We have the answer to a question posed here earlier this month. That was after the Merck/Incyte failure of a combination of Keytruda and Incyte’s IDO (indole 2,3-dioxygenase) inhibitor. That mechanism was supposed to increase T-cell activity, but the trial showed it to have no effect on Keytruda’s efficacy at all. Earlier IDO trials had not gone well for other companies, but there had been hopes for this one.
Just as there were hopes for another inhibitor that Bristol-Myers Squibb had bought from Flexus (which is quite a tangled tale in itself). I wondered at the end of that last post if the Merck/Incyte failure meant that the BMS/Flexus effort was doomed as well – everyone who follows this area was wondering the same thing – but as some readers pointed out, the Flexus inhibitor did have a somewhat different mechanism of action, so there was at least a chance.
Scratch that. Yesterday, Andy Biotech noticed (and posted on Twitter) that the two Phase III trials had quietly been scrapped on clinicaltrials.gov. So I think we can say that (at least as currently configured) the excursion into IDO inhibitors has been a costly mistake. And remember, as is almost always the case in these things, that it didn’t look like it was going to be any such thing. IDO inhibition made sense in terms of what we knew about its biochemical pathway and the workings of T-cells, which is why you saw several companies taking a whack at it (Pfizer was in the area as well, and there are others whose preclinical programs you never even heard about). All in vain.
There’s a great big central problem of drug discovery for you: how do we go into the clinic (but avoid spending Phase III levels of money) to find these things out? Better yet, how do we avoid developing such things in the first place, if they’re going to do this to us? Billions of dollars, literal billions, are stacked up waiting for anyone who can start to begin to do such things. Just to pick on a recent hyped-up press release, could BenevolentAI’s “machine brain” have warned people off? Would anyone have believed them if they had? (I doubt that very much, for both questions).
No, the problem is that we’re doing things that no one has tried to do before, and we’re doing them on what is clearly incomplete information. And the only way to make it more complete is to. . .go ahead and do those things,apparently, and at great cost. Could you have warned everyone, in convincing fashion, not to chase IDO inhibitors? CB1 antagonists for obesity? Cathepsin K inhibitors? Anti-amyloid antibodies? Mixed PPAR ligands? CETP inhibitors? Substance P inhibitors? Gamma-secretase inhibitors? And I’m just picking ones off the top of my head that had multiple large research organizations working on them – there are plenty more where that came from, especially if you just bring in the targets that were disastrous for just one or two companies.
All of these looked like worthwhile ideas at one point, and uncounted sums of money were spent on them (money from sales of other drugs to other customers and directly from investors). All of it could have been put to better use, but could you have done better? Sent people into areas that were less likely to fail, or found out that these mechanisms had something wrong with them without all the time, effort, and money? Come on down and try it.