Ultragenyx and Mereo BioPharma Report Phase 2 Data Showing Reduced Fracture Rates with Setrusumab in Osteogenesis Imperfecta Patients

Ultragenyx Pharmaceutical Inc. and Mereo BioPharma Group plc have reported positive results from the Phase 2 portion of their Phase 2/3 Orbit study involving the drug setrusumab, aimed at treating osteogenesis imperfecta (OI). As of May 24, 2024, the data indicate that setrusumab significantly reduces fracture rates and enhances bone mineral density (BMD) over a 14-month period.

The study measured the annualized fracture rate among patients undergoing treatment. Results showed a remarkable 67% reduction in the rate of radiologically confirmed fractures, dropping the median annualized fracture rate from 0.72 to 0.00 (p=0.0014) over an average treatment duration of 16 months. These statistics exclude certain types of fractures, maintaining consistency with the Phase 3 study’s primary efficacy endpoint.

In addition to reducing fractures, setrusumab significantly improved BMD. At the 12-month mark, lumbar spine BMD saw a mean increase of 22% from baseline (p<0.0001), and the BMD Z-score improved by +1.25 (p<0.0001), indicating substantial normalization. Consistency in these improvements was noted across different age groups (5 to <26 years old) and OI sub-types studied.

Gary S. Gottesman, M.D., Professor at Washington University School of Medicine, highlighted the drug's effectiveness in reducing fracture incidence and improving BMD, suggesting continuous positive responses over the long term. Eric Crombez, M.D., Chief Medical Officer at Ultragenyx, indicated that the improvements in BMD suggest the creation of stronger bones, which translates to a significant reduction in fractures across various OI types and age groups.

The study reported no treatment-related serious adverse events. The most common adverse events included infusion-related reactions and headaches, but no hypersensitivity reactions to setrusumab were observed.

The setrusumab Phase 3 program involves two late-stage trials targeting pediatric and young adult patients across OI sub-types I, III, and IV. The pivotal Phase 2/3 Orbit study enrolled 24 patients in its Phase 2 portion to determine optimal dosing, and the Phase 3 portion has added 158 patients across 11 countries. The primary efficacy endpoint is the annualized clinical fracture rate, and all participants will transition to an extension period with open-label setrusumab following the Phase 3 primary analysis.

The global Phase 3 Cosmic study involves younger patients aged 2 to <7 years and compares setrusumab to intravenous bisphosphonates (IV-BP) therapy. This study has enrolled 69 patients across 21 sites in 7 countries.

OI is a genetic disorder affecting bone metabolism, primarily caused by mutations in the COL1A1 or COL1A2 genes. These mutations lead to brittle bones, high fracture rates, and various skeletal deformities. Setrusumab, a fully human monoclonal antibody, works by inhibiting sclerostin, a negative regulator of bone formation. In mouse models, anti-sclerostin antibodies have been shown to enhance bone formation, mass, and strength.

Mereo BioPharma completed the Phase 2b Asteroid study in 2019, which demonstrated setrusumab’s dose-dependent and statistically significant effects on bone formation and density in adults with OI. Ultragenyx and Mereo BioPharma are collaborating on the global development of setrusumab, continuing to conduct comprehensive late-stage programs.

Ultragenyx is a biopharmaceutical company dedicated to developing treatments for rare and ultra-rare genetic diseases, while Mereo BioPharma focuses on innovative therapeutics for rare diseases, with setrusumab and alvelestat as its primary candidates.

Continued research and successful clinical trials could eventually bring setrusumab to a broader patient population, potentially providing a new, effective treatment for those living with OI.