Clinical BET Inhibitor RG6146 Demonstrates Potent and on-Target Activity in Pre-Clinical Models of Hematological Malignancy and Combines with Anti-CD20 and BCL-2 Inhibition to Provide Superior Efficacy

Bromodomain and extra terminal (BET) family of bromodomains BET proteins are epigenetic 'readers' that bind acetylated histone residues and transcription factors at the chromatin interface and drive the expression of oncogenic transcription programs. BET inhibition using small molecules is an anti-cancer strategy being evaluated in early phase clinical trials. RG6146 is a novel small molecule, non-covalent inhibitor of (BET) family of bromodomains and potently inhibits BRD2, BRD3, BRD4 and BRDT. RG6146 is in clinical development for hematological malignancies including diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and solid tumors including triple negative breast cancer and ovarian cancer. In this study, we comprehensively examined the pre-clinical activity of RG6146 in vitro and in vivo in hematological cancer cell lines and xenograft models.

RG6146 demonstrated broad activity across a panel of hematological and solid cancer cell lines in vitro . Cell lines derived from hematological malignancies were among the most sensitive to RG6146 with IC50s ranging from 0.02 uM to 5 uM, with an average of 0.39 uM (n=38 lines) in sensitive cell line lines. Sensitivity to RG6146 was accompanied by potent down-regulation of c-myc and induction of apoptosis. IC50s in Diffuse Large B-cell Lymphoma (DLBCL) cell lines averaged 0.05 uM, compared to multiple myeloma (MM) cell lines which demonstrated on average 10 fold greater sensitivity.

The anti-tumor activity of RG6146 was tested in xenograft models representing Non-Hodgkins lymphoma (NHL) and MM. Consistent with in vitro findings, RG6146 displayed potent single agent activity in MM xenograft models with distinct %TGI ranging from (86-94) or tumor regression, compared with NHL models which displayed less single agent activity. To explore the potential utility of RG6146 in combination with other oncology agents, double and triple combinations with the BCL-2 selective inhibitor, venetoclax, and anti-CD20 antibody, obinutuzumab, were tested in the WSU-DLCL2 NHL model. While there was no enhanced efficacy observed for the double combinations of either RG6146 or venetoclax with obinutuzumab over obinutuzumab alone, the triple combination of RG6146, venetoclax and obinutuzumab resulted in distinct tumor regressions and prolonged tumor growth control. The combination of RG6146 and venetoclax were well tolerated and showed superior efficacy and induced tumor regressions in MM xenograft model KMS-12BM which harbors the translocation t(11:14).

Together these data indicate that RG6146 is a potent BET-bromondomain inhibitor with potential utility in hematological malignancies, including NHL and MM, and may enhance the efficacy of other oncology agents such as CD20 antibodies and Bcl-2 inhibitors.