Ultragenyx Pharmaceutical Inc. and Mereo BioPharma Group plc have reported topline results from the pivotal Phase 3 ORBIT and COSMIC trials evaluating setrusumab (UX143) in patients with osteogenesis imperfecta (OI), a rare genetic disorder characterised by brittle bones and a high risk of fracture.
The Phase 2/3 ORBIT study enrolled 159 pediatric and young adult participants aged 5 to 25 in its Phase 3 portion, while the Phase 3 COSMIC study enrolled 69 children aged 2 to under 7.
In both trials, the primary endpoint — reduction in annualized clinical fracture rate — did not reach statistical significance versus comparator arms (placebo in ORBIT and intravenous bisphosphonates in COSMIC). However, secondary endpoints demonstrated statistically significant improvements in bone mineral density (BMD) across both studies, consistent with treatment effects observed in earlier Phase 2 data. Safety findings were in line with prior experience, with no new safety signals reported.
In ORBIT, BMD improvements versus placebo were clear, but a lower-than-expected fracture rate in the placebo arm limited the ability to demonstrate a statistically significant reduction in fractures. In the younger COSMIC population, higher baseline fracture rates and numerically meaningful reductions in fracture incidence were observed with setrusumab compared with active control, although these did not meet prespecified statistical thresholds.
Outlook and implications
Commenting on the readout, Mereo CEO Denise Scots-Knight said that while the results were disappointing with respect to the primary endpoint, the companies plan to conduct further analyses to better understand treatment effects across patient subgroups and clinical measures beyond fractures — particularly in pediatric populations where unmet need remains high.
To preserve cash, Mereo is scaling back pre-commercial and manufacturing investments and shifting focus toward maximizing value across its broader rare-disease portfolio, including partnered assets such as alvelestat in alpha-1 antitrypsin deficiency–associated lung disease. As of Sept. 30, 2025, the company reported approximately $48.7 million in cash reserves, which it said should support continued operations as strategic priorities are refined.