nicolas_
I sometimes feel as if I’m hammering away at a nail that’s already well below the surface of the wood when I come around to today’s topic, but then I realize that no, it really does need to be said.
A lot of people really don’t know how to deal with results from drug trials. That’s especially true for the general public, of course, but it’s more true than it should be for people in the field as well. Results that look promising can in fact evaporate on closer scrutiny, and this happens rather often. You can get the opposite, too, where something that didn’t look good actually comes through. But those are more rare, since the odds are against any new treatment working at all (never forget the overall clinical failure rate of about 85%).
The usual situation, sadly, is that if the results don’t look worse in a larger trial or with more access to data, that’s a win, and this is an outlook with current relevance.
These thoughts come up now in relation to molnupiravir (MRK). That’s one of the many pandemic stories in the gigantic triple-decker novel that we’ve all been living in for the last couple of years, so here’s a refresher for this particular plot thread.
It’s a small molecule aimed at viral polymerase activity, and it was discovered before the current coronavirus pandemic. At the time it was heading the clinic as a possible influenza drug, but it was rapidly repurposed to see if it could be useful against SAR-CoV-2.
Most of these repurposing ideas are long shots, but in this case, there was more hope, because molnupiravir seemed to have a broad spectrum of potent activity against viral polymerase enzymes. The initial Phase II data in the spring of 2021 were underwhelming, though. This was obviously not going to be a pandemic wonder drug, and the question became whether it was going to be of much use at all.
But later that year the story flipped around: another trial showed what looked like strong evidence for efficacy, and optimism returned – for a bit. The subsequent FDA advisory committee meeting had more data available, though, and the more you looked at the results the less impressive they were. The problem was that the interim look at the trial data was quite different from the final numbers. Basically, the latter stages of the clinical trial were pretty terrible, and it dragged the overall efficacy numbers down into a real gray area. Keep in mind that all of these trials were in unvaccinated patients, too.
Molnupiravir got approved in the end, but with a real lack of enthusiasm. It and Pfizer’s (PFE) Paxlovid (a viral protease inhibitor) are still the main antiviral weapons, and from what I can see, molnupiravir is doing what business it does because of the ritonavir component in the Paxlovid dosing, which is given along with actual antiviral drug ingredient.
Ritonavir is an inhibitor itself of a prime drug-metabolizing enzyme in the liver (CYP3A4), and without it you don’t get much antiviral activity, because the protease inhibitor drug part of the combo (nirmatrelvir) is then chain-sawed in the liver and disappears rapidly. Problem is, there are a lot of other medications that are also cleared (at least in part) by CYP3A4, and their dosages and schedules are already built to take that into account.
So, patients who have some pre-existing conditions can face a real problem with Paxlovid – it’ll throw off all their other drug regimens – and some of them have been getting molnupiravir instead, particularly in Europe.
Is it doing them any good, though, in light of the disappointing overall data package? Well, we now have the results of a large, controlled trial in the UK (thanks to Eric Topol of Scripps on Twitter for the notice). It’s a 25,000-patient adaptive trial design, open-label (which frankly tends to give you more optimistic-looking results in many cases than a double-blind).
The participants were randomized to standard-of-care or that plus molnupiravir (800mg bid for five days, a course of treatment that 95% of them completed). Everyone in the trial was confirmed to have coronavirus infection, and the patients were either 50 or older, or 18 or older with comorbidities. 99% of them had had at least one coronavirus vaccination. The endpoint was straightforward: all-causes hospitalization or death within 28 days.
The overall hospitalization/death rates were low – this isn’t 2020, and the vaccinations really do have a strong effect on preventing those outcomes. But the rates of the control group and the +molnupiravir group were statistically identical.
The latter had somewhat lower viral loads overall and slightly shorter times to recovery, and that’s good, but it appears that molnupiravir is doing nothing to improve the (already low) number of previously vaccinated patients who go on to experience serious disease. This is the first comprehensive look at this sort of population, and the first to study the situation with largely Omicron-infected individuals as well. And you’d have to say that the benefits are slight. Adverse events were very low and identical between the two groups.
How does this compare with the benefits of Paxlovid?
Its data in unvaccinated patients definitely looked stronger than molnupiravir’s in a similar population. I took the drug myself when I got infected back in May, having moved into the 60-and-over demographic with high blood pressure as well, judging that there was a reasonable chance of benefit with what seemed to be a low risk of adverse events. Unless you count the taste of the stuff, which is pretty darn adverse. But I didn’t have as much data to back that up at the time.
Just in the last few days, though, we’ve gotten some, and it’s encouraging. This analysis of data from thousands of hospitals and clinics strongly suggests that Paxlovid does in fact reduce rates of hospitalization and death, and it does so both in vaccinated and unvaccinated patients. Now, this is observational data, so there are controls missing that would be present in an intentional trial, but everything at least is pointing in the right direction in a very large data set. And those benefits become more solid with increasing age of the patients, as you’d expect.
So, it looks like I made the right call in May, and it looks like Paxlovid is indeed a useful drug in older patients (but likely not in younger ones, unless they’re also unvaccinated).
So, the picture does seem to be coming into focus. Paxlovid is looking much more useful than molnupiravir, with the latter being (apparently) no use at all in preventing severe outcomes. But in order to get these results, you have to keep asking, and asking in as controlled and organized a fashion as you can manage, and in the largest population you can get. It’s tedious and expensive and slow, isn’t it? There are some ways to speed things up, no doubt, but none of them are going to be as fast as you’d hope. Real answers come hard.
Editor’s Note: The summary bullets for this article were chosen by Seeking Alpha editors.
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