Ultragenyx, Moreo Shares Sink after Phase 3 Miss on Primary Endpoint

Rare Daily Staff

Ultragenyx Pharmaceutical and its partner Moreo Biopharma said the phase 3 Orbit and Cosmic studies of their experimental therapy setrusumab for the rare bone condition osteogenesis imperfecta failed to achieve statistical significance on the primary endpoints of reduction in annualized clinical fracture rate compared with placebo or bisphosphonates.

Both studies achieved the secondary endpoints of improvements in bone mineral density compared with the control groups, and no change was observed in the safety profile.

News of the results sent Ultragenyx shares down more than 40 percent and Moreo shares down more than 90 percent in midday trading. Ultragenyx said it is evaluating its planned operations and will promptly define and implement significant expense reductions. Moreo said it is carefully managing its cash resources with immediate reductions in its pre-commercial and manufacturing activities, while it continues to advance partnering discussions for alvelestat, the company’s experimental therapy for alpha‑1 antitrypsin deficiency–associated lung disease

Osteogenesis imperfecta, or OI, includes a group of genetic disorders that impact 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, which increase bone brittleness and contribute 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, and there are no globally approved treatments for the condition.

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, and in mouse models of OI, anti-sclerostin antibodies have been shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels.

In the Orbit study, participants experienced statistically significant improvements in bone mineral density compared with placebo, at levels consistent with the treatment effect observed in the phase 2 portion of the study, but these changes were not accompanied by a corresponding reduction in annualized fracture rates, and the placebo group had a low fracture rate.

In the pediatric Cosmic study, patients had a substantially higher baseline fracture rate than those enrolled in Orbit, and in this younger population, meaningful improvements in bone mineral density were associated with a reduction in annualized fracture rate for setrusumab-treated patients compared with bisphosphonate-treated patients, though the reduction did not reach statistical significance.​

Ultragenyx is conducting additional analyses on data across both studies, including other bone health and clinical endpoints beyond fractures, to assess next steps for the program given the totality of the data.

“We are surprised and disappointed by these results given the promising data from our phase 2 study and the lack of approved treatment options available to patients with OI who live with significant pain, disability, and disease burden,” said Emil Kakkis, president and CEO of Ultragenyx. “We continue to explore the data to gain a deeper understanding of the findings.”