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SILVER SPRING, Md. -- An FDA advisory committee voted overwhelmingly to recommend approval for the bone anabolic agent romosozumab (Evenity).

Members of the Bone, Reproductive and Urologic Drugs Advisory Committee voted 18-1 in support of FDA approval, concluding the agent's benefits outweigh its risks for the proposed indication of osteoporosis in postmenopausal women at high risk for fracture.

Specifically, this is defined as postmenopausal women with a history of osteoporotic fracture and multiple risk factors for fracture, and also includes those who've failed on other osteoporosis therapies.

The most common reasons committee members cited for backing romosozumab's approval included established efficacy and the need for new osteoporosis therapy options for this population. However, most members stated the sponsor's proposal to include a boxed warning, which will list potential cardiovascular (CV) safety risks, solidified their support for approval.

Some members also mentioned that their vote was contingent on the completion of a high-quality, post-approval observational study, to which the drug's developer, Amgen (in partnership with UCB), has already agreed.

However, two members who voted in favor of the drug did so for a narrower indication, restricting use to a lower CV-risk population.

The single "no" vote came from a member who cited CV concerns as the reason, and favored a pre-approval, rather than a post-approval, study.

If approved, the humanized monoclonal antibody would be a first-in-class sclerostin inhibitor. Recommended dosing for romosozumab is once a month in two 105-mg injections, for a total 210-mg subcutaneous dose. Therapy would be limited to 12 months as trial data indicated the effects on bone mineral density leveled off thereafter.

This was the second review cycle for the drug; the FDA rejected an initial application in July 2017 after CV concerns were raised in two ongoing trials. The application was resubmitted a year later.

Romosozumab's efficacy wasn't disputed at the meeting. In , FDA reviewers agreed that "the applicant has established the effectiveness of romosozumab for the treatment of postmenopausal osteoporosis." This was demonstrated in a 24-month placebo-controlled trial reporting a 73% (95% CI 53%-84%) relative risk reduction in morphometric vertebral fracture after 12 months.

After the first year, all patients were switched to denosumab (Xgeva and Prolia), where there was a sustained 75% (95% CI 60%-84%) relative risk reduction by 24 months compared with placebo. At 12 months, there was also a 36% (95% CI 11%-54%) relative risk reduction in clinical fracture.

A second phase III trial reported similar efficacy with romosozumab when compared with alendronate (Fosamax) rather than placebo, and a relative risk reduction of 50% (95% CI 34- 62) for new morphometric vertebral fracture at 24 months.

However, the clinical program saw an increase in major adverse CV events (MACE) tied to the investigational treatment, mainly driven by an increased incidence of MI and stroke. In a meta-analysis combining events from all three trials, there was a 40% increased risk for MACE (HR 1.40, 95% CI 0.99-1.99).

Amgen argued that the benefit of significantly reducing fracture risk outweighs the "possible increased risk of MI and stroke." To mitigate concerns, Amgen proposed a boxed warning and other information about CV risks on the label. The company also promised a "robust non-interventional post-marketing cohort study" which is planned "to exclude a 2-fold risk of MACE in postmenopausal women at high fracture risk receiving romosozumab compared with those receiving other osteoporosis therapies."

"Evaluation of this possible risk in the intended U.S. patient population and the timely data availability afford advantages over other trial options to further investigate the relationship between romosozumab and CV events," Amgen stated in .

During a nearly hour-long public comment period, healthcare professionals and patients offered mixed support from the drug. Advocates spoke in favor of new therapy options, particularly for survivors of hormone-related cancers who are at a higher risk for osteoporosis. Others called for a CV safety outcomes study to be completed before considering approval.

Pre-vote, committee members unanimously agreed that CV safety has not been adequately characterized through the sponsor's existing data. But they debated what the best type of CV study would be -- observational versus randomized; pre-approval versus post-approval.

"I think a post-approval study is appropriate," said A. Michael Lincoff, MD, of the Cleveland Clinic. "I don't think withholding this therapy for years while we study this is warranted. But I think that databases and various types of existing data that's passively collected will be sufficient," although he acknowledged that a randomized trial would still be best.

But Pamela Shaw, PhD, of the University of Pennsylvania School of Medicine in Philadelphia, disagreed. "I can't imagine a registry or passive database that would allow us to do this reliably. Relying on observational data only post-approval, I don't think will help us answer [the question of CV safety] reliably. We just won't have correct comparisons. We will look at groups of people, but we won't be able to reliably compare them." Shaw ultimately voted in favor of approval, however.

Committee members also discussed narrowing the proposed indication to a smaller, low CV risk population, such as excluding women with a history of MI or stroke. But most panelists said the broader indication was acceptable with a boxed warning.

Although the FDA is not required to follow its advisory committees' recommendations, it typically does.

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