
Gilead should ditch remdesivir and focus on its simpler and safer ancestor - phonon
https://www.statnews.com/2020/05/14/gilead-should-ditch-remdesivir-and-focus-on-its-simpler-safer-ancestor/
======
refurb
As someone who has been on the corporate side of this type of debate, I can
assure you that Gilead has several magnitudes of more information about both
of these molecules than the author has.

And as others have mentioned, the only data for the alternative molecule is
animal data versus remdesivir which already has phase 3 data. Sure, the other
drug might be better, but it might not work at all.

~~~
fao_
Sure, and that can include unpublished negative data.

Ben Goldacre (a Senior Clinical Research Fellow at the Centre for Evidence
Based Medicine in the Department of Primary Care in the University of
Oxford{0}), wrote in his book Bad Pharma, about an instance where a specific
subset of SSRIs were given to eight(?) year olds for clinical depression. What
the GPs prescribing them didn't know, however, was that the suicide rate for
those children would go _up_ after prescription. The pharmaceutical company
_knew about this_. It was a negative result, and was unpublished.

This is just a single example I've pulled from the book, and the book covers
only a smidgen of the hundreds of thousands of cases of incompetence and
malice perpetrated by pharmaceutical companies over the last 20 years. You can
find more information about this by him here (
[https://www.theguardian.com/commentisfree/2008/jan/26/badsci...](https://www.theguardian.com/commentisfree/2008/jan/26/badscience)
), here ( [https://blog.ted.com/5-prescription-drugs-doctors-had-no-
ide...](https://blog.ted.com/5-prescription-drugs-doctors-had-no-idea-could-
hurt-their-patients/) ), and more information in general here (
[https://www.bmj.com/open-data](https://www.bmj.com/open-data) ), and here (
[https://www.livescience.com/8365-dark-side-medical-
research-...](https://www.livescience.com/8365-dark-side-medical-research-
widespread-bias-omissions.html) )

Pharmaceutical companies' _only_ duty is to turn a profit to their
shareholders. If they spend five or ten years developing a drug that they find
has either no or negative use, then in the eyes of the shareholders, they have
_wasted_ that money. The duty of the company is to find a use for the drug
regardless of whether it is useful or not, regardless of whether there is a
more beneficial alternative.

{0} - I copied this line, sue me :)

~~~
elliekelly
This is exactly why Gilead won’t allow the similar drug to be used in cats.
They don’t want to know about negative side effects that might then hinder the
drug’s approval for use in humans.

If ever there has been a business decision to illustrate the whole “putting
profits over people” this is it. And sunk costs, too.

~~~
refurb
Where are you getting this from? The only mention of cats in the article is
actual data of the drug in cats.

 _When GS-441524 was used to treat cats with feline infectious peritonitis, a
progressive and usually fatal disease caused by a coronavirus, it displayed
remarkable safety and therapeutic efficacy, with 96% of cats recovering after
treatment._

~~~
elliekelly
Apologies, I meant to say I had submitted the article on HN a few days ago and
it seems I forgot. Link here:
[https://www.theatlantic.com/science/archive/2020/05/remdesiv...](https://www.theatlantic.com/science/archive/2020/05/remdesivir-
cats/611341/)

------
pazimzadeh
Remdesivir and GS-441524 triphosphate are nucleoside analogs that inhibit
polymerase activity. These are notorious for breeding resistance due to
polymerase variability amongst viruses.

So even if they can get it manufactured, it's is a short term boon and long
term, questionable.

It's critical to find drugs that target other parts of the virus' life cycle
to include in a combination therapy.

Source: conversation with Sean Whelan
[https://en.wikipedia.org/wiki/Sean_Whelan_(scientist)](https://en.wikipedia.org/wiki/Sean_Whelan_\(scientist\))

------
this_user
The article only mentions tests of GS-441524 on animals, but not humans,
whereas remdesivir empirically seems to be reasonably safe in humans.
Switching from the one thing that actually possesses efficacy in humans to
something that has mainly been tested on cats seems like an unnecessary gamble
at this point.

~~~
icegreentea2
Ideally we could work on both. Remdisivir is apparently nightmareish to
produce - it's unlikely that that Gilead can fully capture all the value on
the market with it alone, especially if another another therapeutic becomes
available.

That said, it makes plenty of sense why you would begin with your drug that
has already passed clinical trials. I'm a bit disappointed that the article
didn't emphasis this point. I'm certain the authors know about it, and even if
they aren't out writing a hachet job, it can make this piece seem like one.

