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How remdesivir works, and why it's not the ultimate coronavirus killer (scopeblog.stanford.edu)
160 points by chmaynard 11 days ago | hide | past | web | 100 comments | favorite





There's a nice diagram from Science that shows how Remdesivir and other potential anti-coronavirus drugs work: https://science.sciencemag.org/content/sci/368/6493/829/F1.l...

The picture is from https://science.sciencemag.org/content/368/6493/829 published "22 May 2020" at the time when less was known about Chloroquine and hydroxychloroquine than today about treating Covid-19 (1). That's the needed perspective when watching the picture, where the rest is still relevant.

-----

1)

E.g. June 23, 2020 "NIH: Trial Investigating Hydroxychloroquine for COVID-19 Stopped"

https://www.empr.com/home/news/hydroxychloroquine-trial-halt...

17 June 2020 "“Solidarity” clinical trial"

https://www.who.int/emergencies/diseases/novel-coronavirus-2...

"hydroxychloroquine does not result in the reduction of mortality of hospitalised COVID-19 patients, when compared with standard of care."

And before, Jun. 9, 2020: "Three big studies dim hopes that hydroxychloroquine can treat or prevent COVID-19":

https://www.sciencemag.org/news/2020/06/three-big-studies-di...


Is any of these studies using Zinc? We know that a lot of people have both Vitamin D and Zinc deficiency. How HCQ works is to transport the Zinc into the cell so that Zinc can stop the RNA replication. (I’m a layman here, but it’s what I’ve managed to understand after deliberate research)

Thus, HCQ without Zinc is like using a bucket but forgetting the water to stop the fire. Just throwing buckets at the fire isn’t gonna work much when there’s no water in the bucket.

Have a look at this [1] studies that shows around a 9% less mortality when treated with Zinc and a even more when treated EARLY with HCQ PLUS Zinc. (Please take a look at the numbers in the last table, it’s very clear that HCQ + Zinc reduces mortality)

[1]: https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v...


I think there are 2 hypothesis for HCQ. One is that it blocks autophagosome-lysosome fusion. The second is that it is a Zinc ionophore, which enables Zinc to enter cells to stop viral replication. It seems that almost all the studies are not using Zinc. Here is a retrospective observational study showing effectiveness of HCQ+Zinc. It is a mystery to me why this second path doesn’t get more attention. Quercetin is also a Zinc ionophore. So Quercetin+Zinc should also be studied.

https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v...


From the very paper linked by the parent and the parent-parent:

"This was an observational retrospective analysis that could be impacted by confounding variables"; "We also do not have data on the time at which the patients included in the study initiated therapy with hydroxychloroquine, azithromycin, and zinc." "The cohorts were identified based on medications ordered rather than confirmed administration, which may bias findings towards favoring equipoise between the two groups." "In light of these limitations, this study should not be used to guide clinical practice."


So, good reason to have a more clinical trial for testing HCQ + ZINC + Azitromycin vs HCQ alone (vs NO Medicine). But that's something I'm not seeing at the moment, which is a shame.

230 studies looking at Hydroxychloroquine [1]

Only 10 studies looking into HCQ and Zinc [2]

[1]:https://clinicaltrials.gov/ct2/results?cond=Covid-19&term=hy...

[2]:https://clinicaltrials.gov/ct2/results?cond=Covid-19&term=hy...


This recent research from China suggest another possibility..that it acts as an ACE2 blocker.

https://www.biorxiv.org/content/10.1101/2020.06.22.164665v1....


The problem is that this crank doctor from France used exactly this treatment (Zinc+HCQ) in a crappy study and proclaimed it as hugely successful.

This was then picked up by a crowd of "right wing deplorables" up to and including the orange man in the white house.

The scientific establishment can not allow this bunch of clowns to turn out right, thus further inquiry is being suppressed.

Call it a conspiracy theory, but that's exactly how human egos have played a role in the history of science.


And Hesperidin+Zinc


From that link:

"AAPS files with the court a chart showing how countries that encourage HCQ use, such as South Korea, India, Turkey, Russia, and Israel, have been far more successful in combatting COVID-19 than countries that have banned or discouraged early HCQ use, as the FDA has."

However: that chart is totally misleading, it's a typical "non sequitur". "Case fatality rate" is just a ratio "death" through "cases". Where those with weaker symptoms are recognized as "cases" the rate is lower. How they are recognized is not the same across different countries.


Agreed. Excess mortality is the real measure.

Note, you seem to be posting studies that did not pair HCQ with zinc, _and_ are not using it prophylactically. Is my understanding correct?

