GoKawiilThere exist drug classes that seem, in retrospect, cursed. As these chemicals worm their way through the clinical trial system, they consume billions of dollars along the way, and squelch through thousands of sick patients. When finally it dawns on everyone how useless the whole endeavour was, the drugs life is at last cut short, nothing useful left in its destructive wake. The prototype here are amyloid-beta drugs. These are Alzheimer’s treatments that are widely perceived as immense disappointments, with the negative sentiment even leaking to the broader public. To be fair to these chemicals, the story here is a bit more complicated than the tabloids let on. Lots of amyloid research was not fake, and the drugs may genuinely be useful for early-stage Alzheimer’s. But they remain, regardless, disappointments.
Beyond amyloid-beta, which has been steadily disappointing for awhile now, there is one other such category of drug whose particular dance has just recently wrapped up. It may very well someday gets its chance in the spotlight, but it will take time. Because it—just like every other chemical in this class—shares a searing, burning radioactivity. You should not touch them. You should not suggest touching them. In fact, no serious person should touch them for years to come, because to do so will be to receive the scorn of other serious people.
What I am talking about are, of course, TIGIT drugs.
TIGIT emerged in the wake of boundless enthusiasm from over a century of grueling cancer immunotherapy research. Much of this work went nowhere, but a small fragment of it helped produce the most valuable molecule in existence: Keytruda (pembrolizumab). This drug was so astonishingly, grossly successful that it would be barely an exaggeration to credit Keytruda with creating a Big Pharma. Since its approval in 2014, it has saved millions of years’ worth of patient lives, and will likely continue to save millions more.
So, if you worked in pharma R&D in the mid-2010’s, and you were on the hunt for the next big thing, “something like Keytruda” was the most attractive thing on the board. And TIGIT drugs were supposed to be that.
An explanation of what TIGIT actually is would require you to hold roughly seven concepts in your mind at the same time, the names of which—in characteristic immunology fashion—are not helpful in the slightest. What is important to understand is that TIGIT is a particular protein, and theorized to be another immune-system brake. The aforementioned century of immunology research had already proven that these brakes mattered: Keytruda worked by blocking a different brake and allowing immune cells to attack tumors again. TIGIT seemed to offer the same promise, since tumors appeared to exploit it to quiet nearby immune cells. But this story was set to be even more intriguing. Unlike Keytruda’s target, TIGIT sat at an especially busy intersection of immune regulation. Blocking it might not merely release one brake, but rather two brakes and one accelerator, tilting the local immune environment towards such an absurdly anticancer direction that it was unthinkable that it wouldn’t be clinically effective.
So, the theory went: block TIGIT, or create an ‘anti-TIGIT’ drug, and you’ve got something even better than Keytruda on your hands.
Dollar signs appeared in the eyes of nearly every pharmaceutical executive upon learning this. Roche was the first here, their group establishing the above scientific observations, publishing them in a 2014 paper. "The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function”. The molecule that emerged from this work was something called tiragolumab; the first anti-TIGIT drug to exist.
Its initial clinical debut was at ASCO 2020, a major oncology conference. There, Roche discussed the results of a 135-patient phase 2 trial in metastatic non-small-cell lung cancer, randomizing patients one-to-one to the standard-of-care, plus either tiragolumab or placebo. The combination produced a response rate of 31% versus 16% in the placebo. Tiragolumab seemed to work. Yes, it wasn’t a cure for cancer, but neither was Keytruda, which still managed to rake in nearly ten billion dollars a year. The FDA granted tiragolumab a breakthrough designation in January 2021 on the basis of that study, and, within a year, Roche began to spin up phase 3 trials.
Blood was in the water for TIGIT, and though Roche was first to bite, others followed. Merck had vibostolimab. BMS had BMS-986207. BeiGene had ociperlimab, for which Novartis paid $300 million in early 2021 for co-development rights. Arcus had domvanalimab, for which Gilead in late 2020 paid $175 million up front plus a $200 million equity position in the company. iTeos, a little Belgian immuno-oncology outfit, had something called EOS-448, which GSK licensed in mid-2021 for $625 million upfront. Everyone wanted a bite and was willing to pay for it.
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