People, Startups

One more gig: Steven Paul decides to extend a 35-year track record with one last shot at a big development program

Steven Paul was ready to hang up the lab coat when he stepped down near the beginning of the year as CEO of the gene therapy startup Voyager. After 35 years spent doing stints as a prominent top investigator at the National Institute of Mental Health, leading the early-stage neurosciences group at Eli Lilly and as a co-founder at Sage and Voyager, seeing out his career on some high-profile biotech boards like Alnylam seemed just right.

And then Karuna came calling, and yanked him right back into the day-to-day game of drug development.

This morning Paul is stepping out as the new chief executive of a startup which wants to show that one of the drugs he once championed at Lilly can now be readied for prime time as a significant new anti-psychotic for schizophrenia — and then some.

Andrew Miller

Until today, Paul was the chairman at Karuna. But just after completing a $42 million round — with a new crossover raise in the offing — Paul is back as the main man in charge. He’s taking the place of founder Andrew Miller, who is transferring to a new post as chief operating officer.

What brought him back to the helm? Xanomeline. 

Newly arrived at Lilly in the early ’90s, xanomeline was one of the lead drugs Paul inherited in the neurosciences pipeline. There was reason to believe that the drug would improve symptoms of Alzheimer’s in patients, with a tested ability to hit the M1 and M4 muscarinic receptors, with some activity on M2 and M3.

“We did see an effect on memory,” Paul told me in a preview of today’s announcement, “similar to Aricept. What was quite surprising, we measured psychotic symptoms in a demented elderly subgroup that had psychosis. And what we saw was a nice dose-dependent reduction in paranoia, vocal outbursts and so on, compared to placebo.”

What they also saw was a not-so-nice set of anticholinergic adverse effects, about what you would expect now in a muscarinic receptor agonist. Lilly, meanwhile, was off to establish the mega-blockbuster Zyprexa, and another drug tied to severe weight gain and more was not in the cards.

There it would have ended, except for research suggesting that a combination approach adding trospium chloride to the mix for a new drug they’ve dubbed KarXT could block the side effects and leave the anti-psychotic effect in place. And there’s additional research to underscore its potential in pain as a non-opioid. 

It’s not a big crew. Paul counts about 6 key staffers at Karuna, with plenty of outsourced help. But it’s growing as they plot a big Phase II to nail down evidence of efficacy and safety among schizophrenic patients. That trial will get underway in a couple of months now, as Karuna raised more cash and lays the foundation for what could be one big pivotal trial to put themselves over the top — or join the heap of neurosciences failures that have accumulated over the past decade.

“I worked closely with Steve at Sage Therapeutics and his experience and creativity in the field is rare,” said Bob Nelsen, managing director of ARCH Venture Partners and a board member at Karuna. “KarXT’s potential to meet unmet patient need is exciting and Steve’s experience is perfectly aligned to support Karuna’s goal of delivering first-in-class drugs for treating psychosis, cognitive impairment, and pain.”

Paul has been thinking about this for years. Now he has the chance of proving this theory. And he couldn’t be more eager about the opportunity.


Image: Steven Paul. KARUNA


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