Ultragenyx and partner Mereo reported that setrusumab failed to meet primary endpoints in two Phase III trials for brittle bone disease (osteogenesis imperfecta), prompting immediate operational reassessment. The Orbit (NCT05125809) and Cosmic (NCT05768854) programs did not achieve statistically significant reductions in annualized clinical fracture rate despite showing improvements in bone mineral density. Companies cited low fracture rates in placebo arms and baseline differences between cohorts as complicating factors. Ultragenyx said the trials did deliver consistent BMD gains, mirroring Phase II results, but the disconnect between BMD improvements and fracture reductions led to the regulatory and commercial uncertainty. The companies signaled they will evaluate the programs and implement “significant expense reductions,” indicating potential reprioritization of pipelines and near-term cost cutting. Analysts and investors should watch for formal restructuring and any guidance on salvage strategies for the anti‑sclerostin approach.