Merck's Molnupiravir - The First Covid-19 Pill (maybe)

[Lani]

WASHINGTON — Merck & Co. said Friday that its experimental Covid-19 pill reduced hospitalizations and deaths by half in people recently infected with the coronavirus and that it would soon ask health officials in the U.S. and around the world to authorize its use.

If cleared, Merck's drug would be the first pill shown to treat Covid-19, a potentially major advance in efforts to fight the pandemic. All Covid-19 therapies now authorized in the U.S. require an IV or injection.

Merck and its partner Ridgeback Biotherapeutics said early results showed patients who received the drug, called molnupiravir, within five days of Covid-19 symptoms had about half the rate of hospitalization and death as patients who received a dummy pill. The study tracked 775 adults with mild-to-moderate Covid-19 who were considered higher risk for severe disease due to health problems such as obesity, diabetes or heart disease.



Merck’s pill works by interfering with an enzyme the coronavirus uses to copy its genetic code and reproduce itself. It has shown similar activity against other viruses.

https://www.nbcnews.com/news/us-news/me ... 0-n1280536

[tek]

Merck’s pill works by interfering with an enzyme the coronavirus uses to copy its genetic code and reproduce itself.

It's a virus 'bortion pill!
My religion prevents me from taking it!
/s

[bill_g]

Merck’s pill works by interfering with an enzyme the coronavirus uses to copy its genetic code and reproduce itself.

It's a virus 'bortion pill!
My religion prevents me from taking it!
/s

Unfortunately, that is probably not far off the mark. I can hear that argument already.

[bill_g]

WASHINGTON — Merck & Co. said Friday that its experimental Covid-19 pill reduced hospitalizations and deaths by half in people recently infected with the coronavirus and that it would soon ask health officials in the U.S. and around the world to authorize its use.

https://www.nbcnews.com/news/us-news/me ... 0-n1280536

Yea Science! Go Team!

[Slim Cognito]

Oh please, oh please, oh please...



Just had a thought. Doesn't Merck make ivermectin? If so, you know what happens next.

[Sam the Centipede]

Excellent news! It's a neat mode of action, rather like a cat walking across a keyboard when the virus is replicating its RNA.

I read up a little about it. To avoid sending people to sleep inadvertantly, my off-the-cuff lay synopsis is under the spoiler:

► Show Spoiler

First a little context, some high school genetics:

RNA is a long string of nucleosides, and, as anybody who has ever taken any interest in genetics knows, the information encoded in RNA (and DNA) is represented by the order of 4 different types of nucleosides along the strand, usually denoted A, C, G and U (or T for U in DNA). Each new virus needs a new strand of RNA. For genes that code for proteins (all the genes of SARS-CoV-2, iirc), each group of 3 nucleosides constitutes a codon, and each codon represents one amino acid in the final polypeptide or protein, so, for example, a CCA codon indicates a molecule of histidine (an amino acid) should be included at that point.

Replication of DNA in large organisms (plants, animals, humans) is very accurate, with complex machinery to ensure this. It needs to be accurate because errors can lead to organisms lacking essential proteins, cells becoming cancerous or other problems. Replication of viral RNA doesn't include the same error checking and repair mechanisms, so many more errors occur. When generating millions of viruses, it doesn't matter if lots are skanky, viruses don't have parental care, nobody loves them. (There are still errors in DNA replication in plants, animals, etc., creating variation, which is the mother lode of evolution, but that's not relevant here.)

Some theorists posit that RNA viruses are on the brink of "error catastrophe", where a small increase in the error rate of RNA replication can lead to extinction of the population.

Back to the drug…

Molnupiravir is a trade name, the chemical formula is N⁴-hydroxycytidine. Note the last part of the name: cytidine is the C of the A/C/G/U code, N⁴-hydroxycytidine is an analog which is similar but not identical to cytidine. This compound confuses the viral RNA polymerase as it tries to copy one RNA strand to make another, and the high rate of errors forces this "error catastrophe", not enough viable virus.

