Safety & Tolerability of Biologics Dubai, United Arab Emirates January 19th, 2009 Prof. Joachim R. Kalden Director emeritus Department of Internal Medicine III Div. of Molecular Immunology Niklolaus-Fiebiger-Center University of Erlangen-Nuremberg

Overview Monitoring of safety: registries Safety: Tuberculosis Safety: Serious infectious events Safety: Malignancy Safety: Lymphoma

European registries Post approval commitment to EMEA that Wyeth would monitor safety Professional Societies independently supported establishment of registries to monitor safety Established in a number of countries independently but with different approaches, with or without Reference groups Efficacy endpoints

Why important? Only source of comparisons with competitors Providing rich stream of data for differentiation Currently under analysed – registries focusing on limited number of questions Potential for pooled analyses to give even greater power

Why are registries important to Wyeth Meet post approval commitment Large cohorts of Enbrel patients treated in clinical practice Source of comparative data with MAbs Resource for evaluation of safety and efficacy Potential to combine data to provide increased power to undertake analyses of rare events

Original registries Sweden ARTIS – nationwide but organised on a regional basis –STURE – Stockholm registry –SSAGT – Southern Sweden Both ARTIS and the regional registries publish results No concurrently recruited controls but use other RA cohorts for reference UK BSRBR - national registry powered to detect 2 fold increase in lymphoma in comparison to a DMARD treated cohort Germany RABBIT – national registry to describe the long term effectiveness –treatment continuation –clinical outcomes –long term hazards –direct and indirect costs Comparison with conventional DMARD treatment from national database These 3 registers meet together annually with companies Use standard report which is sent companies twice a year for inclusion in safety reports to regulators

Estimates of patient numbers CountryStarted Date of Estimate Total TNFi Controls Sweden National DB UK Germany National DB France Spain N/A Norway DMARDs Denmark None Czech Switzerland SCQM Total44781

Monitoring of safety: problems Controlled trials Relatively few pts, not the same patient population as in clinical practice, seldom long-term, randomisation may create well-balanced comparator Spontaneous reporting Very low reporting rates; only certain adverse drug reactions (with attribution) Long-term observational studies Difficult to obtain enough compliance, need for comparator data

Advantages and disadvantages of registries Advantages Usually much larger than clinical trials Greater power than RCTs to detect rare events Enrolment reflects clinical practice Potential for studying numerous outcomes Suited to long term follow-up Can examine complex situations not suited to RCTs Results can usually be generalised Disadvantages Non randomised, subject to bias Confounding by indication Missing data Potential for confounding Channelling bias Choice of reference group

Conditions Where Mechanism of Action Differences May Affect Safety Profile TB Serious Infectious Events (SIEs) Malignancy

Tuberculosis (TB)

FDA MedWatch spontaneous reporting system (AERS): 2001 TB associated with infliximab 70 reported cases of TB after treatment with infliximab for a median of 12 weeks 40/70 had extra- pulmonary disease Normal Post-infliximab Keane J. et al. NEJM 2001;345:

Inhibition of IFN gamma Effect of drugs on IFN  production in whole blood cultures stimulated with M tb culture filtrate. Median and interquartile ranges n=15 Saliu et al. J Infect Dis 2006.

TB associated with clinical trials: T B events despite screening Anti-TNF AgentRequired Screening for TB TB Event Rate (per 1000 pt-yr) Etanercept (soluble receptor) Not mandated Pooled analysis of all clinical trials across indications (Europe / N. America) 4 (N=11,390; 2 cases TB) 0.11 Adalimumab (mAb) Yes Pooled analysis Europe Pooled analysis N. America REACT Trial Infliximab (mAb) Yes Pooled analysisNot available START Trial Infliximab vs abatacept trial Certolizumab (mAb) Yes Pooled analysisNot available RAPID I Trial RAPID II Trial

Enbrel and TB: Portugal 2.3% (4/171) 1.5% (8/456) 0.3% (1/333) TB events associated with anti-TNF agents were compared for 960 pts treated between 1999 – 2005 in Portugal*: * 13 events total: 9 RA (n=639); 3 AS (n=200); 1 PsA (n=101). Fonseca JE et al. Acta Reumatol Port. 2006;31:

