Remdesivir: Goldilocks Drug

Recently, the World Health Organisation announced the results of a clinical trial called SOLIDARITY that had investigated the effectiveness of the drug remdesivir for treating Covid-19. The trial results suggest that this anti-viral drug has little or no impact on a patient’s chances of surviving the illness. Following that announcement, a row has blown up with the drug's developers, Gilead Sciences, who cite the use of remdesivir in the apparently successful treatment of Donald Trump, and some other smaller trials, which also appear to show that remdesivir does make a difference. Independent statistician Richard Peto, though, hired by the WHO to scrutinise their results, has dismissed Gilead’s criticism saying the results are reliable. So where does this leave us? One possibility is that we might be treating the wrong groups of people. Used in the right set of patients, at the right time, says Harvard's Roger Shapiro to Chris Smith, it might be quite effective…

Roger - I think of Remdesivir as a Goldilocks drug. And what I mean by that is people who are too early in the disease, or don't have a very severe disease, we won't see an effect with remdesivir because almost everybody will get better in that group. Too late in the illness, and among those with very severe disease who are requiring mechanical ventilation, in those people we're not seeing an effect with remdesivir either because they're at a point of illness where a drug that targets the virus is not really helping them. And what they really need is steroids to lower their immune response to the virus. But that middle group, those who are on oxygen and early in the disease, they're the ones who are in that just right sweet spot where remdesivir can benefit them.

Chris - Do you think that's why Donald Trump did well, because he was got at, very early on in illness?

Roger - I think Donald Trump was the ideal person to get this drug because he was very early in his illness and he did appear to have a drop in his oxygenation, suggesting that he was heading down towards a more severe illness. I don't know that this is why Donald Trump got better quickly because he also received several other agents, including an experimental antibody, that may have benefited him. But I do think that he was right in that Goldilocks zone of who might benefit from Remdesivir.

Chris - Do we know then who the right people are? The right Goldilocks individuals? Have we got some insights into what the right time is to intervene, and in whom, now with this?

Roger - I think we really are learning that now. I think that it's very clear late in the disease, mechanically ventilated patients, that ship has sailed and they are not benefiting from this drug. It's very clear that those who are hospitalised and receiving oxygen, but not yet on mechanical ventilation, those are the people that are definitely benefiting. And in that group, those who are the closest to their symptom onset, they seem to benefit the most. And in the best trial of this, there was a three-fold reduction in mortality in that subset.

Chris - Putting all that together then, when a person catches coronavirus and we intervene with Remdesivir at the right time in the right person, what do you think is going on that means that they don't then turn into a person who's severely unwell?

Roger - It gets a little complicated because the people who do poorly with COVID-19 are those whose immune systems can not lock onto and control the virus. And so at seven to 10 days into the illness, there's a subset of people who will, basically their immune system is still calling for help and saying, "we are not handling this. We are not fixing this, send more cells and more reinforcements". And when those reinforcements are, for whatever reason, unable to lock onto the virus, those are the ones who really get into trouble with this disease. And at that point in the illness, it's too late for the antiviral to work. Because at that point, the immune system has gone into overdrive and it's really causing the harm that we see in many of our hospitalised intubated patients.

Chris - So by intervening early, in the right person, you basically stop the production of virus before it breaches some kind of critical threshold and drives the immune system into this sort of tail spin from which it's very hard for it to pull out. And, and it's actually the immune response that goes on to, in a person who's going to become severely unwell, kill the patient.

Roger - Yes, that's right. And I think the reason that we see the benefit of the remdesivir in the hospitalised patients who are receiving low oxygen is that those are the patients who might be heading in that direction. And if we go too far back into the community and we give remdesivir to everybody, well, we're going to be giving a lot of unneeded Remdesivir because most people's immune systems are able to lock on and control the virus. By targeting those admitted to the hospital often because their oxygen levels are below 94%, they're on the path towards that overstimulated immune response that causes people so much harm. And if we're at that junction and remdesivir can help a certain subset of them kind of handle the virus, damp down that stimulation early enough in the process, then I think that is the reason why in that subset, we see a mortality benefit from using this drug.