Many existing and new drugs have been examined for potential efficacy against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) agent that triggered the ongoing massive pandemic of coronavirus disease 2019 (COVID-19). Among these, immunomodulatory drugs have been prominent since most of the tissue damage and organ injury in severe or critical COVID-19 is traceable to the dysregulated inflammatory response set off by the virus.
A new study, released as a preprint on the medRxiv* server, describes how a team of international researchers explored the efficacy of four monoclonal antibodies that antagonize powerful pro-inflammatory pathways. The team sought to determine which were useful in treating critically ill COVID-19 patients on organ support.
These preliminary findings show that of the three drugs tested – tocilizumab, sarilumab, and anakinra – the first two may enhance survival and shorten the duration of organ support.
Further research, as well as rigorous peer review of the current study's data, will be needed to establish the validity of these initial findings.
Corticosteroids and tocilizumab have been extensively used in patients hospitalized with COVID-19 to reduce the need for mechanical ventilation and other organ support. Tocilizumab is an interleukin-6 receptor antagonist, and so is sarilumab. Anakinra is an endogenous IL1 receptor antagonist, may also be useful as it is used to treat autoimmune conditions.
The current study is a follow-up report of the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) comparing the two IL-6ra antagonists with each other, as well as with anakinra and a control group receiving standard care.
An earlier REMPA-CAP report showed that tocilizumab and sarilumab had equivalent efficacies in their therapeutic area. This led to randomized allocation of patients with COVID-19 and severe pneumonia in the active intervention group to one of these drugs or to anakinra.
Of the critically ill participants, all but four were on some form of respiratory or cardiovascular support when randomized, including nasal oxygen, non-invasive and invasive mechanical ventilation. Just over 970 patients were on tocilizumab, 485 on sarilumab, ~380 on anakinra and ~420 were in the control group.
What were the findings?
Both tocilizumab and sarilumab improved the median days without organ support, but not anakinra, compared to the standard care group.
The number of days without organ support was 7 and 9 for patients on tocilizumab and sarilumab, compared to zero for either anakinra or controls. The use of the former two compounds was associated with 50% better odds for weaning off organ support.
The probability that tocilizumab or sarilumab are the optimal interventions in their domain was only 28% and 47%, respectively, though both are very similar in their utility. Anakinra was clearly inferior to the other two.
When survival at discharge was examined, the researchers found that among the tocilizumab and sarilumab cohorts, two-thirds survived at hospital discharge. The number was slightly lower, at 60%, for anakinra. Compared to the 63% survival in the control group, the odds of survival were 42% and 51% higher with tocilizumab and sarilumab, respectively, but not higher for anakinra.
Thus, while the first two were almost certainly superior to the control intervention, the latter was distinctly inferior. Both IL 6ra agents improved 90-day survival and shortened the duration to discharge from the ICU and from the hospital.
Both showed similar efficacy irrespective of invasive mechanical ventilation and C-reactive protein values, but anakinra showed no benefit over the control.
What are the implications?
The findings corroborate the earlier REMAP-CAP reports of the efficacy of the two IL 6ra drugs relative to standard of care for critically ill patients, and similarly, those of the RECOVERY trial indicating tocilizumab efficacy in hospitalized patients. The researchers thus add sarilumab to the repertoire of effective drugs, widening the availability of IL 6ra antagonists for the treatment of more patients.
Why was anakinra not useful in this cohort? The researchers suggest they may simply have chosen the wrong dose, though this is unlikely based on the model they used to determine the drug regimen. An alternative explanation is that IL 1 inhibition may be useful only in patients who are not critically ill, an effect that is not visible in this small sample.
The REMAP-CAP design allows generalizability of the findings to a wider population of critically ill patients, because of the involvement of multiple centers in many different countries. The randomized allocation of patients to the tocilizumab and sarilumab treatment arms also allows further evaluation of their relative efficacy to continue. Thus, the accrual of more data on their treatment effects.
The team concludes:
In adult patients with COVID-19 receiving organ support in intensive care, the IL-6 receptor antagonists, tocilizumab and sarilumab, are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.