Welcome to another MedCram COVID-19 update. We're going to talk about this new medication,
Molnupiravir, which is an oral antiviral medication for the treatment of mild to moderate COVID-19
in at-risk adults. Let's look at the mechanism of how this medication works and see how effective it
is at doing what it's supposed to do. On the left here we have Molnupiravir, which gets metabolized
to this thing on the right, which is an analog of a nucleotide. We're going to talk more about why
that's important and how that fits into how this medication prevents the replication of the virus.
So here we're going to review how the SARS-CoV-2 virus infects the cell and replicates,
and as you can see here on the left side of the screen, the SARS-CoV-2 viral particle infects the
cell through the ACE-2 receptor and releases its messenger RNA. This messenger RNA then goes on
to replicate itself, as we will review right now. As you can see here, the viral particle
as it's about to infect the cell, you can see here clearly that there is a messenger RNA
and that messenger RNA comes into the cell. In the cell already are things called ribosomes,
and the ribosomes will latch on to this messenger RNA from the SARS-CoV-2 virus,
and the result of that will be proteins that are being made. One of those proteins is RNA-dependent
RNA polymerase, and this enzyme is extremely important for replication of the SARS-CoV-2 virus.
So here we have the original messenger RNA from the virus and what will happen is the RNA-
dependent RNA polymerase will then go and start to copy that messenger RNA that came out of the
virus, and what you will get normally is another strand that is complementary to it. And then
the RNA-dependent RNA polymerase will once again copy that strand, and you'll get the original back.
It will copy that strand and get the complement, and then it will copy it again and get the
original strand. And the reason why this works is because in the original strand
there are pairing mechanisms. So what do we mean by that? We mean that if there is a U, it
will be paired with an A. And if there is a C it will be paired with a G and vice versa.
Now this type of arrangement allows you to keep the sequences the same, and so you can continue to
replicate the virus, and it is true to the original. And it's important to understand that the fidelity
of those letters be kept the same because these letters are codes for amino acids, which then
turn into proteins, and those proteins have to be made up of the same amino acids. If they're not,
the proteins are not going to work in the same way that they should be working. That's known as
mutations, and those mutations can change the amino acids, which can then cause changes in
the proteins. So the bottom line is that the virus wants to make sure that those letters are
lined up in the same way and say the same thing, replication after replication after replication.
There is even in RNA-dependent RNA polymerase a proof-reading mechanism that looks for mistakes
and tries to correct it. Mistakes pop up very, very rarely, and this is where we get variants that we
see in the population. What Molnupiravir attempts to do is to mess up this pairing mechanism.
So let's say, for instance, there is a U-C-A-G in the original strand. What would happen in the
presence of Molnupiravir? Well, U would still bind with A, and C would still bind with G, but A would
bind with Molnupiravir and G would also bind with Molnupiravir. The problem is that
the next time it would be copied to replicate this, A would then go back to U, this G would go back to
C, but the problem is that the Molnupiravir analog could be A or G, and the Molnupiravir again
could be A or G. So just to be clear, Molnupiravir is a substrate of RNA-dependent RNA polymerase, and
it out-competes the other nucleotides, so that instead of a G binding to a C, that Molnupiravir
comes in and binds to the G instead instead of a T coming in to bind with the A, the Molnupiravir
takes the place of the T and binds to the A. And so what you can see very clearly is that after
a while, the As and the Gs will get mixed up, and that will cause some pretty disastrous mutations,
so that the virus can't replicate. The other thing that happens here is that Molnupiravir
can escape proofreading capability, which means that these mutations cannot be corrected by
the virus. The reason why it's able to escape proofreading capability has been thought to be due
to the stability of the Molnupiravir A bond and the Molnupiravir G bonds ,which are highly stable.
So the scientists at Merck engineered a randomized placebo-controlled trial
to measure the efficacy of Molnupiravir in patients with SARS-CoV-2 positivity before they had
symptoms for longer than five days ,so that was one of the entry criteria. The other entry criteria is
that obviously it had to be outpatient. These are people who are not hospitalized with COVID-19.
And also there had to be at least one comorbidity or risk factor.
So they have to be over the age of 60, or they had heart disease, or they had diabetes or obesity.
And then they randomized them to either Molnupiravir or to placebo, and what they did
is what they normally do in these kinds of studies, which is to have a data safety monitoring board
peek in at the data independently to see if there is an endpoint that has been met so
they know whether or not to stop the study early, because if there is a huge difference or there is
a difference in side effects, it would be unethical to continue the trial. They would have to stop the
trial, and so that's exactly what they had as they started out looking at these patients -- and the end
point in this case was death or hospitalization. They looked at the incidence of any adverse events,
the incidence of drug related adverse events, and also discontinuation of the study drug. Now just so
you're aware, there were no subjects in this study that were pregnant. That was an exclusion criteria.
