A Third Rock Ventures-incubated startup called Marea Therapeutics debuted Tuesday with $190 million to advance a drug for a genetic target for cardiometabolic diseases.
The San Francisco-based biotech has licensed a Novartis antibody targeting ANGPTL4, a gene long tied to risk of heart disease and cardiac events, which is already in a Phase 2 study. Josh Lehrer joined as CEO in October after leading gene-editing startup Graphite Bio, and Ethan Weiss is Marea’s chief scientific officer and a co-founder — having shut down his University of California, San Francisco lab in 2022 to work full-time on the company.
“This is the first time I’ve ever had a paycheck that doesn’t come from the University of California,” said Weiss, who came to UCSF 26 years ago and is still treating patients at its hospital as he jumps into the biotech industry for the first time.
Marea started out of a pandemic-era chat in August 2020 between Weiss and Charles Homcy, now a partner emeritus at Third Rock. The two discussed areas still unaddressed in cardiometabolic health, despite major advances with GLP-1 agonists for obesity, Lp(a)-targeted therapies for heart disease, and success with other heart-related genetic targets like PCSK9, ANGPTL3, and APOC3.
The two agreed on a need for finding different drugs, Weiss said, especially to improve insulin resistance and potentially alter the distribution of fat on the body, rather than just losing weight. In searching for genetic targets with human validation, ANGPTL4 was “very much at the top of the list,” Weiss said.
After nearly four years of quietly gearing up, Marea has raised a $190 million combined Series A and B that will take it deeper into the clinic, including plans to start a Phase 2b study in the first half of 2025. Investors beyond Third Rock include Sofinnova Investments, venBio, Forbion, and Perceptive Xontogeny Venture Fund. Ted Love, the former CEO of Global Blood Therapeutics, chairs its board. The company currently has about 10 employees.
‘Perceived safety overhang’ dampens ANGPTL4 interest
The ANGPTL4 gene plays a role in regulating how the body processes fat. The company will be nearly alone in pursuing a drug targeting it, however — though not for lack of recognition of the gene.
In 2016, Regeneron linked ANGPTL4 with heart disease in a New England Journal of Medicine paper using large-scale human genetics data. But that paper also revealed why the drug industry has stayed away, with safety signals coming up in animal testing, mainly lymphadenopathy, or the swelling of lymph nodes. Regeneron never advanced an ANGPTL4-targeting antibody beyond mice and primates.
“One of the reasons we have a first-in-class asset with really no competition is there’s been a kind of perceived safety overhang,” Lehrer said.
Technically, there is at least one competitor: A tiny Swedish biotech called Lipigon Pharmaceuticals is advancing an antisense oligonucleotide against ANGPTL4 into Phase 2.
Marea’s team felt more certain about the target after completing some of their own, as-of-now unpublished research. Weiss said they ran a prospective analysis that identified about 17 or 18 people from the UK Biobank’s genetics data who were living with their ANGPTL4 gene knocked out and who had also received abdominal MRI scans.
Marea’s team presented those MRI scans to a radiologist, who found no evidence of inflammation, increases in lymph nodes, or collection of fluid in the stomach, Weiss said, which were the key safety worries raised in other animal studies.
“That was a big step in making us feel comfortable,” Weiss said.
Investors commonly asked Weiss why this target was overlooked by so many in the industry if it’s so promising, Weiss said. He responded with a comparison to house hunting that he heard from a real estate agent.
“The property you want to buy is the property with a fixable problem, not the property that’s perfect because you’ll overpay,” he said. “But also not a property with an unfixable problem. You don’t want to buy something with, like, nuclear waste on your property. This, to me, fell into the category of there’s a problem here, it scared a lot of really smart people away, but we think it’s fixable.”
Lehrer and Weiss also reviewed Phase 1 results from the ex-Novartis antibody at the licensing table. Those results, too, remain unpublished, but Lehrer said the data showed a single dose having good safety and tolerability. He added they have not seen any lymph node changes in humans treated with the antibody.
Beyond ANGPTL4, Lehrer said Marea is building a pipeline that includes a homegrown program that is “pretty close” to nominating a development candidate. He said the company will likely disclose more on other targets later this year.