Elvn-001, a Next Generation ATP-Competitive ABL1 Tyrosine Kinase Inhibitor for the Treatment of Chronic Myeloid Leukemia (2022)

Of the six small-molecule ABL1 tyrosine kinase inhibitors (TKIs) that have received FDA-approval for the treatment of BCR-ABL1-driven Chronic Myeloid Leukemia (CML), five (Imatinib, Nilotinib, Dasatinib, Ponatinib, Bosutinib) target the ATP-binding site in the kinase domain. While each of these TKIs provides added value to the arsenal of treatments for CML, these agents suffer from selectivity issues, inhibiting a number of off-target kinases that drive an array of dose-limiting toxicities (DLTs) which constrain their ability to fully engage ABL1 and drive maximal efficacy. In addition, the emergence of on-target resistance against these TKIs, such as the highly prevalent T315I mutation at the gatekeeper position of the active site, is common and represents a significant clinical challenge. The recently approved ABL1 TKI Asciminib is an allosteric inhibitor that interacts with the unique myristoyl binding pocket of ABL1 and therefore possesses high kinome selectivity and an improved tolerability profile. Despite its unique binding mode, clinical activity against the T315I mutant requires a dose five times higher than that approved for the broader third-line or greater patient population, which leads to issues with tolerance. In addition, emergent on-target resistance remains a challenge, particularly with respect to mutations within the myristoyl pocket as well as select active site mutants. Here we report the discovery of ELVN-001, a potent ATP-competitive small-molecule ABL1 TKI which, unlike the majority of currently approved ABL1 TKIs, is highly selective in both biochemical and cell-based assays versus the kinome in general as well as the key off-target kinases KDR, c-KIT, PDGFR and SRC, which are associated with a variety of DLTs including myelosuppression, edema, pleural effusions, hypertension, and certain cardiovascular events. ELVN-001 exhibited potent pharmacodynamic (phosphorylated CRKL) and anti-proliferative activity in vitro against BCR-ABL1-driven CML cell lines with comparable or superior activity to the approved therapies. Evaluation of ELVN-001 against Ba/F3 cell lines expressing a panel of clinically relevant BCR-ABL1 TKI-resistant mutants demonstrated activity of ELVN-001 against many of these mutants, including T315I as well as two myristoyl pocket mutants (A334P, P465S) which are highly resistant to asciminib. Cell-based mutagenesis screens using Ba/F3 BCR-ABL1 cells confirmed a concentration-dependent reduction in outgrowth of resistant clones, which generally narrowed to a select subset of P-loop mutations. Consistent with previously reported findings for ponatinib, while ELVN-001 showed little to no activity against cells expressing a subset of T315I-inclusive BCR-ABL1 compound mutants, the addition of Asciminib resulted in varying degrees of re-sensitizing these mutants to ELVN-001. Importantly, ELVN-001 possessed a favorable absorption, distribution, metabolism, elimination, and toxicity profile, as determined from both in vitro and in vivo studies, that readily translated into favorable pharmacokinetic properties in all preclinical species evaluated. Accordingly, administration of doses of ELVN-001 corresponding to well-tolerated free drug exposures in rats and non-human primates readily translated to mouse in vivo tumor xenograft models of efficacy, including a model of T315I CML. These anti-tumor activities also compared favorably to currently approved therapies when evaluated head-to-head in these studies. Together, these findings support ELVN-001 as an extremely selective, novel ATP-competitive inhibitor of ABL1 kinase with superior pharmacokinetic and tolerability properties compared to currently approved TKIs and which retains activity against T315I and other key on-target resistance mutations, warranting its further investigation in patients with TKI-resistant/intolerant CML.