So, again, as we mentioned, they stopped the study early, and that's called a planned intervention
analysis. And when they did that, they found that there were 385 subjects in the Molnupiravir group
and 377 in the placebo group, and when they looked at the analysis, they found that 28 patients have
been hospitalized, or about 7.3 percent, and in the placebo group, 53 have been hospitalized, or 14.1
percent. There were no deaths in the intervention group and eight deaths in the placebo group.
The incidence of any adverse events was 35 and 40 percent respectively. The incidence of drug related
adverse events was 12 percent and 11 percent respectively. And the discontinuation of this study medication in the
first group the Molnupiravir group was 1.3 percent .and in the placebo group discontinuation
was 3.4 percent. So if you look at this data, you'll see here that there was about a 50 percent
reduction in hospitalization. The numbers were so small for death that we can't really say
what the mortality rate reduction is in this medication. Adverse events was about the same.
I think the reason why they may have a higher discontinuation rate in the placebo, because it
looks as though this medication may be effective enough that the symptoms from covid were actually
causing discontinuation of the placebo. Of course, that's mere speculation at this point. By the way,
this p-value was 12 10,000ths and a p-value of less than 0.0012 is highly statistically significant.
Usually in most studies, a value of less than 0.05 is considered statistically significant.
The other interesting thing about this as well is that the SARS-CoV-2, when looked at
a little bit more deeply, had similar efficacy whether it was delta, gamma, or mu variants.
So if we review the characteristics of Molnupiravir, we see that it is actually pretty
effective: 50 percent reduction in hospitalization, and there were no deaths at all in the interim
analysis in the intervention group. Realize that monoclonal antibodies, which have been studied,
have about an 85 percent reduction. The other thing I would mention with monoclonal antibodies
for the treatment of COVID-19 is that we have a greater body of research on monoclonals, but the
advantage that Molnupiravir has is that it's an oral medication, and that may not seem like a big
deal, but it's much easier to arrange for patients to get oral medication than to have to go to an
infusion clinic and get intravenous medication, especially in areas where infusion clinics may
not be readily available. And along those lines, with oral medication they can be started much more
easily and faster. For instance, if somebody went into a clinic to get tested and they were found
to be positive, then there could be medications given to them almost immediately and that would
be much easier than having them get an appointment at an infusion center or an emergency room with
monoclonal antibodies. So there's definitely a practical advantage here with oral medication
over IV infusion. And of course a medication that we know very well is Tamiflu, which is indicated
for influenza and that would be an example of an oral medication for a viral infection. The downside
is it's about seven hundred dollars a course, so it's not cheap but it is easier than intravenous.
And if you think about the fact that you would have to have a nurse or some technician and
then a facility to infuse the IV, that is a lot of cost that doesn't get put into the final equation.
It also seems to be safe at least in the immediate period, at least according to the results of this
study. The question though is long-term and of course, we just don't have that data at this point,
and we're sure that there will be more studies in the future on this medication. In an article
earlier this year, which we will put the link to in the description below, Dr. Ron Swanstrom, PhD
and Biochemistry Professor at University of North Carolina Chapel Hill said that side effects
concerns have been raised about whether Molnupiravir could be metabolized into a precursor
of DNA. He went on to explain that it could enter the host cell nucleus leading to oncogenesis.
Robert Shafer, Research Professor at Stanford University in California, however, noted that
Molnupiravir is only used in the short term twice daily for five days, as opposed to chronic use.
Professor Ashley Brown, Associate Professor at the Institute for Therapeutic Innovation
at the University of Florida Orlando, said that polymerase inhibitor side effects have improved
over the years and while mutagen side effects were concerned early in development in HIV,
they've eased in available hepatitis treatments. Dr. Ron Swanstrom added, however, due to the need
for longer term safety data Molnupiravir may be limited to patients at high risk of developing
severe disease, and that's exactly what we saw the company limit this medication to in the phase
three trials. So more along the way of long-term safety data. I found this article interesting in
Medical News Today, titled "Molnupiravir vs. COVID-19: Will the drug live up to the hype?" and it
was both written and fact-checked recently, and under the heading of safety concerns, it does
mention that there were some experts in the past that have raised concerns about the safety of a
drug that works by causing mutations. And as we've just shown Molnupiravir causes the viral RNA to
mutate. The bigger question is whether or not Molnupiravir would cause mutations in the host cells
themselves, and there's at least one study in animal cell cultures that found mutations in
cells treated with Molnupiravir. Dr. Simon Clark, Associate Professor of Cellular Microbiology at
the University of Reading in Great Britain, said it's worth noting that people involved in the
trial were instructed to abstain from heterosexual sex or use contraception. While this is a routine
practice with some other medicines, such as cancer chemotherapy, it suggests that the drug has the
potential to cause birth defects, should someone become pregnant. Professor William Schaffner, who is
an Infectious Disease Specialist at the Vanderbilt University School of Medicine was less concerned
about the possible genetic implications saying quote "the FDA would certainly not have permitted
clinical trials in humans if they thought there was any reasonable danger going on." He said animal
studies showed no adverse effects. Obviously more information is needed to clarify these issues,
and we will be watching out for more information as it becomes available.
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