3 ms·

"Researchers have developed", yeah. When I read such things, I always recall https://en.wikipedia.org/wiki/Epimerox https://en.wikipedia.org/wiki/Epimerox - thi

"Researchers have developed", yeah. When I read such things, I always recall https://en.wikipedia.org/wiki/Epimerox https://en.wikipedia.org/wiki/Epimerox - this thing promised wonders - very broad spectrum, very low toxicity - and, most importantly, it was targeting a conservative essential protein - so nearly zero resistance. And there were no updates for more than a decade. Something developed in a lab is something we, most likely, will never see - and will never know why the thing didn't reach the 2nd stage (or the 1st).

kingkawn 5mo ago
This is because a broad spectrum antibiotic with low resistance is an essential public good that will likely rapidly be made generic by either legal action or international disregard for copyright law. So no major pharma companies will want to invest resources into the development of something like this, and governments are not under the gun enough to produce new abx to invest the billions needed to get it through the approval process. The compromise is to leave it sitting at this phase until some disaster creates enough public incentive to socialize the completion of its development.
arcticfox 5mo ago
This story actually checks out, which is quite the condemnation of our American drug development system. One thing bugs me though - why don't other countries with different research structures pick this up and run with it?
- toast0 5mo ago
  I agree... Medication Resistant bacteria is a problem everywhere. There's probably no money in a new antibiotic, but... Having something new to fight TB would be nice, and there's still prestige, even if you "just" brought it to market and didn't discover it. I would think there are pharma teams in China or India, maybe even Russia that could replicate and further develop something like this, given the initial paper and PR.
  - awesome_dude 5mo ago
    My immediate thought - there probably are these teams overseas doing these things - just, our media/markets shun them. I mean, the covid vaccinations - people are/were doing their nut about the Euro/US versions, but the Russians had their own, the Chinese had two, and I am aware that the Chinese were handing it out to other countries as part of their aid programs (the effectiveness of those vaccines, however, has been questioned, especially in comparison to the Euro/US ones, but I'm not sure if that's reality or politics, it's so damned hard to tell these days)
- cyberax 5mo ago
  > This story actually checks out, which is quite the condemnation of our American drug development system. Oh yeah, "corporations", "end-stage capitalism", blah blah. The reality is that 95+% of drug candidates fail the trials. And a lot of them only fail during the Phase-3 where the efficacy is tested. It's likely that large companies tried it in-house and found that it's either too toxic or is ineffective in-vivo.
  - vazma 5mo ago
    I guess you are right but can you please provide a source of the failed trials for this case!
    - cyberax 5mo ago
      Looks like there are none, which is the typical result. If you worked in a drug-discovery-adjacent field, this is an utterly normal scenario: 1. University/startup company finds a promising drug candidate that works in-vitro. They make a press-release, researchers write their theses, and move on. 2. Drug companies pick that up and run small-scale tests. These tests are negative, usually because of unexpected toxicity. Looking at the molecule in question, it's likely what happened here. It's a covalent inhibitor, meaning that it permanently binds with the protein. It's also allosteric, meaning that it binds to the target enzyme but not at the actual active site. This is a huge red flag for toxicity, because it's likely going to bind to other proteins that can have similar configurations. 3. But the underlying idea is sound, so companies keep working on alternative approaches. They are likely looking for non-covalent compounds now, or for things like "suicide inhibitors". 4. You'll see actual trials in 10-15 years after the initial press-release. Most likely for completely different compounds, targeting the same mechanism.
