Zanubrutinib is a potent and highly selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK), with demonstrated near complete BTK occupancy in peripheral blood mononuclear cells (PBMCs).¹ It has exposure coverage above its IC₅₀ during the entire dose interval for both BID and QD dosing schedules.²

Zanubrutinib is currently being evaluated in over 35 trials across 29 countries. In head-to-head clinical trials, zanubrutinib demonstrated a more favorable safety profile with fewer cardiovascular toxicities than ibrutinib.  Zanubrutinib’s non-cardiac safety profile is consistent with that reported for other BTKis.^3,4 Zanubrutinib is the only BTKi with proven superiority of PFS vs ibrutinib in the ALPINE trial, which included high-risk relapsed/refractory chronic lymphocytic leukemia (CLL) patients with del(17p)/TP53 and uIGHV.³

Zanubrutinib combination studies include sonrotoclax (BCL2 inhibitor), tislelizumab (anti-PD-1 mAb), BGB-10188 (PI3Kδ inhibitor), obinutuzumab (anti-CD-20 mAb), rituximab (anti-CD-20 mAb), lenalidomide + rituximab, and venetoclax (BCL2 inhibitor).

References

1. Tam, C. S. et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851–859.
2. Tam, C. S., Ou, Y. C., Trotman, J. & Opat, S. Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib. Expert Rev. Clin. Pharmacol 2021;14(11):1329-1344.
3. Brown, J. R. et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: Final comparative analysis of ALPINE. Blood 2024; blood.2024024667.
4. Dimopoulos, M. A, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: Final analysis from the randomized phase III ASPEN study. J. Clin. Oncol. 2023;41(33):5099-5106.

Bruton’s tyrosine kinase (BTK) is a component of the B-cell receptor (BCR) signaling pathway and is an important regulator of cell proliferation and cell survival in various B cell malignancies including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström’s macroglobulinemia (WM) and marginal zone lymphoma (MZL). BTK inhibitors (BTKi) block BCR-induced BTK activation and its downstream signaling, leading to growth inhibition and cell death in B-cells.¹

Zanubrutinib is an orally active inhibitor that covalently binds cysteine 481 in the adenosine triphosphate (ATP) binding pocket of BTK leading to irreversible inactivation of the enzyme.² Zanubrutinib was designed to minimize off-target inhibition of TEC and EGFR family kinases. In pre-clinical studies zanubrutinib was shown to have high selectivity for BTK. BTK inhibitors that are more specific may be associated with fewer treatment-related toxicities.²

References

1. Pal Singh, S., Dammeijer, F. & Hendriks, R. W. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol. Cancer 2018;17:57.
2. Tam, C. S. et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851–859.

Zanubrutinib is indicated for the treatment of adult patients with:

• Mantle cell lymphoma (MCL) who have received at least one prior therapy.*
• Waldenström’s macroglobulinemia (WM).
• Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen.*
• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy.*

*Indication approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Please see full US Prescribing Information for important information on approved uses.

For a complete list of zanubrutinib monotherapy and combination clinical trials, view the pipeline.