COVID-19 drugs that work

[jyl]

Originally Posted by RWebb

remedsivir was developed for ebola, so you might think it could be improved for this virus

OTOH, the mode of action suggests not, and that side effects will always be present

I read an interesting article, will try to find it, where electron microscopy was used to in essence film remdesivir (actually its metabolite) in action versus the SARS2 virus in cells. I only skimmed the article, but what I took away is that the drug is effective at getting itself incorporated in the RNA created by SARS-CoV-2 and other coronaviruses, which renders the RNA then ineffective at replicating in the cell. The problem is that each unit (don’t know the term) of drug that gets incorporated is then “out of action”, and there is only a certain amount of drug that can be infused into the patient (I don’t know what the adverse effect threshold is, but there must be one) and then only some of that drug is present in the areas attacked by the virus (respiratory system etc). So if the drug is given to a patient who already has advanced disease and high viral load, it can only do so much. You’d think that, like many anti-virals, remedsivir might work better if dosed much earlier in the infection. But the limited supply and need for IV make that tough - unless you’re a VIP.

Here
https://science.sciencemag.org/content/early/2020/04/30/science.abc1560

[jyl]

Interesting article on favipiravir. https://www.nytimes.com/2020/05/05/business/japan-avigan-coronavirus.html#click=https://t.co/a7EX1Awj96

This is a Japanese developed and made drug, one of the drugs that the Chinese approved for covid back in February.

http://www.chinadaily.com.cn/a/202002/17/WS5e49efc2a310128217277fa3.html

Curiously, many “news” reports said it was a Chinese-developed drug and called it “favilavir” or “fapilavir” e.g. https://www.zmescience.com/ This could just be misreporting, or Chinese disinformation because they don’t want to be seen using a Japanese drug, but anyway most of the “cure for Covid found” stories running in February picked up the erroneous “Chinese-developed” and “favilavir” descriptions.

No, the Chinese didn’t have real data supporting these approvals, just anecdotal reports and tiny, poorly run clinical trials from the chaos of Wuhan. The biggest driver (my opinion) was probably a political imperative to be seen as “having found a treatment” preferably with a home-grown drug. The others included hydroxychloroquine and remdesivir. I think a Chinese entity filed for a Chinese patent on remdesivir around that time, and various Chinese pharma companies started making remdesivir (but not very well, as I’ve previously mentioned).

I haven’t heard of any success for favipiravir in clinical trials for covid. The drug seems to have sunk back into obscurity outside of Japan - a somehow-got-approved drug that doesn’t seem to be effective at treating any disease and can cause major birth defects.

Until reading the NYT article below, I didn’t realize that the Japanese govt seems to be doing with favipiravir what the US govt has been trying to do with hydroxychloroquine - use the govt’s influence and bully pulpit to push a drug into widespread use before and without sufficient data showing its efficacy or safety.

Incidentally, I think Trump has stopped publicly pushing HCQ as a covid treatment. At least I haven’t heard of him doing so lately. I don’t know if political appointees are still trying to pressure for the drug’s use, or if they’ve decided to wait for better data.

[sammyg2]

Very preliminary, but ......

Man-made antibody 'neutralizes' coronavirus for first time, study shows
By Chris Ciaccia

Though there is currently no known scientific cure for the disease known as COVID-19, researchers have created an antibody "that neutralizes SARS-CoV-2" in cells, offering the potential for prevention and treatment.

The study notes the antibody, known as 47D11, was created in a lab environment and was able to inhibit the spike protein found in SARS-CoV-2, the virus that causes COVID-19, as well as SARS-CoV.

"Our data show that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through a yet unknown mechanism that is different from receptor-binding interference," the researchers wrote in the study. "Alternative mechanisms of coronavirus neutralization by RBD-targeting antibodies have been reported including spike inactivation through antibody-induced destabilization of its prefusion structure17, which may also apply for 47D11."

SARS-CoV is also known as severe acute respiratory syndrome (SARS), which first surfaced in 2002 in China and resulted in the 2002-2004 outbreak of the virus.

