AstraZeneca Efzimfotase Alfa Misses Primary Endpoint in HPP Trial

AstraZeneca on 11 October 2026 reported full results from the HICKORY Phase III trial of efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy, in adolescents and adults aged 12 years and older with hypophosphatasia (HPP) who had not previously been treated with Strensiq (asfotase alfa). The trial did not achieve statistical significance on its primary endpoint: at week 25, the least squares (LS) mean difference versus placebo in change from baseline on the Six-Minute Walk Test (6MWT) was 17.05 metres (SE 12.223; p=0.1675) in the overall population. The results were presented the same day in an oral session at the 2026 American Society for Bone and Mineral Research (ASBMR) Annual Meeting in Boston, Massachusetts.

AstraZeneca (AZN ) said the lack of statistical significance was largely due to better-than-expected results observed in the adult-onset HPP placebo group. The week-25 analysis compared 84 patients treated with efzimfotase alfa against 40 patients on placebo. In a post hoc analysis at week 25, 45.2% of patients treated with efzimfotase alfa achieved the minimum clinically important difference (MCID) from baseline in 6MWT, defined as 43 metres in adolescents and 31.1 metres in adults, compared with 30.0% in the placebo group, an odds ratio of 2.50 (95% CI: 1.06, 5.91; nominal p=0.0363). The company characterized the result as a 2.5-fold higher odds of achieving a clinically meaningful 6MWT response.

On key secondary endpoints at week 25, the company reported nominally significant improvement in FACIT-Fatigue, with an LS mean difference of 5.74 (SE 1.733; nominal p=0.0016) versus placebo. Other key secondary endpoints numerically favoured efzimfotase alfa: the 30-second Sit-to-Stand (30s-STS) test showed an LS mean difference of 0.42 (SE 0.455; nominal p=0.3581), the Lower Extremity Functional Scale (LEFS) a difference of 3.56 (SE 2.173; nominal p=0.1055), and BPI-SF Pain Severity a difference of -0.60 (SE 0.300; nominal p=0.0508).

Prespecified Subgroups and Open-Label Extension

In a combination of prespecified subgroups of adolescents and adults with paediatric-onset HPP (n=60), efzimfotase alfa achieved an LS mean difference of 35.6 metres (SE 16.87; nominal p=0.0386) on the 6MWT at week 25, which AstraZeneca described as nominally significant and clinically meaningful. The company also reported nominal significance in this subgroup on 30s-STS (LS mean difference 1.3; SE 0.61; nominal p=0.0384) and BPI-SF Pain Severity (LS mean difference -1.0; SE 0.45; nominal p=0.0260). LEFS and FACIT-Fatigue in the subgroup showed LS mean differences of 3.7 (SE 3.31; nominal p=0.2645) and 3.5 (SE 2.64; nominal p=0.1876), respectively.

In the prespecified subgroup of adults with adult-onset HPP (n=64), the 6MWT LS mean difference was -2.70 metres (SE 17.32; nominal p=0.8764). AstraZeneca described nominally significant and clinically meaningful improvement on FACIT-Fatigue (LS mean difference 7.41; SE 2.29; nominal p=0.0021) and clinically meaningful improvement on LEFS (LS mean difference 3.5; SE 2.91; nominal p=0.2376) in this subgroup. The 30s-STS and BPI-SF Pain Severity endpoints showed LS mean differences of -0.43 (SE 0.62; nominal p=0.4927) and -0.26 (SE 0.40; nominal p=0.5222), respectively.

Kathryn Dahir, MD, Director of the Programme for Metabolic Bone Disorders at Vanderbilt Health and lead investigator in the HICKORY trial, said: “These results from the HICKORY Phase III trial signal benefits across multiple clinically relevant endpoints and represent an important step toward potentially bringing this advanced enzyme replacement therapy to a broad range of people who may benefit.”

