Remdesivir and chloroquine effectively inhibit coronavirus (2019-nCoV) in vitro | Hacker News Reader

Remdesivir and chloroquine effectively inhibit coronavirus (2019-nCoV) in vitro

nature.com

91 pointsguybedo68 comments

Not just in vitro - Italian media reported today that the two Chinese tourists who fell ill in Rome have been successfully treated with Remdesivir (freely provided by Gilead). Source (Italian): https://www.corriere.it/cronache/20_febbraio_26/coronavirus-...

While that's good news - it isn't statistically significant.

You need to do a double-blind test to confirm results.

This is an example of real-world evidence (https://en.wikipedia.org/wiki/Real_world_evidence), gathered outside the context of any kind of drug trial, blinded or not.

While these two outcomes may not achieve statistical significance in the mathematical sense...

- there are compelling mechanistic hypotheses for why the treatments might work

- drug doses are being supplied for free by manufacturers

- infected people don't have the luxury of time to wait for RCT results

Most importantly, a placebo controlled RCT would be unethical for a disease with high mortality rates.

You would run a randomized controlled trial with treatment control (not placebo controlled) when we have an effective treatment. These are about as good as it is assumed placebo effects figure the same in all tested treatment groups.

A double blind study is currently done in China, results should be there in a couple weeks.

A new trial is being run in Nebraska too.

Well that seems unreasonable? Double-blind just gives better comparability of results with lower N. Statistics wouldn't object to, say, giving all Italian patients the treatment and most Chinese patients not. You'd just end up with a more complex model and wider uncertainty, but if the medicine worked on a noticeable scale, you'd pick it up eventually.

This is practically ancient news at this point. RCTs are already underway in China and now starting up in the US. The question that hasn't been well answered anywhere is, assuming it does prove to work, can we make enough of this stuff in the space of time to really make a difference? What would that look like? Would we need to stop producing other drugs to switch over production lines? Etc. What that would look like would be interesting to read about.

Industrial chloroquine manufacturing was developed in the 1940s. There is an extensive description in this 1949 article from Industrial and Engineering Chemistry:

"Chloroquine Manufacture"

https://sci-hub.tw/10.1021/ie50472a002

I mention chloroquine specifically because

a) It looks like it was effective at a lower concentration than remdesivir, according to this Nature article.

b) It's a simpler molecule. High volume production started back during World War II.

Apparently Bayer was able to manufacture and ship an order of 300,000 chloroquine phosphate pills in 24 hours. I don't know exactly what that means, but it's definitely good.

https://www.shine.cn/biz/economy/2002202403/ https://tribune.com.pk/story/2162276/1-pakistan-effective-dr...

I'd imagine they can. I read just yesterday there were something like 8 Chinese companies now making knockoff remdesivir, patents be damned.

I certainly hope patents be damned at a time like this. Maybe once everything is settled they can get a pay out. But if they can conscript human bodies to die in trenches they can borrow fictional gifts to fictional people

That would certainly incentivize pharma to develop the next antiviral, wouldn’t it?

If there's no humans left, they'd have 100% of the market.

They're still going to get paid a hell of a lot of money if this drug works. It's not just going to be taken from them without any kind of compensation at all from the US Government and others.

That's getting close to false dichotomy: rely on patents or get no research. Maybe a different financial model is required these days. Not everything needs to reach late stage capitalism.

Chloroquine is extremely common and can be bought in big bottles at your local grocery store.

Actually it can't. Doses over 3g (12 pills) tend to be fatal so a big bottle at the grocery store would be a bad idea.

I bought some. My experience - Bali - no one had any. Singapore - rare, need a persceiption. UK can get from online pharmacists by saying you are going to a malarial area. (£13 for 20 tabs) which is what I did. India it's about 1 or 2p/tab but they are not officially allowed to ship overseas. I got quoted $90 to ship 600 tabs overseas.

Not in the US. Nobody makes it here. Over $250 per 12 tablets at Kaiser. HCQ (hydroxychloroquine) is still used for autoimmune disease and is a lot cheaper.

Definitely. The State Department has a set of pages noting that mosquitoes with malaria have developed chloroquine resistance in every country with malaria, and recommends other drugs instead. The main manufacturer of chloroquine, Bayer, stopped producing it a while back. Not sure who if anyone even makes it these days. I'm assuming the Chinese trials are using some old stock.

They restarted old lines. These are not terribly hard to make. There was just no demand.

Do you know they (the Chinese presumably, if not who) restarted old lines, or are you guessing that you think they did?

It would be great if chloroquinine is back in production.

Cranking away: https://www.shine.cn/biz/economy/2002202403/

>Multinational and local drugmakers are speeding up manufacturing and supply of chloroquine phosphate after the anti-malarial drug was included in the latest version of treatment guidelines for novel coronavirus pneumonia by the National Health Commission.

>China Resources Group now has inventory of more than 325,000 boxes and is preparing for further demand

It was reported in the news. Also Bayer donated a bunch to China from their stock in Pakistan. It's possible that HCQ, which is widely available, has similar effectiveness.

