COVID Remdesivir - a possible treatment for COVID-19?

[Ygggdrasil]

Given that it is an anti-viral drug designed to prevent viral replication, I have trouble understanding why it was originally thought that it should be given only to patients in whom the virus had become well-established. I don't think there was evidence that the drug produced results only for those kinds of patients. In fact, evidence published in August showed that remdesivir was not effective on such patients (see post #16 above).

A major consideration for EUAs and drug approval is a risk-benefit analysis. Evidence for benefit can be weaker if treating a high risk population. Treating people with more mild symptoms, many of whom would recover without pharmaceutical intervention, requires a higher standard of evidence for efficacy and safety.

I agree that it is likely better to treat early with remdesivir, but I have not carefully looked at the clinical trial data to judge the EUA.

 

[OCR]

.
As Andrew Mason said, and the way I read it, the EUA has been updated. . .

https://www.gilead.com/-/media/files/pdfs/remdesivir/eua-fda-authorization-letter.pdf?la=en&hash=FD3737583BE0E4DF710ADB36AEAA2DBD

On October 1, 2020, having concluded that revising this EUA is appropriate to protect the public health or safety under Section 564(g)(2) of the Act, FDA is reissuing the August 28, 2020, letter in its entirety with revisions incorporated to the scope and conditions of authorization designating Gilead Sciences, Inc. and its authorized distributors as the responsible parties for the distribution of Velkury.

Carry on. . .

.

 

[Andrew Mason]

I see that https://finance.yahoo.com/m/4beac4a3-0cd2-352a-9f70-9e1cef539232/a-study-testing-lilly%27s.html?siteid=yhoof2&yptr=yahoo They were combining Lilly's antibody treatment (which is similar to Regeneron's antibody treatment) with remdesivir. According to this report:

The pause is notable for two reasons. Lilly's investigational antibody drug is similar to the Regeneron Pharmaceuticals Inc.'s experimental antibody treatment that was prescribed to President Donald Trump. It is also the third major clinical trial in this pandemic to be paused for safety reasons, which experts say is a common occurrence but likely one being scrutinized given the lack of treatment or prevention options against the coronavirus.

This may be a reference to a recent case in which combined antibody/remdesivir treatment was given, after which the patient experienced delusions of absolute immunity as well as exacerbation of pre-existing delusions of grandeur and invincibility.

AM

 

[Ygggdrasil]

A new large randomized controlled trial from the WHO finds no evidence that remdesivir decreases COVID-19 mortality:

One of the world’s biggest trials of COVID-19 therapies released its long-awaited interim results yesterday—and they’re a letdown. None of the four treatments in the Solidarity trial, which enrolled more than 11,000 patients in 400 hospitals around the globe, increased survival—not even the much-touted antiviral drug remdesivir. Scientists at the World Health Organization (WHO) released the data as a preprint on medRxiv last night, ahead of its planned publication in The New England Journal of Medicine.

https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatments

On remdesivir specifically, the Science news piece says:

Remdesivir, which attacks a specific enzyme in several RNA viruses and was previously tested against Ebola, was initially seen as a promising candidate. 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. Two smaller trials found few significant benefits. Remdesivir received an emergency use authorization from the U.S. Food and Drug Administration (FDA) in May for severe COVID-19 patients that was later expanded to include all patients.

But the Solidarity trial suggests the drug does little in severe cases. Of 2743 hospitalized patients who received the drug, 11% died, versus 11.2% in a control group of roughly the same size. The difference is so small it could have arisen by chance.

When the authors pooled Solidarity’s data with those from the three other trials, they found a slight reduction in mortality that wasn’t statistically significant either. "This absolutely excludes the suggestion that remdesivir can prevent a substantial fraction of all deaths,“ the authors write. "The confidence interval is comfortably compatible with prevention of a small fraction of all deaths but is also comfortably compatible with prevention of no deaths.”

Here's the non-peer-reviewed pre-print posted on medRxiv:

Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1

Abstract:

BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs.

METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry.

RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration.

CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials.

 

[Andrew Mason]

A new large randomized controlled trial from the WHO finds no evidence that remdesivir decreases COVID-19 mortality:

If remdesivir is effective in blocking viral RNA transcription and, therefore, viral replication, what these trials suggest is that once the virus has infected enough cells (through the ACE2 entry mechanism), the serious potentially fatal COVID pneumonia that develops cannot be stopped by just attacking the virus.

