I would agree, and looking at the earliest trials, most if not all were severe cases require oxygen or ventilation. Remdesivir may be more effective at the onset of symptoms, and perhaps one still needs something like Regeneron's monoclonal antibody cocktail.Ygggdrasil said:Another potential interpretation of the data is that remdesivir is not effective if administered late in the course of the infection (e.g. at the point at which patients need to be hospitalized), . . .
Yes, but why would remdesivir be effective only if administered early? Why does Tamiflu work that way? I can see two reasonable interpretations of such a result but there may be others.Ygggdrasil said:Another potential interpretation of the data is that remdesivir is not effective if administered late in the course of the infection (e.g. at the point at which patients need to be hospitalized), which is consistent with our experience with other antivirals like Tamiflu. For example, Tamiflu is effective at decreasing the duration and severity of illness for the influenza virus, but only if taken within 36-48 hours of the onset of symptoms.
https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatmentsAndrew Mason said:Yes, but why would remdesivir be effective only if administered early? Why does Tamiflu work that way? I can see two reasonable interpretations of such a result but there may be others.
AM
If I understand it correctly, remdesivir interferes with RNA replication by interfering the the function of the RNA polymerase (RdRP) in transcribing viral RNA. See the drawing in post #11 above, for example. It does this by delivering a nucleoside analogue that is similar to adenosine which is then taken up by the RdRP molecule and inserted into the RNA transcript instead of normal adenosine. This, apparently, terminates further replication so the proteins essential for viral replication cannot be made with the defective RNA transcripts.Tom.G said:https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatments
In a U.S. trial with more than 1000 COVID-19 patients published last week, those who received remdesivir had a shorter recovery time than patients in the control group, but there was no significant difference in mortality.
Cheers,
Tom
p.s. It may have been in another article; around the same time the above appeared I stumbled across the speculation that remdesivir can inhibit the free virus but when the virus gets into a cell all bets are off. That could explain the early usefulness.
Andrew Mason said:Since RNA replication occurs in the nucleus of the host cell, one would need to ensure that a good supply of the therapeutic nucleoside analogue in remdesivir is present in the nucleus of the host cell. If that can be accomplished by having enough of the remdesivir nucleoside taken up by the virus prior to cell entry, that might work, perhaps even better. I am not qualified to say whether viral uptake of remdesivir prior to cell entry occurs or is even possible and I was unable to find anything on this.
According to the Wikipedia article and this paper, much of the time remdesivir is converted outside the cell, removing the pro-drug part and leaving the active nucleotide part GS-441524 in the extracellular plasma rather than inside the cell. According to the authors, that may explain why remdesivir is not as effective as originally hoped.Ygggdrasil said:Like most nucleoside analogs, remdesivir is a pro-drug that is administered in an inactive form that is able to enter cells by crossing the plasma membrane. Once inside the cell, cellular enzymes will convert the drug into its active form, where it can incorporated into viral RNA by the virus's RdRp. See the diagram here for more information: https://en.wikipedia.org/wiki/Remdesivir#Pharmacology
Thanks for that. I found this paper which explains that RNA viruses that replicate in the cytoplasm appear to make their own little organelles in the cytoplasm in which to carry out RNA replication:Ygggdrasil said:Also, viral RNA replication occurs in the cytoplasm.
Cytoplasmic Viral Replication Complexes said:Whereas eukaryotic cells sequester and organize their genome replication and transcription in the nucleus, many RNA and some DNA viruses carry out viral genome replication and transcription in the cytoplasm. To establish efficient genome replication and shield it from host defenses, including crucial intrinsic and innate defenses, many or most of these cytoplasmically replicating viruses organize their genome replication and transcription in organelle-like compartments (Novoa et al., 2005). These replication compartments or factories often are associated with the sites of subsequent stages in the viral replication cycle, including particle formation and virus budding.
