The PCSK9 Drugs — Epic success or epic failure?

This week, an FDA advisory committee recommended approval for the potent cholesterol-lowering drugs, evolocumab and alirocumab. The funny-sounding medications are called PCSK-9 inhibitor drugs. (Keep reading; I’ll tell you more.)

Advisory committee members felt the benefits of the drugs outweighed the potential risks, especially in high-risk patients, such as those with Familial Hypercholesterolemia (FH).

The FDA usually–but not always–follows the recommendation of the advisory committee. A final decision from FDA will come later this summer.

In reading this piece, keep in mind that the goal of cholesterol drugs is to reduce the risk of heart attacks, strokes and death. It’s easy to get side-tracked into thinking a drug is good if it lowers cholesterol. Changing lab values is worthless unless those changes result in better outcomes in the future.

I re-read both the Osler (evolocumab) and Odyssey (alirocumab) studies in the NEJM. This class of drugs and the story of their development is fascinating.

PCSK9 Biology:

We know that people with a rare DNA sequence variant in the gene encoding PCSK9 have very low LDL levels and low rates of heart disease.

So what do you do?

You develop a monoclonal antibody to simulate the favorable genetic variant. That’s exactly what the makers of the PCSK9 inhibitors have done.

And it’s nifty biology.

But the clinical science is early. So very early.

The PCSK9 story turns on the LDL hypothesis: The concept that lowering LDL levels reduces cardiac events is controversial. Some believe statin drugs provide their benefit by other means (pleiotropic effects), and that the LDL lowering is just a surrogate we can measure. In support of this argument is that not all cholesterol-lowering drugs improve outcomes, and, statins improve outcomes in high-risk patients with normal LDL levels. On the other side, believers in the lower-LDL-is-better camp got a (little) boost recently from the results of the IMPROVE-IT trial. Recall that IMPROVE-IT showed that the addition of ezetimibe to simvastatin in high-risk patients after an acute coronary syndrome slightly improved cardiac outcomes over 7 years.

PCSK9 inhibitors are no ezetimibe. These drugs are special. They are given as monthly injections and they lower LDL levels a lot.

Cognition worries:

In short-term studies, PCSK9 drugs appear mostly safe, except, in both the Osler and Odyssey studies, researchers noted a small but consistent signal for cognitive problems with both drugs. It’s important to note that these were short-term studies over 1-2 years. What happens to cognitive function over years is an open question.

Outcomes:

On the matter of whether the LDL-lowering injections reduce cardiac events, post-hoc analyses of both studies looked slightly favorable. But the numbers of events were small, the follow-up short, and Osler/Odyssey were not designed to look at outcomes. They were safety trials not outcome trials. The bottom-line is we don’t know, yet.

Ongoing Studies:

We will, however, eventually know whether the drugs reduce cardiac events. A 27,000-patient-strong clinical trial, called Fourier has finished enrollment, and results are predicted to come in 2017.

My 2015 take:

My take of this class of drugs is it’s too early to say.

It’s more than likely these drugs will improve outcomes. But maybe not. Or maybe just a little.

It’s also possible benefit could be negated by adverse neurologic issues.

Another unknown is patient selection.

There is clearly an unmet for patients with familial hypercholesterolemia. In these patients, the gamble of PCSK9 inhibitors looks favorable. Another group in which the gamble looks good is super-high-risk secondary prevention patients with true statin intolerance.

That last phrase highlights a problem: Which patients are truly statin intolerant? Statin intolerance is a gray area. In my opinion, unless FDA approval comes with strict wording, indication creep is likely. My real-world view makes me worry about this. Marketing to patients and doctors will be strong. Influential key opinion leaders will exert great influence. The hype train will have momentum. I can see it already. “What would you rather do: take a pill everyday or get a shot once a month?”

What about Value?

Value is benefit over cost. Now we have a big problem. We don’t know the benefits of PCSK9s–or whether there are benefits. But we do have an idea of costs—they will be high. Some have estimated $350-1000 per month.

I ask you to put on your public health hat. Consider three givens: 1) Heart disease is a huge public health problem. 2) There exist disparities in cardiac care in the public realm. 3) We have limited budgets.

The problem, then, is who should pay for these drugs?

Should patients be expected to shoulder a portion of the cost – which of course would force each patient to make a value judgment: Is it worth paying for an exciting but unproven medicine?

But if we force patients to pay parts of the costs, that only increases the disparities in care, as only the rich could afford the expensive drugs.

Yet we surely can’t afford to pay for these drugs on a grand scale. Estimates range into the billions of dollars for the unproven medicines. And if we try to cover these costs, what will be the results of taking those dollars away from other heart-healthy projects, like building parks, bike lanes and other lifestyle programs?

One of my cognitive biases is that the idea of getting health from pills or shots is deeply flawed.

This story is just getting started. It’s going to be a great ride. It could be an epic advance for cardiac disease or it could be an epic failure.

JMM

To listen to my views on the these drugs and many other cardiac news stories, click here for an archived list of video-blogs and podcasts on theheart.org | Medscape Cardiology.