Copied biopharmaceuticals are finding a market in many parts of the world. However, there are still several regulatory, clinical efficacy and safety, and economic issues with respect to the therapeutic value of approved biosimilars
Institute of Physiology
University of Luebeck
Since the patents of several biopharmaceuticals have expired, less costly copied products (“biosimilars”, US term: “follow-on biologics”) from companies other than the innovators are capturing the market in the European Union (EU) and other parts of the world. In contrast to small chemical drugs, biopharmaceuticals are engineered in living cells, exhibit a complex three-dimensional structure and are heterogeneous, particularly in the case of glycoproteins. Therefore, the marketing rules for generic drugs have been modified for the legal approval of biosimilars. Herein, issues are considered that need further clarification with respect to the propagation of biosimilars, whereby the emphasis is on the blockbuster drug epoetin.
The Committee for Medicinal Products for Human Use (CHMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) has first developed an overarching guideline defining the requirements to show “the similar nature, in terms of quality, safety and efficacy” of biosimilar versus originator products, and subsequently more detailed guidelines on general quality (ie, posttranslational modifications and purity), non-clinical and clinical (safety, efficacy and immunogenicity) and class-specific issues for the marketing authorisation of biosimilar recombinant human erythropoietin (rhEPO, epoetin), insulin (rhIN), somatotropin (rhGH), granulocyte-colony stimulating factor (rhG-CSF), and (as a reflection paper) interferon (rhIFN). Actually, the statutory requirements have led to the application withdrawal respectively rejection of copied rhINs and rhIFNs.
Biosimilar rhEPOs, rhGHs and rhG-CSFs have been launched in Europe. The drug substances must be similar to reference products available in the EU. However, the underlying production process can differ. Eg, the originator rhGH Humatrope is engineered in transformed E. coli, but the biosimilar Valtropin in transfected Saccharomyces cerevisiae.
According to the EMEA, there can be no automatic substitution of a biosimilar for the original product:”…the decision to treat a patient with a reference or a biosimilar medicine should be taken following the opinion of a qualified healthcare professional.” (Doc. Ref. EMEA/74562/2006). In legal terms, the question arises, here, as to who is a qualified healthcare professional” (physician, pharmacist, commercial hospital director?).
The therapeutic indications for a biosimilar can be extrapolated in the approval process (see, for example the usages of rhEPOs or rhG-CSFs). However, extrapolation between different administration routes is permitted. Here, care has to be taken in clinical routine, because different substances can have the same International Nonproprietary Name (INN; see below). On the other hand, biosimilars containing identical substances are often co-marketed by several companies under different brand names.
The US Food and Drug Administration (FDA) is in the act of having a similar approach as the EMEA with regard to approval standards for follow-on biologics. Eg, FDA approval was granted for a follow-on rhGH (Omnitrope) in 2006. Japan’s Ministry of Health, Labour and Welfare (MHLW) has recently issued guidelines for the approval of biosimilars.
Significance of glycosylation isoforms
Recombinant glycoproteins for therapy are manufactured in mammalian (generally CHO: Chinese hamster ovary) cells transfected with the appropriate human cDNA. Transformed bacteria such as E. coli and transfected yeast or filamentous fungi are only useful for the fermentation of medicinal products lacking biologically relevant glycans such as rhIN or rhGH. Both CHO (lenograstim) and E. coli (filgrastim) derived rhG-CSFs
are in clinical use, although the latter possesses an additional N-terminal methionine and lacks the O-glycan present in endogenous G-CSF.
In viewing EPO, its three complex-type N-glycans have a major role in receptor binding affinity and elimination kinetics. All rhEPOs (epoetins) differ slightly in the structure of their glycans. The main bioprocess factors determining the type of glycosylation isoforms are (i) the host cell, (ii) the culturing conditions and (iii) the purification procedures. According to the INN Expert Group of the WHO, differences in the glycosylation pattern of the epoetins should be indicated by product specific Greek letters added (alfa, beta, etc). INNs are important for pharmacists and physicians with respect to substitution decisions and postmarketing surveillance records.
There is a dilemma with the naming. Firstly, even the two originator epoetin alfa formulations (Epogen, Eprex) are not fully identical. Secondly, one epoetin alfa biosimilar (HX575) has received EMEA approval under the INN “epoetin alfa” (Binocrit/epoetin alfa Hexal/ Abseamed) despite its-slightly- different carbohydrate pattern compared to the originator (Eprex/Erypo), whereas another epoetin alfa biosimilar (SB309) has received EMEA approval under the INN “epoetin zeta”
(Silapo/Retacrit). In July 2009, the CHMP has recommended
marketing authorisation for a novel CHO cell-derived biosimilar rhEPO, “epoetin theta” (Biopoin/Eporatio/Ratioepo), which is a biosimilar to epoetin beta (NeoRecormon). The politics in naming renders it difficult for the non-expert to realise “what’s in the name”. Remember that-for further confusion-epoetin delta (Dynepo; dropped in 2009) was obtained from viral promoter-transfected human cells and epoetin omega (Repotin; marketed in South Africa) is produced in EPO cDNA-transfected baby hamster kidney cells (BHK, derived from a genus differing from CHO).
In comparison to the EMEA-approved biosimilar rhEPOs, the quality of several epoetin alfa copies produced in Asian and Latin American countries is reportedly less satisfying. On careful examination, some products exhibited major isoform differences, showed batch-to-batch variations in biological activities, contained aggregates or were contaminated with endotoxin.
