In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

P1, N=33, Not yet recruiting, Montefiore Medical Center

P1, N=340, Recruiting, Eli Lilly and Company | Trial completion date: Dec 2028 --> Oct 2027 | Trial primary completion date: Dec 2028 --> Oct 2027

P1, N=340, Recruiting, Eli Lilly and Company | Trial completion date: Oct 2027 --> Dec 2028 | Trial primary completion date: Oct 2027 --> Dec 2028

P1, N=340, Recruiting, Eli Lilly and Company | Trial completion date: May 2028 --> Oct 2027

The pharmacologic inhibition of BRG1 using two selective inhibitors, BRM014 and FHD-286, revealed marked sensitivity in Ph-like B-ALL cell lines, whereas KMT2A -R B-ALL was resistant...These results support the advancement of BRG1-directed strategies as a viable treatment approach for patients with Ph-like B-ALL, with the potential to improve outcomes in this high-risk population. Higher levels of BRG1 correlate to poor clinical outcomes in Ph-like but KMT2A -R B-ALL Inhibition of BRG1 induces cell cycle arrest in Ph-like cells in vitro and extends the survival of mice in pre-clinical in vivo studies.

P1, N=340, Recruiting, Eli Lilly and Company | N=160 --> 340 | Trial completion date: Oct 2027 --> May 2028

DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies.

P1, N=144, Active, not recruiting, Foghorn Therapeutics Inc. | Recruiting --> Active, not recruiting

This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.

Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials.

P1, N=160, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting