The preclinical discovery and development of zanubrutinib for the treatment of chronic lymphocytic leukemia.

Introduction: The history of treating chronic lymphocytic leukemia (CLL) inflected in 2014 with the Food and Drug Administration's (FDA) approval of ibrutinib, the first-in-class small molecule inhibitor of the Bruton's tyrosine kinase (BTK). Zanubrutinib is a 2^nd generation covalent BTK inhibitor developed and manufactured by BeiGene.

Areas covered: In this review, the authors trace the arc of zanubrutinib development from the preclinical phase through the two landmark phase 3 studies in the CLL space, ALPINE and SEQUOIA. The authors cover contemporary management strategies in CLL and highlight the areas of need that zanubrutinib was designed to mitigate.

Expert opinion: Zanubrutinib entered a fray of novel, exciting therapies for CLL. As the second of two 2^nd generation covalent BTK inhibitors its path to prominence in CLL management was narrow. Emphasis during development on kinase selectivity and enhanced bioavailability identified a molecule with superior efficacy and tolerability; hierarchical endpoints in trial design allowed for efficient acquisition of comparative data. Zanubrutinib is endorsed by the National Comprehensive Cancer Network as a preferred, category 1 recommended treatment choice for CLL. Future efforts in combination therapies and response-directed treatment breaks will hopefully lead to still further improvements in use.