FDA advisory panel backs approval of PCSK9 inhibitors

Issue: July 2015

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted in June to recommend approval of two PCSK9 inhibitors for the reduction of LDL in certain patient populations.

The committee recommended that alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), both fully human monoclonal antibody PCSK9 inhibitors, receive approval for patients with familial hypercholesterolemia (FH) and for patients at high or very high risk for CV events who are unable to reach LDL targets despite maximally tolerated statin therapy. The panel suggested that indications for other patient populations wait until the results of CV outcome trials are known; panelists who voted against recommending approval wanted to withhold approval until those trials are completed. The ODYSSEY OUTCOMES trial of alirocumab and FOURIER trial of evolocumab are underway, but results are several years away.

Brendan M. Everett

During the discussion of alirocumab, the committee voted 13-3 that the benefits of alirocumab exceed its risks. In a primary analysis of 10 phase 3 randomized studies of alirocumab, 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 (Zetia, Merck; P = .014 for a background 20-mg rosuvastatin regimen in one trial; P < .01 for all other values).

Panel member Brendan M. Everett, MD, MPH, assistant professor of medicine at Harvard Medical School, who voted yes, said “this drug could offer substantial benefit to patients with heterozygous FH.” He said he was “worried about the opportunity cost to [the patients] of waiting 2 years or so until potential approval of the drug based on outcomes.”

Benefits of evolocumab

The committee voted 15-0 that the benefits of evolocumab outweigh its risks for patients with homozygous FH (HoFH), and 11-4 that its benefits outweigh its risks in at least one non-HoFH population. Amgen submitted four 12-week trials showing a 60% to 67% reduction in LDL and a 52-week trial showing a 57% to 59% reduction in LDL for those in non-HoFH populations assigned evolocumab. In two studies of patients with HoFH, those treated with evolocumab had a 31% reduction in LDL at 12 weeks and a 20% to 25% reduction in LDL at 24 weeks.

“I’m motivated to make that vote because I think these individuals have an unmet need and they have an urgent need for therapy,” said Robert J. Smith, MD, chairperson of the committee and professor of medicine in endocrinology at Alpert Medical School of Brown University, Ocean State Research Institute and Providence Veterans Administration Medical Center, Providence, Rhode Island.

Both therapies are administered by subcutaneous injection.

Decision applauded

Experts interviewed by Cardiology Today also backed the FDA advisory committee’s decision to recommend approval for the highest-risk patients now, but emphasized that the outcome trials need to be completed.

Steven E. Nissen

Joseph S. Alpert

“This was a good outcome, and I do think that this was in the public interest to get these drugs to market now for a limited population,” Steven E. Nissen, MD, FACC, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, said in an interview. “This will be a major step forward and a terrific tool for those patients who are very difficult to treat.”

Joseph S. Alpert, MD, MACP, professor of medicine at the University of Arizona College of Medicine, said that “at least in the short term, [alirocumab and evolocumab] are safe and effective, and they do appear with what data we have to decrease outcomes just as statins do.” However, he noted that “there should be very strict postmarketing surveillance” after approval, because many of the patients who will receive them in the real world are different from those in the trials.

Michael H. Davidson

Seth S. Martin

Michael H. Davidson, MD, FACC, FNLA, professor and director of the lipid clinic at the University of Chicago Pritzker School of Medicine, said more populations should have been recommended for immediate indication. “I was disappointed that the panel did not recommend approval for statin intolerance, which is difficult to define, but from a patient perspective is clearly a real issue,” he said. “The FDA panel vote is a sober reminder that there are many skeptics who want outcome trials before utilizing these very effective and well-tolerated agents.”

Seth S. Martin, MD, assistant professor of medicine at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, said the outcome studies will play a major role in wider use. “One important issue that the panelists raised is that they do not want to see approval now lead to significant dropout from the ongoing outcome trials,” he said. “It’s a valid concern.” Alpert, Davidson, Martin and Nissen are members of the Cardiology Today Editorial Board.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain and Adam Taliercio

Disclosures: The members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, Alpert and Martin report no relevant financial disclosures. Davidson reports consulting for Amgen and Sanofi/Regeneron. Nissen reports chairing a trial of evolocumab and serving on the steering committee of the outcomes trial for Pfizer’s bococizumab, but receives no remuneration.