How Good is Remdesivir? 31% better than nothing?

[red-beard]

https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

Recovery time is accelerated by 31% and the mortality rate is reduced to 8% vs 11.6% for those given the drug vs. plecebo (33% reduction).

I would love to see the actual data and the R-squared of the comparison two groups. In one of my stat's courses (for design changes), if the effect is under 50%, you might have something else affecting the results and you need to go looking.

[IROC]

The actual data isn't very good. Or maybe it should be said that the study wasn't very good. A good commentary:

https://sciencebasedmedicine.org/covid-19-out-of-control-science-and-bypassing-science-based-medicine/

A quote relative to the Remdesivir studies:

STAT, in its breathless coverage, failed to emphasize that the University of Chicago studies, along with other Gilead-sponsored trials that are running simultaneously, are not randomized and have no placebo control arm. As Mullane even told her colleagues, without a randomized placebo control there is no way to know if the drug works better than no drug at all.

It goes on to say that - in the middle of the trial - they changed the endpoints (the criteria they we using for assessment). Generally a huge red flag.

[red-beard]

The study I put up was randomized and had placebo controls.

Here is when they started, back in February:

https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins

[red-beard]

Originally Posted by IROC

The actual data isn't very good. Or maybe it should be said that the study wasn't very good. A good commentary:

https://sciencebasedmedicine.org/covid-19-out-of-control-science-and-bypassing-science-based-medicine/

A quote relative to the Remdesivir studies:

It goes on to say that - in the middle of the trial - they changed the endpoints (the criteria they we using for assessment). Generally a huge red flag.

Wow! I fully read the part on Remdesivir and it was NOT good.

He excoriates the "studies" on Chloro-quinine.

[Eric Coffey]

Well, at least you will pay extra for that marginal efficacy (the ICER-recommended price-per-course is +/- $4500).

[pmax]

Originally Posted by IROC

The actual data isn't very good. Or maybe it should be said that the study wasn't very good. A good commentary:

https://sciencebasedmedicine.org/covid-19-out-of-control-science-and-bypassing-science-based-medicine/

A good read but I don't think Dr Gorski is aware of this study from the American heart association, who should know a thing or two about the risk, which correlates with Dr Raoult and Zev's reports and all the other countries using it widely.

https://www.ahajournals.org/doi/10.1161/CIRCEP.120.008662
29 Apr 2020

Conclusions
In the largest reported cohort of COVID-19 patients to date treated with chloroquine/hydroxychloroquine {plus minus} azithromycin, no instances of TdP or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy.

[pmax]

Originally Posted by red-beard

Wow! I fully read the part on Remdesivir and it was NOT good.

This is the worst part of the offense.

When it comes to remdesivir, based on one trial and ignoring a negative trial, Dr. Fauci has declared remdesivir to be, in essence, the de facto standard of care for treating hospitalized patients with COVID-19. That premature adoption means we might never know how well it actually works or if it even does work.

[jyl]

Very common in drug trials for the benefit to be modest (like, survival extended by 6 months, or recovery rate improved by only 20%) but the statistical significance very strong.

I think the reason is that there are many factors that we don’t understand. Out of 100 patients, the drug is actually only working on the 20 who have a certain genetic profile, and it is working super well for them, but we don’t know that, so we see sort of a modest benefit overall with large variability between patients.

You see that a lot in cancer drugs - for the “average” patient their survival is only extended a few months, but for 5-10% of patients, they are still alive years later. It isn’t just randomness, there is a reason, but we (I mean “we” as in humankind, the scientists, not me personally or investors generally, of course) just don’t know enough yet to identify which patient will be in which group.

Increasingly, though, drug researchers are starting to target drugs to very specific types of patients or very specific subtypes of disease (often cancers) and getting remarkable results in those very narrow groups.

So little is known about covid - people seem to forget that this is a brand new disease, just appeared a few months ago - that the researchers are doing things on the fly and figuring it out as they go.

In the NIAID trial, it was initiated and the trial design done in, I think, February (?). At that point almost nothing was known about the behavior of the covid disease beyond some anecdotal stuff from the chaos of Wuhan and some basic biology of the virus. Gilead had this “general purpose” antiviral that in principle might work on most coronaviruses, and had shown itself to be sort of a “jack of all trades master of none” - it kind of worked in Ebola but not as well as the better drugs, etc.

In normal times, multiple years of work would have been done before the first human covid patient was dosed in a remdesivir trial, and by the time you got to a phase 3 trial in four years, the endpoint would be very well figured out, so any change to the endpoint would indeed be very suspicious. But here they jumped straight into a 1000 person phase 2/3 trial with their best early guess at a reasonable endpoint. Before the 100th patient was enrolled, more had been learned about the typical course of covid cases, they reworked their modeling, and realized that the original endpoint would probably need a much larger trial to show statistical significance. But a much larger trial would take much longer, and right now everyone is trying to move at warp speed. So they adjusted the endpoint to something that had a better chance of yielding a definitive answer. Makes sense.

I have a suspicion, totally unproven, that NIAID also saw the ridiculous pressure that the administration was putting on the FDA to approve HCQ as a covid treatment, and that made them want to get data from the remedsivir trials sooner rather than later. But that’s just my speculation.

