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CANTOS: Canakinumab reduces risk for major CV events in patients with MI, inflammatory atherosclerosis
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In patients with prior MI and inflammatory atherosclerosis, canakinumab in combination with standard-of-care therapy reduced risk for major adverse CV events, according to the topline results of the CANTOS study announced by Novartis.
According to a press release from Novartis, the phase III study of canakinumab, also known as ACZ885, met its primary endpoint of reduction in major adverse CV events, defined as CV death, nonfatal MI and nonfatal stroke. Median follow-up for the 10,061 patients in the study was 3.8 years.
"Despite current treatment, about 25 percent of [MI] survivors will have another [CV] event within 5 years, making the outcome of the CANTOS study a promising new development for patients," Vas Narasimhan, MD, Global Head, Drug Development and Chief Medical Officer, Novartis said in the release. “ACZ885 is the first and only investigational agent which has shown that selectively targeting inflammation reduces [CV] risk. Our priority now is to thoroughly analyze these important data and discuss them with regulatory agencies."
According to the release, canakinumab inhibits inflammation caused by overproduction of interleukin-1 beta by blocking its action for a sustained period of time.
Approximately 40% of MI survivors have increased risk for recurrent MI, stroke, and CV death due to high-risk inflammatory atherosclerosis, the company stated in the release.
Canakinumab was approved by the FDA in 2009 to treat cryopyrin-associated periodic syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome in patients 4 years of age and older. In 2013, it was approved for the treatment of systemic juvenile idiopathic arthritis in patients 2 years of age and older. In 2016, it was approved for treatment of tumor necrosis factor receptor associated periodic syndrome, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency and familial Mediterranean fever. It is marketed by Novartis for those indications under the brand name Ilaris.
In a phase 2, double blind, randomized, placebo-controlled trial published in October 2016 in the Journal of the American College of Cardiology, canakinumab did not significantly affect vascular function or structure vs. placebo in 189 patients with atherosclerotic disease and type 2 diabetes or impaired glucose tolerance.
At 1 year, the change between the canakinumab and placebo groups in mean carotid artery wall area was –3.37 mm2 (P = .06), proximal ascending aorta wall area was –19.07 mm2 (P = .13), proximal descending aorta wall area was –4.36 mm2 (P = .66), distal descending aorta wall area was –6.36 mm2 (P = .46), ascending aorta distensibility was 0.03 x 103 mm Hg-1 (P = .87), proximal descending aorta distensibility was 0.06 x 103 mm Hg-1 (P = .78) and distal descending aorta distensibility was 0.06 x 103 mm Hg-1 (P = .82), according to the findings. However, compared with placebo, the canakinumab group had significant reductions in high-sensitivity C-reactive protein at 3 months (geometric mean ratio [GMR] = 0.568; 95% CI, 0.436-0.74) and 1 year (GMR = 0.56; 95% CI, 0.414-0.758).
Full results of CANTOS will be submitted for presentation at an upcoming medical meeting and for publication in a peer-reviewed journal, according to the release. – by Katie Kalvaitis and Dave Quaile
Disclosure: Narasimhan is an employee of Novartis.
Editor’s Note: This article was updated on June 23, 2017 with background information on canakinumab.
Perspective
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Carl J. Pepine, MD, MACC
Announcement of topline results of the CANTOS trial by Novartis in late June provide the first direct evidence that suppressing residual inflammation, over and above everything else that we do for secondary prevention, appears to be beneficial for the CV system. This study has been 6 years in the making and had planned to end in 2019 (ClinicalTrials.gov; NCT01327846). The investigators enrolled more than 10,000 patients with a prior MI, who had a C-reactive protein level ≥ 2 mg/L, and they were randomly assigned to receive either canakinumab or placebo. The primary outcome was time to first occurrence of CV death, non-fatal MI or stroke. CANTOS also evaluated safety and tolerability of quarterly subcutaneous injections of canakinumab in combination with standard of care in these post-MI patients.
The results were announced via a Novartis press release and we anxiously await presentation of the data at scientific sessions of the European Society of Cardiology Congress in August in Barcelona and publication in a peer-reviewed journal. Nonetheless, the initial announcement is exciting and provides direct evidence to support the suppression of residual inflammation hypothesis to reduce residual risk.
Canakinumab has an interesting history. It is a human monoclonal antibody that targets interleukin-1 beta. It is FDA-approved for use in the United States as a once-monthly injection for patients with active systemic juvenile idiopathic arthritis to provide relief of symptoms including fever and painful and/or swollen joints.
The CANTOS trial has two substudies: one examines effects on carotid plaque by MRI and the other looks at insulin secretion and insulin sensitivity in the subgroup of patients with diabetes. So stay tuned.
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