Setrusumab (UX-143) for the Potential Treatment of Osteogenesis Imperfecta
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Setrusumab is a fully humanized monoclonal antibody being investigated for the potential treatment of osteogenesis imperfecta (OI), commonly known as brittle bone disease.1
It is designed to inhibit sclerostin, a mechanism of action that is anticipated to improve bone formation and strength, with the potential to reduce fractures and improve quality of life for people living with OI.1,2
Mereo BioPharma and Ultragenyx are collaborating on the development of setrusumab (UX-143) globally, based on a license agreement that was signed in December 2020.2 There are currently two ongoing registrational clinical trials to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV. Mereo retains rights to commercialization in Europe/EEA and the U.K.
About osteogenesis imperfecta
Osteogenesis imperfecta (OI) is a group of rare systemic connective tissue disorders, most commonly caused by pathogenic variants in genes that encode type I collagen production. It is characterized by low bone mass, increased bone fragility, and a predisposition to fractures, often from minimal or no trauma.3
The condition is lifelong and variable in severity, ranging from mild forms with few fractures to severe cases with significant skeletal deformities and functional impairment. The estimated prevalence of OI is between 1 in 10,000 and 1 in 20,000 individuals globally.3
OI can affect people’s lives in a multitude of ways, from frequent fractures and skeletal deformities to constant chronic pain, respiratory insufficiency and hearing loss.1 And each person’s experience is different.
Click through to Rare Disease Day 2025 to learn more about the experience of living with OI.
Orphan Drug Designation of setrusumab
OI is recognized as an area of high unmet medical need. Setrusumab has been granted Orphan Drug Designation in the EU and the U.S., meaning it is officially acknowledged by the regulatory authorities to be targeting a rare and serious condition.4,5
PRIority MEdicines (PRIME) designation
In Europe, setrusumab has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA), and has been accepted in the EMA’s Adaptive Pathways program.6 The PRIME program is aimed at supporting the development of medicines that target an unmet medical need.6
Breakthrough Therapy designation
In October 2024, setrusumab received Breakthrough Therapy designation from the FDA.7 The FDA’s decision is based on preliminary clinical evidence, including the positive 14-month results from the Phase 2 portion of the Orbit trial, and from the completed Phase 2b ASTEROID trial in adult patients.7
Breakthrough Therapy designation aims to expedite the development and review of drugs that are intended to treat serious or life-threatening diseases and whose preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over existing therapies.8
Orbit Phase 2/3 clinical trial program
The Phase 2 portion of the Orbit trial enrolled 24 patients and was randomized 1:1 to test two doses of setrusumab, 20 and 40 mg/kg, with 20mg/kg being taken forward into the Phase 3 portion of the study.2
Ongoing Phase 3 Orbit clinical trial for setrusumab
The Phase 3 part of the trial has enrolled 159 patients, with a 2:1 randomization to receive setrusumab or placebo, with a primary endpoint of the rate of annualized clinical fractures. After achieving the trial primary endpoint, all patients will transition to an extension period and receive open-label setrusumab. The Phase 3 part of the clinical trial program, led by Ultragenyx, completed enrollment in April 2024,2 and the top-line data are expected before the end of 2025.
