Interview with Dr Andrew Ip, a specialist in hematology/oncology at the John Theurer Cancer Center at Hackensack University Medical Center, USA, who has been involved in research on tocilizumab use in COVID-19 patients.
Why did you choose tocilizumab to treat patients with COVID-19 pneumonia?
Andrew Ip: Tocilizumab is a monoclonal antibody that inhibits the interleukin-6 (IL-6) receptor. IL-6 is a powerful inflammatory cytokine prevalent during severe inflammatory responses, as in the case of severe COVID-19 patients. We chose to study tocilizumab since the John Theurer Cancer Center has a strong clinical experience using it to treat severe inflammatory responses in cancer patients receiving cellular therapy. We also noted early in the pandemic a strong rationale and early clinical reports from the scientific community that this therapy may be effective to suppress the hyperinflammatory state observed in severe COVID-19 patients.
There are a number of clinical trials testing the effects of tocilizumab in COVID-19- associated pneumonia patients: two at least, one from Roche (the CONVACTA study) and another from Sanofi (the Kevzara trial), had to be stopped because they did not meet their primary endpoints. However, Roche has just reported that the EMPACTA trial had results similar to those reported by you and Professor Guaraldi, the first author of this clinical study.
Can you comment on why you think the same drug is producing such different results in trials?
Andrew Ip: It is clear that tocilizumab is a drug that needs to be given in a very specific time window or severity stage of COVID-19. When we use it in our cancer population, we only give it when patients meet certain criteria of severe inflammatory status – similarly, COVID-19 patients should be given a drug like tocilizumab when hyperinflammation, or overactive immune response, is causing patients to worsen, not because of active viral replication.
While the final results of COVACTA are not yet released, I suspect the overall population studied may have received the drug too early, and thus the study did not meet its primary endpoint. It is also important to note that the Kevzara trial, whose results are also not fully released, noted a trend in decreased mortality for the critically ill.
For EMPACTA, the trial seems to reduce the need for mechanical ventilation, and thus intensive care unit (ICU)-level care, but did not seem to lower mortality at the 28-day mark. Similarly a recent randomised trial from Hermine et al. (CORIMUNO-19-TOCI-1) that studied critically ill COVID-19 patients showed a decreased intubation or mortality rate at 14 days, although not at 28 days. Also, in a much larger US observational study of critically ill COVID-19 patients (STOP-COVID), Gupta et al. showed decreased mortality in patients who received tocilizumab within two days of entering the ICU.
Patient selection is crucial for clinical research. Since minorities have been more affected, especially in the US, do you think we might see country-specific or population-specific results from drug trials on COVID-19?
Andrew Ip: Currently, evidence shows that COVID-19 affects minority populations (African-American, Latino) in the US much more than other ethnic populations. In a global pandemic, precision medicine focused on different geographic or ethnic populations is needed, as it is likely that inherent biologic differences may affect outcomes for different minority groups. EMPACTA should be applauded for focusing on minority racial and ethnic groups across the Americas and Africa. In general, US drug trials have notoriously struggled to include adequate representation from these minority groups. I hope we do see more population-specific results, specifically for minority populations, in the near future.
What is the future of tocilizumab use in COVID-19?
Andrew Ip: I firmly believe immunomodulating drugs such as tocilizumab are very important in decreasing adverse outcomes for COVID-19 patients. The current data available, including from Dr Guaraldi’s study and ours, highlight that there may be a role for tocilizumab in the more severe and critically ill population. Despite randomised clinical trials showing varied results for tocilizumab, there is likely a therapeutic window for tocilizumab to truly benefit severe or critical COVID-19 patients. Further randomised clinical trials are ongoing, including the RECOVERY trial in the UK, that may better inform treatment guidelines utilising tocilizumab.
Where do you think should be the focus of research against SARS-CoV-2?
Andrew Ip: At this time, COVID-19 outpatient management needs to be prioritised, as much as the deluge of studies on drugs to prevent patients from dying once they are inpatients or hospitalised. Practical oral drugs in the outpatient setting are needed, especially in high-risk populations.