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G-CSF: The original Innovator

Sandoz’s (Princeton, NJ) Zarzio rode the first wave into the U.S. biosimilars market after it received FDA approval last week. Zarzio is similar to Amgen’s (Thousand Oaks, CA) Neupogen and both of these medications are recombinant versions of the “go to” stimulator for white blood cell production—known as granulocyte-colony stimulating factor (G-CSF).

White blood cells (WBC) are the front line troops that protect the body from infection and disease and are produced when G-CSF is released from bone marrow. G-CSF beefs up the immune system when it binds to receptors on the precursor to WBCs, known as hematopoietic stem cells. This attachment initiates the differentiation and maturation of the stem cell so it can graduate to become a WBC.

Patients undergoing chemotherapy and bone marrow transplants run low on WBCs and an infusion of Neupogen or Zarzio elicits the same G-CSF action—increased immune response. While both drugs are potential lifesavers, the real story is how the FDA decided to classify these two biologics. Let’s take a look at the science and policy behind biosimilars.

Similar, not Identical

Biologic drugs are made by transferring the gene for a therapeutic protein into a bacterial or mammalian cell. That production cell makes the protein that corresponds to the transferred gene.

Gene sequences for therapeutic proteins are publicly available. In theory it should be straightforward to make a copycat version of any biologic drug. In practice, however, many external factors influence the final, intricately-folded protein structure. Recall that it is imperative the protein be folded correctly because protein structure influences protein function. If the protein structure is not correct, the protein may not work.

The precise manufacturing conditions are considered proprietary because the process of growing cells influences the final structure of the protein. Even slight differences in the cells themselves can affect the final structure. Cell lines originating from different manufacturers are not identical, even if both are Chinese hamster ovary cells—a biomanufacturing favorite.

These factors give rise to the saying “the product is the process,” and is the reason biosimilar drugs are not considered identical to the source biologic. Therefore, biosimilars are required to undergo at least some clinical testing to confirm safety and efficacy prior to approval.

TERM OF THE WEEK: WHITE BLOOD CELL

White blood cells, also called leukocytes, are any of the various colorless cells of the immune system that circulate mainly in the blood and lymph.  B-cells, T-cells, macrophages, monocytes, and granulocytes are specialized white blood cells.

INTERCHANGEABLITY DENIED

Zarzio and Neupogen are approved for the exact same indication. The twist is that Zarzio is not designated as interchangeable with Neupogen. Therefore, a pharmacist is not allowed to substitute one drug for another because the FDA does not consider Zarzio to be identical to Neupogen. Here is a fact highlighted in their different International Nonproprietary Names (INN): Neupogen’s is filgrastim and Zarzio’s is filgrastim-sndz.

Why is the FDA hesitant to give a biosimilar interchangeable status with the brand name biologic? Immunogenicity—the ability to provoke an immune response. All biologics are potentially immunogenic, so switching biologics is a safty concern.

THE CHASE IS ON

Biosimilars stem from Congress’ passage of the Patient Protection and Affordable Care Act five years ago. The bill authorized the FDA to approve biosimilars as a means to lower the cost of biologic drugs, which Congress hoped would herald in a new era for healthcare. Are lower healthcare costs for biologics eminent?  Below are some top selling biologics and the biosimilar rivals chasing them.

Biosimilars in the pipeline

 

Learn more about biosimilars. Check out our earlier issue, Biosimilars: Ready Or Not, Here They Come.

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