Efficacy and Safety Evaluation of ALXN1850 in Pediatric Patients with Hypophosphatasia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of ALXN1850 compared to placebo on radiographic outcomes in pediatric participants with **hypophosphatasia** (HPP) who have not previously been treated with asfotase alfa. This is clinically relevant as it aims to determine the potential of ALXN1850 to improve bone health and structure in children affected by HPP, a rare metabolic bone disorder characterized by defective bone mineralization.

Secondary objectives include:

• Assessing the efficacy of ALXN1850 versus placebo on functional outcomes in the same population.
• Evaluating the effect of treatment on fatigue, pain, and health-related quality of life outcomes.
• Assessing treatment satisfaction with ALXN1850.
• Evaluating the safety and tolerability of ALXN1850 administered for up to 24 weeks.
• Evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of ALXN1850 over a 24-week period.
• Assessing immunogenicity to ALXN1850 throughout the study duration.

The clinical trial involves a total of **34 participants** diagnosed with **hypophosphatasia** (HPP), focusing on pediatric subjects who have not previously been treated with asfotase alfa. The study population comprises children aged between 2 and 12 years, including both male and female participants. The selection criteria ensure that participants have documented evidence of HPP-related rickets and serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted normal range. Additionally, participants must meet specific genetic or biochemical criteria related to the ALPL gene or pyridoxal phosphate (PLP) levels. The trial includes a vulnerable population, as it involves children, and requires informed consent from legal guardians and assent from the participants where applicable. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of ALXN1850 in pediatric participants with **hypophosphatasia** who have not previously been treated with asfotase alfa. The trial will involve participants aged 2 to less than 12 years and will be conducted over an estimated period ending on December 31, 2027. The study will commence recruitment on March 15, 2024, and will include multiple study visits to assess the primary and secondary endpoints.

Participants will undergo an initial **screening** visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis of hypophosphatasia, and laboratory findings. Following successful screening, participants will be randomized to receive either ALXN1850 or a placebo, administered via **subcutaneous injection**. The trial will consist of a **Randomized Evaluation Period** lasting 169 days, during which the primary endpoint, the RGI-C score, will be assessed. Secondary endpoints will include changes in the Rickets Severity Score, 6MWT, and various quality of life measures.

Study visits will be scheduled at regular intervals to monitor safety, efficacy, and pharmacokinetic parameters. Participants will be required to attend follow-up visits to evaluate changes from baseline in clinical and laboratory parameters. The end-of-study visit will occur at the conclusion of the Randomized Evaluation Period, where final assessments will be conducted. The expected length of participant involvement is approximately 156 days, with conditions for early termination including adverse events or non-compliance with study protocols.

The clinical trial involves the administration of **ALXN1850**, an experimental medication formulated as a **solution for injection**. The active substance, ALXN1850, is classified under the **ATC code A16AB**, which pertains to enzymes. The medication is produced by Alexion Pharmaceuticals, Inc. and is administered via **subcutaneous injection**. The dosing schedule is designed to ensure participant safety and compliance, with a maximum treatment period of 156 weeks. The trial aims to evaluate the efficacy of ALXN1850 in pediatric participants aged 2 to less than 12 years with **hypophosphatasia** who have not previously been treated with asfotase alfa.

In addition to the experimental treatment, a **placebo** product, referred to as the ALXN1850 placebo product, is utilized in the study. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the double-blind nature of the trial. The placebo is also administered as a solution for injection via subcutaneous injection. The use of a placebo control allows for a rigorous assessment of the efficacy and safety of ALXN1850 by providing a baseline for comparison.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the RGI-C score at the end of the Randomized Evaluation Period, specifically on Day 169. Secondary endpoints include changes from baseline in the Rickets Severity Score (RSS) at the end of the Randomized Evaluation Period, as well as various functional and quality of life measures. These include the 6-Minute Walk Test (6MWT) and its predicted percentage for participants aged 5 years and older, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2) for those aged 4 years and older, and the Peabody Developmental Motor Scales, Third Edition (PDMS-3) for participants under 4 years of age. Additionally, changes in health state scores using the EQ-5D-Y and its proxy version, the Pediatric Outcomes Data Collection Instrument (PODCI) Parent global function score, the Adolescent Pediatric Pain Tool (APPT) score, and the Pediatric FACIT-Fatigue scores will be evaluated.

Further assessments include the Treatment Satisfaction Questionnaire for Medication (TSQM-9) score, incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), adverse events of special interest (AESIs), and adverse events leading to study intervention discontinuation or interruption. Pharmacokinetic (PK) parameters such as AUC(0-24h) and C(trough) will be estimated, along with pharmacodynamic (PD) parameters including changes in plasma concentrations of PPi, PLP, PA, and the PLP/PL ratio. The incidence and response categories of anti-drug antibodies (ADA), as well as neutralizing antibody (NAb) incidence and titers, will also be monitored. These efficacy parameters will be measured and collected at specified timepoints, with the primary focus on the end of the Randomized Evaluation Period, Day 169.