Remdesivir - a possible treatment for COVID-19?

[Andrew Mason]

For anyone following Remdesivir as a treatment for COVID 19:

• this New England Journal of Medicine report on Gilead's remdesivir and this NIH/NCBI article explain how it works. The NIH paper has a nice chart showing how different drugs might interfere with viral replication.
• The recent phase 3 trial results reported by Gilead are reported here.

Remdesivir is "intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases". I am not sure whether this disables the RNA polymerase from functioning or whether it causes RNA polymerase to produce defective viral mRNA transcript (eg. by inserting a few of these modified adenosine molecules instead of normal adenosine during transcription). In any event, this prevents replication of the virus by inhibiting RNA polymerase function.

This is not my area, but seems to me that to be really effective, such a drug has to be able to selectively enter cells i.e. enter only cells infected by a virus. Otherwise, the drug would enter healthy cells and interfere with normal RNA transcription and damage or kill them. If Remdesivir could be modified to somehow identify cells infected by SARS-CoV-2 and enter only those cells, there could be huge potential for this drug. I would appreciate hearing from others who have a background in molecular biology.

AM

 

[Ygggdrasil]

SARS-CoV-2, the virus that causes COVID-19, has an RNA genome. Therefore, to copy its RNA genome in order to make new copies of the virus, the virus requires an RNA-dependent RNA polymerase (RdRP)—that is, an enzyme that makes RNA by reading off of an RNA template. The RdRP enzyme is encoded by the viral genome, so remdesivir targets a protein present only in virally-infected cells, not an enzyme present in all human cells.

Furthermore, the viral RdRP enzyme is very different from the DNA-dependent RNA polymerases that are present inside normal human cells and involved in transcription (copying the genetic information from DNA to mRNA so that information could be translated into protein by the ribosome). AFAIK, there are no functional RNA-dependent RNA polymerases encoded in the human genome.

 

[Andrew Mason]

SARS-CoV-2, the virus that causes COVID-19, has an RNA genome. Therefore, to copy its RNA genome in order to make new copies of the virus, the virus requires an RNA-dependent RNA polymerase (RdRP)—that is, an enzyme that makes RNA by reading off of an RNA template. The RdRP enzyme is encoded by the viral genome, so remdesivir targets a protein present only in virally-infected cells, not an enzyme present in all human cells.

Furthermore, the viral RdRP enzyme is very different from the DNA-dependent RNA polymerases that are present inside normal human cells and involved in transcription (copying the genetic information from DNA to mRNA so that information could be translated into protein by the ribosome). AFAIK, there are no functional RNA-dependent RNA polymerases encoded in the human genome.

Thanks for your very helpful explanation.

So does that mean that the intracellular adenosine analogue that Remdesivir delivers is taken up only by the viral RNA dependent polymerase (RdRP) and not the host cell's RNA polymerase nor in its RNA transcripts? If so, how would that occur?

AM

 

[Ygggdrasil]

So does that mean that the intracellular adenosine analogue that Remdesivir delivers is taken up only by the viral RNA dependent polymerase (RdRP) and not the host cell's RNA polymerase nor in its RNA transcripts? If so, how would that occur?

Even though the SARS-CoV-2 RdRP and cellular RNA polymerases perform similar chemical reactions, the structures of the active sites are slightly different, and chemists can exploit these differences to design drugs that can bind to the RdRP but not to cellular RNA polymerases. This ability to discriminate between similar types of active sites enables a number of important drugs, such as the nucleoside analogs used as reverse transcriptase inhibitors in anti-HIV therapy (which can bind to the active site of HIV reverse transcriptase, but not similar cellular DNA polymerases) or kinase inhibitor drugs like Gleevec used in anti-cancer therapy (which can selectively bind to the active sites of specific cellular protein kinases without binding to all of the various protein kinases in the body).

Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499

 

[Andrew Mason]

Even though the SARS-CoV-2 RdRP and cellular RNA polymerases perform similar chemical reactions, the structures of the active sites are slightly different, and chemists can exploit these differences to design drugs that can bind to the RdRP but not to cellular RNA polymerases. This ability to discriminate between similar types of active sites enables a number of important drugs, such as the nucleoside analogs used as reverse transcriptase inhibitors in anti-HIV therapy (which can bind to the active site of HIV reverse transcriptase, but not similar cellular DNA polymerases) or kinase inhibitor drugs like Gleevec used in anti-cancer therapy (which can selectively bind to the active sites of specific cellular protein kinases without binding to all of the various protein kinases in the body).

Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499

Thanks so much for your very clear response and link. The article appears to have been published today so it is about as up-to-date as possible.

It appears that the Remdesivir ATP molecule (RTP) with its modified adenosine attaches to the RNA primer strand at the first base pair which terminates further RNA transcription. So that answers my initial question.

Since Remdesivir was designed as a general anti-viral and seemed to work well on SARS-CoV which has a slightly different shaped RNA polymerase than SARS-CoV-2, a bit of tweaking of the drug shape/binding sites might be all that is needed for a really effective treatment of COVID-19.

I will take some time to go through the article over the weekend. This approach to drug "engineering" is really fascinating stuff.

AM

 

[Ygggdrasil]

Thanks so much for your very clear response and link. The article appears to have been published today so it is about as up-to-date as possible.

For such a rapidly moving field as COVID-19 research, the actual published scientific literature is actually a bit out of date. For example, the Science paper that was just published today was first released as a (non-peer reviewed) pre-print on April 9. So, even for research that is quite timely, the published scientific literature can be months behind (more typically, the peer review process takes 0.5-1+ years, inserting further delays between when a research finding is first made and when it is formally published).

Since Remdesivir was designed as a general anti-viral and seemed to work well on SARS-CoV which has a slightly different shaped RNA polymerase than SARS-CoV-2, a bit of tweaking of the drug shape/binding sites might be all that is needed for a really effective treatment of COVID-19.

Yes, it is likely that remdesivir could be modified to have better activity against SARS-CoV-2 (IIRC, remdesivir was originally designed against the Ebola virus). However, it would likely take quite a long time to optimize the drug and for the drug to go through clinical trials before it could be approved for widespread use in patients. Such a drug would likely not be able to help with the current outbreak but would help if vaccination cannot fully eradicate the disease or if we encounter a new zoonotic Coronavirus in the future (with three new coronaviruses emerging in the past 20 years, we are almost certain to see other new coronaviruses in the future).

 

[Andrew Mason]

Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499

That paper examines the structure of the RdRp molecule and the way that Remdesivir interferes with the RdRp function in replicating the viral RNA genome. The authors mention another similar drug EIDD-2801 that shows even greater effectiveness in blocking viral RNA replication in SARS-CoV-2:

"In particular, EIDD-2801 has been shown to be 3 to 10 times as potent as remdesivir in blocking SARS-CoV-2 replication (36). The N4 hydroxyl group off the cytidine ring forms an extra hydrogen bond with the side chain of K545, and the cytidine base also forms an extra hydrogen bond with the guanine base from the template strand. These two extra hydrogen bonds may explain the apparent higher potency of EIDD-2801 in inhibiting SARS-CoV-2 replication."

EIDD-2801 is just entering Phase 2 trials

AM

 

[Andrew Mason]

One possible problem with the remdesivir approach is that it functions only after the virus has infected the cell. Since lung epithelial cells express multiple ACE2 receptors a cell can be attacked by several viruses and unless the drug is 100% effective in stopping replication the virus may still proliferate and cause a lot of damage.

However... used in conjunction with another imperfect drug that reduces the virus' ability to get into cells, might provide an effective therapy for COVID.

