PRODUCT INN REFERENCE AUTHORIZATION Omnitrope

PRODUCT INN REFERENCE AUTHORIZATION Omnitrope Genotropin 12/04/2006 somatropin Valtropin (W/D) Humatrope 24/04/2006 Abseamed Binocrit Epoetina alfa hexal Retacrit Silapo Biograstim Filgrastim ratiopharm WP Ratiograstim Tevagrastim Filgrastim Hexal Zarzio epoetin alpha Eprex 28/08/2007 epoetina zeta 18/12/2007 filgrastim Neupogen 15/09/2008 06/02/2009 Nivestim 08/06/2010 Grastofil 18/10/2013 Ovaleap follitropin alpha Gonal-F 27/09/2013 Inflectra Remsima infliximab Remicade 10/09/2013 follitropin Gonal-F Under review Insulin glargine Lantus Under review trastuzumab Herceptin Not submitted yet

Competizione; accesso al mercato; risorse per migliorare 1877: A dead heat at the Oxford Vs Cambridge University Boat Race in 1877 Gare in concorrenza diretta hanno portato ad un abbassamento dei prezzi di oltre il 75% rispetto al periodo precedente la scadenza brevettuale

Overview of currently approved biosimilar products in Europe* Omnitrope Human growth hormone (somatropin) Abseamed Binocrit Epoetin Alfa Hexal Retacrit Erythropoietin (epoetin alfa, zeta) Silapo Biograstim Zarzio Nivestim nulocyte colony-stimulating Ratiograstim Filgrastimfactor Tevagrastim Hexal Anti-TNF- monoclonal antibody (infliximab) Grastofil Inflectra Remsima Follicule-stimulating hormone (follitropin alfa) Ovaleap 2006 2007 2008 2009 2010 2013 *None FDA-approved as of February 2014 2 FDA, Food and Drug Administration 1. EMA. European Public Assessment Reports. Biosimilar Medicines Authorized by the Agency [website]. Accessed Feb 5, 2014; 2. FDA. Information for Consumers Biosimilars [website]. Accessed Feb 5, 2014

1. Remicade: Label Full Prescribing Information, P3 Trial (NCT00269867), Journal Article Lipsky et al, 2000. N Engl J Med. 2000 Nov 30;343(22):1594-602 2. CT-P13: PLANETRA P3 Trial (NCT01217086), Abstract 1: EULAR12-2238, Abstract 2: EULAR12-2547..P Kinetic data for CT-P13 is reported for patients with ankylosing spondylitis Remicade: ATTRACT 1 CT-P13: PLANETRA 2 1 O Endpoint Results Efficacy ACR20 at wk 30 (PP) ACR20 at wk 30 (ITT) ACR20 at wk 54 Mean change from baseline (vdh- S Total) Pbo + MTX -- 20% 17% 6.9 R 3 mg/kg (q8wk) -- 50% 42% 1.3 R 10 mg/kg (q8wk) -- 52% 59% 0.2 CT-P13 60.9% 73.4% -- -- IFX 3 mg 58.6% 69.7% -- -- 2 O Endpoint Results Efficacy ACR50 at wk 30 ACR70 at wk 30 5% 0% 27% 8% 31% 18% 42.3% 20.2% 40.6% 17.9% Adverse Events Safety Study-Related AEs Related infection >=1 Infusion reaction Tuberculosis Serious adverse events Serious infections Serious infusion reactions Antinuclear antibodies Antibodies against doublestranded DNA 21% 8% 0% 26% 0% 11% 2% 0% 68% 10% 20% 8% 0% 62% 10% 35.2% 15.3% 5% 3 pts 35.9% 16.9% 6% 1 pt

INDICAZIONI: rheumatoid arthritis, adult Crohn s disease, paediatric Crohn s disease, ulcerative colitis, paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis

Lo studio del biosimilare FSH Setting: Infertile ovulatory women undergoing ART Gonal-F Ovaleap patients 145 152 Number of oocytes retrieved primary endpoint 12.0 + 6.8 12.2 + 6.2 Total dose (S.E.) 1614 + 484 1539 + 495 # pts with dose increase 43.2% 35.9% # patients with dose decreases 15.1% 15.0% Ongoing pregnancy rate 0.34 0.28

What is a relevant end-point for equivalence and are all extrapolations equal??

Primi 20 principi attivi per consumo (a valore) Rank Consumi a valore 2013 (Migliaia di ) Variazioni % 2013 vs 2012 Quota di mercato ITALIA 8.585.043 5,3% 100,0% TRASTUZUMAB 232.484-0,4% 2,7% ETANERCEPT 214.272 3,2% 2,5% ADALIMUMAB 212.804 12,1% 2,5% EPOETINA ALFA 180.113-0,2% 2,1% INTERFERONE BETA 1A 178.984 3,3% 2,1% IMMUNOGLOBULINA UMANA NORMALE 177.906 4,8% 2,1% RITUXIMAB 174.078 1,0% 2,0% IMATINIB MESILATO 159.812-1,3% 1,9% OCTOCOG ALFA (FATTORE VII COAGULAZ) 135.226-0,2% 1,6% BEVACIZUMAB 133.856 4,7% 1,6% EMTRICITABINA TENOFOVIR DISOPROXIL 128.795-1,1% 1,5% LENALIDOMIDE 124.082 6,5% 1,4% EFAVIRENZ EMTRICITABINA TENOFOVIR DI 108.511 2,3% 1,3% RANIBIZUMAB 106.675 85,7% 1,2% INFLIXIMAB 103.859 1,1% 1,2% PEMETREXED DISODICO 89.940-0,5% 1,0% ALBUMINA UMANA 84.048-7,4% 1,0% ENOXAPARINA SODICA 83.720 10,7% 1,0% PACLITAXEL 83.215 6,4% 1,0% BORTEZOMIB 78.358 5,9% 0,9% TOTALE PRIMI 20 2.790.738 4,4% 32,5% TOTALE ALTRI 5.794.305 5,7% 67,5%

Ongoing phase III trials with Anti-HER2 ABs Adjuvant: - Pertuzumab + Trastuzumab vs Trastuzumab (Aphinity) - Trastuzumab Emtansine vs Trastuzumab + Pertuzumab (Kaitlin) - Trastuzumab Emtansine vs Trastuzumab (no pcr after neoadjuvant therapy) (Katherine) Neo/adjuvant: - Taxane + Pertuzumab + Trastuzumab vs Trastuzumab Emtansine + Pertuzumab (Kristine) Advanced: - 1 line: Trastuzumab + Taxane vs Trastuzumab Emtansine vs Trastuzumab Emtansine + Pertuzumab (Marianne) - 2 line: Pertuzumab + TPC vs TPC (Traetment of Phisician Choice)

Clinical complexity may not correlate only with molecular structure

Clinical experience (PASS, PAES, submissions of PSUR, use in Europe, scientific evidence of prescriptive behaviors) or ad hoc studies modify the clinical complexity