Ultragenyx Announces Phase 3 Orbit and Cosmic Results for Setrusumab (UX143) in Osteogenesis Imperfecta
Rhea-AI Summary
Ultragenyx (NASDAQ: RARE) reported Phase 3 results for setrusumab (UX143) in osteogenesis imperfecta from the Orbit and Cosmic studies dated Dec 29, 2025. Neither trial met the primary endpoint of a statistically significant reduction in annualized clinical fracture rate versus placebo (Orbit) or bisphosphonates (Cosmic). Both studies did achieve the secondary endpoint of statistically significant improvements in bone mineral density (BMD) versus comparators. Safety findings showed no change in the safety profile. Ultragenyx said it will implement significant expense reductions while performing additional analyses of other bone-health and clinical endpoints to define next steps for the program.
Positive
- Both studies showed statistically significant BMD improvements
- Pediatric Cosmic showed BMD gains linked to fracture reductions (not significant)
- Company expects continued revenue from four approved products
Negative
- Neither Phase 3 study met the primary fracture-rate endpoint
- Orbit had a low placebo fracture rate, limiting efficacy signal
- Company will implement significant expense reductions
News Market Reaction
On the day this news was published, RARE declined 42.32%, reflecting a significant negative market reaction. Argus tracked a peak move of +30.2% during that session. Our momentum scanner triggered 49 alerts that day, indicating elevated trading interest and price volatility. This price movement removed approximately $2.42B from the company's valuation, bringing the market cap to $3.30B at that time. Trading volume was very high at 3.3x the daily average, suggesting heavy selling pressure.
Data tracked by StockTitan Argus on the day of publication.
Market Reality Check
Peers on Argus
Pre-news, RARE was down 1.13%. Peers showed mixed moves: several modest declines (e.g., SLNO −2.87%, NAMS −1.09%) while SRRK gained 0.44%, pointing to stock-specific rather than broad sector dynamics.
Historical Context
| Date | Event | Sentiment | Move | Catalyst |
|---|---|---|---|---|
| Dec 19 | Inducement grants | Neutral | +3.7% | RSU inducement grants to newly hired non-executive officers. |
| Nov 24 | Investor conferences | Neutral | +2.3% | Participation in December healthcare investor conferences and webcasts. |
| Nov 21 | Inducement grants | Neutral | -2.4% | Additional RSU inducement awards to non-executive officers. |
| Nov 04 | Q3 earnings | Neutral | -3.0% | Q3 2025 results with revenue growth but continued sizable net loss. |
| Nov 04 | Royalty sale | Positive | -3.0% | Sale of 25% additional Crysvita royalties to OMERS for $400M. |
Recent news flow has mostly seen price reactions directionally consistent with the perceived neutrality or positivity of announcements, with one notable negative reaction to a funding/royalty deal.
Over the last few months, Ultragenyx reported multiple corporate and financial updates, including RSU inducement grants on Nov 21 and Dec 19, 2025, conference participation plans on Nov 24, and Q3 2025 results plus a $400 million Crysvita royalty sale on Nov 4. Price reactions ranged from about +3–4% to around −3%, with the royalty monetization and earnings drawing negative moves despite their strategic focus. Against this backdrop, the current Phase 3 miss and planned expense cuts represent a clinical and operational setback relative to prior growth- and funding-focused communications.
Market Pulse Summary
The stock dropped -42.3% in the session following this news. A negative reaction despite BMD improvements would fit a pattern where markets respond strongly to clinical outcomes and prior funding actions, including a $400 million royalty sale that drew a decline. The miss on primary fracture endpoints and announced expense reductions could amplify concerns already present from sizeable net losses in recent reports. Attention would likely center on whether other late-stage programs and planned gene therapy launches can offset this OI setback over time.
Key Terms
primary endpoint medical
secondary endpoint medical
bone mineral density medical
bisphosphonates medical
annualized fracture rate medical
gene therapy medical
AI-generated analysis. Not financial advice.
Neither study achieved its primary endpoint of reduction in annualized clinical fracture rate compared to placebo (Orbit) or bisphosphonates (Cosmic)
Both studies achieved the secondary endpoint of improvements in bone mineral density with strong statistical significance
The Company will implement significant expense reductions
NOVATO, Calif., Dec. 29, 2025 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced results from the Phase 3 Orbit and Cosmic studies for setrusumab (UX143) in Osteogenesis Imperfecta (OI). Neither study achieved statistical significance against the primary endpoints of reduction in annualized clinical fracture rate compared to placebo or bisphosphonates, respectively. Both studies achieved the secondary endpoints of improvements in bone mineral density (BMD) against comparators. There was no change in the safety profile observed.
“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. “We continue to explore the data to gain deeper understanding of the findings.”
Orbit and Cosmic Results
In the Orbit study, participants experienced statistically significant and substantial improvements in BMD compared to placebo, at levels consistent with the treatment effect observed in the Phase 2 portion of the study. These BMD 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 BMD 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.
Ultragenyx 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.
The Company will implement expense reductions
Ultragenyx is evaluating its planned operations and will promptly define and implement significant expense reductions.
Dr. Kakkis continued: “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.”
About the Setrusumab Phase 3 Program
Ultragenyx is developing setrusumab in pediatric and young adult patients across OI sub-types I, III and IV with two late-stage studies: the pivotal Phase 2/3 Orbit study and Phase 3 Cosmic study.
The global, seamless Phase 2/3 Orbit study is evaluating 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, and a primary efficacy endpoint of annualized clinical fracture rate.
The global Phase 3 Cosmic study evaluated the effect of setrusumab on reduction in annualized fracture rate in patients aged 2 to <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 (IV-BP) therapy.
About Setrusumab (UX143)
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. In mouse models of OI, the use of anti-sclerostin antibodies was shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels.
About Osteogenesis Imperfecta (OI)
Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately
About Ultragenyx
Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.
The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.
For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com.
Forward-Looking Statements and Use of Digital Media
Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, including the company’s plans to define and implement expense reductions, business plans and objectives for UX143, expectations regarding the tolerability and safety of UX143, and future clinical and regulatory developments for UX143, including next steps for the UX143 program, are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, the ability of the company and Mereo BioPharma to successfully develop UX143, the risk that fast track or breakthrough designations by the FDA may not lead to faster development or regulatory review or approval process and does not increase the likelihood that UX143 will receive marketing approval, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to adverse side effects, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, the potential for any license or collaboration agreement, including the company’s collaboration agreement with Mereo to be terminated, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements.
For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 5, 2025, and its subsequent periodic reports filed with the SEC.
In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/).
Ultragenyx Contacts
Investors
Joshua Higa
ir@ultragenyx.com
Media
Jess Rowlands
media@ultragenyx.com
FAQ
What did Ultragenyx announce about setrusumab (UX143) Phase 3 results on December 29, 2025?
How did Orbit vs placebo perform on fractures and BMD for UX143 (RARE)?
Did the pediatric Cosmic study show fracture benefits for UX143 (RARE)?
What safety signals were reported for setrusumab (UX143) in the Phase 3 trials?
How will the Phase 3 results affect Ultragenyx (RARE) near-term plans?
