Anti-Interleukin 17A Monoclonal Antibody Secukinumab Reduces

11/6/2011

Anti-interleukin 17A monoclonal antibody Financial Disclosure* Consulting fees and/or research grants from AstraZeneca, BMS, Centocor, I. McInnes secukinumab reduces signs and symptoms of GSK, Merck, Novartis, Novo Nordisk, Pfizer, Roche, UCB psoriatic arthritis in a 24-week multicenter, double- J. Sieper None blind, randomized, placebo-controlled trial J. Braun None P. Emery None Consulting fees and/or research grants from Abbott, Amgen, AstraZeneca, D. van der Heijde BMS, Centocor, Chugai, Eli-Lilly, GSK, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth J. Isaacs None I. McInnes1, J. Sieper2, J. Braun3, P. Emery4, D. van der Heijde5, J. Isaacs6, G. Dahmen7, J. Wollenhaupt8, H. Schulze-Koops9, S. Gsteiger10, A. Bertolino11, W. Hueber11 and G. Dahmen None 12 P. P. Tak J. Wollenhaupt None 1University of Glasgow, Glasgow, United Kingdom, 2Charitè Campus Benjamin Franklin, Berlin, Germany, H. Schulze-Koops None 3Rheumazentrum Ruhrgebiet, Herne, Germany, 4University of Leeds, Leeds, United Kingdom, S. Gsteiger Employee, Novartis Pharma AG 5Leiden University Medical Center, Leiden, The Netherlands, 6Newcastle University and the Freeman Hospital, Newcastle-upon-Tyne, United Kingdom, A. Bertolino Employee, Novartis Institutes for BioMedical Research 7Praxis fuer klinische Studien, Hamburg, Germany, 8Eilbeck Hospital, Hamburg, Germany, W. Hueber Employee, Novartis Institutes for BioMedical Research 9 Klinikum Innenstadt der Ludwig-Maximilians-Universität, Munich, Germany, Consulting fees and/or research grants from Abbott, Arthrogen b.v., 10 11 Novartis Pharma AG, Basel, Switzerland, Novartis Institutes for BioMedical Research, Basel, Switzerland, AstraZeneca, Bristol Myers Squibb, ChemoCentryx, Eli-Lilly, Novartis, 12AMC/University of Amsterdam, Amsterdam, The Netherlands P. P. Tak NovImmune, NovoNordisk, Pfizer, Merck, MerckSerono, Roche Pharmaceuticals/Genentech. After study completion, became an employee of GlaxoSmithKline Study sponsored by Novartis Pharma AG, Basel, Switzerland *As reported for this presentation 2

Secukinumab: Secukinumab: A fully human monoclonal antibody that inhibits IL-17A A fully human monoclonal antibody that inhibits IL-17A

Naïve T cell IL-1, IL-6, IL-21, IL-23 Naïve T cell IL-1, IL-6, IL-21, IL-23 induces induces differentiation to... differentiation to... Th17 Th17

Can also be Can also be converted to converted to other types of IL-17A other types of IL-17A T cells T cells Produces a Target cell, e.g. synoviocytes, Produces a Target cell, e.g. synoviocytes, range of other keratinocytes, neutrophils, range of other keratinocytes, neutrophils, immune chondrocytes, and osteoclasts immune chondrocytes, and osteoclasts mediators mediators

Release of inflammatory Release of inflammatory cytokines X cytokines X Inflammation IL-17A binds to IL-17 receptor IL-17A bound to secukinumab X Proliferation prevents IL-17A from binding to receptor and Tissue Remodeling 4

Secukinumab in Psoriasis IL-17A, A Pro-inflammatory Cytokine and Novel Target in Psoriatic PASI 75 response rates in a Phase II i.v. dose-finding study Arthritis

• Psoriatic arthritis (PsA) is a chronic, immune-mediated inflammatory 3 mg/kg 10 mg/kg 3x10 mg/kg Placebo disease affecting 7–40%1 of patients with psoriasis 100 90 • PsA patients exhibit increased levels of IL-17 production2 80 83% 75% – IL-23 triggers IL-17 production by T cells and non-T cells which could play a part in 70 synovitis, enthesitis, cutaneous psoriasis and bone destruction mechanisms3 60 • In PoC and phase II trials, secukinumab has shown therapeutic potential 50 for rheumatoid arthritis4,5, ankylosing spondylitis6 and in moderate-to- 40 40% severe plaque-type psoriasis7,8,9 30

