Nonclinical Safety Assessment of Zanubrutinib: A Novel Irreversible BTK Inhibitor

Zanubrutinib an oral irreversible Bruton’s tyrosine kinase (BTK) inhibitor, is under development for the treatment of a variety of B-cell malignancies and has received accelerated approval by the US Food and Drug Administration for treatment of adult patients with mantel cell lymphoma who have received at least one prior therapy. Zanubrutinib moderately inhibited the human ether- à -go-go-related gene channel with half maximal inhibition concentration (IC 50 ) of 9.11 µM and showed neither effects on the cardiovascular system functions in telemetry-implanted dogs nor on the respiratory and central nervous system functions in rats. No toxicologically significant changes were noted in rats and dogs at the systemic exposure ratios (area under the curve ratio between animals and humans at the therapeutic dose) up to 26- and 15-fold for 26-weeks and 39-weeks of treatment, respectively. Zanubrutinib was not genotoxic. Fertility studies showed no abnormal findings in both male and female rats at the systemic exposure ratios of up to 12-fold; embryo-fetal studies showed no fetal lethality or teratogenicity in rabbit or rat fetuses at the systemic exposure ratios of up to 25- and 16-fold, respectively, except for 0.3% to 1.5% of 2 or 3 chambered hearts in rat fetuses; pre- and postnatal developmental toxicity showed no effects in rats at the systemic exposure ratios up to 16-fold except for an increased incidence (26% to 42%) and severity of various ophthalmic lesions in treated groups compared to the concurrent control group (26%). These nonclinical study results suggest that zanubrutinib has a broad safety window and an optimal safety profile while treating patients with advanced cancers.