AstraZeneca’s enzyme replacement therapy (ERT) candidate, efzimfotase alfa, has failed to demonstrate significant benefits over placebo in a late-stage trial in rare bone and muscle-targeting metabolic disease, hypophosphatasia (HPP).
This late-stage miss stems from the Phase III HICKORY study (NCT06079281), in which AstraZeneca’s rare disease arm, Alexion Pharmaceuticals, pitted efzimfotase alfa against placebo in adults and adolescents with HPP. Patients enrolled in this study had not received prior treatment with Alexion’s marketed enzyme replacement therapy, Strensiq (asfotase alfa).
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During the trial, efzimfotase alfa offered a 17.05-meter baseline improvement in the six-minute walk test (6MWT) after 25 weeks of treatment. However, this value failed to trump the improvements in the same endpoint attained by patients in the placebo group, resulting in the trial missing its primary endpoint. In a statement, AstraZeneca called the placebo results from HICKORY “better-than-expected.”
Despite this primary endpoint miss, a post-hoc analysis of the study did reveal that 45.2% of patients treated with efzimfotase alfa achieved a minimum clinically important difference (MCID) from baseline in the 6MWT over 30% in the placebo arm. This means that treatment with efzimfotase alfa offered a 2.5-fold higher chance of a patient receiving a clinically meaningful response in the 6MWT, when MCID is classified as 31.1 and 43-meter improvements in walking distance within adults and adolescents, respectively.
On top of this sign of efzimfotase alfa’s efficacy, the drug also offered significant improvements to patients’ self-reported levels of fatigue over placebo. Meanwhile, the drug also demonstrated a nominally significant 35.6-meter benefit versus placebo in 6MWT values – an event observed in a combination of prespecified subgroups of patients with paediatric-onset HPP.
In a prespecified subgroup of adults with adult-onset HPP, efzimfotase alfa demonstrated clinically meaningful improvement in the key secondary endpoint of the Lower Extremity Functional Scale (LEFS) and nominally significant and clinically meaningful improvement in FACIT-Fatigue.
While efzimfotase alfa may not have offered significant benefits in the general population during the HICKORY study, AstraZeneca rare disease’s SVP and head of development, regulatory and safety, Gianluca Pirozzi, noted that the company will forge on with its efforts to bring the drug to patients with HPP – a rare, genetic condition characterised by weak bones and teeth due to the insufficient deposit of key minerals like calcium and phosphorus.
This comes as patients currently have access to limited treatment options, with Strensiq being the only drug approved in the US for HPP. According to analysts at GlobalData, the parent company of Clinical Trials Arena, blockbuster Strensiq’s sales will peak in 2027 at just over $2bn, before dropping by over 35% to the end of the forecast period in 2032.
However, AstraZeneca is not the only one looking to enter the HPP market, as BioMarin acquired Alesta Therapeutics and its candidate, ALE1, for $490m in August 2026. Researchers are currently evaluating ALE1, an inorganic pyrophosphate-lowering therapy, through a Phase I/IIa clinical trial (NCT07179640).
