FDA panel recommends approval of evolocumab

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of evolocumab for reduction of LDL.

The committee voted 15-0 that the benefits of evolocumab (Repatha, Amgen), a fully human monoclonal antibody PCSK9 inhibitor, outweigh the risks in patients with homozygous familial hypercholesterolemia (HoFH), and 11-4 that its benefits outweigh its risks in at least one patient population other than HoFH.

Amgen is seeking indications for the reduction of LDL and changes to other lipid parameters in adults with primary hyperlipidemia or mixed dyslipidemia, including statin-intolerant patients, either alone or in combination with other lipid-lowering therapies; and for the reduction of LDL and other lipid parameters in adults and adolescents aged 12 years or older with homozygous familial hypercholesterolemia, in combination with other lipid-lowering therapies.

In the vote regarding patient populations aside from HoFH, most of those who voted yes cited patients with heterozygous familial hypercholesterolemia and those at high or very high risk for CV events who cannot achieve LDL targets despite maximally tolerated statin therapy as populations for whom the drug should be approved.

“I’m motivated to make that vote because I think these individuals have an unmet need and they have an urgent need for therapy, so I am unwilling to wait for the period of time of completion of outcome trials before giving them this option,” Robert J. Smith, MD, chairperson of the committee and professor of medicine (endocrinology), Alpert Medical School of Brown University, Ocean State Research Institute and Providence Veterans Administration Medical Center, Providence, Rhode Island, who voted yes, said. “This is not to say that I am totally convinced that the LDL lowering we see will play out into [CV] benefit. It’s a willingness in my view to accept that uncertainty while we figure that out. So it becomes absolutely critical to complete adequate [CV] trials to answer the true outcome benefit.”

Those who voted no for non-HoFH populations primarily did so because of limited safety data and concern about whether LDL is an appropriate surrogate for CV outcomes. A CV outcomes trial for evolocumab, FOURIER, is currently being conducted, but results are several years away.

“Accelerated approval was not an option … and it would have allowed us to be reassured that a [CV] outcome trial would be completed,” William R. Hiatt, MD, FACP, FAHA, professor of medicine, division of cardiology, University of Colorado School of Medicine, and president, Colorado Prevention Center, Denver, said. “Without that option, we are going to expose a large patient population to a drug that has a very limited safety database and absolutely no evidence of clinical benefit.”

He added that he was concerned that “a yes vote means we support LDL as a surrogate under all conditions. That, therefore, increases the probability that new drugs testing novel mechanisms that don’t work through LDL receptors get approved based on LDL.”

While the panel was unanimous in its approval for patients with HoFH because of the severity of the disease and the limited options available for this population, it was split on whether to recommend approval of a dose of 420 mg once every 2 weeks in addition to one of 420 mg every month.

The FDA is not required to follow the advice of its advisory committees, but it usually does. – by Erik Swain

Reference:

EMDAC Clinical Briefing Document. BLA 125522.

Disclosure: The members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee report no relevant financial disclosures.