~~~
refurb
In a world of limited resources, you have to make a call on which leads move
forward in development. You can't move every program forward.

And yes, remdesivir is a beast to make, but I don't think supply is an issue
at all. They just packaged up and distributed 150 kg of it.

~~~
ggm
Are we in a world of limited resources in this specific sense? We're in a
world of 3 trillion dollar re-ignite the economy. Whats the resource
limitation here?

~~~
Slartie
Money does not magically create the personnel qualified in scaling up drug
production, nor does it magically make the necessary, specialized machinery
appear. Furthermore, as described in the article, the manufacturing appears to
rely a lot on various businesses which each perform one specific step with a
compound and hand over the result to the next, and Gilead's core work seems to
be to find these businesses, provide missing know-how, and coordinate all of
their work such that the timelines and amounts produced line up. Just dumping
money into an economy also does not magically make such specialized businesses
appear all of a sudden; self-organizing systems like modern capitalistic
economies require time to adjust to big changes in demand or supply of certain
goods or services.

~~~
ggm
I dislike Trump on principle and from the other side of the fence. I am a
natural born 'big government' person. From my side of the fence, the one thing
Trump said which made sense was: "there are 15 good candidate vaccines: we are
pursuing all of them"

That is exactly how the manhattan project ran: Thermal Diffusion, Gaseous
Diffusion, Centrifuge and Calutron were all followed up, and it wound up that
Thermal fed Calutron to increase yield but gaseous diffusion and centrifuges
are what we use now. The point here is that they didn't penny-pinch "which one
is better" they did them _ALL_

------
conistonwater
Cynical summary, basically: "The first patent on GS-441524 was issued in 2009,
while the first patent for remdesivir was issued in 2017."

~~~
jacob019
So greed and our patent system are getting in the way of saving lives.

~~~
forgotmylogin2
If our patent system didn't exist, the drug would have never been developed in
the first place.

~~~
michaelmrose
Prove it.

------
aazaa
Interesting article, but it could have done a better job of explaining the
chemistry.

Remdesivir is a prodrug, meaning it must be metabolized (chemically processed)
in the body to the active form. Think of it like this:

R-OPX -> R-OH -> R-OPPP

where OPPP is the triphosphate and X is the thing the body hacks off. R-OPPP
is the active form of Remdesivir. Your body must perform the net reaction
R-OPX -> R-OPPP before it can use the drug.

GS-441524 is R-OH in the above equation.

X is non-trivial to build and install, and it looks like it required a lot of
work.

But as these things often happen, nature doesn't give e hoot about the
medicinal chemist's net-o hypothesis (R-OPX is better) and does what it will
do. It turns out the fancy targeting component PX isn't necessary for efficacy
in animals. You get even better results using plain old R-OH.

Even better, R-OH is the starting material for R-OPX, so you save yourself
some reactions to boot.

At this point a lesson pops up that gets forgotten time and again in drug
discovery programs:

ALWAYS RUN THE CONTROL IN ANIMALS - RUN IT EARLY. NO EXCEPTIONS AND NO
EXCUSES!

Also, there is enormous resistance to running the control, because of course
it can't work - it's the control and doesn't conform to the neat-o hypothesis.

In this case, the control is R-OH. It was run, but not early enough it seems
to prevent the R-OPX train from leaving the station. Once a team starts
running with a compound it can be very difficult to pull them back.

Now, this is just speculation taking the article as gospel. It's almost
impossible to know for sure what really happens inside drug companies because
the trade secret/IP protection culture is so ingrained. Not only that, but I
could be misinterpreting the facts presented in the article.

Of course, none of this addresses the main problem with Remdesivir: it can't
be orally dosed. You need to get injected multiple times. And that's probably
going to be in a clinic, and done by people wearing full PPE. An oral drug
would allow you to buy pills and convalesce at home, conserving valuable
hospital resources.