But it may also be that remdesivir by itself - just blocking RNA transcription - is not enough to stop the virus since it will not block 100% of the time. Since the SARS-CoV-2 virus replicates very quickly inside infected cells, remdesivir will just slow down replication. This article suggests that to also stop the virus one also has to block the proof-reading function that the virus employs after RNA transcription.

AM

 

[Ygggdrasil]

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.

 

[Astronuc]

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), . . .

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.

When I had the flu, I received Tamiflu between 18 to 24 hours after symptoms developed. It was Sunday night when I awoke with a fever measuring about 102-103°F and a mild cough. Earlier I had started coughing but thought it might be an allergy. I saw a doctor on Monday morning, but didn't get Tamiflu until the afternoon, which was the soonest the pharmacy could do whatever they did to get it. I still had a fever and the cough had become stronger. The fever started to break Monday night and was much less on Tuesday morning. The cough persisted though through Thursday. I was quarantined until Friday, and only went to work for half a day, wore a mask and socially distanced.

Where we were in May - Potential Treatments for SARS‐CoV‐2 Infection
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.969
Lots of choices, and lots of unknowns.

 

[Andrew Mason]

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.

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

 

[Tom.G]

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

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]

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.

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.

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.

AM

 

[Ygggdrasil]

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.

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

Also, viral RNA replication occurs in the cytoplasm.

 

[Andrew Mason]

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

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.

Also, viral RNA replication occurs in the cytoplasm.

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:

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

 

[Andrew Mason]

I see that remdesivir has just been given approval by the FDA for persons over 12 years of age and 40 kg. in weight who are hospitalized. This appears to be based mainly on one trial that appears to show that remdesivir reduces recovery times by about a third. Pediatric use will continue to be under a modified Emergency Use Authorization.

AM

 

[Andrew Mason]

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:

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.

AM

 

[Ygggdrasil]

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.

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 compatments as well.

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:

How would a drug target such a complex? Are there any other drugs that act in a similar way?

 

[Andrew Mason]

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.

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.

As I understand it, the portal that allows RNA molecules to exit the viral endosome is not an open door. It is opened, presumably, to let RNA transcripts out but remains closed to molecules in the cytoplasm entering.

How would a drug target such a complex? Are there any other drugs that act in a similar way?

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.

AM

 

[Filip Larsen]

From an article on Arstechnica, I understand that WHO last week issued the results of a large study finding no benefit from Remdesivir treatment.

https://arstechnica.com/science/202...vid-19-but-global-study-finds-it-doesnt-work/

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.

 

[Andrew Mason]

The final report on remdesivir is now published (Nov. 5/20): The conclusion is as previously reported:

"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. "

AM

 

[Ygggdrasil]

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.

Work 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.who.int/news-room/featu...st-the-use-of-remdesivir-in-covid-19-patients

Popular press coverage:

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.

https://www.statnews.com/2020/11/19/who-recommends-against-remdesivir-covid-19/

 

[Andrew Mason]

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/

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.

My sense is that an anti-viral drug is only going to be effective if administered very early after infection begins or before infection occurs.

On a side-note, remdesivir combined with another anti-viral drug that operates differently, might be more effective.

The authors of this recent paper report that combining EIDD-2801 (similar to remdesivir but a bit more effective against SARS-CoV-2) and another anti-viral nelfinavir produced improved results in cell-culture:

"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

 

[Ygggdrasil]

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.

 

[Ygggdrasil]

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.

 

[Andrew Mason]

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

 

[Andrew Mason]

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."

 

[Astronuc]

From Merck - https://www.merck.com/news/ridgebac...tigational-covid-19-therapeutic-molnupiravir/

Wikipedia - https://en.wikipedia.org/wiki/Molnupiravir

 

[Ygggdrasil]

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.

 

[Ygggdrasil]

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.

 

[Andrew Mason]

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

 

[Ygggdrasil]

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).

 

[Andrew Mason]

It appears that Merck is getting serious about molnupiravir (EIDD-2801). It just announced an agreement with the U.S. Government for molnupiravir as an anti-viral for treatment of Covid-19.

AM