Marea Therapeutics launches to target remnant cholesterol

It all started with a tweet. Ethan J. Weiss, then a cardiologist at the University of California, San Francisco (UCSF), posted about his growing interest in the mechanisms of metabolism and weight gain. In particular, Weiss had taken note of a protein called angiopoietin-like 4 (Angptl4), which blocks lipoprotein lipase (LPL), regulating where and when the body stores fat.

Someone commented on the tweet, Weiss recalls, directing him to a company that had a molecule targeting Angptl4: Novartis. The Swiss pharma giant was looking to out-license the drug candidate. By spring 2022, Weiss had closed a deal giving the rights to that molecule to his new start-up, Marea Therapeutics.

Marea formally launched on Tuesday, with the molecule already in Phase 2 clinical trials. The $190 million that Marea has in venture funding—a series A led by Third Rock Ventures and a series B co-led by Sofinnova Investments, Forbion, Perceptive Xontogeny Venture Fund, and venBio—is meant to help see that study through to completion.

Marea is testing the hypothesis that by blocking Angptl4 and changing LPL activity, its lead drug candidate—a monoclonal antibody called MAR001—will accomplish a number of things. Those benefits would include lowering remnant cholesterol, improving adipose tissue and metabolic function, and reducing cardiovascular events like heart attacks. Targeting remnant cholesterol instead of low-density lipoprotein, often called “bad cholesterol,” is a relatively new concept, but remnant cholesterol appears to be a stand-alone risk factor for clogged arteries, heart attacks, and strokes (Eur. Heart J. 2021, DOI: 10.1093/eurheartj/ehab432).

“It seemed like overnight, this idea went from this concept Ethan [Weiss] was telling me about… and then there was a program,” says CEO Josh Lehrer, who joined the start-up in October 2023. “The big idea here is that maybe we’re sort of missing something in focusing on total body weight and classical risk factors.”

For Weiss and Lehrer, the start-up is also a personal reunion. The two met during their medical training and stayed in touch over the years, even as their career paths diverged. Weiss went on to academia, while Lehrer turned to industry, working first at Genentech, later at Global Blood Therapeutics, and then at Graphite Bio, which wound down last year.

It was Charles Homcy, a partner emeritus at Third Rock and fellow UCSF professor, who first lured Weiss away from academia. Weiss became an entrepreneur-in-residence at Third Rock after learning that Homcy wanted to investigate ways to treat cardiology patients with underlying metabolic issues. He ultimately resigned from his faculty position to help found the start-up and now works full time as its chief scientific officer. Other founders include biochemist Stephen O’Rahilly of the University of Cambridge and chemist Joshua Rabinowitz of Princeton University.

Marea has other preclinical programs in the works, although Lehrer and Weiss declined to unveil any specific timelines or targets. Weiss alluded to potential combination therapies down the line.

“As a relative newcomer-slash-outsider . . . the low-hanging fruit’s been picked,” Weiss says. “Our job in the next generation of drug development is going to be things like novel combinations.”