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Etanercept (Enbrel ® ) Safety Review March 4, 2003

Etanercept (Enbrel ® ) Safety Review March 4, 2003. Presentation Outline. Introduction Dan Burge, MD Etanercept Clinical Profile Pharmacovigilance General Safety Malignancy/Lymphoma Epidemiology of Lymphoma in RA Alan Silman, MD Lymphoma and Etanercept Dan Burge, MD

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Etanercept (Enbrel ® ) Safety Review March 4, 2003

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  1. Etanercept (Enbrel®) Safety ReviewMarch 4, 2003

  2. PresentationOutline Introduction Dan Burge, MD Etanercept Clinical Profile Pharmacovigilance General Safety Malignancy/Lymphoma Epidemiology of Lymphoma in RA Alan Silman, MD Lymphoma and Etanercept Dan Burge, MD Heart Failure Experience Ongoing Pharmacovigilance Summary C2

  3. Jeffrey Borer, MD Division of Cardiology The New York Hospital Cornell University Medical Center New York, New York Mary K. Crow, MD Dept. of Rheumatology Cornell University Hospital for Special Surgery New York, New York Annette Langer-Gould, MD Dept. of Health Research and Policy Stanford University School of Medicine Palo Alto, California Alan Silman, MD Epidemiology Research Unit University of Manchester Medical School ARC Professor of Rheumatic Disease Epidemiology,University of Manchester Manchester, United Kingdom Julie Vose, MD Department of Internal Medicine Section of Oncology/Hematology University of Nebraska Medical Center Omaha, Nebraska Consultants C3

  4. Etanercept: Distinctive Properties • Only soluble receptor TNF antagonist • Fully human protein • Low immunogenicity • Does not bind compliment and is not associated with compliment mediated cell lysis • Dosing schedule maintains stable serum concentrations • No pharmacokinetic interaction with methotrexate C4

  5. Etanercept: Sustained Benefit With Corticosteroid Reduction Long-Term Efficacy Reduction in Corticosteroids 10 30 TENDER P< 0.0001 JOINTS 25 Prednisone (mg/day) SWOLLEN JOINTS 20 5 Median Joint Count 15 10 5 0 0 Baseline N=385 4 Years N=267 0 1 2 3 4 5 6 Median (Interquartile range) Time on Therapy (years) Moreland 2002 ACR abstract 1427 C5

  6. 75% 72% 71% 70% 59% ERATrial Monotherapy2 years DMARD FailuresPhase 2 Monotherapy3 months DMARD FailuresPhase 3 Monotherapy6 months DMARD Failures MTX Combo6 months DMARD Failures Phase 3/EU Monotherapy6 months Etanercept: Consistent and Substantial Efficacy Percentage of Patients Achieving ACR 20 Bathon J. N Engl J Med. 2000:343:1586-1593. Moreland LW, et al. N Engl J Med. 1997;337:141-147. Weinblatt ME, et al. N Engl J Med. 1999;340:253-259. Moreland L, et al. Ann Intern Med. 1999;130:478-486. European Etanercept Investigators Group. EULAR 2000, Nice, France. C6

  7. Etanercept: Milestones 1990 P75-TNF receptor cloned 1993 First administration to RA patient 1998 FDA approval for RA (alone or with MTX) 1999 FDA approval for JRA 2000 FDA approval as initial therapy for RA FDA approval for inhibition of radiographic progression 2001 FDA Arthritis Advisory re: TNF Antagonists Safety 2002 FDA approval for psoriatic arthritis (alone or with MTX) 2002 FDA approval of three year efficacy and safety data in RA C7

  8. Etanercept Pharmacovigilance Program • Ongoing clinical studies (over 3,000 patients) • Long-term open label extension studies (n ~1,600) North America and Europe • Safety trial of RA patients with comorbidities (n=1,000) • Combination DMARD studies (n ~ 800) • Observational studies (over 12,000 patients) • Juvenile rheumatoid arthritis registry (n=600) • RADIUS I and II: observational studies (n=10,000) • European RA registries (n ~ 1,600) Germany Sweden United Kingdom C8

  9. Etanercept Pharmacovigilance Program (continued) • Epidemiologic studies Ingenix UnitedHealthcare (n ~ 50,000 rheumatic disease patients): establishing background incidence of adverse events in rheumatic disease populations • Continued surveillance of facilitated post-marketing adverse event reports • 1.2 Million phone contacts in 150,000 patients • Each call is an opportunity for reporting • 88% adverse event reports are patient initiated • Half of health care provider reports are patient initiated C9

