Ultragenyx Phase III Data Reveal Limits of Bone Density Endpoints in Rare Bone Disease

US-based Ultragenyx Pharmaceutical reported Phase III data from two late-stage studies evaluating setrusumab, a fully human monoclonal antibody (mAb), in osteogenesis imperfecta (OI), a rare genetic disorder marked by fragile bones and recurrent fractures. While both trials demonstrated statistically significant improvements in bone mineral density (BMD), neither met its primary endpoint of reducing annualized clinical fracture rates compared with standard comparators (1). These data underscore the persistent challenges in translating surrogate bone metrics into clinical benefit (2).

Setrusumab works by inhibiting sclerostin, a negative regulator of bone formation. The trial results come from the pivotal Orbit study and the pediatric Cosmic study, which collectively assessed the mAb across multiple osteogenesis imperfecta subtypes and age groups. The findings highlight broader questions facing bone-targeting biologics, including endpoint selection, trial design in rare diseases, and the clinical relevance of bone density improvements (3).

“We are surprised and disappointed by these results given the promising data from our Phase II 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, MD, PhD, CEO and president of Ultragenyx, in a Dec. 29, 2025 company press release (1). “We continue to explore the data to gain deeper understanding of the findings.”

Why did the Phase III trials fail to reduce fracture rates despite BMD gains?

In the global Phase II/III Orbit study, which enrolled patients aged 5 to 25 years, setrusumab produced substantial and statistically significant increases in BMD compared with placebo. These improvements were consistent with earlier Phase II findings, the company stated in its release, reinforcing the drug’s biological activity as a sclerostin inhibitor (1). However, fracture outcomes did not mirror these gains.

A key factor was an unexpectedly low fracture rate in the placebo group, limiting the ability to detect a statistically significant difference between treatment arms. This result highlights a recurring issue in rare disease trials, in which heterogeneous disease severity and evolving standards of care can complicate endpoint interpretation (4).

In the Phase III Cosmic study, which enrolled younger patients aged 2 to <7 years, baseline fracture rates were higher than in the Orbit study. In the Cosmic study population, improvements in BMD were associated with a numerical reduction in fracture rates compared with intravenous bisphosphonate therapy. However, the difference did not reach statistical significance, falling short of the primary endpoint (1).

What do these results mean for bone-targeting biologics in rare diseases?

Preclinical data with setrusumab in mouse models of OI showed normalization of bone mass and strength, supporting the therapeutic rationale for the biologic. The Phase III outcomes, however, reinforce the gap that can exist between mechanistic promise and clinical endpoints, such as fracture reduction (5).

The divergence between BMD improvements and fracture outcomes raises questions relevant to the broader biopharmaceutical industry. Regulators and developers continue to debate whether bone density can serve as a reliable surrogate endpoint in rare skeletal disorders, particularly when fracture events are infrequent or variable over time (6).

“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 III readout in Angelman syndrome,” Dr. Kakkis stated in the release (1).

Ultragenyx reported no change in the safety profile across either study and is conducting additional analyses across both datasets, including evaluation of other bone health and clinical endpoints beyond fractures. It will evaluate its planned operations and implement significant expense reductions, reflecting the broader financial implications of late-stage trial setbacks.

References

1. Ultragenyx Pharmaceutical. Ultragenyx Announces Phase 3 Orbit and Cosmic Results for Setrusumab (UX143) in Osteogenesis Imperfecta. Press Release. Dec. 29, 2025.
2. Li, Z.; Chines, A. A.; Meredith, M. P. Statistical Validation of Surrogate Endpoints: Is Bone Density a Valid Surrogate for Fracture? J. Musculoskeletal Neuronal Interact. 2004, 4 (1), 64–74
3. Xu, H.; Wang, W.; Liu, X.; et al. Targeting Strategies for Bone Diseases: Signaling Pathways and Clinical Studies. Signal Transduction Targeted Ther. 2023, 8 (1), 202. DOI: 10.1038/s41392-023-01467-8
4. Videnovic, A.; Pfeiffer, H. C. V.; Tylki-Szymańska, A.; et al. Study Design Challenges and Strategies in Clinical Trials for Rare Diseases: Lessons Learned from Pantothenate Kinase-Associated Neurodegeneration. Front Neurol. 2023, 14, 1098454. DOI: 10.3389/fneur.2023.1098454
5. Gyawali, B.; Hey, S. P.; Kesselheim, A. S. Evaluating the Evidence Behind the Surrogate Measures Included in the FDA's Table of Surrogate Endpoints as Supporting Approval of Cancer Drugs. EClinicalMedicine 2020, 21, 100332. DOI: 10.1016/j.eclinm.2020.100332
6. Bouxsein, M. L.; Delmas, P. D. Considerations for Development of Surrogate Endpoints for Antifracture Efficacy of New Treatments in Osteoporosis: A Perspective. J. Bone Miner. Res. 2008, 23 (8), 1155–1167. DOI: 10.1359/jbmr.080301