Foghorn Therapeutics Announces Updates for Selective ARID1B, CBP, and EP300 Degrader Programs

Analysis reveals significant industry trends and economic implications

Release Date

2025-10-31

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

Foghorn Therapeutics announced updates on its Selective ARID1B, CBP, and EP300 degrader programs. The Selective ARID1B degrader selectively binds and degrades ARID1B and may be relevant in solid tumors. The Selective CBP degrader is on track for non-GLP toxicology studies in Q4 2025, with potential in EP300-mutant cancers and ER+ breast cancer and IND-ready in 2026. The Selective EP300 degrader demonstrates efficacy and favorable tolerability in preclinical models in hematological malignancies.

Key Highlights

  • Selective ARID1B degrader selectively binds and degrades ARID1B, potentially relevant in solid tumors.
  • Selective CBP degrader is on track for non-GLP toxicology studies in Q4 2025 with potential in EP300-mutant cancers and ER+ breast cancer; IND-ready in 2026.
  • Selective EP300 degrader demonstrates efficacy and favorable tolerability in preclinical models in hematological malignancies.
  • Foghorn to host a virtual investor event today, October 30, 2025, at 12 p.m. ET

Emerging Mechanism of Action

Emerging Mechanisms of Action for Solid Tumors

Recent publications highlight several promising mechanisms of action for solid tumor treatments:

  • Early Detection Technologies: Multicancer early detection (MCED) assays using blood-based technologies are being developed to detect multiple cancer types at early stages, particularly for cancers without current screening options. MRI integration in screening pathways shows substantial benefits for prostate cancer diagnosis.

  • Drug Repurposing: Mebendazole (MBZ), an FDA-approved anthelmintic, shows promise for triple-negative breast cancer (TNBC) by reducing proliferation, inducing apoptosis, and preventing metastases. Similarly, Auranofin (AUR), an anti-rheumatic drug, demonstrates efficacy in rhabdomyosarcoma through thioredoxin reductase (TXNRD) inhibition.

  • DNA Damage Response Inhibitors: Various inhibitors including PARP inhibitors with CNS penetration, ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors show therapeutic potential across multiple cancers. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumors.

  • Endoplasmic Reticulum Stress Targeting: Transducin beta-like 2 (TBL2) facilitates cell proliferation by upregulating ATF4 expression in lung adenocarcinoma. Marizomib (MZB), an irreversible proteasome inhibitor, induces apoptosis in melanoma cells through endoplasmic reticulum stress.

  • Tumor Microenvironment Modulation: E7130 inhibits microtubule dynamics, suppresses cancer-associated fibroblasts (CAFs), promotes remodeling of tumor vasculature, and reduces circulating TGF-β1 in plasma.

  • PI3K/AKT/mTOR Pathway Inhibition: mTOR inhibitors show promising results in pleural mesothelioma, with AZD8055 demonstrating sensitivity across established and primary patient-derived cell models. The PI3K/mTOR/DNA-PK inhibitor LY3023414 exhibited sensitivity in most cell lines. Mefenamic acid has shown anticancer activity against osteosarcoma by inhibiting this pathway.

  • Immunotherapy Advances: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have shown promising outcomes. T-cell immunoglobulin and ITIM domain (TIGIT) is under investigation with promising results in lung cancer. WNK3 has been identified as a novel regulator of PD-L1 expression, with WNK463 enhancing T-cell-mediated antitumor activity.

  • Novel Targeted Approaches: Trop2-targeted therapies, particularly antibody-drug conjugates (ADCs), have revolutionized outcomes for patients with Trop2-positive tumors. Sphingosine kinase 1 (SphK1) inhibitors show promise for neuroendocrine prostate cancer treatment.

  • Combination Therapies: The combination of fluzoparib (PARP inhibitor) and chidamide (HDAC inhibitor) showed synergistic effects against natural killer/T-cell lymphoma. Metformin combined with cyclophosphamide enhances tumor response to adoptive cell therapy or immune checkpoint blockade.

  • Nanomedicine Strategies: Advanced delivery systems including PLGA nanoparticles, carbon nanotubes, and drug-loaded liposomes are being developed to target the PD-1/PD-L1 axis, with novel nanoplatforms designed to induce DNA damage and pyroptosis while enhancing tumor-specific adaptive immunity.

Emerging End Points

Key Endpoints Emerging for Solid Tumors

Recent publications highlight several emerging endpoints for solid tumor clinical trials. Composite outcome measures such as progression-free survival (PFS) and disease-free survival are increasingly used as surrogate end points in oncology research, often serving as the primary end point of pivotal trials for regulatory approvals. These endpoints combine distinct events like tumor growth, new lesions, and death into a single time-to-event end point, increasing statistical power and decreasing required follow-up periods.

