Abstract B002: Pharmacodynamics and antitumor mechanism of the BRG1/BRM (SMARCA4/2) inhibitor FHD-286 in a Phase 1 study in subjects with AML or MDS
Authors: Collins Mike , Thomsen Astrid , Elliott GiNell , Wan Jessica , Horrigan Kim , Delestre Laure , Penard-Lacronique Virginie , De Botton Stephane , Fiskus Warren , Bhalla Kapil N. , DiNardo Courtney , Agresta Samuel , Piel Jessica , Hentemann Martin 
Published: December 2023

Abstract
BRG/Brahma-associated factors (BAF) chromatin remodeling complexes are critical to the regulation of cellular differentiation and are implicated in cancer and other diseases. FHD-286 is a first-in-class dual inhibitor of the BAF catalytic subunits BRM and BRG1 (SMARCA2/4) that is being developed for the treatment of advanced hematologic malignancies. We previously reported that extended exposure of acute myeloid leukemia (AML) cells to FHD-286 led to upregulation of the myeloid maturation marker CD11b, downregulation of BRG1, and decreased cell proliferation. Morphologic features of differentiation were also observed, suggesting that BAF functions to maintain AML cells in an undifferentiated state and that FHD-286 may inhibit AML cell growth by overcoming this differentiation block. Biomarkers identified from these nonclinical studies were analyzed in a Phase 1 dose escalation study of FHD-286 monotherapy in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS) (Study FHD-286-C-002). Flow cytometric analysis was performed on serially collected peripheral blood mononuclear cells (PBMCs) from a total of 31 subjects across 4 dose cohorts (2.5, 5, 7.5 and 10 mg once-daily). Peripheral blasts showed time- and dose-dependent upregulation of myeloid maturation markers, including CD11b and CD64, and concomitant decreases in BCL2, CD34, and BRG1. At the highest dose, substantial biomarker modulation was evident beginning at Cycle 1 Day 15 (C1D15), whereas significant modulation was not observed before C2D1 at the lower dose levels. Single cell RNA sequencing of bone marrow aspirates revealed distinct populations of blasts expressing leukemic stem cell (LSC) markers versus those expressing myeloid differentiation markers. In the majority of on-treatment bone marrow samples, blast populations expressing LSC markers were reduced, while populations expressing myeloid differentiation markers were expanded in a generally dose-dependent manner. Evidence of differentiation was also observed by morphological assessment of patient bone marrow samples. Importantly, these effects were observed in subjects with a wide range of mutation profiles, including those considered high risk. In summary, analysis of patient samples from Study FHD-286-C-002 revealed dose-dependent impacts on stemness and maturation markers in peripheral and bone marrow blasts. These results suggest that FHD-286 forces stem-like blasts to mature, possibly reducing their capacity for self-renewal, and leading to a gradual reduction in circulating blasts. Consistent with this, decreases in bone marrow and peripheral blast counts were observed across cohorts. These findings suggest combining FHD-286 with cytoreductive agents may be a promising strategy to target both LSC-like and proliferative blasts, which is supported by nonclinical data showing enhanced antitumor activity with various combination partners.
Citation Format: Mike Collins, Astrid Thomsen, GiNell Elliott, Jessica Wan, Kim Horrigan, Laure Delestre, Virginie Penard-Lacronique, Stephane De Botton, Warren Fiskus, Kapil N. Bhalla, Courtney DiNardo, Samuel Agresta, Jessica Piel, Martin Hentemann. Pharmacodynamics and antitumor mechanism of the BRG1/BRM (SMARCA4/2) inhibitor FHD-286 in a Phase 1 study in subjects with AML or MDS [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B002.