Biologic agents are complex protein monoclonal antibodies
such as adalimumab and ustekinumab, and genetically
engineered recombinant fusion proteins such
as etanercept. These agents have added greatly to the therapeutic
armamentarium in treating moderate to severe psoriasis.
Patients with severe psoriasis are at an increased risk for
depression, diabetes, and cardiovascular disease.1 Unfortunately,
these biologic agents access to patients with moderate
to severe psoriasis are often limited because of their cost. A
National Psoriasis Foundation (NPF) 2007 study reveled that
over 50% of patients with moderate to severe psoriasis in the
United States of America are treated only with topical therapy.2
Armstrong et al reviewing an NPF survey from 2003-2011 determined
that 25% of patients with moderate to severe psoriasis
were not receiving any treatment.3 Treatment with biologic
agents have not only proven to be extremely efficacious in the
treatment of psoriasis, they have also shown to improve quality
of life and decrease depression and anxiety. Unfortunately,
access is often limited due their excessive cost, which inhibits
a large percentage of psoriasis patients from receiving biologic
treatment. The recent and future expiry of data protection or
patents for the first biologic agents has opened the door to developing
biological products similar to these products.
In March 2010, the FDA was given explicit authority to review
and approve biosimilars.4 The FDA includes consideration of
public information on previously approved biologic agents as
a critical element in the approval of a biosimilar, providing the
biosimilar is considered highly similar to the original reference
drug. This allows biosimilar development not to based on their
safety and efficacy, but rather on chemical and biologic similarities
to the proprietary drug.
Utilizing molecular, analytical, toxicology, physiochemical, and
pharmacodymic knowledge from the reference product also
known as originator ie, adalimumab, ustekinumab, infliximab,
etenercept, there could be an abbreviated pathway in the development
of biosimilars and hence decrease their costs. It cost
between 800 million-1.2 billion dollars to develop a new biologic
agent. The cost of developing a biosimilar, depending upon
whether a Phase III trial will be mandated by the FDA, is between
75-300 million dollars. Unfortunately, whereas most generic
medicines, which are small molecules, are 30% of the cost of the
brand name, biosimilars may still cost 70% of the originator price.
There is a difference between generics as we know them
and biosimilars. Small molecule generics are efficiently approved
by the FDA if they show blood levels ie, bioavailability
of 75% or more relative to the parent compound. It is relatively
easy to determine through analytic chemistry that the
generic medicine is a molecular equivalent to the originator,
and subsequently to determine blood levels. In the case of
biosimilars, blood levels are not the only criteria. Biologic
agents vary based upon the cell type, the recombinant DNA
technique, the medium, and the process that is utilized for its
production. Proteins can vary in amino acid modifications,
glycosylation variants, and tertiary and quaternary structure
alterations. Even if the amino acid sequence of two proteins
are identical, post-translational modifications, three-dimensional
structures and aggregation may alter the behavior
of a protein drug. A slight variation in any of these parameters
could result in slightly different epitope, or a different
glycosylation. These minor changes can result in a different
biologic molecule with different affinities to binding sites, and
a different immunogenic profile.5 Post translational modifications
also include deamination, oxidation which can alter
protein structure and cause aggregation which can cause immunogenicity.
Amino acid isomerization is another form of
post-translational modification ie, aspartic acid, can isomerize
to iso-Aspartic acid possibly resulting in immunogenicity.
Fortunately, technologic advances utilizing functional assays
and genetic expression have helped in assessing differences.
These analytical methods have been necessary to determine
current differences in the manufacturing processes for some
biologics, ie, batch to batch.
Analytical techniques, functional assays, as well as genetic
expression techniques have been utilized to evaluate batch to
batch differences from the originator and can also help determine
differences between the originator and biosimilar.6
Primary structure medications secondary to amino acid modifications
or glycosylation variants can be evaluated via mass
spectroscopy and NMR spectroscopy. In regards to tertiary and
quaternary structure the two main techniques for evaluating protein
structure are X-ray crystallography and NMR. However, they
are impractical because for X-ray crystallography the protein
must be crystallized and NMR tends to be too time consuming.
Since many aspects of tertiary and quaternary structure are
determined by disulphide bonds, knowing their location and
verifying their correct position utilizing enzymatic digests and
comparing them to the originator can help verify similarity. Ion
mobility spectrometry (IMS) evaluates the protein confirmation
in gas phase and can also help compare it to the originator.7
Biosimilar developers do not have access to either the originator
company’s proprietary data or manufacturing process,
and therefore need to develop their own processes to develop
a biosimilar as chemically close as possible to the
originator. As mentioned the question of quality attributes,
strength and purity are especially important in the context of
manufacturing process changes that occur in the production
