Dear FDA: Resist the Urge on PCSK9 Drugs

John Mandrola


June 16, 2015

Last week, an FDA advisory committee recommended approval of two proprotein convertase subtilisin kexin 9 (PCSK9)–inhibitor drugs. A formal decision is expected later this summer. The FDA usually follows the advice of its advisory committees, but not always.

This is a big moment in cardiology. It is also a huge gamble for the FDA.

I believe the FDA should break with its advisory committee and say no.

Not yet. It's too early to unleash these drugs on American patients and doctors.

Here are four reasons.

Target Confusion

The first reason the FDA should say no (not yet) is the target. PCSK9 drugs lower LDL cholesterol. That fact is clear. But our target is not a lab value; it's heart disease.

Any doctor who sees patients knows heart disease comes from many things. These factors, which affect individuals in genetically varied ways, accumulate over years, not months. LDL-C may be important, or very important, but it is just one risk factor. Even in patients with familial hypercholesterolemia, LDL-C may be one of many risk factors.

The stunning LDL-C lowering from PCSK9 drugs might prevent future heart attacks, strokes, and deaths. The key word in that sentence is might. We don't know. The biology of these drugs is beautiful, but that beauty should not obscure the current state of knowledge.

What we know now is that PCSK9 drugs are effective at LDL-C lowering. That is it. The OSLER[1] and ODYSSEY[2] trials were not powered to look at outcomes. Those data are forthcoming in the FOURIER trial, which has completed enrollment of 27,000 subjects, and results are expected in 2017. Why not wait?

Do No Harm

The second reason the FDA should hold off is the risk. The mission statement of the FDA says its charge is to "protect the public health by [ensuring] the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation."

What I read into that is harm avoidance. In this way, I see the FDA's role as similar to a physician's. Yes, we want to benefit our patients, but the guiding principle must be to avoid harm. This is especially critical when treating people for something (an MI, stroke, or death) that has yet to happen. Having a high risk for a disease is not the same as having a disease.

It is true; in both the OSLER and ODYSSEY studies, evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) looked reasonably safe. But follow-up was only 11 months in OSLER and 78 weeks in ODYSSEY. That's too short. Heart-disease prevention is not a 2-year endeavor.

In both studies, more patients on the PCSK9 inhibitor reported neurocognitive effects. That may be significant. Is it implausible to think cholesterol might be important for brain cells? Here, let's also be mindful of euphemism. "Neurocognitive function" is a fancy way to say "think." Thinking is what makes us human. So if we think of this issue from a patient-centered standpoint, how many humans would trade a dull mind for a possible benefit 2 to 10 years in the future?

History Casts Doubt

The third reason the FDA should say no is historical. The use of surrogate markers for cardiac drugs has proven to be a bad gamble. We can point to niacin[3], fibrates[4] and cholesteryl ester transfer protein (CETP) inhibitors[5] as evidence of that failure. Although statin drugs are potent LDL-C lowering agents and proven effective in reducing cardiac events in high-risk patients, no one argues these drugs don't have important pleiotropic effects. The case of ezetimibe is hardly supportive of the LDL-C hypothesis. In the IMPROVE-IT[6] trial, the tiny absolute benefit of ezetimibe (composite end point) was achieved against simvastatin—a straw-man comparator if there ever was one.

Distractions—Benefits Missed

The fourth reason the drugs are not ready is the potentially harmful effects of distraction and benefits missed. Many have argued, including patients with familial hypercholesterolemia, that PCSK9 drugs should be approved now because of the benefits missed while waiting for the FOURIER data. Of course, this assumes positive results are forthcoming.

Another way to look at benefits missed is to imagine the devastating impact of all that will not occur if these expensive drugs are approved. If we spend billions of dollars on these drugs—and make no mistake, if the FDA approves them, we will spend billions, then that takes money (and attention) away from many other facets of heart disease prevention.

Look at the case of ezetimibe, the last drug approved without outcomes data. Billions were spent on a drug with minimal to no effect on outcomes. What were the benefits missed of those billions? Healthcare budgets are limited. If we spend money on unproven drugs, we aren't spending it on cardiac rehab programs, parks, bike lanes, school nutrition programs, and many other useful heart-healthy public-health projects.

2017 is just around the corner. I say the FDA should resist the urge. Protect the public. Do no harm.



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