Foghorn Therapeutics announces new preclinical data at AACR

Foghorn Therapeutics (FHTX) announced new preclinical data for medicines, including FHD-909, a SMARCA2 selective inhibitor, and the Selective CBP degrader program at the 2025 American Association for Cancer Research annual meeting. Enhanced anti-tumor activity with FHD-909 in combination with standard-of-care chemotherapies, anti-PD-1 pembrolizumab and several novel KRAS inhibitors in NSCLC animal models warrants clinical exploration. Selectively blocking SMARCA2 activity is a synthetic lethal strategy intended to induce tumor death while sparing healthy cells. SMARCA4 is mutated in up to 10% of NSCLC alone and frequently co-occurs with KRAS mutations, resulting in poor clinical outcomes upon treatment with KRAS or checkpoint inhibitors. FHD-909 monotherapy selectively inhibits SMARCA4 mutant cancer cells in vitro, is well tolerated, and demonstrates robust anti-tumor efficacy in SMARCA4 mutant NSCLC xenograft models. FHD-909 shows additive activity with standard-of-care chemotherapies and synergistic activity in multiple combinations including KRAS G12C, KRAS G12D, and pan-KRAS inhibitors, as well as anti-PD-1 pembrolizumab. Findings support further clinical exploration. FHD-909 is a highly selective SMARCA2 inhibitor in ongoing Phase 1 evaluation in patients with SMARCA4 mutations who have exhausted standard treatment options. Newly diagnosed patients with SMARCA4 mutated NSCLC have worse prognosis and shorter survival compared to their wild-type counterparts. Selectively blocking the enzymatic activity of SMARCA2 is a promising synthetic lethal strategy intended to induce tumor death while sparing healthy cells. FHD-909 is a first-in-class oral, selective SMARCA2 inhibitor with high selectivity over its closely related paralog SMARCA4. First-in-human trial of FHD-909 will evaluate patients with SMARCA4 mutated locally advanced or metastatic solid tumors who have exhausted standard treatment options. Upon completion of the dose escalation part of the study, two separate expansion cohorts will enroll either patients with NSCLC or with other advanced solid tumors harboring eligible SMARCA4 alteration. Selective CBP degraders have combinatorial benefit with approved chemotherapies and targeted agents in solid tumors beyond EP300-mutant cancers. CBP and EP300 are highly similar acetyltransferases that share a bi-directional synthetic lethal relationship but are challenging to drug independently, and dual inhibition is associated with dose-limiting toxicities. Previously, we showed our selective CBP degraders have potent antiproliferative activity in EP300-mutant cancers. Synergistic combination activity demonstrated, including with paclitaxel and CDK4/6 inhibitor abemaciclib in ER+ breast cancer. Findings support combination opportunities for selective CBP degraders in solid tumors beyond EP300-mutant cancers. A potent and selective heterobifunctional degrader of EP300 has significant preclinical activity in hematological malignancies. Historically, selectively drugging EP300 has been challenging due to the high similarity between EP300 and CBP, while dual inhibition of CBP/EP300 has been limited by dose limiting toxicities. EP300 lineage dependencies are further characterized in multiple myeloma and diffuse large B cell lymphoma. Anti-proliferative activity in a broad range of hematological malignancies in vitro, including DLBCL, multiple myeloma, and follicular lymphoma. Achieved in vivo efficacy in the Karpas422 germinal center B-cell-like-DLBCL xenograft model. No thrombocytopenia observed in mice at efficacious doses. Targeted selective EP300 degradation shows promise as a well-tolerated and effective treatment strategy to treat advanced hematological malignancies. Successfully developing potent and selective degraders of ARID1B. ARID1B is a major synthetic lethal target implicated in up to 5% of all solid tumors. Attempts to selectively drug ARID1B have been challenging because of the high degree of similarity between ARID1A and ARID1B and the lack of enzymatic activity to target. Developed highly potent and selective binders to ARID1B. Achieved selective degradation of ARID1B. Program update expected in 2H 2025.