Schadenfreude versus optimism in drug development

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I wrote a post for the RoP fellowship about how optimism drives progress in difficult industries like pharmaceuticals, and how a culture of pessimism might act as an impediment to progress. Appreciate any feedback.

Last week, Endpoints put out a widely-read article noting how the leading AI-native biotech start-ups have so far failed to live up to expectations. AI-for-drug-discovery pioneers Exscientia, BenevolentAI, and Recursion have seen their first crop of drugs bomb in clinical trials, be abandoned by partners, or otherwise suffer setbacks. Recursion, for one, is lagging far behind its early goal of putting 100 drugs into clinical trials in 10 years (so far, it’s managed four). Although it’s still early days for AI, it’s not a great start.

Yet what struck me about the article was not so much the content, but the response. I noticed in the reaction to that article a sort of glee in failure, or schadenfreude, among some of the biotech commentariat. It’s not the first time I’ve noticed this type of reaction. There is often a quickness to take pleasure in the downfall of people or companies associated with bold, even hubristic claims — particularly if they were relative newcomers to the industry.

“Haha, yes! Finally they know our pain.” says the grizzled industry veteran. “They were such fools to think it would be easy; biology is our god — and she hates us!”

When 90% of drugs fail in clinical trials, it’s no wonder the industry has developed an allergic reaction to hype. Bluff and bluster dissolves in the acid empiricism of the randomised clinical trial: “Show me the data,” says the industry vet.

Although AI is a rich vein of hype, it’s far from the only source. Take EQRx, a (now defunct) biotech with the stated ambition of reducing drug costs by undercutting expensive brands with cheap, fast-to-market copycats. If EQRx were successful, they’d have been the Lidl or Kirkland signature of biotech — with ‘own brand’ versions of blockbusters like Keytruda and Ibrance. As the CEO Alexis Borisy said in a launch interview:

“At EQRx we are trying to rethink, reimagine, reengineer the whole way that we make medicines from creating them, proving they work, and getting them to patients… our ambitions are large, we want to have our first drug on the market within five years. We’d like to have 10 on the market within 10 years. By 15 years we want to have literally dozens and dozens of these great innovative new medicines at a radically more affordable price on the market.”

But even copying established drugs is no trivial feat, and EQRx imploded before bringing even one drug to market. The pricing and regulatory hypothesis behind the business was flawed, yes, and in many ways EQRx’s failure was entirely predictable: there were no shortage of post-failure “I told you so’s.”

Personally, I’m glad EQRx tried. Innovation isn’t helpful if it’s unaffordable, and the current drug pricing trajectory is not sustainable long-term. The answer is not to throw up our hands and say “that’s just how it is,” and that EQRx were foolish to think otherwise.

On the one hand, scepticism is often warranted. Biotech is complicated and biological data are often ambiguous, which makes it all too easy to obfuscate in order to take advantage of desperate patients and unsophisticated investors. Those in the industry should be calling out bad actors.

On the other hand, it’s almost tautological to say that biotech is a difficult industry. Every drug development program has warts, and it’s easy to predict failure; if you simply predict any given drug will fail you’ll be right about 90% of the time. Pessimism sounds smart, even if it’s not.

Anyone who has been around in biotech long enough has accumulated plenty of scar tissue. In Derek Lowe’s words, “the default setting for people in the pharmaceutical industry is a sort of enlightened pessimism.” Risk aversion is endemic in the industry, and a career can be built on saying ‘no.’ The fibrotic effect of experience can be tough to resist, but someone needs to be willing to say ‘yes’ if we are to make progress.

It takes champions to drive any drug through development. It takes people who are unreasonably optimistic about their likelihood of success to found industry-defining companies. Often, such people are prone to hyperbole: Bob Swanson, the co-founder of Genentech along with Herb Boyer, painted a suitably grand vision in their 1976 business plan:

“With Genentech’s technology, microorganisms could be engineered to produce needed protein to meet the world food needs or to produce antibodies to fight viral infection. Any product produced by a living organism is eventually within the company’s reach.”

Genentech fell short of this original vision, of course. Yet, along the way it still managed to kick-start the biotech industry, develop the first recombinant insulin, and pioneer therapeutic monoclonal antibodies.

We should welcome people with a vision to do things better in our industry. And while bold visions often seem naïve to veterans, naïveté can be a blessing. Herb Boyer agrees:

“I always maintain that the best attribute we had was our naïveté. . . . I think if we had known about all the problems we were going to encounter, we would have thought twice about starting. . . . Naïveté was the extra added ingredient in biotechnology.”

If we keep believing drug development is near-impossible, it might just stay that way. And while the latest suite of AI tools seems likely to be an incremental advance, stacking incremental advances is how we’ve made extreme cumulative gains over many years.

The industry needs optimists to push it forwards. In the words of Karl Popper:

“Optimism is a duty. The future is open. It is not predetermined. No one can predict it, except by chance. We all contribute to determining it by what we do. We are all equally responsible for its success.”

So yes, let’s be critical of hype and hubris – another Theranos helps nobody. But let’s also be careful not to dissuade optimism. Drug development is unreasonably hard, so it needs unreasonably optimistic people.

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