Cosmic Phase 3 clinical trial
In patients aged 2 to <7 years, the open-label, randomized, active-controlled Phase 3 Cosmic trial is evaluating setrusumab compared to intravenous bisphosphonate (IV-BP) therapy on annualized total fracture rate. Cosmic completed full enrollment with 69 patients and the top-line data are expected before the end of 2025.2
ASTEROID Phase 2b dose-finding clinical trial
Setrusumab’s Phase 2 clinical trial program included the ASTEROID trial (2017–2020), a Phase 2b dose-finding trial that recruited a diverse population across the most common types of OI, involving 112 adult patients aged 19 to 74 years.10
The unmet need in osteogenesis imperfecta
The current treatment landscape includes a multidisciplinary approach combining physiotherapy, orthopedic interventions, and pharmacological therapies.11,12 There are currently no FDA- or EU-approved therapies for OI, although neridronate is approved for use in Italy. Bisphosphonates (BPs) are primarily approved for the treatment of osteoporosis, but they are also used off-label for OI.12
Despite bisphosphonates being the mainstay treatment for OI, there are no established consensus guidelines for their indication and administration for this condition.13 These drugs work by inhibiting the activity of osteoclasts, the cells responsible for bone resorption.14 Although demonstrated to successfully increase bone mineral density (BMD), by reducing bone resorption, there is a lack of data to support BPs in reducing fracture risk and frequency in patients with OI.15
Bone fragility and fracture risk are universal features of OI and fractures are often underreported.16,17 Primary and secondary complications of fractures cause a significant burden for patients, caregivers and healthcare systems.18,19,20
Given the impact of fractures, there is a need for new treatments for OI which target and address the risk of fractures.21
Investigational therapies for OI
As understanding of osteogenesis imperfecta (OI) advances, investigational therapies are being explored to address the underlying mechanisms of bone fragility beyond current standards of care. These emerging approaches include targeted biological agents such as sclerostin inhibitors, which aim to enhance bone formation via modulation of the Wnt signalling pathway, and hormone-based treatments that stimulate osteoblast activity or inhibit bone resorption.14 While still under clinical evaluation, these therapies represent a shift towards anabolic strategies that may complement or offer alternatives to antiresorptive agents like bisphosphonates.14
Abbreviations
EMA, European Medicines Agency; FDA, Food & Drug Administration; IV-BP, intravenous bisphosphonate; OI, osteogenesis imperfecta; PRIME, priority medicines.
References
- Glorieux FH et al. J Bone Miner Res. 2017;32(7):1496–504.
- Ultragenyx. Ultragenyx Announces Completion of Enrollment in Phase 3 Orbit and Cosmic Studies Evaluating Setrusumab (UX143) for the Treatment of Osteogenesis Imperfecta (OI). Ultragenyx. Published April 30, 2024. Accessed May ,2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-completion-enrollment-phase-3-orbit-and.
- Rauch F et al. Lancet. 2004; 363(9418):1377–1385
- European commission. Community Register of orphan medicinal products. European commission. Published June 29, 2016. Accessed September 02, 2025. Union Register of medicinal products - Public health - European Commission.
- FDA. Search Orphan Drug Designations and Approvals. FDA. Published February 29, 2016. Accessed September 02, 2025. Search Orphan Drug Designations and Approvals.
- European Medicines Agency (EMA). PRIME: priority medicines. European Medicines Agency (EMA). Published 2015. Accessed May, 2025. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicines.
- Ultragenyx. Ultragenyx Receives Breakthrough Therapy Designation for Setrusumab (UX143) in Osteogenesis Imperfecta. Published October 7, 2024. Accessed September 02, 2025. Ultragenyx Receives Breakthrough Therapy Designation for Setrusumab (UX143) in Osteogenesis Imperfecta—Ultragenyx Pharmaceutical Inc.
- FDA. Breakthrough Therapy. FDA. Published April 01, 2018. Accessed May, 2025. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy.
- Mereo Biopharma. Mereo Biopharma Receives FDA Rare Pediatric Disease Designation For Setrusumab for the Treatment of Osteogenesis Imperfecta. Mereo Biopharma. Published September 24, 2020. Accessed September 02, 2025. Mereo BioPharma Receives FDA Rare Pediatric Disease Designation for Setrusumab for the Treatment of Osteogenesis Imperfecta.
- Glorieux FH et al. J Bone Miner Res. 2024;39(9):1215–28.
- Marr C et al. J Multidiscip Healthc. 2017;10:145–155.
- Drake MT et al. Mayo Clin Proc. 2008;83(9):1032–1045.
- Garganta MD et al. BMC Musculoskelet Disord. 2018;19(1):344.
- Rossi V et al. Curr Opin Pediatr. 2019; 31(6): 708–715.
- Dwan K et al. Cochrane Database Syst Rev. 2016;(10):1465–1858.
- El-Gazzar A et al. Int. J. Mol. Sci. 2021;22:625.
- Folkestad L et al. J Bone Miner Res. 2017;32(1):125–134.
- Song Y et al. Osteoporos Int. 2019;30:461–486.
- Swezey T et al. Osteoporos Int. 2019;30(2):507–511.
- Darbà J et al. J Med Econ. 2020;23(12):1435–1440.
- Liu W et al. J Clin Endocrinol Metab. 2023;108(7):1787–1796.