A heartless cynic might wonder "hey guys, what took you so long?". N⁴-hydroxycytidine and its effect was first described in the 1970s (for E. coli bacteria), and research has been continuing since, especially since the 1980s. It has this effect on a wide range of viruses but I don't know if it's actually used much in medicine.

Of course, hard work takes time. Experiments with ferrets were reported in January 2021 in Nature (Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets). Ferrets are close relatives of mink, and perhaps people remember the problems with infected mink in Denmark last year? Denmark was planning to cease fur farming anyway, and they found that mink were transmitting SARS-CoV-2 between each other and their keepers, so there was a lot of culling. To clarify: MK-4482 and EIDD-2801 are more alternative designations for this molecule.

So, less cynically, going from experiments in animals to human trials in well under a year is excellent progress!

And a course of 10 oral capsules over 5 days (used in the trials) seems a very acceptable regime.

Perhaps the reason for the shortage of antivirals is that the public health approach to viruses is generally to vaccinate against them? So antivirals have not been a priority? Maybe there are other issues with these antivirals? Perhaps they can interfere with our own DNA replication or RNA transcription? I don't know, perhaps somebody will find out??

[humblescribe]

Oh please, oh please, oh please...



Just had a thought. Doesn't Merck make ivermectin? If so, you know what happens next.

I do not think Merck manufactures Ivermectin. They do manufacture a similar anthelmintic, Panacur, for ruminants and other quadrupeds.

https://www.merckvetmanual.com/pharmaco ... imidazoles

My biochemistry and organic chemistry was eons ago. Suffice to say that Ivermectin is not a benzimadazole. Ivermectin has a different mechanism to rid an animal of internal parasites.

[p0rtia]

Cool! Thanks, Sam.

[Suranis]

Merck does make Ivermectin

https://www.merck.com/news/merck-statem ... -pandemic/

[W. Kevin Vicklund]

Oh please, oh please, oh please...



Just had a thought. Doesn't Merck make ivermectin? If so, you know what happens next.

Yep, I've already seen the alt-meds spinning the usual conspiracy theory. "Merck doesn't support ivermectin because they can make more money off the new pill." "If they supported ivermectin, they couldn't make back the money they spent on molnupiravir research."

[Suranis]

Pffeiser has their own pill in Development

https://www.pfizer.com/news/press-relea ... l-covid-19

Pfizer Starts Global Phase 2/3 EPIC-PEP Study of Novel COVID-19 Oral Antiviral Candidate for Post-Exposure Prophylaxis in Adults
Monday, September 27, 2021 - 06:45am

EPIC-PEP (Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis) is the third study launched in this global clinical research program.
New study will evaluate novel protease inhibitor (PF-07321332, co-administered with a low dose of ritonavir) for prevention of illness in adults living in the same household as someone with COVID-19
PF-07321332 has been specifically designed to be administered orally, so that it can potentially be administered at the first sign of infection with, or exposure to, SARS-CoV-2, without requiring patients to be hospitalized

NEW YORK--(BUSINESS WIRE)-- Pfizer Inc. (NYSE: PFE) today announced the start of the Phase 2/3 EPIC-PEP (Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis) study to evaluate the investigational novel oral antiviral candidate PF-07321332, co-administered with a low dose of ritonavir, for the prevention of COVID-19 infection. This Phase 2/3 trial is part of a global clinical research program and is enrolling individuals who are at least 18 years old and live in the same household as an individual with a confirmed symptomatic SARS-CoV-2 infection.