[8-10] For clarity, the term “biosimilar” should thus be restricted to EMEA-approved biopharmaceuticals in order to avoid biased perception of the different drugs.
Another critical aspect relates to the bioactivity of the epoetins, which need to be calibrated by bioassay in mice according to the European Pharmacopoeia (Ph.Eur. monograph 1316).11 Owing to the poor accuracy of the in vivo bioassay, the monograph notes: “The estimated potency is not less that 80% and not more than 125% of the stated potency. The fiducial limits of error of the estimated potency are not less than 64% and not more than 156% of the stated potency.” This regulation allows for major variations in bioactivity. Eventually, all EMEA-approved epoetins comply with the requirements.
 Substance HX575 has proved therapeutic equivalence with Eprex/Erypo in chronic renal failure (CRF) patients on haemodialysis. The batches of substanc SB309 under study were 10% less active than the reference product. However, this difference was apparently not caused by underdosing of the biosimilar product, but was due to a higher originator’s syringe
content than its nominal dose.
Indications based on extrapolation
By data extrapolation, HX575 and SB309 have also received marketing authorisation for i.v. administration in adult CRF patients on peritoneal dialysis or not yet undergoing dialysis and in paediatric CRF patients on haemodialysis, i.v. or s.c. administration in adult patients receiving chemotherapy for malignancies, and patients prior to major elective orthopaedic surgery (HX575) respectively on an autologous blood donation programme (SB309).
There have been cases of anti-EPO antibody (Ab)-mediated pure red cell aplasia (PRCA) in CRF patients receiving s.c. recombinant erythropoiesis stimulating proteins (ESPs). The transient increase in ESP-induced PRCA that occurred following a change in formulation of a specific brand of Epoetin alfa (Eprex/Erypo) brought enforced attention to the immunogenic potential of biopharmaceuticals.
The probability of antibody formation increases when a therapeutic protein is altered, such as due to aggregation, misfolding or oxidation. There are no reliable preclinical models to investigate the immunogenicity of a novel biopharmaceutical, or of established products on a change in the production processes or the formulation. Safety data can only come from clinical experience and post marketing surveillance. Along these lines, a study to evaluate the efficacy, safety and immunogenicity of s.c. HX575 in CRF patients was terminated because of unexpected anti-EPO antibody formation. On the other hand, in October 2009, the Commission of the European Communities has granted authorisation for the epoetin beta biosimilar “epoetin theta” (Biopoin/Eporatio/Ratioepo) for both i.v. and s.c. use in CRF patients.
Biopharmaceuticals obtained by means of recombinant DNA, controlled gene expression and antibody methods have provided major therapeutic benefits. Themedicines for human use include hormones, cytokines,thrombolytics, enzymes, vaccines and antibodies. Thebiopharmaceutical market is growing continuously. On the one side new drugs are developed. On the other side, an increasing number of biosimilars are being launched, as the patents of the original products have expired, primarily in the EU. The biopharmaceutical market is lucrative. Health care providers welcome the biosimilars for their lower costs. In addition, the competition has led to price reductions of originator medicines and promoted the development of “secondgeneration products” with improved pharmacokinetic properties (Table 1).
The manufacture of biopharmaceuticals demands biotechnological skills and elaborated equipment ensuring consistency of good quality products. From a technological view, of major importance are a great host cell mass, a high recombinant protein expression level, and efficient purification processes. Quality issues relate to the exact identity and proper conformation of the therapeutic protein. It is mandatory to remove process-related impurities (ie, pathogenic agents, host cell proteins, nucleic acids, toxins, leachables, heavy metals, etc) and product-related impurities (ie, aggregates, degradation products and undesired protein variants). Because the costs for commissioning bioprocess plants are relatively high, the biosimilar producers are in general well-established generic pharmaceutical companies, some of which may found partnerships with smaller biotechnological companies. They focus on blockbuster products respectively high-growth seg-ments. Eg, the number of recombinant ESPs increased from 3 to 13 brands (in reality to 8 different substances) on the EU market between 2007 and 2010. It remains to be seen whether all of the products will find a ready market. The success will depend on the marketing strategies and field staff, the medical indications, the clinical outcome, the market potential, the competitive situation at the time the products are launched, and reimbursement from the health care providers. Indeed, one rhEPO (epoetin delta) has already been dropped for economic reasons.
1. Kramer I. J Endocrinol Invest 2008;31:479–88.
3. Frank RG. New Engl J Med 2007;357:841–3.
5. Jelkmann W. Nephrol Dial Transplant 2007;22:2749–53.
6. www.who.int/medicines/services/inn/ ColeteBioRevdoc%2008-11-07_2_.pdf.
7. Deechongkit S, Aoki KH, et al. J Pharm Sci 2006; 95:1931–43.
8. Schmidt CA, Ramos AS, et al. Arq Bras Endocrinol Metab 2003;47:183–9.
9. Schellekens H. Eur J Hosp Pharm 2004;3:43–7.
10. Park SS, Park J, et al. J Pharm Sci 2009;98:1688–99.
11. Anonymous. European Pharmacopoeia 2002: 1123–8.
12. Jelkmann W. Nephrol Dial Transplant 2009; 24:1366–8.
13. Schellekens H. Drug Discov Today 2009;14:495–9.
14. Schellekens H. Nephrol Dial Transplant 2005;20(Supplement 6):vi3–vi9.