We have more good news on the small-molecule anti-Covid front. We’ve already seen what look like strong results with molnupiravir, the Merck/Ridgeback/Emory transcriptase inhibitor. Everyone has been waiting on the results of Pfizer’s protease inhibitor (PF-07321332, now named Paxlovid), which would represent is the first small molecule trial results from a compound that was explicitly aimed at a SAR-CoV-2 protein (here it is in complex with the protease target itself). Remember, molnupiravir is more of a general viral RNA transcriptase inhibitor, and was around before we knew about the current coronavirus.
We’re getting the protease inhibitor news well before it was expected, because the results were so strong. Told you it was good news! Pfizer’s press release this morning says that when its EPIC-HR trial ran its scheduled interim analysis, it showed an 89% reduction in hospitalization or death when the drug was given to high-risk patients within 3 days of symptom onset, and 85% reduction when given within 5 days. There have, in fact, been no deaths at all in the treatment groups after 28-day follow-up. The trial has now been stopped due to efficacy (they had only made it up to 70% enrollment by that point), and the company is moving up its EUA application as quickly as possible. Note that the treatment regime includes a smaller dose of ritonavir, which is in there not for its antiviral activity (it’s useless as a direct antiviral against the coronavirus), but for its CYP-inhibiting properties, slowing down the metabolic clearance of the actual drug.
Step back for a moment and consider that this is really as fast as you could possibly expect a new, targeted small-molecule drug to ever be developed. Pfizer has a history in the antiviral protease world, so they had the expertise (and the screening collection!) to get a strong start. But here we are, less than two years after the emergence of this pathogen, with a bespoke drug against it. That’s the speed record, and I think that it will be very, very hard to break – and I hope that we never have to try! It’s a remarkable accomplishment.
I look forward to more details than we have now, but these are obviously strong numbers. Pfizer obviously split out the treatment groups by timing of the dose, and earlier is clearly better. But if you take it crudely as “Everyone dosed with the drug out to five days from symptoms”, then there were 9 people in the treatment group hospitalized out of 996 total and zero deaths, compared to 68 hospitalized out of 997 patients and ten deaths. So if indeed we can eliminate almost 9 out of 10 hospitalizations and virtually all deaths in high-risk patients with an oral drug that’s given only once symptoms appear, the course of the pandemic can clearly be altered. And then remember the strong molnupiravir results, and remember that that drug still has a trial to report where it’s used as a prophylactic treatment in high-risk patients as well: all this has to be the best treatment news we’ve had since the beginning of the pandemic. Previous successes (such as the use of dexamethasone) have helped save people once they’re in the hospital, but we’re now talking about keeping them from ever being hospitalized in the first place. And we can add in the fluvoxamine results that I blogged about yesterday, too, on what’s probably the anti-inflammation front.
Let’s think about some of the implications: first, an utterly obvious question is whether molnupiravir and Paxlovid can be combined into a cocktail regimen, as we have seen for other viral diseases like HIV and Hepatitis C. Those are by far the most successful small-molecule antiviral treatments ever discovered, and there seems to be no reason why this situation wouldn’t be similar. Why would you want to do this? Well, increased efficacy, clearly, but also to decrease the chances of a resistant coronavirus emerging. We already have evidence that it’s difficult to develop resistance to molnupiravir (because of its mechanism, which differs from other commonly used transcriptase inhibitors). But molnupiravir hasn’t been given to millions of patients yet. I have not yet seen similar in vitro resistance experimental results with Pfizer’s protease inhibitor, but you’d have to expect that resistance is easier to develop. Giving the two drugs at the same time would then be even more in Pfizer’s interest, as it would help to protect the efficacy of their compound. Meanwhile, avoiding a drug-resistant strain of the coronavirus would certainly be in the interest of the rest of the world. Now, there’s no reason to assume that such a protease-resistant form of the virus would be able to compete with wild-type Delta in the general population, but we would very much not want to find out the hard way.
Second, we have to think about distribution and price. Merck has already announced that it will license out its molnupiravir IP to the UN’s Medicines Patent Pool, which will have the effect of making the drug much cheaper in developing countries and more widely available as other generic companies produce it. Pfizer is going to have to address this issue as well. The chemical synthesis of these compounds is technologically much more straightforward than that needed for the mRNA vaccines, and there should be no reason that the process can’t be run by any country with competent generic drug manufacturers. Pfizer has said that it is “committed to working toward equitable access” and that it is “exploring potential contract manufacturing options”. They had better.
Third, picture what effect this will have on the pandemic and on its treatment options. The hope is that this sort of small-molecule treatment will be able to keep the vast majority of coronavirus patients out of the hospital, which will obviously be a huge help for overburdened healthcare systems around the world. The availability of an oral pill regimen that keeps the disease from getting bad (and from killing you!) will come as a great relief psychologically. The vaccines have been tremendous – it’s even better not to get the coronavirus in the first place, and I don’t even want to think about what the Delta wave would have looked like without them. But there are breakthrough infections that no one is happy about, and even more than that there are just too many people unvaccinated – which is especially galling in countries that have plenty of free vaccine waiting for everyone, but that’s another subject.
But one thing that this oral treatment option will probably do is push the monoclonal antibodies even further off to the side. They’re given i.v. in a hospital setting, and the plan is to keep people from ending up in the hospital in the first place. This should also push remdesivir demand down to zero. It was never a very effective drug, even under the most optimistic view of the data, and now there would seem to reason for it to be used at all. And perhaps we can all stop hearing about ivermectin and hydroxycholoquine and all the other things that have by now been shown over and over not to be useful, but that may be too much to hope for. At any rate, as treatment options expand, that stuff is going to look even more perverse than it does already, which is saying something.
All in all, it appears that we are turning yet another corner in the story of our fight against this virus – and perhaps there aren’t many more of them coming? We have vaccines and now we have effective drugs to be given early in the course of the disease. How many infectious diseases have more than that? Think about it – why shouldn’t we now be able to beat this pandemic back into the ground? Let’s get on it.
