The Bone, Reproductive and Urologic Drugs Advisory Committee of the FDA voted 18-1 Wednesday in favor of recommending approval of a biologics license application for the monoclonal antibody romosozumab for the treatment of osteoporosis in postmenopausal women at high risk for fracture, with two of 18 “yes” votes supporting a different indication for the drug.
In committee discussions both before and after the vote, panel members unanimously called for additional data regarding the cardiovascular safety of romosozumab (Evinity, Amgen), with most members supporting either a randomized controlled trial or an observational study conducted after approval.
“There is a tremendous need for this medication, and there is an amazing amount of morbidity and mortality with this disease,” Frederick G. Kushner, MD, FACC, FAHA, FSCAI, FACP, clinical professor of medicine at Tulane University School of Medicine and Louisiana State University Health Science Center, said after his “yes” vote supporting the original indication. “[Romosozumab has] proven its efficacy, and the safety issue is still unknown, but I would vote for approval with a black box warning and a post-marketing study that would include, possibly, a prespecified registry trial to identify patients that may or may not be at increased risk.”
The committee discussed two questions focusing on CV safety before voting on whether the overall risk-benefit profile of romosozumab is acceptable to support approval. Questions included whether the CV safety of romosozumab has been adequately characterized and whether the indication for the drug should be narrowed to adults at high risk for fracture with low CV risk.
Romosozumab works by binding and inhibiting the activity of the protein sclerostin and, as a result, has a dual effect on bone, both increasing bone formation and decreasing bone breakdown. The dose is given once monthly, and treatment duration is limited to 1 year.
The committee meeting follows a complete response letter issued by the FDA in July 2017 for romosozumab, asking Amgen to add safety and efficacy data from the ARCH and BRIDGE trials into the drug application. In ARCH, postmenopausal women with osteoporosis assigned to romosozumab saw a 50% reduction in the relative risk for spinal fracture, a 19% reduced risk for nonvertebral fracture and a 72% reduced risk for clinical fracture; however, a 2.5% incidence of CV events after 12 months was reported. In BRIDGE, the incidence of positively adjudicated serious adverse CV events in men was 4.9% in the romosozumab group and 2.5% in the placebo group, according to Amgen. The incidence of positively adjudicated CV death was 0.6% in the romosozumab group and 1.2% in the placebo group.
The original application, submitted to the FDA in September 2016, was based on efficacy and safety data from the FRAME study, which did not show an increase in CV risk. Amgen and UCB resubmitted their application to the FDA in July, this time proposing to narrow the indication to treatment of osteoporosis in postmenopausal women at high risk for fracture. Amgen is also proposing a Boxed Warning as well as a Warning and Precaution for CV risk.
Both patient and consumer representatives on the committee expressed reservations about the available study data after voting. Michele Orza, ScD, chief of staff at the Patient-Centered Outcomes Research Institute in Washington, D.C., and acting consumer representative for the committee, ultimately voted “yes” but supported a different indication for the drug.
“I was going to vote ‘no,’ because I was leaning toward [requiring] a pre-approval study,” Orza said after her vote. “I was trending toward ‘yes’ because of the need and the benefit that could come from this. There needs to be a [risk evaluation and mitigation strategy] considered, I would like to see help for patients and clinicians to really make this risk-benefit tradeoff together. That’s going to take not only what FDA puts on the label, but what the clinical societies come up with in their guidelines. At the individual basis, it’s going to be tough call.”
Thomas J. Weber, MD, associate professor of endocrinology, metabolism and nutrition at the Duke University Medical Center in Durham, NC, who also supported approval with an alternative indication, said that given the uncertainty regarding CV risk with romosozumab, restricting the labeling to exclude patients with a prior myocardial infarction or stroke within the past year “seems reasonable,” as indicated with a black box warning.
“We do have other FDA approved options for osteoporosis, so we’re not leaving people untreated,” said Webber, who recommended removing an indication requirement that patients be considered intolerant to other available osteoporosis therapies before receiving romosozumab.
Sundeep Khosla, MD, director of the Center for Clinical and Translational Science at Mayo Clinic, who voted in favor of the drug with the original indication, noted that who is most likely to prescribe the therapy will make tracking patients who receive the drug in a post-approval study easier.
“This drug is not going to be prescribed by primary care providers,” Khosla said before the vote. “It will be prescribed by subspecialists who are invested in the treatment and care of osteoporosis. It will be much easier to have tracking of these patients than if it was used in a primary care setting.
“I want to emphasize the remarkable efficacy of this drug,” Khosla said. “Truly, it’s better than anything we’ve seen before, and I don’t want the panel to lose sight of that fact.”
The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.
The Ministry of Health, Labour and Welfare in Japan granted a marketing authorization for the drug on Jan. 8, and the European Medicines Agency is also considering approval. – by Regina Schaffer
Amgen briefing information. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM629458.pdf. Accessed Jan. 15, 2019.
FDA briefing information. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM629456.pdf. Accessed Jan. 15, 2019.
Editor's note: This article was updated on January 16 to include details of the committee vote. This article was further updated on January 30 to correct Weber's institution.