Ultragenyx Announces Phase 3 Orbit and Cosmic Results for Setrusumab (UX143) in Osteogenesis Imperfecta

About this update from Ultragenyx Pharmaceutical Inc.

Neither study achieved its primary endpoint of reduction in annualized clinical fracture rate compared to placebo (Orbit) or bisphosphonates (Cosmic) Both studies achieved the secondary endpoint of improvements in bone mineral density with strong statistical significance The Company will implement significant expense reductions NOVATO, Calif. , Dec. 29, 2025 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced results from the Phase 3 Orbit and Cosmic studies for setrusumab (UX143) in Osteogenesis Imperfecta (OI). Neither study achieved statistical significance against the primary endpoints of reduction in annualized clinical fracture rate compared to placebo or bisphosphonates, respectively. Both studies achieved the secondary endpoints of improvements in bone mineral density (BMD) against comparators. There was no change in the safety profile observed. “We are surprised and disappointed by these results given the promising data from our Phase 2 study and the lack of approved treatment options available to patients with OI who live with significant pain, disability, and disease burden,” said Emil Kakkis , M.D., Ph.D., chief executive officer and president of Ultragenyx. “We continue to explore the data to gain deeper understanding of the findings.” Orbit and Cosmic Results In the Orbit study, participants experienced statistically significant and substantial improvements in BMD compared to placebo, at levels consistent with the treatment effect observed in the Phase 2 portion of the study. These BMD changes were not accompanied by a corresponding reduction in annualized fracture rates and there was a low fracture rate in the placebo group. In the pediatric Cosmic study, patients had a substantially higher baseline fracture rate compared to the patients enrolled in Orbit. In this younger patient population, meaningful improvements in BMD were associated with a reduction in annualized fracture rate for setrusumab treated patients compared to bisphosphonate treated patients, though the reduction did not meet statistical significance. Ultragenyx is conducting additional analyses on the data across both studies, including on other bone health and clinical endpoints beyond fractures, to assess next steps for the program given the totality of these data. The Company will implement expense reductions Ultragenyx is evaluating its planned operations and will promptly define and implement significant expense reductions. Dr. Kakkis continued: “While we are disappointed by these results, we continue to build our commercial revenue from four approved products and prepare for a transformational year ahead with potentially two near-term gene therapy launches and a pivotal Phase 3 readout in Angelman syndrome.” About the Setrusumab Phase 3 Program 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. The pivotal Phase 3 portion of the study enrolled 159 patients at 45 sites across 11 countries, with participants randomized 2:1 to receive setrusumab or placebo, and a primary efficacy endpoint of annualized clinical fracture rate. The global Phase 3 Cosmic study evaluated the effect of setrusumab on reduction in annualized fracture rate in patients aged 2 to

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