Ultragenyx Pharmaceutical Inc. and Mereo BioPharma Group plc announced that the randomized, placebo-controlled Phase 3 portion of the Orbit study evaluating UX143 (setrusumab) in pediatric and young adult patients with osteogenesis imperfecta (OI) is progressing toward a final analysis consistent with the original plan, around the end of the year.
The Data Monitoring Committee (DMC) met and informed the companies that UX143 demonstrates an acceptable safety profile and recommended continuing the study to the final analysis. While the companies had hoped to stop the study early, they will proceed with the planned timeline for both the Orbit and Cosmic studies.
"Based on the feedback we hear from investigators and families who participated in the studies, we are confident that increasing bone mass leads to stronger bone, less fractures, and improved physical abilities," said Emil D. Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx. "While we had hoped to be able to stop the study early, we look forward to having results from both Orbit and Cosmic around the end of this year."
Phase 3 Clinical Program Design
Ultragenyx is developing setrusumab in pediatric and young adult patients across OI sub-types I, III and IV with two late-stage studies: the pivotal Phase 2/3 Orbit study and 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. In the Phase 2 portion, 24 patients were randomized 1:1 to receive setrusumab at one of two doses to determine the optimal dosing strategy for Phase 3. All patients from the 40 mg/kg dosing cohort have been transitioned to 20 mg/kg of setrusumab.
The pivotal Phase 3 portion of the study has enrolled an additional 159 patients at 45 sites across 11 countries, with subjects randomized 2:1 to receive setrusumab or placebo, and a primary efficacy endpoint of annualized clinical fracture rate. All patients will transition to an extension period and receive open-label setrusumab after the Phase 3 primary analysis is complete.
The global Phase 3 Cosmic study is an open-label, randomized, active-controlled study in patients aged 2 to <7 years. Patients are randomized 1:1 to receive setrusumab or intravenous bisphosphonates (IV-BP) therapy to evaluate reduction in the annualized fracture rate. The Cosmic study has enrolled 69 patients at 21 sites across 7 countries.
Statistical Analysis and Timeline
Patients will continue dosing in the ongoing Phase 3 Orbit and Cosmic clinical studies with the final analyses to be conducted after patients have been on therapy for at least 18 months. The threshold for the Phase 3 Orbit final analysis is p<0.04 and for the Phase 3 Cosmic final analysis is p<0.05.
Consistent with the statistical analysis plan, data from the Cosmic study were not analyzed at this interim timepoint. Study conduct is going well and safety in this younger patient population is consistent with the safety profile in the other studies.
Mechanism of Action and Preclinical Evidence
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. In mouse models of OI, the use of anti-sclerostin antibodies was shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels.
In 2019, Mereo BioPharma completed the Phase 2b dose-finding study (ASTEROID) for setrusumab in 112 adults with OI. The ASTEROID study demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI.
Disease Background and Unmet Need
Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately 85% to 90% of OI cases are caused by genetic variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. The collagen mutations in OI can result in increased bone brittleness, which contributes to a high rate of fractures.
Patients with OI also exhibit inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility and weakness. OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are globally approved for OI, which affects approximately 60,000 people in commercially accessible geographies.
Regulatory Status and Partnership
Setrusumab has received orphan designation for osteogenesis imperfecta from the European Commission and the FDA, PRIME designation from the EMA, and has Breakthrough Therapy designation and rare pediatric disease designation from the FDA.
Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally based on the collaboration and license agreement between the parties. The partnership with Ultragenyx includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained EU and UK commercial rights and will pay Ultragenyx royalties on commercial sales in those territories.
