Foghorn Therapeutics Advances Multi-Target Protein Degrader Pipeline with FHD-909 Phase 1 Trial Progressing
Key Insights
Foghorn Therapeutics reported continued progress in its Phase 1 dose escalation trial of FHD-909 for SMARCA4 (search)-mutated cancers, primarily targeting non-small cell lung cancer patients.
The company's selective CBP degrader entered non-GLP toxicology studies in Q4 2025 with potential applications in EP300-mutant cancers and ER+ breast cancer, targeting IND readiness in 2026.
Preclinical data showed the selective EP300 degrader demonstrated broad anti-tumor activity across over 70% of hematological malignancy sub-lineages tested, differentiating it from dual CBP/EP300 approaches.
Foghorn Therapeutics reported significant progress across its protein degrader pipeline during its third quarter 2025 financial update, with multiple programs advancing toward clinical development and demonstrating promising preclinical activity across various cancer types.
The company's lead program, FHD-909 (LY4050784), continues to progress in its first-in-human Phase 1 multi-center dose escalation trial targeting SMARCA4 (search)-mutated cancers, with non-small cell lung cancer (NSCLC) as the primary target population. According to CEO Adrian Gottschalk, enrollment in the trial is progressing well and remains on track.
FHD-909 Shows Combination Potential
FHD-909 is a first-in-class oral SMARCA2 (search) selective inhibitor that demonstrated high selectivity over its closely-related paralog SMARCA4 (search) in preclinical studies. The compound targets two proteins that serve as catalytic engines across all forms of the BAF complex, employing a synthetic lethal strategy designed to induce tumor death while sparing healthy cells.
Preclinical data revealed enhanced anti-tumor activity when FHD-909 was combined with standard-of-care chemotherapies, anti-PD-1 pembrolizumab, and several novel KRAS (search) inhibitors in NSCLC animal models. SMARCA4 (search) mutations occur in up to 10% of NSCLC cases and are implicated in a significant number of solid tumors.
"Based on our preclinical monotherapy and combination data, we are enthusiastic about the development of FHD-909 with the goal of developing it as a front-line therapy in NSCLC," Gottschalk stated.
Selective Degrader Programs Advance
CBP Degrader Program
Foghorn's selective CBP degrader entered non-GLP toxicology studies in Q4 2025, with IND readiness anticipated in 2026. The program targets CBP, an acetyltransferase closely related to EP300, designed to exploit synthetic relationships in EP300-mutated cancers including endometrial, cervical, ovarian, bladder, and colorectal cancer.
The lead candidate CBPd-171 (search) demonstrated several promising characteristics in preclinical studies:
- Highly potent and selective activity
- Anti-tumor activity in EP300 mutant solid tumors and CBP-dependent cancers, including potential in ER+ breast cancer
- No significant impact on platelet counts with megakaryocytes spared
- Long Acting Injectable (LAI) formulation optimized for subcutaneous injection weekly or every other week
EP300 Degrader Shows Broad Hematological Activity
The selective EP300 degrader program, targeting hematological malignancies and prostate cancer, demonstrated robust preclinical results that differentiate it from dual CBP/EP300 approaches. Key findings included:
- Broad anti-tumor activity in over 70% of all hematological sub-lineages tested
- VHL-based selective degrader showing impressive efficacy in multiple myeloma without hematological toxicities including thrombocytopenia
- Full efficacy in IMiD-resistant multiple myeloma cell lines
- Favorable tolerability profile with widespread potential for combinations
IND-enabling studies for the EP300 degrader are expected in 2026, with a focus on multiple myeloma and diffuse large B-cell lymphoma.
ARID1B Degrader Targets Solid Tumors
The selective ARID1B (search) degrader program is progressing toward in vivo proof of concept in 2026, with potential relevance in up to 5% of solid tumors. The program targets ARID1B in ARID1A (search)-mutated cancers, exploiting the dependency created when ARID1A, the most mutated subunit in the BAF complex, is lost.
Recent preclinical data presented at the TPD and Induced Proximity Summit included:
- Development of VHL and cereblon-based bifunctional degraders with potential for oral delivery
- Selective degradation of ARID1B achieved
- Modulation of downstream target genes following ARID1B degradation
The program has potential applications in endometrial, gastric, gastroesophageal junction, bladder, and non-small cell lung cancers.
Strategic Partnership and Financial Position
Foghorn maintains a strategic collaboration with Eli Lilly, including a 50/50 U.S. co-development and co-commercialization agreement for its selective SMARCA2 (search) oncology program. The collaboration encompasses both selective inhibitor and degrader approaches, plus an additional undisclosed oncology target and three discovery programs.
The company reported a strong financial position with $180.3 million in cash, cash equivalents, and marketable securities as of September 30, 2025, providing a cash runway into 2028. Third quarter collaboration revenue increased to $8.2 million compared to $7.8 million in the prior year period, driven by continued advancement of programs under the Lilly collaboration.
Research and development expenses decreased to $20.0 million from $24.7 million in the prior year quarter, while the company reported a net loss of $15.8 million compared to $19.1 million in the same period last year.