Expanded access programs for Remdesivir
gilead.com
gilead.com
I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
This is why I thought Pr Raoult was advocating for the use of chloroquine in the early days of the disease, combined with prompt testing.
But it seems that anti-virals (like the study mentioned in this post and other studies in the US and Europe) are tested on patients in critical phase, i.e. with serious cases of pneumonia. Am I missing something or should we not expect anti-virals to be of much use in those cases, as it is too late, we are not dealing with a virus but with a pneumonia?
[1] see this useful video: https://www.youtube.com/watch?v=BtN-goy9VOY
Without getting overly technical, there's also some atypical results in some of the labs that seems to indicate that the virus is just overwhelming parts of their immune system, which are in collapse. This can drive up other parts that are inflammatory in nature leading to the cytokine storm and ARDS which comes on very rapidly. However, the fact that things like steroids are leading to WORSE outcomes suggests that the immune suppression is very unhelpful which suggests the problem is more that tissues are just getting overwhelmed with virus.
I’ve tried googling but came up empty besides a paper on “ glucocorticoids” which seems to be something to do with cortisol shots for reduced inflammation, which has immune suppression tendencies.
Is that what you mean? And if yes, is this for all levels of steroids or just some particular types? (IE steroids in an asthma inhaler vs cortisol shot vs anabolic steroids).
Yes. This is the reason why they're used in the first place.
> steroids in an asthma inhaler
Yes, but an entire year's worth of asthma inhaler is like one dose of oral prednisone, so the impact is quite low and you should not stop using your inhaler.
> cortisol shot
Yes.
> anabolic steroids
Yes.
Hormones are signalling molecules that get transported throughout your body.
Steroid hormones are chemicals that are both a steroid and a hormone. Not all steroids are hormones (ex cholesterol) and not all hormones are steroids.
A subgroup of steroid hormones is corticosteroids. A subgroup of corticosteroids is glucocorticoids, (most of?) which exhibit strong effects on the immune system (roughly speaking, they suppress the immune system and reduce inflammation).
With a target sample size of 3000 individuals it would have at least sufficient numbers to show if it's actually viable, helps a little, or does not help at all.
[1] https://clinicaltrials.gov/ct2/show/NCT04308668?term=hydroxy...
Frankly, if it is only modestly effective, it should still be given to everyone without contraindications.
Efficiency only becomes important in a year or two when there are competing therapies.
When the choices are Chloroquine or Hopes and Prayers, Chloroquine is the obvious choice (for those that don't have the contraindications, of course -- for those patients, you'd need more evidence to know that the benefits outweighed the risks)
There are apparently a large number of cases that work differently, with hypoxemia prior to any evidence of severe lung dysfunction:
https://www.atsjournals.org/doi/pdf/10.1164/rccm.202003-0817...
There are also discussions of this phenomenon on Twitter by emergency medicine professionals from NYC, e.g.
https://twitter.com/ericleemd/status/1243613497243639809
Some of them propose that early mechanical ventilation in these patients can actually cause lung damage.
That tweet is interesting. Some folks are starting the theorize that many of the pneumonia (especially, bilateral) diagnoses based on CXR might be mistaken.
The most interesting hypothesis I have encountered (way too little evidence yet to do anything but study it) is that the virus is directly interfering with haemoglobin saturation, and that the abnormal CXR is actually looking at tissue damage caused by haemoglobin degradation somewhat akin to that found in Malaria patients.
That hypothesis intends to explain the apparent efficacy of chloroquine, magnified when taken by patients early in the disease, by hypothesizing a similar mechanism of action in COVID as in Malaria -- not by being antiviral, but by inhibiting heme polymerase.
The apparent antiviral properties of the treatment are then merely keeping the patient healthy and lung-damage-free while the immune system does its thing.
If that were true, then treating COVID patients for pneumonia could be highly counterproductive.
Of course, even if the hypothesis is correct, there might be some COVID patients who do develop a bacterial secondary pneumonia -- that is an uncommon-but-not-rare complication of all respiratory illnesses. That might also explain why Azithromycin seems to make Chloroquine more effective -- each drug helping a different subset of patients, rather than actually as a combined effect.
As I say, though, there is nowhere near enough evidence yet for this hypothesis -- but it is pretty interesting. It is probably worth a study or two to evaluate.
It is a neat hypothesis in that it takes a wide variety of disparate and otherwise apparently contradictory datapoints from clinical experience and weaves them together into a coherent narrative.
Of course, that it makes a good narrative is in no way evidence for it's truth, no matter how much we humans love good narratives.
The reasons for this are unknown, but it is an active area of research. Some doctors are beginning to call for treating covid patients like they altitude sickness.[1]
Disclaimer: I'm not a doctor or an expert.
Chloroquine is suspected to have general prophylactic abilities (like Remdesivir), but also hypothesized that if taken with Zinc, [1] acts as an ionophore with which Zn2+ ions can inactivate the first part of the viral replication step. But at this time, clinical trials for HCQ have been somewhat mixed, with small N-size studies reporting weak benefits or lack of benefits. I don't know of any RCTs that include Zn2+ in the treatment group along with HCQ. It's still as yet unclear.
