COVID Transmissions for 3-4-2021
Drug day!
Good morning and welcome to COVID Transmissions.
It has been 472 days since the first documented human case of COVID-19. In the year 472, Mount Vesuvius erupted, spewing ash over much of Europe, with some apparently depositing quite a ways away, in Constantinople (now Istanbul, as you may have heard—I won’t speculate as to why, it’s none of my business).
In today’s issue we have a bit of a palate-cleanser from the vaccine news—I discuss some recent COVID-19 drug studies. It may not be obvious, but even with universal vaccine availability, we are going to need COVID-19 drugs. Eradication of this pathogen is not on the table right now or anytime soon, and there are going to be people who cannot be vaccinated. We need treatments to help those people and keep them alive if they should become infected with COVID-19.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
IL-6 receptor antagonists appear effective in the treatment of severe COVID-19
New science sometimes means I have to retract past things that I said. On 12-10-2020, I reported the results of a trial looking at tocilizumab, an antibody-based drug that prevents the action of the inflammatory cytokine IL-6. IL-6 is involved in a lot of the pathways that give rise to disease in COVID-19, so suppressing its activity was an early target in COVID-19 treatment.
In that trial, it looked like tocilizumab didn’t work. There was no reduction in the number of patients intubated or in the number of patients who died.
However, two new sets of results have become available. One is a preprint from the RECOVERY trial, found here: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1
In this trial, there were over 4000 patients, comparing receipt of tocilizumab to receipt of usual care. Risk of becoming intubated or dying in patients who were not yet intubated was around 15% lower for patients who received tocilizumab. That’s a modest effect, but it’s an effect and that’s better than nothing. In all patients, the risk of death was 14% lower in patients who received tocilizumab, but that hides an important finding of the trial. When patients were examined according to various characteristic-based subgroups, those patients who also received corticosteroid treatments (like dexamethasone, one of the earliest effective COVID-19 treatments) had a much lower chance of death if treated with tocilizumab than if treated with usual care—about 20% lower. This suggests that we should also investigate that combination specifically, rather than as a subgroup. I’d also feel pretty comfortable saying patients should get the combination based on these results alone—around 1600-1700 patients in each arm got corticosteroids, so I think there’s a big enough sample there to feel pretty confident that the combination works well.
At any rate, this study gives us some good evidence for tocilizumab with a much larger sample size than the study I covered back in December.
Then there are results published in the New England Journal of Medicine, from the REMAP-CAP trial, which looked at two IL-6 receptor antagonists in severe COVID-19, tocilizumab again and then another candidate called sarilumab. This trial primarily looked at the number of days that patients were able to stay off organ support machines on either drug. With the IL-6 receptor antagonists, median days off of these machines (such as ventilators) were 10 for tocilizumab, 11 for sarilumab, and 0 for control treatment. That’s clearly a very large benefit for the drugs; if you can stay off mechanical organ support for that long, it might mean the infection has begun to resolve. And then, of course, there is survival, where patients appeared to be about 61% more likely to survive for at least 90 days if they received the IL-6 receptor antagonists compared with control. This was a smaller trial than RECOVERY, though, with only about 1/10th as many patients.
You may read it here: https://www.nejm.org/doi/full/10.1056/NEJMoa2100433
Still, both studies reveal an effect for these IL-6 receptor antagonist therapies. That’s good news!
Convalescent plasma is not very effective against COVID-19
Although it was a promising treatment early on in the COVID-19 pandemic, a meta-analysis of four published clinical studies and 6 unpublished studies has revealed that convalescent plasma—that’s blood plasma from people who have recovered from COVID-19—is just not very effective against COVID-19. This meta-analysis was published in JAMA: https://jamanetwork.com/journals/jama/fullarticle/2777060
Basically, when all the results from all of these trials are pooled, there are even odds of survival with or without convalescent plasma treatment. That’s disappointing.
However, we have better treatments than convalescent plasma, now. I’ve described at least one today, but there are also the monoclonal antibody cocktails, such as the Regeneron antibody cocktail REGN-COV2, that are effective options. So what this tells us is that it’s well past time to put aside the imprecise tool of convalescent plasma and pick up the more precise tool of targeted, specifically-developed antibody therapies.
What am I doing to cope with the pandemic? This:
Enjoying being able to spend part of the evening in the sunshine
Sometimes, it’s the little things. We’re nearing the end of winter and the sun is now out for a brief time after 5 PM, so I can get out and ride a bike in it or walk around. It’s really nice to be able to get some recreation outside again.
Daylight savings will start relatively soon—March 14th—and add even more time to this, which is nice. Even though I don’t think daylight savings time is a terribly good idea.
Reader David E. Rendsburg had the following comment fleshing out the exact timing for full vaccine availability in the US:
It is actually 3 months to Biden's timeframe - end of May. It also means though that end of May is when everyone *could* get a first shot (but everyone won't by then) and which means that its end of June before "everyone" would be vaccinated.
This is correct—Biden said late May, which would suggest 10-12 weeks from now. I just stuck to how many months until May. One point worth making here is that Biden’s timing refers to when we will have enough doses for every American adult. I imagine that vaccination will be opened to everyone substantially before that date, so earlier in May; the supply will not come all at once right at the end of May. Tony Fauci recently said he thought that vaccination might be opened to everyone in May, a revision from his original estimate of April.
Regardless, I could be wrong about my judgment on this, and there may be delays, so maybe it could take until June if we’re being very conservative in our estimation. Anyway, here’s the reply I made, with another point regarding when everyone could be vaccinated—something I didn’t speculate on in my original post:
Yes, if we count by weeks it's strictly about 10-12 weeks from now. I just went with counting the month numbers--maybe a little imprecise, but I don't think the date that Biden provided is going to be terribly precise either. To be super conservative, one might expect the vaccine to actually become fully and widely available in June anyway, pricing in some shipping and capacity expansion delays.
And yes, of course, if we have it available for all US adults, it will still take an additional period of time for everyone to actually get vaccinated (even with a single-shot vaccine like the J&J offering).
So, to cover all my bets, I’d say that in the next 2 to 4 months, vaccination will be made available to everyone in the US. It may take some time after that until everyone who wants a vaccine actually gets one, though.
Speaking of that, reader Ferret left the following comment:
Do you have any sense of the connection between that expedited vaccine production schedule and any improvement in the downstream pipeline? Getting vaccine produced quicker doesn't necessarily move up the schedule to get sufficient people vaccinated if we can't actually schedule appointments to get vaccinated any faster, right?
It’s a good question, and there are a lot of moving parts, many of which I don’t know about. I gave an answer to this that I’m not really satisfied with:
I have little sense of this, partly because I think at that point the vaccination campaign goes hyperlocal. I think it stops being an affair of exclusively large centers and large pharmacy chains, and becomes something that numerous clinics and individual private doctor's offices are offering as well. So I really don't know what the logistics or the capacity are going to look like at all.
I'm a clinical trial communications and virology expert, after all. It's just not my area of expertise.
I’m going to look for more information on capacity expansion so I can try to write about this in the future. If anyone reading this has any special expertise on the matter, I’d be interested in hearing from you.
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See you all next time.
Always,
JS