Thanks, that enabled me to find the 1/28 donation news:

https://www.marketscreener.com/BAYER-AG-436063/news/Bayer-to...

It mentions "antibiotics and analgesics" but not quinine, but I'll accept you've seen a more detailed report.

I was unable to find a report saying that Chloroquine lines have started back up.

By HCQ do you mean Quinine Hydrochloride as is found in Tonic Water? Do you have any links to studies showing it has "similar effectiveness" as Chloroquine in treatment? I'm taking Quinine Hydrochloride at present since it's harmless and available, but have not seen any studies about it specifically regarding the new virus.

HCQ is hydroxychloroquine, an antimalarial that is still widely available because it is used for autoimmune diseases. It is a prescription only drug. The antiviral property is described in this Lancet article: https://www.thelancet.com/journals/laninf/article/PIIS1473-3...

Thanks!

It is made and used in some countries. Belize for example has non resistant malaria.

Not original poster, but thinking this was a joke about Tonic water that contains Quinine, a close relative of Chloroquine.

Wikipedia says chloroquine is 'a quinine' - is the only joke that the amount in tonic water isn't enough to have the desired effect?

That is (historically) why it's there (and called 'tonic') after all, for malaria, which is also mentioned as a use on the chloroquine page.

Apparently there is a study just starting related to coronavirus and hydroxychloroquine.

See: https://clinicaltrials.gov/ct2/show/NCT04261517

You're right about it being much cheaper. A bit over a decade ago, I was looking into a 2-year supply of antimalarial medication for an extended stay in a place where malaria is a big problem, and where I would not have ready access to refill such medication. That amount of chloroquine would have cost me many thousands of dollars.

A doctor recommended hydroxychloroquine instead and after I demonstrated my intent to be abroad for such an extended period (had to show documents) a compounding pharmacist filled the prescription for around USD $20.

What country are you in? It's a semi-controlled substance that tends to be out of stock everywhere I've looked.

Yup, it's about $15 for 30 pills in my country (brand name, not generic), which isn't cheap, but pretty affordable.

> can we make enough of this stuff in the space of time to really make a difference?

Many drugs are made in China too - terrible irony

Just a reminder that other antivirals like remdesivir that Gilead manufactures retail for $2k for a 30-day supply in the US, despite costing roughly $40 in other first world countries, and multiple US insurance companies needed to be sued before they would cover them. To put this in perspective, transmission of HIV could be virtually eliminated in the US if some of those antiviral drugs were made available to at-risk populations.

Should there be a pandemic-level outbreak in the US, I just hope cost and IP laws aren't the bottlenecks when it comes to preventing the spread of, and recovery from, this disease.

> To put this in perspective, transmission of HIV could be virtually eliminated in the US if some of those antiviral drugs were made available to at-risk populations.

No, the biggest issue with preventing HIV transmission is stigma of the disease

Besides, Gilead, much like every other large pharmaceutical company, has patient access programs to ensure that anyone who needs their medications can get them: https://www.gilead.com/purpose/medication-access/us-patient-...

> Besides, Gilead, much like every other large pharmaceutical company, has patient access programs to ensure that anyone who needs their medications can get them

Not if they're on Medicaid or Medicare[1], which some providers through those programs only very recently began to cover the medications due to lawsuits against them.

Also, the co-pay coupon card only covers up to $7,200 in co-pays per year[1].

There is also the income gap where someone could make too much money to qualify for their program, despite having no insurance, bad insurance or catastrophic insurance plans. A contractor responsible for their own health insurance might find themselves in that income gap.

And this program is at the discretion of Gilead, who can deny, change or discontinue it at any moment.

[1] https://www.truvada.com/how-to-get-truvada-for-prep/truvada-...

The existence of "patient access programs" are symptoms of the problem, not cures for the problem.

Remdesivir isn't approved anywhere for use, it's still treated as an experimental drug. Are you referring to Kaletra (lopinavir/ritonavir) that is also effective against COVID-19?

Remdesivir is the drug that is mentioned in the OP, but I am specifically talking about emtricitabine/tenofovir and tenofovir alafenamide, the only two drugs in the US approved for prevention of HIV tranmission, both of which are manufactured by Gilead and cost $2k for a 30-day supply.

The only reason these drugs exist is because companies like Gilesd developed them in the first place. You can’t pay $40 for a drug that doesn’t exist.

What we should be pushing for is a change in circumstances that get those in other countries to pay their fair share so Americans don’t bear the entire burden of incentivizing bringing drugs to market.

Preserving incentives matters.

The US is only 4.29% of the global population. Massively over paying for medication in the US has limited impact on research budgets as much of that is eaten up by advertising etc.

According to this chart[0], world healthcare spending was $7.7 trillion in 2016, of which $3 trillion (39%) was spent by the USA. The USA really does do most of world healthcare spending, disproportionate to its population.

[0] https://www.emergobyul.com/resources/worldwide-health-expend...

Revenue on it’s own is meaningless in this context. All those US drug advertisements are paid for with US heathcare spending along with endless paperwork, insurance profits etc.

(I object to you calling revenue meaningless when you brought up country population.)