The virus, linked to horseshoe bats, resulted in 774 known deaths, according to the Centers for Disease Control and Prevention.

The 47D11 antibody is known as a monoclonal antibody, which has been used for cancer drugs previously, according to the Mayo Clinic.

Monoclonal antibodies are defined as "laboratory-produced molecules engineered to serve as substitute antibodies," the Mayo Clinic added.

It's early in the development process of any potential drug, but it's promising nonetheless, the researchers noted.

"...This is the first report of a (human) monoclonal antibody that neutralizes SARS-CoV-2. 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition," the researchers wrote.

The researchers continued: "This antibody will be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2. Neutralizing antibodies can alter the course of infection in the infected host supporting virus clearance or protect an uninfected host that is exposed to the virus. Hence, this antibody – either alone or in combination – offers the potential to prevent and/or treat COVID-19, and possibly also other future emerging diseases in humans caused by viruses from the Sarbecovirus subgenus."

The study was published in the scientific journal Nature Communications.

[sammyg2]

Link:

https://www.nature.com/articles/s41467-020-16256-y.pdf

[RWebb]

[jyl]

Another observational (not randomized, not blinded) study of HCQ finds no benefit, this is a large one, 1300 patients.

There is a randomized, placebo controlled trial underway to see if HCQ has any *preventative* effect when given to healthy persons who have had recent contact with Covid infected. It is a large trial (1,000 patients planned) and has already had two interim analyses where the trial was not stopped for futility or for safety (which is a possible good sign, but still just reading tea leaves). Third interim analysis today, some possibility trial might be stopped because it is getting hard to enroll subjects (per lead investigator), if so data will be submitted for publication.

Not sure how interesting a preventative effect will be (like, who would you give drug to? HCW? relatives of sick? essential workers? how will you decide if odds of having contracted covid and then developing a severe case outweigh the potential adverse effects of HCQ? tricky.)

But still interesting.

There’s still the large treatment trials of HCQ ongoing as well.

[Geary]

Years ago, Fauci claimed HCQ worked on similar viruses ..
https://www.youtube.com/watch?v=JKmPVmoetm8

[RWebb]

even SARS COV 1 is only 80% similar

[jyl]

Positive data from small Hong Kong trial of a “cocktail” (interferon beta 1b, ritonavir, lopinavir, ribavirin) vs control (ritonavir + lopinavir). Cocktail shortened time to negative virus test by about half, statistically significant. No significant imbalance in adverse effects. Patients were mild cases, control arm reached negative virus test in 7 days after first dose. Some imbalance in patients in the arms, with the “cocktail” arm patients having fewer underlying conditions and fewer males. Authors think interferon beta likely the main factor. ritonavir + lopinavir were part of Chinese list of recommended treatments in February, which is probably why they were used as the control, but subsequently failed to show efficacy in a randomized trial.

Suggests interferon beta should be tested in larger trials, and indeed there are other trials of this and other interferons ongoing.

Interferon beta 1b was used for multiple sclerosis until superseded by newer drugs. The main patents are expired. I don’t know anything about supply or manufacturing process.

[RWebb]

[jyl]

Small trial (no control arm, only 25 patients) of treatment with transfusion oof convalescent plasma (plasma from recovered Covid patients). Patients were severely ill, over half on ventilators and rest on oxygen. 18 were discharged, one died, 4 remained hospitalized with severe disease, by end of three week trial. (I must have missed a couple in counting.)

Since there’s no control arm, hard to say if these patients did better than you’d expect with no treatment. But 18/25 recovered seems promising.

https://www.medrxiv.org/content/10.1101/2020.05.08.20095471v1

Takeda and others are working on convalescent plasma programs.

On the vaccine front, four programs are in the lead, in terms of clinical trial progress. Moderna has finished a phase 1 (no data yet) and will start ph 2 shortly. CanSio [EDIT Sinovac] (I think that’s name, a Chinese biotech) is starting a phase 1/2 in Canada soon (maybe has done a ph 1 in China, not sure). Oxford University/Astrazeneca are either in or soon starting ph 1. Pfizer/BionTech ditto. These programs could in theory have vaccines approved and in production by year end - if the vaccines work, big if. There are some 60 more vaccine programs behind them.