BIOBADASER: Risk and incidence of TB in Spain Treatments starts Patient-years of exposure to TNF antagonists Cases TB rate per 100,000 p/y RR vs. general population (IC 95%) RR vs. EMECAR (IC 95%) <March 20028, (384–642)19 (11–32)5,8 (2,5–15,4) >March % compliance <100% compliance 8,717 4,576 4, (103–285) 43 (11–175) 311 (181–636) 7 (3–13) 1,8 (0,28–7,1) 13 (6–25) 2,4 (0,8–7,2) Undetermined 4,8 (1,04–44,3) Annual incidence rate / 100,000 p. y. General population 25; EMECAR (RA pre-biologic era) Carmona et al. Arthritis Rheum 2005; 52(6): ; Gómez-Reino et al. Arthritis Care & Research 2007.

BSRBR: Anti-TNFs and risk of TB Dixon WG et al. THU0134. EULAR 2008

RATIO: Factors predictive of TB Last anti-TNF received No. of casesHR (95% CI) vs etanercept P-value Adalimumab ( )0.006 Etanercept35 Infliximab58.63 ( )0.02 Use of specific biologics is predictive of TB in anti-TNF- treated patients (n=67) Incidence TBC 39.2/100,000 pt/year ETA: 6.0/100,000 pt/year INF or ADA: 71.5/100,000 General Population: 8.7/100,000 pt/year Two thirds (30/45) of the patients who developed TB had negative skin tests Tubach F et al. OP EULAR 2008

Serious Infectious Events (SIEs)

Etanercept and serious infectious events Pooled analysis of randomised clinical trials for Enbrel in RA Serious infectious events No difference vs. placebo Hamza S et al. EULAR 2007 ARD 2007;66(2): THU0153 Abstract

Etanercept and opportunistic infections Pooled analysis of randomised clinical trials for Enbrel in RA Opportunistic infections No difference vs. placebo Hamza S et al. EULAR 2007 ARD 2007;66(2): THU0153 Abstract

BSRBR: Etanercept and mAbs vs. DMARDS SIE rates relative to DMARDS in first 90 days of therapy ETNINFLIXADAL Dixon WG et al. A&R 2007;56(9):

RABBIT: Etanercept and SIEs - Herpes virus infections RABBIT Registry (Germany)* Evaluated RA patients for reactivation or first infection of Herpes virus infections (Varicella Zoster Virus, Herpes simplex Virus) “Our data suggest a different mode of action of TNF  antibodies and the soluble TNF receptor fusion protein etanercept in respect to the reactivation of a latent herpes infection.” Reactivation of Herpes virus infections suggest a loss of cell- mediated immunity Hazard Ratio P value Etanercept Infliximab Adalimumab Risk of Infection vs. Control *Strangfeld A. et al. Oral Presentation Abstract OP0214 Friday June 15, 2007 EULAR 2007

ARTIS: Hospitalisation risk for infection – all anti-TNFs Time since treatment start Year 2 Year 3 Year 1 Relative risk (9.5% CI) Askling J, et al. Ann Rheum Dis :1339–44

ARTIS: Serious infection rate in patients treated with a 2nd TNF antagonist First TNF inhibitorSecond TNF inhibitor Infections leading to hospitalisation/100 patient-years All TNF inhibitor-treated patients (n=4,167) Patients hospitalized prior to treatment with TNF inhibitor (n=2,692) First TNF inhibitorSecond TNF inhibitor Infections leading to hospitalisation/100 patient-years Crude Incidence Adapted from Askling J, et al. Ann Rheum Dis :1339–44

Malignancies

Malignancy Lower Risk Higher Risk Lymphoma only All malignancies Skin cancer (OR) (OR) (OR) Point Estimate95% CIAnalysesNumber of Patients Malignancy Risk: ENBREL vs. control, derived from a large patient database* *Wolfe F and Michaud K. A&R 2007;56: ;

