Merck dangles up to $425 million to team with Flagship’s Foghorn Therapeutics on drugging the shape of DNA
Two years after it first emerged from stealth mode, Flagship’s Foghorn Therapeutics has nabbed its first Big Pharma partner as Merck signs on to the biotech’s vision of drugging the very shape of DNA.
The deal, worth up to $425 million but with the upfront cash undisclosed, comes as Foghorn nears a pivot to a clinical stage biotech. The Cambridge-based company has added nearly 60 staffers from the 25 it had when it first emerged out of Flagship and, CEO Adrian Gottschalk said, they have finally refined the screening technology at the heart of the company, with plans to file their first IND towards the end of the year.
“In the last 6 months, actually prior to the conversations with Merck, we had industrialized our ability to interrogate the biology,” Gottschalk told Endpoints News. “We’ve made some very nice progress, really starting from scratch several years ago.”
First founded in 2016, Foghorn is one of a spate of recent biotechs that try to treat cancer by targeting how genes are expressed, as opposed to trying to change the genes themselves or inhibit the proteins they code for. Michael Gilman’s Arrakis Therapeutics is built, like Foghorn, on drugging DNA regulators called transcription factors and earlier this year got $190 million upfront and “several billion” in milestones for a deal with Roche. Syros, another Flagship-backed company, attracted considerable buzz several years ago by going after so-called “super-enhancers,” though they have since struggled to find traction in the clinic. More broadly, the still-juvenile field has yielded few major in-human successes.
Merck has already signaled its belief in the approach, at least in certain manifestations. Last year, they bought up Peloton Theraepeutics and its late-stage, kidney cancer transcription factor drug for $1 billion in cash and another $1 billion in milestones.
Foghorn’s twist, Gottschalk said, is looking at how these factors interact with these spherical structures on top of DNA, called chromatin remodeling complexes. Basically, human DNA contains billions of genes, not all of which are turned on at any point in time or in any cell. That DNA sits in tightly compacted strands called chromatin at the nucleus at the center of the cell, and one of the ways the body can decide which genes need to be turned on is to open and close those strands.
The molecular thing that determines whether and where genes are turned on is the interaction between those transcription factors that carry instructions and the chromatin remodeling complex that does the opening and closing. Foghorn compares it to air traffic control, the two types of proteins telling the genes where to launch and where not to launch. And Gottschalk cited data that suggest around 25% of cancers can be chalked up in part to those biological controllers getting their signals crossed.
For the last four years, Foghorn has developed a high-throughput screening system to allow their scientists to model both the transcription factors and the remodeling complexes and figure out which molecules can modulate each. Though “high-throughput screening” is about as common a word in the drug industry these days as “pancakes” are in the diner industry, Gottschalk said that was no easy feat. The chromatin remodeling complexes are just that — complex — and they needed to set up a system that could handle proteins as much as ten times as large as the ones most screens handle.
Under the new deal, Merck has essentially licensed one of the factors Foghorn has just begun testing, buying exclusivity on any potential drugs that emerge to target it. Internally, meanwhile, Gottschalk said that after years building their systems, the company is preparing to soon bring a few of its 10 preclinical and unnamed programs into the clinic for several genetically-defined cancers that currently have few good treatment options.
“I think this biology has been unexplored and unexploited as drug, and I think the time is right,” Gottschalk said.