Efficacy and Safety Evaluation of Setrusumab in Osteogenesis Imperfecta: A Randomized Phase 2/3 Study with Dose-Evaluation and Placebo-Controlled Phases

The primary objective of this study is to identify a **setrusumab** dosing strategy in subjects with **osteogenesis imperfecta** (OI) during Phase II. In Phase III, the study aims to evaluate the effect of setrusumab versus placebo on the reduction in fracture rate, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull. This is clinically relevant as it seeks to establish an effective treatment regimen for reducing fracture incidence in patients with OI, a condition characterized by fragile bones.

Secondary objectives include:

• Phase II - Evaluate the pharmacokinetics (PK) of setrusumab doses in subjects with OI.
• Phase II - Determine the pharmacodynamic (PD) effects of setrusumab on bone formation and turnover markers.
• Phase II - Evaluate the effect of setrusumab on lumbar spine bone mineral density (BMD).
• Phase II - Evaluate the safety profile of setrusumab for the treatment of subjects with OI.
• Phase II - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI.
• Phase III - Evaluate the effect of setrusumab vs placebo on reduction in fracture rate.
• Phase III - Evaluate the effect of setrusumab vs placebo on lumbar spine BMD.
• Phase III - Evaluate the effect of setrusumab vs placebo on clinical outcome assessments including subject-/caregiver-reported assessments of physical function, pain, and health-related quality of life.
• Phase III - Assess the safety profile of setrusumab.
• Phase III - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI.

The clinical trial involves a total of **121 participants** diagnosed with **osteogenesis imperfecta (OI)**, specifically Types I, III, or IV, confirmed by genetic testing. The study population includes both **males and females** aged 5 to less than 26 years at the time of informed consent. Participants are required to have experienced at least one fracture in the past 12 months or multiple fractures in the past 24 months. The trial population was selected based on specific inclusion criteria, including a serum 25-hydroxyvitamin D level of at least 20 ng/mL at screening, with supplementation allowed if initial levels are below this threshold. Participants must be willing to abstain from bisphosphonate therapy during the study and adhere to contraceptive measures if of childbearing potential. The trial also requires participants to provide access to their medical records for data collection purposes. The study includes a vulnerable population, emphasizing the need for informed consent or assent, as appropriate, and the ability to comply with study requirements.

The clinical trial is designed to evaluate the **efficacy** and safety of **setrusumab** in subjects with **osteogenesis imperfecta** (OI). This study is structured as an operationally seamless, randomized Phase 2/3 trial, consisting of a Phase 2 single-blind, dose-evaluation phase and a Phase 3 double-blind, placebo-controlled phase. The trial aims to identify an optimal dosing strategy for setrusumab in Phase 2 and to assess its effect on fracture rate reduction in Phase 3. The trial is expected to run from June 2023 to May 2026, with participant involvement lasting up to 24 months.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of OI Type I, III, or IV, and recent fracture history. The screening visit will also include assessments of serum 25-hydroxyvitamin D levels and a review of medical records. Following the screening, eligible participants will be randomized to receive either setrusumab or a placebo, administered as a solution for infusion via intravenous use. Study visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetics, with primary endpoints including the percent change in serum P1NP from baseline at Month 1 for Phase 2 and the annualized rate of radiographically-confirmed fractures for Phase 3.

Secondary endpoints will evaluate additional parameters such as serum setrusumab concentration, bone turnover markers, and changes in DXA lumbar spine BMD z-scores. Participants will be required to adhere to the study visit schedule and comply with all assessments. The end-of-study visit will conclude the trial, with final evaluations and data collection. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial is not categorized as low intervention and follows EMA guidelines for Phase II/III clinical trials.

The clinical trial involves the administration of **Setrusumab**, a fully human immunoglobulin G subclass 2 (IgG2) lambda anti-sclerostin neutralizing monoclonal antibody. Setrusumab is provided in the form of a **solution for infusion** and is administered via **intravenous use**. The dosing regimen for Setrusumab is determined based on a milligram per kilogram (mg/kg) basis, with a maximum daily dose of 20 mg/kg. The total treatment period for Setrusumab is set at 24 weeks. The medication is of biological/biotechnological origin and is not formulated specifically for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes the use of a **placebo** control, which is a **dextrose/glucose 5% solution in water**. This placebo is utilized to maintain the double-blind nature of the Phase 3 portion of the trial, allowing for an unbiased assessment of Setrusumab's efficacy and safety. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding is maintained. The placebo does not contain any active pharmaceutical ingredients and serves as a comparator to evaluate the therapeutic effects of Setrusumab in subjects with **osteogenesis imperfecta**.

The efficacy of **Setrusumab** in the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase II, the primary endpoint is the percent change in serum P1NP from baseline at Month 1. Secondary endpoints include serum setrusumab concentration at scheduled time points, baseline-corrected area under the effect curve (AUEC) for serum P1NP over 1- and 2-month timeframes, percent change from baseline in bone turnover markers such as P1NP and OCN over time, and change from baseline in DXA lumbar spine BMD z-scores over time. Additionally, the percent change from baseline in DXA lumbar spine BMD over time, frequency, severity, and relationship to treatment of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and the incidence of anti-setrusumab binding and neutralizing antibodies at scheduled time points will be evaluated.

In Phase III, the primary endpoint is the annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull, at the primary analysis. Secondary endpoints include the annualized rate of all radiographically-confirmed fractures, change from baseline in DXA lumbar spine BMD z-score at the primary analysis, and change from baseline at the primary analysis for POSNA-PODCI Sports/Physical Functioning and Pain/comfort subscale scores for subjects under 18 years of age at screening, as well as SF-36 PF and BP Domain Scales for subjects 18 years of age and older at screening. The frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs, along with the incidence of binding and neutralizing anti-setrusumab antibodies at scheduled time points, will also be assessed.