Canakinumab ‘not ready for prime time’ in reducing CV mortality in patients with inflammation
CHICAGO — Although previous results from the CANTOS study have demonstrated that targeting inflammation could significantly improve cardiovascular mortality outcomes, the drug its researchers used to test their hypothesis, canakinumab, comes with its own host of issues and is “not ready for prime time,” according to Leonard H. Calabrese, DO, vice chairman of rheumatic and immunologic disease at the Cleveland Clinic.
“The implications of CANTOS were great, and targeting inflammation works and has a lot of advantages, but this drug is not going to be ready for prime time,” Calabrese said, addressing attendees at the 2019 Interdisciplinary Autoimmune Summit. “It’s a biologic, and we need a better strategy.”
CANTOS, a large, international, multicenter trial, studied canakinumab (Ilaris, Novartis), a biologic IL-1 inhibitor, as an intervention against inflammation. Researchers found that antibodies against interleukin-1 did not affect lipids, with no differences in LDL or HDL, but reduced high-sensitivity C-reactive protein. During remarks on the study when it was released in 2018, Calabrese said its results represented a new way to combat cardiovascular risk in autoimmune and inflammatory diseases, stating that “inflammation is the new cholesterol.”
However, Calabrese now cautioned that CANTOS’ findings come saddled with multiple caveats.
“The findings were very interesting and it got everyone excited, but the problem with this study was that you are taking people with no immune-mediated inflammatory disease and putting them all on a biologic. They are taking injections and there is baggage with biologics, and there were adverse events and serious infections, and deaths,” he said. “Also, with the effect size, you don’t have to be a statistician to see that it wasn’t dramatic. So, you say, ‘This is really not ready for prime time,’ and the FDA was unenthusiastic about moving forward with this.”
However, other studies are currently evaluating other, less toxic agents, including methotrexate, colchicine and others in the Cardiovascular Inflammation Reduction Trial (CIRT), with the aim of improving mortality by targeting inflammation, according to Calabrese.
“There has been trial, after trial, after trial, demonstrating that rheumatoid arthritis, which is a disease with attendant cardiovascular risk, when treated with methotrexate could drive down cardiovascular risk,” he said. “The evidence is strong.”
Unfortunately, recent results from CIRT have been a “tremendous, profound disappointment,” according to Calabrese. The study demonstrated that methotrexate failed to reduce IL-1beta, IL-6 or C-reactive protein, and did not reduce cardiovascular events compared with placebo.
Another study, which tested low-dose methotrexate in 150 patients with well-controlled HIV in the AIDS Clinical Trials Group, similarly proved disappointing, Calabrese said. Published in Clinical Infectious Diseases in September, the results demonstrated that methotrexate not only failed to have any impact on vascular reactivity, but was also toxic in this population.
“Where does that leave us with anti-inflammatories in cardiovascular disease? I have seen people comment that the field is dead,” Calabrese said. “However, there are other people saying this is just helping us define the target. IL-1 may be the target, but we just need better mousetraps.”
He added, “My conclusions are that we are closer to the beginning than to the end, knowing the questions is more important than knowing the answers, and immunology is the field of surprised that should prepare us for future surprises.” – by Jason Laday
Calabrese L. Advances in Basic & Clinical Immunology. Presented at: Interdisciplinary Autoimmune Summit 2019; April 5-7, 2019; Chicago.
Disclosure: Calabrese reports consulting and/or speaking fees from AbbVie, BMS, Celgene, Crescendo, Genentech, Gilead, GSK, Horizon, Janssen, Novartis, Pfizer, Sanofi-Regeneron and UCB.