Edit: Five - Novavax has a vaccine candidate entering ph 1 shortly with support from CEPI (foundation). Of course, this stock went from $256 to $2 in 3 years on two failed RSV vaccine trials.

Because the manufacturing supply will be far short of demand initially and probably for all of 2020/2021, and because even a so-so vaccine with limited data will be approved, this is not the usual winner take all market. The first several vaccines to be approved will probably all be able to sell as much as they can produce for the first couple years. Sales will probably be geographically constrained at first - Oxford/Astra’s vaccine has been promised exclusively to the UK at first, CanSio (?) will presumably supply only China at first, etc.

Price is a big question mark, the pharma that tries to gouge on price will be crucified, but even at $100/dose (no idea if that’s realistic), if the market is a few billion people, that’s a lot of revenue. If the vaccines end up being only temporary in effect, that’s even “better” from a commercial standpoint.

[jyl]

There’s obviously the question of if a vaccine for SARS-CoV-2 is even feasible. No real idea from me. But vaccines have been in development for SARS and MERS, a MERS vaccine recently reported positive ph 1 data (safety ok, desired antibody response seen). I think (?) there are vaccines for some veterinary coronaviruses, admittedly not highly effective ones. The various programs are trying a range of approaches. So, there’s reason for hope, I think/hope.

[RWebb]

a vaccine is likely to not be very lived; educated guesses are 1-2 years (based on comparisons with other related viruses)

beats Noroviruses, which are limited to a few months

OTOH, work on other coronaviruses may result in a new way to target vaccines ... stay tuned

[jyl]

Originally Posted by RWebb

a vaccine is likely to not be very lived; educated guesses are 1-2 years (based on comparisons with other related viruses)

biotech/pharma investors everywhere are licking their lips so hard they need Chapstick

OTOH, work on other coronaviruses may result in a new way to target vaccines ... stay tuned

now hold on here, let’s not rush into anything THAT new - maybe after ten years of development . . . safety first

[RWebb]

now I heard that co.s that developed new drugs after an epidemic rarely did really well

maybe from MarkupWatch or some other suspect source?

anyway, I decided not to buy GILD

[jyl]

Originally Posted by RWebb

now I heard that co.s that developed new drugs after an epidemic rarely did really well

maybe from MarkupWatch or some other suspect source?

anyway, I decided not to buy GILD

I’d guess that’s probably true, but with any luck this virus keeps coming back and remains lethal to corporate profits :-)

[reachme]

100% true. Radithor has been used for decades

Radithor made by Bailey Labs has been written up in the Wall Street Journal, was started by a ex Harvard guy that uses the principle of radiation hormesis and has reviews by Eben Byers from Yale that are still glowing. This is the best recommendation I can give you looking for drug suggestions on a car forum.

[jyl]

https://www.bloomberg.com/features/2020-gilead-remdesivir-coronavirus-treatment/?sref=T96IplOq

Interesting article on Gilead and remdesivir.

[group911@aol.co]

This one about them is interesting. https://www.theatlantic.com/science/archive/2020/05/remdesivir-cats/611341/

Originally Posted by jyl

https://www.bloomberg.com/features/2020-gilead-remdesivir-coronavirus-treatment/?sref=T96IplOq

Interesting article on Gilead and remdesivir.

[jyl]

The serious trials of HCQ continue. In addition to the prevention trial I mentioned before, there is a French randomized trial comparing remdesivir, hydroxychloroquine, and ritonavir-lopinavir "head to head". This trial was supposed to enroll 3000 patients, is only at 700, had another interim analysis this week, review committee decided to continue the trial.

Trial design provided that committee would stop an arm if the interim analysis showed it was clearly inferior to the others. Which suggests that none of the three arms is clearly inferior to the others. That could mean that none are showing strong efficacy. Ritonavir-lopinavir already failed in a randomized controlled trial.