Remdesivir - a possible treatment for COVID-19?

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Ygggdrasil
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New paper on the mechanism of action of remdesivir:

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir
Kokic et al. Nat Commun. 12: 279 (2021)
https://www.nature.com/articles/s41467-020-20542-0?s=09 (open access)

Abstract:
Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
 
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  • #52
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A new paper published in Nature suggests that the EIDD-2801 drug (also a ribonucleoside analog like remdesivir) is effective at treating and preventing SARS-CoV-2 infection in experiments using mice:

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801
https://www.nature.com/articles/s41586-021-03312-w

Abstract:
All known recently emerged human coronaviruses probably originated in bats1. Here we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbour endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for coronavirus infection. Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II–III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.
 
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  • #53
Andrew Mason
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A new paper published in Nature suggests that the EIDD-2801 drug (also a ribonucleoside analog like remdesivir) is effective at treating and preventing SARS-CoV-2 infection in experiments using mice:

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801
https://www.nature.com/articles/s41586-021-03312-w
Thanks for bringing attention to this paper.

EIDD-2801 looked like a much better candidate for SARS-CoV-2 than remdesivir as early reports indicated it was 3 to 10 times more effective in vitro in blocking replication of the virus. One other big advantage of EIDD-2801 over remdesivir is that it can be taken orally in a pill whereas remdesivir must be injected.

Ridgbackbio, a small Florida company, has partnered with Merck and they are conducting four trials under the name Molnupiravir/MK-4482:
https://clinicaltrials.gov/ct2/show/NCT04575597
https://clinicaltrials.gov/ct2/show/NCT04575584
https://clinicaltrials.gov/ct2/show/NCT04405739
https://clinicaltrials.gov/ct2/show/NCT04405570

I expect that once effective treatment for COVID-19 is available, things will start getting back to normal. Anti-virals like EIDD-2801 will be important. But we will still need an effective treatment for severe COVID cases (iNKT therapy looks interesting, by the way, as does hrsACE2 and Angiotensin (1-7)).

AM
 
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Update on EIDD-2801/molnupiravir/MK-4482:

Merck and Ridgbackbio just released preliminary results of their Phase 2 trial for their anti-viral drug, molnupiravir. It appears to be more effective than remdesivir (and has the added advantage of being taken orally in a pill). According to Merck:
  • "At day 5, there was a reduction (nominal p=0.001, not controlled for multiplicity) in positive viral culture in subjects who received molnupiravir (all doses) compared to placebo: 0% (0/47) for molnupiravir and 24% (6/25) for placebo."
 
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Here's a good article with more background on EIDD-2801/molnupiravir/MK-4482: https://blogs.sciencemag.org/pipeli...-last-of-the-small-molecule-coronavirus-hopes

Also, here's a recently published paper describing phase 1 clinical trial data on the safety of the drug, which showed that the drug appears to be safe and well tolerated with fewer adverse events observed than in the placebo group:

Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2
https://aac.asm.org/content/early/2021/02/24/AAC.02428-20

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.

Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.

EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.

Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.
 
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  • #57
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Merck released interim results from two phase 2 trials of molnupiravir, one in outpatients and one in hospitalized patients: https://www.merck.com/news/merck-an...r-the-treatment-of-mild-to-moderate-covid-19/

In the outpatient study (n = 302 participants), Merck writes "The percentage of patients who were hospitalized and/or died in Part 1 of the MOVe-OUT study was lower in the combined molnupiravir-treated groups versus the placebo arm; the number of events reported are not sufficient to provide a meaningful measure of clinical effect." In other words, the data showed some signs of benefit, but the data were not statistically significant (i.e. we can't be sure the effects are real). The data give some signs from RT-qPCR testing that it may reduce viral load. Based on these results, the company is proceeding with a larger phase 3 trial.

In the study of hospitalized patients (n = 304 participants), Merck writes "Following an interim analysis of data, it was concluded that the study was unlikely to demonstrate a clinical benefit in hospitalized patients. The decision was made to discontinue the study." This result is consistent with what has been seen with other antiviral drugs like Tamiflu -- antivirals are not very effective when administered late in infection and have the best chance of being effective if administered early.

Here's a good blog post discussing the trial data in more detail: https://blogs.sciencemag.org/pipeline/archives/2021/04/15/merck-keeps-plowing-on

In particular, the blog writes:
What I’m seeing here is an attempt to do everything possible in the Phase III to find patients in which molnupiravir will actually show a useful effect. That’s fine, but we need to realize what that means: the “molnupiravir as game-changer” story is probably now dead. There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.
 
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In particular, the blog writes:....There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.
It does appear that a single mode of attack may not be enough to tackle SARS-CoV-2.

I would be interested to see what a combination of EIDD-2801/molnupiravir and hrsACE2/APN01 would be like. The hrsAC2 would slow the ability of the virus to enter cells while the EIDD-2801 would interfere with viral replication within cells.

But I still think the most effective therapy will be to repair the damage to the RAS system due to loss of ACE2 function. hrsACE2 not only interferes with the virus entering via the ACE2 receptor (thereby taking out the ACE2 receptor function) but it also appears to carry out the ACE2 receptor function despite not being membrane-bound. Another candidate that shows promise is Angiotensin (1-7) and a drug, TXA127, which is an enzyme that converts Angiotensin II to Angiotensin 1-7, which is essentially what the ACE2 receptor does.

AM
 
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Antivirals typically need to be taken early on during the course of an infection in order to be effective (e.g. in the case of the anti-influenza medication, Tamiflu). The hrsACE2 drug is a biologic drug that would likely need to be taken intravenously. The advantage of molnupiravir is that it can be taken orally, which would make it easier to give to patients at the onset of symptoms. If molnupiravir does not turn out to be effective enough on its own, a good strategy would be to combine with other orally available antiviral drugs such as the protease inhibitor drugs currently under development. Indeed, antiviral treatment strategies for HIV and Hepatitis C both involve combining drugs that target the viral polymerase and protease enzymes (of course, HIV and Hep C are both viruses that replicate more slowly than SARS-CoV-2).
 

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