LOXO-305, A Next Generation Reversible BTK Inhibitor, for Overcoming Acquired Resistance to Irreversible BTK Inhibitors

The irreversible BTK inhibitors ibrutinib and acalabrutinib have transformed the treatment of several B-cell malignancies. However, their clinical benefit is limited by off-target toxicity, leading to high rates of treatment discontinuation, and acquired resistance, due to BTK C481 substitutions that prevent irreversible BTK inactivation.