The ODYSSEY of PCSK9 Inhibitors: What Might It Mean for Guidelines

Interview | At the ACC.15 64th Scientific Session & Expo in beautiful San Diego, CA, CardioSource WorldNews: Interventions spoke with Jennifer G. Robinson, MD, MPH, professor of Epidemiology at the College of Public Health and professor of Internal Medicine at the University of Iowa. Dr. Robinson discussed the ODYSSEY trial, which explored the reduction in LDL by adding alirocumab to background statin therapy.

CSWN: Now, if we could for a moment talk about, overall, what went on in ODYSSEY and what did you learn?

Jennifer G. Robinson, MD, MPH: So this is the ODYSSEY long-term trial of the alirocumab—one of these new PCSK9 monoclonal antibodies. This was the largest and the longest trial really designed to look at safety, as well as efficacy, over 78 weeks of therapy. So we published that in a very high risk group of patients—about 20 percent of people with familial hypercholesterolemia—we [lowered] LDL from 122 on maximal statin and lipid-lowering therapy down to about 50: so a 60 percent
reduction in LDL adding alirocumab to background statin therapy.

It seemed to be quite well tolerated, overall. In this study, there were a few excess events numerically, but not statistically significant—neurocognitive and things like that, [or] there was a significant difference in injection site reactions, as you’d expect for, you know, an injectable, but still in common about 5 percent. But the kind of surprising thing, and what we actually reported this last summer, was a very surprising early reduction in cardiovascular events over the 78 weeks of the trial. About a 50 percent reduction in heart attack, stroke, cardiovascular death and unstable angina.

Some of that was seen early with statins, too—that some of the benefit was pretty early—but this is really early.

Yes. And this is on top of background statin therapy. And while that’s really important because it’s not definitive by any means because it’s like 50 to 60 people who had events, but we’ve had such a long list of failures of things added to background statin therapy that didn’t reduce cardiovascular events, or actually were harmful, so we’re excited that this is going to be a promising LDL-lowering drug that reduces cardiovascular events and our armamentarium. And it reduces LDL a lot, which is very exciting.

Before we talk about guidelines, which I do want to get to, there were a couple of other papers here that were of interest.

Simultaneously with our ODYSSEY long-term paper was another paper on another PCSK9 inhibitor called evolocumab, and it was a similar idea. They took all the people from their shorter-term studies and rolled then into a long-term extension, so these people had been followed for about a year. It was bigger—about 5,000 people. [It involved] evolocumab versus placebo on top of background statin therapy. For most people—not everyone—they saw the identical thing. You could almost superimpose those Kaplan-Meier curves on top of each other—50 percent reduction right away in those cardiovascular events. So, I mean, we’re excited to see the ODYSSEY long-term going, “Woah!” But then to see it duplicated. I think that’s really important that we’re on the right track with this class of drugs.

In ODYSSEY, what was the duration between therapies?

Uh, so the dose is 150 every two weeks for alirocumab. In the evolocumab it was 140 every two weeks. So and about another 60 percent reduction, so, you know, fairly equivalent in LDL lowering efficacy after two doses.

And patients didn’t mind?

Well, you know, they don’t. I mean, we were surprised that they didn’t mind really. And it’s an auto-injector pen. I’m not going to grab my fat and show you how they do it! But, you know, it’s pretty straightforward how to do it. Of course, you have to understand who’s in these trials. It’s people who signed up for a trial of an injectable drug.

Many had familiar hypercholesterolemia. You know, when you’ve got lots of relatives dropping dead in their 30’s and 40’s, you’re highly motivated to treat your cholesterols. But it’s really been remarkable how well accepted it’s been. I mean it’s really high tech. You know, it’s these monoclonal antibodies. I mean, I think people think it’s kind of an exciting way to treat cholesterol, which is interesting.

You know, there was the TNT trial, the Treating to Target Trial, and we have kind of a treating to no target world now in terms of guidelines.

You’re talking about my guidelines. I was the vice chair for the 2013 ACC/AHA Guidelines.

So what does this mean when we have data like this and a world where targets become less important?

It means we were exactly on track with what we said in the guidelines. You know, we’re charged at looking at randomized trials and coming up with a set of guidelines. And when we looked at the clinical trials, almost all of which were statin trials, in a broad range of people, we found overwhelmingly evidence that statins reduce cardiovascular events and death. You know, they reduce it in direct proportion to how much you lower LDL. Nobody titrated to goal, so we actually couldn’t figure out what the right goal might be from this data.

And, actually, as they kept doing the trials, you know, they started with the really high cholesterol and then kept whittling down so that people by the end had cholesterols of 70 in their trials, and they still benefited. So we want to get rid of goals because we don’t know what they are, but we also want to get rid of them because we want to get rid of treatment thresholds. Because if you have an LDL goal of 100, that means you don’t treat people whose LDL is less than 100, and that’s about 40 percent of diabetics you would deny statin therapy.

So there were just a whole bunch of reasons that we took a step back. Now, what is the right goal? We have now since we’ve put out our guidelines—so you make a guideline, and then everybody runs to their dataset to prove you wrong.

No... Really?

‘Cause that’s the fun of academia! But [the response has] been actually resoundingly supporting this new approach of really maximizing statin therapy. And I just saw an abstract here at the meeting today: once you are on high intensity statin, your LDL level didn’t matter, so it’s [about] being on the high intensity statin, not what LDL you achieve.

And what’s the right level, right? Because with these PCSK9 inhibitors, we presented another paper here today—or a poster here—[in which] we pooled all the ODYSSEY alirocumab studies to date: about over 5,000 people. About 800 have had consistently low LDLs—two or more consecutive LDLs less than 25. There doesn’t seem to be any particular safety signals. And actually there’s a little signal of a little bit more cardiovascular event reduction. So we’ll find out. You know, we’ve got big, multiple ongoing cardiovascular outcome trials with these PCSK9 inhibitors, which we need to really establish how much event reduction is going to occur in a bigger population, and also the long-term safety.

Assuming no surprises, what role will PCSK9s play?

Well, I think short-term, both of the two companies have filed with the FDA for an LDL lowering indication, which we expect before this summer even or this end this fall, so I think those are really going to be targeted on LDL lowering high risk groups—people with genetic hypercholesterolemia who definitely need more LDL lowering—and then people who are statin intolerant, high risk people who can’t take the maximum dose of statin who would benefit from some more LDL lowering.

The broader question is, “Should we be routinely adding PCSK9 inhibitors to statin therapy in everybody to reduce risk?” I think we’re going to have to wait for the cardiovascular outcome trials.

Keywords: ACC Publications, CardioSource WorldNews Interventions, Angina, Unstable, Antibodies, Monoclonal, Cholesterol, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Public Health, Risk, Stroke, Trinitrotoluene

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