Lessons learned from biosimilar epoetins and insulins

Abstract

Patients with diabetes and renal failure may already be receiving biosimilar epoetin and may receive biosimilar insulin in the near future. Because these biosimilar pharmaceuticals (or follow-on biologics) are complex protein molecules manufactured in lengthy and inherently variable processes involving living organisms, they have the potential to induce an immunogenic, rather than a therapeutic, response. This response is dependent as much on the method of manufacture and formulation, as on the protein itself. Apparently small and innocuous differences in manufacture and formulation can lead to unforeseen clinical consequences. This article discusses two case studies illustrating this principle, that of three insulin formulations which were physicochemically similar to comparator insulins, but with pharmacokinetic and pharmacodynamic profiles sufficiently different to have potentially serious clinical consequences and that of Eprex, for which an apparently minor change in one formulation caused an upsurge of cases of pure red cell aplasia which resulted in fatalities or complete transfusion dependence. Comprehensive and rigorous testing and long-term pharmacovigilance programmes are essential to detect and forestall such consequences.

Epoetin Biosimilars in Europe: Five Years On

“…Immunogenicity can arise from minor changes in manufacturing and may emerge early or only after long-term exposure [33,34], underscoring the need for effective pharmacovigilance. for SB309 was pre-defined but not met and a post-hoc correction factor in the maintenance study was required to bring the parameters within the range [29].…”

The Biosulin equivalence in standard therapy (BEST) study − a multicentre, open-label, non-randomised, interventional, observational study in subjects using Biosulin 30/70 for the treatment of insulin-dependent type 1 and type 2 diabetes mellitus

“…Some of the concerns have been legitimate, with a number of biosimilar insulins failing to meet stringent registration standards. [4] However, ongoing vigilance and extensive clinical trials will continue to be required to ensure the safety and efficacy of new biosimilar insulins.…”

The advent of biosimilars for the treatment of diabetes: current status and future directions

“…This was the case for recombinant human erythropoietin (epoetin alpha), for which an increased frequency of pure red cell aplasia (PRCA)-a rare, potentially fatal condition caused by the formation of anti-epoetin antibodies neutralizing both the exogenous product and endogenous erythropoietin-was observed when the reference product manufactured by Amgen (Thousand Oaks, CA) under the brand name of Epogen was licensed to Ortho Biotech (Bridgewater, NJ), under the trade name of Eprex. Retrospective analyses concluded that the differential rates of PRCA (which was associated with Eprex administration in more than 90 % of cases) was attributed to minor changes in the buffer formulation and the use of different prefilled syringes resulting in an increased immunogenicity of the therapeutic protein [18,19].…”