As an aside, you typically use a prodrug because you think it will lead to
better drug properties than the parent compound. An interesting example is the
case of Claritin/Clarinex. The former is the prodrug form of the latter. It
turns out the latter is at least as good if not better than the prodrug.
Another case of not running the control early, I suspect.

~~~
maxerickson
Your first 6 paragraphs are not clearer than the article:

 _Some background: Remdesivir works by interfering with the cellular machinery
that allows viruses to replicate inside a human host. It is a pro-drug,
meaning it must be metabolized and undergo a sequence of five bioactivation
steps before it becomes GS-441524 triphosphate, the active compound that
impedes viral replication.

Remdesivir isn’t Gilead’s only antiviral nucleoside analogue. The company has
also developed GS-441524, another pro-drug that, as its name suggests, the
body also converts into GS-441524 triphosphate, but in just in three steps.
GS-441524 is easier to synthesize than remdesivir, requiring three steps
instead of the seven needed for remdesivir._

You've omitted the "antiviral nucleoside analogue" jargon but run off into the
weeds relative to the comparisons of the number of bioactivation and synthesis
steps.

------
scythe
This seems like the sort of argument that should be distributed in the peer-
reviewed literature to scientists, not on a news website.

I am far from average in my consumption of medical literature--I read several
papers every week and have some (limited) background in biophysics.
Nonetheless, this debate is miles over my head. One would need to know a great
deal about pharmacology to evaluate this article. There are lots of reasons to
use one prodrug over another; likewise, there are a great deal of differences
between animal models and humans.

See also this reddit comment:

[http://reddit.com/r/chemistry/comments/fv8p4k/comment/fmhydy...](http://reddit.com/r/chemistry/comments/fv8p4k/comment/fmhydym)

~~~
wyxuan
Stat is a health website for scientists and it’s not really meant for general
consumption, but yeah.

------
raphlinus
This Atlantic piece has excellent background, including the astonishing
effectiveness in cats against FIP, and questions about Gilead's motivations
for prioritizing studies of one vs the other:
[https://www.theatlantic.com/science/archive/2020/05/remdesiv...](https://www.theatlantic.com/science/archive/2020/05/remdesivir-
cats/611341/)

Edit: I see goatinaboat also posted the link (I searched for a bit of the url
that was elided).

------
goatinaboat
If they do, they should allow its use for sick cats
[https://www.theatlantic.com/science/archive/2020/05/remdesiv...](https://www.theatlantic.com/science/archive/2020/05/remdesivir-
cats/611341/)

~~~
HarryHirsch
Does it work in the feline at all? FIP is a deadly disease, if the compound
was any good word of mouth would spread amongst veterinarians. Unfortunately,
the outcomes are not encouraging.

~~~
tyingq
It sounds like they are very aware. [https://www.avma.org/javma-
news/2020-01-15/fip-drugs-continu...](https://www.avma.org/javma-
news/2020-01-15/fip-drugs-continue-show-promise-while-being-sold-black-market)

------
abhisuri97
Okay so...I'm actually in a rare position where I _might_ be able to
contribute to discussion on this! Brief caveats: am undergrad pre-med, but
also took an infectious diseases grad class at Penn that spent a week diving
into one of the papers cited in this article (when the authors mentioned the
two compounds "showed no statistically significant difference in potency"). I
think it's worth exploring what the authors of that paper actually meant to
assess for. (also @HN please shoot me down if anything I say is inaccurate,
also I do think the authors make other valid points, just not so much in
reference to this particular aspect)

The paper in question is here
([https://mbio.asm.org/content/9/2/e00221-18](https://mbio.asm.org/content/9/2/e00221-18))
and they're looking at table 1. First of all, the paper didn't set out to
actually determine whether GS-441524 is better than GS-5734 (aka remdesivir).
It mainly set out to show that remdesivir could work against coronaviruses in
general (this was written back in 2018, so they were focusing on SARS and MERS
only). Furthermore, all of these experiments were in vitro with a model
betaCoV, murine hepatitis virus, so results shouldn't necessarily mean much
for human populations. But down to the nitty-gritty:

