Tocilizumab, Sarilumab Reduce Mortality Rates in Those Severely Ill With COVID-19

Treatment with interleukin-6 (IL-6) receptor antagonists tocilizumab and sarilumab resulted in improved outcomes, including survival, among critically ill patients with coronavirus disease 2019 (COVID-19) receiving organ support in intensive care.

Preliminary results of an ongoing international trial were published ahead of print and have yet to be peer-reviewed. Thus far, only corticosteroids have been shown to improve survival for patients severely ill with COVID-19.

“The benefit from corticosteroids in critically ill patients supports the concept that an excessive host inflammatory response is responsible for much of the morbidity and mortality from COVID-19,” the authors wrote.

As part of the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), individuals were assigned to interventions across multiple domains, including immune modulation therapy.

Tocilizumab and sarilumab are monoclonal antibodies used to treat arthritis and other inflammatory conditions via inhibition of membrane-bound and soluble IL-6 receptors. In the current study, patients in the immune modulation therapy domain were randomized to receive tocilizumab, sarilumab, an IL-1 receptor antagonist (anakinra), an interferon beta-1a, or no immune modulation (control group).

All patients included in the trial were aged 18 or older, has suspected or confirmed COVID-19, were admitted to an intensive care unit (ICU), and received respiratory or cardiovascular organ support. Individuals were recruited from 113 sites across 6 countries.

Previous trials of IL-6 receptor antagonists conducted on patients with less severe cases of COVID-19, and excluding those already receiving respiratory support, found no clear evidence that tocilizumab was effective at preventing disease progression or benefitted overall survival.

“However, it is important to note that in our trial, patients had to be enrolled within 24 hours after starting organ support. This may be an important factor to maximize effectiveness; treating critically ill patients early, while any developing organ dysfunction may be more reversible,” the researchers explained.

The study’s primary outcome was respiratory and cardiovascular organ support-free days up to 21 days, and all deaths within the hospital were assigned the worst outcome (–1). Among survivors, a higher number represented faster recovery.

Between April and November 2020, 895 patients were randomized to receive immune modulation interventions (tocilizumab, n = 366; sarilumab, n = 48; control, n = 412; other interventions within the domain, n = 69).

Of the roughly 700 patients enrolled after June 17, following the announcement of positive results from the RECOVERY trial on dexamethasone efficacy, 93% were treated with corticosteroids at enrollment or within 48 hours.

Roughly one-third of patients also took remdesivir, a drug that was approved by the FDA in October, but was subsequently not endorsed by a World Health Organization (WHO) panel citing a lack of evidence on improved mortality.

In the current study, the researchers found:

• Median (interquartile range [IQR]) organ support-free days were 10 (IQR, −1 to 16), 11 (IQR, 0-16), and 0 (IQR, −1 to 15) for the tocilizumab, sarilumab, and control groups, respectively
• Compared with the control group, median adjusted odds ratios (ORs) were 1.64 (95% credible interval [CI], 1.25-2.14) for tocilizumab and 1.76 (95% CI, 1.17-2.91) for sarilumab, yielding > 99.9% and 99.5% posterior probabilities of superiority
• Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for controls
• Hospital mortality pooling both IL-6 receptor antagonists was 27.3% (108/395)
• Compared with controls, the median adjusted ORs for hospital survival were 1.64 (95% CI, 1.14-2.35) for tocilizumab and 2.01 (95% CI, 1.18-4.71) for sarilumab, yielding 99.6% and 99.5% posterior probabilities of superiority

Notably, data showed those treated with either IL-6 receptor antagonist in addition to corticosteroids exhibited greater improvements compared with singular interventions, suggesting a combination of treatments may be the most beneficial in this population.

Treatment with tocilizumab or sarilumab also resulted in improvements in 90-day survival, time to ICU and hospital discharge, and improvement in the WHO ordinal scale at day 14. Nine serious adverse events were reported in the tocilizumab group compared with 11 in the control group and none in the sarilumab group.

“I think it’s a huge result,” Anthony Gordon, MD, MBBS, the trial’s lead researcher, told The New York Times. “Showing that drugs that are available and can be used to save lives, in this pandemic, is a wonderful achievement.”

In response to the findings, the British government issued guidance encouraging providers to use the 2 drugs to treat severely ill patients.