To use HIV as an example, every infected T cell releases ~50,000 virions when it bursts. So that's ~10^4 times the number of infected cells. So during an infection only 10^9 of your 10^13 cells would need to be infected to get up into the 10^13 range. That's obviously a TINY fraction at 10^9/10^13 = 10^-4. So saying there's trillions of viruses in your body during a major infection like COVID is hardly an exaggeration. 10^15 may or may not be though, in fairness.
Compare that to the amount of virus you'd be exposed to in the air though in a COVID ward and its just totally negligible. Unless you're getting injected with virions, it's just not relevant to the progression of your infection when you're already a week into it. I'd be shocked if you could daily environmental viral loads above 10^6.
So fine I'll revise it to 6-9 orders of magnitude. The point stands though, it's just not relevant to your immune system compared to the virus it has to deal with from your own cells.
There isn't a shortage of participants, and at that scale we'll know soon enough if Trump's wonder drug does something. Probably it won't.
Will it work? If it was a runaway success, I would have expected any of the current clinical trials to be cut short as the difference between placebo and non-placebo patients would have been obvious. That hadn't happened. I'm still hoping it has some positive effect.
The drug also had to administered through an IV over several days. It is not a pill you take. If it works, this makes treatment a little bit more difficult. You can't just give patients a pill and send them home.
I'm glad to hear this!
>we continue to provide remdesivir on an individual compassionate use basis for children and pregnant women.
Can someone explain this logic to me? The safety and efficacy is not known, so we're going to give it to the most vulnerable people first?
And pregnant women? That's hard to reconcile with common sense.
Compassionate uses are hail marys and are used appropriately.
Essentially, if a patient has no other options and might die, the FDA allows the use of unproven drugs.
It’s tough to worry about a future when you don’t have one.
Nobody said the studies should take 5-10 years. Obviously this should be weighted against the urgency.
That being said, I think it is fine if the government buys these supplies. I also think it is fine if a company wants to donate.
It's also not entirely clear what it means to provide the drugs "at no cost" (later on it says "no charge", but in a separate sentence), nor is it clear how long this promise will last.
This is not the same as, say, an ISP making excessive profits by manipulating the market and building themselves a quasi-monopoly, or a bank harvesting profits by taking huge risks with the understanding that the Federal Reserve will bail them out if everything blows up. The ISP isn't innovating, isn't creating anything, they're merely an engine for spending and allocating resources. The bank isn't creating anything either, they're just moving money around and playing social engineering games with society. Complaints about profits in these industries are totally reasonable, since these companies are basically just middlemen sucking money from the economy in order to maintain the plumbing.
But to complain about excessive profits in an industry whose entire purpose is to discover new things? That makes no sense to me. What alternative would you prefer?
How would you react to a situation in which small companies discovered new drugs for ~$10 million, building on public research, and then were purchased by larger pharma companies for ~$300 million, and in which the large pharma companies aimed to earn ~$1-5 billion before the patents on the small company's invention expire?
A) the viability initial drug discovery and subsequent development costs, and
B) The time value of money.
For A) success rates of 5000:1 are not uncommon. Discovery is at the very beginning of this process [1],which can take 12–15 years and cost in excess of $1 billion [2]
B) A 1 to 5 billion dollar return on a 300 million acquisition is likely a loosing proposition for most pharma companies due to risk and the time value of money. If you have a 300m acquisition, 700m additional dev costs, a 50% time discount, and a 50% chance of success, you are already up to 4 billion in revenue needed to break even. This article [3] provides a balanced overview of the finical aspect and is written by a scientist trying to give away a cure for his terminal wife.
[1] https://en.wikipedia.org/wiki/Hit_to_lead [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157/ [3] http://www.cureffi.org/2019/04/29/financial-modeling-in-rare...
It's definitely true that companies also attempt to make new drugs in-house, but I can't readily recall a recent blockbuster drug made in this way.
The expensive part of bringing new drugs to market is testing in humans. Perhaps the US could bear some of these costs while, in exchange, shortening or eliminating patent protections.
In the case of the taxpayers and grants, i think it is important to keep in mind that these are explicitly given without strings attached or rights reserved because society decided that we want to encourage private research. It is fair to argue that perhaps we should change the model moving forward, but I find it fairly offensive when folk claim a retroactive ownership on this basis.
>Thus the eventual vendor of a drug won't necessarily have 5000:1 odds, but instead will be able to review and purchase the most promising candidate drugs based on data generated by other companies.
I wholeheartedly agree. the long >5000:1 is at discovery, i.e. the basic research that is often publicly funded. Once drugs have gone through enough screening to be used, the probability of approval is up to about 10:1 [1]. A lot of the bigger sales take place between phase 1 and 2, which probability of approval is up to perhaps 25%. Research institutions and early developers get paid based on the potential value and risk, and are not taken advantage of. The fact that companies often outsource early develop doesn't invalidate the their claim to their profits.
>The expensive part of bringing new drugs to market is testing in humans. Perhaps the US could bear some of these costs while, in exchange, shortening or eliminating patent protections.
This is an interesting idea. Two additional options that you may want to consider that wouldn't stifle development are expedited approval and government manufacture of generics. Due to the time value of money, faster approval increases the profitability of new drug development and without increasing prices to consumers. For generics, drug profits after loss of exclusivity are so far out that they don't significantly weigh in on the decision to develop a product or not.