All biologics are inherently immunogenic, which means they are capable of provoking an immune response that stimulates the production of anti-drug antibodies (ADAs).24 The formation of ADAs over time compromises the effectiveness of biologic DMARDs, ultimately leading to treatment failure.24 Factors that affect immunogenicity include the molecular composition of the drug, patient factors, and possibly disease pathology. For example, a comparison of the CT-P13 arms of the PLANETRA and PLANETAS studies shows that a higher percentage of RA patients developed ADAs than AS patients.9 This is one example of why some experts have voiced concerns about extrapolating findings of biosimilarity from a study in one patient population to another patiednt population when approving the drug.22 In his February testimony before the ADAC, Dr Worthing advised the FDA to use caution when “considering approving extrapolation of biosimilar products for indications where the reference biologic has already been approved in the absence of safety data specific to the biosimilar agent and the patient population in question.”18
Dr Kay pointed out that the clinical trials of biosimilars for RA and ankylosing spondylitis found no increase in immunogenicity with the biosimilar. “In fact, the etanercept biosimilar manufactured by Samsung Bioepis induced ADAs in a smaller proportion of patients than did the reference etanercept,” he said. Another concern some have expressed is that switching between the biosimilar and reference drug could increase immunogenicity. “There are data from clinical trials that show no significant loss of efficacy or increase in immunogenicity or other safety concerns after patients have been transitioned from the reference product to the biosimilar,” Dr Kay said.
Summary and Clinical Applicability
The growing use of expensive biologics has led public and private insurers in the United States to impose cost-sharing burdens that place these drugs out of reach for many patients. To date, the FDA has approved only 1 biosimilar. However, the FDA is anticipating a marked increase in the biosimilar market as more patents expire for brand-name biologics. Many biosimilars for chronic inflammatory illnesses like RA are in development, and recently the ADAC has voted to back an infliximab biosimilar (Remicade).
Thus far, data from studies of promising biosimilars in RA have established that these drugs, which have the same primary amino acid structure as the reference drug, also have similar mechanisms of action, pharmacokinetics, efficacy, safety, and immunogenicity to the reference drug. Many states will allow clinicians who have concerns about the interchangeability of a biosimilar to request no substitutions for a brand-name biologic.
Figure. Comparison of the standard development process for a new drug and the development process for a biosimilar. Image courtesy of the FDA.4
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