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Friday, 15 November 2013

New Drug Approvals 2013 - Pt. XVIII - Obinutuzumab (GazyvaTM)




ATC Code: L01XC15
Wikipedia: Obinutuzumab

On November 1, 2013 the FDA approved obinutuzumab (GazyvaTM) for use in combination with chlorambucil (a nitrogen mustard alkylating agent) for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). CLL is the most common type of Leukaemia accounting for 35% of all reported Leukaemias (See CRUK CLL page). In a randomized three-arm clinical study, the combination of obinutuzumab (in combination with chlorambucil) improved the progression-free survival (PFS) of patients to 23.0 months compared to 11.1 months for chlorambucil alone.


Obinutuzumab (CHEMBL1743048) is a humanized anti-CD20 monoclonal antibody of ca. 150 kDa molecular weight. Its target, the B-lymphicyte antigen CD20, is the product of the gene MS4A1 (Uniprot: P11836; ChEMBL: CHEMBL2058; canSAR target synopsis. The CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes. Obinutuzumab mediates B-cell lysis through three main routes:
  • Engagement of immune effector cells, resulting in antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis
  • Direct activation of intracellular death signaling pathways
  • Activation of the complement cascade.
>obinutuzumab
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGR 
IFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNV 
FDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD 
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY 
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK 
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK/
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQ 
LLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELP 
YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
VTHQGLSSPVTKSFNRGEC

The geometric mean (CV%) volume of distribution of obinutuzumab at steady state is approximately 3.8L. The terminal clearance is 0.09 (46%) L/day and the terminal half-life is ~28.4 days.

Obinutuzumab has been issued with a boxed warning because of the following observed events: Reactivation of Hepatitis B Virus (HBV), in some cases resulting in fulminant hepatitis, hepatic failure, and death; and causing Progressive Multifocal Leukoencephalopathy (PML) resulting in death.

GazyvaTM is produced by Genentech, Inc. The full Prescribing Information is here.

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