In figure 1 of the paper, the authors do in vitro experiments to show that
both GS-441524 and remdesivir reduce their model CoV viral titer. However,
they show a major difference. Remdesivir has an EC50 (dose at which 50% of
viral replication is inhibited) that is much lower than GS-441524. This is
great because you don't need as much remdesivir to inhibit viral replication.
One area where GS-441524 did beat remdesivir was cytotoxicity (CC50 = dose at
which 50% of cells w/the drug is killed). You want as high a CC50 as possible.
So that would mean that remdesivir is technically more toxic to cells;
however, it's effective dose is so low that you wouldn't need to give a dose
large enough to kill off any cells. You can use a handy metric known as the
selective index (CC50/EC50) to measure the tradeoff. High selective index =
high efficacy without killing off your own cells. In this case, remdesivir has
a higher selective index compared to GS-441524.

Now onto what the article referred to. The authors made their in vitro studies
slightly more relevant to humans by using human epithelial cells and this time
actual SARS CoV and MERS CoV virus and measured EC50 and CC50 again for both
GS-441524 and remdesivir. The authors report some +/\- standard deviation
ranges. From intro stat, I think one of the conclusions about looking at
overlapping standard deviation bars is that no conclusion can be made about
whether or not the differences are statistically significant or not! I
encourage people to take a look at the table itself and make your own
conclusions
([https://mbio.asm.org/content/9/2/e00221-18#T1](https://mbio.asm.org/content/9/2/e00221-18#T1))

The rest of the paper focused on remdesivir and showed a number of things. It
showed it was most effective early post infection (in vitro) and it highly
inhibited viral replication when viral exonuclease was knocked out (indicating
that remdesivir messes with the function of that). It also showed (via serial
passage experiments...basically think about it as mini-artificial selection)
that nucleoside analog drugs will tend to favor the selection for two RNA-
dependent RNA polymerase mutant viruses that confer resistance to the
nucleoside drugs! But they showed in the next figure that these mutant viruses
have a reproductive disadvantage compared to their wild type CoV.

Now for my 2 cents: I think that remdesivir was favored primarily because it
was being used for anti-viral treatment in Ebola virus trials...but it was
falling out of favor for Ebola treatment because of other monoclonal antibody
cocktail treatments that show better survival rates (ref PALM trial:
[https://www.nejm.org/doi/full/10.1056/NEJMoa1910993](https://www.nejm.org/doi/full/10.1056/NEJMoa1910993)).
Sooo I guess gilead had this drug lying around, and they had a good idea as to
its mechanism of action...so why not apply it for Sars CoV2?

------
exabrial
Both would be my preference

------
jakeogh
Meanwhile... [https://bpa.st/43UA](https://bpa.st/43UA)

and Senegal [https://youtu.be/iBma_0oAiMI](https://youtu.be/iBma_0oAiMI)

------
Medicalidiot
There are a few things that cause me serious frustration. One is when a lay
person will talk about medicine.

Making drugs is a ridiculous process. I had the pleasure of listening to a
physical chemist describe every single step it took for his team at Abbott
labs to take Lopinavir/ritonavir to market. It is incredible how difficult it
is to go from novel molecule to phase IV. Every single thing he did he had to,
by FDA guidelines, be written and documented appropriately. Everything is
highly scrutinized. With medicine we need to be right and we need strong
scrutiny, because when there isn't oversight shortcuts are made. That's just
the federal guidelines, the chemistry behind drug production, and this is
something I find interesting but strongly dislike the amount of math behind
physical chemistry, is intimidating. Some of the questions that need to be
answered are: Does this molecule affect any enzyme? Is this enzyme
hypothesized to be in a disease process? What is the structure of this
molecule? How is it made? How can we make more? How can we make more more
efficiently? Does this drug work in people? What's the dose that needs to be
given to have an effect? What is the dosing ranges for a given drug? What are
the serious side effects? What are the moderate/mild side effect? How is this
drug cleared/excreted? Are there certain populations which this is
contraindicated in?

These are some of the main questions that are answered when taking a drug to
market, which is why it usually takes 10 years and billions to go from novel
molecule to FDA approved drug.

~~~
phonon
The people who wrote the article are not lay people.

