Ultragenyx Drug for Brittle Bone Disease Fails to Reduce Fractures in Pivotal Trials

NOVATO, CA – December 29, 2025 – In a significant setback for patients with Osteogenesis Imperfecta (OI), Ultragenyx Pharmaceutical Inc. announced today that its experimental drug, setrusumab, failed to meet its primary goals in two late-stage clinical trials. The studies, known as Orbit and Cosmic, did not show a statistically significant reduction in fracture rates, a devastating blow for a community that has long awaited an approved treatment for the genetic disorder characterized by extremely brittle bones.

The news came as a shock to many, given the drug's promising performance in earlier studies. Setrusumab, a monoclonal antibody designed to inhibit sclerostin and thereby promote bone growth, was seen as a potential breakthrough for OI. Instead, the company is now faced with disappointing results and the need to implement significant expense reductions.

“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, in a statement. “We continue to explore the data to gain deeper understanding of the findings.”

The Paradox of Density Without Strength

The Phase 3 program for setrusumab consisted of two global studies targeting different age groups within the OI population. The Orbit study enrolled 159 patients between the ages of 5 and 25, comparing setrusumab to a placebo. The Cosmic study focused on a younger pediatric cohort of 69 patients aged 2 to under 7, comparing the drug against the current standard of care, intravenous bisphosphonates.

The primary endpoint for both trials was the same: a reduction in the annualized rate of clinical fractures. On this crucial measure, neither study succeeded. This failure strikes at the heart of the therapeutic goal for any OI treatment, as frequent and debilitating fractures are the disease's most prominent and life-altering feature.

However, the trial results presented a complex and somewhat paradoxical picture. While setrusumab failed to prevent fractures, it succeeded on a key secondary endpoint: improving bone mineral density (BMD). In both the Orbit and Cosmic studies, patients treated with the drug experienced statistically significant and substantial improvements in BMD compared to their respective control groups. This suggests the drug was biologically active and working as intended on a physiological level, making bones appear denser on medical scans.

The critical disconnect—denser bones that did not translate to fewer breaks—is now the central question for Ultragenyx researchers. In the Orbit study, the company noted that the group receiving the placebo had an unexpectedly low fracture rate, which made it statistically challenging to demonstrate a benefit for setrusumab. In the pediatric Cosmic study, where baseline fracture rates were much higher, there was a numerical trend toward fewer fractures in the setrusumab group compared to those on bisphosphonates, but the difference was not large enough to meet the threshold for statistical significance.

A Community's Hope Deferred

Osteogenesis Imperfecta is a group of severe genetic disorders that disrupt the body's collagen production, a protein essential for bone structure. This results in bones that are exceptionally fragile and prone to fracture from even minor impacts. The condition, which affects an estimated 60,000 people in commercially accessible regions, leads to a lifetime of challenges, including chronic pain, bone deformities, abnormal spine curvature, decreased mobility, and short stature.

Currently, there are no globally approved treatments that address the underlying mechanisms of OI. Patients are typically managed with supportive care, including physical therapy, surgery to insert rods into long bones, and off-label use of bisphosphonates, drugs that slow bone loss but do not promote the formation of new, healthy bone. The development of setrusumab, which works by blocking sclerostin to increase new bone formation, was based on the hope of fundamentally improving bone strength, not just preserving it.

Preclinical studies in mouse models of OI had shown that anti-sclerostin antibodies could increase bone formation, normalize bone mass, and significantly improve bone strength. The success on the bone mineral density endpoint in the human trials seemed to confirm part of this hypothesis, but the failure to prevent fractures leaves the path forward for the drug uncertain. Ultragenyx has stated it is conducting additional analyses on the data, including other bone health metrics, to determine the next steps for the program.

Ultragenyx Pivots to Future Pipeline

In the wake of the trial results, Ultragenyx announced it will move swiftly to redefine its operational plans and implement significant cost-saving measures. Such moves are common in the biopharmaceutical industry when a high-profile, late-stage asset fails, as companies must conserve capital to fund other promising programs.

Dr. Kakkis sought to reassure investors and stakeholders by highlighting the company's broader portfolio and future prospects. The company is not solely dependent on setrusumab's success, generating revenue from four currently approved products for other rare diseases. This existing commercial foundation provides a buffer against the clinical setback.

“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,” Dr. Kakkis stated. This strategic pivot signals that while the journey for setrusumab has hit a major roadblock, the company's focus is already shifting to its next wave of potential therapies, underscoring the high-risk, high-reward nature of developing treatments for rare diseases.