AstraZeneca's efzimfotase alfa posts mixed Phase III results for pediatric hypophosphatasia

Alexion, AstraZeneca's (LSE/STO/NYSE: AZN) rare disease unit, reported the results from a three-trial Phase III program for efzimfotase alfa in hypophosphatasia (HPP), with the pediatric arm meeting its primary endpoint and but falling short in the adolescent/adult arm, producing a mixed picture that complicates the path to a broad label.

The trial specifics

The MULBERRY trial is a randomized, double-blind, placebo-controlled Phase III study enrolling 29 treatment-naïve pediatric patients (ages 2 to under 12) with HPP across 14 countries. CHESTNUT is a randomized, open-label, active-controlled Phase III trial enrolling 43 pediatric patients previously treated with asfotase alfa (AstraZeneca's Strensiq). HICKORY is a randomized, double-blind, placebo-controlled Phase III study enrolling 124 treatment-naïve adolescents and adults across 17 countries. Together the program enrolled 196 patients across 22 countries.

In MULBERRY, efzimfotase alfa met its primary endpoint, demonstrating statistically significant improvement in the Radiographic Global Impression of Change (RGI-C) score at week 25 versus placebo, a measure of skeletal mineralisation. The key secondary endpoint, change from baseline in Rickets Severity Score, also reached statistical significance. Additional secondary measures of physical function and motor proficiency supported the primary finding, though no effect sizes or p-values were disclosed. In CHESTNUT, the primary endpoint was safety-focused — incidence of treatment-emergent adverse events — and the drug was described as well-tolerated with maintenance of bone health on radiographic secondary endpoints at week 25, consistent with Strensiq's established profile. No TEAE rates were reported numerically.

The more complex story comes from HICKORY. Efzimfotase alfa did not achieve statistical significance on the primary endpoint — change from baseline in the Six-Minute Walk Test (6MWT) at week 25 — in the overall adolescent and adult population. Alexion attributed the miss to better-than-expected placebo performance in the adult-onset subgroup, a phenomenon not uncommon in functional outcome trials in heterogeneous rare disease populations. In prespecified subgroups of adolescents and adults with pediatric-onset HPP, the drug showed nominally significant improvements in 6MWT, physical function, and pain reduction. The overall population showed nominally significant improvement in FACIT-Fatigue. Early open-label extension data from HICKORY at week 48 showed continued improvement, and placebo patients who crossed over showed benefit after 24 weeks on treatment — directionally supportive but uncontrolled.

The mechanistic and industry context

Efzimfotase alfa is a recombinant enzyme replacement therapy designed to restore deficient alkaline phosphatase (ALP) activity, the enzymatic deficit underlying HPP. The disease, caused by loss-of-function variants in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP), leads to accumulation of ALP substrates including inorganic pyrophosphate, which inhibits bone mineralization and produces rickets, fractures, muscle weakness, and systemic features including fatigue and pain. Approximately 80% of HPP patients are adults, and an estimated 11,500 individuals carry a diagnosis across the US and major European and Asian markets, with a US diagnosed prevalence of approximately 2.8 per 100,000.

The comparator of direct relevance is asfotase alfa (Strensiq), also developed by Alexion and the only approved disease-modifying therapy for HPP in the US and EU — where its label covers perinatal/infantile- and juvenile-onset disease only, with no approved pharmacologic option specifically for adult-onset HPP. Strensiq requires three to six subcutaneous injections per week, a burden that has been a consistent limitation in a lifelong condition. Efzimfotase alfa is dosed once every two weeks subcutaneously, a roughly 6- to 12-fold reduction in injection frequency, and is designed for lower injection volume. CHESTNUT directly compared the two molecules in a pediatric switch design, and efzimfotase alfa maintained bone health outcomes at week 25 while meeting its primary safety endpoint — providing the closest available head-to-head signal, albeit in an open-label, non-inferiority-framed design.

The regulatory question that follows from HICKORY is whether the primary endpoint miss in the overall adult population will constrain the eventual label to pediatric and adolescent patients with pediatric-onset disease, or whether the subgroup and extension data will be sufficient to support a broader indication that includes adult-onset HPP — the population currently without any approved therapy. Regulators have historically been cautious about granting broad labels based on subgroup-driven analyses, particularly when the overall trial primary endpoint is not met. The heterogeneity of HPP, with its wide spectrum of severity and age of onset, creates genuine endpoint selection challenges: functional walk tests may be less sensitive in adults with milder or more chronic disease, as the placebo performance in HICKORY suggests.

The program nonetheless represents the most extensive clinical dataset assembled in HPP to date, spanning treatment-naïve children, Strensiq-experienced children, and a treatment-naïve adolescent and adult population that includes adult-onset patients — the first registrational trial to do so. Alexion said the data will be presented at a forthcoming medical meeting and submitted to global regulatory authorities.

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