AM

 

[Andrew Mason]

It looks like the Trump administration thinks remdesivir may be a cure for COVID-19. They have just bought up the entire world supply for the next 3 months. That's 500,000 doses. Europe is a tad upset. Someone should tell the EU to approach Merck and Ridgebackbio to purchase supplies of EIDD-2801, which Ridgeback says it has been producing. Remdesivir is injected whereas EIDD-2801 is taken as a pill so EIDD-2801 is easier to deploy and, apparently, easier to manufacture. The owners of Ridgebackbio say they will have 1 million doses available by fall.

AM

 

[Ygggdrasil]

One possible problem with the remdesivir approach is that it functions only after the virus has infected the cell. Since lung epithelial cells express multiple ACE2 receptors a cell can be attacked by several viruses and unless the drug is 100% effective in stopping replication the virus may still proliferate and cause a lot of damage.

However... used in conjunction with another imperfect drug that reduces the virus' ability to get into cells, might provide an effective therapy for COVID.

AM

At least for some viruses, nucleoside analogues can function to prophylacticaly prevent infections. For example, Truvada, a mixture of the nucleotide analogue tenofovir and the nucleoside emtricitabine, is FDA approved as a pre-exposure prophylaxis (PrEP) medicine to prevent HIV infection.

Of course, retroviruses are different than coronaviruses, so the situation could be very different. However, there is data from monkeys that prophylactic administration of remdesivir can prevent disease from the MERS Coronavirus (https://www.pnas.org/content/117/12/6771):

Abstract:
The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS Coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel Coronavirus 2019-nCoV.

 

[Andrew Mason]

At least for some viruses, nucleoside analogues can function to prophylacticaly prevent infections. For example, Truvada, a mixture of the nucleotide analogue tenofovir and the nucleoside emtricitabine, is FDA approved as a pre-exposure prophylaxis (PrEP) medicine to prevent HIV infection.

Of course, retroviruses are different than coronaviruses, so the situation could be very different. However, there is data from monkeys that prophylactic administration of remdesivir can prevent disease from the MERS Coronavirus (https://www.pnas.org/content/117/12/6771):

Thanks for the link.

It seems, though, that the prophylactic effect is not due to remdesivir preventing the virus getting into the cell but is the result of getting a headstart on the virus by getting the remdesivir nucleotide analogue RTP into the cells so that when the virus enters the cells the RTP is already there and able to insert itself into the viral RNA polymerase, stopping viral replication from the outset of infection. If remdesivir has no serious side effects it may be able to function as a prophylactic but at $2,000+ per dose and the fact that it has to be taken intravenously may make that somewhat impractical.

The HIV drug cocktail approach is to attack the HIV virus at several stages in its replication cycle, including impeding its ability to enter cells. Although, as you say, the HIV is a retrovirus that does not use an RNA transcriptase, the use of a multi-stage approach to attacking the virus has been very effective in controlling HIV and preventing AIDS. It seems to be a reasonable way of approaching SARS-CoV-2, which has at least 4 stages where small molecule drug intervention could be effective:

This article, just published yesterday, seems to suggest that approach might work with SARS-CoV-2. Some of these drugs that seem to work to stop SARS-CoV-2 replication are already approved for HIV and other viruses, so it may be relatively quick to get FDA approval. I wonder if anyone has looked at COVID-19 stats for people taking anti-HIV medication...

AM

 

[Ygggdrasil]

Thanks for the link.

It seems, though, that the prophylactic effect is not due to remdesivir preventing the virus getting into the cell but is the result of getting a headstart on the virus by getting the remdesivir nucleotide analogue RTP into the cells so that when the virus enters the cells the RTP is already there and able to insert itself into the viral RNA polymerase, stopping viral replication from the outset of infection. If remdesivir has no serious side effects it may be able to function as a prophylactic but at $2,000+ per dose and the fact that it has to be taken intravenously may make that somewhat impractical.

Agreed. An IV drug is not very practical as a prophylactic.

The HIV drug cocktail approach is to attack the HIV virus at several stages in its replication cycle, including impeding its ability to enter cells.

