An Analysis of the US Biosimilars Development …

1 B i o s i m i l a r s MARKETS. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution by Ronald A. Rader N. o consensus concerning Table 1: Percentage of reference products biosimilar-related with patents expiring after market and data terminology and definitions exclusivity expirations has yet been achieved (1 3). Patents United European Biosimilars may be defined as Expire After States Union biopharmaceuticals slated for generic- Data exclusivity 87% 86%. drug like, abbreviated, (12 years) (10 years). comparisons-based approvals through Orphan 96% 96%. exclusivity (7 years) (10 years). a formal biosimilar approval pathway in the United States, European Union, and/or other highly regulated and Biosimilar markets in other developed countries based on a countries , Canada and Japan demonstration of substantial (bio) also are small parts of the big similarity to a reference product.

2 Picture. Overall, Biosimilars have yet As required in the United States, receive conventional full market to make a real impact on the biosimilar active agents (those approval. Biobetters generally involve biopharmaceutical market. With the involving recombinant proteins) must the same or similar active agent, United States being the primary be identical in primary sequence with either in a different physical form ( , market for innovative pharmaceuticals their reference products. Analytical different formulation or slow-release and US payers fully expected to force and comparative bioequivalence/ complex) or as a chemical substructure rapid, widespread adoption of less- pharmacokinetic (PK) clinical testing ( , PEGylated or expressed as a expensive biosimilar products, the must support a lack of significant fusion protein).

3 Country will be the most important differences (particularly in efficacy The European Union is years ahead market for Biosimilars by far. and safety) between the biosimilar and of the United States, having approved The Biotechnology Information the reference product. Biosimilars is its first biosimilar in 2006 with over a Institute (BII) began an effort late in also sometimes used to refer to dozen biosimilar filings approved since 2011 to develop the most biogenerics, including the ~150 mostly then. Uptake has been slow or comprehensive pipeline database for lower-end knock-offs of established negligible in nearly all European Biosimilars and biobetters. FirstWord major-market innovator products not countries, however, with the total Pharma published a print-format made to good manufacturing practice market for all EU Biosimilars around version of it in September 2012 (5).

4 (GMP) standards and sold in lesser- US$400 $500 million at most. That And later this year, BII will launch a regulated international markets. equates to an average of about more extensive online database (6). Biobetters refers to rather (bio) $40 million/year market for each This project involves two major tasks: similar follow-on biopharmaceuticals product, an inadequate market by most projecting patent and other that are too dissimilar (based on pharmaceutical (and particularly, exclusivity expirations for all potential analytical, preclinical, and/or clinical biopharmaceutical) standards. About US and EU reference products . testing) to their reference products to $400 million is more typical for a single completed for 119 potential reference receive biosimilar approval.

5 They mainstream biopharmaceutical product. products so far, nearly all recombinant 16 BioProcess International 11(6)s J une 2013 Supplement Figure 1: Biosimilar launchable dates Table 2: Some major recombinant products and classes with Biosimilars and biobetters currently in Development version of a blockbuster (a market of $50 100 million/year) is an attractive Product or Product Class Sales (US$billions) Biosimilars Biobetters proposition, particularly considering Humira (adalimumab) $ 13 7. that the costs for biosimilar Remicade (infliximab) $ 9 9. Development of Biosimilars should only Enbrel (etanercept) $ 21 8. rarely exceed that level. Such costs are Rituxan (rituximab) $ 30 17. generally projected to be about $25 60.

6 Herceptin (transuzumab) $ 24 12. million (but can be much higher for Lantus (insulin glargine) $ 5 2. some products, such as when purchase Avastin (bevacizumab) $ 14 9. of the reference product for trials could Neulasta (pegfilgrastim) $ 14 9. cost tens of millions alone). Lucentis (ranibizumab) $ 2 2. Herein I concentrate primarily on Aranesp (darbepoetin alfa) $ 4 2. Biosimilars , but biobetters also will be Epogen/Procrit (epoetin alfa) $ 69 26. major competitors taking market share Novoseven (coagulation factor VIIa) $ 8 12. from originator products. They will be Neupogen (filgrastim) $ 52 17. just as important as Biosimilars and Insulin and analogs 40 53. new me-too/same-indication innovator Tumor necrosis factors (MAbs/inhibitors) 44 19.

7 Products as future competitors on the Interferons (alfa) 55 48. market. Interferons (beta) 23 23. Somatropins 28 17. When Can Biosimilars Factors VIII 4 21. Enter the US Market? MAbs and antibody fragments 145 91. Biosimilars cannot be marketed until Cancer-targeted proteins (non-MAb) 264 159. all relevant government-granted Cancer-targeted MAbs 77 59. exclusivities have expired for their associated reference products: proteins, with this information now worldwide sales over $100 billion (7). granted patents, multiple and integrated into the BIOPHARMA The primary targets for US biosimilar diverse types of which protect nearly (reference products) database (7) Development will be those every reference product to varying continuous compiling all recombinant proteins, including extents to effectively provide market Biosimilars and biobetters reported in monoclonal antibodies (MAbs), and a exclusivity (Other factors, such as Development along with related few high-purity protein products.)

8 So patent extensions, can make patent- companies' involvement from all most biosimilar targets are current based market exclusivity last longer.). nonproprietary sources. US-marketed recombinant market exclusivity granted by therapeutics, particularly those with regulatory agencies, primarily related Target Reference Products sufficiently large markets to make to orphan-drug status (seven years in Much as with generic drugs, even a small percentage profitable for the United States, 10 in the European essentially every currently successful competing Biosimilars (and biobetters). Union). biopharmaceutical is or will be a Obviously, the prime reference data exclusivity granted by potential target for Biosimilars product targets are those enjoying the regulatory agencies, with the US.

9 Development . Currently more than highest sales. Currently 40 Biosimilars legislation giving reference 425 biopharmaceutical products are recombinant proteins have blockbuster products (those with full BLAs) 12. approved in the United States and/or ( $1 billion/year) markets, and another years of data exclusivity after full European Union, including more than 18 have sales between $500 million approval, during which the US FDA. 140 recombinant proteins approved in and $1 billion. Even attaining just a will not approve a biosimilar based on the former with total annual 5 10% market share with a biosimilar a given reference product (the 18 BioProcess International 11(6)s J une 2013 Supplement European Medicines Agency grants Figure 2: Numbers of Biosimilars and biobetters by stage of Development 10 years of such protection).

10 400. BII estimated US and EU 350 Total biosimilar and biobetter launchability Number of Products 300 Biosimilars dates for 119 candidate reference 250. products, nearly all of them Biobetters recombinant but including a few 200. nonrecombinant proteins (not 150. vaccines and blood products). The 100. launchability date for a biosimilar is 50. the latest expiration date for relevant 0. patents as well as data and market Preclinical Phase 1 Phase 2 Phase 3 Marketed exclusivity. Because biobetters involve full approvals (and thus are not affected by data exclusivity), their The average period of US How Many Products launchability dates would be simply reference-product patent expirations Are in the Pipeline? the latest date of patent expiration or after a product's original approval is The BII pipeline database currently market exclusivity granted.