Ultragenyx and Mereo announced that setrusumab failed to meet primary fracture endpoints in two late-stage trials, prompting an immediate reassessment of operations and planned expense reductions. The Orbit (Phase II/III) and Cosmic (Phase III) trials missed statistically significant reductions in annualized clinical fracture rate (AFR) despite showing meaningful bone mineral density (BMD) gains. Setrusumab is a fully human anti-sclerostin monoclonal antibody developed to increase bone formation in osteogenesis imperfecta (brittle bone disease). Ultragenyx reported substantial BMD improvements consistent with earlier phase data, but low fracture rates in the placebo arm and mixed baseline fracture burdens limited demonstration of clinical fracture benefit. The companies said they will evaluate clinical development, commercial plans, and operating expenses. The results underscore the challenge of translating BMD improvements into fracture reductions in heterogeneous pediatric and young-adult OI populations and will likely reshape near-term strategy for stakeholders focused on anti-sclerostin approaches.