In general, HIV drug cocktails are designed to target multiple stages of the HIV replication cycle (such as those that combine reverse transcriptase inhibitors with protease inhibitors). However, the prophylactic drug Truvada combines two different reverse transcriptase inhibitors, so it is only targeting one step of the HIV life cycle (which occurs after viral entry).

This article, just published yesterday, seems to suggest that approach might work with SARS-CoV-2. Some of these drugs that seem to work to stop SARS-CoV-2 replication are already approved for HIV and other viruses, so it may be relatively quick to get FDA approval. I wonder if anyone has looked at COVID-19 stats for people taking anti-HIV medication...

Note that the figure you posted is based on the assumed mechanism of action of drugs under investigation to treat COVID-19. Of the drugs listed, only one (remdesivir) has strong evidence of efficacy. Others, in particular hydroxychloroquine and the protease inhibitors (lopinavir and danoprevir), have had various studies conclude that they are not effective at treating COVID-19. Indeed, the CDC recommends against the use of hydroxychloroquine as well as lopinavir and other HIV protease inhibitors for COVID-19: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/

 

[Andrew Mason]

Note that the figure you posted is based on the assumed mechanism of action of drugs under investigation to treat COVID-19. Of the drugs listed, only one (remdesivir) has strong evidence of efficacy. Others, in particular hydroxychloroquine and the protease inhibitors (lopinavir and danoprevir), have had various studies conclude that they are not effective at treating COVID-19. Indeed, the CDC recommends against the use of hydroxychloroquine as well as lopinavir and other HIV protease inhibitors for COVID-19: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/

All good points.

My purpose in posting the diagram was to just show the points at which drug intervention could occur, not to suggest the drugs to be used. APN001, which delivers an extra-cellular recombinant human ACE2 receptor, might assist in step 1, for example, in reducing the rate of entry of the virus into cells. When combined with some of the viral RNA polymerase inhibitors (remdesivir, EIDD-2801 or the five drugs listed in the Science Daily article published June 30) the combination might be much more effective than any individual drug.

AM

 

[Andrew Mason]

Someone should tell the EU to approach Merck and Ridgebackbio to purchase supplies of EIDD-2801, which Ridgeback says it has been producing. Remdesivir is injected whereas EIDD-2801 is taken as a pill so EIDD-2801 is easier to deploy and, apparently, easier to manufacture. The owners of Ridgebackbio say they will have 1 million doses available by fall.

It looks like Merck/Ridgebackbio is taking on Gilead's remdesivir with EIDD-2801. My bet is that EIDD-2801 will become the preferred treatment for two reasons:

1. it appears to be 3 to 10 times as potent as remdesivir in blocking SARS-CoV-2 See: second last paragraph of this paper.
2. EIDD-2801 is taken orally while remdesivir is injected.

[Note: It appears that EIDD-2801 has just been renamed MK-4482. See also this Wikipedia article]

 

[Andrew Mason]

SARS-CoV-2, the virus that causes COVID-19, has an RNA genome. Therefore, to copy its RNA genome in order to make new copies of the virus, the virus requires an RNA-dependent RNA polymerase (RdRP)—that is, an enzyme that makes RNA by reading off of an RNA template. The RdRP enzyme is encoded by the viral genome, so remdesivir targets a protein present only in virally-infected cells, not an enzyme present in all human cells.

This recently published paper by a group from Pakistan shows the results of computer modeling of the RdRP in SARS-CoV-2 and SARS-CoV (the latter being over 96% the same as the RdRP in SARS-CoV-2). The paper is based entirely on "in silico" (i.e. computer) analyses of binding energies of various drug candidates at various locations on the SARS-CoV RdRP molecule. Based on their computer analyses, the authors predict that Galidesivir and two novel proteins would be good candidates as anti-polymerase drugs for SARS-CoV-2:

"Our study indicates that the novel predicted drug-like compounds CID123624208 and CID11687749 have a strong affinity with the residues of the RdRp catalytic domain (Figs. 6, 7). Strong S-score, binding energy, and RMSD values suggest that these compounds could be used as potential inhibitors against the RdRp of SARS-CoV-2. Numerous other viral inhibitors have also been reported which are in clinical trials including Remdesivir, Sofosbuvir Galidesivir etc., for which we have already tested with virtual screening [67]. However, some of them are stated in Table 2 with their S-score and RMSD values. Thus, in summary, Galidesivir and the two drugs-like compounds CID123624208 and CID11687749 screened in the present study could more likely have potential as therapeutic drugs targeting SARS-CoV-2. "

AM

 

[Andrew Mason]

It appears that Remdesivir by itself is not going to be the magic cure for infected COVID-19 patients: Remdesivir disappoints in COVID-19 study (Aug. 21)

I don't find it at all surprising that Remdesivir is not effective at a later stage of infection. Remdesivir prevents viral replication. But if the patient is at a late stage of infection, most of the ACE2 expressing cells in the lungs have been infected and there are none left to carry out the important function of breaking down the Angiotensin II (AngII) enzyme. At that point, the virus is no longer the cause of lung damage. It is the unregulated levels of AngII that does that.

I would be interested to see if Remdesivir (or the possibly more effective oral therapy EIDD-2801/MK-4482) is effective in stopping infection at an early stage or preventing it in high risk populations (such as health care workers).

AM

 

[atyy]

I would be interested to see if Remdesivir (or the possibly more effective oral therapy EIDD-2801/MK-4482) is effective in stopping infection at an early stage or preventing it in high risk populations (such as health care workers).

Is it too expensive to give it out widely at an early stage? Are there early markers of those who are in whom the disease is likely to be severe, so that they can be given Remdesivir early?

 

[Ygggdrasil]

It appears that Remdesivir by itself is not going to be the magic cure for infected COVID-19 patients: Remdesivir disappoints in COVID-19 study (Aug. 21)

I don't find it at all surprising that Remdesivir is not effective at a later stage of infection. Remdesivir prevents viral replication.

This is in line with our experience with other antivirals like Tamiflu. Tamiflu is effective at preventing infection and in shortening the duration of symptoms, but it only helps reduce the duration of symptoms if taken in the first 36 to 48 hours of illness.

But if the patient is at a late stage of infection, most of the ACE2 expressing cells in the lungs have been infected and there are none left to carry out the important function of breaking down the Angiotensin II (AngII) enzyme. At that point, the virus is no longer the cause of lung damage. It is the unregulated levels of AngII that does that.

I'm not sure we have enough evidence to say that it is unregulated levels of AngII that are directly causing the damage. There is a lot of going on inside the lungs during the later stages of infection and it could be that AngII upregulation is a symptom of the disease and not a cause. There are a variety of hypotheses surrounding the main causes of mortality from COVID-19 ranging from "cytokine storms" to blood clotting, and it's still an open question (and the question may not have one single answer for every patient). Dexamethosone seems to reduce mortality in severe COVID-19 cases, which seems to point to some contribution from inflammation and overactivation of the immune system (consistent with the cytokine storm hypothesis), though anti-IL-6 treatments have not shown clinical effectiveness, arguing against a role for it in the disease. There is some evidence suggesting that AngII-receptor blockers have a weak protective effect in COVID-19 patients (though others that observe no effect), but I would want to see more clinical data on the efficacy of AngII-receptor blockers before I believe the AngII hypothesis.

 

[jim mcnamara]

See Medcram (on Youtube) for a model: start with lecture 67.
Per the above after several lectures that assemble a more complete model:
Pathogenesis does indeed start with ANG II, but it is a lot more complex, involving the formation of Von WilleBrand Body strands that precipitate microarterial clotting. These clots are found extensively at autopsy, in the lungs, and elsewhere, unfortunately. They are apparently peculiar to Covid 19 patients and not found in Infuenza victims. The cytokine cascade is initiated by the alveolar macrophages response to damage tissues.

There are three major types of alveolar cell. Two types are pneumocytes or pneumonocytes known as type I and type II cells found in the alveolar wall, and a large phagocytic cell known as an alveolar macrophage that moves about in the lumens of the alveoli, and in the connective tissue between them.

