Only the paranoid survive, and the CEO’s paradox, from Aoife Brennan

How CEOs are managing through uncertainty, and why ‘boring’ naked mAbs are the smart move in one field

Leading companies through the turbulence of the past few years and the uncertainty of the next ones takes not just resilience, but an ability to grapple with the CEO’s paradox, according to Climb Bio President and CEO Aoife Brennan.

This paradox requires preparing for repeated setbacks while planning optimistically, a duality that has been the story of biotech since the outbreak of the pandemic, said Brennan, speaking on The BioCentury Show.

“We’ve reached a point of everyone expecting that it will get better, but also preparing for it not to be the case, because this time last year we were hoping that J.P. Morgan was going to bring a new enthusiasm, and new opportunity in the New Year, and it didn’t materialize,” said Brennan, adding the same had happened the year before.

Brennan joined  Climb Bio Inc. (NASDAQ:CLYM) in June, after having served as CMO and then CEO of Synlogic Inc., a company she had to shutter after discontinuing a Phase III trial in February. That journey, against the backdrop of the pandemic and then the extended bear market, has forged a philosophy that embraces complexity and relies on building optionality.

“There’s just lots of uncertainty in the world,” said Brennan. Even in a situation where interest rates seem to be coming down and trending in the right direction, uncertainties such as the new administration and the regulatory environment are on executives’ minds. “I think CEOs as a group have become super resilient over the last couple of years and ready for different eventualities and curveballs to come our way, which, I think, is actually a really healthy way to operate,” she added. “You know, they say only the paranoid survive.”

Her decision to join Climb Bio came after taking other CEOs’ advice to not rush into the next role, and keep options open, a behavior that’s counterintuitive for many. “CEOs tend to be decisive — tend to like to make quick decisions and to move on things,” said Brennan.

While Synlogic had a new modality — engineered bacterial therapeutics — with novel and complex manufacturing, Climb Bio has a naked mAb against CD19 with a pipeline-in-a-product strategy for various immune indications. Here, there’s a fair amount of competition and tremendous interest, but mostly with products with more complex modalities.

“It’s kind of moved ahead of some of the other B cell targets in terms of its interest based on some of the clinical validation that has occurred just this year alone. I think there are many compelling datasets,” said Brennan. “And we know it’s differentiated from CD20 — it’s not just old wine in new barrels.” So the modality choice becomes key. 

CAR Ts are effective, “but will probably remain limited to a small subset of patients with severe disease,” she believes, and there are allogeneic NKs, CAR Ts, bispecific antibodies and mAbs. “The modality that has the best validation is the naked antibody,” said Brennan. While there’s Uplizna inebilizumab from  Amgen Inc. (NASDAQ:AMGN) approved in neuromyelitis opticum spectrum disorder (NMOSD) and in Phase III for myasthenia gravis and IgG4-RD, Brennan sees potential beyond Amgen’s rare neurological indications into other areas.

“What’s more interesting as a clinical developer is how we can think about learning from their program, and think about dosing and making sure that we get the right dose that doesn’t leave any efficacy on the table — how we can think about finding the right patients who are going to really have the best benefit from this approach.”

The simple modality is an advantage, she argues. “We see that while CD19 as a space is crowded, there are multiple CAR T programs and T cell engagers. There aren’t that many companies pursuing a little old boring antibody like we are.”  She added, “if I’m an investor, I kind of like boring. Many of the sexy companies have blown up in the last couple of years.”