Yesterday (10/01/21 for historical context), there was quite a stir after a press release by Merck Pharmaceuticals after reports that their new antiviral medication, molnupiravir. They claim it shows benefits in early COVID-19. In this post, I plan on updating the newest data that comes out regarding this medication using real data. For now, all we have is press-release data.
I am not going to go over what’s in the media because, well, screw the media. I don’t trust them. The commentary I will add is that I get excited about therapies that will keep patients out the ICU. I never want to meet these patients. If this leads me to be unemployed, so be it. I can become a full time blogger, podcaster, influencer, investor, whatever. Let’s just keep people from dying from COVID-19. Check out the addendum on 11/28 at the end of this post. Second addendum on 12/23 with the NEJM publication.
What is Molnupiravir?
Molnupiravir is an “orally administered form of a potent ribonucleoside analog that inhibits the replication of SARS-CoV-2”.
Press-Release Data on Molnupiravir
At 6am on 10/01/21, so that pre-market traders can go on a frenzy, Merck Pharmaceuticals put out a Press Release with the headline “Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study”. The main headline thereafter is that “at the Interim Analysis, 7.3 Percent of Patients Who Received Molnupiravir Were Hospitalized Through Day 29, Compared With 14.1 Percent of Placebo-Treated Patients Who were Hospitalized or Died”. The p-value is tiny at 0.0012 which bodes well.
What does this really mean? First, it is not a cure for COVID-19. It does keep patients out of the hospital, though. The number needed to treat to keep a single person out of the hospital is 14.7 if you plug in the numbers into the nifty NNT calculator. Again, it is not a cure, but it helps. I’ve taken issue with this before, but the headline states “molnupiravir reduced the risk of hospitalization or death by approximately 50%”.
This sounds like a lot, but if they were to say 14.7 people will have to be treated to benefit one person, then that doesn’t sound as sexy. There were zero deaths in the molnupiravir group and 8 in the control group. Saving lives is quite important. Molnupiravir had a 0% incidence of death while the control group had a 2.1% incidence in death (in patients with at least one risk factor for a poor outcome).
MOVe-OUT trial on Molnupiravir
The trial from which this data came out was a phase III trial. That means that it’s almost ready to get the green light. But this press release came from interim analysis which means the full trial is not yet complete. These data come from the interim analysis. What is an interim analysis, you ask? Well, when a study is being conducted, a point is pre-specified where the teams are going to take a look at whether they’re causing harm, seeing a benefit, or are seeing futility in their study. Even though the full trial is not yet complete, per the press release, “recruitment into the study is being stopped early due to these positive results” by the FDA and an independent Data Monitoring Committee. Hopefully this means that the manuscript will be knocked out shortly for us to dissect.
775 patients were looked at in this interim analysis. They have already recruited 90% of the entire 1550 patients planned. They were started on either Molnupiravir or placebo within 5 days of randomization. This means they started early. This is of utmost importance because it is my opinion that if you start early, the better the outcome. Once they’re in my ICU, it’s too late. The formal inclusion criteria states “Had initial onset of signs/symptoms attributable to COVID-19 for ≤5 days prior to the day of randomization and at least 1 of the following sign/symptom attributable to COVID-19 on the day of randomization.”
They enrolled patients with risk factors.
I also appreciate that they included patients who had at least one risk factor associated with poor disease outcomes. Those risk factors included obesity, age greater than 60, diabetes and heart disease. They did not specify anything whatsoever about vaccination status which is a question I have. It’s a remarkable international study so I’d venture to say that the vast majority were unvaccinated especially since they started the study in October of 2020. If you care to see the inclusion and exclusion criteria for this study, I recommend you check out the study page on clinicaltrials.gov listed here. The bulk of exclusions include patients with poor renal function, certain HIV patients, patients with liver dysfunction (hepatitis B or C, elevated LFT’s, etc.), thrombocytopenia.
Should Molnupiravir work against the variants?
The MOVe-OUT trial has looked into the variants and they state “to date, the Delta, Gamma, and Mu variants have accounted for nearly 80% of the evaluable cases in the trial”. We will have to wait for the subgroup analysis in the formal publication for the actual details on this.
What adverse effects were seen?