  10. Clinical Trial Commercial Experience FDA Advisory Committee Date Patients Pt-Yrs Patients Pt-Yrs May 1998 745 491 -- -- August 2001 2664 3389 >111,000 >116,000 March 2003 3839 8336 >150,000 >230,000 Clinical Trials: 1084 patients in 5th year of therapy 390 patients in 6th year of therapy Over 230,000 Patient-Yearsof Etanercept Experience C10

  11. Serious Adverse Event Rates in Etanercept Patients Similar to Placebo and Stable Over Time SAE / patient-year in North America Controlled Trials Long-Term Etanercept C11

  12. Serious Infection Rates in Etanercept Patients Similar to Placebo and Stable Over Time Serious Infections / patient-year in North America Controlled Trials Open-label Etanercept C12

  13. PresentationOutline Introduction Dan Burge, MD Etanercept Clinical Profile Pharmacovigilance General Safety Malignancy Epidemiology of Lymphoma in RA Alan Silman, MD Lymphoma and Etanercept Dan Burge, MD Heart Failure Experience Ongoing Pharmacovigilance Summary C13

  14. The Surveillance, Epidemiology, and End Results (SEER) Program • National Cancer Institute’s cancer registry • Data based on 11 population-based cancer registries and 3 supplemental registries • Covers approximately 14% of US population • Provides incidence, prevalence and mortality data for cancers Standardized Incidence Ratio = Observed/Expected C14

  15. *Derived from NCI SEER database, adjusted for age and gender Total Malignancies Not Increased in Clinical Trials Controlled Trials All Trials Control Etanercept Etanercept Observed 5 11 55 Expected* 3.57 8.80 56.2 SIR 1.40 1.25 0.98 C15

  16. Malignancies Rates are Stable Over Time All Etanercept Clinical Trials Malignancies / 100 patient-years C16

  17. SIR with 95% Confidence Intervals for All Malignancies in Clinical Trials All Sites Breast Digestive Respiratory Female Genital Male Genital Urinary System Oropharyngeal Lymphoma Endocrine Skin1 Neurologic Leukemia Myeloma Other 0 1 2 3 4 5 6 7 8 9 10 Risk Ratio 1. Exclude basal cell and squamous cell. C17

  18. PresentationOutline Introduction Dan Burge, MD Etanercept Clinical Profile Pharmacovigilance General Safety Malignancy/Lymphoma Epidemiology of Lymphoma in RAAlan Silman, MD Lymphoma and Etanercept Dan Burge, MD Heart Failure Experience Ongoing Pharmacovigilance Summary C18

  19. Background Epidemiology of Lymphoma in RA Alan Silman, MD Director, Arthritis Research Campaign’s Epidemiology Research Unit University of Manchester Medical School ARC Professor of Rheumatic Disease Epidemiology,University of Manchester Manchester, United Kingdom C19

  20. Components of Lymphoma Risk in Etanercept Treated Patients • Background population risk • Risk attributable to RA per se • Increased risk attributable to severe RA • Increased risk attributable to prior exposure to: • Other immunosuppressives (azathioprine, methotrexate) • Other biologic agents C20

  21. Measures of Risk • Standardized Incidence Ratio = Observed Expected • Attributable (Absolute) Risk = Observed – Expected • Attributable Risk Fraction = Observed – Expected Expected C21

  22. Example • Observed Incidence = 3/1000 pyr • Expected Incidence = 2/1000 pyr • SIR = 3/2 = 1.5 • Absolute Risk = 3/1000 – 2/1000 = 1/1000 pyr • ARF = 3/1000 – 2/1000 = 0.33 (33%) 3/1000 C22

  23. Considerations in Determination of Risk • Background incidence in comparable population • Accurate exposure data • Completeness of follow-up • Population characterization (age, gender, race, etc.) • Disease/treatment characterization • Accurate and complete detection of incident cases • Case ascertainment • Case validation C23

  24. Other Methodological Issues • Lymphoma rare and risk estimates have wide confidence intervals • Surveillance bias – are early lymphomas likely to be due to drug or better detection • Influence of dose • Ever/never, duration etc • Influence of length of follow up • Follow up periods may not have equivalent risk C24

  25. Variation in Lymphoma Incidence:RA Populations C25

  26. Increased Risk of LymphomaIn RA Patients* *Based on data generated prior to the availability of TNF antagonists C26

  27. Available Evidence on Lymphoma • Clinical Trials • Post-Marketing Safety Surveillance • Histology • Conclusions C27

  28. Cases Patient-years Expected SIR 95% Confidence Intervals 6 8336 2.59 2.31 0.85 – 5.03 SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population Lymphoma during clinical trials C28

