Ultragenyx and Mereo Report Positive Data in Phase 2/3 Study in Rare Bone Disease

Rare Daily Staff

Ultragenyx Pharmaceutical and Mereo BioPharma Group reported positive data from the dose-selection phase 2 portion of their phase 2/3 Orbit study of their experimental therapy setrusumab showed rapidly induced bone production in patients with the rare bone disease osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately 85 percent to 90 percent of OI cases are caused by mutations 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, including at atypical sites. Patients with OI also exhibit increased bone resorption (breakdown of old bone) and inadequate production of new bone, which leads to decreased bone mass, bone fragility and weakness. OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are approved for the condition.

Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a protein that acts on a key bone-signaling pathway that inhibits the maturation and activity of bone-forming cells. The goal of blocking inhibitory effects of sclerostin is to increase new bone formation, bone mineral density and bone strength. Sclerostin inhibition also reduces excessive bone resorption, which enhances its impact on bone density. In mouse models of OI, the use of anti-sclerostin antibodies was shown to stimulate bone formation, improve bone mass and density, and increase bone strength against fracture force testing.

The companies said setrusumab demonstrated statistically significant increases in levels of serum P1NP, a sensitive marker of bone formation across all patients. It also led to a significant improvement in bone mineral density.

The large increase in bone mineral density observed in the Orbit patient population over the first 3 months was consistent with the rapid increase in serum P1NP levels and was similar to results that took 1 year to achieve in the ASTEROID study in adult OI patients. Lumbar spine BMD data were available in 17 of 24 Orbit patients at the three-month timepoint. Treatment with setrusumab for three months resulted in an increase in lumbar spine bone mineral density from baseline of 9.4 percent at 20 mg/kg. Treatment with 40 mg/kg resulted in a 9.8 percent. Patients on placebo at the three-month timepoint showed no significant change in bone mineral density.

“The dramatic lumbar spine BMD improvements in children at three months show that growing bones are more dynamic, and we anticipate the potential for a greater effect on bone formation and strength in younger patients with maturing bones,” said Eric Crombez, chief medical officer at Ultragenyx. “Based on the reports from study investigators, we’re encouraged by the impact setrusumab appears to be having on bone health so far.”

As of the data cut-off, there have been no treatment-related serious adverse events observed in the study. Reported adverse events have been generally consistent with those observed in the ASTEROID study and include infusion associated events, headache and sinusitis. There have been no reported hypersensitivity reactions related to setrusumab. There were no safety-related differences observed between dosing groups or age groups.

Photo: Eric Crombez, chief medical officer at Ultragenyx