Third Rock’s New Revolution Looks to Squeeze More Drugs From Nature

Xconomy San Francisco — 

Over and over, drugmakers have turned discoveries in nature into human medicine. Aspirin came from the willow plant, and the cholesterol-lowering statins originated in fungi.

But once the foundation of the drug business, so-called natural products have fallen out of favor in our high-tech age. Third Rock Ventures thinks it can go back to nature as a source, thanks to an Illinois chemistry professor’s technology, which it is using as the basis for a new startup called Revolution Medicines.

The bicoastal venture firm, with offices in Boston and San Francisco, has launched Revolution by itself with a $45 million Series A round. It will be based in Redwood City, CA. The huge Series A sum isn’t unusual for Third Rock, which prefers to enter emerging fields of biomedical science with as few partners and as much money as possible. It’s currently investing from its third fund.

The problem with natural products is that nature doesn’t care about human health. Bacteria, plants, even sea cucumbers have evolved molecular properties to help themselves, and some of those properties might happen to help us. But the molecules in question often have harmful effects, too, and they are typically so complex that skilled chemists struggle to create synthetic versions that alleviate those problems.

Many drug companies now prefer to design drugs from scratch with computational tools, based on ever-growing knowledge of human biology and genetics. But the lure of compounds with powerful drug-like effects, already road-tested by evolution in bacteria and other organisms and waiting to be tailored for human use, is strong.

Natural product synthesis remains a widespread discipline in academic labs, and was rather exuberantly celebrated in a 2004 special issue of the journal Proceedings of the National Academy of Sciences: “There are those who will proudly and bravely proclaim that they enter total synthesis campaigns for the intellectual challenge and sheer excitement of the endeavor. Such synthetic odysseys, like Odysseus’ journey to Ithaca from Troy, provide wonderful opportunities for discoveries and inventions and ideal arenas to educate and train young practitioners of the art of synthesis.”

The technology behind Revolution aims to make that synthesis much easier. According to its inventor, Martin Burke of the University of Illinois at Urbana-Champaign, it breaks complex molecules derived from natural products down to smaller chemical units, which Burke (pictured) calls “chemical building blocks.”

Each block can then be manipulated—theoretically, the toxic parts can be removed or blunted—then reassembled into better versions. “We can understand atom by atom how they work,” Burke said.

Burke, Revolution’s founder and scientific advisory board chairman, said he was inspired in graduate school to do with small molecules what had been done with peptides and oligonucleotides. Those naturally occurring chains that build proteins, RNA, and DNA are now easily synthesized into practically any sequence a researcher wants to use and purchased from a catalog. “I was blown away how the field of science could put together all those other molecules,” Burke said.

Burke developed his chemical synthesis platform in concert with his research into a well-known medical mystery: how the compound amphotericin B worked to kill fungi. Derived from a bacterium 60 years ago, amphotericin B is a great example of a natural product that could use a lot of improvement.

It’s been used under several brand names for more than 50 years to treat severe fungal infections, and it’s a cornerstone of public health. But it’s notoriously toxic, especially to the kidneys, earning it the nickname “ampho-terrible.”

Breaking down and building new forms of amphotericin B with their new synthesis platform, Burke and colleagues found that the old theory about its mechanism of action—the way it killed fungi—was wrong.

Now one of those new forms, without the elements that created the nasty side effects, is Revolution’s lead product. It won’t be called amphotericin-B—Burke jokingly suggested the name “ampho-terrific”—but it will have some of the chemical fingerprints of its parent. (And it will be novel enough to protect with a patent.)

No compound from Burke’s platform has been tested in humans to see if the modifications work. Third Rock partner Mark Goldsmith, who is taking the helm as president and CEO of Revolution, declined to estimate when the amphotericin-B derivative would reach clinical trials.

That said, Third Rock hasn’t committed $45 million on its own just to get a better antifungal drug. Goldsmith said Burke’s platform should find new insights and develop new drugs from various complex, naturally occurring molecules. Burke last year published work that showed most of the polyenes, a class of compounds that include antimicrobials such as amphotericin-B, as well as compounds like beta-carotene used in dyes, could be broken down into building blocks, modified, and reassembled.

When asked what else the platform could modify, Goldsmith would only say, “We’re optimistic about the broader utility. Stay tuned.”

The company will announce more executive appointments soon, said Goldsmith. Burke is keeping his academic post and will not take an executive position at Revolution, which is soon to occupy labs and offices in Redwood City.

Third Rock partners often run the firm’s portfolio companies for a year or more on an interim basis, then circulate back to the firm to build new companies. Like Nick Leschly did when he left Third Rock to run Bluebird Bio (NASDAQ: BLUE) full time, however, Goldsmith, who is based in the firm’s San Francisco office, said he would also break that cycle. He’ll continue to serve on the board of his previous companies, including Nurix, but he won’t build any new ones. “We don’t have any plans to hire a new CEO for Revolution,” he said. “I’m deeply committed to the mission of the company.”

Part of that mission, he said, is to become a fully integrated drug company, with operations from drug discovery to commercialization.

Third Rock is no stranger to exploring nature for products. In 2012 it launched Warp Drive Bio, an ambitious venture to sequence tens of thousands of microbial genomes, then search them for clues to novel drugs. Goldsmith said Revolution won’t expect to share knowledge that its portfolio mate has gleaned about natural product development.