FHTX

Foghorn Therapeutics Inc.

NASDAQ · HEALTH CARE · PHARMACEUTICAL PREPARATIONS

2.08

−0.01 −0.48%

USD · close Oct 30

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MKT CAP $123.5MP/E —DIV YIELD —FCF YIELD -68.24%REV TTM $36.7M +52.0%NET INCOME −$64.6MNET CASH $48.2M52W 1.85 – 7.07SEC XBRL · TTM TO Invalid Date

How FHTX rewrote its risk factors

10-K ITEM 1A · FY2024 → FY2025

Text kept

78%

of sentences unchanged

Added

140

new sentences

Dropped

149

sentences removed

Length

−206

words, now 40,434

New in FY2025

At present, we are working on more than seven programs with one clinical-stage drug candidate currently in Phase 1 development.
We believe Foghorn has the potential to be a major biopharmaceutical company with our current pipeline addressing more than 20 tumor types impac ting more than 500,000 patients annually.
We combine our genomic and epigenomic tools, our proprietary high throughput screening technology and our expertise in medicinal chemistry to develop enzymatic inhibitors, protein degraders and transcription factor disruptors that target the chromatin regulatory system.
Our Gene Traffic Control platform encompasses the following: • Target Identification and Validation— We use genomic screens, and a suite of epigenome sequencing and computational tools, including aspects of artificial intelligence and machine learning, to characterize, identify, and validate targets within the chromatin regulatory system.
Our epigenome sequencing tools allow us to understand the mechanisms of how our drugs are modifying the chromatin structure.
We develop both heterobifunctional degraders and molecular glues that serve to bridge an interaction between an E3 ligase and target protein of interest.
We have developed capabilities with long-acting formulation of our protein degraders, which we believe have the potential to enable enhanced convenience and route of administration. • Translation to Clinic and Identification of Biomarkers —Early in the drug discovery process, we use various genome and epigenome analyses to understand the mechanism of the genetic dependency of the disease on the chromatin regulatory system.
We have assembled an exceptional team of 106 employees as of December 31, 2025.
For example, using our proprietary platform, we have disclosed four distinct targets: SMARCA2, CBP, EP300 and ARID1B , that have genetically determined dependencies within the chromatin regulatory system.
We intend to use our platform to develop novel product candidates to further deepen our precision therapeutics approach in oncology and beyond and believe we have the potential to file four INDs over the next two years. • Harness our platform to develop novel product candidates to address therapeutic areas beyond oncology.
The Lilly collaboration includes a U.S. co-development and co-commercialization agreement for the selective SMARCA2 oncology program and an additional undisclosed oncology target.
Our Approach to Drugging the Chromatin Regulatory System We are focused on developing small molecule product candidates that target the chromatin regulatory system through the use of enzyme inhibitors and protein degraders . • Enzyme inhibitors .
These candidates are either heterobifunctional or molecular glue degraders which serve to specifically recruit a target to an E3 ligase component, resulting in the removal of the target protein by the cell’s native protein degradation system.
Our Gene Traffic Control platform encompasses the following: • Target Identification and Validation • Production of Chromatin Regulatory System Components at Scale and Proprietary Assays • Discovery and Optimization of Chemical Matter • Development of Targeted Protein Degraders • Translation to Clinic and Identification of Biomarkers The key features and capabilities of our platform are described below: Target Identification and Validation We use genomic screens and a suite of epigenome sequencing and computational tools to characterize, identify and validate targets within the chromatin regulatory system.
We use a mix of internal and external data sets to understand relationships and synthetic lethality across and within a range of cancer cell lines. • Perform broad epigenome sequencing to validate dependencies in vitro .
We apply cutting edge epigenome sequencing tools in combination with proprietary tool compounds to further validate targets and enhance our understanding of the impact of drugging the chromatin regulatory system.
These tools allow us to rapidly understand the gene expression profiles of specific cancer cell lines, the open / closed state of chromatin, and give us mechanistic understanding of how components of the system work together. • Apply machine learning and artificial intelligence (“AI”) to enhance discovery efforts.
We use AI systems, such as AlphaFold and ColabFold, to predict protein structures where experimentally solved crystal structures are not available in the Protein Data Bank.
These predicted models inform the design of protein constructs for discovery targets and serve as references for our internal crystal structures.
