3 ms·

I work in the side of academia that feeds drug leads to pharma and have seen this process. The big problem aside from time is cost and scale. You might start w

by jdoe2020 2y ago

I work in the side of academia that feeds drug leads to pharma and have seen this process. The big problem aside from time is cost and scale. You might start with either a million compound in silico 10000 compounds in a high throughout enzyme screening program. You might get 500 hits with reasonable affinity which you put those in cell cultures and get 50 compounds. Then you go a small scale mouse study and may get 5-10 decent hits that don't have very obvious tox issues. Then you do a large mouse study of those for efficacy. You will get 1-2 compounds that may be suitable to go into people and there is maybe a 10% chance you get through phase III and onto the market. Usually there is also a step in monkeys before it goes into people. The main issue here is that at each of those steps the cost scales 10-100x so you really, really need cut cost as much as possible and eliminate non promising candidates. Realistically if a molecule doesn't work in mice sure it could work in humans, but you'd be better off just doing the mouse study so you only need to run one trial instead of 10 and use the savings to invest in other trials. Human trials are insanely expensive. One of my colleagues works at a company that pays well over $100k for a single primate for preclinical testing. Doing it in people is even more expensive with the massive costs of just organizing and insuring a trial. Comparatively it is very easy and cheap to inject a couple dozen mice with a drug and watch them for 6 months. Also mixing trial candidates is a really bad idea, CYP liver enzyme reactions are a real thing and are often very different for humans and animals. Doing it with one drug is dangerous enough, but mixing 25 where one may inhibit decomposition of another is a recipie for dead people. You'd also need a very very large number of people (likely thousands) to deconvolute the statistical noise.

BenFranklin100 2y ago
To add to your point, over the least decade animal models are increasingly being seen as models of specific mechanisms, rather than as complete models of a human disease. To relate this back to the AD field, researchers have developed mouse models to better understand the specific steps in the development of a form of angiopathy seen in humans, cerebral amyloid angiopathy; that is, amyloid plaques that develop on blood vessels. This is being done in the hope that these models will elucidate the basic biology of CAA, and thus help researchers make more informed no/go decisions about CAA therapies in humans.
- jdoe2020 2y ago
  This is really good point. People underestimate he degree failed trials have value in understanding the basic science behind diseases, especially mechanistically complex ones.
hirvi74 2y ago
I appreciate you listing some of the complexities and issues of human trials. I learned some new information and perspectives that I have not considered before. However, I am not entirely convinced such trials could still not be efficiently and ethically conducted in some way. If I can have little "Organ Donor" checkbox on my license, then I do not see why I could not have a little "Alzheimer's Experiment Donor" checkbox either. I'm not saying it would be easy to conduct, and obviously there would have to be more stipulations than I have mentioned. Alzheimer's is an ultimately fatal disease and ain't a pretty way to go out. What do these sufferers have to lose? You can't kill a deadman.
- AbstractH24 2y ago
  Rationally what you are saying makes sense, but the problem with progressive diseases like Alzheimer’s is not just defining the point at which quality of life is so poor you might as well throw spaghetti at the wall with the hope of helping society if not the individual, but also getting people and their caretakers to admit they’ve reached that point. Then there is potential legal liability if someone disputes a doctor’s choice after the fact.
- jdoe2020 2y ago
  I mean for AD it could perhaps be useful (of course it would not work for most other diseases) but legally that is very dicey because of informed consent. TBH we are not even sure if AD is one even one disease or if it multiple masquerading as one. We aren't even sure if amalyoid beta is a major contributor or cause. Or if it is an effect of the disease. The field is fraught with controversy and even seminal papers have been retracted. But getting back to that lack of understanding of the root cause this is why mice are useful, if we have a reproducible AD like phenotype in a transgenic mouse line that gives us some fundamental understanding of the underlying disease process in a way that likely wouldn't be possibly in a possibly polymorphic human disease population. You can also dose the mice at the same point in the disease process which is very useful in getting statistical significance for an effect. I also don't think you'd get enough people and they would be spread out all over the country. Hard to administer your proprietary drug in 100 different nursing homes. Much easier to walk down the mouse facility in the basement

BenFranklin100 2y ago

To add to your point, over the least decade animal models are increasingly being seen as models of specific mechanisms, rather than as complete models of a human disease. To relate this back to the AD field, researchers have developed mouse models to better understand the specific steps in the development of a form of angiopathy seen in humans, cerebral amyloid angiopathy; that is, amyloid plaques that develop on blood vessels. This is being done in the hope that these models will elucidate the basic biology of CAA, and thus help researchers make more informed no/go decisions about CAA therapies in humans.

jdoe2020 2y ago
This is really good point. People underestimate he degree failed trials have value in understanding the basic science behind diseases, especially mechanistically complex ones.

hirvi74 2y ago

I appreciate you listing some of the complexities and issues of human trials. I learned some new information and perspectives that I have not considered before. However, I am not entirely convinced such trials could still not be efficiently and ethically conducted in some way. If I can have little "Organ Donor" checkbox on my license, then I do not see why I could not have a little "Alzheimer's Experiment Donor" checkbox either. I'm not saying it would be easy to conduct, and obviously there would have to be more stipulations than I have mentioned. Alzheimer's is an ultimately fatal disease and ain't a pretty way to go out. What do these sufferers have to lose? You can't kill a deadman.

AbstractH24 2y ago
Rationally what you are saying makes sense, but the problem with progressive diseases like Alzheimer’s is not just defining the point at which quality of life is so poor you might as well throw spaghetti at the wall with the hope of helping society if not the individual, but also getting people and their caretakers to admit they’ve reached that point. Then there is potential legal liability if someone disputes a doctor’s choice after the fact.
jdoe2020 2y ago
I mean for AD it could perhaps be useful (of course it would not work for most other diseases) but legally that is very dicey because of informed consent. TBH we are not even sure if AD is one even one disease or if it multiple masquerading as one. We aren't even sure if amalyoid beta is a major contributor or cause. Or if it is an effect of the disease. The field is fraught with controversy and even seminal papers have been retracted. But getting back to that lack of understanding of the root cause this is why mice are useful, if we have a reproducible AD like phenotype in a transgenic mouse line that gives us some fundamental understanding of the underlying disease process in a way that likely wouldn't be possibly in a possibly polymorphic human disease population. You can also dose the mice at the same point in the disease process which is very useful in getting statistical significance for an effect. I also don't think you'd get enough people and they would be spread out all over the country. Hard to administer your proprietary drug in 100 different nursing homes. Much easier to walk down the mouse facility in the basement