Foghorn Therapeutics Presents New Preclinical Data on Potential First-in-Class BRM Selective Inhibitor FHD-909 and Selective CBP and Selective EP300 Degrader Oncology Programs - Seite 2

Presentation Highlights

FHD-909 Program
BRM and BRG1 are highly homologous and mutually exclusive subunits of the BAF complex. BRG1 mutations occur in a variety of tumor types, including approximately 10% of non-small cell lung cancers (NSCLC), and result in tumors being dependent on BRM activity for their survival. Selectively blocking BRM activity is a promising synthetic lethal strategy to induce tumor death while sparing healthy cells. However, the ATPase domains of BRM and BRG1are 92% identical which has made identifying a selective BRM inhibitor challenging.

Poster 3230 / 14: Discovery of selective BRM (SMARCA2) ATPase inhibitors for the treatment of BRG1 (SMARCA4) mutant cancers
Preclinical data presented at AACR support FHD-909 as an oral, novel, potent and selective BRM inhibitor with robust anti-tumor monotherapy activity:

• ~ 30-fold selectivity for BRM inhibition over BRG1 in cell-based assays
• Dose-dependent and robust tumor growth inhibition and regression as a monotherapy in multiple BRG1 mutant xenograft models
• Favorable tolerability with dose dependent modulation of BRM target genes in vivo
• Lilly plans to file an IND application for potential first-in-class orally bioavailable, selective BRM inhibitor, FHD-909, with initial focus in BRG1 mutated NSCLC in Q2 2024

Selective CBP and Selective EP300 Degrader Programs
CBP and EP300 are paralog histone acetyltransferases involved in many cellular processes. Dysregulation of one or both is implicated in various cancer types, and functional genomic screens have suggested a synthetic lethal relationship in tumor cells. Attempts to selectively inhibit CBP or EP300 individually have been challenging due to the high homology between the two proteins. Additionally, dual inhibition of CBP/EP300 has led to hematopoietic toxicity.

Selective CBP Program
Poster 6067 / 26: Identification of selective CBP degraders with robust preclinical PK, PD, efficacy, and safety across solid tumor indications
Preclinical pharmacodynamic and pharmacokinetic data presented at AACR support the identification of potent and selective CBP degraders with anti-tumor activity across various EP300 mutant cell lines from multiple indications:

• Deep and sustained CBP degradation leading to significant tumor growth inhibition in mouse xenograft solid tumor models
• Robust monotherapy anti-tumor activity that was not associated with significant body weight loss
• In vivo, no evidence of thrombocytopenia, which is attributed to the sparing of megakaryocytes, nor evidence of anemia
• Long-acting CBP-selective protein degrader formulations with first-in-class potential for patients with tumors harboring EP300 mutations

Selective EP300 Program