 

[Andrew Mason]

Is it too expensive to give it out widely at an early stage? Are there early markers of those who are in whom the disease is likely to be severe, so that they can be given Remdesivir early?

At $2,340 per patient on government health programs and $3,120 per patient on private insurance it is not cheap but if it was effective in preventing the disease in high risk patients, the savings in treatment costs would make it worthwhile. One problem is that it has to be administered intravenously, which makes it more difficult to manage if the patient is not in a hospital.

AM

 

[Tom.G]

What tiny air bubbles are teaching doctors about how COVID-19 damages the lungs

A study done at Mount Sinai Health in New York City indicating capillary damage in lungs.
https://www.latimes.com/science/sto...cientists-to-new-coronavirus-clue-lung-damage

 

[Andrew Mason]

I'm not sure we have enough evidence to say that it is unregulated levels of AngII that are directly causing the damage. There is a lot of going on inside the lungs during the later stages of infection and it could be that AngII upregulation is a symptom of the disease and not a cause.
...
There is some evidence suggesting that AngII-receptor blockers have a weak protective effect in COVID-19 patients (though others that observe no effect), but I would want to see more clinical data on the efficacy of AngII-receptor blockers before I believe the AngII hypothesis.

But blocking Ang II would not be enough to replace the ACE2 function. ACE2 does more than simply reduce the amount of Ang II: it cuts the Ang II peptide to create Ang-(1-7) which is an important enzyme in the Renin-Angiotensin System. As this paper states:

Furthermore, the ACE2-Ang–(1-7)-MasR pathway is anti-inflammatory. Thus, ACE2 not only breaks down Ang II but also produces a vasodilator anti-inflammatory molecule, Ang–(1-7) (26).

AM

 

[Andrew Mason]

See Medcram (on Youtube) for a model: start with lecture 67.
Per the above after several lectures that assemble a more complete model:
Pathogenesis does indeed start with ANG II, but it is a lot more complex, involving the formation of Von WilleBrand Body strands that precipitate microarterial clotting. These clots are found extensively at autopsy, in the lungs, and elsewhere, unfortunately. They are apparently peculiar to Covid 19 patients and not found in Infuenza victims. The cytokine cascade is initiated by the alveolar macrophages response to damage tissues.

There are three major types of alveolar cell. Two types are pneumocytes or pneumonocytes known as type I and type II cells found in the alveolar wall, and a large phagocytic cell known as an alveolar macrophage that moves about in the lumens of the alveoli, and in the connective tissue between them.

Thank-you for posting this video which explains the relationship between ACE, ACE2, Ang II and endothelial cell dysfunction leading to blood clots in the lungs, which is strongly associated with COVID-19 lung damage and mortality. It can be found here:


It seems that there is a strong association between Von Willebrand Factors (VWF) in the blood and endothelial cell dsyfunction leading to blood clots in the lungs. There may be an association between COVID mortality and blood types based on the different VWF levels associated with different blood types.

AM

 

[Andrew Mason]

I highly recommend the whole series of videos on Youtube that Jim McNamara suggested done by pulmonologist Dr. Roger Seheult. He explains how the loss of ACE2 function in epithelial cells of the lung and other tissue caused by SARS-CoV-2 can upset the Renin-Angiotensin System leading to catastrophic tissue damage.

SARS-CoV-2 is able to enter and damage or destroy only cells that express the ACE2 receptor on its surface. But the damage that it leaves in its wake goes well beyond those cells. The loss of ACE2 receptor function causes a serious imbalance in the Renin-Angiotensin System that results in an increase in blood factors that cause clots in the Aveoli of the lungs, leading to catastrophic loss of lung function. There does seem to be a lot of evidence that this is what is happening.

Should the virus itself be the principal target or should be we looking more at mitigating the effect of the loss of the ACE2 function?