The criticism of the remdesivr data and emergency approval - at least, the comments that aren’t total tinfoil idiocracy - basically boil down to
- A too-small trial in China failed to show efficacy. Yup, if your trial is only 240 patients the drug will have to be very efficacious to get a positive result. And this drug isn’t.
- Gilead’s own trials were open label. Yup, those trials weren’t for approval, they were for Gilead to get more information to decide if they were going to start spending hundreds of millions to ramp up manufacturing “at risk”, i.e. before approval. Basically those were the equivalent of the phase 1 trials that the drug would have gone through in normal times.
- NIAID’s trial changed endpoint at about 1/10th enrollment. Already discussed.
- The drug isn’t very effective. Absolutely true, it wasn’t developed for covid and the mechanism probably limits how effective it can be (why is too long a topic to go into here). It is modestly / moderately effective, that’s it.
- Fauci called it the “standard of care”. I wonder if people even understand what this term means? SOC means the best treatment currently known to be available. It doesn’t mean a great or even good treatment, or that something better won’t come along tomorrow (as everyone hopes). In cancer, for instance, the standard of care may merely extend your life a few months - but as inadequate as that is, it is still the SOC.

[IROC]

I'll admit I know nothing about this subject, but we are doing a lot of basic research on the SARS-Cov-2 virus here at work and so I have been listening to what the scientist say. What they are saying is that we don't know much about it. We are studying it at its very basic level - spike protein interactions with cell membranes and RNA replication within the host cell. And, something about proteases (see - I have no idea). My take-away is that we still don't have much knowledge in the exact mechanisms this virus uses to infect and replicate. Without that knowledge, designing effective treatments is difficult.

I'm very excited about the prospects for a treatment, but I have also been here on the sidelines of basic research for a long time and I have learned to be very careful (not cynical), but careful about jumping to conclusions with little evidence to back them up.

[IROC]

This is what we're doing here at ORNL. I'm in the neutron scattering side. I have been working 9-11 hours a day since February...

https://www.youtube.com/watch?v=-okT36zYdD0&feature=share&fbclid=IwAR07eHYtJTKX6ZkkUZ3Zd8wS1zyFOYd1LhUoKiy_U 325FBJc_k6pm5hh5Ww

[DanielDudley]

So far it sounds like we haven't found the silver bullet.

[jyl]

Originally Posted by IROC

This is what we're doing here at ORNL. I'm in the neutron scattering side. I have been working 9-11 hours a day since February...

https://www.youtube.com/watch?v=-okT36zYdD0&feature=share&fbclid=IwAR07eHYtJTKX6ZkkUZ3Zd8wS1zyFOYd1LhUoKiy_U 325FBJc_k6pm5hh5Ww

very cool!

[RWebb]

Originally Posted by IROC

I'll admit I know nothing about this subject, but we are doing a lot of basic research on the SARS-Cov-2 virus here at work and so I have been listening to what the scientist say. What they are saying is that we don't know much about it. We are studying it at its very basic level - spike protein interactions with cell membranes and RNA replication within the host cell. And, something about proteases (see - I have no idea). My take-away is that we still don't have much knowledge in the exact mechanisms this virus uses to infect and replicate. Without that knowledge, designing effective treatments is difficult.

I'm very excited about the prospects for a treatment, but I have also been here on the sidelines of basic research for a long time and I have learned to be very careful (not cynical), but careful about jumping to conclusions with little evidence to back them up.

As a research scientist in biology, my perspective is a bit different. I am amazed at how quickly we have learned so many things about this virus, including the mechanism of action of the spike protein.

I agree that we lack knowledge of some critical pieces of information regarding infection dynamics (maybe not at the mechanistic level tho).

I also expect that really effective vaccine development will be difficult, partly due to mutability and so will development of drugs to treat infected individuals, partly due to the difficulty of detecting viral RNA from host RNA (ours). It is such a basic mechanism of cellular replication that the virus hijacks...

BTW, who is the linebacker doing the narration in the first part of that video?

[IROC]

He's the guy that runs what we call the "Manufacturing Demonstration Facility". Basically our 3D printing research and all that. I won't mention his name, but I know him personally. Really, really sharp guy.

[Tobra]

Originally Posted by DanielDudley

So far it sounds like we haven't found the silver bullet.

There is no silver bullet

[RWebb]

Originally Posted by IROC

He's the guy that runs what we call the "Manufacturing Demonstration Facility". Basically our 3D printing research and all that. I won't mention his name, but I know him personally. Really, really sharp guy.

I figure everybody at your 'place' is really, really sharp - likely even the secretaries are... I can only go by analogy to the guys I know at Larry Livermore

He looks like a 2nd career in the NFL would also work...

Feel free to confer kudos to him - I guess transfer, not confer

[red-beard]

Originally Posted by RWebb

I figure everybody at your 'place' is really, really sharp - likely even the secretaries are... I can only go by analogy to the guys I know at Larry Livermore

He looks like a 2nd career in the NFL would also work...

Feel free to confer kudos to him - I guess transfer, not confer

They hired the first Mrs. Beard, so they couldn't be too smart