Biosimilars, Generic Versions of the First Generation of Therapeutic Proteins: Do They Exist?

Abstract

This contribution describes the present regulatory status in the EU of biosimilars, the generic versions of the first generation of therapeutic proteins. It points out why and where recombinant protein molecules and low-molecular-weight drugs differ in their behaviour and why biosimilars should be handled differently than generic low-molecular-weight drugs. This information is important for practitioners (pharmacists and physicians) while selecting the best supplier of a therapeutic protein.

Bioequivalence between novel ready-to-use liquid formulations of the recombinant human GH Omnitrope and the original lyophilized formulations for reconstitution of Omnitrope and Genotropin

“…For small molecules, the standard bioequivalence approach has been developed and applied successfully for decades to assess therapeutic interchangeability of two preparations with one chemically identical active component (8). Since biopharmaceuticals differ from small-molecule drugs in complexity and proof of essential similarity cannot be achieved in such products (9), the bioequivalence approach was modified for biopharmaceuticals, and the concept of 'biosimilarity' was introduced indicating that the products are considered to be similar in terms of quality, safety, and efficacy (10)(11)(12). Biosimilar in the case of recombinant proteins generally means that preparations contain the same protein backbone according to the amino acid sequence, have similar pharmacokinetic and pharmacodynamic properties, exhibit a similar safety profile and similar therapeutic efficacy tested in accurate clinical studies, and therefore, can be considered interchangeable (11,13).…”

“…to posttranslational modification, complex formation, or degradation resulting in different distribution of (micro) heterogeneity of the individual preparations (11,12). To define acceptance criteria, the European Medicines Agency (EMEA) developed general guidelines on biosimilar drugs (14-16) as well as specific guidelines for individual biosimilar substances including rhGH (17,18).…”

Biosimilar insulin as an alternative for the original products

“…There are many factors determining the occurrence of immunogenicity: individual characteristics of the patient, progression of a disease, and even the therapy itself. Due to the fact, that the biosimilar drugs can be potentially immunogenic (as opposed to the small-molecule pharmaceuticals), even slight structural changes can significantly affect the immunogenic potential of the final product [12,13].…”

A European perspective on the market accessibility of biosimilars

“…In contrast, lowmolecular weight, small-molecule drugs are produced by well-controlled and highly reproducible chemical reactions; they are molecules with a small, well-defined and stable chemical structure, and can be completely characterized by analytical methods. 1,2 Importantly, and in contrast to small-molecule drugs, biopharmaceuticals are potentially immunogenic. In this respect, subtle structural differences (eg, consequent to small differences in the number and type of product variants) may significantly affect the immunogenic potential of the drug product.…”

“…5 On the other hand, product-or processrelated impurities can also provoke an immune response. 1,6 When all intellectual property protection, data, and marketing exclusivity for the reference biopharmaceutical have expired, "copying" and marketing of these biological substances can be offered by any other biotech company. To date, biosimilars of recombinant human erythropoietins (epoetin alfa and epoetin zeta), granulocyte colony-stimulating factors (filgrastim), and human growth hormones (somatropin) have entered the European market (see Table 1).…”