As has been painfully obvious, small-molecular therapeutics have been largely a missing therapeutic option during the pandemic. Remdesivir got a lot of attention last year – remember those days? – but as better data from larger trials have come in, the excitement has waned. Recently the European DisCoVeRy effort reported on a trial of the drug versus standard of care, with over 800 participants split 50/50 into treatment and control groups. This trial found no significant differences in clinical outcomes at all. This was an open-label trial, but a well-run one, with viral loads being randomized between the two groups and so on. A number of subgroup analyses were looked at to see if remdesivir showed any particular signs of utility, but frankly, it didn’t. This could be because the median time after symptoms was 9 days for the patients in the study, but that’s pretty much the hospitalized cohort that the drug is being used for in the first place. On the basis of this and other similar reports, it’s hard to see what remdesivir is really doing for anyone, and I would hope that it’s being dropped from such treatment regimes. The likelihood was always small for such a compound really helping once the disease is so well established.
Edit: well, one day after this post comes word (via press release, anyway) that remdesivir actually does seem to lower the chances of being hospitalized if given very early. Conceptually, I’m glad to see that, and it fits in with what everyone has been thinking about antiviral therapy. But in this study, the drug was given i.v. for three days, which is something of disconnect if you’re trying to keep someone out of the hospital, isn’t it? So it’s difficult to see how this is going to help out much in real practice. It does, though, heighten the interest in the trials mentioned below that are trying to use these compounds to prevent Covid infections in the first place. Can’t get much earlier than that!
Next we have molnupiravir from Merck (and Ridgeback, and Emory), and I last wrote about them here. It’s another polymerase inhibitor (remdesivir’s mechanism as well), and it had likewise been in development before the pandemic. Phase III data on this one is highly anticipated, and there are two trials underway, from what I can see: there’s MOVe-AHEAD, which is looking at the compound as a preventative of coronavirus infections in roughly 1300 participants who are at elevating risk of contracting the disease, and MOVe-OUT, which is the trial that I wrote about in that last link. Merck bailed out on the part of the trial that studied hospitalized patients (that established-disease problem again), but they’re continuing to look at outpatient therapy in milder disease. That part of MOVe-OUT is targeting over 1500 patients at full enrollment, and it looks like they’re at somewhere between 1100 and 1200 now. Earlier in the year, they hoped to be able to read out on this one around now or on into October, but now they’re talking about November/December (more on this below).
And there’s AT-527 from Atea, partnered with Roche. That one has the RNA polymerase inhibition as well as activity against the nsp12 polymerase enzyme. This is the candidate I know the least about on this list, to be honest. There were reported Phase II results in late June, showing reduced viral load in 62 patients, for what that’s worth. My own take is that such results are good to hear, but that they’re in the necessary-but-not-sufficient category. You need to show effect on the course of disease. Trials are ongoing to do just that, with more results expected (last I heard) sometime later this year.
Finally, there’s a different mechanism in trials from Pfizer, the first clinical look at a “main protease” inhibitor, PF-07321332. This target was discussed here on the blog in this post. That drug candidate is being given along with ritonavir, presumably because of the latter’s inhibition of the CYP3A4 metabolic enzyme (ritonavir per se does not seem to have any activity against the coronavirus). A trial in diagnosed patients at risk of severe disease began in July, and first patients were dosed earlier this month in another trial looking at patients who are not at such risk. It’s very good to see this in the clinic, since you’ll note that all successful antiviral therapeutic regimens have simultaneous administration of drugs with more than one mechanism. I do realize that we’re talking about basically two viruses there, but the point is valid! My next column in Chemistry World goes into this issue as well; I’ll post a link as soon as it’s live.
A reader sent me a message this morning wondering about the timelines on the Merck trials, as in whether they’re slipping, and if so, whether Pfizer is being overoptimistic in their own patient accrual targets. It’s worth keeping an eye on this. With the amount of Delta cases out there, at least that variable isn’t going to be slowing the trials down much (plenty of patient out there, sadly). But I wonder about the preventative trial with molnupiravir – I see that the criteria include not being vaccinated (first dose) more than seven days before starting participation in the trial. There are still way too many of those people, of course, but with a majority of over-18s having had at least one dose, it’s still not as easy to enroll people as it would have been last year. That makes you wonder if people who are unwilling to get vaccinated might also be unwilling to participate in a trial of an investigational coronavirus drug. From all appearances, many unvaccinated coronavirus patients seem to have no such worries about taking monoclonal antibodies, but I don’t know where a small molecule trial falls on that spectrum.
So let’s watch those trials with timelines in mind. It looks like the very best we could hope for is some sort of readout for one or another of them by the end of the year – will we make that, or will we still be waiting in January to see if any of these drugs might be beneficial?