AM
Wolff et al Science 11Sept20 said:The double-membrane–spanning molecular pore revealed here may constitute the exit pathway for coronaviral RNA products from the DMV’s interior toward the cytosol, with the large and multifunctional nsp3 being its central component. Although the exact mode of function of this molecular pore remains to be elucidated, it seems to be a key structure in the viral replication cycle that is likely conserved among coronaviruses and thus may offer a coronavirus-specific drug target.
Andrew Mason said:Further to the second part of my post 42 above, the dynamics of Coronavirus replication seems to be an area that is getting some attention. The Coronavirus creates a double membrane replication organelle in the cell cytoplasm to a create a sealed replication compartment where the RNA transcription takes place. This recent paper provides a graphical explanation of the complex processes that take place.
It appears, therefore, that unless remdesivir's active nucleotide is present in these organelles, it will not be able to affect viral RNA transcription. So a big question would seem to me to be: "how does remdesivir get transported into these double membrane organelles?". I suspect that unless the active part of remdesivir is already present in the cytosol of the host cell when the cell gets infected by the SARS-CoV-2 virus, it will not likely be present inside these organelles and will, therefore, be ineffective in blocking RNA transcription. If that is the situation, then administering remdesivir to prevent infection or at a very early stage of infection might be the better course.
The paper (also available https://spmlaw.ca/PF/Coronavirus_replication_1395.full-1.pdf) focuses on the exit pathway from these replication organelles (to allow the viral RNA transcripts to exit to permit protein synthesis in the host cell ) and a particular double membrane-spanning pore that the authors discovered. They suggest that this pore could be a key structure for viral replication and may be a good drug target:
In order to carry out RNA transcription, there must be an abundant supply of A, C, G, and U nucleotides available inside the double-membrane compartment. I was thinking, however, that these would be present and acquired when the membranes are formed in the cytoplasm.Ygggdrasil said:Remdesivir is a pretty small molecule and if pores are visible by electron microscopy and allow RNA molecules to pass through, I suspect nucleotides like remdesivir's activated form would be able to freely diffuse into the compartments as well.
If one could determine the molecular structure of the molecules that make up the portal, could a drug developer fashion a protein complex that could attach to the portal and block it? One could then determine corresponding mRNA template(s) and manufacture the blocking molecule as a drug.How would a drug target such a complex? Are there any other drugs that act in a similar way?
According to preliminary results from the Solidarity trial—reported online last week ahead of its planned publication in the New England Journal of Medicine—remdesivir was given to 2,743 patients, and their outcomes were compared with those of 2,708 patients given standard treatments. Between the two groups, WHO found that remdesivir did not reduce mortality. It also did not change how many patients progressed to needing mechanical ventilation, nor did it change the proportion of patients discharged after seven days of hospitalization.
Final Report on Remdesivir - New England Journal of Medicine 5Nov20 said:"Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. "
https://www.who.int/news-room/featu...st-the-use-of-remdesivir-in-covid-19-patientsWork on this began on 15 October when the WHO Solidarity Trial published its interim results. Data reviewed by the panel included results from this trial, as well as 3 other randomized controlled trials. In all, data from over 7000 patients across the 4 trials were considered.
The evidence suggested no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes.
https://www.statnews.com/2020/11/19/who-recommends-against-remdesivir-covid-19/In a https://www.bmj.com/content/371/bmj.m3379 issued Thursday night, the WHO’s Guideline Development Group said that it now has a “weak or conditional recommendation against” using remdesivir in hospitalized patients because of clinical trial data that showed the drug did not increase survival. The group’s review also found the drug had no meaningful effect on whether patients would need to be put on ventilators.
The group cautioned that its recommendations were based on “currently available data” and that the certainty of the evidence was low.
[...]
the WHO’s group noted that because of the cost of remdesivir, the resources needed to deliver it intravenously, and the potential harm to patients, it should be not given until there was better evidence for it.
