Have you ever heard of Nivien Therapeutics? Unless you follow the oncology world pretty closely, probably not. But they are – well, were – a startup out of Harvard that was working on a promising approach to overcoming chemotherapy resistance in pancreatic cancer. Now that’s what we call an “unmet medical need”, considering the steepness and swiftness of the death rates from resistant pancreatic tumors, and Nivien’s approach was a new one. They were targeting the Hippo pathway, which is normally a regulator of organ size during development. It was first discovered in Drosophila, and as is often the case the fruit flies led to an even more complicated situation in humans and other mammals on further research. The YAP/TAZ/TEAD transcription factors are involved in both the Hippo pathway and in many tumor types, though, which suggested that there could be an application in oncology. More specifically, it appeared that the YAP pathway itself might be one of the regulators of a general drug resistance pathway in tumor cells and that this had therapeutic potential.
Well, did it? Here’s an essay on Medium from founder Nathaniel Brooks Horwitz, and here’s an epitaph from John LaMattina at Forbes. Those, and my switch to the past tense in the above paragraph, will give you the short answer: it turns out that inhibition of this pathway is (A) possible but (B) not enough to be useful for cancer patients. I would not like to try to count the number of times I have experienced something similar over my career. Those have been within the structure of larger companies with more things going, so they didn’t wind up costing everyone their job as can happen with a startup, but it is a very common story on any scale. John LaMattina makes the same point, and he is also most definitely in a position to know from personal experience as well. Most ideas for new drugs, and new modes of action for drugs, don’t work out. Nivien didn’t even get to human trials themselves, with their famous 90% failure rate, but anyone who’s done this work will tell you that preclinical failure rates are no joke, either.
And both Horwitz and LaMattina are right that hardly anyone outside the industry seems to know this. That’s been one of the purposes of this blog from the beginning, to get across what it’s really like to do drug research (and to get across just how difficult and tricky it can be). The two opposite errors in talking about this work are to despair of anything and to hype everything, and you have to walk between those. The despair part is illustrated by my often-used example of not turning into the guy in the conference room who sits in the back and says “Yeah, that’s not gonna work” to every idea. You’re right 95% of the time, but to what end? And as for the hype part, here’s Horwitz:
It’s easy to accidentally generate the impression of an imminent win. Often, new biotechnologies really are revolutionary. Many companies, however, generate this impression intentionally, even when undeserved.
Raising money, recruiting people and building a movement around your mission almost demands irrational optimism, especially in failure-riddled drug development.
There is an allure and a danger to believing in something like this, giving it your all, and seeking to convince others to do the same while knowing the chances of success are lean. No one wants to commit to a marginal endeavor.
But employees want transparency. Investors want a fair bet. And patients, who know more than anyone, want honesty. They are not one-liners for your PR machines or slides for your pitch decks. Now, reading the latest and greatest biotech PR, I’m furious when I see overstated results and oversold potential.
That’s exactly the territory. Realism would demand that you make clear that you are very likely to fail, but that will not bring you any resources to even get that far. But the kinds of stories that some investors (and some journalists, and some patients) might want to hear the most are not the true ones, and that’s not good, either. Unfortunately, the field is absolutely drenched with that oversold potential, and there’s probably no way to keep that from happening, humans being what they are.
Horwitz’s essay is an honest look at just what it’s like to work out on the cutting edge of the business – new company, new mode of action, new chemical matter, new employees, new funding – and the story he tells is how most of those stories go. Just not quite all. And it’s that “not quite all” that keeps this whole business rolling. . .