RARE Daily

Ultragenyx and Mereo Positive Phase 2 Data in Rare Bone Diseases Trial

June 12, 2024

Rare Daily Staff

Ultragenyx Pharmaceutical and Mereo BioPharma Group reported positive 14-month results from the phase 2 portion of the ongoing phase 2/3 Orbit study of their experimental therapy setrusumab that showed continued to significantly reduce incidence of fractures in patients with osteogenesis imperfecta with at least 14 months of follow-up.

Treatment with setrusumab also resulted in ongoing and meaningful improvements in lumbar spine bone mineral density at month 12 without evidence of plateau, they said.

Osteogenesis imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately 85 percent to 90 percent of OI cases are caused by genetic variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. The collagen mutations in OI can result in increased bone brittleness, which contributes to a high rate of fractures. Patients with OI also exhibit inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility and weakness. OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are globally approved for OI.

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.

The large reduction in annualized radiologically confirmed fracture rate previously reported in patients treated for a minimum of 6 months was sustained in patients treated for at least 14 months with a high degree of significance. The median annualized rate of radiologically confirmed fractures across all 24 patients in the two years prior to treatment was 0.72.

Following a mean treatment duration period of 16 months, the median annualized fracture rate was reduced 67 percent to 0.00. The annualized fracture rate excluded morphometric vertebral fractures and fractures of the fingers, toes, skull, and face, consistent with the phase 3 study primary efficacy endpoint.

The reduction in annualized fracture rates was associated with continued, clinically meaningful increases in [bone mineral density] BMD. Tests conducted at the 12-month timepoint demonstrated that treatment with setrusumab resulted in a mean increase in lumbar spine BMD from baseline of 22 percent across all age groups (5 to < 26 years old), a further improvement from 14 percent observed at six months of treatment.

As of the data cut-off, there were no treatment-related serious adverse events observed in the study. Reported adverse events were generally consistent with those observed in the Asteroid study with infusion-related events and headache determined to be the most common adverse events related to the study drug. As of the data cut-off, there were no reported hypersensitivity reactions related to setrusumab.

“The clinically meaningful continued improvement in BMD suggests that new and stronger bone is being created that has resulted in an important reduction in fractures across age groups and types of OI,” said Eric Crombez, chief medical officer at Ultragenyx. “With our phase 3 Orbit and Cosmic studies fully enrolled we now look forward to the possibility to bring this potential new treatment to a larger number of patients living with OI.”

Photo: Eric Crombez, chief medical officer at Ultragenyx

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