During the last decade, the availability of biological therapies has revolutionized the treatment of rheumatoid arthritis. Biologicals, unlike small-molecule chemical drugs, are extremely complex molecules, making producing biosimilars far from a simple process.
Use of biological disease-modifying anti-rheumatic drugs (B-DMARDs) has improved the outlook for patients not fully responding to conventional DMARDs. The need for biosimilar products with comparable efficacy and safety to B-DMARDs is discussed by Professors Giovanni Lapadula and Gianfranco Ferracioli, highlighting the possible issues that will govern their validation.
FDA, in its draft guidelines, requires that biosimilars applications be based on structural and functional characterization, as well as analytical studies demonstrating that the biological product is ‘highly similar’ to the reference product in both animal studies and in a clinical study (or studies) – proving ‘biosimilarity’. Such studies must include the assessment of immunogenicity, pharmacokinetics and pharmacodynamics, demonstrating safety, purity, and potency in indication(s) for which the reference product is licensed. EMA, in addition, requires a comparative efficacy clinical trial, showing clinical comparability and immunogenicity assessments and risks in different indications.
It is important to note that one amino acid substitution or difference renders a molecule ‘not-biosimilar’. Many biologicals are antibodies, i.e. proteins that have undergone post-transcriptional modification. As a result, micro-variations – such as asparagine deamidation – can occur, affecting the three-dimensional structure and antigen-binding properties of the molecule. Thus, they are unlikely to be structurally identical in terms of tolerability, immunogenicity and safety. Trials therefore have to be designed to show the clinical bioequivalence of the biosimilar and the reference biological. Thus, once biosimilarity has been demonstrated, the risks of alternating or switching should not be greater than with repeated use of the reference biological and thus interchangeability should be possible.
Lapadula et al. highlight that other issues ensue when interchangeability of biosimilars and originator biologicals is in place. This includes tolerability in combination with conventional drugs, e.g. methotrexate, antimalarials, is the same; extrapolation to other indications and application of the indications in paediatric illnesses, etc.; may be possible.
The clinical bioequivalence of all biosimilars must be demonstrated in clinical trials, notes Lapadula. Immunogenicity must be tested, pharmacokinetic analysis in humans is essential, and safety must be assessed thoroughly to confirm the ‘bio-identity’ and ‘biosimilar interchangeability’ of any molecule.
There are currently no biosimilar monoclonal antibodies approved by FDA for treatment of rheumatic diseases. In Europe, EMA approved two applications for marketing authorization of infliximab biosimilars on 28 July 2013.
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