20 • The present proof-of-concept study explored the efficacy of secukinumab PASI 75 response response rates 75 (%) PASI 10 10% in patients with moderate-to-severe PsA 0 0 1 2 3 4 5 6 7 8 9 10 11 12 1Cuchacovich R S et al. Lancet 2009: 605-606; 2Jandus C et al. Arthritis Rheum. 2008:2307–2317; 3Sato K et al. J Exp Time (weeks) Med. 2006: 2673–2682; 4Hueber W et al. Sci Transl Med. 2010;2:52ra72; 5Genovese M et al. ACR 2010;Abstract No: 4405; 6Baeten D et al, EULAR 2011, OP0174; 7Papp KA et al. Oral presentation at: 20th Congress of the EADV; October 21, 2011; Lisbon, Portugal. Abstract 0626; 8Rich PA et al; Oral presentation at: 20th Congress of the EADV; October 21, 2011; Lisbon, Portugal. Abstract 0627; 9Papp KA et al. Oral presentation at: 20th Congress of the EADV October 21, 5 2011; Lisbon, Portugal. Abstract 0630. 6

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CAIN457A2206: Phase II Proof-of-Concept Study Design Study Design and Treatment Secukinumab i.v. versus placebo

Study design

• Randomized, double-blind, placebo-controlled, multicenter study

Induction period Follow-up • The study was conducted in 11 centers in 3 countries: Germany, The Netherlands = Secukinumab i.v. Wk 24 and United Kingdom Wk 0 Wk 3 Wk 12 = Placebo i.v.

Secukinumab 2 x 10 mg/kg Key inclusion criteria (N = 28) R* • PsA diagnosed according to the CASPAR (ClASsification Criteria for Psoriatic ARthritis) criteria, and Placebo (N = 14) – Involvement of at least three swollen and tender peripheral joints Wk 6 (PE) – PGA ≥ 40 (VAS 0-100mm)

– Inflammatory pain ≥ 40 (VAS 0-100mm) 42 subjects were randomized in a 2:1 ratio. Primary endpoint: ACR 20 after 6 weeks – Disease is inadequately controlled on at least one DMARD given for at least 3 months at Key secondary endpoints: ACR 50, ACR 70, PsARC, MASES, AEs the maximum tolerated dose

*R, Randomization; Wk, weeks; PE, Primary Endpoint 7 8

Study Endpoints Patient Disposition

Primary endpoint • Proportion of patients achieving ACR20 response at Week 6

– Considered statistically significant if one-sided p-value <0.1 Patient Disposition Secukinumab Placebo Total Key Secondary endpoints (N=28) (N=14) (N=42) n (%) n (%) n (%) • Proportion of patients achieving ACR50 and ACR70 responses (Week 1, 2, 6, 8, 12, 16 & 28) Completed 25 (89.3) 10 (71.4) 35 (83.3)

• Proportion of patients achieving PsARC response (Week 1, 2, 6, 8, 12, 16 & 28) Discontinued 3 (10.7) 4 (28.6) 7 (16.7) Excluded from PD* analysis due to 4 (14.3) 1 (7.1) 5 (12) • Safety and tolerability protocol violations† • Pharmacokinetics Reasons for discontinuations: Post-hoc analyses Withdrawal of consent 2 (7.1) 3 (21.4) 5 (11.9) • CRP analysis (Week 1, 2, 6, 8, 12, 16 & 28) Unsatisfactory therapeutic effect 1 (3.6) 1 (7.1) 2 (4.8) • Subgroup analysis: primary endpoint for TNF-α inhibitor naïve versus TNF-α inhibitor pre-exposed patients

*PD set includes the patients who received the allocated treatment; the safety set are all patients who received the study medication regardless of treatment assignment;†including 3 Inclusion/Exclusion criteria violations, 1 Serious adverse CRP, C-reactive protein 9 event and 1 disallowed medication prior to Week 6 10

