Ultragenyx Pharmaceutical reported that its experimental antibody setrusumab (UX143) did not meet the primary endpoint of reducing the annualized fracture rate in two Phase 3 studies for osteogenesis imperfecta (OI). The Orbit study, which enrolled 159 patients, and the Cosmic study, with 69 patients, both failed to achieve a statistically significant fracture‑rate reduction versus placebo or bisphosphonates, respectively.
Despite the primary‑endpoint miss, both trials showed significant improvements in bone mineral density (BMD). The BMD gains confirm the drug’s mechanism of action—sclerostin inhibition—but the data suggest that the increase in bone density did not translate into a measurable reduction in fractures at the current dosing or study duration.
The setback undermines a key pillar of Ultragenyx’s rare‑disease pipeline and has prompted the company to announce a plan for significant expense reductions. Management said the company will conduct additional analyses of the data and determine next steps for UX143, while shifting focus to its commercial portfolio of four approved products and other pipeline assets, including two near‑term gene‑therapy launches and a pivotal Phase 3 readout in Angelman syndrome.
CEO Emil Kakkis expressed disappointment, noting that the results were “surprising and disappointing given the promising data from our Phase 2 study and the lack of approved treatment options for patients with OI.” He added that the company remains committed to exploring the data, building commercial revenue, and preparing for a “transformational year ahead.”
Investors reacted negatively to the news, citing concerns about the company’s pipeline viability and the announced expense‑cutting measures. The failure to meet the primary endpoint and the need for cost discipline have heightened scrutiny of Ultragenyx’s financial outlook, which already includes a negative EBITDA of $508.7 million and a 20.63% year‑over‑year revenue growth.
Looking forward, Ultragenyx will reassess the development strategy for setrusumab, evaluate the feasibility of continuing the program, and focus on accelerating its other assets. The company’s emphasis on commercial revenue and gene‑therapy development signals a strategic pivot to diversify risk and pursue higher‑impact therapies in the rare‑disease space.
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