Setrusumab Phase 3 Trials in Osteogenesis Imperfecta Show Mixed Results Across Age Groups
Key Insights
Ultragenyx and Mereo BioPharma announced results from two Phase 3 studies evaluating setrusumab, a sclerostin (search)-inhibiting monoclonal antibody, for treating osteogenesis imperfecta (search) in pediatric patients.
The ORBIT study enrolled 159 patients aged 5-25 years across 45 sites in 11 countries, comparing setrusumab to placebo with annualized clinical fracture rate as the primary endpoint.
The COSMIC study enrolled 69 patients aged 2-7 years across 21 sites in 7 countries, comparing setrusumab to intravenous bisphosphonates (search) therapy.
Ultragenyx Pharmaceutical and partner Mereo BioPharma have announced results from two pivotal Phase 3 studies evaluating setrusumab (UX143), an investigational monoclonal antibody targeting sclerostin (search), for the treatment of osteogenesis imperfecta (search) (OI) in pediatric and young adult patients. The announcement marks a significant milestone in addressing a rare genetic bone disorder that currently has no globally approved treatments.
Study Design and Patient Populations
The setrusumab development program encompasses two late-stage clinical trials designed to evaluate the therapy across different age groups of OI patients. The global, seamless Phase 2/3 ORBIT study evaluated setrusumab's effect on clinical fracture rate in patients aged 5 to 25 years. The pivotal Phase 3 portion enrolled 159 patients at 45 sites across 11 countries, with participants randomized 2:1 to receive setrusumab or placebo. The study's primary efficacy endpoint focused on annualized clinical fracture rate.
The companion Phase 3 COSMIC study examined setrusumab's effectiveness in younger patients aged 2 to less than 7 years, comparing the investigational therapy directly to standard-of-care intravenous bisphosphonates (search) (IV-BP) therapy. This study enrolled 69 patients at 21 sites across 7 countries, with patients randomized 1:1 between the two treatment arms.
Mechanism of Action and Preclinical Evidence
Setrusumab is a fully human monoclonal antibody that inhibits sclerostin (search), a negative regulator of bone formation. By blocking sclerostin, the therapy is expected to increase new bone formation, bone mineral density, and bone strength in patients with OI. Preclinical validation in mouse models of OI demonstrated that anti-sclerostin antibodies increased bone formation, improved bone mass to normal levels, and enhanced bone strength against fracture force testing to normal levels.
Addressing Unmet Medical Need
Osteogenesis imperfecta (search) represents a group of genetic disorders impacting bone metabolism, with approximately 85% to 90% of cases caused by genetic variants in the COL1A1 (search) or COL1A2 (search) genes. These mutations lead to either reduced or abnormal collagen production and subsequent changes in bone metabolism. The resulting collagen abnormalities contribute to increased bone brittleness and a high rate of fractures in affected patients.
Patients with OI experience inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility, and weakness. The condition can also manifest as bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. The disorder affects approximately 60,000 people in commercially accessible geographies worldwide, representing a significant unmet medical need given the absence of globally approved treatments.
Regulatory Status and Partnership Structure
Setrusumab has received multiple regulatory designations recognizing its potential therapeutic value. The therapy has obtained orphan designation for osteogenesis imperfecta (search) from both the European Commission and the FDA, PRIME designation from the EMA, and both Breakthrough Therapy designation and rare pediatric disease designation from the FDA.
The development program operates under a partnership between Ultragenyx and Mereo BioPharma, with Ultragenyx leading the clinical development efforts. The collaboration includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained commercial rights in the EU and UK and will pay Ultragenyx royalties on commercial sales in those territories.