Melissa Walton-Shirley


March 16, 2015

I predict our FDA won't be able to help themselves. In all likelihood, they will allow the star compound of the American College of Cardiology (ACC) 2015 Scientific Sessions, evolocumab (Repatha, Amgen), to come to market without waiting for "hard outcomes." I predict they will do it for a variety of reasons, chief of which is the irrefutable fact that it lowers LDL levels to nadirs that only genetically blessed, anorexic, exercise-addicted vegetarians can achieve.

I've not seen an LDL level of 45 mg/dL since I was an embryo; I probably didn't have an LDL level that low even at the dawn of my existence. But the thought of my 199-mg/dL level dropping to a nearly nonexistent 45 mg/dL is mesmerizing. In truth, that possibility mesmerizes nearly everyone, because it is subhuman, at least with regard to the modern-day humans of industrialized societies.

Ultralow LDL levels are desirable for good reason. They are tied to a reduction in hard outcomes, and there is no better LDL-lowering compound on the current market with a discontinuance rate of only 7%. I always expect a phone call within 3 months from at least a third of my new statin starters. They will have complaints of muscle aches and fatigue. A goodly portion of them will just drop it on their own and report it to me on their next visit, or they will gently lie to me and tell me they are taking it when they are not.

The reason for focusing our gushing attention on this new compound is obvious. There is no compound on the planet that has ever demonstrated so much hope, so we are tempted to extrapolate. More salient to this discussion, we are already extrapolating. The company is surely already printing the T-shirts (and maybe rightly so). The press is rolling. Investments must be returned.

But not so fast! Remember the HATS trial? Remember that small subset of patients that saw a (crazy) >70% reduction in event rates? Remember the compound niacin? After decades of making our patients flush and itch, and after millions of prescriptions were written for this "too-good-to-be-true" medication, AIM-HIGH told us it really was. Niacin is now defunct: the sad rapper sitting on the sidewalk, head down, sunglasses cast aside; his posse's in the club with the latest new kid on the block who's probably wearing a jacket with PCSK9 emblazoned on the back.

I understand that niacin isn't evolocumab. We have much larger cohorts with this compound than with the initial niacin trials. Niacin and the monoclonal antibodies have no similar mechanism of action, but they might someday share a history of a rush to judgment. I admit that preliminary data for evolocumab looks great, but there is a reason why we call it "preliminary."

Dreaming Now, Of Course

I'd like to see statins banished from our armamentarium of pharmaceuticals. They are difficult to take and difficult to prescribe. We are treating some populations who probably don't need them, like mature women with clean coronary calcium scores. There are those patients on certain calcium-channel blockers for whom simultaneous statin use is a theoretical concern and certainly produces a mountain of autogenerated paperwork that we have to deal with at the end of the day. We drive up the cost of healthcare by measuring liver panels and creatine-phosphokinase (CPK) levels and, at the same time, cast aside the muscle aches in patients whose CPKs are normal.

Statins have come and stayed with a lot of baggage, but if I were a statin right now, I'd be sweating it. The best they can hope for is a comfortable coexistence with these new compounds, but I hope their days are numbered. I predict that the cost of the newer compounds combined with a fear of needles will be all that will save them.

It is for these reasons that I desperately want this evolocumab to work. I want it to be safe. I want it to be the best thing since sliced gluten-free bread dotted with olive oil. I might want to inject myself a couple of times per month someday (perhaps only once?) because I'm a statin noncandidate with myasthenia gravis (gratefully in remission) who has a father with a CABG at age 67, stents, devices, heart failure, a MitraClip, and a TAVR. My uncle experienced his first MI at age 39. I admit that the need for LDL lowering has definitely crossed my mind. Truthfully, it's always in the back of my mind.

With regard to FDA approval, I just ask that we wait for hard outcomes and a little more safety data. We need to pick apart the 0.9% incidence of neurocognitive events on therapy vs the 0.3% incidence off therapy. All of this information is coming down the pike. It's within reach. The FOURIER data is slated for presentation around 2017; only 2 years away! Surely the niacin debacle haunts us. It absolutely should haunt all trialists forever, and it should spur our patience.

In due time, I'll be the first to celebrate the success of the PCSK9 class, but to prove it works, you gotta show me something besides how great you look on paper. You need to live longer, have fewer events, and tolerate it well. That is the sacred triad within which every single cholesterol-affecting drug in the universe should fit before our FDA or the CE Mark approves it for mass consumption.

Now for the reality check. In a few months, I will likely be able to take an envelope, Johnny Carson style, place it on my forehead, blow it open, and say, the word "evolocumab." Then I'll read the newly minted rhetorical question, "What was the last compound approved by the FDA without hard end points?" Sigh.

What do you think the FDA should do with evolocumab?


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