By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team

One of the wonders of nature is how our DNA is compressed over a million times to fit into the nucleus of each of our cells. This compressed form of DNA is called chromatin. Tightly packed chromatin is inaccessible and thus prevents gene expression. An important biological system is needed to unpack chromatin to make our DNA and our genes accessible for transcription.

The chromatin regulatory system provides an important mechanism in regulating gene expression. This system is comprised of three components: chromatin remodeling machines, transcription factors and other converging pathways. It orchestrates the movement of molecules that turn genes on and off by enabling the unraveling of chromatin and allowing gene expression to occur.

Chromatin dysregulation – when this system goes awry – is implicated across a wide range of diseases and has historically not been accessible for study, understanding or drugging. Recent work has highlighted that more than 25 percent of cancers have a mutation in a key component of this system – the chromatin remodeling machines. Furthermore, transcription factors, another important element of this system are mutated or over-expressed in roughly one third of cancers according to a recent cancer genome atlas study.

Foghorn® Therapeutics Inc. is discovering and developing an unprecedented class of medicines targeting diseases with genetically determined dependencies on the chromatin regulatory system via its Gene Traffic Control™ Product Platform. Foghorn was launched in 2017 with a $50 million funding commitment from Flagship Pioneering®.

Leading Foghorn’s team is President and CEO Adrian Gottschalk. Prior to joining the company, Gottschalk was at Biogen for 13 years, where he most recently served as Senior Vice President and the Neurodegeneration Therapeutic Area Head. When asked why he jumped from big biotech to a startup, Gottschalk stated that it was the vision and potential broad impact of the science.

“The breadth and impact on disease of targeting the chromatin regulatory system is profound. The science struck me as leading to an entirely new wave of medicines that could change the lives of people with cancer and other serious diseases. It was unlike anything I had seen before,” he said. Gottschalk holds a BS in biochemistry from Texas A&M University and an MBA and MS from the Sloan School of Management at MIT and Harvard/MIT Health Sciences and Technology Center.

The crux of what makes Foghorn different is the ability to study the interworking of the chromatin regulatory system in context. The basis for targeting the system came from the company’s scientific founders, Cigall Kadoch of Dana-Farber Cancer Institute, Harvard Medical School and the Broad Institute and Gerald Crabtree of the Howard Hughes Medical Institute (HHMI) and Stanford University. Over the past three years, the Foghorn team has built on the learnings from Kadoch and Crabtree to develop an integrated and scalable platform that enables high-throughput drug discovery and development efforts.

“It really starts with the context of genetics,” Gottschalk shared. “Once you can take a granular view of the genetics influencing disease, then you’re a step closer towards identifying where the breakdown is taking place and solving the problem. There are an incredible number of mutations in and around this important regulatory system. We have a deep understanding of the chromatin regulatory system and have a platform that allows us to determine how mutations and genetics cause dependencies on this system.  This is the basis for how we target various aspects of this system.”

Foghorn’s Gene Traffic Control Product Platform can be described using the following analogy: similar to how airports need air traffic control to direct the movement of aircraft, our cells need a system to direct the movement of molecules that turn genes on and off. The cell’s gene traffic control is the chromatin regulatory system.

The Gene Traffic Control Product Platform allows the company to target the system in ways that have not yet been possible. “Previous attempts to drug parts of the chromatin regulatory system suffered from a lack of insights into how the whole system functions. In contrast, our Gene Traffic Control Product Platform allows us to interrogate the biology in the right context and actually identify viable targets and potential drug candidates,” Gottschalk said.

Gottschalk was careful to distinguish this work from gene editing. “We’re not changing anyone’s genes,” he emphasized. “We’re drugging the system that’s regulating genes.”

Gottschalk believes that Foghorn’s approach will have a huge impact on the overall industry. “We target a fundamental system that controls gene expression, enabling a specific approach with the potential to impact patients with a high unmet need. Disease dependencies associated with chromatin dysregulation are estimated to impact approximately 2.5 million cancer patients in G7 countries and chromatin dysregulation is further implicated in neurological, autoimmune, and other serious diseases.”

Technology is an important part of driving this novel approach, with much of it being proprietary trade secrets. “What I will say is we have industrialized a whole suite of biophysical, biochemical and cellular-related assays, allowing us to discover chemical matter for small molecule drug development,” Gottschalk shared. “No other company in the world can study and drug the chromatin regulatory system in such a systematic way.”

“The reason why we’re unique is not just our proprietary technology, but also because at this time, no medicines exist for the specific breakdowns with the machinery we are pursuing,” Gottschalk shared. “I’m not saying there’s no treatments for those cancers, but they’re not targeting the specific disease dependencies in the chromatin regulatory system that Foghorn is able to address.”

Moving to the pipeline, Gottschalk cited that the chromatin regulatory system is “target rich” and thus there’s no shortage of options. “We are currently in pre-clinical stages of development and moving to the clinic next year. We are rapidly advancing over 10 programs across a wide range of cancers – both rare and more common.”

Gottschalk was also enthusiastic about the hire of Carl P. Decicco as CSO late last year. Across his 30+ year career, Decicco has put approximately 200 drugs into the clinic and has already and will continue to add value to Foghorn as the company moves towards the clinic. More recently, Foghorn appointed Sam Agresta as CMO and Allan Reine as CFO and their oncology and financial expertise will be beneficial to the company as it continues to expand.

Another key to accelerating drug development at Foghorn is partnerships; this has been true since the company’s inception. “It’s essential for startups like ours to be able to dial up and dial down certain parts of what we do very quickly,” Gottschalk said. “WuXi AppTec is actually a very important partner. Working with WuXi AppTec has been critical to managing the growth of the company as we’ve been able to get the right team in quickly.”  

Looking ahead, Foghorn’s aim is to become an integrated biotech company. “Going from discovery to the clinic and from the clinic to commercialization, each of these steps is a cultural evolution,” Gottschalk said. “We have to constantly be asking ourselves questions, we need to be willing to challenge the ‘sacred cows’ of how we do things so that, at the end of the day, we can achieve our goals while staying true to our core values.” He indicated that in the end, “if you get the right people, you’ll give yourself the best chances to get the science right.”

Gottschalk offered his commentary on the industry and key challenges Foghorn has overcome as it looks towards the clinic. “The first and biggest hurdle was industrializing our proprietary drug discovery platform, simply because it had never been done before,” he said. “Another barrier was finding chemical matter that can be advanced to become a drug. We are now ready to advance some of our programs to the clinic, which is a great milestone.”

Looking forward to how things might look in 2030, Gottschalk is optimistic. “If you look at the past decade, the therapies that the industry is now bringing to patients are really transformative.” He suggested that the low conversion rate across the drug development process will improve for certain types of treatment, and that this combined with further investment will result in more FDA approvals, on average.

As for Foghorn, Gottschalk is similarly optimistic. “It’s our plan to reach commercial stage sometime in the next 5 years.” He smiled as he stated, “the beauty of working in biotech now is that we have massive opportunities to make a huge difference for people. I really believe that Foghorn is in a position of leadership in the area of chromatin regulation, which makes me personally grateful that I have this opportunity. You can do many things in life and I show up to work every day really excited about what we’re doing.”

“I personally believe that Foghorn is blazing the trail for the fourth wave of cancer therapies and may even have the potential to deliver cures,” he predicted. “My hope is for Foghorn to make a lasting impact in oncology and other serious diseases, and I am confident that our unique approach will help us get there.”