For example: https://www.sciencemag.org/news/2020/06/three-big-studies-di... links to https://www.recoverytrial.net/files/hcq-recovery-statement-0... which does not mention zinc, and it's patients admitted to the hospital (not prophylactic). Digging further, to the source given in that pdf, not a mention of zinc: https://www.recoverytrial.net/@@search?SearchableText=zinc which is the whole point of using HCQ in the first place.


> you seem to be posting studies that did not pair HCQ with zinc

I'm just posting studies that were the basis for what FDA decided June 15, 2020 (1):

"FDA has revoked the emergency use authorization (EUA) to use hydroxychloroquine and chloroquine to treat COVID-19 in certain hospitalized patients when a clinical trial is unavailable or participation is not feasible. We made this determination based on recent results from a large, randomized clinical trial in hospitalized patients that found these medicines showed no benefit for decreasing the likelihood of death or speeding recovery."

And I don't have more information than that.

1) https://www.fda.gov/drugs/drug-safety-and-availability/fda-c...


Note that while AAPS presents as a proper organisation, its previous greatest hits include HIV denialism, vaccine/autism conspiracy theory pushing and “smoking is fine actually” stuff. It’s not a proper medical organisation. If it said water was wet, I would be checking.

Thanks. It also has just 5000 members!

From Wikipedia:

"The Association of American Physicians and Surgeons (AAPS) is a conservative non-profit association founded in 1943. The group was reported to have about 5,000 members in 2014. The association has promoted a range of scientifically discredited hypotheses, including the belief that HIV does not cause AIDS, that being gay reduces life expectancy, that there is a link between abortion and breast cancer, and that there is a causal relationship between vaccines and autism. It is opposed to the Affordable Care Act and other forms of universal health insurance."

https://en.wikipedia.org/wiki/Association_of_American_Physic...


Where does dexamethasone fit in? Does it target part of the viral lifecycle or simply treat the effects?

The first week or two, your immune system ramps up to fight the infection. During this battle, the collateral damage is what gives you symptoms like joint pain, runny nose, sore throat, etc. Near the 3rd week of infection, 85% of patients are recovering and feeling better because their immune response has naturally turned itself off. For some reason, this doesn't happen in about 15% of patients. We call this a 'cytokine storm'. This is where your immune system has gone nuclear and is still destroying anything and everything it sees, including normal healthy tissue. This can ultimately lead to multi-organ failure and death if it can't be stopped. Dexamethasone tamps down that immune response, allowing your body to heal. Obviously it has to be timed right. It doesn't do anything to the virus, only your immune response.

To connects the dots, pathological cytokine release syndrome is highly likely to be causing the (extremely rare) instances of stroke in non-elderly COVID-19 patients, organ damage, etc.

I get incredibly annoyed when people act like (a) these strokes / organ damage are happening in significant quantities and (b) that it’s unique to SARS-2


I thought the clotting caused by SARS-CoV-2 was thought to be the cause of strokes. ...as well as other thrombosis late stage patients are getting.

...at least that's what the clinical updated from the NYC doctors group is reporting on TWIV podcast each week.


> extremely rare

Is it? From all lab confirmed cases in USA until end of May, almost every 200th in age group 20-29 was admitted to ICU. Almost every 100th in age group 30-39. (1)

Admitted to ICU means "probably considered intubation (or received it immediately)" Which is very, very unpleasant thing:

https://en.wikipedia.org/wiki/Tracheal_intubation

Is that "extremely rare" to you?

(In the USA there are 7.2% inhabitants aged 20-29, 6.7% aged 30-39. Even if the number of "unconfirmed but infected" is 10 times higher, that still gives around 24000 people in the USA aged 20-39 needing ICU, or 8 times more than died on 9/11. And those are just provably "non-elderly". All those 40 and older would need even much more ICU beds. I hope it's obvious that if there are not enough ICU beds much more people would die.)

1) It can be calculated from https://www.cdc.gov/mmwr/volumes/69/wr/mm6924e2.htm For 20-29 182469 confirmed, 864 ICU, for 30-39 214849 confirmed, 1879 ICU. (Additionally, males were admitted to ICU almost twice as much as females)


The comment said "(extremely rare) instances of stroke", not ICU admissions.

Are you saying cytokine storms are the only mechanism causing thrombosis in COVID-19? I was under the impression that SARS-2 itself also had the ability to cause clots. Is that incorrect?

https://www.nature.com/articles/d41586-020-01824-5

"The [steroid] drugs suppress the immune system, which could provide some relief for patients whose lungs are ravaged by an overactive immune response that sometimes manifests in severe cases of COVID-19. But such patients may still need a fully functioning immune system to fend off the virus itself."

"no effect on mild infections"

Basically if taken too early it does the wrong action, but it helps some of those already on oxygen. And it's cheap.


