What is the founding story of Foghorn Therapeutics?

The underlying science came out of the labs of Gerald Crabtree, at Stanford, and Cigall Kadoch, a doctoral student in Gerald’s lab. They were working on the biology of the chromatin regulatory system, and Cigall was faced with the challenge of starting a company or staying in the academic world. She opted for a middle ground that allowed her to still be engaged, while continuing her work as an academic scientist. She connected with Doug Cole, a managing partner at Flagship Pioneering and Cigall’s idea resonated focused on the chromatin regulatory system with the Flagship team.

They helped incorporate it, set up the initial infrastructure, and early financing. Flagship played a very significant role in the private rounds and helped guide the company.

For a long time, this biology was thought to play more of a housekeeping role within the cell. It was there but not well understood and not thought to be relevant in different diseases. Over the last decade, due to work by Cigall, Gerald and others, we realized this was far from the truth. This biology is playing a central role in orchestrating, controlling and regulating gene expression. Consequently, when you dig into it, you start discovering that it is implicated in a wide range of diseases.

It’s a greenfield opportunity that holds tremendous promise – Foghorn is now starting to realize some of that potential.

Can you provide an overview of Foghorn’s Gene Traffic Control Platform and how it enables new target identification and validation?

Our scientific approach starts with the underlying genetics. Mutations occur in the biological machinery or in the cancer cell, and in some cases they are dependent on the chromatin regulatory system for survival, and therefore effectively impact gene expression. Once we have figured out the mutation location, we can then use tools like CRISPR to validate if we hit the specific target.

The other part of our platform has the ability to produce the different components of this chromatin regulatory system. There are two principal components that we are focused on; chromatin remodeling complexes and transcription factors. The complexes are multi assemblies of proteins and contain a motor, which serves the principal purpose of localizing onto chromatin (a compressed form of DNA) and unpacking it (going from DNA to RNA to protein). We are also able to study and understand the interaction of chromatin remodeling complexes with transcription factors – these are homing beacons that localize the complex to the right location to ensure that the appropriate gene is opened and expressed. If this process goes awry, it can result in pretty serious diseases like cancer and others.

Because we have become experts at producing the different elements, we are able to study them in a host of biochemical, biophysical as well as cellular related assays. We can do this at scale, and we have generated a suite of high throughput screens that allows us to screen the different relevant targets within the system using those two key components. This is something we believe is unique to Foghorn and not easily replicable.

We are proud that all of the pipeline candidates we are pursuing have come from our platform. We have not in-licensed drugs from any other company at this point, it has all come through different screens that we run internally.

In the backend, we ensure that we understand the specific patient populations that then tie back to either the genetic dependency or the suppression of certain elements of this chromatin regulatory system.

What are the biggest challenges associated with bringing a new class of therapeutics to market?

We are subject to the challenge that most companies pushing the frontier of medicine are in: Until you have proven your platform, everyone wonders whether it is real. The biggest hurdle is overcoming the skepticism that exists in people's minds about new science, new medicines, and answering questions around safety and efficacy.

There are no drugs in the clinic or approved that go after specific targets and the chromatin regulatory system in the way we are. Therefore, in my mind, we have absolutely validated the importance of this biology at this point.