Biosimilars today and tomorrow

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1 Biosimilars today and tomorrow Dr. Jörg Windisch, Head Global Technical Development PMCA Impuls Vienna, April 23, 2012 a Novartis company

2 Patient access is at risk because biosimilars are expensive... Estimated daily treatment costs 1 in USD per day 22 The Biologics Boondoggle A breast cancer patient s annual cost for Herceptin is $37,000 People with rheumatoid arthritis or Crohn s disease spend $50,000 a year on Humira and those who take Cerezyme to treat Gaucher disease.spend a staggering $200,000 a year 1 the top six biologics already consume 43% of the drug budget for Medicare Part B Small molecule drugs Biopharmaceuticals 1 Source: NY Times, March Text footer (change in > View > Header and Footer) March

3 ...and there are many By 2016, seven of the top 10 pharmaceuticals worldwide will be biologics 1 Product Type 2016 Rev. (USD bn) 1. HUMIRA Biologic AVASTIN Biologic RITUXAN Biologic ENBREL Biologic CRESTOR Small molecule SERETIDE/ADVAIR Respiratory / device REMICADE Biologic HERCEPTIN Biologic REVLIMID Small molecule LANTUS Biologic Rev. (USD bn) 1 Source: Evaluate Pharma, Sandoz analysis 3 Text footer (change in > View > Header and Footer) March

4 Biologics are more complex than small molecules Aspirin small chemical molecule Molecular weight = 180 Daltons 0 amino acids Calcitonin simple biologic Molecular weight = 3,455 Daltons ~ 32 amino acids - w/o host cell modifications - produced in yeast, bacteria Erythropoietin complex biologic Molecular weight = 30,600 Daltons ~ 165 amino acids - with host cell modifications (e.g. glycosylation) - produced in mammalian cells 4 Text footer (change in > View > Header and Footer) March 2011

5 and are produced from living organisms Modify host cells (e.g., bacteria, mammalian yeast) to produce recombinant proteins Grow cells under controlled conditions (fermentation) Extract, refold, purify (downstream) generate drug substance Formulate to stable finished drug product (vial, syringe, cartridge). 5 Text footer (change in > View > Header and Footer) March 2011

6 Sandoz is a leader in developing and manufacturing biosimilars Biologics development and manufacturing experience: 66 years of experience in pharmaceutical biotechnology 32 years of experience in rec. therapeutic proteins Extensive experience with novel biologics, from peptides to mabs In house development capabilities: Own labs for all key activities, ~550 associates in development, plus Novartis In house manufacturing capabilities: Dedicated microbial (E. coli, yeast) and cell culture facilities, 8 API lines up to L; plus fill & finish lines Biosimilars expertise: Pioneer successfully developed 3 biosimilars WW 8-10 molecules in development, esp. mabs, multiple clinical trials ongoing (e.g. ph III rituximab, pegfilgrastim) 6 Text footer (change in > View > Header and Footer) March 2011

7 Biosimilars are recognized around the world as safe and effective medicines EU draft general guidelines adopted First biosimilar Somatropin approved and launched in EU First Epoetin approved and launched in EU First Filgrastim approved in EU Draft EMA mab guidelines Final EMA mab guidelines We are confident that if a product gets an MA from the Commission... the product is as safe and effective as any other product authorised by the Commission." - Nicolas Rossignol, former administrator of EC pharma division 1 Japan regulatory guidelines First biosimilar approved and launched in Japan & Canada US regulatory pathway US draft guidelines 1 Source: Speech at EGA Biosimilars conference 2008, quoted in Scrip 7 Text footer (change in > View > Header and Footer) March

8 Biosimilar applications in Europe to date the regulatory systems works reliably Trade Name Common Name (INN) Biosimilar Sponsor Reference Product Decision Date Decision Omnitrope Somatropin Sandoz Genotropin Approve April 12, 2006 Valtropin Somatropin BioPartners Humatrope Approve April 24, 2006 Biferonex Interferon beta-1a BioPartners Avonex Reject Feb. 19, 2009 Alpheon Interferon alfa-2a BioPartners Roferon-A Reject June 28, 2006 Binocrit Epoetin alfa Sandoz Eprex Approve Aug. 28, 2007 Epoetin alfa Hexal Epoetin alfa Hexal Eprex Approve Aug. 28, 2007 Abseamed Epoetin alfa Medice Eprex Approve Aug. 28, 2007 Retacrit Epoetin zeta Hospira Eprex Approve Dec. 18, 2007 Silapo Epoetin zeta STADA Eprex Approve Dec. 18, 2007 Insulin Rapid Marvel Insulin Marvel Humulin Withdraw Jan. 16, 2008 Insulin Long Marvel Insulin Marvel Humulin Withdraw Jan. 16, 2008 Insulin 30/70 Marvel Insulin Marvel Humulin Withdraw Jan. 16, 2008 Biograstim Filgrastim CT Arzneimittel GmbH Neupogen Approve Sep. 16, 2008 Filgrastim Ratiopharm Filgrastim Ratiopharm GmbH Neupogen Approve Sep. 16, 2008 Ratiograstim Filgrastim Ratiopharm GmbH Neupogen Approve Sep. 16, 2008 Tevagrastim Filgrastim Teva Generics GmbH Neupogen Approve Sep. 16, 2008 Zarzio Filgrastim Sandoz Neupogen Approve Feb. 6, 2009 Filgrastim Hexal Filgrastim Hexal Neupogen Approve Feb. 6, Text footer (change in > View > Header and Footer) March 2011 Nivestim Filgrastim Hospira Neupogen Approve Jun. 8, 2010

9 Non-comparable copy biologics not approved in highly regulated markets are NOT biosimilars Isoelectric focusing gels Non-comparable copy biologic biosimilar NOT similar to Reference E Approved biosimilar in EU NO difference to originator Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E Sample Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43 7 Brockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15: Text footer (change in > View > Header and Footer) March

10 Innovation required in both technical development and clinical development Key challenges Time & investment Significant expense (USD m) Long time to develop (7-10 years) Technical development Achieving highly similar to match originator molecule profile Matching final dosage form of originator Clinical development Use of novel endpoints and populations to confirm biosimilarity (not de novo safety/efficacy) Clinical trial design to support extrapolation across indications and interchangeability 10 Text footer (change in > View > Header and Footer) March

11 Example: Epoetin alfa - summary of clinical experience > patient years total COMPARABILITY PAC Clinical safety & efficacy Clinical PK / PD In vitro pharmacology and preclinical studies In vitro pharmacology and preclinical studies Biological quality assessment 1700 pts treated in phase IV setting, more than 2200 in non-interventional trials Clinical safety and efficacy shown in 3 phase III studies Comparable PK / PD shown in 6 phase I studies for s.c. and i.v. 4 week subchronic toxicity study PK/PD study Local tolerance study In vivo assay and in vitro testing demonstrates full biological functionality Comprehensive Physical characterisation molecular analysis Demonstration of structure and purity at protein and carbohydrate levels 11 Text footer (change in > View > Header and Footer) March 2011

12 Monoclonal antibodies are complex... Bacteria, Yeast Mammalian Peptide protein Protein (no sugars) protein Glycoprotein (with sugars) Aspirin 0.18kDAa 1x 19x 105x 122x 170x 833x calcitonin, ~3.5 kda filgrastim ~19 kda somatropin ~22 kda 12 Text footer (change in > View > Header and Footer) March 2011 epoetin ~30 kda mab, ~150 kda

13 ... but can be thoroughly characterized using state-of-the-art analytical science Biological characteristics Physicochemical characteristics N-terminal heterogeneity Pyroglutamate formation Other modifications Fab Fc Effector functions - Complement interaction - Fc Receptor interaction CH2 C H 3 - S - S - - S - S - Heavy chain 13 Text footer (change in > View > Header and Footer) March COO - S S S S Amino acid modifications Deamidation, Oxidation, Glycation, Isomerization Fragmentation Cleavage in hinge region, Asp-Pro Oligosaccharides Fucosylation, Sialylation, Galactosylation,... Disulfide Bonds Free thiols, disulfide shuffling, thioether C-terminal heterogeneity Lysine processing, Proline amidation

14 Today s analytical science provides full understanding of a mab Attributes: Primary structure Mass Disulfide bridging Free cysteines Thioether bridging Higher order structure N- and C-terminal heterogeneity Glycosylation (isoforms, sialic acids, NGNA, fucosylation, alpha gal, site specific) Glycation Fragmentation Oxidation Deamidation Aggregation 14 Text footer (change in > View > Header and Footer) March 2011 Proteins can be well characterised at least up to the complexity of monoclonal antibodies Primary structure determined from recombinant DNA sequence and fully accessible to analytical verification Set of orthogonal analytical methods available to characterize the identity and amount of related variants with high sensitivity Glycosylation profile can be comprehensively determined with regard to identity and content of individual glycans with high sensitivity Accurate and relevant bioassays for pivotal biological functions available Methods e.g.: MS (ESI, MALDI- TOF/TOF, MS/MS) Peptide mapping Ellman s CGE SDS-PAGE CD H-D exchange FT-IR HPLC HPAEC IEF 2AB NP-HPLC SE-HPLC FFF AUC DLS MALLS

15 Orthogonal bioassays addressing multiple functions CDC complement dependent cytotoxicity C1 Membrane attack complex Target cell Target cell Fc γ RIIIa PCD Effector cells (NK cells) ADCC Antibody dependent cellular cytotoxicity Programmed cell death ( apoptosis ) Blocking / / Inhibiting RB Soluble Target 15 Text footer (change in > View > Header and Footer) March 2011

16 Variability in original biologics 2,0 1,6 1,2 0,8 0,4 0,0 Unfucosylated G0 [% of glycans] Expiry Date Pre-Shift ADCC Potency [% of reference] Pre-Shift Post-Shift Post-Shift Schiestl, M. et al., Nature Biotechnology 29, , 2011) Monitoring batches of an approved mab revealed a shift in quality Shift in glycosylation (structure) pattern results in different potency in cell-based assays (function) Indication of a change in the manufacturing process Such shifts observed in several original products Products found to be equally safe and effective post-shift by regulators (EMA, FDA) Expiry Date 16 Text footer (change in > View > Header and Footer) March

17 Biosimilars must be systematically engineered to match the reference product Reference product Clinical 2. Confirmation of biosimilarity 1. Target directed development Target range Drug product development PK/PD Preclinical Purification process development Process development Biological characterization Bioprocess development Recombinant cell line development Analytics Physicochemical characterization Leveraging biological variability 17 Text footer (change in > View > Header and Footer) March 2011

18 Target directed process development Example: Adjusting ADCC in clone selection ADCC (%of Reference) Range of orginator on market too narrow to deduce S/F-relationship bg0-f [rel. %] Quality Attribute [%] 10 Parental Cell Line Pools Variability observed during cell line development enables elucidation of quantitative S/Frelationship Screening of bioreactor conditions Clones Clones Clones Final Clone Cell Line X Cell Line X Cell Line X Cell Line X Pool A Pool A Pool B Pool B 18 Text footer (change in > View > Header and Footer) March 2011

19 Pre-clinical and clinical development of biosimilar is a four-step process Average time Characteristics 1 Pre-clinical 6 12 months Abbreviated pre-clinical program Toxicology, efficacy/ safety in relevant species models Consider 3 R (replacement, reduction, refinement strategy to reduce animal studies 2 Phase I (PK/PD) 9 12 months Demonstration of PK/PD equivalence in a sensitive population - can be healthy volunteers Same posology is appropriate as confirmed by bioequivalence studies No phase II dose finding studies are needed 3 Phase III (confirmatory) 2 4 years Demonstration of similarity in terms of efficacy and safety in ONE indication, but not patient benefit per se Sensitive primary endpoints may be different from those used in originator trials, e.g. response rate vs. progression free survival or overall survival Sufficient for extrapolation across indications, if mechanism of action is similar 4 Post-approval trials Variable Additional data to meet regulatory needs 19 Text footer (change in > View > Header and Footer) March

20 While Sandoz is well positioned in biosimilars, originators are entering the space Technical expertise of a pharma company Commercial expertise of generics company #1 with ~50% share in biosimilar regulated markets 1 Leading pipeline with 8-10 molecules for US, Canada, Europe, Japan and Australia; based on IMS and company reports Note: all trademarks in this presentation are the property of their respective owners 20 Text footer (change in > View > Header and Footer) March 2011

21 Successful commercialization of biosimilars requires interaction with broad group of customers Patients Pharmacists KOLs Physicians Governments / MoHs Hospitals Payors / PBMs Wholesalers / distributors 21 Text footer (change in > View > Header and Footer) March 2011

22 However, a tailored commercial approach is required for biosimilars by product, market and channel Approach for commercial success varies significantly by product, country, and channel Need to focus resources on highest impact areas given typically lower investments than originators Successful commercial model can range from tender management to fully branded approach Examples of somatropin Key Success Factors (KSFs 1 ) Promotional activities (materials, reps) Key account management Tender management Market access Medical science liaisons 1 Not a major KSF Major KSF Patients kits/ training 22 Text footer (change in > View > Header and Footer) March 2011

23 UK example: Biosimilars expand access to G-CSF 1 UK G-CSF volume growth Percent change vs. previous year Sep Biosimilars approved G-CSF prevents hospital re-admissions due to infections Many physicians have moved G-CSF back to 1 st -line cancer treatment due to lower biosimilars cost Sandoz s Zarzio (G-CSF) Patient Support Kits expand patient access: Patients self-administer at home Substantial efficiency savings 1 Granulocyte colony stimulating factor SOURCE: IMS, NHS 23 Text footer (change in > View > Header and Footer) March 2011

24 Summary More than 15 years of experience with biosimilars Development of biosimilars requires lots of expertise, time and money these are not generics! Approval of biosimilars is rigorously managed by EMA No safety issues with marketed products after 6 years and millions of treatments Biosimilar mabs will reach the market soon, forming the next wave of more complex and very powerful products Commercialization of biosimilars requires a tailored approach, closer to original products and much different from generics There is a significant commercial opportunity and many originator companies are entering the biosimilars business Biosimilars are expanding patient access already today 24 Text footer (change in > View > Header and Footer) March