Great writeup. I'm curious, what happened at the preclinical stage? What mouse models did they test on? Were the results in mice as impressive as Keytruda's? With this much money being poured into trials, I can only imagine seismic preclinical efficacy.
Great history of TIGIT. So many people claimed "see I told you so" publicly at the first signs of failure, but behind closed doors there was a lot disbelief that the target didn't work.
There is such a long and growing list of I/O targets tried next to PD-(L)1 that have bit the dust. IDO was the OG surprise failure story, but TIGIT took it to another level. Funny to think it's just CTLA-4 that has really made it to the finish line. LAG-3 partially too, I guess. Although, that may only be relevant in melanoma.
I've advocated for more companies flipping the script on these failed I/O targets. Perhaps they may not work in Onc, but if you flip the signaling maybe they'll work in autoimmune. We've seen some success with CD40 and OX40 (but also some failures), but would be interesting for someone to look into agonizing TIGIT, IDO, etc in other TAs.
This is so depressing. Is principled biology even possible or is every trearment forever going to live in the dumpster of "mechanism of action not fully understood?" Are we just too dumb?
I'm trying to save Civilization by drawing attention to an extraordinary moment that's trying to happen. The monks Theory of Everything is explaining mystery after mystery after mystery while our scientists are saying crazy things and admitting that they can't make sense of any of the crazy things they are saying and now cannot understand 95% of the universe.
We need to quickly start solving our problems which this allows us to do otherwise we will resort to violence to solve our problems. I was hoping that you would help me avoid that by letting me somehow talk to your audience or maybe write an article with you to your audience about this exciting moment and get some attention that it deserves?
In finance/tech, bubbles are good for investors who got out at the top, and good for citizens who stayed uninvolved, and very bad for shmucks who bought in too late. We end up with all this useful, somewhat general purpose, capital that ends up being a subsidy for future innovation, paid for by the people who went bust. Is there a similar dynamic at all in pharma that can soothe the pain from all this wasted capital? The target didn't work, is there any underlying infrastructure (outside of more researchers who've cut their teeth) that will be repurposed and could lead to later breakthroughs?
Great story that illustrates many themes in drug development: herding, overcommitment, and the basic unfairness of nature. I too would be interested to know the preclinical evidence in more detail though - how convincing was it really?
Great writeup. I'm curious, what happened at the preclinical stage? What mouse models did they test on? Were the results in mice as impressive as Keytruda's? With this much money being poured into trials, I can only imagine seismic preclinical efficacy.
Great history of TIGIT. So many people claimed "see I told you so" publicly at the first signs of failure, but behind closed doors there was a lot disbelief that the target didn't work.
There is such a long and growing list of I/O targets tried next to PD-(L)1 that have bit the dust. IDO was the OG surprise failure story, but TIGIT took it to another level. Funny to think it's just CTLA-4 that has really made it to the finish line. LAG-3 partially too, I guess. Although, that may only be relevant in melanoma.
I've advocated for more companies flipping the script on these failed I/O targets. Perhaps they may not work in Onc, but if you flip the signaling maybe they'll work in autoimmune. We've seen some success with CD40 and OX40 (but also some failures), but would be interesting for someone to look into agonizing TIGIT, IDO, etc in other TAs.
Wrote about that briefly a while back: https://www.bigpharmasharma.com/p/flipping-the-script-on-failed-immuno?utm_source=publication-search
This is so depressing. Is principled biology even possible or is every trearment forever going to live in the dumpster of "mechanism of action not fully understood?" Are we just too dumb?
We’re probably too dumb yeah
now do LAG3 😭
Loved reading this! Great storytelling
Has anyone tried an fc-active TIGIT bi-specific that would kill T cells less but would bind to another tumour antigen?
I'm trying to save Civilization by drawing attention to an extraordinary moment that's trying to happen. The monks Theory of Everything is explaining mystery after mystery after mystery while our scientists are saying crazy things and admitting that they can't make sense of any of the crazy things they are saying and now cannot understand 95% of the universe.
We need to quickly start solving our problems which this allows us to do otherwise we will resort to violence to solve our problems. I was hoping that you would help me avoid that by letting me somehow talk to your audience or maybe write an article with you to your audience about this exciting moment and get some attention that it deserves?
In finance/tech, bubbles are good for investors who got out at the top, and good for citizens who stayed uninvolved, and very bad for shmucks who bought in too late. We end up with all this useful, somewhat general purpose, capital that ends up being a subsidy for future innovation, paid for by the people who went bust. Is there a similar dynamic at all in pharma that can soothe the pain from all this wasted capital? The target didn't work, is there any underlying infrastructure (outside of more researchers who've cut their teeth) that will be repurposed and could lead to later breakthroughs?
Great story that illustrates many themes in drug development: herding, overcommitment, and the basic unfairness of nature. I too would be interested to know the preclinical evidence in more detail though - how convincing was it really?
Enjoyed reading this.
How difficult is it to define an acronym(?) used 41 times in an article?
is it useful to know that it stands for ‘T cell immunoreceptor with Ig and ITIM domains’
Thanks for writing this.