Bruton’s tyrosine kinase (BTK) plays a central role in B-cell receptor signaling and is a clinically validated target in B-cell malignancies and autoimmune disease. In oncology settings, treatment-associated resistance to covalent and non-covalent BTK inhibitors, including mutations that preserve BTK’s scaffolding functions, underscores the need for therapies that act through a differentiated mechanism of action enabling more complete target control.
Bexobrutideg is an orally bioavailable heterobifunctional degrader designed to eliminate both wild-type and mutant BTK through cereblon-mediated ubiquitination and proteasomal degradation. Preclinical studies demonstrated potent, and selective degradation of BTK, sustained pharmacodynamic activity at low drug concentrations, and robust efficacy in models of B-cell malignancy and autoimmunity, including settings of CNS involvement.
In clinical evaluation, bexobrutideg has demonstrated potent BTK degradation, CNS exposure, and encouraging signs of clinical activity across a spectrum of hematological malignancies. Notably, durable and deepening responses have been observed in the setting of CLL, including CLL with CNS involvement. In addition, exposure response analysis in patients suggests that bexobrutideg is a wide therapeutic index drug, offering the possibility for use in combination as well as in indication outside of oncology. Collectively, these findings establish bexobrutideg as a first-in-class BTK degrader with the potential to overcome limitations of inhibitors and expand therapeutic options for patients with B-cell malignancies and autoimmune disease.