  29. Cases Patient-years Expected SIR 95% Confidence Intervals 6 8336 2.59 2.31 0.85 – 5.03 SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population Lymphoma during clinical trials Lymphoma SIR by disease duration Time to onset: Median years (range): 2.6 (0.4-4.8) C29

  30. Cases Cases Patient-years Patient-years Expected Expected SIR SIR 95% Confidence Intervals 95% Confidence Intervals 9 6 8336 > 8336 > 2.59 2.59 2.31 < 3.47 0.85 – 5.03 1.59 – 6.59 SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population Lymphoma during clinical trials Lymphoma cases during and after clinical trials completion C30

  31. Cases Cases Patient-years Patient-years Expected Expected SIR SIR 95% Confidence Intervals 95% Confidence Intervals 6 6 8336 8336 2.59 5.70 1.05 2.31 0.85 – 5.03 0.39 – 2.29 SIR for Lymphoma in Etanercept Clinical Trials Relative to RA Population Lymphoma during clinical trials (relative to general population) Lymphoma cases in clinical trials (relative to RA population)* *Benchmark factor of 2.2 for RA population C31

  32. Post-Marketing Lymphoma Reports Reported cases*: 70 / 140,000 pts Reporting rate: 0.3 / 1000 pt-yrs Demographic characteristics of patients Female 69% Mean age 61 years Past or concurrent MTX 60% *Data through November 2, 2002 C32

  33. Lymphoma Reporting Rates from Commercial Experience are Stable Over Time 200 By report date 160 By diagnosis date 120 Reports per 100,000 pt-yrs 80 40 0 11/98-4/99 5/99-10/99 11/99-4/00 5/00-10/00 11/00-4/01 5/01-10/01 11/01-4/02 5/02-10/02 Data through November 2,2002. Error bars represent the upper limit of exact 95% confidence intervals. C33

  34. Clinical Trials and Post-marketing Reports (Pooled) Lymphoma Subtypes *Proportions represented in SEER database C34

  35. Histology of Non-Hodgkin’s Lymphomas Similar to RA Population1 Histology Etanercept Reports2 RA3 Non-RA Controls3 Diffuse large cell 43% 38% 43% Mantle cell 5% 0% 2% Peripheral T cell 8% 2% 4% Follicular 16% 33% 27% Small lymphocytic lymphoma/B-cell CLL 22% 14% 12% Waldenstrom’s Macro. 5% NA NA Marginal zone 0% 7% 0% Other NA 2% 2% 1 Histopathology report available in 67% of lymphoma reports 2 Data through November 2, 2002, combined clinical trials and post-marketing reports 3 Kamel et al. J. Rheum.1999 C35

  36. ConclusionsLymphoma Incidence Consistent with Background RA • Lymphoma reports with etanercept are rare • Comprehensive pharmacovigilance program has been in place for 4-1/2 years • The rate observed in clinical trials is consistent with the expected rate observed for RA (SIR=2.31) • Post-marketing experience is compatible with clinical trial experience • The proportion of histologic subtypes comparable with background • Six years of sustained therapy has revealed no increase in incidence C36

  37. Amgen Initiatives • Update label to describe experience • Submitted October 2002 (Adverse Reactions) • Describes lymphoproliferative disorders from post-marketing and clinical studies • Lymphoproliferative disorders, including lymphoma, have been reported from patients on etanercept • Rates similar to RA population • Presentations at scientific meetings • ACR, Sabath et al, Arth.Rheum., 2002 • EULAR, Sabath et al, Ann Rheum Dis., 2002 • Large, long-term clinical trials • Observational studies / registries in over 12,000 patients • Epidemiologic studies • Safety surveillance of post-marketing reports C37

  38. PresentationOutline Introduction Dan Burge, MD Etanercept Clinical Profile Pharmacovigilance General Safety Malignancy/Lymphoma Epidemiology of Lymphoma in RA Alan Silman, MD Lymphoma and Etanercept Dan Burge, MD Heart Failure Experience Ongoing Pharmacovigilance Summary C38

  39. RENAISSANCE (n = 925) Placebo (n = 309) Etanercept 25mg x biw (n = 308) Etanercept 25mg x tiw (n = 308) RECOVER (n = 1123) Placebo (n = 373) Etanercept 25mg x q wk (n = 375) Etanercept 25mg x biw (n = 375) Etanercept CHF Trials Design Analysis of Combined Data RENEWAL (n = 2048) Trials discontinued after pre-specified interim analysis determined study was unlikely to demonstrate benefit. C39