World medicine spending[0]: $1.2 trillion

US prescription drug spending[1][2]: $348 billion (29% of world spending)

US drug advertising[3]: $30 billion (1% of US drug spending)

Health insurance net earnings[4]: $23 billion (0.8% of US drug spending)

[0] https://www.statista.com/statistics/280572/medicine-spending...

[1] Median estimate from https://www.healthaffairs.org/do/10.1377/hblog20180726.67059...

[2] Another source puts the US proportion of pharmaceutical revenue at 33%: https://www.statista.com/statistics/784420/share-of-worldwid...

[3] https://www.seattletimes.com/business/us-medical-marketing-r...

[4] https://naic.org/documents/topic_insurance_industry_snapshot...

~$30 billion / 348 Billion is not (1% of US drug spending) Of note prescription drugs are not the only medical advertising, but they do represent a rather large share.

Population creates limits for the amount of useful medication that can be provided, inefficiency is practically unbound. It’s not that on it’s own say Heath insurance overhead and profit is that expensive it’s simply yet another implementation detail unrelated to actually providing heathcare.

If the price of a drug then is 50x in the US (as in this case), and the US buys it at the same rate as the rest of the world, then sales to the US would account for ~70% of the revenue. To attain the same revenue with a constant global price, would require an increase of just over 3x of that lower non-US price point. The original characterization ("What we should be pushing for is a change in circumstances that get those in other countries to pay their fair share so Americans don’t bear the entire burden of incentivizing bringing drugs to market.") doesn't seem particularly incorrect.

Prices and consumption are linked. US drug companies spend a lot on Advertising to promote pill popping, but that’s not free. Further, they rarely collect the full sum from insurance companies or Medicare.

It’s the odd case of people in the US avoiding heathcare due to costs, where others seek it out when unnecessary.

Six months ago, the drug that costs $2k now cost $1800 for a 30-day supply. A year ago it was $1600, and about two years ago it was $1400. The patent expires this year.

Gilead did not develop or discover emtricitabine, university research through NIH grants did. Tenofovir was discovered via university research in Prague.

discovery != bringing a drug to market

Hydroxychloroquine and chloroquine were successful in malaria prophylaxis on a weekly dosing. Someone should start a trial among medical personnel to see if it is effective in coronavirus prevention. These are non-specific antivirals. Once virus takes hold, they have not yet been proven to be that effective in clinical settings.

Why does astronomically priced remdesivir take precedence in most mentions when, from the chart, chloroquine seems to have a similar inhibition rate, a slightly lower cytotoxicity, and a much lower cost?

Clinical trials for Remdesivir are ongoing.

There are some problems with the Chinese trials, which were the first to start twenty days ago:

https://clinicaltrials.gov/ct2/show/NCT04252664

https://clinicaltrials.gov/ct2/show/NCT04257656

Trials were run in Wuhan by popular demand but the epicenter with a very over-burdened medical system was probably not the best choice as trial site. Recruitment of mild/moderate cases were particularly problematic because these were not treated in hospitals in Wuhan at that time (you had to have a serious enough case to have a real hospital bed). It is also hard to find patients who have not tried other medication per the recruitment criteria.

The US organized trial https://clinicaltrials.gov/ct2/show/NCT04280705 just started but is designed to be a lot more flexible and will show results a lot sooner if Remdesivir is actually as effective as we all hope it to be.

The drug was also shown to be effective against SARS.

But didn't malaria develop chloroquine resistance in some areas? Whats stopping sars-cov-2 from mutating like that?

I'd say we should cross that bridge when we get to it.

Well to start, one's a parasite and one's a virus.

One thing at a time.

Chloroquine update - "Xu Nanping, vice minister of science and technology, at a press conference in Beijing" Feb 21:

>Chloroquine Phosphate, which has been used for more than 70 years, has been tested in 135 cases in Beijing and southern China's Guangdong Province. Among them, 130 patients have light and common symptoms, and five are severe patients.

>None of the patients with light and common symptoms have developed severe symptoms. Four severe patients have been discharged from hospital, and one has seen severe symptoms mitigated to normal, Xu said. http://www.china.org.cn/china/2020-02/22/content_75732846.ht...

which sounds promising.

The guy in Washington was near death until Remdesivir was administered. He was released a few days later.

Cool stuff.

I'd love to understand the mechanism of action of chloroquine. Does the paper touch on that?

https://doi.org/10.1186/1743-422X-2-69

>>We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations.

>>Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV

This paper is a month old. I don't understand why this isn't common knowledge yet.

If this stuff is working, why haven't we seen the death rates start falling?

They have fallen these last days in China, if that means anything.

I thought the name looked familiar. I'm not a doctor and I only googled for 10 minutes. I tore my achilles last year. I would never take this drug. I hope I'm off base.

Wiki breadcrumbs

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

https://en.wikipedia.org/wiki/4-Aminoquinoline

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

https://en.wikipedia.org/wiki/Quinolone_antibiotic#Tendons

Chloroquine =/= quinolone class of antibiotics

Quinolone is some nasty (but effective) stuff. Chloroquine has a more benign side effect profile.

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