of biologic agents. The reason for these process changes
could be process improvements, scale changes, site transfers,
or simply new batches.
Most biologic agents are glycoproteins, and even a well-controlled
product may consist of proteins with the same amino
acid sequences with many different glycosylated compositions.
A correspondence in Nature Biotechnology by Schiestl
et al8 compared the different pre- and post-change batches of
Enbrel Utilizing glycan mapping, cation exchange chromatography
(CEX), and antibody-dependent cellular cytotoxicity in
vitro bioactivity (ADCC) revealed a highly consistent profile
for batches until the end of 2009. After 2009 major differences
were found in the glycosylation profile. Enbrel continued to
remain on the market with unaltered labels implying that the
observed changes did not result in an altered clinical profile
and was acceptable by health authorities.
Immunogenicity however is a concern, and evaluation of small
differences in glycoprotein structures resulting in immunogenicity
will have to be evaluated. Unfortunately, analytical data
or animal data cannot predict immune responses in humans.
Weise et al, American Society of Hematology 10/31/12.9
Another concern is the potential of protein biopharmaceuticals
to form aggregates. Monomer proteins can form dimers, either
reversible or irreversible, and particles may contain up to trillions
of monomeric units. Aggregation cannot only decrease
efficacy by reducing dosing concentration of drug, but they can
also give rise to adverse toxicological and immunological responses.
Size exclusion chromatography (SEC) is a simplistic
low cost approach to characterize protein aggregates. Orthogonal
analytical methods such as field flow fractionation can
provide an additional level of assurance that SEC lacks.
The properties of a biologic agent that elicits an immunologic
response are poorly understood and cannot be predicted from
in vitro or in vivo (animal) testing, or even from the epitope
or analytic chemistry of the molecule. Only clinical trials can
provide this information. Analytical methods will continue to
make rapid progress, however their capabilities and limitations
need to be understood. The costs of the development of
these technologies would have to be shared by smaller biotech
companies that could not afford the high cost of these
methods. Hence, post-marketing studies to detect immunogenicity
may be required.
The burden of proof initially will be determining that the physicochemical
and biological characteristics of the biosimilar are
equivalent to the originator. The more analytical testing ie,
chromatography, capillary electrophoresis, antibody affinity,
pharmacodynic, genetic markers that show equivalency the
more likely that the biosimilar is identical to the originator, and
therefore will not require large and costly Phase III trial.
CT-P13 is a biosimilar infliximab that was compared to to
innovator infliximab in in-vitro analytical studies. Similar infrared
spectroscopy, tumor necrosis factor alpha neutralizing
potency, and complement dependent cytotoxicity were noted.
Subsequently, two clinical trials compared CT-P13 to infliximab
in ankylosing spondylitis and in combination with methotrexate
in treating rheumatoid arthritis. Results were similar between the
two cohorts.10 At weeks 14 and 30 ACR 20, 50, and 70 were similar
between CT-P13 and Infliximab, and in the AS group the clinical
responses were also similar. Antibody responses at week 24
were 27% for CT-P13 and 23% for the infliximab monotherapy in
AS 50% of both the CT-P13 and innovator had antibodies at week
30. Since Inflixiamb is licensed for treatment in Crohn’s disease
and ulcerative colitis, psoriasis, and psoriatic arthritis studies are
useful to support CT-P13 for treatment of these diseases.
On June 28, 2013 the EMA (European Medicine Agency) recommended
that CT-P13 be granted marketing authorization for
the treatment of rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis, psoriasis, and Crohn’s disease and ulcerative
colitis. In the USA the patent for innovator infliximab does not
expire until September 2018. Its patent expiration in the European
Union is not until August 2014, and it will not be marketed
until after that date.10 Its launch however, in eastern and central
Europe where patents are not in effect, is expected in 2013.
Demonstration of equivalence would mean the biosimilar have
the same dose and frequency of administration as the originator.11 An important question is whether, for example, a biosimilar
of an antibody to TNF alpha in rheumatoid arthritis be extrapolated
to their use in psoriasis. Another relevant question is will
the prescriber know if the proprietary drug is given to the patient
or will the pharmacist on their own initiative be able to give the
patient a biosimilar without contacting the physician?
The oversight of biosimilars in Europe is based on similarity
to a reference monoclonal antibody in terms of safety and
