We flip now to the second of the controversial papers revealed in late 2022 on COVID-19 — specifically the PANORAMIC study of molnupiravir versus usual care in outpatients with the disease. This one is controversial not as a result of the research was poorly performed, or unimportant, however as a result of molnupiravir has, from the beginning, been a contentious remedy for this illness.
Carried out in the UK, PANORAMIC was impressively massive, enrolling over 25,000 individuals. Eligible contributors had signs for five days or fewer, and have been both older than 50 or had comorbidities identified to extend the severity of the illness. Randomization was to open-label molnupiravir or regular care. The first endpoint was hospitalization or dying. Importantly, 94% of the contributors had already obtained three doses of a COVID-19 vaccine.
The primary research outcomes have been damaging — hospitalization or dying occurred in just one% of contributors in each teams. Critical opposed occasions have been evenly matched between arms.
On the plus aspect, individuals assigned to obtain molnupiravir had a considerably sooner time to restoration, 9 vs. 15 days, which yielded a >99% likelihood of the molnupiravir being superior to regular look after this protocol-specified endpoint. Energetic remedy additionally decreased healthcare utilization, and diminished viral load in comparison with regular care.
The vital view of molnupiravir: Nice research in a extremely related inhabitants — those that usually are not simply “absolutely vaccinated,” but additionally boosted. On this context, molnupiravir did nothing to scale back the intense outcomes of hospitalization or dying.
And ignore these time to restoration outcomes. It’s an open-label research, with individuals getting lively remedy after all pondering that what they’re getting is working. The placebo impact in remedy trials might be huge.
Solely this isn’t a innocent placebo — it’s an antiviral with a regarding mechanism of motion, inhibiting viral replication by rising the frequency of viral RNA mutations. Such a course of might conceivably spawn extra contagious or extra immune evasive SARS-CoV-2 variants, one thing we undoubtedly wish to keep away from.
Plus, there’s the continuing concern about mutagenesis, which has implications for these of reproductive age, and might need different long-term security points.
Lastly, molnupiravir isn’t low-cost. Don’t be fooled that it’s “free”, or lined by insurance coverage, or authorities packages. It’s $700 for a five-day course, one other drawback it has in comparison with placebo.
Now that we all know this large, well-done research is damaging, can we take molnupiravir off the remedy pointers fully, please? Or contemplate withdrawing the Emergency Use Authorization?
For additional concise, and (largely) vital ideas, learn the responses to this put up:
— Patrick Kenney, MD (@PatrickKenney7) January 13, 2023
The supportive view of molnupiravir: Nice research — helps put this remedy within the current-world context of COVID being milder in people who find themselves vaccinated or who’ve immunity from prior illness, or each.
And although molnupiravir made no distinction within the main endpoint (which was reassuringly uncommon in each arms), that sooner time to restoration sounds fairly nice. It’s higher than we’ve seen in open-label research of influenza remedy, so it’s unlikely simply because of the unblinded research design.
Given the choice of recovering from a nasty respiratory tract an infection in 2 weeks with no remedy, versus lower than 10 days with molnupiravir — and no main uncomfortable side effects — I’ll take the latter, thank you.
And dropping viral load would possibly cut back family transmission, and velocity time to with the ability to get again to work and different actions. Each huge wins.
Plus, let’s have a look at molnupiravir within the context of different remedy choices:
- Nirmatrelvir plus ritonavir has many drug interactions, so can’t be given to a few of our sufferers at highest threat for extreme COVID.
- Remdesivir within the outpatient setting sounds nice, however anybody who’s tried to arrange 3 consecutive days of intravenous remedy for sufferers within the ambulatory setting know this can be a tall order, certainly.
- The monoclonal antibodies are toast.
Molnupiravir clearly has a position.
My tackle molnupiravir: We have to acknowledge that the medical information on this drug are combined — at finest. Within the blinded part 3 research, MOVe-OUT, the sufferers receiving remedy who had pre-existing immunity to SARS-CoV-2 didn’t profit in any respect — in truth, the placebo group did higher. And the research on hospitalized sufferers, MOVe-IN, was additionally damaging.
Additionally, there are legit issues about its mechanism of motion, each associated to variant technology and mutagenicity.
Briefly, there are glorious explanation why the popular remedies for non-hospitalized high-risk adults within the NIH Treatment Guidelines usually are not molnupiravir, however nirmatrelvir boosted with ritonavir or intravenous remdesivir. A footnote reads, “Molnupiravir seems to have decrease efficacy than the opposite choices.”
However as I wrote previously when the info from PANORAMIC have been first launched, this enchancment in time to restoration does stand out, and it’s believable that secondary transmission can be diminished. So I don’t suppose that molnupiravir is ineffective — particularly given the constraints of our different remedy choices.
So again to the rules, which state molnupiravir ought to be utilized in high-risk outpatients with COVID “…when the popular therapies usually are not accessible, possible to make use of, or clinically acceptable.”
Excellent, and it’s precisely what I’ve been doing.
In the meantime, can we get some additional information on different remedy choices which might be simpler or safer to make use of? I’m pondering particularly the unboosted protease inhibitors ensitrelvir* and EDP-235, interferon lambda — and perhaps even low-cost (and really protected) metformin.
(*A really clever ID PharmD has kindly knowledgeable me that the drug interactions with this protease inhibitor are more likely to be simply as advanced as with nirmatrelvir plus ritonavir. Oh nicely.)