11^th European Biosimilars Congress April 26-27, 2018 Rome, Italy

Parastoo Azadi received her BSc in Chemistry in 1987 from University of North London, UK and her PhD Degree in Biochemistry in 1991 from Imperial College of Science and Technology, University of London, UK studying structural characterization of carbohydrates and glycoproteins by mass spectrometry. She is currently the Executive Director of the Analytical Service and Training at the Complex Carbohydrate Research Centre, USA where she oversees and manages the analytical services and training of glycoconjugates such as glycoproteins, polysaccharides and glycolipids. She was a Senior Scientist at SGS prior to joining the Complex Carbohydrate Research Centre in 1994.

Production of high-quality pharmaceutical recombinant therapeutic glycoprotein with consistency in glycan quality is still challenging. Since glycans are responsible for bioactivity, solubility, immunogenicity, and clearance rate from circulation, it is vital to have detailed map of glycans in therapeutic glycoproteins. However, due to the enormous diversity of carbohydrate structures and their heterogeneity, this still remains one of the bottlenecks of full structural characterization. Detailed glycoprotein structural analysis has to be able to identify the peptide sequence where the glycans are attached, as well as the structure of the glycan portion, including oligosaccharide sequence and glycosyl linkages. We will detail methods for mass spectrometry (MS) experiments on both released glycans (“glycomics”), as well as on intact glycopeptides (“glycoproteomics”) using EDT, HCD and CID fragmentation pathways that are needed for quantitation and full elucidation of the structure of glycoproteins. Additional data will be shown where a combination of 2D-NMR, glycosyl composition and glycosyl linkage analysis, will provide information on the glycan topology as well as detection methods for potential non-human modifications that could arise from mammalian expression systems such as Galα1-3Gal and N-glycolylneuraminic acid (NeuGc). Our consolidated experiments will outline all the necessary information pertaining to the glycoprotein, including glycan fine structure, attachment site, and glycosylation degree to be obtained pharmaceutical recombinant glycoproteins.

Cecil Nick holds BSc (Hons) in Biochemistry from the University of Cape Town, South Africa. He has been the Regulatory Affairs Professional for over 30 years. He has expertise in monoclonal and biosimilars, having worked on over 20 such programs, engaged in over 50 interactions and meetings with regulatory agencies in the EU, US, Canada, Australia, Mexico, Brazil and supported 6 submissions in the EU and US. He has also participated extensively in industry and international meetings on the subject. Prior to joining Parexel, he served as Regulatory Manager at Novo Nordisk Ltd, Fellow of TOPRA and has been a Guest Lecturer at Cardiff University for MSc in Clinical Research and Greenwich University for MSc in Pharmaceutical Sciences courses and Biotech Module Leader for the TOPRA MSc course. He was on the Editorial Panel of Scrip Clinical Research and has authored many articles on Regulatory and Clinical Development Issues.

The prevailing view is that the structure of biosimilars cannot be established or even manufactured to be identical to the original product. This residual uncertainty needs to be addressed by bridging clinical data, which generally includes a PK (pharmacokinetic) and a therapeutic equivalence trial. However, very limited consideration has been given to what this residual uncertainty is and the extent to which such trials could be suitable or are necessary to address this perceived uncertainty. While it is true that structural differences are possible between the reference product and the biosimilar and that such differences may impact PK, potency, immunogenicity and safety, the generally proscribed clinical trial program may not always be the appropriate approach to discerning the impact of such differences. In fact such structural changes have also been observed to occur due to process changes introduced in the manufacture of the reference product with no requirement for supporting clinical data. Looking at this objectively, PK can usually be effectively addressed in clinical trials often in healthy subjects; in most cases these are relatively straight forward trials to perform and provide clear evidence for PK equivalence. Potency on the other hand is generally required to be studied in therapeutic trials but the value of such trials is debatable. Often the therapeutic dose may lie on the flat part of the dose response curve so that even if a difference in potency existed it would not be detected whereas in vitro methods are far more sensitive to detect differences. There are also considerable challenges in designing and executing therapeutic equivalence trials whereas in fact it is immunogenicity and safety where residual uncertainty remains, and which needs to be addressed in clinical trials.

Dominic Seitz is a Director in the Life Sciences Division of Simon-Kucher & Partners dedicated to the company’s pharma consulting business. He joined the company in July 2012. He advises the world’s leading pharmaceutical and biotech companies in strategic direction setting for business unit, market access and pricing strategies across a wide variety of therapeutic areas and international markets. Since 2015, he has supported numerous clients in their biosimilar launch readiness activities for Europe.

Markets with biosimilar competition have suffered massive price erosion over the last 2-3 years. There are two reasons for it. One reason is that biosimilar manufacturers have been very aggressive on pricing from the very beginning. Another reason is that payers have become more active in managaing Therapeutic Areas (TAs) with biosimilar competition by implementing numerous mechanisms to drive uptake. From biosimilar quotas to national and regional tenders or prescribing guidelines for physicians — the list of payer tools to push biosimilar uptake is manifold and effectiveness varies across markets and TAs. So not all down on price? Not in all markets!. In tender markets obviously it is all down on price. Biosimilars have made the race over originators by offering up to 70% or 80% discount on their list price. So there is simply no golden rule to pricing in those markets. That is different in non-tender markets though. Here manufacturers have more leeway to differentiate on price and beyond price. Understanding market mechansisms and limitations of payer steering can lead to significant upside in revenue and profit potential. Strategic pricing leaving room to maneuver on one hand and innovative, smart access models on the other hand can be two key drivers to differentiate in an undifferentiated market setting. At the European Biosimilar Conference I would like to speak more about and share my experience on different payer management styles to manage biosimilars today in key European markets, biosimilar pricing strategies, main reasons for failure, and ways how to differentiate beyond price.