      - awesome_dude 5mo ago
        There was what I thought was a breakthrough in Schizophrenia diagnosis and treatment - the University of Washington held that groups of genes acting in concert were causing the disease, and, in fact, there were multiple variants of genes producing (what had always been suspected) different diseases that were bing lumped together. For the longest time I had been trying to figure out why nobody was taking the research seriously, why there weren't diagnostic kits available that determined which variant people were actually suffering from, and using the appropriate drug regime to manage the specific condition the patient had. Then, last year I saw a paper being discussed (some 5 - 10 years after the initial paper), and it was building on the Washington research - it appears to me now (keeping in mind that I am a layman and an outsider) that the research /had/ been taken seriously, but it's seen as a signpost on the pathway rather than the destination.
- elzbardico 5mo ago
  American salaries and research funding are way bigger. The best scientists around the world have a strong incentive to emigrate. And the ones who don't, can't do much with the scarce funds they have, compared to America.
NDlurker 5mo ago
It was pretty common for message board users to come together to do group buys for novel research chemical synthesis 15-20 years ago. Not sure why things like this would be any different.
cubefox 5mo ago
Similar thing, permanent anti-cavity bacteria: https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-the https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-th... The patents expired, so nobody can raise the hundreds of millions to do the phase II/III safety trials.
- fakedang 5mo ago
  It depends - if someone uses the same compound but provably for a different indication (like maybe anti-periodontic diseases or something) or for a different intake mechanism, they could get another patent and proceed with trials. Granted, it's not going to be easy because the original patent has expired so it's going to be very easy for an upstart Indian company to conduct basic clinical trials, use part of the data of the second patent's holder to prove equivalency (they did this test so we don't need to do this test), and then get approved through an accelerated pathway in the FDA. Which is why even well-capitalized players will shy away from what could be a cash cow.
  - cubefox 5mo ago
    Anti-periodontic diseases are highly irrelevant compared to cavities. Not even the original cavity application did manage to get enough funding at the time. So there will be no Indian upstart, there is and likely will be nobody who invests the money into ultra expensive trials. The ship has sailed.
    - fakedang 5mo ago
      I wasn't trying to quote a directly applicable example, just wanted to illustrate a potential pathway for post-expiry commercialization.
maxbond 5mo ago
Is this particular drug head and shoulders above other candidates? Is it possible that the reason it hasn't gotten attention is because researchers have been looking at other cheaper or more promising candidates? (I do not know, I am genuinely asking.)
- pshirshov 5mo ago
  Same thing - I do not know. It got pretty decent media coverage back then - and nothing since.
strbean 5mo ago
See also https://en.wikipedia.org/wiki/Double-stranded_RNA_activated_caspase_oligomerizer https://en.wikipedia.org/wiki/Double-stranded_RNA_activated_... This one is quite tinfoil-hat inspiring, as the research was moved to defense-focused Draper Labs and then immediately disappeared.
katzito 5mo ago
Can't make moneyz if it works too wellz.

