COMMENTARY

CANTOS: Future Promise for Targeting Inflammation in CVD

Clyde W. Yancy, MD, MSc; Robert A. Byrne, MB BCh, PhD

Disclosures

September 07, 2017

Clyde W. Yancy, MD, MSc: Hello. This is Clyde Yancy, professor of medicine and chief of cardiology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. I'm here at the European Society of Cardiology (ESC) meeting, and I'm delighted that I have Robert Byrne with me from the German Heart Center in Munich, Germany. We're going to discuss the results of a fascinating trial, which was also released at the ESC 2017 meeting in its opening session. That was the CANTOS trial.[1] Robert, welcome. How are you?

Robert A. Byrne, MB BCH, PhD: Thanks. Great. Nice to be here.

Dr Yancy: Give me your initial impression of the CANTOS trial. I thought it was fascinating.

Dr Byrne: Yes, I think there was definitely a lot of excitement about this study. We've just seen the results and we're still digesting them in many respects, but I suppose this is a study that tested the anti-inflammatory treatment of atherosclerotic disease, and it's really the first study in this field that has been positive. It's generated a lot of excitement.

Dr Yancy: Right. Let's take a step back and try to step this up. The argument goes like this: We know that we still have an incredible number of preventable events, secondary events after a primary myocardial infarction. We know that we have targeted dyslipidemia as a way in which to modify those hopefully preventable events. We have a lot of enthusiasm now, that the new PCSK9 inhibitors do in fact reduce the incidence of a subsequent myocardial infarction in the highest-risk population.

We have always had some concerns, some curiosity, that targeting dyslipidemia wasn't the only way to get there. To Dr Ridker's credit, for the past 20 years he's been a proponent that the inflammatory cascade may be yet another pathway by which subsequent atherosclerotic events might occur. By targeting the circuit marker, hs-CRP [high-sensitivity C-reactive protein], having seen that before in the JUPITER Trial[2] as a marker and now looking at it specifically—not just as a marker, but as a target for therapy—we get to this point, as you say for the first time, taking a potent anti-inflammatory agent and trying to see if we can modify the natural history of cardiovascular disease. Talk to me about methodologically what was done in CANTOS?

High-Inflammatory-Risk Patients

Dr Byrne: They were patients who were post-myocardial infarction, and you know that they're high-risk when you look at the placebo rate of events at 5 years—it was pretty much 25%. I think they definitively enrolled patients who had high residual risk despite being treated with optimal medical therapy. A very high proportion of patients were on statin therapy (almost 95%). If you look at the LDL cholesterol in these patients at admission, it was just over 80 mg/dL. These patients were certainly well treated.

Dr Yancy: They might have been candidates for the PCSK9 inhibitor therapy.

Dr Byrne: Exactly. What differentiated these patients, or how they selected them out, was the level of hs-CRP, which is a nonspecific marker of inflammation. They wanted to enroll patients with high residual inflammatory risk, despite optimal treatment with statins, because we know from the JUPITER study as well that statins are quite good at reducing hs-CRP. They focused on patients who had hs-CRP of greater than 2 mg/L.

Dr Yancy: When you look at that median hs-CRP value of 4.1 mg/L, you realize that that's quite high; the ordinal number doesn't sound so high, but it should be considerably less than 1 mg/L. A level of 2 mg/L in the JUPITER trial was elevated. This is substantially elevated. To their credit, they wanted to find a unique cohort of individuals, where an inflammatory signal might in fact define their residual risk and then proceed forward with therapy. Talk some more about what was done.

Dr Byrne: The patients had to be at least 30 days after myocardial infarction, which I think is important to remember. We can't generalize these results to patients who've just had an acute myocardial infarction. They randomized them to receive placebo or three doses of the interleukin-1 (IL-1) antagonist: 50 mg, 150 mg, or 300 mg. Initially they had planned just to look at 150 mg and 300 mg, but for regulatory issues, they were asked to change the study design and also include a 50-mg-dose arm, so they had three treatment groups and a placebo group. The treatment was administered every 3 months subcutaneously.

Dr Yancy: This treatment was canakinumab, a monoclonal antibody that is an IL-1 receptor antagonist. The half-life is considerable. They were actually able to dose this drug just once every 3 months, which is a remarkable treatment strategy when you think about the science behind this, that this antibody could attenuate the production of interleukin over an extended period of time.

Dr Yancy: Let's get to the results. What was discovered?

Dr Byrne: They first looked at how this impacted hs-CRP. They saw a significant reduction in hs-CRP, with a dose-dependent effect. At 50 mg to 150 mg, you're seeing greater reduction in hs-CRP and then somewhat of a plateau effect between the 150-mg and 300-mg doses.

Dr Yancy: It looked as if the 150-mg dose settled out as the reasonable dose; would you agree?

Dr Byrne: I think so. When you look at the [Kaplan-Meier] curves, there was a slight additional lowering of the curves with the 300-mg dose, but it didn't seem to be significant. I think 150 mg is the dose we're looking [at going forward].

