least-squares mean difference of 17.05 metres versus placebo (p=0.1675), which did not reach statistical significance. AstraZeneca attributed the result partly to better-than-expected outcomes in the adult-onset HPP placebo group.

In a post hoc analysis, 45.2% of treated patients achieved the minimum clinically important difference (MCID) in walking distance, compared with 30.0% receiving placebo. The odds ratio was 2.50 (95% CI: 1.06–5.91; nominal p=0.0363). However, this exploratory finding does not overturn the unsuccessful primary endpoint.

Treatment Responses Differed by Disease Onset

In the prespecified paediatric-onset subgroup, efzimfotase alfa achieved a 35.6-metre difference in 6MWT versus placebo (nominal p=0.0386). The subgroup also showed nominally significant improvements in the 30-second Sit-to-Stand test (difference: 1.3; p=0.0384) and Brief Pain Inventory-Short Form (BPI-SF) Pain Severity score (difference: −1.0; p=0.0260).

By contrast, the adult-onset subgroup showed no improvement in walking distance versus placebo (difference: −2.70 metres; nominal p=0.8764). However, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score improved by 7.41 points (nominal p=0.0021). The Lower Extremity Functional Scale difference was 3.5 points (p=0.2376), which was not statistically significant.

These findings suggest differences in the observed effects on mobility and fatigue across subgroups. However, the results do not establish that disease onset predicts treatment response, particularly given the unsuccessful primary endpoint and the exploratory nature of nominal significance testing.

Fatigue Improvement and Longer-Term Findings

In the overall population, efzimfotase alfa improved FACIT-Fatigue scores by 5.74 points versus placebo (nominal p=0.0016). Differences in the 30-second Sit-to-Stand test, Lower Extremity Functional Scale and BPI-SF Pain Severity score favoured treatment but did not reach nominal statistical significance.

During the open-label extension, patients continuing treatment showed mean improvements in 6MWT distance of 44.1 metres at week 37 and 61.9 metres at week 49, measured from week 1. Patients who switched from placebo to efzimfotase alfa at week 25 improved by a mean of 43.0 metres at week 49, measured from week 25.

These findings indicate continued improvement during treatment, but the open-label extension lacked a concurrent placebo comparison, limiting conclusions about long-term treatment effects.

Safety and Regulatory Status

AstraZeneca reported that efzimfotase alfa was generally well tolerated across its Phase III programme. A pooled analysis of the HICKORY and MULBERRY trials found a fivefold lower annualised injection-site reaction rate than rates reported in Strensiq registrational trials during the first 24 weeks. Patients receiving efzimfotase alfa also had a median of 98.8% injection-site-reaction-free days. These historical comparisons were not derived from a direct randomised head-to-head trial.

The US Food and Drug Administration (FDA) has accepted efzimfotase alfa’s Biologics License Application and granted Priority Review for patients aged two years and older, with a regulatory decision anticipated in the first half of 2027. The application draws on three Phase III trials: HICKORY (NCT06079281) in adolescents and adults, MULBERRY (NCT06079359) in previously untreated children, and CHESTNUT (NCT06079372) in children previously treated with Strensiq.

Clinical Implications

HICKORY’s failure to meet its primary endpoint limits the strength of the efficacy conclusions for the overall adolescent and adult population. The subgroup findings and continued improvements in the open-label extension provide additional evidence for regulatory assessment, but require cautious interpretation. The FDA’s review will consider the broader clinical programme rather than treating the HICKORY subgroup results as confirmatory evidence on their own.

Reference

Efzimfotase alfa showed numerical improvement in Six-Minute Walk Test achieving mean difference of 17.05 metres vs placebo in treatment-naïve adolescents and adults with hypophosphatasia at week 25 in HICKORY Phase III trial, Astra Zeneca, 11 October 2026

Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants with HPP Who Have Not Previously Been Treated with Asfotase Alfa (HICKORY), ClinicalTrials.gov ID NCT06079281