Abstract
Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.
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References
Besbes S, Mirshahi M, Pocard M, et al. New dimension in therapeutic targeting of BCL-2 family proteins. Oncotarget. 2015;6(15):12862–71.
Seymour J. ABT-199 for chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2014;12(10):698–700.
Su J, Zhou L, Xia MH, et al. Bcl-2 family proteins are involved in the signal crosstalk between endoplasmic reticulum stress and mitochondrial dysfunction in tumor chemotherapy resistance. Biomed Res Int. 2014;2014:234370.
AbbVie Inc., Genentech Inc. Venclexta™ (venetoclax): US prescribing information. 2016. http://www.fda.gov. Accessed 21 Apr 2016.
US Food and Drug Administration. Venetoclax (Venclexta) tablets. 2016. http://www.fda.gov. Accessed 2 May 2016.
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.
Vogler M, Dinsdale D, Dyer MJ, et al. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol. 2013;163(1):139–42.
Cao Y, Yang G, Hunter ZR, et al. The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;170(1):134–8.
Ackler S, Oleksijew A, Chen J, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3(5):e00178.
Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28(1):210–2.
Peirs S, Matthijssens F, Goossens S, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124(25):3738–47.
Li L, Pongtornpipat P, Tiutan T, et al. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia. 2015;29(8):1702–12.
Ko TK, Chuah CT, Huang JW, et al. The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget. 2014;5(19):9033–8.
Phillips DC, Xiao Y, Lam LT, et al. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015;5:e368.
Chonghaile TN, Roderick JE, Glenfield C, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014;4(9):1074–87.
Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705–15.
Zhao X, Bodo J, Sun D, et al. Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways. Br J Haematol. 2015;168(5):765–8.
Matulis SM, Gupta VA, Nooka AK, et al. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016;30(5):1086–93.
Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood. 2013;121(12):2285–8.
Vaillant F, Merino D, Lee L, et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell. 2013;24(1):120–9.
Fresquet V, Rieger M, Carolis C, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123(26):4111–9.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.
Salem AH, Agarwal S, Dunbar M, et al. Effect of low and high fat meals on the pharmacokinetics of venetoclax, a selective first-in-class bcl-2 inhibitor. J Clin Pharmacol. 2016. doi:10.1002/jcph.741.
Agarwal SK, Hu B, Chien D, et al. Evaluation of rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a Bcl-2 inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol. 2016. doi:10.1002/jcph.730.
Lymphoma Association. Leukaemia and lymphoma - what’s the difference? 2011. http://www.nhs.uk/ipgmedia/national/Lymphoma%20Association/Assets/Leukaemiaandlymphoma-thedifference.pdf. Accessed 2 May 2016.
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016. doi:10.1016/S1470-2045(16)30019-5.
Jones JA, Wierda WG, Choi MY, et al. Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib [abstract no. 7519]. In: ASCO Annual Meeting; 2016.
Ma S, Brander DM, Seymour JF, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1B study. Blood. 2015;126(23):830.
Salles GA, Boyd TE, Morschhauser F, et al. Updated safety and preliminary efficacy data from a phase 1B study combining venetoclax (GDC-0199, ABT-199) with bendamustine/rituximab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia [abstract]. Blood. 2015;126(23):829.
Flinn IW, Brunvand M, Choi MY, et al. Safety and efficacy of a combination of venetoclax (GDC-0199/ABT-199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia-results from a phase 1b study (GP28331) [abstract]. Blood. 2015;126(23):494.
Gerecitano JF, Roberts AW, Seymour JF, et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-hodgkin lymphoma [abstract]. Blood. 2015;126(23):254.
Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory non-hodgkin lymphoma: responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses [abstract no. S1348]. Haematologica. 2014;99(Suppl 1):525.
De Vos S, Swinnen L, Kozloff M, et al. A dose-escalation study of venetoclax (ABT-199/GDC-0199) in combination with bendamustine and rituximab in patients with relapsed or refractory non-hodgkin’s lymphoma [abstract]. Blood. 2015;126(23):255.
Tam CSL, Roberts AW, Anderson MA, et al. The combination of ibrutinib and venetoclax (ABT-199) to achieve complete remissions in patients with relapsed/refractory mantle cell lymphoma: preliminary results of the phase II AIM study [abstract no. 7548]. In: ASCO Annual Meeting; 2016.
Kumar S, Vij R, Kaufman JL, et al. Phase I venetoclax monotherapy for relapsed/refractory multiple myeloma [abstract no. 8032]. In: ASCO Annual Meeting; 2016.
Moreau P, Chanan-Khan AAA, Roberts AW, et al. Phase Ib venetoclax combined with bortezomib and dexamethasone in relapsed/refractory multiple myeloma [abstract no. 8011]. In: ASCO Annual Meeting; 2016.
Konopleva M, Pollyea DA, Potluri J, et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia (AML) [abstract]. Blood. 2014;124(21):118.
Pollyea DA, Dinardo CD, Thirman MJ, et al. Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥65 years ineligible for standard induction therapy [abstract no. 7009]. In: ASCO Annual Meeting; 2016.
Lin TL, Strickland SA, Fiedler W, et al. Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥65 with acute myelogenous leukemia [abstract no. 7007]. In: ASCO Annual Meeting; 2016.
Seymour J, Roberts A, Stilgenbauer S, et al. Reduction of tumor lysis syndrome (TLS) risk in chronic lymphocytic leukemia (CLL) patients treated with ABT-199 (GDC-0199): results of modifications to dosing schedule and TLS prophylaxis [abstract no. P868]. Haematologica. 2014;99(Suppl 1):321.
U.S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). 2016. http://www.fda.gov. Accessed 29 Apr 2016.
Mobasher M, Huang J, Elstrom RL, et al. Multicenter, phase III, open-label, randomized study in relapsed/refractory CLL to evaluate the benefit of GDC-0199 (ABT-199) plus rituximab compared with bendamustine plus rituximab [abstract no. TPS7120]. In: ASCO Annual Meeting; 2014.
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The preparation of this review was not supported by any external funding. During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. E. D. Deeks is a salaried employee of Adis, Springer SBM.
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Deeks, E.D. Venetoclax: First Global Approval. Drugs 76, 979–987 (2016). https://doi.org/10.1007/s40265-016-0596-x
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DOI: https://doi.org/10.1007/s40265-016-0596-x