Ultragenyx and Mereo Report Positive Interim Phase 2 Data for Setrusumab in Rare Bone Disorder

Rare Daily Staff

Ultragenyx Pharmaceutical and Mereo BioPharma Group reported interim data from the phase 2 portion of the phase 2/3 ORBIT study demonstrating that treatment with setrusumab significantly reduced incidence of fractures in patients with osteogenesis imperfecta with at least six months of follow-up and continues to demonstrate ongoing and meaningful improvements in lumbar spine bone mineral density.

The data were presented in a late-breaker presentation at the American Society for Bone and Mineral Research 2023 Annual Meeting.

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. Patients with OI also exhibit 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 OI, which affects approximately 60,000 people in the developed world.

Setrusumab (UX143) 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.

As of the cut-off date and following at least six months of treatment with setrusumab, the annualized fracture rate across all 24 patients in the phase 2 portion of the study was reduced by 67 percent. In the 2 years prior to treatment with setrusumab all patients experienced at least 1 fracture. The median annualized fracture rate of 0.72 in the two years prior to treatment was reduced to zero during the mean treatment duration period of 9 months. Following initiation of treatment with setrusumab, 20 patients experienced no radiographic-confirmed fractures, and four patients experienced seven radiographic-confirmed fractures in five separate events. These fractures exclude fractures of the fingers, toes, skull, and face consistent with the phase 3 study design.

“I have not yet encountered a patient with a fragility fracture while on setrusumab, and this may result from setrusumab’s effects on the skeleton, improving the rate of new bone formation and bone quality,” said Gary Gottesman, professor of Pediatrics and Medicine, Washington University School of Medicine. “Some of the kids feel well enough they are participating in activities that they might normally avoid and have suffered some relatively minor fractures.”

The reduction in annualized fracture rates was associated with a clinically meaningful increase in bone mineral density (BMD). At the six-month timepoint, treatment with setrusumab resulted in a mean increase in lumbar spine BMD from baseline of 13 percent at the low dose and 16 percent at higher dose, which represents the same substantial mean improvement in Z-score of +0.85 for both dose groups at six months compared to a combined mean baseline Z-score of –1.68. The small apparent difference in BMD change from baseline is likely related to differences in patients assigned to the two treated groups. There was no statistically significant difference in BMD percent change or Z-score change from baseline between the two dosing cohorts.

“These data provide compelling evidence that improved bone mineral density, resulting from this unique mechanism of action, reduced the risk of fractures and that treatment with setrusumab could allow patients with OI to lead much more active lives with fewer fractures,” said Eric Crombez, chief medical officer at Ultragenyx.

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. There have been no reported hypersensitivity reactions related to setrusumab. There were no notable safety-related differences observed between dosing groups or age groups.

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. In the phase 2 portion, 24 patients were randomized 1:1 to receive setrusumab at one of two doses to determine the optimal dosing strategy for phase 3. The pivotal phase 3 portion of the study, currently enrolling, will include approximately 195 patients at 50 sites across 12 countries, randomized 2:1 to receive setrusumab or placebo, with a primary efficacy endpoint of annualized clinical fracture rate, excluding fingers, toes, skull, and face. All patients will transition to an extension period and receive open label setrusumab after the phase 3 primary analysis is complete.

In 2019 Mereo BioPharma completed the phase 2b dose-finding study for setrusumab in 112 adults with OI, which demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI.

Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally based on the collaboration and license agreement between the parties. The companies have developed a comprehensive late-stage program to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV.

Photo: Eric Crombez, chief medical officer at Ultragenyx