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Generic Biopharmaceuticals

A number of these biopharmaceutical drugs have come off, or are due to come off, patent in the near future. These drugs are worth in excess of $80 Bn in Europe alone. [1]

Originator Year of patent expiration
Herceptin 2014
Enbrel 2015
Lucentis 2016
Humira 2018
Avastin 2019
Table1: Biopharmaceutical blockbusters patent expiration. [2]

This has led to an eruption in activity around the development of generic versions of these blockbusters.  These generic versions have been given various names including biogenerics, follow-on biologics, biosuperiors, and second/third generation antibodies, however, the adopted and accepted name is biosimilars. [3]


Biosimilars

Exact copies of originator biopharmaceuticals are impossible to produce due to the previously mentioned complexity and inherent heterogeneity they possess.  A biosimilar can be described as a copy of an already authorized biological medicinal product which demonstrates similarity in physicochemical characteristics, efficacy, and safety, based on a comprehensive comparability exercise. [4] Biosimilar manufacturers must develop their own manufacturing process with the ability to produce a product as similar to originator as possible due to the originator's reference material and manufacturing process being proprietary. 

The quality attributes of the biosimilar and the originator will be different due to differences in the manufacturing process.  This is to be expected and is not a matter of concern as it has been accepted as par for the course for biopharmaceutical production.  Such differences can arise from variations in expression systems, fermentation and purification processes, and the use of excipients. [5]

In contrast to traditional small molecules where identical copies of the originator drug are possible, the standard generic approach of establishing bioequivalence via competitive bioavailability studies is insufficient. A biosimilar's critical quality attributes are assessed by clinical studies where their physicochemical properties, safety and efficacy are tested for comparability against the originator.  A biosimilar may also be exposed to non-clinical assessment if deemed necessary.  The repeating of phase I and III clinical trials, and thereby enrolment of several hundred patients, has led to a recent study putting estimated clinical costs alone at $8.5-35 M compared with a total cost of $5 M for developing a generic small molecule drug. [6,7]

Again, in contrast to small molecules where an 80% reduction in price can be expected following release of generic product(s), the same cannot be said for biopharmaceuticals. [8] The regulatory framework is currently much more established in Europe than in the US with an excess of 15 biosimilars already on the market. [7]
This includes the first monoclonal antibodies (mAbs) Remsima and Inflectra (Infliximab/Remicade), which gained approval in 2013. [9]

Such is the sensitivity and complication around biosimilar development that relatively minor adaptations to the manufacturing process of an originator biologic can lead to significant changes in product performance.  When Genzyme tried to increase the manufacturing scale of Lysozyme, (alglucosidase alfa) a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease, from 160 L to 2000 L the FDA concluded that the larger scale produced product was too different from the originator small scale produced product to be considered the same. [10] The larger scale produced variant required a separate Biologics License Application (BLA) primarily due to concerns around the difference in the glycosylation profiles.  The ‘new’ product is commercially known as Lumizyme and gained FDA regulatory approval in May 2010. [11]


Biobetters

It is worth noting that whilst the term ‘biobetter’ is used in common parlance, and appears widely in scientific literature, it is not a regulatory accepted term.  It is widely credited to Mr G. V. Prasad, CEO of Dr Reddy’s Laboratories, at a bio-investor’s conference in Mumbai, India, in 2007. [12]  The terms ‘follow-on biologics’ and ‘next generation bio-therapeutics’ are also commonly used and are more accurate.  However, given the proliferation of the term biobetter, we will continue to use it through the remainder of CHROMacademy.

A biobetter is best described as offering at least one of the following benefits over the originator biopharmaceutical;

  • An  improvement in in-vivo (taking place or occurring in a living organism) efficacy
  • An increase in the duration of action
  • A reduction in the dosing frequency or amount
  • These may also lead to a reduction in the cost of the medication

A biobetter must target the same antigen (a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies), more specifically epitope (the specific part of the antigen to which the antibody binds) as the originator biopharmaceutical but has been specifically modified to offer superior performance.  In terms of monoclonal antibodies, this has primarily focused on adaptations to the glycosylation profile (glycoprofile) in order to improve effector functions (a biological response whereby killer cells are released that will neutralize and destroy the identified toxin or antigen) or improve serum half-life (the period of time required for the concentration or amount of drug in the body to be reduced by one-half) via optimization of the Fc domain (the fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system).

 

[1] IMS Health. Searching for Terra Firma in the Biosimilars and Non-Originator Biologics Market. February 2014

[2] Clinical Pharmacist, November 2014, Vol 6, No 9, online | URI: 20067091

[3] Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10:345–352

[4] Committee for Medicinal Products for Human Use.Biosimilar Guidelines & 3. European Commission. Directive 2001/83/EC Art.10(4) and Part II of the Annex I of Directive 2001/83/EC, as amended. EudraLex, Volume 1, Pharmaceuticallegislation medicinal products for human use

[5] Weise, M. et al. Nat. Biotechnol. 29, 693 (2011)

[6] GaBI Online - Generics and Biosimilars Initiative. Relative effectiveness and cost minimisation for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Mar 23].
Available from: www.gabionline.net/Biosimilars/Research/Relative-effectiveness-and-cost-minimisation-for-biosimilars

[7] OHE briefing. What is the Role of HTA for Biosimilars. April 2014

[8] Simoens S, Verbeken G, Huys I. Market access of biosimilars: not only a cost issue. Oncologie. 2011;13(5):218-21 and GaBI Online - Generics and Biosimilars Initiative. Generics grab 80% share of US market and fill 78% of prescriptions [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Mar 23].
Available from: www.gabionline.net/Reports/Generics-grab-80-share-of-US-market-and-fill-78-of-prescriptions

[9] European Medicines Agency, News, June 2013 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001837.jsp&mid=WC0b01ac058004d5c1

[10] http://www.in-pharmatechnologist.com/Ingredients/Myozyme-becomes-Lumizyme-after-biologics-scale-up

[11] http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm213282.htm

[12] DePalma A. Will biobetters beat biologics? October 2011 [homepage on the Internet]. [cited 2014 Nov 10].
Available from: http://social.eyeforpharma.com/forecasting/will-biobetters-beat-biologics

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