By Thomas M. Burton
A Food and Drug Administration advisory committee on Wednesday
recommended that the agency approve Amgen Inc.'s
cholesterol-lowering drug Repatha, the second in a class of
promising heart medicines that could change medical practice and
generate billions of dollars in sales.
The panel voted 11-4 to recommend the FDA approve Repatha,
saying its benefits outweighed its risks. But panel members
expressed concerns that Amgen primarily relied on studies that
lasted only 12 weeks.
The committee also voted 15-0 to recommend approval of Repatha's
use in a rare subset of familial hypercholesterolemia, a genetic
disease causing extremely high cholesterol. The population of this
subset, called homozygous familial hypercholesterolemia, has been
estimated as low as one in 1 million people.
The overall approval recommendation would endorse injections
either monthly or every two weeks.
The panel voted on the injectable Amgen drug a day after it
recommended approval of the drug Praluent, from Sanofi SA and
Regeneron Pharmaceuticals Inc. The committee members expressed
concerns both days about the fact that both drugs' FDA applications
are largely based on lowering LDL, or "bad" cholesterol, not on
avoiding bad outcomes like heart attacks. The panelists worried
that, while LDL cholesterol has proved a good early measure--or
"surrogate endpoint"--of whether statin drugs like Lipitor reduce
heart disease, that may not be the case with this new class of
medicines.
"It would be important to have clinical evidence of benefit, and
a surrogate is not adequate," said panel member William R. Hiatt, a
cardiologist at the University of Colorado. Some other panelists
felt that patients with extremely high cholesterol need a powerful,
cholesterol-lowering agent, like Repatha.
Amgen stock rose 0.5% to $155.55 in 4 p.m. trading on
Wednesday.
Repatha, generically called evolocumab, "results in
statistically significant reductions in LDL cholesterol of
approximately 60% after 12 and 52 weeks of treatment," according to
an FDA analysis of clinical-trial data. The primary studies lasted
12 weeks.
Reviewers from the FDA noted that historically, "reduction of
LDL cholesterol alone has been viewed favorably as a surrogate
outcome if the reduction was sufficiently robust" and there weren't
safety red flags linked to the drug. But there have been some
trials in recent years showing that lowering LDL doesn't always
reduce heart disease, according to the analysis.
Some prominent cardiologists who weren't on the panel said the
way the Amgen drug works is similar enough to that of statins, so
that lowered LDL cholesterol should mean better outcomes. Steven E.
Nissen, chairman of cardiovascular medicine at the Cleveland
Clinic, said, "There are some times that surrogate endpoints are
useful." This is such a case, he said in an interview.
One panel member, Philip Sager of Stanford University, said he
voted in favor of approving the drug "because of the large, unmet
medical need."
Martha Nason of the National Institute of Allergy and Infectious
Diseases voted against recommending approval. "I don't put much
stock in 12-week safety data," she said.
The FDA often follows the recommendations of its advisory
panels, but it isn't required to do so.
Amgen issued a statement after the votes, saying "there is a
critical need for additional treatment options for patients who are
unable to control their high cholesterol" and that it looks
"forward to continuing to work with the FDA as they complete their
review."
The drug maker has already fully enrolled a study of 27,500
patients to see if Repatha does in fact lower the rate of heart
attacks and other cardiovascular events compared to statin drugs
alone. Amgen said the study should produce results by 2017.
Several speakers at the FDA advisory hearing were patients with
the genetic high-cholesterol disorder, who said they need more
treatment options.
Regarding safety, an FDA reviewer said "there were no marked
disparities in deaths, serious adverse events or adverse events
leading to discontinuation" of the Amgen drug. However, FDA
officials speaking at the panel meeting expressed some reservations
about the relatively short, 12-week duration of the completed,
controlled Repatha studies, involving 3,152 patients.
The 60% reduction in LDL within weeks is unusual for a drug and
very hard for patients to achieve with diet and exercise alone.
Still, the question is whether that reduction, from a drug working
in a novel way, reduces disease. The class of drug works by
blocking the protein called PCSK9 that interferes with the liver's
ability to clear bad cholesterol from the bloodstream.
"Regardless of how confident we may be in the 'LDL hypothesis,'
we must remember that LDL cholesterol remains a surrogate and not a
clinical outcome that reflects how patients feel, function or
survive," wrote James P. Smith, a doctor and deputy director of the
FDA drug center's division of metabolism and endocrinology
products.
Write to Thomas M. Burton at tom.burton@wsj.com
Access Investor Kit for Amgen, Inc.
Visit
http://www.companyspotlight.com/partner?cp_code=P479&isin=US0311621009
Subscribe to WSJ: http://online.wsj.com?mod=djnwires