FDA advisory committee votes to recommend approval for alirocumab

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee today voted 13-3 that the benefits of LDL lowering via alirocumab, a human monoclonal antibody PCSK9 inhibitor, exceed its risks, and recommended approval for certain patient populations.

All panel members who voted yes indicated that they would recommend approval of alirocumab (Praluent, Sanofi/Regeneron) for the treatment of patients with heterozygous familial hypercholesterolemia, citing a particularly strong unmet need in this population. Several also said that they would support approval for patients at high CV risk whose hypercholesterolemia has not been adequately controlled by maximally tolerated statin therapy. Many on the panel also supported approval for patients at high CV risk whose hypercholesterolemia has not been adequately controlled by maximally tolerated statin therapy.

However, the majority of the committee expressed reservations about use of alirocumab in a broader range of patients without a demonstrated effect on CV outcomes as indicated by a clinical trial, and several panel members indicated that LDL was not a sufficient surrogate endpoint for CV outcomes.

“I no longer think we are in an LDL surrogate era,” said Peter W.F. Wilson, MD, director of epidemiology and genomic medicine at Atlanta Veterans Administration Medical Center, explaining his negative vote. “We’ve got to get new LDL-affecting and lipid-affecting molecules for CV outcomes right, right out of the box. I think what’s missing is a program that really targets [familial hypercholesterolemia] patients, and I think such a thing could be developed rather rapidly … and address some of our concerns.”

While some panel members said that they would prefer to see results from an ongoing CV outcomes trial evaluating the drug prior to approval, others felt that the need among patients with familial hypercholesterolemia was more pressing.

“This drug could offer substantial benefit to patients with heterozygous [familial hypercholesterolemia], and I'm worried about the opportunity cost to them of waiting 2 years or so until potential approval of the drug based on outcomes,” said Brendan M. Everett, MD, MPH, assistant professor of medicine at Harvard Medical School. He added, however, that he would restrict approval to this population only. “[An] outcomes trial is of fundamental importance for all other populations in question," Everett said.

Sanofi/Regeneron presented data on the efficacy of alirocumab across 10 multicenter, phase 3, randomized trials covering 5,296 patients, including 3,188 who received alirocumab. Five trials compared alirocumab vs. placebo and five compared alirocumab vs. ezetimibe (Zetia, Merck), at doses of 75 mg or 150 mg twice weekly.

The placebo-controlled trials incorporated patients with heterozygous familial hypercholesterolemia or patients at high CV risk who were already on a maximally tolerated statin dose. One ezetimibe-controlled trial included statin-intolerant patients, and one included patients at moderate CV risk who were not treated with background lipid-modifying therapy, according to the briefing document.

In a primary analysis incorporating a mixed-effect model and assessing the intent-to-treat population in all 10 studies, the researchers observed a 36% to 61% decline in LDL from baseline with alirocumab, with a treatment difference of 39% to 62% vs. placebo (P < .0001 for all) and of 24% to 36% vs. ezetimibe (P = .014 for a background 20-mg rosuvastatin regimen in one trial; P < .01 for all other values).

The safety of alirocumab was assessed across the 10 phase 3 trials as well as four phase 2 studies, including a total of 3,340 patients who received alirocumab. Nine of these studies were placebo-controlled and five were ezetimibe-controlled. The researchers observed no significant differences in the incidence of mortality, serious adverse events or treatment discontinuation due to adverse events across the trials.

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

Reference:

EMDAC Clinical Briefing Document. BLA 125559.