Venetoclax (Venclexta)

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Mechanism of action

From the NCI Drug Dictionary: An orally bioavailable, selective small molecule inhibitor of the anti-apoptotic protein Bcl-2, with potential antineoplastic activity. GDC-0199 mimics BH3-only proteins, the native ligands of Bcl-2 and apoptosis activators, by binding to the hydrophobic groove of Bcl-2 proteins thereby repressing Bcl-2 activity and restoring apoptotic processes in tumor cells. Bcl-2 protein is overexpressed in some cancers and plays an important role in the regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival. Compared to the Bcl-2 inhibitor navitoclax, this agent does not inhibit bcl-XL and does not cause bcl-XL-mediated thrombocytopenia.

Preliminary results

Acute myeloid leukemia

  1. Abstract: Marina Konopleva, MD, PhD, Daniel A. Pollyea, MD, MS, Jalaja Potluri, MD, Brenda J. Chyla, PhD, Todd Busman, MS, Evelyn McKeegan, PhD, Ahmed Salem, PhD, Ming Zhu, PhD, Justin L. Ricker, MD, PhD, William Blum, MD, Courtney D. DiNardo, MD, Martin Dunbar, DRPH, Rachel Kirby, Nancy Falotico, Joel D. Leverson, PhD, Rod A. Humerickhouse, MD, PhD, Mack Mabry, MD, Richard M. Stone, MD, Hagop M. Kantarjian, MD and Anthony G. Letai, MD, PhD. A Phase 2 Study of ABT-199 (GDC-0199) in Patients with Acute Myelogenous Leukemia (AML). ASH 2014 abstract 118 link to abstract

Chronic lymphocytic leukemia

  1. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Enschede SH, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 6. [Epub ahead of print] link to original article PubMed

Mantle cell lymphoma

  1. Abstract: Matthew Steven Davids, John Francis Seymour, John F. Gerecitano, Brad S. Kahl, John M. Pagel, William G. Wierda, Mary Ann Anderson, Nikita Rudersdorf, Lori A. Gressick, Nicholas P. Montalvo, Jianning Yang, Ming Zhu, Martin Dunbar, Elisa Cerri, Sari H. Enschede, Rod Humerickhouse, Andrew Warwick Roberts. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): Responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol 32:5s, 2014 (suppl; abstr 8522) link to abstract

Waldenström macroglobulinemia

  1. Abstract: Matthew Steven Davids, John Francis Seymour, John F. Gerecitano, Brad S. Kahl, John M. Pagel, William G. Wierda, Mary Ann Anderson, Nikita Rudersdorf, Lori A. Gressick, Nicholas P. Montalvo, Jianning Yang, Ming Zhu, Martin Dunbar, Elisa Cerri, Sari H. Enschede, Rod Humerickhouse, Andrew Warwick Roberts. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): Responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol 32:5s, 2014 (suppl; abstr 8522) link to abstract

History of changes in FDA indication

  • 5/7/15: Granted FDA Breakthrough Therapy designation "for the treatment of chronic lymphocytic leukemia (CLL) in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation."

Also known as

GDC-0199