In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab () for another 12 months. This study, dubbed , followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, , was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.