ADAGEN (PEG-bovine adenosine deaminase) manufactured by Enzon Pharmaceuticals was the first PEGylated protein approved by
FDA in March 1990. It is used to treat X-linked severe combined immunogenicity syndrome, as an alternative to bone marrow
transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated protein
and peptide pharmaceuticals have followed, and many others are under clinical trial or under development stages (see Tables I and II). On Mar. 27, 2012, FDA announced the approval of the first PEGylated peptide, Peginesatide, for the treatment of anemia
associated with chronic kidney disease.
Table I: Table of PEGylated pharmaceuticals (brand name) currently on the market in reverse chronology by FDA approval year
with sponor and indication.
Although PEG has been successfully used in increasing the half-life of proteins and peptides, there are some challenges and
concerns, in particular, risk associated with chronic administration of high dose PEGylated peptides (3). Although, PEGs can
be filtered through the kidneys over time, high doses of PEGylated peptides and proteins can cause accumulation of the bioconjugate
at the target organ and at other organs in the body. The clearance rate of peptides and proteins is lower when they are conjugated
with a large steric moiety such as PEG. At high doses of the PEG conjugate, the metabolic system can be overloaded, resulting
in poor clearance of the peptide or protein. Ultimately, any observed toxicity due to high doses of the PEG conjugate is dependent
on the design of the conjugate (i.e., the location of PEG on the molecule in relation to the active part of the peptide),
the target organ, the conjugate's mechanism of action, and the toxicological action of the peptide or protein on nearby organs.
Table II: Peptide Bioconjugates currently marketed or in clinical trials. Data source: reference 4.
PEGylation of peptides has a number of analytical hurdles that may become more of a concern for regulatory authorities. The
economic cost of PEG derivatives and their availability are also of concern. The yield of PEGylation is typically in the range
of 45% to 60% and therefore, for every unit of bioconjugate, twice as much PEG would have to be purchased. A contract manufacturer
views the purchase of PEG in similar terms to the purchase of other raw materials such as amino acids. Amino acids cost approximately
$1 per gram at large scale whereas PEG can cost in the range of $200–$500 per gram. Conversely, the innovator of a PEGylated
peptide may view a fair cost comparison to be between the peptide and PEG, in which case the PEG may be lower in cost. As
the scale of a peptide project increases from hundreds of grams to several kilograms, the cost of PEG in the manufacturing
of PEGylated peptides will probably become the main driving cost of manufacture. Ultimately, the deciding factor on the economies
of using a PEG bioconjugate would be dependent on the dosage of the final drug.
Many PEGs are unique and are only available from one PEG vendor. This single sourcing is of concern because as projects mature
and commercialize, it is important to have alternative sources of raw materials to mitigate risk. The single source of PEG
also raises the question of how generic companies can enter the market with PEGylated biosimilars. From the innovators point
of view, the use of a PEG with a proprietary linker may provide exclusive patent protection even though royalties may be required
by the PEG raw-material vendor. From a risk-mitigation stand point, a single vendor source would have to provide some sort
of contingency plan in transferring their proprietary linker technology to a third party in the event the operations of the
single-vendor source shut down for an extended period of time.