Additionally, we use AI systems to predict patient tumor burden when direct measurements are not available and predict potential patient response to treatment using novel biomarkers.
Additionally, we use large-language models to summarize collections of related biological pathways and processes and to enable non-computational scientists to aid our discovery efforts. • Validate dependencies in vivo .
We also apply epigenome sequencing tools in the animal model setting to identify potential biomarkers.
Development of Targeted Protein Degraders For targets in the portfolio whose biology demonstrates that degradation could offer a therapeutic advantage, we develop small molecule heterobifunctional or molecular glue degraders.
This know-how and capabilities include: • Proprietary library of linkers and E3 ligase binders for heterobifunctional degrader development; • Proprietary screening strategy for novel molecular glue discovery; • Biochemical, biophysical, and cellular assays that characterize protein degrader mechanism of action and guide optimization, including degradation kinetics, ubiquitination, and permeability; • Biochemical and cellular ternary complex assays, ternary complex structural determination; • Molecular and protein:protein interaction interface prediction modeling and compound docking programs; • Global proteomics and mass spectrometry to measure selectivity in an unbiased fashion; • Induced proximity and proximity labeling capabilities for exploration of novel approaches; • Oral and long-acting formulation of protein degraders which enhances route of administration and/or decrease frequency of delivery; • Degraders compatible with antibody conjugation and delivery as degrader antibody conjugates; and • Development of a new ligases and effector proteins, which have potential to degrade transcription factors and other important factors.
Early in the drug discovery process, we use various genome and epigenome analyses to understand the genetic dependency of the cancer on the chromatin regulatory system.
The Lilly collaboration includes a U.S. co-development and co-commercialization agreement for the selective SMARCA2 oncology program.
In February 2024, Lilly declared FHD-909, a first-in-class SMARCA2 inhibitor, a development candidate pursuant to the Lilly Collaboration Agreement and in May 2024, the IND was cleared.
According to data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program (“SEER”), in the United States, cancer of the lung and bronchus is the third leading cancer by estimated cases and deaths annually, with an estimated 227,000 new cases diagnosed and 125,000 deaths in the United States each year.
Up to two thirds of NSCLC patients who are ineligible for or resistant to treatment with targeted therapies such as EGFR or ALK have tumors that express PD-L1 and are candidates for immunotherapies with or without conventional chemotherapy.
Despite the availability of both targeted and immunotherapies, the prognosis in NSCLC remains poor, with an overall relative five-year survival for all patients diagnosed with lung cancer of 28.1 percent, according to SEER.
A First-in-Human Phase 1 Trial of FHD-909 in Advanced Solid Tumor Patients with SMARCA4 Mutations Figure 7.
FHD-909 in Combination with Pembrolizumab Shows Significantly Enhanced Anti-Tumor Activity in A549 CD34 + HSC Humanized Xenograft NSCLC Model Selective SMARCA2 Degrader Our other approach to selective SMARCA2 modulation consists of protein degrader molecules that activate the cell’s ubiquitin proteasome degradation system to selectively destroy SMARCA2.
We have shown that it is possible to identify protein degraders that lead to the destruction of SMARCA2 while leaving SMARCA4 virtually untouched.
Selective Degradation of SMARCA2 Figure 8.
Selective CBP Degrader for EP300 Mutated and CBP Dependent Cancers CREB binding protein (CBP) serves as a critical co-activator for transcription factors involved in signaling pathways in a subset of cancers including bladder, endometrial, colorectal, breast, gastric and lung.
CBP and E1A-binding protein (EP300) are paralog chromatin regulators and histone acetyltransferases with highly homologous domain structure and architecture.
Selectively targeting CBP has applications in tumors with EP300 mutations and in CBP-dependent cancers including but not limited to endometrial, cervical, ovarian, bladder, colorectal and ER+ breast cancer.
According to Clarivate, the annual U.S. incidence of these cancers exceeds 500,000.
We are developing a selective CBP degrader and plan to exploit the bi-directional synthetic lethal relationship it shares with its paralog acetyltransferase, EP300, to identify and treat those patients with EP300 mutated cancers.
As seen in Figure 10 below, the degrader denoted as FHT-CBPd-9 appears well-tolerated based on the limited mouse body weight percentage changes and achieves tumor growth inhibition in the bladder model and tumor regression in the gastric model.

and 100 more.

Gone since FY2024

At present, we are working on more than eight programs with one clinical-stage drug candidate currently in Phase 1 development.
We believe Foghorn has the potential to be a major biopharmaceutical company with our current pipeline addressing more than 20 tumor types impacting more than 500,000 new patients annually.
We combine our genomic and epi-genomic tools, our proprietary high throughput screening technology and our expertise in medicinal chemistry to develop enzymatic inhibitors, protein degraders and transcription factor disruptors that target the chromatin regulatory system.
Our Gene Traffic Control platform encompasses the following: • Target Identification and Validation— We use genomic screens, and a suite of epi-genome sequencing and computational tools, including aspects of artificial intelligence and machine learning, to characterize, identify, and validate targets within the chromatin regulatory system.
Our epi-genome sequencing tools allow us to understand the mechanisms of how our drugs are modifying the chromatin structure.
We develop both heterobifunctional degraders and E3-agnostic molecular glues that serve to bridge an interaction between an E3 ligase and target protein of interest.
We have developed capabilities with long-acting formulation of our protein degraders, which we believe has the potential to enable enhanced convenience and route of administration.
In addition, we are developing binders to a new ligase, UBR5.
UBR5 operates in the nucleus to degrade various transcription factors, and our goal is to develop a new option to degrade transcription factors and other important targets. • Translation to Clinic and Identification of Biomarkers —Early in the drug discovery process, we use various genome and epi-genome analyses to understand the mechanism of the genetic dependency of the disease on the chromatin regulatory system.
We have assembled an exceptional team of 112 employees as of December 31, 2024.
For example, using our proprietary platform, we have disclosed four distinct targets: SMARCA2, ARID1B, CBP and EP300, that have genetically determined dependencies within the chromatin regulatory system.
We intend to use our platform to develop novel product candidates to further deepen our precision oncology pipeline and believe we have the potential to file four INDs over the next two years. • Harness our platform to develop novel product candidates to address therapeutic areas beyond oncology.
The Lilly collaboration includes a co-development and co-commercialization agreement for the selective SMARCA2 oncology program and an additional undisclosed oncology target.
Our Approach to Drugging the Chromatin Regulatory System We are focused on developing small molecule product candidates that target the chromatin regulatory system through the use of enzyme inhibitors, protein degraders and transcription factor disruptors. • Enzyme inhibitors .
These candidates are either heterobifunctional or molecular glue degraders which serve to specifically recruit a target to an E3 ligase component, resulting in the removal of the target protein by the cell’s native protein degradation system. • Transcription factor disruptors .
These candidates are direct small-molecule disruptors of the protein-protein interactions between transcription factors and chromatin remodeling complexes.
For transcription factor targets, we are leveraging where appropriate protein degradation and/or small molecule disruptors that can bind either to the transcription factor or its relevant binding partner (e.g., the BAF chromatin remodeling complex).
Our Gene Traffic Control platform encompasses the following: • Target Identification and Validation • Production of Chromatin Regulatory System Components at Scale and Proprietary Assays • Discovery and Optimization of Chemical Matter • Development of Targeted Protein Degraders • Translation to Clinic and Identification of Biomarkers The key features and capabilities of our platform are described below: Target Identification and Validation We use genomic screens and a suite of epi-genome sequencing and computational tools to characterize, identify and validate targets within the chromatin regulatory system.
We use a mix of internal and external data sets to understand relationships and synthetic lethality across and within a range of cancer cell lines. • Perform broad epi-genome sequencing to validate dependencies in vitro .
We apply cutting edge epi-genome sequencing tools in combination with proprietary tool compounds to further validate targets and enhance our understanding of the impact of drugging the chromatin regulatory system.
These tools allow us to rapidly understand the gene expression profiles of specific cancer cell lines, the open / closed state of chromatin, and give us mechanistic understanding of how components of the system work together. • Apply machine learning and artificial intelligence to enhance discovery efforts.
