Ultragenyx Faces Securities Class Action After Phase 3 Setrusumab Trial Failures

Ultragenyx Pharmaceutical Inc. announced on December 29, 2025 that both its Phase 3 Orbit and Cosmic studies for setrusumab (UX143) in Osteogenesis Imperfecta (OI) had not achieved statistical significance against the primary endpoints of reduction in annualized clinical fracture rate compared to placebo or bisphosphonates, respectively. The company attributed the study failure to a low fracture rate in the placebo group of Orbit and a trend that fell shy of statistical significance in Cosmic. On this news, the price of Ultragenyx stock fell more than 42%.

Multiple law firms have announced federal securities class action lawsuits filed against Ultragenyx and certain of its officers on behalf of all persons and entities that purchased or otherwise acquired Ultragenyx securities between August 3, 2023 and December 26, 2025. The complaints allege that defendants created the false impression that they possessed reliable information pertaining to the effects of setrusumab on patients with variable types of Osteogenesis Imperfecta, while also minimizing risk that patients in Ultragenyx' Phase III Orbit study would fail to achieve a statistically significant reduction in annualized fracture rate, such that the second interim analysis could be performed and presented to the investing public.

The lawsuits further allege that Ultragenyx' optimism in the Phase III Orbit study's results and interim analysis benchmark were misplaced because Ultragenyx failed to convey the risk associated with basing such threshold figures on Phase II results that had no placebo control group for appropriate comparison and thus had not ruled out that the reduction in annualized fracture rate from that study could merely be triggered by an increased standard of care and the placebo effect of being provided a novel treatment. Investors have until April 6, 2026 to request that the Court appoint them as lead plaintiff.

The announcement followed an earlier disclosure on July 9, 2025, when Ultragenyx revealed that the Phase III Orbit study failed to achieve statistical significance for the second interim analysis and that Phase III Orbit and Cosmic studies would be progressing toward final analysis. Following that July announcement, the stock fell more than 25%.

In the Orbit study, participants experienced statistically significant and substantial improvements in bone mineral density compared to placebo, at levels consistent with the treatment effect observed in the Phase 2 portion of the study. However, these bone mineral density 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 bone mineral density 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. Both studies achieved the secondary endpoints of improvements in bone mineral density against comparators, and there was no change in the safety profile observed.

The global, seamless Phase 2/3 Orbit study evaluated 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. The global Phase 3 Cosmic study evaluated the effect of setrusumab on reduction in annualized fracture rate in patients aged 2 to less than 7 years compared to bisphosphonates. The Cosmic study enrolled 69 patients at 21 sites across 7 countries with patients randomized 1:1 to receive setrusumab or intravenous bisphosphonates therapy.

The chief executive officer and president stated the company was surprised and disappointed by these results given the promising data from the Phase 2 study and the lack of approved treatment options available to patients with OI who live with significant pain, disability, and disease burden. The company 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. Ultragenyx is evaluating its planned operations and will promptly define and implement significant expense reductions.

The chief executive officer continued that while disappointed by these results, the company continues to build 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.

Separately, Ultragenyx reported quarterly results for the period ended December 2025, posting a loss of $1.29 per share versus the consensus estimate of a loss of $1.20. This compares to a loss of $1.39 per share a year ago. The company posted revenues of $207 million for the quarter ended December 2025, surpassing the consensus estimate by 2.01%. This compares to year-ago revenues of $164.88 million.

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. Osteogenesis Imperfecta 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. No treatments are globally approved for OI, which affects approximately 60,000 people in commercially accessible geographies.