Canakinumab fails to improve outcomes at 14 days in COVID-19, myocardial injury
In a new study, interleukin-1-beta inhibition with IV canakinumab in patients hospitalized with COVID-19, myocardial injury and elevated inflammation markers did not appear to improve clinical recovery at 14 days.
However, there was a trend toward clinical improvement at 28 days among patients who received higher-dose canakinumab (Ilaris, Novartis) compared with placebo, according to results of the Three C trial presented at the virtual American Heart Association Scientific Sessions.
“Although COVID-19 is predominantly a respiratory illness, cardiovascular complications result in substantial morbidity and mortality,” Paul Cremer, MD, cardiologist at Cleveland Clinic, said. “Myocardial injury [may] occur in as many as one-third of patients hospitalized with severe COVID-19 infection. Myocardial injury is also associated with higher mortality and an increased systemic inflammatory response ... [which may] result in a so-called cytokine storm. In the cardiovascular system, the consequences are predominantly endothelial cell dysfunction with capillary leak, thrombosis and local tissue injury.
Canakinumab is an anti-inflammatory drug. In the CANTOS trial, canakinumab was shown to reduce recurrent CV events in patients with prior MI and elevated C-reactive protein levels.
“The primary research question of the Three C study therefore relates to whether interleukin-1-beta inhibition with canakinumab can shorten time to recovery in patients with COVID-19, myocardial injury and heightened inflammation,” Cremer said. “This is a proof-of-concept randomized trial, and the results could inform the design and conduct of a larger, more definitive study.”
The researchers enrolled 45 patients (mean age, 69 years; 73% men; 38% Black) hospitalized with COVID-19, high-sensitivity troponin T greater than the 99th percentile upper reference limit, N-terminal pro-B type natriuretic peptide greater than the age-adjusted upper reference limit and CRP greater than 5 mg/dL. Patients were randomly assigned to receive IV canakinumab 600 mg or 300 mg or placebo to evaluate the impact of interleukin-1-beta inhibition on time to recovery and all-cause mortality at 14 and 28 days.
IV canakinumab at 14 and 28 days
The recovery rate ratio at 14 days was 1.2 (95% CI, 0.47-3.03; log-rank P = .47) among patients who received high-dose canakinumab and 0.6 for those assigned low-dose canakinumab (95% CI, 0.22-1.62; log-rank P = .3) compared with placebo.
“Among patients with cardiac injury and heightened inflammation, outcomes were not significantly different at day 14 between patients receiving canakinumab and placebo,” Cremer said. “At 28 days, however, a trend towards clinical improvement was observed with 600 mg of canakinumab, an exploratory endpoint. Importantly, as the intent of this study was to inform a larger trial, all estimates and confidence intervals should be considered hypothesis-generating and are not definitive for treatment effect.”
At 28 days, the recovery rate ratio was 2.15 for high-dose canakinumab (95% CI, 0.91-5.11; log-rank P = .12) and 1.42 for low-dose canakinumab (95% CI, 0.57-3.57; log-rank P = .8) compared with placebo.
Moreover, 68.8% of patients in the placebo group experienced clinical improvement at 28 days, compared with 93.3% of the high-dose canakinumab group and 78.6% of the low-dose canakinumab group (P for trend = .09).
Seven patients died by day 28: three in the placebo group, one in the canakinumab 600 mg group and three in the canakinumab 300 mg group.
In an exploratory analysis that compared CRP at 7 days, researchers observed lower inflammatory biomarker levels in patients assigned high-dose (3.4 mm/dL) and low-dose (6.8 mm/dL) canakinumab compared with placebo (12.5 mm/dL).
Future directions
Regarding future directions, Cremer said the results “suggest the potential utility of targeting interleukin-1-beta to dampen the deleterious auto inflammatory response and SARS-CoV-2 infection with myocardial injury and heightened inflammation.”
Longer follow-up, for example, 28 days vs. 14 days, may be necessary to assess for clinical improvement in these patients and a higher dose of canakinumab may be needed for efficacy, according to Cremer.
“If efficacy is demonstrated in a larger study, canakinumab may represent a potentially important advance in the treatment of COVID-19 infection,” he said.
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Cremer PC, et al. Cardiac Procedural Innovation for Special Patient Groups. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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