A phase 3 trial of AstraZeneca’s rare metabolic disease prospect has missed its primary endpoint, raising doubts about the company’s ability to expand beyond the children served by its existing drug.
The failed study tested the investigational enzyme replacement therapy efzimfotase alfa in adolescents and adults with hypophosphatasia (HPP), which affects bone development. AstraZeneca sells Strensiq for people with infantile- and juvenile-onset HPP. Through the phase 3 Hickory trial, the company aimed to secure a bigger market for its Strensiq successor by showing the therapy works in older patients.
But efzimfotase alfa was statistically no better than placebo at improving results on the six-minute walk test (6MWT) at Week 25, causing the study to miss its primary endpoint. The trial enrolled people 12 years and older with HPP who hadn’t previously received Strensiq.
AstraZeneca attributed the primary endpoint miss to better-than-expected results in the adult-onset HPP placebo group. The company said efzimfotase alfa showed nominally statistically significant and clinically meaningful improvements on the 6MWT in prespecified subgroups with pediatric-onset HPP. Secondary subgroup endpoints measuring physical function and pain reduction also favored the study drug.
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AstraZeneca reported nominally significant improvements on a fatigue scale in the overall population, plus continued improvement in the primary and key secondary endpoints in an open-label extension that tracked patients through Week 48.
Marc Dunoyer, CEO of AstraZeneca’s Alexion rare diease unit, said on an earnings call in February 2025 that efzimfotase alfa was designed to reach six times as many patients as Strensiq. Dunoyer named expanding into adults as a driver of the anticipated jump in the total addressable market. AstraZeneca predicted peak sales of $3 billion to $5 billion—above the $1.7 billion that Strensiq brought in (PDF) last year.
While the adult expansion suffered a setback, AstraZeneca’s push to develop efzimfotase alfa for people with infantile- and juvenile-onset HPP received a boost. The company shared news of the Hickory failure alongside details of the success of the phase 3 Mulberry trial, which enrolled children with HPP who hadn’t received Strensiq.
In that population, AstraZeneca reported a statistically significant and clinically meaningful improvement in bone health from baseline compared to placebo at Week 25, achieving the study’s primary endpoint. The trial also hit a key secondary endpoint that assessed rickets severity. AstraZeneca said assessments of physical function, including the 6MWT, and motor proficiency further supported the study drug.
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Another phase 3 trial, Chestnut, evaluated children who switched from Strensiq to efzimfotase alfa. The study showed efzimfotase alfa was well-tolerated with a favorable safety profile, AstraZeneca said, and maintained the benefit of Strensiq on bone health at Week 25.
The Big Pharma, which has yet to share data from any of the trials, plans to present the results at a medical meeting and submit them to regulatory authorities. If the company is unable to enter the adolescent and adult market, efzimfotase alfa’s prospects will rest on its potential advantages over Strensiq.
Patients in Mulberry received the study drug subcutaneously every two weeks. Strensiq is administered (PDF) subcutaneously three or six times a week, depending on the dose. Dunoyer said last month that the cost of making efzimfotase alfa is “way under” what AstraZeneca spends manufacturing Strensiq.
