Relcobatinib, a highly selective ATP-competitive ABL1 tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia

Relcobatinib (ELVN-001) is a next-generation, investigational, BCR::ABL1 active-site tyrosine kinase inhibitor (TKI) with a unique P-loop folded-in binding mode designed to deliver best-in-class efficacy with an improved tolerability profile over that of other TKIs for the treatment of chronic myeloid leukemia (CML). We demonstrate that relcobatinib has marked selectivity for BCR::ABL1, without inhibition of off-target kinases implicated in toxicities related to other TKIs. Relcobatinib exhibited greater selectivity than other active-site TKIs and demonstrated robust activity in vitro against native BCR::ABL1 and a broad range of clinically relevant TKI-resistant mutants. A BCR::ABL1 mouse xenograft model of human CML showed marked anti-tumor activity with relcobatinib as monotherapy, and, in combination with asciminib, showed further durable tumor regression, supporting the complementary mechanism of action between an active-site TKI and an allosteric inhibitor. Collectively, the preclinical profile of relcobatinib, marked by selective BCR::ABL1 targeting, supports its potential to improve efficacy and tolerability in the treatment of CML and other BCR::ABL1-driven malignancies, as monotherapy and in combination with an allosteric inhibitor.