AstraZeneca HPP Drug Shows Gains Despite Missing Key Phase III Endpoint

Key Points

• Efzimfotase alfa missed HICKORY’s primary endpoint: The treatment produced a numerically greater improvement in six-minute walking distance than placebo, but the difference was not statistically significant at 25 weeks.
• Despite the miss, AstraZeneca reported clinically meaningful improvements in lower-extremity function, pain and fatigue, with some measures reaching nominal statistical significance, particularly among patients with pediatric-onset HPP.
• Regulatory and commercial prospects remain active: Applications are under review, the FDA granted priority review, and AstraZeneca expects peak sales of $3 billion to $5 billion. The therapy’s every-two-week dosing and lower injection-site reaction rate could support adoption versus Strensiq.

Astrazeneca NYSE: AZN presented Phase III data for efzimfotase alfa, an investigational enzyme replacement therapy for hypophosphatasia (HPP), at the American Society for Bone and Mineral Research annual meeting in Boston. The company said the therapy showed improvements in several measures of function, pain and fatigue in adolescents and adults, although the HICKORY trial did not meet its primary endpoint.

HPP is a rare inherited condition caused by deficient alkaline phosphatase activity. The disease can affect patients throughout their lives, with manifestations ranging from life-threatening skeletal and respiratory complications in infants to fractures, chronic pain, fatigue, muscle weakness, tooth loss and disability in adults, according to Gianluca Pirozzi, head of development, rare disease and safety at Alexion.

HICKORY missed primary walking endpoint

The randomized, double-blind, placebo-controlled HICKORY study enrolled treatment-naive HPP patients ages 12 and older. Participants were assigned in a 2-to-1 ratio to efzimfotase alfa or placebo, with 84 patients receiving the investigational treatment and 40 receiving placebo.

The primary endpoint was change in the Six-Minute Walk Test at 25 weeks. Raja Padidela, a consultant paediatric endocrinologist in metabolic bone disease at Royal Manchester Children’s Hospital, said patients receiving efzimfotase alfa walked a numerically longer distance than patients on placebo, but the difference was not statistically significant.

In the open-label extension, patients continuing on efzimfotase alfa recorded a 61.9-meter increase in walking distance over 49 weeks, according to Padidela. Patients initially assigned to placebo and switched to efzimfotase alfa at week 25 showed a 43-meter increase from the start of active treatment.

Among key secondary measures, the study showed clinically meaningful improvements in lower-extremity function, pain severity and fatigue, though only the FACIT-Fatigue result was statistically significant, Padidela said. Pain interference with daily activities and treatment satisfaction also favored efzimfotase alfa and were statistically significant, according to the presentation.

In a prespecified subgroup with pediatric-onset HPP, the treatment produced clinically meaningful improvements in the Six-Minute Walk Test, 30-second sit-to-stand test, lower-extremity function and pain severity. The walking, sit-to-stand and pain results were nominally statistically significant. In the adult-onset subgroup, lower-extremity function and fatigue improved clinically meaningfully, while fatigue was nominally statistically significant.

Company cites placebo variability and patient characteristics

During the question-and-answer session, Pirozzi said the adult-onset population included two placebo patients with unusually large improvements in walking distance, which he said influenced the trial result. He also cited a lower baseline walking distance in the placebo group, the older average age of adult-onset participants, comorbidities and use of assistive devices as factors that could affect Six-Minute Walk Test outcomes.

Pirozzi said the company believes HPP has the same underlying genetic and mechanistic basis across pediatric-onset and adult-onset disease. He added that AstraZeneca designed its program to assess patients across a broader spectrum of HPP, including adults with adult-onset disease and patients without skeletal manifestations.

The company has submitted applications in major geographies and said those filings are under review. Pirozzi declined to speculate on regulatory decisions but confirmed that the U.S. Food and Drug Administration granted priority review for the totality of the data package, including pediatric-onset and adult-onset patients.

Broader Phase III program and tolerability profile

Efzimfotase alfa is designed as a second-generation enzyme replacement therapy based on experience with Strensiq, the only approved HPP therapy. The investigational treatment is administered once every two weeks, compared with Strensiq dosing of three to six times weekly, according to AstraZeneca.

The company said efzimfotase alfa’s enhanced enzyme activity, optimized Fc design, extended half-life and manufacturing process could reduce treatment burden and support broader access. Across the HICKORY, MULBERRY and CHESTNUT Phase III studies, AstraZeneca reported a favorable safety and tolerability profile.

Padidela said participants receiving efzimfotase alfa achieved a median 98.8% of days free from injection-site reactions. The annualized injection-site reaction rate was five times lower than with asfotase alfa, the active ingredient in Strensiq, according to the presentation.

In the pediatric MULBERRY study, efzimfotase alfa improved radiographic bone measures at week 25 versus placebo, including a median Radiographic Global Impression of Change score of positive 1.67 compared with zero for placebo. In CHESTNUT, which assessed children switching from Strensiq, AstraZeneca said adverse events were comparable between switch patients and those remaining on Strensiq, while clinical benefits in bone health, function and quality of life were maintained.

Commercial outlook

Marc Dunoyer, chief executive officer of Alexion and chief strategy officer of AstraZeneca, said available data suggest approximately 14,000 addressable HPP patients across the eight largest markets. AstraZeneca estimates that 20% are pediatric cases, 60% are adults with pediatric-onset disease and 20% are adults with adult-onset disease.

Dunoyer said the company expects efzimfotase alfa growth to come from both patients transitioning from Strensiq and newly treated patients. AstraZeneca reiterated its peak-year sales expectation of $3 billion to $5 billion. Dunoyer said a narrower label would place sales toward the lower end of that range, while a broader label could support results nearer the upper end.

About Astrazeneca (NYSE:AZN)

AstraZeneca PLC is a global biopharmaceutical company headquartered in Cambridge, United Kingdom. Its research, development and commercial operations focus on prescription medicines for serious and chronic diseases, with an emphasis on discovering and delivering innovative therapies rather than operating as a diversified healthcare conglomerate.

The company's principal therapeutic areas include oncology; cardiovascular, renal and metabolic diseases; respiratory and immunological conditions; and rare diseases.

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