FDA Grants Priority Review to Alexion's Efzimfotase Alfa BLA for Hypophosphatasia

The US Food and Drug Administration has accepted and granted Priority Review to the Biologics License Application filed by Alexion查看公司主页, AstraZeneca查看公司主页 Rare Disease, for efzimfotase alfa查看药品详情 in patients with hypophosphatasia (搜索)搜索该疾病 (HPP) aged two years and older, AstraZeneca announced on 18 September 2026. The Prescription Drug User Fee Act action date for the agency's regulatory decision is anticipated during the first half of 2027.

The FDA grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available treatment options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. Regulatory submissions for efzimfotase alfa查看药品详情 are also under review in Japan and other markets.

If approved, AstraZeneca查看公司主页 said efzimfotase alfa查看药品详情 would be the first treatment to address skeletal abnormalities and functional impairments regardless of disease onset, with biweekly dosing.

Marc Dunoyer, Chief Executive Officer of Alexion查看公司主页, said: "Today's Priority Review marks an important step forward for the HPP community and reinforces the potential for efzimfotase alfa查看药品详情 to redefine treatment outcomes." He said the therapy was designed to address the skeletal and functional manifestations of the disease with self-administration every two weeks, and cited five times lower annualised rates of injection site reactions compared to Strensiq查看药品详情, Alexion's approved HPP therapy.

Disease Burden and Target Population

HPP is a rare, chronic, inherited metabolic disease caused by deficient activity of the enzyme alkaline phosphatase查看药品详情 (ALP), which is important for building healthy bones and supporting proper muscle function. It is characterised by defective bone mineralisation, impaired calcium and phosphate regulation and functional impairments such as muscle weakness, neurologic symptoms, generalised fatigue and pain that can be debilitating. The disease can be progressive, and clinical manifestations may occur at any age and evolve over time.

The addressable HPP patient population is estimated at 13,800 across the US, Germany, France, the UK, Italy, Spain, Japan and China, according to AstraZeneca查看公司主页 data on file. Approximately 80% of people living with HPP are adults.

Three-Trial Phase III Programme

The BLA is based on what AstraZeneca查看公司主页 describes as the largest Phase III clinical programme in HPP, comprising three trials. HICKORY enrolled adolescents and adults aged 12 years and older who had not previously been treated with Strensiq查看药品详情 (asfotase alfa查看药品详情); MULBERRY enrolled children aged two to under 12 years who had not previously received Strensiq; and CHESTNUT enrolled children previously treated with Strensiq. The programme enrolled 196 patients spanning children, adolescents and adults with paediatric-onset or adult-onset HPP across 22 countries, the company said when it reported topline results on 31 March 2026.

MULBERRY was a randomised, double-blind, placebo-controlled, multicentre trial that enrolled 29 patients from 14 countries across North America, South America, Europe and Asia. Participants were required to have an HPP diagnosis with HPP-related rickets on skeletal X-rays and low serum ALP activity, and to demonstrate either a variant in ALPL (搜索)搜索该靶点, the gene encoding ALP, or elevated levels of plasma pyridoxal 5'-phosphate (PLP), a biomarker of HPP. Patients were randomised 2:1 to receive efzimfotase alfa查看药品详情 at one of three doses based on predefined weight ranges or placebo, once every two weeks by subcutaneous injection for 24 weeks. The primary endpoint, the Radiographic Global Impression of Change (RGI-C) Score, was assessed at Day 169, with secondary endpoints including the Rickets Severity Score (RSS), the Six-Minute Walk Test (6MWT), the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) and the Peabody Developmental Motor Scales (PDMS-3).

CHESTNUT was a randomised, open-label, active-controlled, multicentre trial in 43 children from seven countries who had received Strensiq查看药品详情 at 6 mg/kg per week for at least six months before the trial, with open growth plates confirmed by X-ray. Participants were randomised 1:1 to efzimfotase alfa查看药品详情 every two weeks or continued Strensiq via three or six subcutaneous injections per week for 24 weeks. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), with key secondary endpoints of change from baseline in RSS and RGI-C.

HICKORY was a randomised, double-blind, placebo-controlled, multicentre trial that enrolled 124 adolescents and adults from 17 countries. Eligible patients had 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 for 24 weeks, with a primary endpoint of change from baseline in 6MWT and key secondary endpoints including the 30-second Sit to Stand test, the Lower Extremity Functional Scale, the Brief Pain Inventory Short Form and the FACIT-Fatigue score. Patients completing each trial's randomised period were eligible to continue into ongoing open-label extension periods.

