Foghorn Therapeutics(FHTX) - 2025 Q4 - Annual Results

Collaboration and Financials - FHD-909 is being developed in collaboration with Lilly, with a significant agreement signed in December 2021, including $300 million cash and $80 million in common stock[9] - The collaboration includes a 50/50 U.S. economic split on the SMARCA2-target program and potential royalties ranging from low double-digit to 20s[9] - The collaboration with Lilly is expected to yield up to $1.3 billion in potential milestones across three programs[9] - Foghorn's cash position is $158.9 million, providing a runway into 2028, with a potential market impact on approximately 2.5 million patients[48] Clinical Development and Pipeline - FHD-909 is currently in Phase 1 clinical trials, targeting SMARCA4-mutant cancers, which account for approximately 10% of NSCLC and up to 5% of all solid tumors[12][14] - FHD-909 aims to become a first-line treatment for SMARCA4-mutant NSCLC, addressing significant unmet medical needs in this patient population[15][16] - The company is advancing multiple preclinical assets towards INDs, including selective inhibitors for SMARCA2, CBP, EP300, and ARID1B[10] - The selective SMARCA2 inhibitor FHD-909 is partnered with Lilly, with a $380 million upfront payment and is currently in Phase 1 trials[48] Efficacy and Mechanism of Action - The overall response rate (ORR) for patients with SMARCA4 mutations is significantly lower compared to those without, highlighting the urgent need for targeted therapies[17] - FHD-909 leverages a synthetic lethal relationship between SMARCA2 and mutated SMARCA4, representing a promising strategy in precision medicine[12][13] - FHD-909 demonstrated significant tumor regression in SMARCA4-mutant NSCLC models at tolerated doses, with a maximum dose of 60 mg/kg[52] - In vivo studies show that combining FHD-909 with cisplatin and pemetrexed enhances antitumor effects, resulting in significant tumor regression[54] - FHD-909 exhibits synergistic activity when combined with KRAS inhibitors in vitro, indicating potential for enhanced therapeutic efficacy[56] - FHD-909 sensitized tumor cells to pembrolizumab, resulting in enhanced anti-tumor activity, with pembrolizumab alone showing no effect compared to vehicle control[59] - Combination of FHD-909 with olomorasib demonstrated synergistic antitumor activity with a significant p-value of <0.05 in NCI-H2030 models[57] - FHD-909 combined with pan-KRAS inhibitor resulted in sustained tumor regression, also showing a significant p-value of <0.05 for the combination group[58] Preclinical Assets and Future Developments - The selective CBP degrader, FHT-171, is IND-ready in 2026, with a focus on CBP-dependent and EP300-mutant cancers, showing increased tolerability compared to non-selective compounds[24] - IND-enabling studies for selective EP300 degraders are planned for 2026, focusing on improved tolerability and deeper efficacy responses compared to non-selective molecules[32] - The selective EP300 degrader EP300d-007 shows superior efficacy in IMiD resistant multiple myeloma models, achieving deeper responses compared to pomalidomide and inobrodib[38] - The ARID1A mutation incidence in endometrial cancers is approximately 66,000 per year in the U.S., with ARID1B being a major synthetic lethal target[41] - The ARID1B degrader treatment has shown effects on downstream target genes, progressing towards in vivo proof-of-concept[47] - The company is advancing multiple preclinical assets towards INDs, including selective degraders for ARID1B and EP300[48] Safety and Tolerability - No significant impact on platelet counts was observed following treatment with selective CBP and EP300 degraders, indicating a favorable safety profile[35] - The long-acting injectable formulation of CBPd-171 enables weekly subcutaneous delivery, showing comparable efficacy to daily injections in gastric cancer models[30] Degradation Mechanisms - Selective degradation of CBP leads to reduced expression of estrogen receptor target genes, resulting in cancer cell growth inhibition[25] - The selective EP300 degrader shows anti-proliferative activity across a broad range of hematological malignancies, with approximately 70% of tested cell lines being sensitive[33] - EP300 degradation results in significant tumor growth inhibition in multiple myeloma and DLBCL models, with fold selectivity exceeding 1000x for certain compounds[34] - Experimental kinetic analysis indicates that degradation rates are crucial for determining the efficiency of protein degraders, with slower rates leading to partial degradation[62] - Prelude's SMARCA2 (VHL) degrader achieved improved degradation metrics compared to SMARCA2 (CRBN) degrader, indicating faster action at high concentrations[64] - Foghorn's analysis of degradation rates aligns with published data, confirming the efficacy of their degraders in achieving significant protein degradation[65]