We have built tools that allow us to mine and interpret external and internal datasets that aid in our discovery efforts yielding unbiased and unsupervised computer analyses to identify targets and genetic dependencies on the chromatin regulatory system and to further understand mechanism of action.
Examples of external data sets include data from the Cancer Genome Atlas and the Broad Institute.
Internal data sets include data from cell lines, data from xenograft models and epi-genomic information (RNA-seq, ATAC-seq, CHiP-seq, SNAP-seq).
We also use these tools in the preclinical stage to evaluate cancer cell lines & patient samples to identify biomarkers for patient stratification and patient population identification. • Validate dependencies in vivo .
We also apply epi-genome sequencing tools in the animal model setting to identify potential biomarkers.
Development of Targeted Protein Degraders For targets in the portfolio whose biology demonstrates that degradation could offer a therapeutic advantage, we develop small molecule heterobifunctional or E3-agnostic molecular glue degraders.
This know-how and capabilities include: • Proprietary library of linkers and E3 ligase binders for heterobifunctional degrader development; • Proprietary screening strategy for novel unbiased and E3-agnostic based molecular glue discovery; • Biochemical, biophysical, and cellular assays that characterize protein degrader mechanism of action and guide optimization, including degradation kinetics, ubiquitination, and permeability; • Biochemical and cellular ternary complex assays, ternary complex structural determination and molecular modeling; • Global proteomics and mass spectrometry to measure selectivity in an unbiased fashion; • Induced proximity and proximity labeling capabilities for exploration of novel ligases; • Oral and long-acting formulation of protein degraders which enhances route of administration and/or frequency of delivery; • Degraders compatible with antibody conjugation and delivery as degrader antibody conjugates; and • Development of a new ligase, UBR5, which has potential to degrade transcription factors and other important factors.
Early in the drug discovery process, we use various genome and epi-genome analyses to understand the genetic dependency of the cancer on the chromatin regulatory system.
The Lilly collaboration includes a co-development and co-commercialization agreement for the selective SMARCA2 oncology program.
In February 2024, Lilly declared FHD-909, a first-in-class SMARCA4 inhibitor, a development candidate pursuant to the Lilly Collaboration Agreement and in May 2024, the IND was cleared.
According to data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program (“SEER”), in the United States, cancer of the lung and bronchus is the third leading cancer by estimated cases and deaths annually, with an estimated 235,000 new cases of lung cancer diagnosed and 125,000 deaths in the United States each year.
Up to two thirds of NSCLC patients who are ineligible for or resistant to treatment with EGFR or ALK targeted therapies have tumors that express PD-L1 and are candidates for checkpoint inhibitor therapies with or without conventional chemotherapy.
Despite the availability of both targeted and checkpoint inhibitor-based therapies, the prognosis in NSCLC remains poor, with an overall relative five-year survival for all patients diagnosed with NSCLC of 26.7 percent, according to SEER.
Selective SMARCA2 Degrader Our other approach to selective SMARCA2 modulation consists of protein degrader molecules that activate the cell’s ubiquitin proteasome degradation system to selectively destroy SMARCA2.
We have shown that it is possible to identify protein degraders that lead to the destruction of SMARCA2 while leaving SMARCA4 untouched.
Selective Degradation of SMARCA2 Figure 6.
Selective CBP Degrader for EP300 Mutated Cancers CREB binding protein serves as a critical co-activator for transcription factors involved in signaling pathways in a subset of cancers including bladder, endometrial, colorectal, breast, gastric and lung.
CBP and EP300 are paralog chromatin regulators and histone acetyltransferases with highly homologous domain structure and architecture.
Data suggest that there are potentially over 100,000 patients with EP300 mutations that could benefit from a therapy selectively targeting CBP.

and 109 more.

Sentence-level comparison of Item 1A in the two most recent 10-Ks (FY2024 ↗, FY2025 ↗). A reworded sentence counts as one dropped and one added, so heavy edits read as low “kept”. Headings and page furniture are stripped; nothing is summarised by a model.

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