Etanercept Immunex BLA 103795/5123

1. EtanerceptImmunexBLA 103795/5123 Arthritis Advisory Committee Bethesda, Maryland June 24, 2003

2. Review Committee • William Tauber, M.D. Chair, Clinical • Chao Wang, PhD Biostatistics • Karen Jones Project Manager • Debra Bower Bioresearch Monitoring • Daniel Kearns Facility Review

3. Indications proposed in current BLA • Enbrel® is indicated for reducing signs and symptoms of ankylosing spondylitis

4. Rationale for Etanercept in AS: I • Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease unknown etiology • Non-Steroidal Anti-inflammatory drugs (NSAIDS) are FDA approved for treatment of signs and symptoms of Ankylosing Spondylitis • Disease Modifying anti-rheumatic drugs (DMARDS(RA)) used for Rheumatoid Arthritis are used in AS but are not FDA approved for use in AS. • Neither NSAIDS nor DMARDS (RA) have been demonstrated to affect the progression of disability with AS.

5. Rationale for Etanercept in AS:II • Tumor necrosis factor (TNF) levels have been shown to be elevated in serum and synovial tissue of patients with AS. • Etanercept is licensed for the treatment of Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis. • AS may share pathogenic mechanisms with these other disorders.

6. Outline of Discussion Topics • Methodology for assessment of short term therapeutic benefit in AS • Phase III trials to investigate the safety and efficacy of etanercept in patients with ankylosing spondylitis • Phase II proof-of-concept trial

7. Ankylosing Spondylitis: Assessment of Short Term Therapeutic Benefit • Assessments in Ankylosing Spondylitis (ASAS) Working Group • 5 domains most important in assessment of short term benefit in AS: • physical function • pain • spinal mobility • spinal stiffness and inflammation • patient’s global assessment.

8. Derivation of ASAS Response Criteria • Analysis of 5 randomized trials of NSAIDS in AS enrolling 1030 patients  6 weeks treatment performed • 4 domains differentiated drug effect from placebo: • Combined into ASAS 20 response criteria • spinal mobility excluded because of lack of responsiveness

9. Phase 3 Protocols: Assessment of Response • Primary Endpoint at end of treatment -ASAS Response Criteria (ASAS 20) at 12/24 wks -An improvement of at least 20%/ 10units Visual Analog Scale (VAS) (0-100mm) in at least 3 of the following domains: o Patient Global Assessment o Average of total and nocturnal pain o BASFI average of 10 questions o BASDAI- average of last 2 questions -Absence of deterioration (20%/10units) in remaining domain

10. Secondary and Other Endpoints • Secondary Endpoints • ASAS 50/70 at 12/24 weeks* • Highest ASAS response achieved • Partial Remission • Other Outcome Endpoints • Individual components of ASAS Instrument • Acute Phase Reactants: ESR, CRP • Spinal Mobility Parameters • Peripheral tender/swollen joint count • Assessor Global Assessment

11. Phase II and III Studies • Phase II • 016.0626 Randomized, double blinded, single center • etanercept 25mg biw vs placebo, 16 weeks (N=40) • Phase III • 016.0037 Randomized, double blinded, multi-center • etanercept 25mg biw vs placebo, 24 weeks (N=277) • 47687 Randomized, double blinded, multi-center etanercept 25 mg biw vs placebo, 12 weeks (N=84)

12. Phase 3 Protocols: Study Population • Inclusion - Men and Women 18-70 years of age -Diagnosis of Ankylosing Spondylitis- mod NY criteria -Active Disease at baseline using (VAS) VAS  30 for avg duration and intensity morning stiffness PLUS VAS  30 for 2 of 3 parameters: -pt global assessment -nocturnal and total back pain -Bath Ankylosing Spondylitis Functional Index (BASFI) 10 question avg VAS

13. Phase 3 Protocols: Study Population • Exclusion -Complete Ankylosis of Spine -DMARDs other than Sulfasalazine, MTX or Hydroxychloroquine -Prednisone >10mg/d or changed w/i 2 weeks baseline -NSAIDS changing

14. Study 016.0037 (Study 1)

15. CSR 016.0037 Clinical Protocol Study Design - n= 277 active AS patients randomized 1:1 Etanercept or placebo for 24 weeks -Randomization stratified for presence of DMARDs (Sulfasalazine, Methotrexate, and Hydroxychloroquine) Dosing -Etanercept 25 mg sc biw or Placebo sc biw

16. CSR 016.0037 Clinical Protocol Primary efficacy analysis - MITT population ( all randomized and 1+ dose given) - ASAS 20 at 12 (and 24 wks) compare etanercept with placebo Cochran-Mantel-Haenszel Test with stratification for DMARDs

17. Study Completion at 12 and 24 wks

18. Demographics 016.0037

19. Baseline Characteristics

20. Extra-Spinal Inflammatory Sx

21. Primary Endpoints

22. ASAS 50 and ASAS 70 • ASAS 50 response computed and analyzed similar to ASAS 20 except that a 50% improvement in 3 of 4 components in addition to 10mm point absolute improvement. Deterioration rules same as ASAS 20 • ASAS 70 similar rules to ASAS 50 except that a 70% improvement needed