“With the continued impact of COVID-19 around the world, we believe that tackling the virus will require effective treatments for people who contract, or have been exposed to, the virus, complementing the impact that vaccines have had in helping quell infections. If successful, we believe this therapy could help stop the virus early – before it has had a chance to replicate extensively – potentially preventing symptomatic disease in those who have been exposed and inhibiting the onset of infection in others,” said Mikael Dolsten, MD, PhD., Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “Given the continued emergence and evolution of SARS-CoV-2 variants and their immense impact, we continue to work diligently to develop and study new ways that our investigational oral antiviral candidate could potentially lower the impact of COVID-19, not only on patients’ lives, but also the lives of their families and household members.”

The Phase 2/3 EPIC-PEP trial is a randomized, double-blind, placebo-controlled study and will enroll up to 2,660 healthy adult participants aged 18 and older. Participants will be randomly assigned (1:1:1) to receive PF-07321332/ritonavir or placebo orally twice daily for 5 or 10 days. The primary objective will assess safety and efficacy for the prevention of confirmed SARS-CoV-2 infection and its symptoms through Day 14. PF-07321332 is an oral antiviral SARS-CoV-2-3CL protease inhibitor, which has an encouraging pre-clinical profile, including potent in vitro antiviral SARS-CoV-2 and broad coronavirus activity. Results from the Phase 1 clinical trial demonstrated that PF-07321332 was safe and well tolerated.

In addition to this study, the global EPIC program consists of multiple ongoing clinical trials, including one in SARS-CoV-2 infected patients who are at high risk of severe illness (including hospitalization or death), which began in July 2021, and another in infected patients who are at standard risk (i.e., do not have risk factors for severe illness), which began in August 2021.

For more information on the EPIC Phase 2/3 clinical trials for PF-07321332, visit clinicaltrials.gov

[Sam the Centipede]

Thanks Suranis! Science doing great stuff again!

More observations from my reading, for those who wish to sound knowledgeable! –

► Show Spoiler

From what I read, Pfizer originally discovered/developed this compound during the SARS outbreak of 2002-3, which was (of course!) caused by SARS-CoV, the older relative of SARS-CoV-2. But SARS fizzled out, so a lot of research was shelved.

Like molnupiravir it impedes viral replication, but it targets a different component of the process.

It interferes with a protease enzyme that the virus needs, specifically 3-CL protease. Quick reminder of basic biochemistry: an enzyme is a molecule (a protein) that makes a biochemical reaction happen, or catalyzes the reaction to go much faster than it would otherwise. Enzyme names conventionally end -ase and the first part of the name indicates either the substrate or function. So a protease acts on some proteins, in the absence of other indications the enzyme typically breaks the compound down.

Why is the 3-CL protease important? Because the virus doesn't directly make the individual proteins it needs to build a new virus. Rather, it makes a large polyprotein which then must be broken apart to form 11 separate and different proteins, a little like cutting apart a string of sausages, snip, snip, snip. The 3-CL protease does that job. The active form of this drug blocks the protease.

The drug administered is not exactly the active form. It has an extra phosphate group stuck on, which makes it soluble (in water), aiding delivery. The body's normal toolkit of enzymes includes phosphatases (see that naming convention again? - phosphat[e] + -ase) which will pull off the phosphate group.

The 3-CL proteases of SARS-CoV and SARS-CoV-2 are very similar and have identical active sites, the part of the enzyme that recognizes where it must do is work. Remember proteins are chains of amino acids – the active site of the enzyme recognizes locations where a glutamine (amino acid) is followed by one of the smaller amino acids and cleaves (cuts) the polyprotein there. The drug fits into the active site and stays there, gumming it up.

Pfizer administer this drug with another antiviral, ritonavir, which is another protease inhibitor, used in HIV/AIDS treatment, acting on the cytochrome system. Perhaps that is to prevent the liver from breaking down the drug too enthusiastically, but I really don't know.

(I'm sure it hasn't escaped people's notice that antiviral drugs are conventionally named ending -vir.)

Other coronaviruses, especially betacoronaviruses (which SARS-CoV-2 is) have similar proteases so this therapy could be of wider applicability. I guess in theory it could be used against some common cold viruses, but the cost/risk-benefit balance is not clear. (Some common cold viruses are coronaviruses, but not all.)