Swedish national registry ARTIS Data compared with Swedish nationwide cancer & census registers ARTIS: Anti-TNF and solid cancers Prevalent RA n = Incident RA n = 3703 RA on anti-TNF n = 4160 n SIR (95% IC) n n All cancers ( ) ( )670.9 ( ) Melanoma ( )40.9 ( )10.3 ( ) Askling et al. Ann Rheum Dis 2005;64:1414–1420

Swedish national registry ARTIS Data compared with Swedish nationwide cancer & census registers ARTIS: Anti-TNF and solid cancers Prevalent RA n = Incident RA n = 3703 RA on anti-TNF n = 4160 n SIR (95% IC) n n All cancers ( ) ( )670.9 ( ) Melanoma ( )40.9 ( )10.3 ( ) Skin (non- melanoma) ( )50.7 ( )113.6 ( ) Lung ( )232.4 ( )101.8 ( ) Askling et al. Ann Rheum Dis 2005;64:1414–1420

ARTIS (2008): No increase in cancer following anti-TNF therapy No. primary cancers Relative risk (95% CI) Compared to national RA cohort Compared to general population Anti-TNF treatment ( )1.04 ( ) No increased cancer risk with anti-TNF therapy Askling J et al. OP EULAR 2008

RA and cancer National Data Base for Rheumatic Diseases (NDBRD) 13,001 RA patients (49,000 p/y) of observation (1998/2005) –At least 1 year of follow-up –49% of whom exposed to biological therapy Cancer rates compared with population rates US National Cancer Institute database Incidence of new cancers in patients with anti-TNF/ without anti- TNF ORs as estimates RR adjusted for 6 confounders: age, sex, education level, smoking history, RA severity and prednisone use Wolfe, ACR 2006 and Arthritis and Rheum 2007

Lymphoma

Lymphoma and rheumatic disease Several studies suggested an increased lymphoma risk in patients with rheumatic disease Risk may be tied to degree of disease severity and inflammation What is the impact of biologics on this?

Lymphoma risk and RA disease activity: Pre-biologics Patients: Swedish in-patient registry with RA 1964–1995, who developed lymphoma > 1 year after discharge (RA and lymphoma diagnosis validated) Controls: Individually matched RA patients without lymphoma from same source (378 cases and controls) All records retrospectively reviewed to assess disease activity and DMARD therapy Baecklund E, et al. Arthritis Rheum. 2006;54:

Outlook TNFalpha antagonists might improve or prevent important comorbidities  Cardiovascular diseases  Lymphomas By:  Decreasing inflammation  Decreasing activation of endothelial cells  Normalizing pathologic lipid profiles  Normalizing insulin resistance

Lymphoma risk and rheumatoid arthritis disease activity Inflammatory Activity Baecklund E, et al. Arthritis Rheum. 2006;54:

No increased risk of lymphoma in RA patients upon treatment with anti-TNF Swedish population-based cohort study of RA pts: one prevalent cohort (n = 53067) one incident cohort (n = 3703) one TNFi -treated cohort 1999 through 2003 (n = 4160) Prevalent and incident RA pts have an increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) RA pts treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) However, after adjustment (sex, age, and disease duration) the risk was not higher than in the other RA cohorts. Askling et al. Ann Rheum Dis 2005;64:1414–1420

Further safety issues 1. Infections 2. Pregnancies 3. Non-tb pulmonary disease 4. Heart failures 5. Surgical issues 6. Vaccination 7. Haematological chances 8. Demylating diseases 9. Allergic reactions

Summary: Areas in which data suggest a difference between mAbs and Etanercept Tuberculosis Risk of developing TB appears to be greater with mAbs than with Etanercept based upon: Pooled analyses of randomized controlled trials Multiple national registries MOA Malignancy Possible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist, including Etanercept, cannot be excluded Further analyses pending Serious Infections Differences in risk for infections may exist between Etanercept and mAbs; however, data are inconclusive RCTs suggest a difference Registries suggest no difference