1. 1 Etanercept Immunex BLA 103795/5123 Arthritis Advisory Committee Bethesda, Maryland June 24, 2003

2. 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. 3 Indications proposed in current BLA Enbrel® is indicated for reducing signs and symptoms of ankylosing spondylitis

4. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14 Study 016.0037 (Study 1)

15. 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. 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. 17 Study Completion at 12 and 24 wks Placebo N=139 Etanercept N=138 Patient Statusn/(%) Randomized no drug 3/142 (2)4/142 (3) Completed 12 wks 134 (96)132 (96) Completed 24 wks 120 (86)126 (91) D/C due AE1(1)7 (5) D/C due LOE13 (9)3 (2) Other5 (4)2 (1)

18. 18 Demographics 016.0037 PlaceboEtanercept CharacteristicN=139N=138 Mean Age(yrs)42 Male76% Caucasian91%94% Mean Weight83.1kg82.2kg HLA-B27+84% Duration AS(yrs)1110

19. 19 Baseline Characteristics PlaceboEtanercept CharacteristicN=139N=138 Patient Global63 Pain (avg n+t)6260 BASFI5652 Inflammation6461 Any DMARD31%32% Corticosteroids14%12%

20. 20 Extra-Spinal Inflammatory Sx Symptom/SignPlacebo N=139 Etanercept N=138 Occular Inflam28%32% Conjunctivitis8%7% Uveitis/iritis31%28% Inflammatory Bowel Disease 4%5% Psoriasis11%8%

21. 21 Primary Endpoints Number (%) Achieving ASAS 20 PlaceboEtanercept Parameter N=139N=138P-Value ASAS 20 12 weeks 38 (27)83 (60)<0.0001 ASAS 20 24 weeks 32 (23)80 (58)<0.0001

22. 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. 23 ASAS 20/50/70 at 12 and 24 weeks 12 weeks 24 weeks

24. 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. 25 ASAS Defined-Partial Remission

26. 26 ASAS Individual Components Mean Percent Improvement from baseline at 12 wks

27. 27 Acute Phase Reactants Mean (median) values during treatment PlaceboEtanercept ParameterN=139N=138 ESR/ BL 25 (17)26(23) 12 weeks26(16)13 (9)* 24 weeks26 (19)11 (7)* CRP/BL 2.0(1)1.9 (1) 12 weeks2.0(1)1(0.2)* 24 weeks2.0 (1)<1 (0.3)* * P value <0.001

28. 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. 29 ASAS DCART 20/40 Exploratory Analysis PlaceboEtanercept ParameterN=139N=138 DCART 20n (%) 12 weeks11 (8)51 (37)* 24 weeks10 (7)46 (33)* DCART 40 12 weeks21 (15)59 (43)* 24 weeks18 (13)57 (41)* * P value <0.001

30. 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. 31 ASAS 20 at 12 weeks: Subset with Psoriasis

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

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

34. 34 Impact of Gender on ASAS 20 -12 wks

35. 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. 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. 37 ASAS 20 at 12 and 24 weeks HLA B27 positive vs negative

38. 38 Adverse Events all Intensities Proportions of Patients (n(%) EventPlacebo N=139Etanercept 138 Any Adverse Event105 (76)99 (72) Infections42 (30)57 (41) Injection site reactions13 (9)41 (30) Injection site ecchymosis23 (17)29 (21) Headache16 (12)19 (14) Accidental Injury6 (4)17 (12) Diarrhea13 (9)11 (8) Rash9 (7)11 (8) Dizziness3 (2)8 (6) Rhinitis9 (7)8 (6) Abdominal Pain7 (5)8 (6) Nausea7 (5) Asthenia7 (5)5 (4)

39. 39 Important Safety Outcomes Safety OutcomesPlacebo N=139 n/N % Etanercept N=138 n/N % Serious Adverse Events5 (4)9 (7) Withdrawals for Safety1 (1)7 (5) Grade 3 /4 Adverse Events/ Infections 4 (3)14 (10) Grade 3 /4 Abnormal Laboratory 0 (0)2 (1)