Medcram 67. (mentioned previously) - Why blood clots form in the lung aveoli due to loss of ACE2 receptor function.
Medcram 69. How supplementation of N-Acetylcysteine can moderate the damage.
Medcram 70. How low glutathione levels contribute to tissue damage.

AM

 

[Andrew Mason]

This recent article suggests that rather than a "cytokine storm", COVID-19 is the result of a "bradykinin storm" initiated by the loss of the ACE2 receptor due to SARS-CoV-2.

It appears that the conclusion was reached on the basis of a super-computer analysis of samples (presumably from COVID infected patients). Here is the original paper.

I am not sure what to make of the paper. The authors say:

"The analyses found that SARS-CoV-2 caused the levels of ACE in the lung cells to decrease, while the levels of ACE2 increased."

This would make sense to me if they had said "Ang-(1-7)" instead of ACE and "Ang II" instead of ACE2.

AM

 

[Ygggdrasil]

This recent article suggests that rather than a "cytokine storm", COVID-19 is the result of a "bradykinin storm" initiated by the loss of the ACE2 receptor due to SARS-CoV-2.

It appears that the conclusion was reached on the basis of a super-computer analysis of samples (presumably from COVID infected patients). Here is the original paper.

I am not sure what to make of the paper.

For my thoughts on the paper see: https://www.physicsforums.com/threads/supercomputer-analysis-of-covid-virus.993135/post-6387959

 

[Andrew Mason]

There has been much discussion in this thread about the mechanism by which SARS-CoV-2 causes respiratory disease. Since the virus enters cells via the ACE2 receptor it destroys ACE2 function. ACE2 performs a key role in regulating the level of the Angiotensin II (Ang II) enzyme.

A recent report from the University of Cincinnati published last week refers to their study of data collected in Ohio which indicates that COVID patients did not have elevated levels of Ang II. However, what they did find were very low levels of Ang-(1,7).

As mentioned on this thread, Ang-(1-7) is produced by the ACE2 receptor cleaving the Ang II enzyme. Thus ACE2 has two important functions: reducing Ang II and producing Ang-(1,7). As reported:

“This is among the first substantial evidence supporting the hypothesis of a potential inhibition of ACE2 activity due to virus binding,” Henry stated. “As angiotensin (1-7) is anti-inflammatory peptide that also dilates the vessels, low levels of this peptide due to [the coronavirus] may promote ARDS. As such, supplementation with synthetic angiotensin (1-7) may be a potential therapeutic target for treating COVID-19.”

AM

 

[Andrew Mason]

I see that Donald Trump began receiving Remdesivir shortly after being admitted to hospital, about a day after testing positive for SARS-CoV-2. This makes sense because its function is to stop viral replication and reduce viral load in the body to prevent COVID from developing. I am not sure why it was thought that Remdesivir should be given to infected patients who had already developed full blown COVID.

AM

 

[jim mcnamara]

The CDC's EUA (Emergency Use Authorization) on Remdesivir stipulates it use, which, IIRC, is for Covid-19 patients who are put on supplemental oxygen at first signs of hypoxia. Only. Not Covid-19 seropositive, and not intubated patients. This is because clinical studies show statistically significant results only for those on oxygen.

@Andrew Mason , so you are correct.

 

[Andrew Mason]

The CDC's EUA (Emergency Use Authorization) on Remdesivir stipulates it use, which, IIRC, is for Covid-19 patients who are put on supplemental oxygen at first signs of hypoxia. Only. Not Covid-19 seropositive, and not intubated patients. This is because clinical studies show statistically significant results only for those on oxygen.

The original EUA issued by the FDA on May 1, 2020 limited emergency use of remdesivir to patients with severe COVID but the revised EUA issued August 28, 2020 broadened that use:

On August 28, 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 reissued the May 1, 2020, letter in its entirety with revisions incorporated to expand the authorized use of Veklury [Gilead's trade name for remdesivir] by no longer limiting its use to the treatment of patients with severe disease.

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).

AM

 

[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