efzimfotase alfa (ALXN1850) / AstraZeneca, Alexion Pharma - LARVOL DELTA

Efzimfotase alfa granted Priority Review in the US as treatment for patients with hypophosphatasia aged 2 years and older (AstraZeneca Press Release) - "The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for its regulatory decision, is anticipated during the first half of 2027....The BLA is based on results from the efzimfotase alfa Phase III clinical program, which is comprised of three trials, HICKORY in adolescents and adults (12 years of age and older) who have not been previously treated with STRENSIQ (asfotase alfa), MULBERRY in children (2 to <12 years of age) who have not been previously treated with STRENSIQ and CHESTNUT in children previously treated with STRENSIQ."

FDA filing • PDUFA • Priority review • Genetic Disorders

Efficacy and Safety of Alkaline Phosphatase (ALP) Enzyme Replacement Therapy (ERT) Efzimfotase Alfa in Adolescents and Adults with Hypophosphatasia (HPP): Results of HICKORY as Part of a Three-Trial Phase 3 Clinical Program (ASBMR 2026) - No abstract available

Clinical • P3 data • Orthopedics

ALXN1850-HPP-301: Phase 3 Study of ALXN1850 versus Placebo in Adolescent and Adult Participants with HPP who have not previously been treated with Asfotase Alfa (clinicaltrialsregister.eu) - P2/3 | N=34 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • ALPL

Efzimfotase Alfa Improves Respiratory Capacity in Muscle Tissue From a Mouse Model of HPP. (PubMed, JIMD Rep) - "In a mouse model of HPP, we show that the altered mitochondrial respiration in skeletal muscle is improved by ERT and that HPP is characterized by altered muscle mitochondrial morphology in humans. Together, these data suggest ERT could improve muscular symptoms in HPP."

Journal • Preclinical • Fatigue • Metabolic Disorders

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=124 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Jul 2028 ➔ Mar 2028

Trial completion date • ALPL

MULBERRY: Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP (clinicaltrials.gov) - P3 | N=30 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Pediatrics • ALPL

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=124 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: May 2029 ➔ Jul 2028

Trial completion date • ALPL

Altered mitochondrial bioenergetics in hypophosphatasia and the influence of efzimfotase alfa (EULAR 2025) - "Altered mitochondrial bioenergetics may be a mechanism of muscle weakness in patients with HPP. The investigational therapy efzimfotase alfa (currently in phase 3 clinical trials) has the potential to benefit patients with muscle weakness. Bone and respirometry analysis in EDL muscle fiber bundles from Akp2GW mice."

Metabolic Disorders

Design of 3 Multicenter, Phase 3, Randomized Trials to Evaluate Efficacy and Safety of the Enzyme Replacement Therapy Efzimfotase Alfa in Patients With Hypophosphatasia (HICKORY, MULBERRY, CHESTNUT) (ESPE-ESE 2025) - P3 | "Introduction: Hypophosphatasia (HPP) is a rare inherited, metabolic disease caused by deficient tissue- nonspecific alkaline phosphatase (ALP) activity and characterized by skeletal and nonskeletal manifestations, including rickets/osteomalacia, fractures/pseudofractures, muscle weakness, and pain, which significantly impact quality of life. Treatment-naive patients have no prior exposure to asfotase alfa. BOT-2, Bruininks Oseretsky Test of Motor Proficiency, Second Edition; LEFS, Lower Extremity Functional Scale; PDMS-3, Peabody Developmental Motor Scales, Third Edition; RGI-C, Radiographic Global Impression of Change; RSS, Rickets Severity Scale; TEAE, treatment-emergent adverse event; TUG, Timed Up-and-Go."

Clinical • P3 data • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Pain

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=124 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Mar 2028 ➔ May 2029

Trial completion date • ALPL

Medical Management of Hypophosphatasia: Review of Data on Asfotase Alfa. (PubMed, Curr Osteoporos Rep) - "Alternatives to asfotase alfa remain limited, but a derivative, efzimfotase alfa, currently undergoes clinical testing. Studies in larger HPP patient populations suggest efficacy of enzyme replacement therapy independent of patient age and time of disease onset."

Journal • Review • Fatigue • Orthopedics • Pain • Pediatrics

CHESTNUT: Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=42 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Pediatrics

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=124 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • ALPL

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=114 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Jul 2028 ➔ Mar 2028 | Trial primary completion date: Dec 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • ALPL

MULBERRY: Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP (clinicaltrials.gov) - P3 | N=30 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Aug 2027 ➔ Apr 2028

Trial completion date • Pediatrics • ALPL

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=114 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Nov 2028 ➔ Jul 2028 | Trial primary completion date: Sep 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • ALPL

CHESTNUT: Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Oct 2027 ➔ Jan 2028

Trial completion date • Pediatrics

Safety, Pharmacokinetics, and Pharmacodynamics of Efzimfotase Alfa, a Second-generation Enzyme Replacement Therapy: Phase 1, Dose-escalation Study in Adults with Hypophosphatasia. (PubMed, J Bone Miner Res) - P1 | "Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. NCT04980248."

Journal • P1 data • PK/PD data • Metabolic Disorders • Pediatrics

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=114 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Aug 2027 ➔ Nov 2028

Trial completion date • ALPL

MULBERRY: Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP (clinicaltrials.gov) - P3 | N=30 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Pediatrics • ALPL

CHESTNUT: Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Pediatrics

CHESTNUT: Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=40 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | N=30 ➔ 40

Enrollment change • Pediatrics

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=114 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Aug 2025 ➔ Nov 2027

Enrollment open • Trial completion date • ALPL

MULBERRY: Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP (clinicaltrials.gov) - P3 | N=30 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Jun 2025 ➔ Aug 2027

Trial completion date • Pediatrics • ALPL

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=114 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Oct 2027 ➔ Aug 2025

Trial completion date • ALPL