With $59M, Casma and Ex-Constellation CEO Take Aim at Cellular Trash

Xconomy Boston — 

Scientists have known for decades that cells can recycle their own trash, but they’ve only recently started to figure out how. Casma Therapeutics is trying to prove that those insights could be useful in treating a wide range of diseases.

Formed by Third Rock Ventures, Casma has secured a $58.5 million Series A round and named Keith Dionne, a longtime Boston-area biotech entrepreneur, its CEO. The Cambridge, MA-based company aims to develop drugs that can induce what’s known as “autophagy,” a process cells use to break down and recycle their waste, like dysfunctional proteins. When that process malfunctions or slows down, cellular garbage builds up and a variety of diseases—from rare genetic diseases to neurodegenerative disorders—ensue. The company came together shortly after key scientific work on autophagy won the Nobel Prize in Medicine in 2016.

Casma emerges at a time when a growing list of biotechs are trying to use chemical drugs to muck with the processes cells use to dispose of trash. Startups including Cedilla Therapeutics, C4 Therapeutics, Kymera Therapeutics, Nurix, Arvinas, and others, for instance, are focusing on “protein degradation,” meaning they are trying to make the cell’s internal garbage disposal system, the proteasome, get rid of harmful proteins. The method is a way for drugmakers to use tools they know well—small-molecule, chemical drugs—to get after disease-causing proteins they previously couldn’t touch. What’s driving the interest, Dionne says, is the recognition that “we can’t always inhibit the formation of negative or toxic molecules inside of a cell,” as chemical-based drugs are often designed to do. (Chemical & Engineering News has more on the field and its evolution here.)

However, protein degradation strategies, Dionne says, are limited to trashing relatively small particles—proteins and peptides—whereas Casma, by harnessing autophagy, can go after not just those, but bigger ones, like dysfunctional mitochondria. Malfunctioning autophagy has been linked to a variety of diseases, from cancer to Parkinson’s disease and type 2 diabetes. Casma lists lysosomal storage disorders, neurodegenerative diseases, muscle, liver, and inflammatory disorders and more among its targets, though it isn’t saying which ones it will target first, just that they’re rare genetic diseases.

The concept of autophagy—where the cell wraps cellular bits in membranes and then drags them to a recycling center called the lysosome—has been known for decades, but what’s been missing is an understanding of how to control it, which genes drive it, and as a result, how to specifically impact it without causing unintended problems. Dionne notes that mTOR inhibitors, for instance, induce autophagy “as one of 30 or 40 different things that they did,” and it’s not clear why.

There was a breakthrough, however: In 2016, Japanese cell biologist Yoshinori Ohsumi won a Nobel Prize for work figuring out the mechanisms underlying autophagy in yeast. Dionne says scientists are just now beginning to be able to precisely induce autophagy by targeting specific proteins or protein complexes involved in the process. Before, “people saw it by chance,” he says.

Ohsumi isn’t a Casma founder, but four other autophagy experts are, including Beth Levine, who runs the Center for Autophagy Research at the University of Texas Southwestern Medical Center. She discovered a genetic driver of autophagy in humans, BECN1, in 1999 (Casma’s other founders are Andrea Ballabio, of the Telethon Institute of Genetics and Medicine (TIGEM) of Pozzuoli; James Hurley of UC Berkeley; and Herbert Virgin, the current chief scientific officer of Vir Biotechnology).

Casma plans to use small molecule drugs to induce autophagy in situations where the process is either slowed down because of disease, or needs to speed up to deal with the buildup of a toxic substance. The goal: stop, or even reverse the course of these diseases, though Casma is a few years from human testing and will have to prove it can interfere with this cellular process without causing other problems. “We think we’re working on a fundamentally safe pathway,” Dionne says. “We just have to induce it in the correct way.”

Dionne, meanwhile, has been an entrepreneur-in-residence with Third Rock Ventures since 2011. Before that, he led and sold two startups, Alantos Pharmaceuticals and Surface Logix. His most recent role before Casma, as CEO of  Constellation Pharmaceuticals, a developer of epigenetic drugs, didn’t end the same way. Third Rock formed Constellation in 2008, and in 2012, Dionne agreed to lead the firm. He took the helm just two months after the company had formed a wide-ranging alliance with Genentech that had a buyout option. The deal fizzled in 2015, and when it did, Dionne expressed regret to Xconomy that it had ever been signed, because it likely prevented Constellation from making an IPO run.

Dionne stepped aside in 2016, returned to Third Rock, and Constellation, still privately held, changed its strategy. Since his return to Third Rock, Dionne has been incubating Casma. He’s seen just how many of the key decisions are made early on with a startup—what strategic direction it will take, what its research capabilities are, how to shape its staff. Making those calls was his original goal when first joining Third Rock in 2011, and now he’s finally getting the chance with Casma.

“I wanted to do this from the beginning, when you really have the chance to mold the company from the very start,” Dionne says. That plan “just took a hiatus during Constellation.”