ACR20, ACR50, ACR70 Responses at Week 6 Demographics and Baseline characteristics The primary endpoint was not met

Demographics and Baseline characteristics Secukinumab Placebo Total Variables ACR20, ACR50, and ACR70 response at Week 6 (N=28) (N=14) (N=42) Female, , n (%) 19 (68) 8 (57) 27 (64) Age (yrs), Mean (SD) 46.7 (11.3) 47.6 (8.1) 47.0 (10.2) 100 Secukinumab BMI (kg/m2), Mean (SD) 31.9 (8.1) 27.5 (4.9) 30.4 (7.5) Placebo *Efficacy analysis set, n 24 13 37 80 Tender Joint Count, Mean (SD) 23.5 (19.4) 22.6 (11.0) 23.2 (16.8) p-value Swollen Joint Count, Mean (SD) 8.3 (5.6) 9.5 (5.4) 8.7 (5.5) Endpoint (Secukinumab vs. placebo) CRP, Median (Min-Max) 5 (0.3-43) 6.2 (1.3-39.7) 5 (0.3-43) 60 DAS28, Mean (SD) 4.8 (1.2) 4.8 (1.2) 4.8 (1.2) ACR20 0.27 43 MASES, Mean (SD) 3.0 (4.1) 3.4 (2.3) 3.1 (3.6) 39 40 38 ACR50 0.39 Psoriatic arthritis, n (%) ACR70 0.40 Oligoarticular 10 (42) 4 (31) 14 (38) 23 Polyarticular 13 (54) 9 (69) 22 (59) 20 17 Distal Interphalangeal joint predominant 1 (4) - 1 (3) Percentage ofresponders Percentage 8 9 Co-existing Psoriasis, n (%) 23 (96) 11 (85) 34 (92) 0 Prior TNF-α inhibitor, n (%) 11 (46) 5 (38) 16 (43) 0 ACR20 ACR50 ACR70 PsARC

*PD set includes the patients who received the allocated treatment; the safety set are all patients who received the study medication regardless of treatment assignment; Tender & swollen joint counts based on 68 and 66 joints respectively 11 12

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Secondary Endpoint Analysis TNF-α inhibitor naïve vs. TNF-α inhibitor pre-exposed patients ACR20, ACR50, ACR70 and PsARC response rate over time ACR20, ACR50, ACR70 response rate at Week 6

ACR20 response rate over time ACR50 response rate over time TNF-α inhibitor naïve patients Secukinumab 80 80 100

Secukinumab Secukinumab Placebo

70 70 Placebo Placebo 80 60 60 62 50 50 60 40 40 30 30 40 25 23 20 20 20 13 15

10 10

ACR20 ACR20 response rate (%) ACR50 ACR50 response rate (%) Percentage of responders 0 0 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28* 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28* ACR20 ACR50 ACR70 Time since dosing (weeks) Time since dosing (weeks) n/N 8/13 2/8 3/13 1/8 2/13 0/8 ACR70 response rate over time PsARC response rate over time TNF-α inhibitor pre-exposed patients Secukinumab 80 80 100

Secukinumab Secukinumab Placebo

70 Placebo 70 Placebo 80 60 60 50 50 60 40 40 30 30 40 20 20 20 20 10 10

10 10

ACR70 ACR70 response rate (%) PsARC response rate (%) Percentage of responders 0 0 0 0 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28* 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28* ACR20 ACR50 ACR70 Time since dosing (weeks) Time since dosing (weeks) n/N 1/10 1/5 1/10 0/5 0/10 0/5 *Week 28 or EOS if early discontinuation; Data shown in the figure is mean (SE) 13 n = number of patients achieving response 14

