FDA Advisers Urge Approval of Romosozumab for Osteoporosis

Alicia Ault

January 17, 2019

A US Food and Drug Administration (FDA) advisory panel has urged the agency to approve romosozumab (Evenity, Amgen/UCB Pharma), a novel treatment for postmenopausal osteoporosis.

The FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 18-1 on January 16 to back approval of the humanized monoclonal antibody, an anabolic agent with a unique mechanism of action. The meeting was held despite the partial shutdown of the FDA because it was funded by user fees paid by Amgen and other drugmakers.

This is Amgen's second try at getting romosozumab approved. The FDA rejected Amgen's first attempt 18 months ago, when one of the trials submitted as part of the biologics license application suggested a higher rate of adverse cardiovascular (CV) events with the agent.

Amgen has now proposed a narrow indication — treatment of osteoporosis in postmenopausal women at high risk for fracture. High risk was defined as having a history of osteoporotic fracture, having multiple risk factors for fracture, or having failed or being intolerant to other available osteoporosis therapy. The label includes a black box warning about use in patients who have previously had a heart attack or stroke.

Sixteen FDA advisers supported this indication, while two said they'd like to see a different indication that better defined patients who could benefit or who might be at risk. The company also proposed conducting a postmarketing observational study to assess the risk for CV events.

The FDA advisers agreed yesterday that romosozumab is effective, but they all said that it remains unclear as to whether the drug raises the risk for CV events.

Noting "a tremendous need for this medication," Frederick G. Kushner, MD, FACC, FAHA, FSCAI, FACP, clinical professor of medicine, Tulane University School of Medicine, New Orleans, Louisiana, said that romosozumab has proven efficacy.

But, "I'm not sure there is a safety signal.... [It] is still unknown," he observed.

The 18 panel members who voted for approval said a postmarketing study should be required. Some said it should be observational, whereas others insisted that it needs to be randomized.

The FDA usually follows its advisers' recommendations. By law, the FDA was required to make a decision on the approval of romosozumab by January 12. The advisory committee allowed for a change in that date.

Ira Loss, senior health care adviser with Washington Analysis, said he expects either a 3-month extension of the user fee date or for the FDA to make a quick decision on approval.

The one panelist who did not favor approval — Natalie Compagni-Portis, the patient representative — said that Amgen should study and clarify any safety risk before romosozumab is marketed. "I think we would be kind of swinging in the dark without having more information," she observed.

"Unbelievable Clinical Potential," but CV Safety Must Be Addressed

Some of the physician panel members, however — while acknowledging that the safety issue must be addressed — were at pains to stress what potential they believe this agent has.

"I just want to emphasize the remarkable skeletal efficacy of this drug," noted panel member Sundeep Khosla, MD, professor of medicine and physiology, Mayo Clinic, Rochester, Minnesota. "Truly, it's more remarkable than anything we've seen," he said. Khosla suggested that Amgen use a registry to gauge romosozumab's risk.

FDA adviser Douglas C. Bauer, MD, professor of medicine, epidemiology, and biostatistics, University of California, San Francisco, agreed: "The drug has unbelievable clinical potential in the osteoporosis arena.

"The question is, how do we reliably counsel patients about the risks and benefits," said Bauer, who said he favored a randomized controlled trial to detail the CV risk.

Beatrice J. Edwards, MD, MPH, FACP, associate professor, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, said it might be hard to tease out which patients are at low risk for CV events, given that "aging itself is a risk factor."

The FDA adviser also said she did not see any biological plausibility to the idea that romosozumab raises CV risk.

Romosozumab inhibits sclerostin, a small protein expressed in osteocytes. The main function of sclerostin is to block bone formation.

In clinical trials, romosozumab, given at a dose of 210 mg subcutaneously monthly for a year, rapidly increases bone formation and simultaneously reduces bone resorption, thereby increasing bone mineral density and reducing fracture risk.

But sclerostin is also present in, for example, the aorta, which has raised questions about a potential interplay with cardiovascular systems.

Approval of romosozumab has been delayed in large part because of safety concerns following the ARCH study, which in May 2017 reported a higher rate of serious adverse CV events with romosozumab, compared with the bisphosphonate alendronate in high-risk female patients with osteoporosis, as detailed by Medscape Medical News.

