ID DB08935 OBINUTUZUMAB C6512H10060N1712O2020S44 146.1 kDa CATEGORY Antineoplastic Agents

DESCRIPTION Obinutuzumab is a humanized monoclonal antibody used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. It was approved by the FDA in November 2013 and is marketed under the brand name Gazyva. There is a black box warning of fatal Hepatitis B Virus (HBV) reactivation and fatal Progressive Multifocal Leukoencephalopathy (PML). INDICATION Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. PHARMACODYNAMICS Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression.

MECHANISM OF ACTION In contrast to rituximab, which is a classic type I CD20 antibody, obinutuzumab binds to type II CD20 antibodies. This allows obinutuzumab to have a much higher induction of antibody-dependant cytotoxicity and a higher direct cytotoxic effect than the classic CD20 antibodies. TOXICITY The most serious toxicities observed with obinutuzumab are Hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML). HBV reactivation can occur with all anti-CD20 antibodies and can result in hepatic failure, fulminant hepatitis, and death. PML occurs as a result of JC virus infection and can be fatal as well. Other common but less serious adverse reactions include infusion reactions (pre-treat with glucocorticoids, acetaminophen, and anti-histamine to prevent this), neutropenia, thrombocytopenia, and Tumor Lysis Syndrome (TLS) (pre-treat patients, especially with a high lymphocyte count and/or a high tumor burden, with anti-hyperuricemics and hydration). It is also recommended to NOT administer live virus vaccinations prior to or during obinutuzumab treatment.

METABOLISM Obinutuzumab is not metabolized by the liver. ABSORPTION Obinutuzumab is administered intravenously, so its absorption is 100%. HALF-LIFE The half life of obinutuzumab is 28.4 days. VOLUME OF DISTRIBUTION = 3.8 L CLEARANCE = 0.09L/day TARGETS B-lymphocyte antigen CD20

GAZYVA DESCRIPTION Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis..Humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B-cells. The molecular mass of the antibody is approximately 150 kDa. Obinutuzumab (GA101) is a novel glycoengineered type II CD20 antibody in development for non-Hodgkin lymphoma. obinutuzumab (GA101) is that the Fc region of the molecule has been glycoengineered to have an increased affinity for FcγRIII receptors expressed on natural killer (NK) cells, macrophages and monocytes, resulting in enhanced antibody-dependent cellular cytotoxicity (ADCC).

CHO cell derived FORMULATION sterile, clear, colorless to slightly brown, preservative free liquid concentrate for intravenousadministration. Humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B-cells. The molecular mass of the antibody is approximately 150 kDa. HALF-LIFE: 28.4 days

Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA Premedicate with glucocorticoid, acetaminophen and anti-histamine. Dilute and administer as intravenous infusion. Do not administer as an intravenous push or bolus. Recommended dose for 6 cycles (28 day cycles): 100 mg on day 1 Cycle 1, 900 mg on day 2 Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, 1000 mg on day 1 of CyclesM

REFERENCES http://www.ncbi.nlm.nih.gov/pubmed/25372850 http://www.ncbi.nlm.nih.gov/pubmed/25355689 http://www.ncbi.nlm.nih.gov/pubmed/25353187 http://www.ncbi.nlm.nih.gov/pubmed/25292485 http://www.ncbi.nlm.nih.gov/pubmed/25163491 http://www.ncbi.nlm.nih.gov/pubmed/25143487 http://www.ncbi.nlm.nih.gov/pubmed/25037849 http://www.ncbi.nlm.nih.gov/pubmed/25190612 http://www.nejm.org/doi/pdf/10.1056/NEJMoa1313984 http://www.nlm.nih.gov/medlineplus/druginfo/meds/a614012.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196549/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881503/?report=reader http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.pdf