It's like what a friends brother (cardiac surgeon) said about clot busting drugs. That knife is sharp on both sides.

The biggest problem with remdesivir is that it is administered intravenously. That makes it very hard to administer unless the patient is in the hospital. What would be ideal is if they had it in pill form, and then anyone with early symptoms could get pills instead. But without that option right now it makes it too late to administer unless the patient is already in severe condition.

They are planning on testing an inhalant version but who knows where that will land in terms of effectiveness. It might make things worse so that is much further out unless things are really lucky, which we haven’t had a lot of with coronavirus.


Take a look at EIDD-2801, it's essentially a pill form of remdesivir.

https://www.thepharmaletter.com/article/ridgeback-bio-triall...


Home infusion medicine is a fairly big, and growing, option in the States. A drug being IV is definitely inconvenient, but there are some options.

Curious, how does that work?

Your physician prescribes an IV medication, and refers you to either a hospital, clinic, or a home infusion provider depending on a variety of circumstances. If you end up with a home IV provider, they process your prescription, ship the drug to your house in a refrigerated container, and schedule a nurse to come out and infuse you. The nurse brings and leaves any supplies you might need.

My nephew receives Remicade infusions to treat Crohn's Disease. He typically receives the treatment at a local, children's hospital; however, due to Covid-19, my sister elected to have an in-home infusion performed. Appears to be a fairly efficient process.

Interestingly, their insurance company has been trying to push them into performing his infusions at home for a couple years, as it is more cost effective. My sister has to fight them on it every couple of months to continue having them performed at the hospital.


Is there a particular reason she insists on having it done at the hospital? Higher standard of care or just being there should anything go awry?

Genuinely curious.


Interesting. Curious to know any FDA approvals for the process or the infusion of this drug? I am curious how the act of processing the prescription and refrigeration can be done safely without compromising the drug itself

Honestly that's starting to get past the parts of that industry I'm really familiar with. I'd have to Google it same as you.

Here's the FAQ page for one of the biggest USA home IV companies. It's a good starting point if you're curious.

https://www.coramhc.com/patients/faqs


Storage and handling is approved when the drug is approved.

Basically you tell the FDA how to store and handle and the FDA says “ok, give me the data that proves the drug is stable under those conditions”.

Beyond that the FDA doesn’t really care who administers it.


Imagine if all high school students got trained on how to start an IV.

Every heroin junkie gives themselves IV injections. It's not hard.

You're right but an injection is not an infusion.

An infusion is something that takes a longer time as the drug is taken slowly into the bloodstream (might be something that takes a couple of hours).


To get their shot. Also, they screw up their veins (see Requiem for a Dream).

I myself have fear of needles, so I'm biased in this sense. I would not use this drug, except with a Oxazepam. Which I prefer not to, as these too are addictive.


> What would be ideal is if they had it in pill form, and then anyone with early symptoms could get pills instead.

This doesn't seem wise; the side effects of remdesivir seem worse than the typical course of a cold/flu.


I am wondering, Wikipedia claims that the active metabolite of this drug is a medicine for cats sold on black market; what is the price? I am sure it is way less than the ridiculous price they want for Remdesivir.

The price they're asking is pretty reasonable. A couple thousand bucks for a few percent increased chance of survival is well below the benchmark set by drugs in less public disease areas. If this was a cancer drug they'd be charging an order of magnitude more.

Edit:

ICER, which is a drug price watchdog, suggested using a value added analysis that the max price remdesivir could justify was 4500[1]. ICER is not pharma's friend, and they dont usually end up suggesting a max price twice what the pharma company charges[2].

[1]https://icer-review.org/announcements/alternative_pricing_mo...

[2]https://www.fiercepharma.com/pharma/parp-drugs-from-az-clovi...


It's not just a good deal for survival, either, it's worth an accounting profit to the hospitals:

> On average, the drug should help reduce hospital costs by $12,000 a patient, said [Chief Executive Daniel O’Day]. Gilead estimated the savings based on data showing that each day of hospitalization costs $3,000 and that patients taking remdesivir are discharged four days sooner than those receiving standard treatment, Mr. O’Day said.

https://www.wsj.com/articles/covid-19-drug-remdesivir-to-cos...


You are do not live in developing world, like I do. Hosptal costs to treat a single patient here is below $3000. So Remdesevir here is completely unaffordable.

Drug companies don't charge american prices outside of this country - they barely charge sticker price within this country. Whatever country you live in in the developing world, the price that Gilead sets for you will undoubtedly be used by politicians here in the US to attack Gilead for overcharging here, asking how it is that they charge thousands of dollars in the US while they only charge a few bucks or even zero dollars through royalty free licensing in [insert country here].

