DISCLAIMER

The contents of the presentation are designed for educational and scientific exchange purposes and are not promotional. They may contain information on investigational products or investigational uses of approved products. No conclusions regarding safety and/or efficacy for such investigational products or uses may be made.

SUMMARY

This preclinical study investigated differences in intrinsic Bruton tyrosine kinase (BTK) inhibition among BTK degraders and determined how these differences influence antitumor activity by comparing two late-stage investigational BTK degraders, BGB-16673 and NX-5948, in preclinical studies. The study assessed how intrinsic BTK inhibition influenced activity in models of E3 ligase-proteasome pathway impairment. Both agents demonstrated comparable BTK degradation potency; however, when cereblon (CRBN)-dependent degradation was pharmacologically blocked, BGB-16673 maintained potent inhibition of BTK phosphorylation (IC50=0.8 nM), whereas NX-5948 showed minimal inhibitory activity. In B-cell lymphoma models, CRBN knockout conferred resistance to NX-5948 but not to BGB-16673. BGB-16673 also retained antiproliferative activity across a broader range of BTK mutations, including mutations associated with resistance to NX-5948. In xenograft models, antitumor activity with NX-5948 was lost in the presence of CRBN loss or BTK-M477P mutation, while BGB-16673 maintained activity.