FDA advisory panel members express concerns with PCSK9 inhibitors

On June 9 and 10, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended the approval of alirocumab and evolocumab to lower low-density lipoprotein (LDL) cholesterol in patients.

The drugs are both injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a new class of medications that are used as monotherapies or in combination with statins. The panel voted 13-3 in favor of alirocumab (Praluent, Regeneron Pharmaceuticals and Sanofi Aventis) and 11-4 in favor of evolocumab (Repatha, Amgen). It also voted 15-0 in favor of evolocumab for patients with homozygous familial hypercholesterolemia, a rare condition.

Still, two members of the committee did not recommend approval for either drug in the larger populations: William Hiatt, MD, of the University of Colorado and the Colorado Prevention Center in Aurora; and Peter Wilson, MD, of Emory University and the Emory Clinical Cardiovascular Research Institute in Atlanta.

Hiatt and Wilson spoke with Cardiovascular Business about their votes and the problems they see with the medications and the FDA drug approval process.

“My fundamental concern is that the requirement to put a new drug on the market that’s designed to prevent heart attack, stroke and vascular death, there should be evidence that it actually does that,” Hiatt said. “Neither sponsor nor the FDA presented any information from the current data that was any hint of benefit in any rigorous way. I think it’s better for approving a whole new class of drugs to treat a major cardiovascular indication should be (evidence) that it actually works. That evidence was not presented.”

Hiatt said he would have liked the trials to have proven the drugs were effective at preventing or delaying major adverse cardiovascular events, which he defined as MI, ischemic stroke and death due to cardiovascular disease. He added that LDL cholesterol is a surrogate marker and has a relationship with the risk of cardiovascular events.

“Many members on the committee felt comfortable approving based on what they presume the relationship to be between lowering LDL cholesterol and clinical benefit -– clinical defined as cardiovascular events,” Hiatt said. “But the problem is, just quite simplistically, that neither development program showed anything that was in any way evidence that the drugs actually worked on improving human health.”

Wilson also had an issue with using LDL cholesterol as the marker. He said LDL cholesterol is “context dependent” and depends on a patient’s reading at baseline. The PCSK9 inhibitors are effective for patients with LDL cholesterol of 160 mg/dL or higher, according to Wilson. However, he said patients with lower readings might not benefit from the drugs.

“We don’t have outcomes; it’s hard to recommend approval without outcomes,” Wilson said. “I’m on the conservative side of assessing these types of new molecules. We have a pretty good portfolio of lipid medications… I’m data driven, and especially when we have expensive new products, we’ve got to be data driven. We cannot just be anecdotal because once we’re there, the products get overprescribed and we don’t even really know how much benefit we’re getting out of these.”

The manufacturers of both drugs have large cardiovascular outcomes trials under way and are expected to release results in the next year or two. Hiatt and Wilson said they would have preferred waiting until then to vote whether to recommend approval.

The FDA is expected to make its approval decision on alirocumab by July 24 and on evolocumab by Aug. 27. The agency often, but not always, follows the recommendations of its advisory panels.

“Let me say this: They’re both terrific drugs at lowering LDL cholesterol,” Hiatt said. “They both represent a huge advance in cardiovascular medicine. We need these drugs on the market at some point in time. And they both work exactly the same way. I think long term, there’s no doubt in my mind that these drugs will show benefit and should get on the market. It’s just that I hate to be in a position today to be forced to vote a drug on the market when I don’t know that it’s actually helping patients. It just seems counterintuitive to me. Despite how strong the LDL hypothesis is, I just felt that that sets a very bad precedent, one that’s been perpetuated by the FDA for many years.”