The FDA subsequently rejected romosozumab and requested more data from the 4000-patient ARCH study, in addition to results from the BRIDGE trial, which was a placebo-controlled trial that evaluated romosozumab in men with osteoporosis.

In BRIDGE, there was also a higher rate of serious CV events with romosozumab vs placebo, but as noted in the FDA briefing documents issued earlier this week: "There were too few events in the small trial in men to draw definitive conclusions."

Amgen had also submitted findings from the large FRAME trial, which was a placebo-controlled trial of romosozumab conducted in more than 7000 postmenopausal women with osteoporosis. That trial, which was reported in September 2016, showed no indication of CV events, and the reduction in fractures seen with romosozumab was deemed "unprecedented."

Considering the Data Second Time Around

"FDA agrees that the applicant has established the effectiveness of romosozumab for the treatment of postmenopausal osteoporosis," the agency observed in the briefing documents.

The adverse CV finding seen in the ARCH trial and the BRIDGE study in men "is FDA's main concern and the reason for convening this advisory committee meeting," it added.

For this go-round, Amgen resubmitted the data from the ARCH trial, and also had the Duke Clinical Research Institute (DCRI) adjudicate the CV events in FRAME and ARCH and had the Thrombolysis in Myocardial Infarction Study Group (TIMI) adjudicate the Duke events.

The FDA said the results from DCRI and TIMI were similar. It focused on the Duke findings, and again found no increase in CV events in FRAME, the placebo-controlled trial. But the ARCH study still yielded disturbing signals.

"The applicant [Amgen] conducted a thorough review and subgroup analyses to identify potential differences in baseline cardiovascular risk between the two trials in women, FRAME and ARCH," the agency noted.

However, it also noted that these were not CV outcome trials. Notwithstanding this, and "using the information available, cardiovascular risk appeared similar between the populations enrolled in the two fracture trials [in women]."

Because there were too few individual CV events, the FDA also conducted a meta-analysis of major adverse cardiovascular events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, of 12-month data for both the FRAME trial and the ARCH study.

Fifty-one patients (0.9%) had MACE in the control groups (ie, either placebo or alendronate) compared with 71 (1.3%) in the romosozumab groups, for a hazard ratio of 1.38 (95% confidence interval, 0.96 - 1.99).

Impossible to Say Whether CV Risk With Romosozumab Is Real

Tae Hyun Jung, PhD, the FDA's statistical analyst, concluded it is hard to tell whether the increased risk seen in the ARCH study "is truly a drug effect, chance finding, or because of a reduced risk of MACE in the alendronate group."

Although it may be biologically plausible that alendronate and other bisphosphonates could have a cardioprotective effect, their very high specificity to bone and osteoclasts would not suggest that such a benefit occurs, the agency noted in the briefing documents. "To date, studies evaluating this question have yielded mixed results."

Scott Wasserman, MD, FACC, vice president of global development at Amgen, said that overall, 60 patients in each of the two studies [FRAME and ARCH] had MACE.

Those are small numbers, but the data suggest that there could be a small risk for CV events in the first 12 months, said Wasserman.

Many panelists said they weren't sure what to make of the safety data.

"We don't have good data to show what sclerostin is doing," observed Clifford J. Rosen, MD, director, Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough.

"That's extremely relevant to the whole point of whether we have biologic plausibility," he explained.

The committee debated what would be the best approach for determining not just whether romosozumab increases CV risk but, if it does, the size of that risk, and also which patients might be most vulnerable.

FDA adviser Tobias Gerhard, PhD, RPh, associate professor of pharmacoepidemiology, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, New Jersey, said that a large, simple trial that included randomization might be appropriate.

"With a purely observational study, you'll find the drug safe no matter what," he indicated.

If Approved, US Will Be Second Market for Romosozumab

If the FDA approves romosozumab, it would be the second approval.

As reported by Medscape Medical News, the drug was approved in Japan on January 8.

David M. Reese, MD, executive vice president of research and development at Amgen, said in a statement issued after the panel meeting, "Despite available therapies, these women who are at high risk for fracture could benefit from an additional treatment option that has the potential to both build new bone and slow existing bone loss."

Amgen is "committed to working with the FDA to help make Evenity available to appropriate patients," said Reese.

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