A Food and Drug Administration advisory committee Wednesday
recommended that the agency approve the cholesterol-lowering drug
Repatha from Amgen Inc., 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 proven 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.
Amgen stock rose 0.5% in after-hours trading to $156.25.
Repatha, generically called evolocumab, "results in
statistically significant reductions in LDL cholesterol of
approximately 60% after 12 and 52 weeks of treatment," an FDA
analysis of clinical-trial data said.
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, the analysis said, there
have been some trials in recent years showing that lowering LDL
doesn't always reduce heart disease.
Some prominent cardiologists who weren't on the committee 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."
But 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 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
also 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 PCSK9 drugs work 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
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