Objective response rate (ORR) continues to be a primary endpoint in many trials, including studies of immune checkpoint inhibitors. Recent examples include the anlotinib study (2022) which used ORR and PFS as primary endpoints. The SHR-1802 anti-LAG-3 trial (2023) used dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) as primary endpoints.

Local control (LC) and safety are emerging as important coprimary endpoints, as demonstrated in a phase 2 trial for unresectable locally advanced non-small cell lung cancer. The EMBARK trial (2023) for prostate cancer used metastasis-free survival as the primary endpoint.

For specific cancer types, tailored endpoints are emerging. In prostate cancer, PSA50 response (50% reduction in prostate-specific antigen) serves as a primary endpoint. For hepatocellular carcinoma, the HCC-specific modified RECIST (mRECIST) better captures tumor response by considering MKI-induced biological modifications and cirrhosis-induced liver changes.

Biomarker-based endpoints are increasingly important. ESR1 mutation testing is recommended in clinical trials and hormonal therapy for breast cancer. Biomarker analysis including PD-L1 expression and genomic mutational analysis are incorporated as exploratory endpoints. Tumor cell content is emerging as an endpoint for studies involving comprehensive genome profiling.

Patient-reported outcomes and quality of life measures are gaining prominence. The TROPiCS-02 trial (2023) for metastatic breast cancer included time to deterioration of global health status and quality of life as secondary endpoints. The DREAMM-2 trial (2023) for multiple myeloma included health-related quality of life (HRQOL) as a secondary endpoint.

Despite these advances, a 2023 analysis found that overall survival (OS) was the primary endpoint in only 14% of trials leading to cancer drug approvals between 2000-2020. Most novel cancer drugs have "typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints."

Future directions include multiparametric models grouping dimensional and functional radiological parameters with biochemical markers, novel imaging techniques beyond size measurements, and circulating tumor DNA assessment as translational endpoints.

Company drugs in pipeline

Foghorn Therapeutics' Pipeline Indications

Foghorn Therapeutics is developing FHD-286, an orally bioavailable, selective inhibitor of BRG1/BRM, which targets the mSWI/SNF chromatin-remodeling complexes (also called BAF complexes). Their pipeline currently focuses on several hematological malignancies:

Acute Myeloid Leukemia (AML)

FHD-286 is under clinical development in Acute Myeloid Leukemia (AML), with particular efficacy demonstrated in specific molecular subtypes:

  • AML with MLL1 rearrangement (MLL1r)
  • AML with mutant NPM1 (mtNPM1)

In these AML subtypes, FHD-286: - Induces differentiation and lethality in cancer cells - Causes perturbed chromatin accessibility - Leads to repression of c-Myc, PU.1, and CDK4/6

Preclinical studies with AML xenograft models have shown that FHD-286: - Reduced AML burden - Improved survival - Attenuated AML-initiating potential of stem-progenitor cells

FHD-286 has demonstrated synergistic effects when combined with other therapies in AML, including: - Decitabine - BET inhibitors (BETi) - Menin inhibitors (MI) - Venetoclax

B-cell Acute Lymphoblastic Leukemia (B-ALL)

FHD-286 has also shown efficacy in B-cell Acute Lymphoblastic Leukemia (B-ALL), with subtype-specific responses:

  • Philadelphia chromosome-like (Ph-like) subtype: Ph-like B-ALL cell lines showed marked sensitivity to FHD-286, and treatment significantly prolonged survival in mouse models

  • KMT2A-rearranged B-ALL: Interestingly, this subtype was found to be resistant to BRG1 inhibition with FHD-286

In Ph-like B-ALL, FHD-286 induces cell cycle arrest through: - Downregulation of cell cycle regulators (CCND3, CDK4, CDK6, E2F1, and MYC) - Upregulation of cell cycle inhibitor CDKN1B (p27)

Mechanism of Action

FHD-286 works by targeting BRG1 (SMARCA4) and BRM (SMARCA2), which are the mutually exclusive core ATPases of the BAF complexes. These complexes enable transcription factors and cofactors to access enhancers and promoters, thereby modulating gene expression in leukemia cells.

This therapeutic approach aligns with the emerging strategy of targeting chromatin regulatory factors in cancer treatment, with FHD-286 showing promising results in specific molecular subtypes of hematological malignancies.