GlaxoSmithKline and Genmab A/S have announced the submission of leukaemia drug Arzerra to the European Medicines Agency (EMA) for a variation in marketing authorisation.
The companies are seeking authorisation for the drug to be used in combination with an alkylator-based therapy for treatment of Chronic Lymphocytic Leukemia (CLL) patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.
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Ofatumumab(trade name Arzerra, also known as HuMax-CD20) is a human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is FDA approved for treating chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in treating Follicular non-Hodgkin’s lymphoma, Diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Ofatumumab has also received conditional approval in Europe for the treatment of refractory chronic lymphocytic leukemia. This makes ofatumumab the first marketing application for an antibody produced by Genmab, as well as the first human monoclonal antibody which targets the CD20 molecule that will be available for patients with refractory CLL.
Chronic lymphocytic leukemia (CLL) is a slowly progressing cancer of the blood and bone marrow. Arzerra (ofatumumab) has been approved by the FDA for treating CLL.
Patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy can be prescribed Arzerra.
People older than fifty are mainly affected by CLL. A group of white blood cells known as B-cells that are part of the body’s immune system is the source of CLL. Every year, about ¼ of people diagnosed with CLL die from the disease.
Arzerra is an anti-CD20 monoclonal antibody that targets a membrane-proximal (which means close to the cell surface), small loop epitope, which is a portion of a molecule to which an antibody binds, on the CD20 molecule on B-cells. This epitope isn’t similar to binding sites that are targeted by other CD20 antibodies that are currently available. The CD20 molecule is highly expressed in most B-cell malignancies, making it a key target in CLL therapy.
MECHANISM OF ACTION:
Binding specifically to both the small and large extracellular loops of the CD20 molecule, Arzerra is an anti-CD20 monoclonal antibody. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule isn’t internalized following antibody binding and it isn’t shed from the cell surface. The Fc domain of ofatumumab mediates immune effector functions to result in B-cell lysis in vitro, while the Fab domain binds to the CD20 molecule. Complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity has been suggested as the possible mechanisms of cell lysis.
Products receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white cells or in an enlarged spleen or lymph nodes. These indirect measures for clinical outcomes are considered reasonably likely to predict that the drug will allow patients to live with fewer side effects of a disease or to live longer. Arzerra was approved under the FDA’s accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs.
To confirm that the addition of Arzerra to standard chemotherapy delays the progression of the disease, the manufacturer of this medication is currently conducting a clinical trial in CLL patients. This is because the accelerated approval process requires further study of the drug.