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At Arrakis, Gilman Teams With Biogen Vets to Target RNA With Pills

Xconomy Boston — 

A year after selling his latest biotech startup—the second since 2012—Michael Gilman is back. He emerged today as chairman and CEO of a two-year-old startup named Arrakis Therapeutics, which aims to use chemical drugs to go after an unlikely target: RNA, the molecules that turn our genetic blueprints into proteins.

Named after the dangerous desert planet in the science fiction epic Dune, Arrakis has also closed a $38.5 million Series A round from three venture firms (Advent Life Sciences, Canaan Partners, and Osage University Partners), two large drugmakers (Celgene and Pfizer), and former Genzyme CEO Henri Termeer. Canaan led the funding.

In Dune, Arrakis is inhabited by deadly giant sand worms and the only place to mine the “spice,” a psychoactive drug that everyone in the universe craves. “There’s essentially a [central nervous system] drug there,” Gilman (pictured) says.

Arrakis the biotech, formed in 2015, is also wading into foreboding territory, pursuing drug development for neurological disorders and other diseases. To do so, it will try to do intentionally using new methods what a few others, Gilman says, have done accidentally: find small molecules—traditional chemical-based drugs—that block the function of RNAs that are causing disease.

A number of chemical drugs either approved or in development that target RNA—like Merck’s ribocil—weren’t known to do so when they were first discovered. Arrakis is taking common tools that drug companies use to search through vast libraries of proteins and adapting them to RNA, Gilman says. Arrakis has come up with new algorithms to help find what could be “druggable” sites on RNA. Once it finds those sites, Arrakis can verify if its small molecules are hitting them just right.

The idea is to get after drug targets inside cells that to date have been out of the reach of small molecules and biologics. Small molecules can slip into cells but often don’t match up with the desired targets, like mismatched keys and locks. Biologics, particularly monoclonal antibodies, are popular because they can be designed to bind to almost any target, but only on the surface of a cell.

Those limitations are significant. They’re the reason that the entire universe of small molecules and biologics can currently only get to a fraction of known targets, and thus, fall short of treating many diseases. The genes Ras and Myc, for instance, have been known for decades to drive a multitude of cancers but have never been successfully drugged.

Newer drug-making methods like RNA interference (RNAi) offer new ways to attack tough targets. RNAi stops specific RNAs from producing disease-causing proteins, such as misfolded transthyretin proteins that clump up inside nerves and other tissues and cause the rare disease transthyretin amyloidosis. But delivering the therapies has proved challenging and limited their use. RNAi has yet to see its first approved drug. It is currently confined to drug targets in the liver.

Arrakis hopes to avoid drug delivery complications by targeting RNA with drugs delivered as pills. But there are other challenges. Art Krieg has been working on RNA therapeutics for decades, and he “completely agrees” with the rationale of of drugging RNAs with small molecules. But in practice, Arrakis is going to have to thread a proverbial needle, says Krieg, who is currently the CEO of Checkmate Pharmaceuticals and not affiliated with the startup. The “huge diversity of RNA” in the body, likely more than 500,000 distinct molecules, means Arrakis will have to hone in on the right target to avoid unintended problems. In different cells, RNAs may have varying ability to bind to small molecules.

“I think they are going to make intelligent choices of what indications to pursue first,” Krieg says.

Shutting down a disease-causing RNA with a small molecules has long been considered futile because RNAs move around so much inside cells and continually change shape as they go about their business. But that conventional wisdom “appears to be false,” Gilman says, citing published work in Nature in 2016 from Scripps Research Institute chemist Matthew Disney and others. “If you can lock one of these [RNA] molecules” into place to keep it from shifting and performing a particular function, like producing a disease-causing protein, he says, “then maybe you can do something interesting.”

Neurology, oncology, and rare genetic diseases have plenty of well-known targets that can’t be drugged by other means, says Gilman. But there’s plenty of work to fine-tune the discovery technology before arriving at a drug candidate, let alone testing one in humans. “We are doing something that hasn’t been done before,” Gilman says.

Arrakis has assembled a group of Biogen (NASDAQ: BIIB) veterans: founder and chief scientific officer Russell Petter, chief business officer Daniel Koerwer, senior VP of biology James Barsoum (who worked with Krieg at another RNA drug developer, RaNA Therapeutics), and now Gilman, who was the executive vice president of research at Biogen before launching his startup career.

He has led and sold two biotech startups, Stromedix and Padlock Therapeutics, since 2012. “We’re getting the band back together,” Gilman says, and that’s a reason why Petter—who Gilman bumped into at a board meeting just months after selling Padlock to Bristol-Myers Squibb—was able to convince him to join.

“Life is short, I want to work on hard and important problems, and I want to spend my time with people I love being around,” Gilman says.

Gilman is an entrepreneur-in-residence at Atlas Venture, which seeded both his previous startups. Atlas isn’t involved with Arrakis, but it has formed a separate startup, yet to be announced, that Gilman says he is also running as well.