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)

Dahir Kathryn M.; Freitas Joao Dinis; Barzano Maria Marfa; Damien Simoneau; Emma Blasi; Qunming Dong; Wei-Jian Pan; Derek Dunn

doi:10.1530/endoabs.110.EP287

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Endocrine Abstracts (2025) 110 EP287 | DOI: 10.1530/endoabs.110.EP287

ECEESPE2025 ePoster Presentations Bone and Mineral Metabolism (142 abstracts)

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)

Kathryn M. Dahir ¹ , Joao Dinis Freitas ² , Maria Marfa Barzano ² , Damien Simoneau ³ , Emma Blasi ² , Qunming Dong ⁴ , Wei-Jian Pan ⁴ & Derek Dunn ⁴

Author affiliations

¹Vanderbilt University Medical Center, Nashville, United States; ²Alexion, AstraZeneca Rare Disease, Barcelona, Spain; ³Alexion, AstraZeneca Rare Disease, Baar, Switzerland; ⁴Alexion, AstraZeneca Rare Disease, Boston, United States

JOINT1791

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. HPP was previously classified into subtypes by age at onset; however, manifestations can change and accumulate over time, suggesting that HPP is a continuous, progressive disease. The objective of the ongoing HICKORY (NCT06079281) and MULBERRY (NCT06079359) trials is to determine the efficacy and safety of efzimfotase alfa, an investigational next-generation ALP enzyme replacement therapy (ERT) for HPP in treatment-naive patients. The objective of the ongoing CHESTNUT (NCT06079372) trial is to determine the safety and tolerability of efzimfotase alfa in patients who initiate treatment after prior treatment with asfotase alfa, a first-generation ERT.

Study Design: HICKORY, MULBERRY, and CHESTNUT are ongoing multicenter, phase 3, randomized, parallel arm trials in patients ≥2 years of age (HICKORY: ≥12 years) with HPP (Table). Each study includes a 24-week randomized period followed by an open-label extension of up to 2.5 years. Weight-based doses of 20, 35, or 50 mg efzimfotase alfa will be administered subcutaneously biweekly. Approximately 184 patients will be recruited globally. This clinical program is the first to evaluate a broad HPP patient population across ages, ages at onset, manifestation types (including no overt skeletal manifestations), and functional endpoints such as the 6-Minute Walk Test (6MWT) and the 30-second Sit-to-Stand Test (STS).

Table
	HICKORY	MULBERRY	CHESTNUT
Design	Randomized, double-blind, parallel arm, placebo-controlled	Randomized, double-blind, parallel arm, placebo-controlled	Randomized, open-label, parallel arm, active-controlled
Treatment groups; allocation	Efzimfotase alfa vs placebo; 2:1	Efzimfotase alfa vs placebo; 2:1	Efzimfotase alfa vs asfotase alfa; 1:1
N (approximate)	~114	~30	~40
Age, y	≥12	2 to <12	2 to <12
Treatment naive^a	Yes	Yes	No
Primary endpoint	6MWT after 24 wk	RGI-C score after 24 wk	Incidence of TEAEs
Secondary endpoints	STS, LEFS, TUG, 6MWT, RGI-C, RSS	RSS, 6MWT, BOT2, PDMS-3,	RGI-C, RSS, 6MWT, BOT-2, PDMS-3
^aPatients in the CHESTNUT trial must have been treated with 6 mg/kg per week asfotase alfa for at least the 6 months before study initiation. 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.