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Third Rock launches biotech targeting ‘notoriously difficult’ DNA regulators

The instructions for making a human are long and complicated. They involve over 3 billion sets of microscopic letters, so tightly coiled that, if unwound, they would be taller than the average person.

The daunting task of reading these instructions involves a type of protein called transcription factors. But, while integral to life, these proteins can also cause disease when they mutate or malfunction.

For drug developers, transcription factors are an attractive target. “Every biotech company that I’ve been a part of has been interested in at least one or two,” said Abbie Celniker, a well-known industry veteran and a partner at the healthcare investment firm Third Rock Ventures. That’s been true since the early 1990s, according to Celniker, who’s worked at high-profile companies including Novartis, Millennium Pharmaceuticals and Genentech.

Decades later, research into transcription factors has yet to translate into actual medicines. The proteins have proven “notoriously difficult” to lock onto, Celniker said, so much so that some consider them undruggable.

But a new company launching Thursday believes it has a solution to this longstanding problem. Fueled with $82 million from Third Rock and a handful of other investors, Flare Therapeutics is trying to make precision medicines for cancer by taking aim at transcription factors.

“There’s been a lot of pioneering and a lot of increased knowledge about the complex structure of transcription factors. And that’s really created just the right moment in time to be thinking about them,” said Celniker, who now serves as Flare’s interim CEO.

The idea for Flare started with Robert Sims, a scientist and researcher who joined Third Rock in early 2019 after more than 11 years at Constellation Pharmaceuticals, a company focused on epigenetics.

Right around the time Sims came on board, the journal Nature Chemical Biology published a paper, wherein an Oxford researcher by the name of Fraydoon Rastinejad detailed how a certain kind of small molecule could help regulate transcription factors. Though he was hesitant to get into such a “hot button” area, Sims said he found the paper fascinating and kept coming back to it during his time as one of Third Rock’s “entrepreneurs-in-residence.”

That paper ultimately provided the foundation for what would become Flare. Sims said his team flew to the United Kingdom right before the pandemic hit to meet with Rastinejad, who has since become a Flare co-founder. Over the next year, they ran experiments to test key concepts, and have developed an approach that Third Rock thinks can successfully drug transcription factors.

“Things just went incredibly well,” said Sims, who’s now Flare’s chief scientific officer. “Fast forward to today, we’re working on three programs, our lead project has gone blazingly fast, and we’re excited to officially launch and to tell the rest of the world about our approach.”

According to Sims, Flare’s work revolves around the shape of transcription factors.

These shapes are crucial. In some forms they turn off genes, in others they turn them on. Sims said one of the big takeaways from Rastinejad’s research is that transcription factors have special regions which are more sensitive, like pressure points. Flare’s aim is to develop synthetic, chemical ligands that bind to these pressure points, thereby controlling their shape and, in turn, gene expression.

Flare also sees its shaped-based approach as being applicable to a wide-range of transcription factors. That’s an important advantage to Third Rock, which tends to prefer investing in technologies that can give rise to multiple drugs.

“This is one of the things that was really exciting to us,” Celniker said, “this systematic approach and its ability to tackle transcription factors as a class, not just on a one-off basis.”

As Flare launches, its initial focus will be oncology, including solid tumors, as there are known links between cancer and mutated transcription factors. However, Celniker said the company also foresees opportunities in neurology and rare genetic diseses, too.

Joining in Flare’s $82 million funding round are Boxer Capital, Nextech Invest, Casdin Capital, Invus Financial Advisors and Eventide Asset Management.

That investor pool is a departure for Third Rock, which has developed a reputation for being very hands on with its portfolio companies and ultimately owning significant stakes in them if they go public.

Celniker admits this latest funding round isn’t typical for a Third Rock company. But, she explained, the speed at which Flare’s work progressed during its seed funding suggested that it needed a large amount of capital to keep an accelerated pace.

“A lot of our companies don’t launch with that much actual progress having been made,” Celniker said. “Working on transcription factors is a full-time job, so we wanted to make sure those guys could focus on that and not necessarily be worried about raising the next round too early.”

Celniker added that Flare expects the latest haul should be enough to get its lead drug candidate into clinical testing. She and Sims wouldn’t specify when they expect clinical testing to begin, but said two to three years is a fair estimate.

“The things that the team has done in the stealth mode has emboldened us,” Sims said. “We learned a lot in a very short amount of time.”

“We have a lot of work ahead of us, but we’ve been able to translate some key concepts” into compounds that have properties which could make them real drugs, he added.