There was really no difference in the incidence of adverse effects between the molnupiravir and placebo groups. There were also no differences in the incidence of drug-related adverse events. During clinical trials, patients sometimes drop out and stop taking the study drug. This happened more often in the control arm (3.4%) than in the study arm (1.3%).
Will Molnupiravir work for hospitalized patients?
It is my personal opinion that this medication will have no role whatsoever in hospitalized patients. The reason why is because this is shown to be efficacious in non-hospitalized patients when provided EARLY in their diagnosis. Once someone even presents to the hospital, they are too far in the inflammatory phase . They are no longer in the viral replication phase where these medication is intended to work.
In addition, if you look up molnupiravir on clinicaltrials.gov, you will see that the study looking at this medication in hospitalized patients has been terminated. ClinicalTrials.gov Identifier: NCT04575584.
Where do we go next?
I suspect that there will be an emergency use authorization for this therapy and a frenzy to get it into pharmacies. The press release states that “Merck expects to produce 10 million courses of treatment by the end of 2021”. They must’ve suspected that this was going to work because “Merck entered into a procurement agreement with the U.S. Government under which Merck will supply approximately 1.7 million courses of molnupiravir to the U.S. government”. Will other countries be able to get their hands on it if/when it is approved? The press release states that strategies have been put in place with other generic manufacturers to make sure people can get this.
What am I waiting for?
First of all, I want to actually read the paper before I get too excited about anything. I want to see the groups of patients this was provided to. Also, I want to see what adverse effects are found. I want to see the subgroup of people who may have been vaccinated. I want to see the demographics of the folks who ended up in the hospital despite this. Seeing if this helps shorten symptoms is also important to me but less so. Is this a cure, nope, but it should help and I look forward to any help we can get.
What will a molnupiravir regimen cost?
I don’t know where this data comes from but outlets are stating $700 of our tax dollars (or printed out of thin air federal reserve money, however you feel fiat currency comes to be) per regimen. So if we do some maths with a NNT of 14 x $700 it will cost us $9800 to keep a person out of the hospital. Is this worth it? Well, I leave that up to you to decide.
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ADDENDUM: UPDATE on 11/28/21
If we come back a couple of paragraphs, you’ll see that in the initial press release the NNT to keep a person out of the hospital or from dying was 14.7. Keep this number in mind as we analyze this press release where they state that “molnupiravir reduced the risk of hospitalization or death from 9.7% in the placebo group (68/699) to 6.8% (48/709) in the molnupiravir group”. Plug this into your nifty NNT calculator and that 14.7 now is up to 34.5 for the same endpoint. It is less efficacious that what we all hoped for.
Now we’re looking at about $23800 to keep a person out of the hospital or from dying. Whether or not this is worth it is up to your opinion but we cannot keep printing money forever. The press release provides fun numbers which make it seem more efficacious than it is like “an absolute risk reduction of 3.0%” and “a relative risk reduction of 30%”.
ADDENDUM #2: Update on 12/23/21
The peer-reviewed paper is now available on NEJM.com. Let’s just say I am quite disappointed in the final trial. If you add the variable of omicron now being the predominant strain in the United States, and the fact that hopefully it remains that it is not as virulent as other strains, then I feel that the NNT to keep someone out of the hospital is going to balloon from 34.5 to a number that is much higher. Given that the final participant was enrolled in early October, then there’s a very small chance any omicron patients were enrolled in this trial.
Other goodies include that 20% of the patients enrolled had positive antibodies, meaning they had natural immunity as none of these patients were vaccinated. In that population, there’s no benefit to providing molnupiravir for their COVID infection. This also goes against what someone said on a popular podcast that someone cannot have COVID twice which I strongly disagree with.
Since now there’s a EUA for this medication, I feel we should be selective to mediate costs. It should only be provided to unvaccinated individuals and those who do not have natural immunity to severe disease. We should also develop a way to differentiate the variant so that we don’t go and treat every omicron case with molnupiravir.
Press Release: https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)
ADDENDUM PRESS RELEASE ON 11/26 but updated here on 11/28
Merck and Ridgeback Biotherapeutics Provide Update on Results from MOVe-OUT Study of Molnupiravir, an Investigational Oral Antiviral Medicine, in At Risk Adults With Mild-to-Moderate COVID-19
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2021 Dec 16. doi: 10.1056/NEJMoa2116044. Epub ahead of print. PMID: 34914868.
Link to Article
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