Hot off the presses: The FDA just approved the first biosimilar drug in the United States. Sandoz's Zarxio is used to boost the production of certain white blood cells in patients who are undergoing cancer chemotherapy, and are immunocompromised. Sarxio will compete with Amgen's Neupogen, which has been used for this purpose since its approval in 1991. 

The thrust of the news is mostly regulatory and economic:

  1. Unlike generic drugs, which are chemically identical in every way to their brand name counterparts, biosimilars are not. They are similar, which really ought to be rather obvious from the name. This makes life more difficult for the FDA, since the rules for pills (also called small molecule drugs) are quite different from those for biological drugs (antibodies, vaccines, proteins, etc).
  2. Although this concept may be difficult for non-scientists to understand, the reason behind it—money—is not.

Sandoz wants to sell Zarxio, presumably at a discount, and cut into Amgen’s sales. This is only the beginning, since the biologicals market is so lucrative that other companies, large and small, are already waiting in line.

Both drugs are “biologicals” — derived from living organisms. These are much harder to make and to purify (see below). Making a biological drug is a little like baking a souffle. One needs to follow the recipe very carefully. A little extra heat, or rough handling and you have either a lousy souffle, or something that is unrecognizable. 

Not only is the biological drug far more difficult to make, but if something screws up here, there can be serious repercussions for those who take the drug. Biologicals must also be administered by injection, since they will be degraded by stomach acid and enzymes. It would not be entirely incorrect to call them "a pharmaceutical pain in the ass."

And, they are very expensive — although biosimilars are likely to be less so. But do you get what you pay for? Maybe. 

At this point, I thought it might be useful to give those without chemical or biological training a simplified explanation of biological drugs. This also speaks directly to the issue of biosimilarity itself. 

As molecules get large, they no longer form crystals. Right away, this makes the production and purification of large molecules much more difficult, since the best way to purify most drugs is to crystallize them. This process usually removes all impurities, leaving one single chemical entity.

Here is an example:

Below is aspirin—a small molecule drug. You can see its size, crystalline form, and formula, which tells you the number of atoms (which determines the size) in the molecule. The corresponding information for Neupogen is also shown. There is a world of difference.


Screen Shot 2015-03-09 at 12.49.27 PM

So, while aspirin can easily be made 100% pure, Neupogen and Zarxio cannot. In fact, to make them, scientists must go through a series of steps that sound like torture (Please do not try to read this. You will want to hang yourself by the end of the second sentence).

“Aggregation may be minimized by controlling process parameters such as temperature, reduction of recombinant protein expression rate, adjusting the codon usage, or by co-expression of plasmid-encoded chaperones… We have thus employed a strategy to recover active protein from inclusion bodies as described by others [32]. This strategy involves three steps: inclusion body isolation and washing; solubilization of the aggregated protein, and refolding of the solubilized protein. Non-ionic detergents such as Triton × were used to solubilize the bacterial cell wall components that contaminate the inclusion body preparation. EDTA was added to chelate divalent metal ions, which maintain the structural integrity of the cell membrane. A second wash procedure incorporated sodium deoxycholate to remove any residual cell debris particles, especially lipopolysaccharides units that contribute to the unacceptable levels of endotoxins in protein preparations from E. coli. The third step using sodium chloride helps displace nucleic acids or any other contaminants that are non-specifically bound to the G-CSF protein in the inclusion bodies by ionic interactions.”

The end result is that even a single batch of biological will contain mixtures of multiple molecules that are related, but not identical to each other. Another batch will be different. And the same drug made by a different company, can be very different. This is the “similar” part of biosimilars.

So, is “similar” good enough?

Who know? Since both the preparation, purification, composition, and analysis of purity of  biosimilars is so different from that of a pill, if this question is even answerable, it will take many patients trying both of them to possibly know. It’s a bit like the store brand version of Hostess chocolate cupcakes. The white squiggly stuff on top just doesn’t taste as good. I think I’ll stick to the original drug, at least for now.