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Review
. 2023 Sep 11;13(1):141.
doi: 10.1038/s41408-023-00902-x.

Zanubrutinib: past, present, and future

Constantine S Tam #  1 , Javier L Muñoz #  2 , John F Seymour  3 , Stephen Opat  4
Affiliations
Review

Zanubrutinib: past, present, and future

Constantine S Tam et al. Blood Cancer J. .

Erratum in

Abstract

In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.

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Conflict of interest statement

JM reports consulting fees from ADC Therapeutics, Alexion, Bayer, BeiGene, BMS, Debiopharm, Epizyme, Fosun Kite, Genmab, Gilead/Kite Pharma, Innovent, Janssen, Juno/Celgene, Karyopharm, Kyowa, MorphoSys/Incyte, Novartis, Pfizer, Pharmacyclics/AbbVie, Seagen, and Servier; research funding from Bayer, Celgene, Genentech, Gilead/Kite Pharma, Incyte, Janssen, Merck, Millennium, Pharmacyclics, Portola, and Seagen; honoraria from Curio, Kyowa, OncView, Physicians’ Education Resource, Seagen, and Targeted Oncology; and speakers bureau for Acrotech/Aurobindo, AstraZeneca, Bayer, BeiGene, Celgene/BMS, Genentech/Roche, Gilead/Kite Pharma, Pharmacyclics/Janssen, Kyowa, Seagen, and Verastem. JFS reports research funding from AbbVie, BMS, and Roche; and advisory board/honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Genentech, Genor Bio, Gilead, Janssen, Roche, Sunesis, and TG Therapeutics. CST received research support from Janssen and AbbVie; received honoraria from BeiGene, AbbVie, and Janssen; and received other remuneration from BeiGene. SO reports funding from BeiGene paid to Monash University, with regards to the submitted work; receiving honoraria and participating on an advisory board for BeiGene, outside the submitted work.

Figures

Fig. 1
Fig. 1. Treatment evolution in chronic lymphocytic leukemia [30, 95, 96].
CAR chimeric antigen receptor, BTK Bruton tyrosine kinase, FCR fludarabine, cyclophosphamide, and rituximab.
Fig. 2
Fig. 2. Number of allogeneic transplantations performed in adult patients with CLL in the US during 2000 to 2020.
Reductions in the number of transplantations in patients with CLL can be observed from 2013 [12]. CLL chronic lymphocytic leukemia.
Fig. 3
Fig. 3. Kinase selectivity of zanubrutinib and ibrutinib [49].
BTK Bruton tyrosine kinase.
Fig. 4
Fig. 4. Zanubrutinib BTK occupancy in peripheral blood mononuclear cells and in lymph nodes by dose regimens relative to those in ibrutinib [52, 54, 97].
aThe clinical significance of having high BTK occupancy in lymph nodes is unknown. BTK Bruton tyrosine kinase, D day, PBMC peripheral blood mononuclear cell, QD once daily, W week.
Fig. 5
Fig. 5. Concentration-time profiles.
Values are shown for A ibrutinib and B zanubrutinib [50, 52, 56]. BID twice daily, BTK Bruton tyrosine kinase, Ctrough predose trough concentration, IC50 half-maximal inhibitory concentration, QD once daily.
Fig. 6
Fig. 6. Key milestones in the development of zanubrutinib.
BTK Bruton tyrosine kinase, CLL chronic lymphocytic leukemia, EC European Commission, EU European Union, IA interim analysis, MCL mantle cell lymphoma, NDA new drug application, PFS progression-free survival, SLL small lymphocytic lymphoma, US United States.
See this image and copyright information in PMC

References

    1. Thandra KC, Barsouk A, Saginala K, Padala SA, Barsouk A, Rawla P. Epidemiology of non-Hodgkin’s lymphoma. Med Sci. 2021;9:5. 10.3390/medsci9010005. - PMC - PubMed
    1. Mafra A, Laversanne M, Gospodarowicz M, Klinger P, De Paula Silva N, Pineros M, et al. Global patterns of non-Hodgkin lymphoma in 2020. Int J Cancer. 2022;151:1474–81. doi: 10.1002/ijc.34163. - DOI - PubMed
    1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–7. doi: 10.1056/NEJM200012143432402. - DOI - PubMed
    1. Bhatt V, Alejandro L, Michael A, Ganetsky A. The promising impact of ibrutinib, a Bruton’s tyrosine kinase inhibitor, for the management of lymphoid malignancies. Pharmacotherapy. 2014;34:303–14. doi: 10.1002/phar.1366. - DOI - PubMed
    1. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood. 2008;111:4916–21. doi: 10.1182/blood-2007-12-129379. - DOI - PubMed

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