Statistically Significant, Clinically Modest Effect

Dr Yancy: If we're building a narrative and we're seeing that there are some people who, after having experienced myocardial infarction, have a residual risk that is related to an inflammatory signal, and that signal is identified by hs-CRP, it could be an epiphenomenon, or it could be a participant in the pathology. You target hs-CRP and you identity the ability to lower it with this monoclonal antibody. What happens clinically? What are the clinical results?

It looks as if the benefit was somewhat on the modest to moderate side, not the dramatic side.

Dr Byrne: Clinically speaking, this was also a positive trial, certainly for the 150-mg dosage. They saw a reduction in the endpoint which was a composite endpoint of cardiac death, nonfatal myocardial infarction, and nonfatal stroke. With the 150-mg dosage, they saw a hazard ratio of about 0.85, so the confidence intervals were just shy of 1. There was multiple testing done in the trials, so they had to correct for this, but the results for this dosage came out as statistically significant.

Dr Yancy: It withstood the statistical rigor and seemingly was the dose where we saw these clinical benefits. As you point out, it looks as if the benefit was somewhat on the modest to moderate side, not the dramatic side. Is that fair?

Dr Byrne: I think that's a fair summary of the data. It seems to be a modest effect. It is statistically significant in this large number of patients—more than 10,000 patients were enrolled. In terms of clinical relevance, it's certainly of borderline clinical relevance. With the 300-mg doses, they saw a treatment effect which was very similar, but due to the statistical testing protocol, it didn't come out as statistically significant. I think this is another reason why the 150-mg dose will be the more attractive dosage moving forward.

Dr Yancy: The excitement here is not specifically that we have this 15% relative risk reduction—that really is a great finding. What's almost spectacular is opening up a brand-new way of thinking about the progression of atherosclerosis. Thinking about modulating an inflammatory cascade as a means to reduce future cardiovascular events, and thinking about how we can enter this realm of modifying what was appropriately described as the inflammasome, and then using new biologic compounds.

For several years we've been asking when the emergence of the biologics will happen in our field. It's starting to happen with the PCSK9 inhibitors, and now we see it again. This really does generate an explosion of new researching opportunities.

Dr Byrne: I agree with you there, and we have had studies before that have successfully targeted CRP. We know that CRP is a downstream marker for inflammation, but it's not centrally involved in the inflammatory pathways and the inflammatory cascades; whereas here, we're targeting for the first time one of the members of this inflammatory cascade, the IL-1 beta, and showing a reduction in inflammation and also in clinical events. I think this opens the field for other studies, which are now going to examine different compounds to attack the inflammatory cascade and see whether it will improve patient outcomes.

Dr Yancy: I completely endorse the notion that we're talking less about CRP. I believe that it still is a surrogate marker, and more about modifying the interleukin pathway—that appears to be where the biology is. Let's make the conversation a little bit large before we close.

Off-Target Effects: Good and Bad

Dr Yancy: When we deal with new drugs of any iteration, we think about off-target effects or side effects and consequences. There are some remarkable observations here with this biologic drug that was used.

Dr Byrne: Yes; certainly this is always going to be the target of a large-scale study like this—to see what comes out in time in these types of lower-frequency events. One thing that stood out from the negative point of view is that there was an increase in leukopenia and an increase in fatal infections when you grouped all of the active treatment groups and compared them against the placebo. These were of relatively low frequency, but it was statistically significant.

On the other side, you're also seeing—in terms of off-target effects—a lot of signal of benefit in terms of inflammatory arthritis conditions and, most noticeably, perhaps, in terms of cancers, which was the subject of an additional publication from the authors.[3]

Dr Yancy: You're almost hesitant to say it—that here's a treatment that might be beneficial for secondary prevention, and as an off-target effect might actually modulate the risk for cancer that's driven by the same interleukin pathways. I think there are pretty provocative signs that are worth future explorations.

Any closing concepts? Any take-home messages you have for the audience?

Dr Byrne: It's definitely a very exciting study; it's a proof-of-concept that targeting the inflammatory pathway can lead to important reductions in events as a means of secondary prevention of atherothrombotic disease events. The clinical benefit, like we said, at this stage is modest. I think we need to learn a little bit more about how this reduction in the primary endpoint was achieved, because it's really only driven by differences in myocardial infarction, and we should have more information on the types of myocardial infarction.

Dr Yancy: That's important because we didn't see differences in stroke or death.

Dr Byrne: No, and finally I think we do need a little more information on these off-target effects in terms of more detail on these fatal infections. For us as physicians, we'd need to know what type of screening to do for patients who are going to be candidates for this therapy as we move forward. We could maybe learn from our rheumatology colleagues, who screen patients routinely who are treated with this type of therapy, in order to try to filter out those who are at high risk for these infection events.

Dr Yancy: Robert, thanks very much for your insight on CANTOS. I hope that those of you watching have been able to feel our enthusiasm, our excitement, about these important new data that suggest that although it's not yet ready for clinical practice, we've got a new direction, new opportunities, new ways of thinking about the progression of cardiovascular disease that really should open up a brand-new arena for both science and therapeutic opportunities. Thank you so very much for listening to our discussion today.

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