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)

Introduction: Hypophosphatasia (HPP) is a rare inherited, metabolic disease caused by deficienttissue-nonspecific alkaline phosphatase (ALP) activity and characterized byskeletal and nonskeletal manifestations, including rickets/osteomalacia, fractures/pseudofractures, muscle weakness, and pain, which significantly impact qualityof life. HPP was previously classified into subtypes by age at onset; however,manifestations can change and accumulate over time, suggesting that HPP is acontinuous, progressive disease. The objective of the ongoing HICKORY(NCT06079281) and MULBERRY (NCT06079359) trials is to determine theefficacy and safety of efzimfotase alfa, an investigational next-generation ALPenzyme replacement therapy (ERT) for HPP in treatment-naive patients. Theobjective of the ongoing CHESTNUT (NCT06079372) trial is to determine thesafety and tolerability of efzimfotase alfa in patients who initiate treatment afterprior treatment with asfotase alfa, a first-generation ERT. Methods : Study Design: HICKORY, MULBERRY, and CHESTNUT are ongoing multicenter, phase 3, randomized, parallel arm trials in patients R2 years of age (HICKORY: R12 years) with HPP ([ Tab. 1 ]). 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. Discussion: 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).