This should not really be surprising given the very weak evidence that remdesivir provided any benefit if given to patients late, after the patient had already become highly infected. At that point, the ACE2 damage has been done by the virus and further tissue damage appears to be due to the body's uncontrolled (by ACE2) immune response.Ygggdrasil said:The WHO issues a conditional recommendation against the use of remdesivir in hospitalized COVID-19 patients, citing lack of evidence of improved survival or other outcomes.https://www.who.int/news-room/featu...st-the-use-of-remdesivir-in-covid-19-patients
Popular press coverage:
https://www.statnews.com/2020/11/19/who-recommends-against-remdesivir-covid-19/
Ivaneski Yao et al said:"Here, we report that combinations of nelfinavir with investigational drug EIDD-2801 and convalescent serum were synergistic against SARS -CoV-2 infection in human lung epithelial Calu-3 cells. "
AM
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.
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.
Thanks for bringing attention to this paper.Ygggdrasil said: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
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.
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.
It does appear that a single mode of attack may not be enough to tackle SARS-CoV-2.Ygggdrasil said: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.
They don't explain much about how their "quantum inspired device" works. But it should be pointed out that there was also this in silico analysis by researchers in India reported in October of last year that also suggested vitamin B12 might be a good anti-viral candidate.pinball1970 said:
Bertolin Weissmann et al said:Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase
The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologues in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified three novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.
AMGilead press release 22Sep21 said:In an analysis of 562 participants randomly assigned in a 1:1 ratio to receive Veklury or placebo, Veklury demonstrated a statistically significant 87% reduction in risk for the composite primary endpoint of COVID-19 related hospitalization or all-cause death by Day 28 (0.7% [2/279]) compared with placebo (5.3% [15/283]) p=0.008.
Reuters 29Sep21 said:Laboratory studies show that Merck & Co's (MRK.N) experimental oral COVID-19 antiviral drug, molnupiravir, is likely to be effective against known variants of the coronavirus, including the dominant, highly transmissible Delta, the company said on Wednesday.
Merck said:"Merck said earlier this year that a small, mid-stage trial found that after five days of molnupiravir treatment, none of the patients taking various doses of the drug tested positive for infectious virus, while 24% of placebo patients did have detectable levels.
Merck is currently conducting two Phase III trials of the antiviral it is developing with Ridgeback Biotherapeutics - one for treatment of COVID-19 and another as a preventive."
https://www.statnews.com/2021/10/01...tients-a-possible-game-changer-for-treatment/An investigational antiviral pill reduced the chances that patients newly diagnosed with Covid-19 would be hospitalized by about 50%, a finding that could give doctors a desperately needed new way to treat the sick, the drug maker Merck announced Friday.
A five-day course of molnupiravir, developed by Merck and Ridgeback Biotherapeutics, reduced both hospitalization and death compared to a placebo. In the placebo group, 53 patients, or 14.1%, were hospitalized or died. For those who received the drug, 28, or 7.3%, were hospitalized or died.
https://www.statnews.com/2021/11/30...rck-covid-pill-after-day-of-tense-discussion/On Tuesday, throughout the hearing of the advisory committee, panelists asked pointed questions of both Merck and the FDA, whose scientists had seemed to back the approval of the medicine in briefing documents released Friday. Among them was how to interpret the change in the results around the drug’s effectiveness. The early results released Oct. 1 showed a 50% reduction in hospitalization, or an absolute decrease of 7%. In the final results, the result shrank to a 30% decrease, or a 3% absolute difference in hospitalization in the full population.
Lindsey Baden of the Brigham and Women’s Hospital, the panel chair, asked early on how this could be. “Help me understand,” he said.
Nicholas Kartsonis, a Merck researcher, explained that the interim analysis was the primary analysis, but also said, at length, that Merck’s scientists had not been able to come up with clear reasons for the result. “I don’t have a satisfying answer to your question but at least that’s the totality of the data we have.”
re: Cost: Molnupiravir is about $700 per dose which compares favourably to remdesivir which costs $2300.Ygggdrasil said:@Ygggdrasil Maybe I have gotten something wrong here but it seems to me that Molnupiravir is expensive and in the end not better than already existing cheap drugs like Fluvoxamine which as we now see have shown their usefulness despite being originally dismissed in a somewhat arrogant way by many.
https://www.nature.com/articles/d41586-021-02988-4
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext