Biosimilars Knowledge Connect Slide Resource This slide deck

Biosimilars Knowledge Connect Slide Resource This slide deck has been designed to be used as a central resource from which pertinent slides can be extracted as needed and is not intended for use in its entirety www. Biosimilars. Knowledge. Connect. com Copyright © 2013 Quintiles

Introduction to biological medicines and biosimilars • A biosimilar is an approved version of a biological medicine with an identical primary amino acid sequence to the originator and developed with the intention to be as close to the originator as possible • Like biological medicines, biosimilars are complex protein molecules that are produced by living organisms • During the past 15 years, biological medicines have had a profound impact on healthcare > primarily in the areas of rheumatology and oncology > as well as endocrinology, cardiology, dermatology, gastroenterology, and neurology • Many of the world’s top-selling medicines are now biological medicines • However, biological medicines are expensive (sometimes by several orders of magnitude more than small-molecule chemical drugs), limiting patient access • As many biological medicines come off patent globally, there is great interest in the development of biosimilars, which are likely to be more affordable 2

The increasing rate of development of biosimilars It has been estimated that 31 different companies were developing biosimilar monoclonal antibodies (as of March 2012), compared with 18 companies as of Sept 2011 – an increase of 67% in a 6 -month period. 1 Biological medicines due to come off patent 2, 3 2010– 2015 Patent expiries expected: 99 2016– 2020 Post– 2020 Patent expiries expected: 91 46 1. Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline. 2. Haag T (Lonza) and Krattiger C (Gf. K). The emergence of biosimilars—How are they different from generics and what are the implications from marketing? Eph. MRA presentation. June 29, 2011. 3. http: //articles. chicagotribune. com/2012 -08 -13/news/sns-rt-elan-spinofftysabril 6 e 8 jd 71 t-20120813_1_tysabri-elan -patent-protection 3

As of Sept 2013, 16 biosimilars have been approved in the EU* Biosimilar Sponsor Reference product Date of approval Medice Arzneimittel Pütter (Germany) Eprex (Janssen) August 2007 CT Arzneimittel Neupogen (Amgen) September 2008 Sandoz (unit of Novartis) Eprex (Janssen) August 2007 Hexal Biotech (owned by Novartis) Eprex/Erypo (Janssen) August 2007 Hexal Biotech Neupogen (Amgen) February 2009 Hospira Enterprises Neupogen (Amgen) June 2010 Sandoz Genotropin (Pfizer) April 2006 Ratiograstim (filgrastim; G-CSF) Ratiopharm (acquired by Teva) Neupogen (Amgen) September 2008 Filgrastim Ratiopharm (filgrastim; G-CSF) Ratiopharm (acquired by Teva) Neupogen (Amgen) September 2008 (withdrawn April 2011**) Hospira Eprex (Janssen) December 2007 Stada Eprex (Janssen) December 2007 Teva Pharma Industries Neupogen (Amgen) September 2008 Bio. Partners Gmbh Humatrope (Eli Lilly) April 2006 Sandoz (unit of Novartis) Neupogen (Amgen) February 2009 Inflectra (infliximab) Hospira Remicade (Janssen) 10 September 2013 Remsima (infliximab) Celltrion Remicade (Janssen) 10 September 2013 Abseamed (epoetin alfa) Biograstim (filgrastim; G-CSF) Binocrit (epoetin alfa) Epoetin alfa Hexal (epoetin alfa) Filgrastim Hexal (filgrastim; G-CSF) Nivestim (filgrastim; G-CSF) Omnitrope (somatropin; human growth hormone) Retacrit (epoetin zeta) Silapo (epoetin zeta) Tevagrastim (filgrastim; G-CSF) Valtropin (somatropin; HGH) Zarzio (filgrastim; G-CSF) *Out of a total of 20 marketing authorization applications. **The marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder. Source: EMA biosimilar EPAR listing: Accessed October 2013. 4

Biosimilars differ from small-molecule generic drugs – manufacture Small-molecule generic Biosimilar Low molecular weight and complexity High molecular weight and complex 3 -D structure Chemical synthesis Produced by living organisms Manufacturing process easy to reverse-engineer Manufacturing process cannot be replicated Identical copy of active ingredient Although required to contain the same primary amino acid sequence, the biosimilar is not identical to the originator, but rather highly similar Even if a biosimilar uses the same human gene as its originator Human gene It will differ in other parts of the process Transfer into host cell DNA vector Cloning into DNA vector Bacterial or mammalian cell produces protein Fermentation Different process = different product Formulation Adapted from The Biosimilars Handbook, Barclays Capital, 11 Feb 2011 5

Biosimilars are subjected to a more rigorous clinical development process than generics Small molecule • Proof of quality and bioequivalence • No substantial clinical data required • Reference to originator’s data Generics Biological medicine • Different manufacturing processes can and often do yield differences in the end product • After the quality of a biological medicine is demonstrated, some non-clinical and clinical studies are necessary • Immunogenic response cannot be predicted and therefore must be tested Biosimilars Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007 6

The potential impact of biosimilars Expected cost savings • A survey conducted in the European Union in 2010 found cost savings in 24 member states where biosimilars were marketed alongside their originators* > There was sustained price discounting in all countries, although this did vary at the country level > Values range from a 5% discount for filgrastim in the UK to a 53% discount for the same medicine in Denmark in 2009 > The availability of biosimilars of somatropin, epoetin alfa, and filgrastim in Europe has led to price discounts relative to their respective originators ranging from 5– 82% > The table below describes the mean price discount of biosimilar versions of the medicines listed relative to their originator products Mean discount in 24 EU member states 2007 2008 2009 Somatropin 25. 4% 25. 9% 14. 1% Epoetin 32. 1% 17. 3% 17. 0% Filgrastim ‐‐‐ 10. 8% 35. 0% *Rovira J, Espín J, García L, and Olry de Labry A. The impact of biosimilars’ entry in the EU market. 2011. http: //ec. europa. eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_012011_en. pdf. 7

Biosimilars can improve healthcare • Biosimilars can enable previously restricted therapies to become part of the accepted standard of care • In the UK, patients have benefited from lower acquisition costs and improvements in the practice of medicine after the approval of a filgrastim biosimilar • This has enabled the routine use of filgrastim (as a biosimilar) as a first-line treatment for the first time UK filgrastim volume growth percent change vs. previous year November 2008 biosimilar approved 17 13 • Many physicians moved filgrastim back to first-line cancer treatment because of lower biosimilars cost • G-CSF prevents hospital readmission owing to infection • Biosimilars are less expensive than originator biologics • Zarzio “patient support kits” expand patient access: – Patients self-administer at home – Efficiency savings repatriated -2 -5 2007 2008 2009 2010 ® Note: Zarzio (filgrastim) is not marketed in the United States. Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (Mc. Camish M and Woollett G. state of the art in the development of biosimilars. 91(3): 405– 417), © 2012 The 8

Biosimilars must undergo rigorous testing • To establish biosimilarity, the sponsor must first show that the candidate is highly similar to the reference originator at the analytical level. This can take multiple iterations in early-stage development before clinical testing may begin • The sponsor must also perform detailed analysis of the originator reference, especially if the structure and biological function is inadequately defined PK/PD Non-clinical Biological characterization Analytics De sig n sp ec ific at io ns Va lid at ion Clinical trials Physicochemical characterization Process development Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (Mc. Camish M and Woollett G. state of the art in the development of biosimilars. 91(3): 405– 417), © 2012 The 9

Examples of copies of biological medicines from largely unregulated markets may not meet today’s rigorous standards • In the past, copies of biological medicines have been produced in some countries where a rigorous regulatory pathway had not been established for biosimilars • These are known as copy-biologics, alternative biologics or intended copies of biological products • They may not meet the current criteria defined by the FDA or EMA for biosimilarity and would not be approved in most regulated markets at the present time without additional testing • As guidelines are established worldwide to standardize the testing of biosimilars for comparability against an originator product, the development of such products becomes less widespread* *Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline. 10

Why immunogenicity testing is essential • To date, there have been no reports of an approved biosimilar being associated with any unusual or unexpected adverse events, although at least two biosimilars that are currently approved in the EU encountered unwanted antibody development during pre -approval clinical studies • For a somatropin biosimilar, non-neutralizing antibodies were triggered by increased levels of HCPs • For an epoetin biosimilar, neutralizing antibodies were triggered leading to premature termination of the clinical trial • Changes in manufacturing process, however, have been associated with problems with immunogenicity even in novel biological medicines • Immunogenicity testing is therefore an essential part of the biosimilar testing process Increased incidence of pure red cell aplasia with EPREX® (epoetin) SC Related to leachables from changes in primary packaging Immunogenicity of GM-CSF Non-immunogenic in immunosuppressed patients Antibodies in non-immunosuppressed patients Thrombopoietin immunogenicity Tryptophan-eosinophilamyalgia syndrome Pegylated r. Hu. MGDF: highly immunogenic persistent thrombocytopenia meant development program was stopped Production strain changed: purification modified. Unrecognized impurity caused EMS (>1300 cases, 38 deaths) Saenger, P. Current status of biosimilar growth hormone. Int J Pediatr Endocroinol 2009; 370329. Bennett, CL et al. Pure red-cell aplasia and epoetin therapy. NEJM 2004; 351: 1403– 8. Mascaro J, presentation. Mexico, August 15, 2007 11

Highly regulated markets ensure safe biosimilar medicines • Biosimilar quality is assured by rigorous testing requirements, which include head-to-head analytical/non-clinical/clinical testing against the reference originator. In addition, the regulatory authorities, such as the European Medicines Agency (EMA) and US FDA, require robustness in manufacturing process • To date, there have been no reports of a biosimilar medicine in highly regulated markets being associated with any unusual or unexpected adverse events as compared to its originator • In Europe, no unusual or unexpected clinical events have been observed with biosimilars of somatropin, epoetin, or filgrastim • In the USA, no unusual or unexpected adverse events have been seen with products approved as follow-on biologics on the basis of abbreviated data packages, including Omnitrope® Mc. Camish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012; 91(3): 405– 417. 12

Biosimilar regulations in EU and USA: different stages of development • The EU pioneered the development of biosimilar regulations • US overarching guidelines issued Product Class Monoclonal antibodies – non-clinical and clinical issues Product Class Specific Guideline: Erythropoietin (revised) EMEA Legislative Pathway 2004 2005 EMEA Regulatory Guidance [Overarching Guideline] under revision Quality Guideline; Non-Clinical and Clinical Guideline (under revision ) 2006 2007 Product Class Specific Guidelines: Insulin, G-CSF, Somatropin 2008 2009 Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alpha 2010 Draft revisions to Product Class Specific Guideline: Insulin, low molecular weight heparin Product Class Immunogenicity Class assessment of Follicle stimulating monoclonal hormone, antibodies Interferonbeta 2011 Public Health Service Act amended to allow the approval of biosimilars 2012 Draft revisions to Overarching Guideline; Quality Guideline; Non -clinical and Clinical Guideline 2013 Overarching Draft Guidelines on biosimilars Europe US http: //www. ema. europa. eu/ema/index. jsp? curl=pages/regulation/general_content_000408. jsp&mid=WC 0 b 01 ac 058002958 c The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010. US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. 13

The definition of ‘biosimilarity’ in the USA vs EU • USA: a biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency” • EU: a similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use and it does not have any meaningful differences from the reference medicine in terms of quality, safety, or efficacy Mc. Camish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012; 91(3): 405– 417. Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. Article 8 of Directive 2001/83, as amended. 14

Requirements of clinical studies in the USA and EU • Once a Phase I study establishes that a biosimilar possesses comparable pharmacokinetic and pharmacodynamic attributes in human subjects to the reference biological medicine, a Phase III study of safety, efficacy, and immunogenicity is usually initiated • Phase III studies use the most sensitive, homogeneous patient population and clinical endpoint to establish the similarity of the biosimilar to the reference and to be able to detect product-related differences • If the mechanism of action (Mo. A) for the reference medicine is known, the biosimilar medicine is expected to have the same Mo. A for the prescribed conditions based on labeling • Uses for the biosimilar medicine in its labeling must “have been previously approved for the reference product” • The extent, duration and timing of studies for evaluation of immunogenicity vary depending on a variety of factors including: > the expected duration of product use, nature of product, known incidence and clinical consequences of immune response for the reference product, results of analytical comparability studies Gravel P, Naik A, Le Cotonnec J-Y. Biosimilar rh. G-CSFs: how similar are they? Targ Oncol 2012; 7(Suppl 1): S 3–S 16. US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. 15

Requirements of clinical studies in the USA and EU • US FDA requires a comparative repeat dose toxicity study in a relevant species (if available) that includes toxicokinetic measurements, systemic exposure, local tolerance, and immunogenicity assessments. EMA suggests a risk-based approach to animal studies, taking into consideration factors such as residual uncertainty at the end of in vitro studies and availability of sensitive species/models for in vivo animal studies • Both EMA and FDA require a sufficient number of product batches to be tested during physiochemical and functional comparative studies to capture the inherent batch-to-batch variability in product characteristics. The biosimilar is expected to exhibit variability similar to the reference medicine Chance K. US Biosimilar Guidelines: Summary and Insights 2012. Regulatory Focus April 2012 Datamonitor; Pharmaceutical key trends 2011—Biosimilar market overview. 16

The biosimilar approval pathways across highly regulated markets are similar Criteria EU and Australia USA Japan Biosimilar pathway status Pathway established Clinical trials Mandatory, but extent negotiable Phase I studies mandatory, Phase III studies may be abbreviated in some situations Reference medicine Both biosimilar and originator must have the same MOA. Reference must be marketed in the EU/Australia although EU guidelines indicate that studies utilizing a foreign reference could be acceptable Both biosimilar and originator must have the same MOA. Reference must be marketed in the USA although US guidelines indicate that studies utilizing a foreign reference could be acceptable Reference must be approved and marketed in Japan Formulation Same strength and route of administration, otherwise further studies required Same strength and route of administration Post-marketing safety surveillance Mandatory along with risk management plan Tailored to the particular safety and effectiveness concerns associated with the reference medicine, its drug class, clinical use elsewhere, and the biosimilar candidate itself Plan must be created to trace adverse events and a drug safety report submitted Datamonitor; Biosimilars global regulatory update, May 2012. Regulatory agency websites. US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. 17

The biosimilar approval pathways across highly regulated markets are similar Criteria EU USA Equivalence margins Not currently defined, but it is expected that equivalence margins will be pre-defined by the sponsor along with a strong scientific justification prior to conduct of clinical trials Extrapolation to other indications Will be permitted providing the mechanism of action is the same as the reference; scientific justifications for extrapolation are required Scientific justification for extrapolation required, even if the biosimilar and reference have the same mechanism of action: § Relevant target receptors for each indication § Pattern of molecular signaling upon receptor binding § Expression and location of target receptors § Relevance of pharmacodynamic measures to mechanism of action § Relevance of pharmacokinetic values in different patient populations § Differences seen in toxicities for the various conditions of use in the various patient populations (non-comparative data) Interchangeability Decision at country level Yes, if assessed by FDA based on adequate clinical data. Substitution decisions made at the state level US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. 18

Comparative biosimilar approval pathways across the world Criteria Canada South Korea India China Biosimilar pathway status Pathway established (2012) No pathway; copy biological medicines approved as new drugs Clinical trials Mandatory, but extent negotiable Phase I studies mandatory, Phase III studies may be abbreviated in some situations Phase I and Phase III trials mandatory Mandatory: Phase I–III studies for copy biological medicines with a reference not marketed in China. Phase III studies for copy biological medicines marketed in China Reference medicine Reference should be approved and marketed in Canada, unless a waiver is approved Reference should be approved and marketed in South Korea Reference should be approved and marketed in India, although some flexibility is allowed if reference is not marketed in India Not defined Interchangeability Decision at province and territory level Not defined Formulation Same dosage, form, and route of administration Dosage, form, and strength must be the same Same strength and route of administration Not defined Postmarketing surveillance Mandatory along with risk management plan and period safety updates Pharmacovigilance plan must be submitted Not defined Datamonitor; Biosimilars global regulatory update, May 2012. Regulatory agency websites. Department of Biotechnology. Guidelines on similar biologics: Regulatory requirements for marketing authorization in India, 2012. 19

EMA and FDA have rigorous standards for biosimilar applications • Biosimilar quality is assured by the rigorous testing that is integral to the development and manufacturing process required by regulatory authorities such as the European Medicines Agency and US FDA • Following 20 marketing applications, the EMA has approved 16 biosimilar medicines* • Thus far, in the absence of differences in biophysical properties between biosimilars and their originators, no significant clinical variation has been observed • Examples of EMA-rejected or withdrawn biosimilar applications: Generic/Reference/ Biosimilar Significant biophysical differences Significant clinical variation from reference Interferon-alfa-2 a/Roferon-A/Alpheon Yes Yes Human insulin/Humulin/Insulin Human Rapid Marvel, Insulin Human 30/70 Mix Marvel, and Insulin Human Long Marvel Insufficient data No Yes No PK Efficacy Tolerability *Post-approval, the marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder (Ratiopharm), so 15 biosimilars are currently available. Ahmed I, Kaspar B, and Sharma, U. Biosimilars: Impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther 2012; 34(2): 400– 419. Mc. Camish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012; 91(3): 405– 417. 20

Regulatory guidelines for biosimilar approvals are developing at different paces Country Inception Approval pathway Argentina Sept 2009 Australia June 2006 Administracion Nacional de Medicamentos, Alimentos y Tecnologia (ANMAT) published biologics and biosimilar approval guidance Agrees to follow CHMP/437/04 Guideline on Similar Biological Medicinal Products Brazil Dec 2010 Resolution 55/2010 regulates all biologic products Canada Mar 2010 Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics China All biologics, original or copy-biologics undergo the same pathway Colombia License for Manufacturing Facilities of Biological Products EU Oct 2005 CHMP/437/04 Guideline on Similar Biological Medicinal Products EU Nov 2010 Guideline on similar biological medicinal products containing monoclonal antibodies India Feb 2012 201 Department of Biotechnology finalizes guidelines for nonclinical evaluation of similar biologics (biosimilars) Japan Mar 2009 Guidance issued by Japan’s Ministry of Health, Labour and Welfare Malaysia July 2008 Guidance Document for Registration of Biosimilars in Malaysia Mexico June 2009 Article 222 of the General Health Law Russia Biosimilars are subject to the same regulations as generics Saudi Arabia Dec 2010 Guidelines on Biosimilars version 1. 1 Singapore April 2010 Appendix 17 of the Guidance on Medicinal Product Registration in Singapore South Korea Sept 2010 Taiwan Nov 2008 Turkey August 2008 Guidelines on the Evaluation of Biosimilar Products Review Criteria for Registration and Market Approval of Pharmaceuticals-Registration and Market Approval of Biological Products Instruction Manual on Biosimilar Medical Products. Adopted EMA guidance into law 2011 USA March 2010 Venezuela August 2000 Law. No. 111– 148, The Approval Pathway For Biosimilar Biologic Products SRPB-R Guidelines: application for Health registry of DNA recombinant products, monoclonal and therapeutic antibodies Datamonitor. Biosimilars global regulatory update, May 2012. European Generic Medicines Association, 2010. 21

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