Just when some thought that IL-6 receptor antagonists as a treatment for severe COVID-19 were dead, a study published in Lancet recently (https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30277-0/fulltext#articleInformation), breathes some new life into IL-6 receptor antagonists for treating severe Covid. However, the new study is a retrospective analysis and the challenge is to figure out how much weight to put into this retrospective analysis, versus results from randomly controlled perspective studies that have now at least partly read out. Conventional wisdom puts its trust in the randomly controlled trials. There was an early report out of China from a small single-arm study of this IL-6 inhibitor in COVID patients (http://www.chinaxiv.org/abs/202003.00026). However, Roche recently pulled the plug on this IL-6 inhibitor, Tocilizumab, based on results of a randomly controlled prospective trial https://www.roche.com/media/releases/med-cor-2020-07-29.htm. And Regeneron's IL-6 inhibitor failed in severely ill patients https://www.reuters.com/article/us-health-coronavirus-regeneron-pharms-idUSKCN2291OD and the critically ill patients https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00, although their international trial continues.
Another somewhat surprising results from this new study in Lancet, is that it did not show statistical significance for steroid use in these intensive care unit patients, even those who were intubated, seemingly at odds with the prior published protective study published in the New England Journal of Medicine https://www.nejm.org/doi/10.1056/NEJMoa2021436. However, the current Lancet study authors did not have data on steroid dosing, and we did not find the specific steroid(s) used identified either in the article, although we had trouble accessing the supplemental material. The authors of the recent Lancet paper suggested that since the baseline mortality of patients in their trial was 64% vs. 41% in the prior dex study, there may have been significantly different patient populations. In sum, it's hard to know if this new study in Lancet shows the weaknesses of retrospective analysis of real-world data or suggests that treatment of Covid-19, especially by immune system modulators, is complex and many factors may play a role in a drug's effectiveness. Our bet is that it's a bit of both.
In the meantime, we are eager to see more results from HGEN's GM-CSF blocker, lenzilumab, in Covid-19. Of course, the promise for lenzilumab is based on a small, 12-patient trial. HGEN emphasizes the distinction between blocking signaling through neutralizing GM-CSF and blocking IL-6 (See slide 13 of this HGEN slide deck https://docs.google.com/viewer?url=https%3A%2F%2F9e234b13-0cc4-4c74-b924-d7874342289e.filesusr.com%2Fugd%2F6ca631_e29dbd7a64144a4ab3cd4ad1ae977a13.pdf). Hopefully, HGEN is correct and this GM-CSF blocker does not share the likely fate of IL-6 receptor inhibitors in Covid, which despite this recent retrospective analysis published in Lancet, are not looking too promising currently.