BCR-ABL inhibitor asciminib (ABL001) meets phase 3 primary endpoint in CML

The phase 3 ASCEMBL study compared asciminib to bosutinib (Bosulif, Pfizer) in chronic phase CML pts treated with at least 2 prior TKIs. Asciminib significantly improved the Molecular Response Rate at 24 wks, the primary endpoint of the study. Data has not been presented.

Asciminib is expected to be the 6th BCR-ABL TKI to come to market. It is also the 3rd Novartis TKI, after imatinib (Gleevec) and nilotinib (Tasigna), approved in 2001 and 2007, respectively.

While the approved TKIs are catalytic inhibitors, designed to occupy the ATP binding site of the BCR-ABL kinase, asciminib functions as an allosteric inhibitor. Asciminib occupies the ABL myristoyl-binding pocket, mimicking the negative regulatory element, myristate, which is lost on fusion of ABL1 to BCR.

Further development includes an ongoing phase 2 study evaluating the combination of asciminib and imatinib. This approach is supported by strong preclinical data demonstrating synergy between ATP-site and allosteric TKIs.

Reference
ASCEMBL: NCT03106779
ASC4MORE: NCT03578367
Hughes et al., NEJM. 2019 (PMID: 31826340)
Eide et al., Cancer Cell. 2019 (PMID: 31543464)