Efzimfotase Alfa Boosts Bone Health in Pediatric HPP Trial

Positive results from the MULBERRY Phase III trial showed that efzimfotase alfa (ALXN1850), an investigational enzyme replacement therapy, demonstrated a statistically significant and clinically meaningful improvement in bone health in children (2 to <12 years of age) with hypophosphatasia (HPP) who have not been previously treated with Strensiq (asfotase alfa) as measured by Radiographic Global Impression of Change (RGI-C) Score at week 25 compared to placebo.¹

These late-breaking results were presented today in an oral session at the 12th International Conference on Children's Bone Health (ICCBH) in Montreal, Canada.

In the MULBERRY trial, patients treated with efzimfotase alfa achieved an observed median RGI-C Score of 1.67 at week 25 compared to an observed median score of 0 in the placebo group, with a median difference of 1.67 (95% CI: 0.66, 2.00; p=0.0003).¹

The study also met its key secondary endpoint in bone health as measured by Rickets Severity Score (RSS), demonstrating a statistically significant improvement at week 25, with an observed median of -1.00 in the efzimfotase alfa group compared to 0 in the placebo group and a median difference of -1.00 (95% CI: -2.00, -0.33; p=0.0008).¹

In addition, efzimfotase alfa demonstrated improvements in secondary endpoints in physical function and quality of life at week 25, including a nominally significant median difference of 9.0 (95% CI: 1.0, 22.0; nominal p=0.0234) in Paediatric Outcomes Data Collection Instrument (PODCI) Global Function normative score and a clinically meaningful improvement in Six-Minute Walk Test (6MWT) with a median difference of 34.5m (95% CI: -27.0, 120.0; nominal p=0.4785) compared to placebo.¹

In the CHESTNUT trial, efzimfotase alfa demonstrated a similar incidence of treatment-emergent adverse events (TEAEs) at week 25 in children (2 to <12 years of age) who switched from Strensiq (90.5%) compared to those who remained on Strensiq (86.4%) with a favourable safety profile. Key secondary endpoints showed that bone health was maintained in children who received efzimfotase alfa after switching from Strensiq at week 25, including an observed median difference in RGI-C Score of 0 in the efzimfotase alfa group compared to the Strensiq group and an observed median RSS of 0 in the efzimfotase alfa group compared to -0.08 in the Strensiq group (median difference 0.08; 95% CI: -0.17, 0.32).¹

Full results from the HICKORY Phase III trial in adolescents and adults (12 years of age and older) with HPP who have not been previously treated with Strensiq will be shared at a forthcoming medical meeting.

Jill Simmons, MD, Director of the Program for Pediatric Metabolic Bone Disorders at Vanderbilt Health, Interim Director of Pediatric Endocrinology and Professor of Pediatric Endocrinology at Vanderbilt University and principal investigator for the CHESTNUT trial, said: "Underlying alkaline phosphatase deficiency in HPP can lead to severe, progressive bone, neurological and functional symptoms in children with detrimental impact to physical and social-emotional wellbeing during a critical stage of development. These positive results, including a statistically significant improvement in bone health and meaningful benefit in physical function, represent a clinically important advancement for children living with this lifelong disease."

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, said: "The efzimfotase alfa Phase III clinical programme represents the largest and most diverse investigation of HPP to date, spanning a broad patient population with a wide range of disease manifestations. By addressing the root cause of HPP, alkaline phosphatase deficiency, efzimfotase alfa has the potential to meaningfully improve outcomes with a convenient, self-administered option for the HPP patient community."

Summary of results at week 25: MULBERRY

RGI-C at week 25

RSS at week 25 change from baseline

Efzimfotase alfa demonstrated a favourable safety profile and was well-tolerated across all three Phase III clinical trials. In a pooled analysis of MULBERRY and HICKORY trials, the annualised Injection Site Reaction (ISR) rate was five times lower with efzimfotase alfa compared to Strensiq in its registrational trials during the first 24 weeks of treatment. In a pooled analysis of MULBERRY and HICKORY, including data from the open-label extension, patients treated with efzimfotase alfa achieved a median of 98.8% ISR-free days while on treatment.¹

Notes

Hypophosphatasia (HPP)
Hypophosphatasia (HPP) is a rare, chronic, inherited metabolic disease caused by deficient activity of the enzyme alkaline phosphatase (ALP), which is important for building healthy bones and supporting proper muscle function.² HPP is characterised by defective mineralisation (the process that hardens and strengthens bones and teeth), impaired calcium and phosphate regulation and functional impairments, such as muscle weakness, neurologic symptoms, generalised fatigue and pain that can be debilitating.^2,3 HPP can be progressive and clinical manifestations may evolve over time. While diagnosis rates vary by geography, there are an estimated 11,500 people diagnosed with HPP across the US, Germany, France, UK, Italy, Spain, Japan and China.^4-7 A recent study from the US estimated diagnosed prevalence at 2.8 per 100,000 people.⁸ HPP affects people of all ages, with approximately 80% of people living with HPP being adults.^2,3,8

MULBERRY
MULBERRY is a global Phase III randomised, double-blind, placebo-controlled, multicentre trial evaluating the efficacy and safety of efzimfotase alfa (ALXN1850) in paediatric patients (2 to <12 years of age) with hypophosphatasia (HPP) who have not been previously treated with Strensiq (asfotase alfa). The trial enrolled 29 patients from 14 countries across North America, South America, Europe and Asia.⁹

