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Novartis Anti-Inflammatory Drug (IL-1ß Inhibitor) Reduces Risk of Cardiovascular Disease and Perhaps Even of Lung Cancer in Patients with Previous Heart Attack and Atherosclerosis

On August 27, 2017, Novartis revealed primary data from CANTOS, a Phase III study evaluating quarterly injections of ACZ885 (canakinumab) in people with a prior heart attack and inflammatory atherosclerosis as measured by high-sensitivity C-reactive protein (hsCRP) levels of >=2mg/L, a known marker of inflammation. Trial participants received either placebo or one of three doses of ACZ885 in combination with current standard of care therapies, with 91% of them taking lipid-lowering statins. The study showed that ACZ885 led to a statistically significant 15% reduction in the risk of major adverse cardiovascular events (MACE), a composite of non-fatal heart attack, non-fatal stroke, and cardiovascular death, compared to placebo (p-value 0.021). This benefit was sustained throughout the duration of the study (median follow up 3.7 years) and was largely consistent across key pre-specified baseline sub groups. The study met the primary endpoint in cardiovascular risk reduction with the 150 mg dose of ACZ885; the 300 mg dose showed similar benefits and the 50 mg dose was less efficacious. The study findings in cardiovascular risk reduction were presented on August 27, 2017 at the European Society of Cardiology (ESC) Congress and published simultaneously in The New England Journal of Medicine. The NEJM article is titled “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.” The details of the additional CANTOS lung cancer findings were also presented at ESC and simultaneously published in The Lancet. The Lancet article is titled “Effect of Interleukin-1β Inhibition with Canakinumab on Incident Lung Cancer in Patients with Atherosclerosis: Exploratory Results from a Randomised, Double-Blind, Placebo-Controlled Trial.” "The results of CANTOS are exciting because we now have clear evidence that in addition to lowering cholesterol, targeting inflammation reduces patients' risk of cardiovascular disease, and perhaps even lung cancer," said Dr. Paul Ridker, MD, CANTOS Study Chairman and Director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston. "On behalf of the entire study team, I would like to thank all of the clinical trial site physicians and healthcare providers, and of course the thousands of patients who participated in this trial over the years, for their passion and dedication to advancing this important research."

"These data are a significant milestone because they show that selectively targeting inflammation with ACZ885 reduces cardiovascular risk and that ACZ885 may also be an important immuno-oncology therapy targeting IL-1ß for lung cancer," said Dr. Vas Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis. "We look forward to submitting the CANTOS data to regulatory authorities for approval in cardiovascular and initiating additional phase III studies in lung cancer."

With more than 10,000 patients enrolled in the study over the last six years, CANTOS was one of the largest and longest-running clinical trials in Novartis' history. Additional positive benefit observed in the CANTOS study was a reduction in the number of patients requiring unplanned re-vascularization for worsening chest pains (unstable angina), a component of the four-point MACE key secondary endpoint.

Treatment with 150 mg of ACZ885 resulted in a: 17% reduction in the relative risk of a composite of non-fatal heart attack, non-fatal stroke, cardiovascular death and hospitalization for unstable angina requiring unplanned revascularizations (p <0.005); 36% reduction in the relative risk of hospitalization for unstable angina requiring unplanned revascularization, as a component of this composite (p <0.021); and 32% reduction in the relative risk of any coronary re-vascularization (p <0.001), which was an exploratory endpoint.

Time to all-cause mortality was also assessed as a secondary endpoint in the study, with 150 mg dose of ACZ885 demonstrating an 8% reduction which did not reach statistical significance. The other key secondary endpoint - new onset of diabetes - was neutral.
A sub-group responder analysis showed that the 50% of patients who achieved an hsCRP value of less than the median at three months after the first injection experienced a 27% relative risk reduction on the primary MACE end-point.

The overall rates of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar to placebo across all ACZ885 doses. During the average follow-up time of 3.7 years, serious infections were reported in 11.3% vs 10.2% and malignancies were reported in 6.4% vs 7.1% of participants (ACZ885 150 mg vs. placebo, respectively). At the 300 mg dose, serious infections were reported in 11.7% vs 10.2% and malignancies were reported in 6.7% vs 7.1% of participants (ACZ885 300 mg vs. placebo, respectively). Fatal infections occurred in about 1 per 1,000 patients on placebo. Although rare, this occurrence was higher in the combined ACZ885 group than placebo. On the other hand, cancer deaths were cut in half by ACZ885 such that there was a non-significant reduction in death from any cause.

CANTOS (NCT01327846) STUDY

The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) (NCT01327846) is a randomized, double-blind, placebo-controlled, event-driven Phase III study designed to evaluate the efficacy, safety, and tolerability of quarterly subcutaneous injections of ACZ885 (also known as canakinumab) in combination with standard of care in the prevention of recurrent cardiovascular (CV) events among 10,061 people with a prior myocardial infarction (MI) and with a high-sensitivity C-reactive protein (hsCRP) level of >=2mg/L. The study evaluated three different doses of ACZ885 vs placebo. The primary endpoint of the study was time to first occurrence of major adverse CV event (MACE), a composite of CV death, non-fatal MI, and non-fatal stroke. Secondary endpoints included time to first occurrence of the composite CV endpoint consisting of CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina requiring unplanned revascularization; time to new-onset type 2 diabetes among people with pre-diabetes at randomization; time to occurrence of non-fatal MI, non-fatal stroke, or all-cause mortality; and time to all-cause mortality. The median follow-up time was 3.7 years. The study ran for approximately six years.

HEART ATTACK AND INFLAMMATORY ATHEROSCLEROSIS

Heart attack occurs in about 580,000 people every year in the five largest European Union countries and 750,000 people in the United States alone. Despite optimal standard treatment, patients who have had a prior heart attack live with a higher ongoing risk of secondary major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. It has been shown that in about 4 in 10 people, this risk is directly related to the increased inflammation associated with inflammatory atherosclerosis as measured by a high-sensitivity C-reactive protein (hsCRP) biomarker level of >= 2mg/L.[6] The recurrent MACE in people with inflammatory atherosclerosis are associated with increased morbidity, mortality, and reduced quality of life, and currently represent a major economic burden on patients and healthcare systems around the world.

ACZ885 (CANAKINUMAB)

ACZ885 (canakinumab) is a selective, high-affinity, fully human monoclonal antibody that inhibits IL-1ß, a key cytokine in the inflammatory pathway known to drive the continued progression of inflammatory atherosclerosis. ACZ885 works by blocking the action of IL-1ß for a sustained period of time, therefore inhibiting inflammation that is caused by its over-production. ACZ885 is the first and only investigational treatment which has shown that selectively targeting inflammation significantly reduces cardiovascular risk.

[Novartis press release] [Eureka Alert press release] [NEJM abstract] [The Lancet abstract]

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