Molnupiravir
This is a “prodrug”, meaning that when it is ingested it is in a form that will convert to an active drug, in this case N4-hydroxycytidine. You don’t need to know what that means; the point is that the reason it can be taken orally is that the active form, that would have been destroyed in the gut, has been modified so that it can pass through the gut and get into the blood stream before the active form is released.
What is the active form?
To understand these types of drugs we can look back at the earliest chemo-therapy drugs for cancer. Cancer is a disease in which one particular cell loses its normal ability to stop dividing. It divides over and over again making more and more cells of the same type. If the original cell was in your kidney, you develop kidney cancer, if it is in your lung, you get lung cancer, etc. If the cell is an antibody producing cell (called a “B-Cell”) then you make more and more of that cell, the cells secrete the same antibody over and over again into the blood and you get a myeloma.
Cancers don’t kill you themselves, they just clog up so many organs, tissues and blood that you die from organ failure or starvation.
Anyway, because the basic issue with cancer cells is that they keep dividing over and over, the most common strategy is to try to kill dividing cells. If you can kill a cell while it divides you will have a good chance of killing the cancer cells. Unfortunately, if you use a shotgun to kill dividing cells you will also kill cells in your body that naturally divide. Cells that normally divide are hair cells and cells in your gut. If those cells die, you lose your hair and have nausea, diarrhea and stomach problems, issues that we are all too familiar with in patients being treated.
So, how do you kill cells that are dividing?
You may remember from HS science that the core of your cell is your DNA molecule. The DNA molecule is composed of 2 chains of “beads” that wrap around each other in “the double helix”. There are only 4 types of beads; just 4 that repeat in varied order through the chains of the DNA molecule. One chain is a direct image of the other chain.
The 4 beads of DNA are called Thymine (T), Cytidine (C), Guanine (G) and Adenine (A). Those 4 beads are assembled in a chain. When DNA replicates, each chain is copied and then the two new chains are reassembled. Wherever there is a T on one chain, there is an A on the other chain and wherever there is a G on one chain there is a C on the other.
One of the first chemotherapy drugs created was something called 5FU. (This is shorthand for 5-fluoro-Uracil; but the chemistry is not important). The drug looks a lot like one of the beads in the DNA chain and if it is around during replication, it can be incorporated into the new DNA molecule being built. BUT!!! This is not the same as the bead it replaces, it has an added piece to it. When it is incorporated into the DNA, it causes problems in replication and in function of the DNA, killing or neutralizing that newly dividing cell.
Molnupiravir is a similar drug; it is a modified version of the “C” bead listed above and can interfere with the replication of the mRNA of viruses in cells.
This strategy, long used for killing dividing cancer cells seems to have promise as anti-viral agents.
The Israelis have shown some exciting experimental results with another anti-cancer drug, EXO-CD24
These approaches are very exciting; however there needs to be some serious caution. When you interrupt the replication of mRNA you can’t target just the virus replication, and replication will be damaged. Fortunately, mRNA is not commonly replicated inside most human cells, so I cannot at this time point to specific areas of potential side effects. The approach of interfering with mRNA replication over a short period of time, in which the bulk of that replication would be associated with virus replication is a very interesting model.
The nucleoside analog (the chemical that is bad version of one of the beads) will need to be studied to determine if while blocking mRNA production it may also interfere with cell division, or production of other vital molecules like tRNA or mitochondrial DNA.
Bottom line:
This is a potentially important development for COVID and for other viral diseases. The association with Merck is very important and clinical trials will be critical.
April 15, 2021
The MOVe-OUT study (this shorthand refers to the study of Molnupiravir in an “outpatient” setting, in other words, in patients who are not hospitalized but have tested positive for the virus and have shown early symptoms) is to determine the efficacy of the drug by looking at how many of the non-hospitalized patients became hospitalized and/or died within 1 month of treatment.
They looked at a total of 302 patients who showed symptoms of the disease but were not hospitalized. They divided that group into 4 subgroups. One group was given sugar pills, and each of the other 3 groups received increasing amounts of the drug, either 200, 400 or 800 milligrams.
What they found was that there were more patients in the sugar pill group that became hospitalized or died than in the combined groups of patients that received the drug. Importantly, they found that in the treated group, the presence of viral RNA, measured by the standard methods was lower on days 5 and 10 after treatment than was found in the sugar pill group. From that they are able to conclude that the drug did, in fact, inhibit the replication of virus in these patients. They also found that after Day 15 after treatment, there was a larger proportion of patients with “undetectable viral RNA” in the treated patients compared to the sugar pill patients.
That result, although not statistically significant since the groups were so small, was deemed to be sufficient to move to the next phase of clinical trials.
There seemed to be an equal percentage of patients reporting side effects whether they were treated with the drug or a sugar pill. Cumulatively over all of the clinical studies, there have not been any incidences of death associated with administration of the drug, or of side effects that were sufficiently severe to result in discontinuation of treatment. (That is good news).
Merck expects to be able to report final results from the Phase 3 trials in late September or early October.
The MOVe-IN study (this is a study like above, but in an “inpatient” setting, in other words for hospitalized patients) enrolled 304 participants in a protocol identical to the MOVe-OUT study above. In this case they wanted to look at recovery rates for a month.
In this case, preliminary data on these patients did not show any benefit from treatment, so Merck has decided to discontinue any further trials. This drug does not appear to have any benefit for patients who have severe disease requiring hospitalization. That is why their press release now includes the words “Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19”
A New Study:
Based on the above results, Merck intends to begin an additional study to see if the drug can be used prophylactically for patients who have been exposed to COVID-19, but who have not yet shown signs of disease. In other words, they want to see if the use of the drug given immediately after someone may have been directly exposed to the virus may reduce the chance of becoming ill. This would open a market for use as a therapeutic treatment given immediately after exposure to prevent you from getting the disease.