Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to setrusumab (UX143) for reducing the risk of fractures in patients aged two years and older with osteogenesis imperfecta (OI) Types I, III, or IV. This designation aims to accelerate the development and review of drugs intended to treat serious conditions and demonstrate significant improvement over existing therapies.
The FDA's decision is supported by encouraging data from the Phase 2 portion of the Orbit study and the completed Phase 2b ASTEROID study. These studies revealed a rapid and clinically meaningful decrease in fracture rates among patients treated with setrusumab. Eric Crombez, M.D., chief medical officer at Ultragenyx, emphasized the importance of this designation, highlighting the seriousness of OI and the potential impact of setrusumab on affected individuals and their families.
Mechanism of Action and Clinical Data
Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a protein that negatively regulates bone formation. By blocking sclerostin, setrusumab is expected to promote new bone formation, increase bone mineral density, and enhance bone strength in patients with OI.
In the Phase 2 Orbit trial, 14-month results demonstrated a 67% reduction in the annualized fracture rate (p=0.0014) and a 22% mean increase in lumbar spine bone mineral density (BMD) from baseline across all age groups (p<0.0001; N=19) after 12 months of treatment. The ASTEROID study also showed that setrusumab had a statistically significant effect on bone density and formation. In the 20mg/kg high dose group, areal BMD at the lumbar spine, measured by DXA, increased by 8.97% at 12 months compared with baseline (p<0.001).
Osteogenesis Imperfecta: An Unmet Need
Osteogenesis imperfecta is a group of genetic disorders impacting bone metabolism, primarily caused by mutations in the COL1A1 or COL1A2 genes. These mutations lead to reduced or abnormal collagen production, resulting in increased bone brittleness and a high rate of fractures. It is estimated that OI affects approximately 60,000 people in commercially accessible geographies, and currently, there are no globally approved treatments for this condition.
Regulatory Status and Ongoing Studies
In addition to the Breakthrough Therapy Designation, setrusumab has been granted Orphan Drug Designation in the United States and EU, as well as Rare Pediatric Disease Designation in the United States. It has also been accepted into the European Medicine Agency's Priority Medicines program (PRIME).
Ultragenyx and Mereo BioPharma are collaborating on the global development of setrusumab. The drug is currently being evaluated in pediatric and young adult patients with OI subtypes I, III, and IV through the pivotal Phase 2/3 Orbit study and the Phase 3 Cosmic study (ClinicalTrials.gov Identifier: NCT05768854).
Ultragenyx's Broader Pipeline
Beyond setrusumab, Ultragenyx is advancing several other gene therapy candidates. UX701, an investigational AAV9 gene therapy for Wilson disease, is being evaluated in a Phase 1/2/3 Cyprus2+ study. Additionally, the Phase 3 GlucoGene study of DTX401, an AAV8 gene therapy for glycogen storage disease type Ia, met its primary and key secondary endpoints, with regulatory discussions planned for 2025. The company is also planning to seek accelerated approval for UX111, an AAV gene therapy candidate for Sanfilippo syndrome type A, with a biologics license application expected in late 2024 or early 2025.