[Fiascoist]

I enjoyed reading this. But, a question. Am I right in understanding this pill works specifically on the virus, in other words, it has to be in your system. It is not a prophylactic, like the vaccine. So, that means taking this only after exposure or a positive test? I still like the idea of it but would like this fleshed out by people who have more knowledge than me.

[Sam the Centipede]

I enjoyed reading this. But, a question. Am I right in understanding this pill works specifically on the virus, in other words, it has to be in your system. It is not a prophylactic, like the vaccine. So, that means taking this only after exposure or a positive test? I still like the idea of it but would like this fleshed out by people who have more knowledge than me.

Yes, these drugs have no long or medium term prophylactic effect. They are principally aimed at an active ongoing infection.

Let's take it from the top, here's my understanding (but correction is always welcome):

Natural infection: provides long(ish) term protection because your immune system learns how to recognize and respond to the virus. The downside is that this response takes significant time, which can be too long, allowing the virus to wreak damage. The quality of the acquired immune memory is more variable than with vaccines.

Vaccines (all types): provide long(ish) term protection by tricking your immune system into building and remembering immunity targeting the virus, so when infected your body responds rapidly with both antibodies (proteins that cling onto the virus) and killer T-cells to clear the infection.

Antibodies, either as convalescent plasma or as monoclonal antibodies of cocktails of monoclonals, remdesivir, etc.: provide protection against current or impending infection by supplying antibodies when the body is not producing many. They buy time while the body mounts its own response. Only one injection into the bloodstream is needed because the body does not actively clear away these new antibodies, so they persist for (probably) weeks, naturally slowly declining. Because the body did not make these antibodies, it doesn't have the genetic recipe so it cannot simply copy them.

Molnupiravir, Pfizer's protease inhibitor, etc.: these only work against an active infection by preventing the virus from making more virus. They are taken as oral drugs daily or twice daily because the body (the liver) naturally clears them rapidly from the bloodstream, as it does many circulating chemicals. They probably have some side effects such that they should only be taken when infection is known or strongly suspected.

Steroids, etc.: act on the symptoms of Covid-19 or to calm an excessively strong immune response.

Hydroxychloroquine: works against a SARS-CoV-2 infection in some human cell types in a laboratory culture but ineffective in human bodies, probably not very harmful.

Ivermectin: no action against this or other viruses, can be very harmful if self-administered.

Bleach-type products, such as MMS, and other quackery: always harmful.

Vitamins: many people are deficient in vitamin D and keeping levels up is necessary for a good immune system. Other food supplements irrelevant except in a general health way.

Prayer: if you think your god(s) will intervene, fine, but the evidence is lacking.

Homeopathy: see prayer, s/god/placebo/

Edit: Corrected some spelling slips due to finger trouble and misfiring autokorekt.

[bill_g]

Concise and to the point. Thank you.

[Fiascoist]

Thanks.

[humblescribe]

I also think that this therapeutic, like most anti-virals, only works in the early stages of infection. Once the viral infection reaches a certain level, the drug is not very effective, if at all.

Unlike antibiotics that can work any time there is a bacterial infection present.

And apologies for not finding that Merck manufactures Ivermectin. I Goggled and Goggled but could not find it. Suffice to say that my Goggling skills ain't so good.

[Sam the Centipede]

Yes, that seems correct. It acts against actively replicating virus. Pfizer say:

We have designed PF-07321332 as a potential oral therapy that could be prescribed at the first sign of infection, without requiring that patients are hospitalized or in critical care.

The trial includes symptomatic non-hospitalized patients. The regime in the trial is 10 doses offered 5 days together with ritonavir to slow down metabolism (deactivation) of the drug. That fits with the growth phase of the virus in typical infections.

Any person at high risk (e.g. immunocompromised people) is certainly well-advised to test at the first suspicion of infection because these oral antiviral therapies and the antibody therapies will be most effective when administered early.