In the open-label extension at week 49, patients continuing efzimfotase alfa showed continued improvement across the primary and key secondary endpoints, and patients switching from placebo following the randomised evaluation period at week 25 demonstrated similar improvement in measures of mobility, physical function, pain and fatigue, the company said. Patients continuing efzimfotase alfa recorded a mean 6MWT change from week 1 of 44.1 metres (SD 60.3) at week 37 and 61.9 metres (SD 78.4) at week 49, while patients switching from placebo recorded a mean change from week 25 of 43.0 metres (SD 71.0) at week 49. AstraZeneca characterized these gains as clinically meaningful improvements in 6MWT distance walked.

Safety, Trial Design and Phase III Programme

AstraZeneca said efzimfotase alfa demonstrated a favourable safety profile and was generally well-tolerated across all three Phase III clinical trials. In a pooled analysis of the MULBERRY and HICKORY trials that included open-label extension data, the annualised injection-site reaction (ISR) rate was five times lower with efzimfotase alfa than the rate observed with Strensiq in its registrational trials during the first 24 weeks of treatment, and patients treated with efzimfotase alfa achieved a median of 98.8% ISR-free days, according to the company.

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety at Alexion, AstraZeneca Rare Disease, said: “The HICKORY Phase III trial builds on the positive results from the MULBERRY and CHESTNUT trials and demonstrates the potential of efzimfotase alfa to address the diverse and complex clinical manifestations of HPP across a broad population of patients.” Efzimfotase alfa has been granted Priority Review by the US Food and Drug Administration for the treatment of patients with HPP aged 2 years and older.

HICKORY is a global Phase III randomised, double-blind, placebo-controlled, multicentre trial that enrolled 124 patients from 17 countries across North America, South America, Europe, Asia and Australia. Eligibility required an HPP diagnosis with either a variant in ALPL, the gene encoding alkaline phosphatase (ALP), or elevated levels of plasma pyridoxal 5′-phosphate, a biomarker of HPP, as well as low ALP levels and two separate 6MWTs below 85% of the predicted distance adjusted for age, sex, weight and height, without a probable cause other than HPP. Patients were randomised 2:1 to receive efzimfotase alfa at one of three doses based on predefined weight ranges or placebo, administered by subcutaneous injection once every two weeks for 24 weeks. The primary endpoint of change from baseline in 6MWT was assessed at the end of the randomised evaluation period on Day 169, alongside key secondary endpoints measuring physical function, pain, fatigue, quality of life and safety.

The broader Phase III programme includes MULBERRY, a randomised, double-blind, placebo-controlled trial that enrolled 29 treatment-naive children aged 2 to under 12 from 14 countries with the Radiographic Global Impression of Change (RGI-C) score as its primary endpoint, and CHESTNUT, an open-label, active-controlled trial that enrolled 43 children previously treated with Strensiq for at least six months from seven countries, with the incidence of treatment-emergent adverse events as its primary endpoint. Results from both trials were presented at the 12th International Conference on Children’s Bone Health, and their open-label extension periods remain ongoing.

HPP is a rare, chronic, inherited metabolic disease caused by deficient activity of the enzyme alkaline phosphatase, characterised by defective mineralisation, impaired calcium and phosphate regulation and functional impairments including muscle weakness, neurologic symptoms, generalised fatigue and pain. The company estimates the addressable HPP patient population at 13,800 across the US, Germany, France, UK, Italy, Spain, Japan and China, and, citing a US prevalence study, states that approximately 80% of people living with HPP are adults. Strensiq, Alexion’s enzyme replacement therapy approved in the US, EU, Japan and other countries for certain patients with HPP, holds orphan drug designation from the FDA, the European Medicines Agency and the Japanese Ministry of Health, Labour and Welfare. Efzimfotase alfa is being developed as a subcutaneous treatment administered every two weeks for patients with HPP aged 2 years and older, including patients without overt bone manifestations. Alexion is AstraZeneca’s rare disease unit and is headquartered in Boston.