Ultragenyx’s Setrusumab Misses Primary Endpoints in Phase 3 OI Trials, Shows Bone Density Gains

Ultragenyx’s Setrusumab Misses Primary Endpoints in Phase 3 OI Trials, Shows Bone Density Gains

By, Admin 2 January 2026

Ultragenyx’s Setrusumab Misses Primary Endpoints in Phase 3 OI Trials, Shows Bone Density Gains

Ultragenyx Pharmaceutical has reported mixed results from its late-stage clinical program for setrusumab (UX143) in osteogenesis imperfecta (OI).

While the drug failed to meet its primary fracture-reduction endpoints, it delivered consistent improvements in bone mineral density (BMD), with no new safety concerns.

What Were the Orbit and Cosmic Studies Testing?

Ultragenyx evaluated setrusumab across two global Phase 3 studies:

  • Orbit study: Patients aged 5 to 25 years, comparing setrusumab with placebo
  • Cosmic study: Pediatric patients aged 2 to under 7 years, comparing setrusumab with intravenous bisphosphonates

Both trials focused on one key goal: Reducing annualized clinical fracture rates in OI patients.

Primary Endpoints: Not Met

Neither study achieved statistical significance on its primary endpoint.

  • In Orbit, fracture rates did not differ meaningfully from placebo
  • In Cosmic, fracture reduction versus bisphosphonates was observed but fell short of statistical significance

A notable factor in Orbit was an unexpectedly low fracture rate in the placebo group.

Secondary Endpoints: Bone Density Improved

Despite missing the primary endpoints, both studies met important secondary goals.

  • Setrusumab produced statistically significant increases in BMD
  • BMD improvements matched effects seen in earlier Phase 2 data
  • In the pediatric Cosmic study, higher baseline fracture risk made BMD gains more clinically meaningful

However, stronger bones did not consistently translate into fewer fractures.

Safety Profile Remains Consistent

Ultragenyx reported no change in the safety profile of setrusumab.

This aligns with earlier studies and supports the drug’s biological activity, even if clinical outcomes fell short.

Why These Results Matter for OI?

Osteogenesis imperfecta is a rare genetic disorder with no globally approved treatments.

Patients face:

  • Frequent fractures
  • Chronic pain
  • Reduced mobility
  • Significant lifelong disability

Setrusumab targets sclerostin, a key inhibitor of bone formation, aiming to address the disease mechanism directly.

What Ultragenyx Is Doing Next?

Ultragenyx is conducting deeper analyses across both trials, including:

  • Additional bone health markers
  • Clinical outcomes beyond fractures
  • Subgroup responses across OI types and age ranges

At the same time, the company is reviewing operations and planning significant expense reductions.

The Bigger Picture for Ultragenyx

While disappointed, Ultragenyx is not stepping back from innovation.

The company is:

  • Growing revenue from four approved products
  • Preparing for two potential gene therapy launches
  • Advancing toward a pivotal Phase 3 readout in Angelman syndrome

Setrusumab’s future remains uncertain, but the data may still inform next-generation OI therapies.

Bottom Line

Setrusumab strengthened bones but did not reliably prevent fractures. For a disease with no approved therapies, even partial success matters—but regulators demand clinical outcomes.

Ultragenyx now faces a tough, data-driven decision on how, or whether, to move this program forward.

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