July 2014 | Volume 13 | Issue 7 | Editorials | 788 | Copyright © July 2014

Jerry Bagel MD

Psoriasis Treatment Center of Central New Jersey
East Windsor, NJ

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