Let’s circle back to remdesivir. We already have the results of the remdesivir Phase II trial that led to its Emergency Use Authorization by the FDA. But now come the first Phase III results, and it’s safe to say that they’re not making anyone happier. The news isn’t bad, but you can’t say it’s particularly good, either.
This was an open-label randomized trial comparing a 5-day course of the drug with a 10-day course. It’s important to note up front that there was no control standard-of-care group, which makes interpretation of efficacy impossible – it pretty much always makes such interpretation impossible (with real-world effect sizes, anyway), which is why you probably shouldn’t run uncontrolled trials unless there seems to be no good alternative. And in this case, the trial was run (earlier this year) in this fashion partly because there were no matched placebo vials available and because getting people out of the hospital and making space for new patients was a priority. There are no viral load figures available, either, because of the variability in the testing (and testing capacity) across the different trial sites at the time.
Using data from about 200 patients in each group, there appeared to be no statistically significant difference in outcomes between 5-day and 10-day treatment. These outcomes include relatively easier-to-measure things like time to improvement, clinical status at day 14 after treatment, recovery and hospital discharge, death, and so on. If you want to talk nonsignificant trends, then the 5-day course of treatment actually looked a bit better, but there are possible reasons for that: more males in the 10-day group and more patients on the more severe end of the disease. So I wouldn’t say that 5-day treatment is superior, but this study does point to 10-day treatment not being superior.
This means that (to date) we have only two controlled clinical studies of the drug (The early “compassionate use” report was uncontrolled and at this point really adds nothing to our understanding). There’s the one in China that was stopped early due to declining enrollment, and that one did not show any difference between the treatment and placebo groups. But the problem is, given the number of patients it ended up with, it wasn’t even powered to show such a difference. Then there’s the NIAID study, the first link in the first paragraph above, which found that 10-day treatment was superior to placebo when you measure for time-to-recovery. The authors of this new paper suggest that their results could mean that a 5-day treatment might then show the same thing (which would have the side benefit of not using up so much remdesivir).
But this work just underscores something that I wish that the general public would take on board: remdesivir is not a cure. Not even close. We don’t have a cure for this disease yet. Remdesivir appears to be better than nothing – if I or someone I knew were in the hospital with the coronavirus, I would expect it as standard of care, and be glad that it was available, but I would not expect it to do anything dramatic. It appears to get people out of the hospital faster – a bit faster – compared to people who don’t get it. No bad thing, not at all, but not what we all want from a therapy, either. I would also definitely consider famotidine. It’s not that we have a lot of solid efficacy data yet, but there is some reason to believe that it helps, and it has an excellent safety profile so on balance I’d say go ahead. You take what you can get, and right now I think that’s pretty much what we can get.
Just this morning, though, comes word of another potential therapy for patients who are in trouble with the “cytokine storm” immune response. In late April we had some early data from France that the anti IL-6 antibody tocilizumab might help with that situation, but now there are some more solid numbers. This is from the University of Michigan system, a controlled observational study with 154 intubated patients, 78 of whom received tocilizumab. It has to be said that the treatment group was slightly younger and slightly less likely to have underlying pulmonary disease, so the results should probably be trimmed down a bit. But the results were good: 45% lower likelihood of death (the preprint’s Figure 2). The secondary endpoint of the trial was assessment on a 6-point disease severity scale, and the treatment group looks better on that one, too (the preprint’s Figure 3A)
There are other things to keep in mind, of course. Knocking down IL-6 activity would be expected to increase the risk of infection in general, and so it proved: the treatment group was twice as likely to develop a further lung infection, generally bacterial pneumonia due to S. aureus. That’s not good, but the time to discharge and fatality rates did not really differ between those who came down with this superinfection versus those who didn’t (and for that we can thank modern antibiotics – since I experienced bacterial pneumonia personally a few years ago, I am very mindful of them!) So this course of therapy is not without complications, but in the end, it definitely appears to have a real benefit.
The hope, then, is that early remdesivir treatment might decrease a patient’s chances of ending up in such bad shape to start with, and that tocilizumab might be the thing to give if things head that way. As with all these bimodal treatment regimes, figuring out when to switch gears will be crucial. But it’s very good to see that there’s something we can do about the cytokine storm, and I look forward to more studies of this kind reading out.
Looking for something even better, are you? Who isn’t? In the next post (probably tomorrow) we’ll look at the latest news on the things that are really going to get us out of this mess: antibodies and vaccines.