  40. Etanercept CHF Trials Primary Efficacy Endpoint: All Cause Mortality/CHF Hospitalization UnadjustedAnalysis* Renaissance 25mg vs. placebo (2x/wk) 25mg vs. placebo (3x/wk) Recover 25mg vs. placebo (1x/wk) 25mg vs. placebo (2x/wk) Renewal BIW + TIW vs. placebo RR = 1.21, p = 0.17 RR = 1.23, p = 0.13 RR = 1.01, p = 0.97 RR = 0.87, p = 0.45 RR = 1.10, p = 0.33 0.5 1.0 1.5 2.0 Risk Ratio *Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers) C40

  41. Renaissance: Randomization Imbalances Favor Placebo Group Etanercept Placebo 25 mg biw 25 mg tiw (n = 309) (n = 308) (n = 308) Afib/flutter(%) 29 36 36 CABG (%) 33 42 41 SBP - mm Hg (median) 110 108 105 DBP - mm Hg (median) 68 66 64 Anti-arrhythmics (%) 15 22 21 6-min walk - meters (median) 295 293 288 C41

  42. Etanercept CHF Trials Primary Efficacy Endpoint: All Cause Mortality/CHF Hospitalization Analysis with Covariates* UnadjustedAnalysis* Renaissance 25mg vs. placebo (2x/wk) 25mg vs. placebo (3x/wk) Recover 25mg vs. placebo (1x/wk) 25mg vs. placebo (2x/wk) Renewal BIW + TIW vs placebo RR = 1.21, p = 0.17 RR = 1.09, p = 0.55 RR = 1.11, p = 0.43 RR = 1.23, p = 0.13 RR = 0.98, p = 0.92 RR = 1.01, p = 0.97 RR = 0.90, p = 0.56 RR = 0.87, p = 0.45 RR = 1.01, p = 0.90 RR = 1.10, p = 0.33 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 Risk Ratio Risk Ratio *Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers) C42

  43. 0.0 0.0 2.5 0.5 1.0 1.5 2.0 Etanercept CHF Trials: Analysis of All Cause Mortality (Secondary Efficacy Endpoint) Analysis with Covariates* UnadjustedAnalysis* Renaissance 25mg vs. placebo (2x/wk) 25mg vs. placebo (3x/wk) Recover 25mg vs. placebo (1x/wk) 25mg vs. placebo (2x/wk) Renewal BIW + TIW vs.placebo RR = 1.27, p = 0.24 RR = 1.13, p = 0.55 RR = 1.37, p = 0.12 RR = 1.22, p = 0.33 RR = 0.68, p = 0.16 RR = 0.66, p = 0.13 RR = 0.83, p = 0.47 RR = 0.85, p = 0.55 RR = 1.13, p = 0.39 RR = 0.96, p = 0.79 2.5 0.5 1.0 1.5 2.0 Risk Ratio Risk Ratio *Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers) C43

  44. New Onset CHF in North American Rheumatic Disease Trials Controlled Trials Control 2 Etanercept 2 All Trials Observed 7 Expected1 15.2 1. Kannel WB, J Clin Epidemiol 53 (2000) C44

  45. Etanercept Label Precaution: Patients with Heart Failure Two large clinical trials evaluating the use of ENBREL in the treatment of heart failure were terminated early due to lack of efficacy. Although the studies did not demonstrate harm, there was a suggestion of worse heart failure outcomes with ENBREL treatment in one of the two trials. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL. Physicians should exercise caution when using ENBREL in patients who also have heart failure. C45

  46. Conclusions • Two large heart failure studies were discontinued due to lack of efficacy • One of two studies showed a trend toward worse heart failure outcomes that diminishes with adjustment for covariates • No evidence from rheumatic disease trials that etanercept increases risk for CHF • Proactive communication in product label and at scientific meetings C46

  47. Extensive Proactive Pharmacovigilance • Large, long term clinical trials • Epidemiologic studies • Observational studies and registries • Safety surveillance and post-marketing reports • Proactive risk communication C47

  48. Ongoing and Future Pharmacovigilance Programs C48

  49. Nearing Completion of Post-Marketing Commitment for Long Term Follow-up • Submitted 3 year data: currently labeled • Submitted 4 year data: January 2003 • Plan to submit 5 year data: August 2003 Ongoing Amgen commitment: continued follow-up for additional 5 years for a total of 10 years C49

  50. Etanercept Summary • Unique mechanism of action • Established track record • Over 9 years experience treating rheumatic disease patients • Over 4 years of clinical practice experience • Robust pharmacovigilance program • Safety profile well established • Benefit / risk highly favorable C50

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