Clinical efficacy and safety of biosimilar epoetin: focus on epoetin zeta

Abstract:

Biosimilars have been developed for several biologic therapeutic agents, including erythropoiesis-stimulating agents. Biosimilars cannot be assumed to be completely identical to the reference product. Several regulatory bodies have issued stringent guidelines to regulate the licensing of biosimilars. These guidelines, although share a unified aim of ensuring the safety and efficacy of biosimilars, show several differences. Such differences may reflect the difficulties facing regulatory bodies in defining a biosimilar, identifying sensitive means to assess equivalence in efficacy, and designing robust methodologies to monitor long-term safety. This review will discuss some of the aspects of differences in licensing requirements for biosimilars, comparing the European Medicines Agency guidelines and the American Food and Drug Administration guidelines. The pathway adopted by the manufacturer of a biosimilar (epoetin zeta) to gain licensing within the European market will be assessed, analyzing its compliance with the European Medicines Agency guidelines for the approval process. Since many patients are likely to be switched from original drugs to biosimilars in future, there is a need to establish strict guidelines on interchangeability and substitution of biosimilars and original products and to make it an integral part of the pre-registration assessment of any biosimilar in future. Eventually, long-term, observational post-marketing data will provide further reassurance on safety and tolerability of biosimilars.

Keywords::

• biosimilars
• erythropoiesis-stimulating agents
• epoetin zeta
• biologic therapeutic agents

Disclosure

The author reports no conflicts of interest in this work.

Supplementary material

The peginesatide story

Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol. The amino acid sequence of peginesatide is unrelated to that of erythropoietin (EPO) and is not immunologically cross-reactive with EPO.¹ Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to other EPO-stimulating agents. In Phase II and III studies in dialysis and pre-dialysis patients, peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients) or darbepoetin given once weekly (non-dialysis patients), in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range.^1,2 Despite published concerns regarding the safety of therapeutic pegylated proteins,³ peginesatide was licensed for treatment of anemia in dialysis patients in the US.

In July 2012, a large dialysis organization with 2,100 centers in the US started treating dialysis patients with peginesatide, with a robust risk evaluation protocol. Although registration trials revealed no new toxic effects, eight cases of anaphylaxis and hypotension among patients in the pilot initiative were reported. As a result, the manufacturer updated the product label with a warning that serious allergic reactions, including anaphylaxis reactions and hypotension, may occur in patients who receive peginesatide.⁴

Six months after pilot initiation, and after more than 60,000 doses of peginesatide were administered to more than 19,000 patients, five patients died from severe anaphylaxis and cardiorespiratory arrest. There were 1.4 anaphylaxis and hypotension events per 1,000 patients.⁵ On February 22, 2013, after the review of data from the pilot initiative, the dialysis organization discontinued administration of peginesatide. On February 23, the manufacturer voluntarily recalled the drug. The recognition of anaphylaxis and hypotension resulted in removal of peginesatide from the market. If it was not for the strict pharmacovigilance protocol initiated by the dialysis provider which implemented the pilot conversion, the immunological potential of the drug would have been missed for several months. This case clearly demonstrates the importance of post-authorization monitoring, pharmacovigilance, and risk mitigation plan.