23. ASAS 20/50/70 at 12 and 24 weeks 12 weeks 24 weeks

24. Partial Remission • Criteria proposed by ASAS Working Group • Value of <20 (on a VAS scale of 0-100) in each of the four ASAS Response Criteria: • Patient Global Assessment • Average of Nocturnal/total back pain • BASFI • Last 2 questions of BASDAI

25. ASAS Defined-Partial Remission

26. ASAS Individual ComponentsMean Percent Improvement from baseline at 12 wks

27. Acute Phase Reactants Mean (median) values during treatment * P value <0.001

28. DCART 20 and DCART 40 • DCART 20= 4 criteria of ASAS Response Criteria + chest expansion( spinal mobility) and CRP( acute phase reactants). DCART 20 same requirements ASAS20 for first 4, the other two 20% improvement relative to baseline w/o absolute numeric change. DCART 20=5 of 6 improvement, no worsening remaining domain. • DCART 40= uses 4 ASAS Response Criteria but requires 40% improvement relative to baseline plus absolute 20 unit(mm) improvement 3 of 4 w/o worsening remaining domain

29. ASAS DCART 20/40 Exploratory Analysis * P value <0.001

30. ASAS 20/12 weeks Non-Skeletal Inflammatory Condition • Similar response rates to etanercept for patients subsetted by whether they did or did not have a history of: • uveitis or iritis( n= 82) • Inflammatory bowel disease(n=13) • bacterial dysentery, urethritis, Chlamydial infection or sexually transmitted disease(n= 24)

31. ASAS 20 at 12 weeks: Subset with Psoriasis

32. ASAS 20 at 12weeks: Subsetted by Baseline Variables • Similar ASAS 20 response rates at 12 weeks in patients subsetted by : • Race • Weight • Disease Duration • Geographic site

33. Impact of Age upon ASAS 20 at 12 wks Quartiles

34. Impact of Gender on ASAS 20 -12 wks

35. ASAS 20 at 12 weeks: Subsetted by Baseline Disease Severity • Similar effect size for ASAS 20 response rates at 12 weeks for patients above or below the median at baseline for: • Average back pain • Patient global assessment • BASFI • BASDAI • Same effect size in presence or absence of Hip Disease

36. ASAS 20 at 12 weeks prior or concomitant meds • Effect size for etanercept at 12 weeks did not appear to be affected by concomitant use of the following medications: • NSAIDS (n=247) • Corticosteroids (n=36) • DMARDs (n=87) • Sulfasalazine (n=59) • Methotrexate (n=32)

37. ASAS 20 at 12 and 24 weeks HLA B27 positive vs negative

38. Adverse Events all Intensities

39. Important Safety Outcomes

40. Percent Serious Adverse Events

41. Withdrawals for Safety

42. Infections: All Intensities

43. Summary: Efficacy • Etanercept 25mg sc biw was superior to placebo in achievement of ASAS 20 Response Criteria at both 12 and 24 weeks. • Treatment difference is 33% • DMARDS did not appear to affect difference • Prognostic factors potentially associated with lower response • Older Age • Female gender • HLA-B27 antigen negative • Concomitant Psoriasis

44. Summary of Safety • Etanercept 25 mg sc biw: higher observed incidence of certain adverse events compared to placebo • Serious adverse events (7% vs 4%) • Withdrawals for Safety (5% vs 1%) • Grade 3 /4 Adverse Events/ Infections (10% vs 3%) • Of the 7 safety withdrawals among etanercept recipients, 4 were for bowel symptoms, of which 2 were Inflammatory Bowel Disease, one a new diagnosis, the other a recurrence.

45. Study CSR-47687 (Study 2)

46. CSR: 47687 Clinical Protocol • Study Design • N=84 active AS patients randomized 1:1 Etanercept or placebo for 12 weeks • Randomization stratified for DMARDs (Sulfasalazine,Methotrexate,Hydroxychloroquine) • Dosing:Etanercept 25mg sc biw or Placebo • Primary efficacy analysis • MITT population (all randomized and one dose given) • ASAS 20 at 12 wks compare etanercept/placebo Cochran-Mantel-Haenszel test with stratification for DMARDs

47. Study 2 Population : Comparison with Study 1 Population • Study 2 population balanced between study arms, comparable with Study 1 population except : • Lower mean weight 75kg vs 82 kg • Prior use of DMARDs 69% vs 31% in study population 1 • Lower incidence of ocular inflammation16% vs 30%, uveitis 22% vs 30%, higher psoriasis 15% vs 10% study1. The incidence of patients with history of IBD was similar at 6% study 2 vs 5% in study 1

48. Primary Endpoint

49. ASAS-Defined Partial Remission

50. Adverse Events all Intensities