Safety Summary Summary

Incidence of Adverse Events • The primary efficacy endpoint was not met at Week 6 Secukinumab Placebo Total Variable*, n (%) (N=28) (N=14) (N=42) Any AE 26 (92.9) 11 (78.6) 37 (88.1) – ACR20 response rate was numerically higher on secukinumab compared with Most common AEs placebo (39% vs. 23%) Nasopharyngitis 7 (25.0) 5 (35.7) 12 (28.6) Headache 6 (21.4) 1 (7.1) 7 (16.7) • Secondary endpoint analyses showed that a proportion of patients on Nausea 4 (14.3) 1 (7.1) 5 (11.9) secukinumab experienced rapid and sustained improvements of clinical Diarrhoea 3 (10.7) 1 (7.1) 4 (9.5) scores up to Week 28 Dizziness 4 (14.3) - 4 (9.5) Pruritus 3 (10.7) 1 (7.1) 4 (9.5) • Post-hoc analyses showed that the subgroup of TNF-α inhibitor naïve Vertigo 1 (3.6) 3 (21.4) 4 (9.5) patients achieved numerically greater response rates compared to the • There were 0 deaths and 7 non-fatal serious adverse events affecting 5 patients entire cohort, but small numbers require cautious interpretation • There were no study discontinuations due to adverse events • Safety profile of secukinumab was favorable, no safety signals were – One patient discontinued treatment due to an SAE (breast cancer) identified • There were 35 infections (26 mild; 8 moderate; 1 severe) in 23 patients – 16 (57%) patients on secukinumab; 7 (50%) patients on placebo • Trends towards a beneficial clinical effect of secukinumab observed in this • One severe adverse event (severe AE) occurred on secukinumab: Cellulitis of the study support the rationale for larger clinical trials designed to assess hand (not study drug related) clinical effectiveness in psoriatic arthritis

*Data for safety population; AE, Adverse Events (Only AEs occurring in more than 3 patients are presented); SAE, serious adverse event 15 16

Acute Phase Reactants CRP levels over time

CRP levels over time

25 Secukinumab

Placebo 20

± 10

Mean CRP (mg/L) Mean CRP (mg/L) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28*

-5 Time since dosing (weeks) BACKUP SLIDES -10 CRP levels at Week 6 compared to baseline (median [range] ): Baseline Week 6 Secukinumab, median [range] 4.9 [0.3, 43.0] 3.0 [0.2, 15.2] Placebo, median [range] 6.2 [1.3, 39.7] 5.0 [0.8, 29.6]

17 CRP, C-reactive protein; *Week 28 or EOS if early discontinuation; Data shown in the figure is mean (SD) 18

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Safety Summary Infections, regardless of study drug relationship Acknowledgements

Infections Secukinumab Placebo Total Variable*, n (%) (N=28) (N=14) (N=42) Infections and infestations 16 (57.1) 7 (50.0) 23 (54.8) Bronchitis 1 (3.6) 1 (7.1) 2 (4.8) Thank you for your participation! Cellulitis 1 (3.6) - 1 (2.4) Germany Jürgen Braun, Georg Dahmen, Hendrik Schulze-Koops, Joachim Gastroenteritis 1 (3.6) - 1 (2.4) Sieper, Jürgen Wollenhaupt Gastrointestinal infection 1 (3.6) - 1 (2.4) The Netherlands Paul P. Tak, Désirée van der Heijde H1N1 influenza 1 (3.6) - 1 (2.4) Helicobacter gastritis 1 (3.6) - 1 (2.4) United Kingdom Paul Emery, John Isaacs, Iain McInnes, Jacob M. van Laar Hordeolum 1 (3.6) - 1 (2.4) Infected bites 1 (3.6) - 1 (2.4) Laryngitis 1 (3.6) - 1 (2.4) Nasopharyngitis 7 (25.0) 5 (35.7) 12 (28.6) Oral herpes - 1 (7.1) 1 (2.4) Paronychia 1 (3.6) - 1 (2.4) Pharyngitis 1 (3.6) - 1 (2.4) Respiratory tract infection - 1 (7.1) 1 (2.4) Rhinitis 1 (3.6) - 1 (2.4) Tonsillitis 1 (3.6) - 1 (2.4) Upper respiratory tract infection 1 (3.6) - 1 (2.4) Urinary tract infection - 1 (7.1) 1 (2.4) Viral infection 1 (3.6) - 1 (2.4)

*Data for safety population 19 Countries and investigator names are arranged in alphabetical order 20