Week-25 Efficacy and Safety Results

MULBERRY met its primary endpoint, with patients treated with efzimfotase alfa查看药品详情 achieving an observed median RGI-C score of 1.67 at week 25 compared with 0 for placebo, a median difference of 1.67 (95% CI: 0.66, 2.00; p=0.0003), according to detailed results released on 28 June 2026 and presented at the 12th International Conference on Children's Bone Health (ICCBH) in Montreal. The trial also met its key secondary endpoint, with an observed median RSS of -1.00 versus 0 for placebo (median difference -1.00; 95% CI: -2.00, -0.33; p=0.0008).

Further secondary endpoints in MULBERRY included a nominally significant median difference of 9.0 in the Paediatric Outcomes Data Collection Instrument (PODCI) Global Function normative score (nominal p=0.0234), a 6MWT median difference of 34.5 metres (nominal p=0.4785), a BOT-2 Strength and Agility composite median difference of 7.0 (nominal p=0.0384) and a combined self- and proxy-reported EQ-5D-Y median difference of 0.14 (nominal p=0.0196).

In CHESTNUT, the incidence of TEAEs at week 25 was 90.5% among children who switched to efzimfotase alfa查看药品详情 compared with 86.4% among those who remained on Strensiq查看药品详情. Bone health was maintained after the switch, with an observed median difference in RGI-C score of 0 and an observed median RSS of 0 in the efzimfotase alfa group versus -0.08 in the Strensiq group (median difference 0.08; 95% CI: -0.17, 0.32).

In HICKORY, efzimfotase alfa查看药品详情 showed numerical improvement but did not achieve statistical significance on the 6MWT primary endpoint at week 25, an outcome AstraZeneca查看公司主页 attributed largely to better-than-expected results in the adult-onset HPP placebo group. The company reported nominally significant improvements in FACIT-Fatigue in the overall study population, and nominally significant benefits in mobility, physical function and pain reduction in a combination of prespecified subgroups of adolescents and adults with paediatric-onset HPP. Initial findings from the ongoing open-label extension showed continued improvement in primary and key secondary endpoints at week 48, and participants who switched from placebo to efzimfotase alfa after the randomised period showed clinically meaningful improvements across multiple efficacy outcomes after 24 weeks of treatment.

Eric Rush, MD, a clinical geneticist at Children's Mercy Hospital Kansas and lead principal investigator in the MULBERRY trial, said in the March announcement: "The results from the global MULBERRY clinical trial demonstrate efzimfotase alfa查看药品详情's potential to address the underlying pathophysiology of HPP and to prevent and reverse the substantial skeletal and functional impacts of this lifelong rare disease."

Injection Site Reactions and Tolerability

AstraZeneca查看公司主页 said efzimfotase alfa查看药品详情 demonstrated a favourable safety profile and was generally well-tolerated across all three trials. In a pooled analysis of MULBERRY and HICKORY, the annualised injection-site-reaction rate was five times lower with efzimfotase alfa than with Strensiq查看药品详情 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 while on treatment, the company reported.

Mechanism and Comparator

Efzimfotase alfa查看药品详情 (ALXN1850查看药品详情) is an investigational enzyme replacement therapy designed to demonstrate efficacy and safety in a broad range of patients with HPP aged two years and older, including patients without overt bone manifestations. It is being developed as a subcutaneous treatment administered every two weeks to replace the deficient ALP enzyme activity that underlies HPP.

Strensiq查看药品详情 (asfotase alfa查看药品详情) is a bone-targeted enzyme replacement therapy designed to address the underlying cause of HPP by replacing deficient ALP, aiming to improve elevated enzyme substrate levels and the body's ability to mineralise bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Strensiq is approved in the US, EU, Japan and other countries for the treatment of certain patients with HPP, and holds orphan drug designation from the FDA, the European Medicines Agency and Japan's Ministry of Health, Labour and Welfare.

Results from the MULBERRY and CHESTNUT trials were presented at the 12th ICCBH, and results from the HICKORY trial will be presented at the upcoming 2026 American Society for Bone and Mineral Research Annual Meeting, AstraZeneca查看公司主页 said.