kingkawn 5mo ago

This is because a broad spectrum antibiotic with low resistance is an essential public good that will likely rapidly be made generic by either legal action or international disregard for copyright law. So no major pharma companies will want to invest resources into the development of something like this, and governments are not under the gun enough to produce new abx to invest the billions needed to get it through the approval process. The compromise is to leave it sitting at this phase until some disaster creates enough public incentive to socialize the completion of its development.

arcticfox 5mo ago

This story actually checks out, which is quite the condemnation of our American drug development system. One thing bugs me though - why don't other countries with different research structures pick this up and run with it?

toast0 5mo ago
I agree... Medication Resistant bacteria is a problem everywhere. There's probably no money in a new antibiotic, but... Having something new to fight TB would be nice, and there's still prestige, even if you "just" brought it to market and didn't discover it. I would think there are pharma teams in China or India, maybe even Russia that could replicate and further develop something like this, given the initial paper and PR.
- awesome_dude 5mo ago
  My immediate thought - there probably are these teams overseas doing these things - just, our media/markets shun them. I mean, the covid vaccinations - people are/were doing their nut about the Euro/US versions, but the Russians had their own, the Chinese had two, and I am aware that the Chinese were handing it out to other countries as part of their aid programs (the effectiveness of those vaccines, however, has been questioned, especially in comparison to the Euro/US ones, but I'm not sure if that's reality or politics, it's so damned hard to tell these days)
cyberax 5mo ago
> This story actually checks out, which is quite the condemnation of our American drug development system. Oh yeah, "corporations", "end-stage capitalism", blah blah. The reality is that 95+% of drug candidates fail the trials. And a lot of them only fail during the Phase-3 where the efficacy is tested. It's likely that large companies tried it in-house and found that it's either too toxic or is ineffective in-vivo.
- vazma 5mo ago
  I guess you are right but can you please provide a source of the failed trials for this case!
  - cyberax 5mo ago
    Looks like there are none, which is the typical result. If you worked in a drug-discovery-adjacent field, this is an utterly normal scenario: 1. University/startup company finds a promising drug candidate that works in-vitro. They make a press-release, researchers write their theses, and move on. 2. Drug companies pick that up and run small-scale tests. These tests are negative, usually because of unexpected toxicity. Looking at the molecule in question, it's likely what happened here. It's a covalent inhibitor, meaning that it permanently binds with the protein. It's also allosteric, meaning that it binds to the target enzyme but not at the actual active site. This is a huge red flag for toxicity, because it's likely going to bind to other proteins that can have similar configurations. 3. But the underlying idea is sound, so companies keep working on alternative approaches. They are likely looking for non-covalent compounds now, or for things like "suicide inhibitors". 4. You'll see actual trials in 10-15 years after the initial press-release. Most likely for completely different compounds, targeting the same mechanism.
    - awesome_dude 5mo ago
      There was what I thought was a breakthrough in Schizophrenia diagnosis and treatment - the University of Washington held that groups of genes acting in concert were causing the disease, and, in fact, there were multiple variants of genes producing (what had always been suspected) different diseases that were bing lumped together. For the longest time I had been trying to figure out why nobody was taking the research seriously, why there weren't diagnostic kits available that determined which variant people were actually suffering from, and using the appropriate drug regime to manage the specific condition the patient had. Then, last year I saw a paper being discussed (some 5 - 10 years after the initial paper), and it was building on the Washington research - it appears to me now (keeping in mind that I am a layman and an outsider) that the research /had/ been taken seriously, but it's seen as a signpost on the pathway rather than the destination.
elzbardico 5mo ago
American salaries and research funding are way bigger. The best scientists around the world have a strong incentive to emigrate. And the ones who don't, can't do much with the scarce funds they have, compared to America.

NDlurker 5mo ago

It was pretty common for message board users to come together to do group buys for novel research chemical synthesis 15-20 years ago. Not sure why things like this would be any different.

cubefox 5mo ago

Similar thing, permanent anti-cavity bacteria: https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-the https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-th... The patents expired, so nobody can raise the hundreds of millions to do the phase II/III safety trials.

fakedang 5mo ago
It depends - if someone uses the same compound but provably for a different indication (like maybe anti-periodontic diseases or something) or for a different intake mechanism, they could get another patent and proceed with trials. Granted, it's not going to be easy because the original patent has expired so it's going to be very easy for an upstart Indian company to conduct basic clinical trials, use part of the data of the second patent's holder to prove equivalency (they did this test so we don't need to do this test), and then get approved through an accelerated pathway in the FDA. Which is why even well-capitalized players will shy away from what could be a cash cow.
- cubefox 5mo ago
  Anti-periodontic diseases are highly irrelevant compared to cavities. Not even the original cavity application did manage to get enough funding at the time. So there will be no Indian upstart, there is and likely will be nobody who invests the money into ultra expensive trials. The ship has sailed.
  - fakedang 5mo ago
    I wasn't trying to quote a directly applicable example, just wanted to illustrate a potential pathway for post-expiry commercialization.

maxbond 5mo ago

Is this particular drug head and shoulders above other candidates? Is it possible that the reason it hasn't gotten attention is because researchers have been looking at other cheaper or more promising candidates? (I do not know, I am genuinely asking.)

pshirshov 5mo ago
Same thing - I do not know. It got pretty decent media coverage back then - and nothing since.

strbean 5mo ago

See also https://en.wikipedia.org/wiki/Double-stranded_RNA_activated_caspase_oligomerizer https://en.wikipedia.org/wiki/Double-stranded_RNA_activated_... This one is quite tinfoil-hat inspiring, as the research was moved to defense-focused Draper Labs and then immediately disappeared.

katzito 5mo ago

Can't make moneyz if it works too wellz.