Saturday, May 23, 2015

Filgrastim Is The First Drug Approved By US-FDA To Treat Radiation Sickness

Filgrastim is a recombinant, non-pegylated human granulocyte colony stimulating factor (G-CSF) analogue manufactured by recombinant DNA technology using a strain of E. coli. Filgrastim is a 175 amino acid chain with molecular weight of 18,800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli [1].

The amino acid sequence is:


Filgrastim is used to treat neutropenia [a condition of an abnormally low number of neutrophils (white blood cells)] stimulating the bone marrow to increase production of neutrophils.

Filgrastim is indicated for the following:

1. Cancer Patients Receiving Myelosuppressive Chemotherapy: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-neoplastic drugs. It can also used for pediatric patients.

2. Patients with Acute Myeloid Leukemia: For the reduction in the duration of neutropenia, fever, antibiotic use and hospitalization.

3. Cancer Patients Receiving Myeloablative Chemotherapy Followed by Bone Marrow Transplantation:  To reduce the duration of neutropenia and neutropenia-related clinical sequelae.

4. Patients with Severe Chronic Neutropenia (SCN): To increase neutrophil counts and to reduce the incidence and duration of infection in patients with a diagnosis of congenital, cyclic or idiopathic neutropenia.

5. Patients with HIV Infection:  For the prevention and treatment of neutropenia.

Filgrastim is marketed under several brand names, including: Neupogen (Amgen), Filcad (Cadila Pharma), Nufil (Biocon), etc. 

On March 6, 2015, the U. S. Food and Drug Administration approved filgrastim-sndz (ZARXIO Injection, Sandoz Inc.), as a biosimilar to US-licensed Neupogen for the five indications for which US-licensed Neupogen is approved. The formulation of ZARXIO differs from that of US-licensed Neupogen in one inactive component.

On March 30, 2015, FDA approved use of Neupogen (filgrastim) to treat adult and pediatric patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome, or H-ARS). Myelosuppression occurs when radiation damages internal organs, including bone marrow. Suppression of the bone marrow blocks the production of blood cells. Neupogen can help patients with H-ARS by facilitating recovery of bone marrow cells that develop into white blood cells, including neutrophils, that help fight off infections. It was approved by FDA based on studies in animals (under the Animal Rule), as studies in humans could not be ethically conducted.

In addition, orphan drug designation was granted for this indication, and this supplemental application received priority review.

The drug, Neupogen, is the first ever approved for the treatment of acute radiation injury.

About Acute Radiation Syndrome [2]

Acute Radiation Syndrome is an acute illness caused by irradiation of the entire body (or most of the body) by a high dose of penetrating radiation in a short period of time, usually a matter of minutes.

Patients exposed to high doses of radiation will not be able to produce sufficient numbers of new white blood cells, red blood cells, and platelets, a condition called myelosuppression. Two major clinical manifestations of radiation bone marrow injury are neutropenia (abnormally low level of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low level of platelets) that directly impact the survival of victims exposed to radiation. Severe neutropenia increases the risk of sepsis and death due to infections, while thrombocytopenia increases the risk of hemorrhage and death due to bleeding.

Until patients' bone marrow recovers and creates enough new blood cells-a slow process-these patients are at a high risk of death from infection and bleeding. Neupogen can effectively reduce the duration and severity of neutropenia and increase survival.

1. Ahmed, K. E.; et. al. Complete sequencing of the recombinant granulocyte-colony stimulating factor (filgrastim) and detection of biotinylation by mass spectrometry. Amino Acids 2010, 38(4), 1043-1049.