Patrice Wendling

November 13, 2017

ANAHEIM, CA ( updated ) — High-sensitivity C-reactive protein (hs-CRP) testing after a single dose of canakinumab appears to identify patients with atherosclerotic cardiovascular disease most likely to benefit from treatment, according to results of a secondary CANTOS analysis[1].

The primary results reported earlier this year provided critical proof of concept that targeting inflammation with the monoclonal antibody reduces CV event rates independent of LDL cholesterol, with the unexpected bonus of lower rates of incident lung cancer and lung-cancer mortality.

But treatment with the orphan drug is costly, associated with a small but significant increase in fatal infections, and delivered what some regarded as an underwhelming 15% reduction in major adverse coronary events (MACE) in the entire CANTOS population.

A secondary analysis, reported here at the American Heart Association 2017 Scientific Sessions and simultaneously published in the Lancet, revealed no baseline characteristics that predicted patients more or less likely to benefit from canakinumab.

However, when the investigators looked at biologic responses to the drug, patients who achieved hs-CRP <2 mg/L at 3 months had an adjusted 25% relative risk reduction in MACE (hazard ratio [HR] 0.75, P<0.0001) and 31% risk reduction in CV death (HR 0.69, P=0.0004) and all-cause mortality (HR 0.69, P<0.0001).

Dr Paul Ridker

For those with an hs-CRP above this threshold, canakinumab had minimal effects on MACE (HR 0.90, P=0.11), CV death (HR 0.99, P=0.95), or all-cause mortality (HR 1.05, P=0.56).

"We believe these observations have clinical importance not only for the pathophysiology of inflammation and future drug development, but also for patient selection, cost-effectiveness, and personalized medicine," primary investigator Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) said during the late-breaking clinical-trial session.

Based on extrapolated 5-year data, he noted that the number needed to treat for MACE was 16 for on-treatment hs-CRP <2 mg/L vs 57 for patients failing to meet this inflammation target.

"The tradition inside cardiovascular medicine until fairly recently has been to treat everybody with everything," Ridker said in an interview. "I think the oncology world got to this issue of personalized medicine more quickly because the drugs they give are highly toxic, so you want to make sure they're targeting the tumor; and they're highly expensive, so you need to identify who benefits to justify the expense.

"I think the introduction of monoclonal antibodies into cardiovascular medicine—the two examples in the last 12 months obviously being the PCSK9 inhibitors and canakinumab—are for the first time pushing us in that direction," he said.

Commenting for | Medscape Cardiology, Dr Donald Lloyd-Jones (Northwestern University, Chicago, IL) said the new data represent a "small step" toward personalized medicine.

"You can see there's a group where you'd want to really push and continue the medication and a group where you'd want to try other strategies," he said. "But an important qualifier is that we don't know how much of that CRP reduction was due to the drug and how much was due to people who were actually successful at changing their lifestyle; successful in losing weight, smoking cessation, and other things that can affect the CRP level."

In an accompanying editorial[2], Drs Erin D Michos and Roger S Blumenthal (Johns Hopkins School of Medicine, Baltimore, MD) observe there could be residual confounding by variables associated with both hs-CRP reduction and CVD outcomes, which limit definitive conclusions about treating to targets.

"Indeed, when the CANTOS authors compared patients achieving the median (58%) or greater percentage reduction in hs-CRP vs not (a definition less influenced by baseline hs-CRP), both groups benefited with substantial overlap in 95% CIs," they write.

The results were consistent, however, across a series of sensitivity analyses, including a causal inference analysis, and across the three doses tested in the study, Ridker noted. The proportion of patients who achieved hs-CRP <2 mg/L was 44%, 55%, and 65% in the 50-mg, 150-mg, and 300-mg groups, respectively, with corresponding HRs for MACE of 0.78, 0.75, and 0.74, respectively.

In addition, the main hazard of canakinumab, fatal infections, was not related to ontreatment hs-CRP levels. "As such, the use of biologic response to canakinumab may also provide a simple selection tool to maximize benefit without increasing clinical hazard," he said.

Discussant Dr Ira Tabas (Columbia University Medical Center, New York City) said the new data, which he described as remarkable, strengthen the study's biological premise but also address some earlier issues, with a greater MACE with all three doses and similar rates of fatal infections among responders and nonresponders.

"Even with all of this benefit there is still quite a high risk, and in my opinion the major reason for this is that we're simply starting too late when the plaques are very complicated," he said. "So I think imperative in this discussion as we move forward is how early can we go."

Other areas of interest going forward include integrating diabetes drugs that show a CV protective effect like sodium-glucose cotransporter 2 (SGLT-2) inhibitors, optimizing the route of delivery, and lowering the cost of the subcutaneously administered anti-interleukin-1 beta antibody.

"In development right now are oral inflammasome inhibitors—I'll remind you that the inflammasome is what gives rise to interleukin-1 beta—and there might be some interesting developments there, not only for delivery and cost, but also for some selectivity in the different types of inflammasomes that may be inhibited," Tabas said.

Dr William Cushman (Memphis Veterans Affairs Medical Center, University of Tennessee), who was not involved in the study, said in an interview, "At this point I'm sure it's extremely expensive and, as Paul pointed out, it's a proof-of-concept study, so we're going to have to learn how to apply it."

He added that the ongoing CIRT trial of methotrexate, led by Ridker, may prove "more practical unless there's a way to get the price of the drug [canakinumab] down."

Novartis global head of drug development, Dr Vasant Narasimhan, said during a recent teleconference, "If we get labeling that would enable us to go forward in a cardiovascular launch targeting this specific patient population, then we'll of course adjust the price accordingly to be reflective of a cardiovascular medicine."

He added, "If that were ultimately not to be the case and we would not have the opportunity to target the medicine, I think we would reconsider whether we'd bring this medicine to market."

Narasimhan also confirmed Novartis will be moving forward with phase 3 studies of canakinumab in the adjuvant non–small-cell lung-cancer setting as well as in the metastatic setting in combination with programmed cell death protein (PD)-1 inhibitors.

The study was funded by Novartis Pharmaceuticals. Ridker has served as a consultant to Novartis and is listed as a coinventor on patents held by Brigham and Woman's Hospital that related to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. Disclosures for the coauthors are listed in the paper. Michos reported honoraria from Siemens Healthcare Diagnostics for serving as a blind adjudicator in a clinical trial. Blumenthal declared no relevant financial relationships.  

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