Biosimilars: What are they, and are they OK?

A big story today is that the FDA, for the first time, has approved a so-called biosimilar drug.

The thrust of the news is mostly regulatory and economic:

1. Unlike generic drugs, which are chemically identical in every way to their brand counterparts, biosimilars are not. They are similar, which really ought to be rather obvious from the name. This is something that the FDA has not dealt with before; the rules for pills (also called small molecule drugs) are quite different.
2. Although this concept may be difficult to understand, the reason behind this trend is not it is money.

The two drugs in question Amgen s Neupogen, the original innovative drug, and Sandoz s Zarxio, the copy (biosimilar) are used to boost white blood cell counts in patients undergoing chemotherapy, to prevent infections in patients who will become immunocompromised from the chemo.

Sandoz wants to sell Zarxio, probably at a discount, and cut into Amgen s sales. In the future, since the biologicals market is so huge, other companies, large and small, will want to do this. (There are also patent issues involved, but these will not be discussed here.)

Both drugs are biologicals drugs derived from living organisms. These are much harder to make and to purify (see below). They are also administered by injection, since they will be degraded by stomach acid and enzymes. And, they are very expensive although biosimilars are likely to be less so. But do you get what you pay for? Maybe. Why?

As molecules get large, they do not form crystals. One of the best ways to purify most drugs is to crystallize them. This process usually removes all impurities, leaving one single chemical entity.

This is not possible with biologicals. Here is why:

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.

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, or the open window in your 25th floor of apartment may start to look tempting):

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 à 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 single batches of biological will be 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?

ACSH s Dr. Josh Bloom says, 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.