Well if you're in the developing world, you will benefit from Gilead's use of price discrimination.

> The company said it has entered into agreements with generic manufacturers to provide the drug at a “substantially lower cost” in developing countries.

https://www.cnbc.com/2020/06/29/gileads-coronavirus-treatmen...


Trump has bought all the remdesivir produced in the next three months.

https://www.theguardian.com/us-news/2020/jun/30/us-buys-up-w...


> A couple thousand bucks for a few percent increased chance of survival is well below the benchmark set by drugs in less public disease areas.

That indeed is the sad state of affairs. Plus, a significant amount of these more obscure drugs may simply be the result of (intentional or unintentional) P-hacking.


Apparently as much as $12,000 for a 12-week course.

https://www.theatlantic.com/science/archive/2020/05/remdesiv...

Gilead is charging less than that for Remdesivir.

https://www.cbsnews.com/news/gilead-coronavirus-treatment-re...


They used to be quite a bit cheaper, around 600$ for an 8 week course.

The price increase is concerning.


I was wrong then. So cat owners should start buying remdesivir then.

> So cat owners should start buying remdesivir then

Yes! For many reasons.

https://www.cdc.gov/media/releases/2020/s0422-covid-19-cats-...


Wow No wonder Latin American countries are using cheap Ivermectin which also has been a success to fight covid19.

And no wonder it's not being researched that much in capitalist countries. It will never be as profitable as these other drugs.


They are trying ivermectin because at this stage of the pandemic you can only do drug repurposing, to get anything new from bench into clinic takes five years. Everyone would love to see 3CL protease inhibitors, but they aren't near ready.

A quick search turns up over two dozen clinical trials with ivermectin, not all of them taking place in threshold countries. Israel, Spain, Mexico, Singapore are all highly developed countries.


Black market cat drugs? Do you have a death wish or something?

People using fish antibiotics on themselves is a thing:

https://www.thebugoutbagguide.com/fish-antibiotics-for-human...


A chemical is a chemical. And people close to dying can be desperate.

> a chemical is a chemical

Is it actually the chemical though? 'Blackmarket pet drug' is the perfect storm of poor accountability. Who the fuck knows what it actually is?


People have looked into drugs for erectile dysfunction that you buy over the Internet. They actually are when they claim to be on the tin and work as advertised. Well, if you rely on repeat customers and word of mouth that's the expected outcome. You'd expect the same for wealthy people with very sick cats.

Sometimes the repeat customers and word of mouth reliance doesn't work out: https://en.wikipedia.org/wiki/2008_Chinese_milk_scandal

I mean, if there's an MSDS, verified structural information, etc, then anyone can know what it is.

Sometimes you have no choice, I guess.

Nucleoside analogs are notorious for breeding resistance, which is why they should ideally be used in combo with other drugs.

IIRC, Gilead has tried to pull this drug off the shelf as a cure multiple times, for different diseases, only to have it proven to not be very efficacious.

As soon as they announced it as a COVID treatment, I assumed it was another cash grab while people are confused, desperate, and scared.


That seems like a pretty cynical take. My understanding is that Gilead has been donating the drug and provided a royalty free license to other pharma companies to manufacture it (not that they could).

They just announced something like a 7K per treatment price schedule for the drug, and it was largely developed at tax payer expense through a DoD scheme, so I’ll stick to my skepticism. The WHO also accidentally released some study data showing that drug showed no improvement in COVID outcomes:

https://www.statnews.com/2020/04/23/data-on-gileads-remdesiv...


I agree that any price is too high if it simply doesn't work. I don't find the public funding critique particularly compelling because it is exactly what the public signed up for. The we fund private medical research and development because we want the more products brought to market by those firms. The reward is that the product exists at all.

I do think that there is a compelling argument for the the government trying to do more drug development and then licensing or open-sourcing the product.


>The reward is that the product exists at all.

Why do VCs get any return from startups? Isn't the reward that the startup exists at all?

Better yet, why does Gilead get to write a press release explaining the reason they're asking $3k per person for the drug is so they can "invest in scientific innovation that might help generations to come"? Isn't the reward the money they initially got from the government?

I am getting pretty sick and tired of public money getting used – and rightly so – to fund innovate medical research, and then any and all benefits or profits from the results of that resesarch being privatized.


VCs get returns because they negotiate them upfront. I have never heard of a VC that donates money and then tries to go back and negotiate terms with the companies that IPO.

If you are tired of giving away public money, negotiate terms.


The financial justification for antivirals is terrible, given alternatives. Hence why we have so few.

So whether the DoD or whatever government branch catalyzed progress doesn't matter much to me.




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