Efzimfotase alfa misses statistical significance on primary walking endpoint but improves fatigue in adolescents and adults with hypophosphatasia in HICKORY Phase III trial

Alexion, AstraZeneca Rare Disease, has reported results from the HICKORY Phase III trial of efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy, in adolescents and adults aged 12 and over with hypophosphatasia (HPP) who had not previously received Strensiq (asfotase alfa). The drug did not reach statistical significance on the primary endpoint, the Six Minute Walk Test (6MWT), but showed a numerical improvement over placebo at week 25. Across the overall population, the least squares mean difference was 17.05 metres (p=0.1675). The company attributed the missed significance largely to placebo group results in adult onset HPP that were better than expected.

A post hoc analysis found that 45.2 per cent of patients on efzimfotase alfa reached the minimum clinically important difference in 6MWT at week 25, compared with 30.0 per cent on placebo. The threshold was 43 metres in adolescents and 31.1 metres in adults. That works out to 2.5 times higher odds of a clinically meaningful walking response (odds ratio 2.50; 95% CI 1.06 to 5.91; nominal p=0.0363).

Among the key secondary endpoints, FACIT Fatigue improved with a nominally significant least squares mean difference of 5.74 against placebo (nominal p=0.0016). The other key secondary measures also numerically favoured efzimfotase alfa. These were the 30 second Sit to Stand test, the Lower Extremity Functional Scale and BPI SF Pain Severity.

In the open label extension, patients who stayed on efzimfotase alfa kept improving through week 49 across the primary and key secondary endpoints, covering walking distance, physical function, pain and fatigue. Those who switched from placebo at week 25 showed similar gains. Patients continuing treatment walked 44.1 metres further than at the start at week 37 (SD 60.3) and 61.9 metres further at week 49 (SD 78.4). Those who switched gained 43.0 metres from week 25 to week 49 (SD 71.0). Both groups passed the threshold for a clinically meaningful change.

Results differed by age of disease onset. In the combined prespecified subgroups of adolescents and adults with paediatric onset HPP, efzimfotase alfa produced a nominally significant and clinically meaningful 35.6 metre advantage in 6MWT over placebo at week 25 (nominal p=0.0386). It also showed nominally significant benefits on the Sit to Stand test (difference 1.3; nominal p=0.0384) and pain severity (difference of minus 1.0; nominal p=0.0260). In the adult onset subgroup, the drug showed a clinically meaningful improvement on the Lower Extremity Functional Scale (difference 3.5; nominal p=0.2376) and a nominally significant, clinically meaningful gain in fatigue (difference 7.41; nominal p=0.0021).

Efzimfotase alfa was generally well tolerated across all three Phase III trials. In a pooled analysis of MULBERRY and HICKORY, the annualised injection site reaction rate over the first 24 weeks was five times lower than that seen with Strensiq in its registrational trials. Including open label extension data, patients on efzimfotase alfa had a median of 98.8 per cent injection site reaction free days while on treatment.

Kathryn Dahir, MD, director of the Programme for Metabolic Bone Disorders at Vanderbilt Health, associate director for clinical research translation, professor of internal medicine in the Division of Endocrinology, Diabetes and Metabolism and lead investigator in HICKORY, said the chronic, progressive burden of HPP in adolescents and adults reaches far, affecting physical function and emotional wellbeing, and can limit people’s ability to live independently, form connections and hold down a job. She said the HICKORY results point to benefits across several clinically relevant endpoints and are an important step towards offering this enzyme replacement therapy to a broad group of people who could benefit.

Gianluca Pirozzi, senior vice president and head of development, regulatory and safety at Alexion, AstraZeneca Rare Disease, said HICKORY builds on the positive MULBERRY and CHESTNUT results and shows the potential of efzimfotase alfa to address the varied and complex clinical features of HPP across a wide patient population. He said that with Priority Review recently granted in the US, the company looks forward to bringing a therapy with favourable tolerability and convenient dosing to the HPP community, including people with limited treatment options.

The HICKORY results were presented in an oral session at the 2026 American Society for Bone and Mineral Research Annual Meeting in Boston, Massachusetts. Results from MULBERRY and CHESTNUT were recently presented at the 12th International Conference on Children’s Bone Health.

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Related Topics and Keywords

AstraZeneca, Efzimfotase alfa, HICKORY Phase III trial, hypophosphatasia, Phase 3 trial