Ultragenyx and Mereo BioPharma have announced positive 14-month results from the Phase 2 portion of the ongoing Phase 2/3 Orbit study, demonstrating that treatment with setrusumab (UX143) continues to significantly reduce the incidence of fractures in patients with osteogenesis imperfecta (OI). The data, as of May 24, 2024, also showed ongoing and meaningful improvements in lumbar spine bone mineral density (BMD) at month 12 without evidence of plateau.
Sustained Fracture Reduction
The study revealed a large, sustained 67% reduction in the annualized fracture rate in patients treated with setrusumab. Specifically, the median annualized rate of radiologically confirmed fractures across all 24 patients in the two years prior to treatment was 0.72. Following a mean treatment duration of 16 months, the median annualized fracture rate was reduced to 0.00 (p=0.0014; n=24). This excludes morphometric vertebral fractures and fractures of the fingers, toes, skull, and face, consistent with the Phase 3 study primary efficacy endpoint.
Improvements in Bone Mineral Density
Treatment with setrusumab also resulted in continued, substantial improvements in bone mineral density (BMD). At the 12-month timepoint, the mean increase in lumbar spine BMD from baseline was 22% (p<0.0001, n=19) across all age groups (5 to < 26 years old). This is a further improvement from the 14% observed at 6 months of treatment. The mean baseline lumbar spine BMD Z-score improved from -1.73 to -0.49 at 12 months, a substantial normalization of +1.25 (p<0.0001, n=18). This is further improved from the mean 6-month Z-score change of +0.85. The improvements in BMD and Z-scores were significant and consistent across all OI sub-types studied.
Expert Commentary
"All indications are that setrusumab is having the effect we hoped for, safely reducing the incidence of fractures and improving BMD in patients with OI," said Gary S. Gottesman, M.D., Professor of Pediatrics and Medicine, Washington University School of Medicine. "The anti-sclerostin antibody appears effective even after a year and remarkably, patients continue to make measurable gains, suggesting we will see an ongoing response over the long term."
Safety Profile
As of the data cut-off, there were no treatment-related serious adverse events observed in the study. Reported adverse events were generally consistent with those observed in the Asteroid study, with infusion-related events and headache being the most common adverse events related to the study drug. There were no reported hypersensitivity reactions related to setrusumab.
Ongoing Clinical Trials
Ultragenyx is developing setrusumab in pediatric and young adult patients across OI sub-types I, III, and IV with two late-stage trials: the pivotal Phase 2/3 Orbit study and the Phase 3 Cosmic study. The global, seamless Phase 2/3 Orbit study is evaluating the effect of setrusumab on clinical fracture rate in patients aged 5 to 25 years. The pivotal Phase 3 portion of the study has enrolled an additional 158 patients. The global Phase 3 Cosmic study is an open-label, randomized, active-controlled study in patients aged 2 to <7 years, randomizing patients 1:1 to receive setrusumab or intravenous bisphosphonates (IV-BP) therapy to evaluate the reduction in total fracture rate. The Cosmic study has enrolled 69 patients.
About Osteogenesis Imperfecta
Osteogenesis Imperfecta (OI) is a group of genetic disorders impacting bone metabolism, often caused by genetic variants in the COL1A1 or COL1A2 genes. These mutations lead to increased bone brittleness, a high rate of fractures, inadequate new bone production, and excess bone resorption, resulting in decreased bone mineral density, bone fragility, and weakness. OI affects approximately 60,000 people in commercially accessible geographies, and there are currently no globally approved treatments for the condition.
Mechanism of Action
Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a negative regulator of bone formation. Blocking sclerostin is expected to increase new bone formation, bone mineral density, and bone strength in OI.