Patients were required to have an HPP diagnosis and the presence of HPP-related rickets on skeletal X-rays and low serum alkaline phosphatase (ALP) activity. Eligible patients also needed to demonstrate either a variant in ALPL, the gene encoding ALP, or elevated levels of plasma pyridoxal 5'-phosphate (PLP), a biomarker of HPP.⁹

Patients were randomised 2:1 to receive efzimfotase alfa at one of three doses based on predefined weight ranges or placebo, once every two weeks via subcutaneous injection for 24 weeks. The primary endpoint Radiographic Global Impression of Change (RGI-C) Score was assessed at the end of the randomised evaluation period (Day 169), along with multiple secondary endpoints measuring skeletal health and physical function, including change from baseline in the Rickets Severity Score (RSS), Six-Minute Walk Test (6MWT), Bruininks-Oseretsky Test of Motor Proficiency Score (BOT-2) and Peabody Developmental Motor Scales Score (PDMS-3).⁹

Patients who completed the randomised evaluation period were eligible to continue into an open-label extension period evaluating the safety and efficacy of efzimfotase alfa, which is ongoing.⁹

CHESTNUT
CHESTNUT is a global Phase III randomised, open-label, active-controlled, multicentre trial evaluating the safety and tolerability of efzimfotase alfa (ALXN1850) in paediatric patients (2 to <12 years of age) with hypophosphatasia (HPP) who have been treated with 6 mg/kg per week of Strensiq (asfotase alfa) for at least 6 months prior to study initiation. The trial enrolled 43 patients from seven countries globally.¹⁰

Patients were required to have an HPP diagnosis and have been treated with Strensiq for at least 6 months before the start of the trial with open growth plates confirmed by X-ray.¹⁰

Patients were randomised 1:1 to receive efzimfotase alfa at one of three doses based on predefined weight ranges once every two weeks or 6 mg/kg/week of Strensiq via 3x or 6x subcutaneous injections per week for 24 weeks. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) at the end of the randomised evaluation period. Key secondary endpoints include change from baseline in the Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C) Score.¹⁰

Patients who completed the randomised evaluation period were eligible to continue into an open-label extension period evaluating the safety and efficacy of efzimfotase alfa, which is ongoing.¹⁰

HICKORY
HICKORY is a global Phase III randomised, double-blind, placebo-controlled, multicentre trial evaluating the efficacy and safety of efzimfotase alfa (ALXN1850) in adolescents (12 to <18 years of age) and adults with hypophosphatasia (HPP) who have not been previously treated with Strensiq (asfotase alfa). The trial enrolled 124 patients from 17 countries across North America, South America, Europe, Asia and Australia.¹¹

Patients were required to have an HPP diagnosis and either a variant in ALPL, the gene encoding alkaline phosphatase (ALP), or elevated levels of plasma pyridoxal 5'-phosphate (PLP), a biomarker of HPP. Eligible patients needed to demonstrate low ALP levels and two separate Six-Minute Walk Tests (6MWTs) below 85% of the predicted distance adjusted for age, sex, weight and height, without a probable cause other than HPP.¹¹

Patients were randomised 2:1 to receive efzimfotase alfa at one of three doses based on predefined weight ranges or placebo, once every two weeks via subcutaneous injection for 24 weeks. The primary endpoint of change from baseline in 6MWT was assessed at the end of the randomised evaluation period (Day 169), along with multiple key secondary endpoints measuring physical function, pain, fatigue, quality of life and safety, including change from baseline in 30-second Sit to Stand (STS) Test Score, Lower Extremity Functional Scale (LEFS) Score, Brief Pain Inventory Short Form (BPI-SF) Score and Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Score.¹¹

Patients who completed the randomised evaluation period were eligible to continue into an open-label extension period evaluating the safety and efficacy of efzimfotase alfa, which is ongoing.¹¹

Efzimfotase alfa (ALXN1850)
Efzimfotase alfa (ALXN1850) is an investigational enzyme replacement therapy (ERT) designed to demonstrate efficacy and safety in a broad range of patients with hypophosphatasia (HPP) aged ≥ 2 years, including patients without overt bone manifestations. Efzimfotase alfa is being developed as a subcutaneous treatment administered every two weeks to replace the deficient alkaline phosphatase (ALP) enzyme activity that is the underlying cause of HPP.

Strensiq (asfotase alfa)
Strensiq (asfotase alfa) is a bone-targeted enzyme replacement therapy (ERT) designed to address the underlying cause of hypophosphatasia (HPP) - deficient alkaline phosphatase (ALP). By replacing deficient ALP, treatment with Strensiq aims to improve the elevated enzyme substrate levels and improve 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. Strensiq has been granted orphan drug designation by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Japanese Ministry of Health, Labour and Welfare (MHLW).

Alexion
Alexion, AstraZeneca Rare Disease, is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and delivery of life-changing medicines. A pioneering leader in rare disease for more than three decades, Alexion was the first to translate the complex biology of the complement system into transformative medicines, and today it continues to build a diversified pipeline across disease areas with significant unmet need, using an array of innovative modalities. As part of AstraZeneca, Alexion is continually expanding its global geographic footprint to serve more rare disease patients around the world. It is headquartered in Boston, US.

AstraZeneca
AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Disease, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide.