Foghorn Therapeutics (NASDAQ:FHTX) President and CEO Adrian Gottschalk said the company was built around the idea that chromatin regulation—and specifically the BAF (SWI/SNF) chromatin remodeling complex—represents a broad and clinically relevant set of oncology targets that have historically been difficult to drug.
Speaking in a fireside chat moderated by Guggenheim senior biotech analyst Michael Schmidt, Gottschalk pointed to genomic sequencing work over the last decade-plus showing that a large portion of cancers contain alterations in chromatin regulatory machinery. He said researchers initially viewed these complexes as “housekeeping” components, but subsequent work has linked them to cancer biology across many tumor types. The difficulty, he said, is that many cancer-associated alterations are loss-of-function events—meaning the protein is missing—while other targets in the system can look very similar in healthy cells, creating selectivity challenges.
Why chromatin targets drew interest—and competition has been limited
Pipeline overview: Lilly-partnered SMARCA2 and three unpartnered programs
Gottschalk highlighted that the company’s most advanced efforts are in partnership with Eli Lilly, based on a collaboration announced in December 2021. The lead partnered program targets SMARCA2, positioned as a synthetic lethal approach in tumors where SMARCA4 is mutated or lost, with a major focus on non-small cell lung cancer (NSCLC).
He also outlined three additional targets the company is pursuing outside the Lilly collaboration:
- CBP: described as relevant in ER-positive breast cancer and in certain synthetic lethal settings.
- EP300: described as a “sister protein” to CBP, with relevance across hematologic malignancies, including multiple myeloma and diffuse large B-cell lymphoma.
- ARID1B: discussed as another target the field has struggled to drug selectively, related to ARID1A biology.
For CBP, EP300, and ARID1B, Gottschalk said Foghorn is pursuing targeted protein degradation to achieve selectivity among closely related proteins.
SMARCA2 strategy, selectivity approach, and patient opportunity in NSCLC
On SMARCA2, Gottschalk said selectivity matters because SMARCA2 and SMARCA4 are highly similar—“90+% the same” in amino acid sequence—and their ATPase pockets are “almost identical.” He said Foghorn’s early advantage was an ability to test chemical matter against the full BAF machinery in its native state, comparing complexes powered by SMARCA2 versus SMARCA4. He added that the partnered SMARCA2 compound binds in an allosteric pocket, avoiding some of the off-target challenges associated with ATPase targeting.
He estimated that SMARCA4 mutations occur in about 5% of all cancers, and said NSCLC has SMARCA4 mutations in about 10% of cases. Of those, he said the collaboration believes roughly “six to seven” out of 10 patients with SMARCA4 mutation may have the relevant loss-of-function alteration anticipated to be responsive to the program’s SMARCA2 inhibitor. Using an annual U.S. NSCLC incidence figure of roughly 200,000 to 230,000 new patients, he estimated on the order of 15,000 U.S. patients annually could be relevant, with the potential to “double or triple” when including Europe, Japan, and other markets.
Clinical status: global Phase 1 with backfilling underway
Gottschalk said the Phase 1 study, run operationally by Lilly with costs shared 50/50, began dosing patients around October 2024. He reported 16 U.S. sites and five sites in Japan open, with additional sites opened in France, Germany, Spain, South Korea during December and January. The trial’s escalation portion allows any solid tumor histology as long as the patient has a SMARCA4 mutation.
He said the collaboration has not yet reached maximum tolerated dose and has been “pleased with the safety and tolerability” observed to date. In the fourth quarter, he said the trial began backfilling cohorts, which could be triggered by achieving an exposure profile believed to reach “IC90 coverage” and/or by clinical activity; he said the partners have not disclosed which of these factors drove backfilling. Enrollment, he said, is going well, and escalation continues.
On timing, Gottschalk said he expects the collaboration to have enough information around the middle part of the year—possibly a few months earlier or later—to decide whether to move into dose expansion. He added that within backfilling, the collaboration is prioritizing NSCLC patients with loss-of-function SMARCA4 mutations.
Monotherapy expectations, combinations, and peer learnings
Gottschalk said he expects—and personally “needs to see”—clinically meaningful single-agent activity for the SMARCA2 program, including objective responses with duration, even while anticipating combination regimens will be important long term. He contrasted outcomes in frontline metastatic NSCLC patients without SMARCA4 mutation versus those with SMARCA4 mutation, saying immunochemotherapy response rates and survival metrics are roughly halved in the SMARCA4-mutated population. He also noted many patients being enrolled in escalation/backfill are in fourth- or fifth-line settings, where survival can be measured in weeks.
He said future development would aim to move “as quickly as we can” into the frontline setting, with combinations likely including pembrolizumab, plus or minus chemotherapy, and that combination cohorts are expected to be part of the expansion phase if the program advances.
Asked about peer validation, Gottschalk discussed Prelude’s SMARCA2 degrader efforts, citing partial responses reported in lung, esophageal, and gastric cancers, and said the discontinuation of those programs reinforced his view that SMARCA2 requires very high target engagement (for degraders, “90+%” and potentially “95+%” sustained). He also said differences between SMARCA4 loss-of-function mutation classes suggest trials should enrich for the most relevant “class one” population to generate a clearer signal.
On wholly owned programs, he said CBP has shown preclinical monotherapy activity in ER-positive breast cancer, including in CDK4/6-resistant models, and that a once-weekly subcutaneous long-acting formulation has completed the in-life portion of a four-week non-GLP tox study, with all animals surviving across low, medium, and high doses. For EP300, he said the program is tracking toward non-GLP tox studies by mid-year, also using a long-acting formulation, and noted a paused cereblon-based degrader approach due to potential issues combining with cereblon-based IMiD therapies in multiple myeloma.
Gottschalk also referenced CellCentric’s clinical work in multiple myeloma as validation, while noting that dual CBP/EP300 inhibition has been associated with myelosuppression and cytopenias; he said Foghorn’s approach aims to avoid that through selectivity in both CBP and EP300 programs.
About Foghorn Therapeutics (NASDAQ:FHTX)
Foghorn Therapeutics is a clinical-stage biotechnology company focused on the discovery and development of novel epigenetic therapies for cancer. The company leverages its proprietary Targeted Protein Discovery Platform to identify and design small-molecule inhibitors that modulate chromatin regulatory proteins involved in tumor growth and survival. By targeting the mechanisms that control gene expression, Foghorn seeks to address unmet needs in oncology through precision medicine.
The company’s lead candidate, FHD-286, is a selective inhibitor of variant SWI/SNF chromatin remodeling complexes and is currently being evaluated in Phase 1 clinical trials for patients with solid tumors harboring specific SMARCA2 and SMARCA4 alterations.
