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.

9 comments

  1. Interesting article here! I’d definitely agree with your assessment that it’s too early to tell. Sometimes things take time to truly understand how effective they’ll be. I definitely hope it ends up being beneficial for those needing their cholesterol lowered.

  2. Like you, I am fascinated by the underlying biology of this idea. However, this is a very poor allocation of resources. Spend these billions on gym memberships and preventative medicine and the savings to the healthcare system will be many fold greater than this injection ever could do, even if it does manage to be effective.

    And frankly, I am skeptical that there won’t be some side effect that kills this drug… making the body attack one of its normal functioning receptors sounds like a recipe for disaster.

  3. The main arguments seem to be:

    (1) There are some patients for whom pcsk9’s are a real benefit

    (2) There are many patients and doctors who will be tempted (and encouraged) to misuse the drugs. Some will make poor decisions. This could cause biological and financial harm.

    If I’m a person with familial hypercholesterolemia, it doesn’t seem right to let the misbehavior of group 2 impact group 1.

    Our society tolerates (even embraces) disparities, limited budgets, and unequal outcomes when it comes to housing, education, food, transportation, recreation, travel and so on….

    On so many issues, the pendulum swings between the invisible hand of the marketplace and equal access for all.

    Few would support either extreme, but I wonder why our society seems to be so uncomfortable with the idea of unequal medical care when (1) we all know it already exists and (2) we accept inequality in so many other fundamental areas.

    $6-12k a year is not small change, but, so many of us spend much more on discretionary items. Telling someone with familial hypercholesterolemia that they can’t have access at any cost because it would be unfair to others would seem a greater harm.

    There’s something to be said for that invisible hand.

  4. I think the key statement in your treatment above is in the last sentences:

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

    Realizing of course that some folks have a predisposition to high cholesterol, but I like your approach to address things that can be impacted without pharma solutions.

  5. The New York Times article about the panels’ recommendations reported the following: if the FDA eventually approves the drugs, they will be allowed to remain on the market even if they fail to reduce heart attacks and deaths in a larger patient population.

    Seriously? That much money per month for a drug that lowered a number but otherwise had no meaningful impact? Guess I don’t understand the reasoning, other than giving pharmas license to recoup their investment.

  6. Well said! As you and others point out, a crazy amount of money spent on this when funding our public health needs would result in a much greater societal impact.

    Perhaps these drugs could be approved for an individual AFTER he/she is compliant with lifestyle changes (diet, exercise, no smoking, etc) and still wants pharma? Tough to accurately enforce, but the focus needs to be on lifestyle improvement first (with only positive side effects) and Pharma only if that isn’t enough.

  7. With FH you can be extremely heart healthy and have large amounts of LDL particle blockage in your cardiovascular system – we’ve all heard stories of people who were in great physical shape and dropped-dead of a heart attack. I was nearly one of those stories.

    Regarding reports of cognitive issues, the number was very small and I can say from firsthand experience, having a coronary artery bypass graft surgery causes one heck of a cognitive event…short term memory gone, lack of concentration and mental fogginess for three months. And while I can’t say for sure, I have to assume, death from heart disease produces the mother of all cognitive events.

    I’m athletic (cycling, rowing, weights), a vegan, on four cholesterol lowing medications, have had 2 major surgeries (CABG and Carotid Endarectomy) and I still can’t achieve my doctor recommended LDL target.

    For us, PCSK9 means hope and living longer than our 30’s or 40’s. If you were in my shoes, you too would be eagerly awaiting the hope of this new option as well..

  8. Nice article! The study that has recently been falsely trumpeted as proving that statins don’t cause memory problems actually showed that use of any lipid-lowering drug whatsoever for just a few weeks increased the likelihood of new memory problems about three and a half times. If this happens to you, you can throw away the pills much faster than you can stop the effects of an injectable that persists in the body for a long time. (Ask anyone who ended up with jawbone necrosis or thigh fractures from osteoporosis drugs.)

    Also, I want to know more about this rare allele that soon we will all be asked to have medically duplicated. A genetic variation that is hugely beneficial, not at all harmful, and yet rare is an unusual thing to see, though recent beneficial mutations do exist. Do carriers of this allele actually live substantially longer than those who lack it? If not, since they are so much less likely to die of heart disease, what ARE they dying of? Oh, and is it known that their cognitive abilities and educational attainment are identical to that of noncarriers?

  9. Going back to the idea of waiting for FOURIER, one should look at https://clinicaltrials.gov/ct2/show/NCT01764633, and in particular, that section which deals with baseline statin dosing

    Biological: Evolocumab (AMG 145)Evolocumab (AMG 145) Drug: Effective statin therapy

    Effective statin therapy defined as greater than or equal to atorvastatin 20 mg or an equivalent statin and ask1] is 20 mg atorvastatin, which is equivalent to 40 mg simvastatin, another “straw-man”, not high intensity statin rx and2] is giving someone in that trial 20 mg atorva a denial of standard care, especially in view of 2013 AHA/ACC guidelines which recommend high intensity statin rx (80 mg atorvastatin as in PROVE-IT TIMI 22) for high risk secondary prevention?If this is another “straw-man” study why do we need to wait until 2017 for its results? These questions need addressing, sooner than later.

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