[Suranis]

And apologies for not finding that Merck manufactures Ivermectin. I Goggled and Goggled but could not find it. Suffice to say that my Goggling skills ain't so good.

In your defense, the company is called different things in different parts of the world.

[northland10]

And apologies for not finding that Merck manufactures Ivermectin. I Goggled and Goggled but could not find it. Suffice to say that my Goggling skills ain't so good.

In your defense, the company is called different things in different parts of the world.

Is Goggled a new thing? Sorry, couldn't let it go. I bet auto-correct was just having great fun with that. Using Safari or Edge? They probably try to limit any version of the word Google just out of spite.

You can Google, you can Bling. You can Yahoo and maybe Lycos. Not sure if you can Alta-Vista anymore. But whatever you do, don't Google your Yahoo. That's reserved for Orly.

[AndyinPA]

And apologies for not finding that Merck manufactures Ivermectin. I Goggled and Goggled but could not find it. Suffice to say that my Goggling skills ain't so good.

In your defense, the company is called different things in different parts of the world.

Is Goggled a new thing? Sorry, couldn't let it go. I bet auto-correct was just having great fun with that. Using Safari or Edge? They probably try to limit any version of the word Google just out of spite.

You can Google, you can Bling. You can Yahoo and maybe Lycos. Not sure if you can Alta-Vista anymore. But whatever you do, don't Google your Yahoo. That's reserved for Orly.

Off Topic

Or you can Duck Duck Go it.

[Tiredretiredlawyer]

I Bingle.

[humblescribe]

And apologies for not finding that Merck manufactures Ivermectin. I Goggled and Goggled but could not find it. Suffice to say that my Goggling skills ain't so good.

In your defense, the company is called different things in different parts of the world.

Is Goggled a new thing? Sorry, couldn't let it go. I bet auto-correct was just having great fun with that. Using Safari or Edge? They probably try to limit any version of the word Google just out of spite.

You can Google, you can Bling. You can Yahoo and maybe Lycos. Not sure if you can Alta-Vista anymore. But whatever you do, don't Google your Yahoo. That's reserved for Orly.

I thought that I was jumping on TFB bandwagon by coining a cutesy word that might find it working its way into the mainstream lexicon on here.

I've seen teh for the; elk for ilk; deninned (or thereabouts) for denied; likely a handful of others that escape my memory. That is why I wrote Goggled instead of Googled. I do not use auto-correct, Safari or Edge. Firefox sans autocorrect.

If I missed your attempt at playful humor, that's on me!

[AndyinPA]

In your defense, the company is called different things in different parts of the world.

Is Goggled a new thing? Sorry, couldn't let it go. I bet auto-correct was just having great fun with that. Using Safari or Edge? They probably try to limit any version of the word Google just out of spite.

You can Google, you can Bling. You can Yahoo and maybe Lycos. Not sure if you can Alta-Vista anymore. But whatever you do, don't Google your Yahoo. That's reserved for Orly.

I thought that I was jumping on TFB bandwagon by coining a cutesy word that might find it working its way into the mainstream lexicon on here.

I've seen teh for the; elk for ilk; deninned (or thereabouts) for denied; likely a handful of others that escape my memory. That is why I wrote Goggled instead of Googled. I do not use auto-correct, Safari or Edge. Firefox sans autocorrect.

If I missed your attempt at playful humor, that's on me!

Actually, I like Goggled. I never use the other; I might use that.

[Foggy]

Change approved. I thought it was an improvement.

I try like heck to avoid creating new ones, like I always want to write "joak" instead of joke, "poast" instead of post (Thanks for that great poast, Rhoda), and maybe a few others. The nightmare of being the admin, if I do it everyone will. I try to use my powers only for good.

But if someone makes up something clever and it catches on, great. No objection. You know how I know for sure?


(I goggled it. Tell me you didn't see that coming.)