~~~
Medicalidiot
Both are involved in discovering novel drug targets, but not in bringing drugs
to market. I know a significant amount of individuals in medical research that
don't know the nuances behind bringing drugs to market.

~~~
phonon
Nice goal-post moving. Maybe you're the lay person? Med school doesn't qualify
you to opine about novel therapeutics.

~~~
Medicalidiot
My best friend is working on novel targets for hepatocellular carcinoma. Does
he know science? Yes. Does he know how to bring a drug to market? God no.
Everyone outside of your field is a lay person.

>Med school doesn't qualify you to opine about novel therapeutics

Actually, it does. Especially when we tried hydroxychloroquine and it didn't
work. When you go to a hospital with medical students 60% of the time our
recommendation to the attending is what the care plan ends up being.

------
DoreenMichele
There's actually a lot of easy ways to combat viral infections. This was well
known in an alternative medicine forum I used to hang out in, which probably
no longer exists because it was a Yahoo group.

I don't really understand why the world is approaching this problem the way it
is. A lot of the things we are doing are very much in the vein of that
Einstein quote about being unable to solve a problem from the same level of
thinking that created.

This pandemic grew out of modern life. It grew out of 7 billion people living
on planet Earth and global travel and Affluenza. We just keep bulling on ahead
with more of the same.

There are fixes, but they aren't likely to come from our current main stream
approaches. And this is problematic because everything we are doing is making
the economy top heavy in a way that's actively hostile to the little guy. This
makes it hard to start small somewhere.

~~~
odonnellryan
What would you propose?

~~~
DoreenMichele
If I thought I could get any real traction, I would run a website talking
about what works. But that's not likely to get traction, so that idea hasn't
gone anywhere. I'm scared to try to develop it because I get so much absolute
shit from people for trying to talk at all about health stuff.

I have a serious medical condition. I'm getting well.

I've done remote work for years. That's a good idea that's helpful for
controlling infection for vulnerable people.

Social distancing is good, but one side effect of all this lock down stuff is
that hours are shortened and this means there are bigger crowds. It has
eliminated the option for me to shop at 2am to avoid people.

I'm for contactless food orders. I have been actively promoted Little Caesar's
pizza portal, ordering ahead (by phone or online) and picking up takeout.

I know lots of things that work. It's not any one thing. I can't tell you in a
single comment. I've been developing these practices for 19 years and I get
nothing but the crap kicked out of me, even when I am just asking questions
for my own edification.

The enormous hostility with which I am met for just trying to talk to people
online is part of a larger pattern of thinking and behavior. It's not just
hostile to me. It's hostile to anyone with a non-main stream approach to
health issues.

Main stream approaches are what got us here. They won't likely get us out.

I will probably be okay. But other people don't need to suffer this much.

~~~
woebtz
You could create a subreddit or something similar instead of a website.

You'd still face traction and backlash issues, but it seems like a lot less
effort and commitment to get started.

~~~
DoreenMichele
Thanks.

I have a subreddit called HealthWorks. It has no real traction.

I have had several health sites over the years. They get no real traction.

The problem is not setting up a website. I have a zillion of them.

The problem is mostly positioning and framing and getting audience engagement.
I've never figured that piece out.

I know a lot about health stuff, so much so that when I begin talking about
what you can do for yourself at home, people get all up in arms and accuse me
of "practicing medicine without a license" and things like that.

I started a site a few weeks back in reaction to the pandemic called Stop
Touching Your Face and someone kindly gave me feedback on positioning it, but
I never developed it. I don't think it works to talk about the pandemic and
try to address the pandemic directly.

I have a health site about my medical condition. I rarely update it.

I am continuing to think on the problem space and I hope to eventually find a
way to talk about stuff and have it go well. But I find it crazy making that
people are openly hostile to the stuff I want to talk about. I don't get that.

You know someone with potential solutions in a life threatening situation and
your response is rage and downvotes instead of trying to help them figure out
how to better talk about it? Are you, like, trying to die or something?

I just honestly don't get that. I never have. It's the same reaction people
with my medical condition give me and it makes no sense to me at all.

