Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of ALXN1850 in Adolescents and Adults with Hypophosphatasia Naïve to Asfotase Alfa Treatment

The primary objective of this study is to assess the **efficacy** of ALXN1850 compared to placebo on functional outcomes in adolescent and adult 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 functional capabilities in individuals affected by HPP, a rare metabolic bone disorder characterized by defective bone mineralization.

Secondary objectives include:

• Evaluating the efficacy of ALXN1850 versus placebo on functional outcomes in both adolescent and adult participants, as well as specifically in adult participants.
• Assessing the treatment effect on radiographic outcomes in adolescent participants.
• Evaluating the effect on health-related quality of life outcomes in both adult and adolescent participants, and specifically in adult participants regarding fatigue, pain, and quality of life.
• Assessing treatment satisfaction, safety, and tolerability of ALXN1850 in both adolescent and adult participants.
• Evaluating the pharmacokinetics/pharmacodynamics (PK/PD) and immunogenicity of ALXN1850 in both adolescent and adult participants.

The clinical trial involves a total of **88 participants** diagnosed with **hypophosphatasia** (HPP), a rare metabolic bone disease. The study population includes both male and female subjects, aged 12 years and older, encompassing adolescents and adults. Participants were selected based on specific inclusion criteria, such as a documented ALPL gene variant or elevated PLP levels, and serum ALP activity below the normal range. The trial also considers functional outcomes, requiring participants to have two separate 6-minute walk tests (6MWTs) below 85% of the predicted distance for their age, sex, weight, and height, without any probable cause other than HPP. The study includes individuals who have not previously been treated with asfotase alfa and are not willing or able to receive it. Participants must adhere to protocol-specified contraception requirements and provide informed consent or assent as applicable. The trial population is characterized by a vulnerable group, indicating the need for careful ethical considerations in the study design and execution.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **ALXN1850** administered subcutaneously in adolescent and adult participants with **hypophosphatasia** who have not previously been treated with asfotase alfa. The trial aims to assess the functional outcomes of ALXN1850 compared to placebo. The study is expected to commence recruitment on April 8, 2024, and conclude by December 31, 2027, with a maximum treatment period of 156 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of hypophosphatasia, and specific laboratory findings. The primary endpoint is the change from baseline in the 6-minute walk test (6MWT) at the end of the randomized evaluation period on Day 169. Secondary endpoints include changes in various functional and quality of life measures, such as the 30-second sit-to-stand test, Lower Extremity Functional Scale (LEFS), and Timed Up-and-Go (TUG) test, among others.

Study visits will include baseline assessments, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to evaluate the overall outcomes. The expected length of participant involvement is approximately 169 days, with conditions for early termination including adverse events leading to discontinuation or inability to comply with the study protocol. Participants will be monitored for the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), and other safety parameters throughout the study duration.

The clinical trial involves the administration of **ALXN1850**, a recombinant alkaline phosphatase, formulated as a **solution for injection**. The pharmaceutical form is specifically designed for **subcutaneous injection**. The trial aims to evaluate the efficacy and safety of ALXN1850 in adolescent and adult participants with **hypophosphatasia** who have not previously been treated with asfotase alfa. The dosing schedule and frequency of administration are determined by the study protocol, with a maximum treatment period of 156 weeks. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** product, referred to as the ALXN1850 placebo product, is utilized in this randomized, double-blinded, placebo-controlled study. The placebo is administered in the same manner as the active treatment, ensuring that the study maintains its blinded nature. The placebo is also formulated as a solution for injection and is administered subcutaneously. The use of a placebo allows for a direct comparison of the efficacy and safety of ALXN1850 against a non-active treatment, providing a robust assessment of the experimental medication's impact on the participants.

The efficacy of ALXN1850 in the treatment of **Hypophosphatasia** (HPP) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the 6-Minute Walk Test (6MWT) at the end of the Randomized Evaluation Period, specifically on Day 169. This test measures the distance a participant can walk in six minutes, providing an indication of functional exercise capacity.

Secondary endpoints include various functional and quality of life assessments. These comprise changes from baseline in the 30-second Sit-to-Stand (STS) test, Lower Extremity Functional Scale (LEFS), and Timed Up-and-Go (TUG) test, all evaluated at Day 169. Additionally, changes in the percentage of predicted 6MWT, RGI-C Score, and RGI-C responder status will be measured. Other assessments include changes in the EuroQoL 5 Dimensions 5 Level (EQ-5D-5L) scale, SF-36v2 PCS score, Brief Pain Inventory-Short Form (BPI-SF), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Pediatric assessments include the Pediatric Outcomes Data Collection Instrument (PODCI) Adolescent Self-reported score, Adolescent Pediatric Pain Tool (APPT) score, and Pediatric FACIT-Fatigue score. The TSQM-9 score will also be evaluated.

Biomarker analysis will involve measuring plasma concentrations of ALXN1850, including Ctrough levels and pharmacokinetic parameters in adolescent participants. Observations will include changes in plasma concentrations of inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), phosphoethanolamine (PA), and the PLP/PL ratio. Immunogenicity assessments will include ADA incidence, response categories, and titer, as well as NAb incidence and titer. These parameters will be collected and analyzed at the end of the Randomized Evaluation Period on Day 169.