40. 40 Percent Serious Adverse Events Placebo N=139 Etanercept N=138 Totals4%7% Accidents1%2% Infection/Fever1%3% Gastrointestinal0%1%

41. 41 Withdrawals for Safety PlaceboEtanercept Total1 (1%)7 (5%) AE: Overall1 (1%)7 (5%) Accidents0 (0)2 (1%) Infections/Fever0 (0)1(1%) Gastrointestinal0 (0)4 (3%) Psychiatric1 (1%)0 (0)

42. 42 Infections: All Intensities Proportions of Patients (n [%]) PlaceboEtanercept EventN=139N=138 Any Infection42 (30)57 (41) Any Infection not URI28 (20)33 (24) URI16 (12)28 (20) Flu syndrome10 (7)5 (4)

43. 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. 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. 45 Study CSR-47687 (Study 2)

46. 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. 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. 48 Primary Endpoint Number (%) Achieving ASAS 20: Week 12 ParameterPlacebo N=39 Etanercept N=45 Completed 12 weeks 100%96% P-Value ASAS 209 (23)27(60)0.0008

49. 49 ASAS-Defined Partial Remission Placebo N=39 Etanercept N=45 Time pointn/(%)n(%)P-Value Week 124 (10)8(18)0.3 Any time5(13)12 (26)0.1

50. 50 Adverse Events all Intensities Proportions of Patients (n(%) EventPlacebo N=39 Etanercept N=45 Any Adverse Event24 (62)25 (56) Infections13(33)16 (36) Injection site reactions6 (15)15 (33) Injection site ecchymosis4 (10)8 (18) Headache4(10)6 (13) Accidental Injury2 (4)0 (0) Diarrhea2 (5)2 (4) Rash0 (0)2 (4) Dizziness1 (3)1 (2) Abdominal Pain3 (8)1 (2) Nausea4(10)3(7) Asthenia1 (3)5 (11)

51. 51 Important Safety Outcomes Safety OutcomesPlacebo N=39 n/N % Etanercept N=45 n/N % Serious Adverse Events0(0)1 (2) Withdrawals for Safety0 (0) Grade 3 /4 Adverse Events/ Infections 2 (5)4 (9) Grade 3 /4 Abnormal Laboratory 0 (0)1 (2)

52. 52 Study CSR: 016.0626 (Study 3)

53. 53 CSR 016.0626 Clinical Protocol Study Design –N= 40 active AS patients randomized 1:1 to Etanercept or placebo for 16 weeks Dosing: Etanercept 25mg sc biw or placebo

54. 54 CSR 016.0626 Clinical Protocol Primary Efficacy Analysis –MITT population ( all randomized and one dose drug) –20% response at 16 weeks in 3 of 5 Pre-specified Ankylosing Spondylitis Criteria (with one of the improved measures being spinal pain or morning stiffness without worsening in the remaining 2. For patients without joint swelling( one of the 5 measured elements) at baseline, improvement was required in 3 of the remaining 4 elements without concurrent worsening in the remaining one.

55. 55 Five Pre-Specified Measures 1.Patient global assessment-5 point scale over the past week, improvement = decrease of 1 2.Nocturnal spinal pain: 100mm VAS, improvement 20% in # mm 3.Duration of morning stiffness; duration of morning stiffness in minutes on the day preceding clinic visit. 20% fewer or more minutes

56. 56 Five Pre-Specified Measures 4.BASFI 10 questions VAS average 5.Swollen joint score: peripheral joint swelling in 44 diarthrodial joints rated on 4 point scale 0=no swelling, 1=mild, 2=moderate,3 = severe. Improvement defined as decrease in joint swelling by 20% in swelling score. If the swollen joint score was 0 at baseline, any increase in score=worsening

57. 57 Primary Endpoint Primary Endpoint: Number(%) Achieving AS Response Criteria PlaceboEtanerceptP-Value Time pointN=20 Week 125 (25)14 (70)0.01 Week 165 (25)15 (75)0.01

58. 58 Ad hoc Analysis: Modified ASAS 20 at 12/16wks Number(%) Achieving ASAS 20 at 12 and 16 weeks PlaceboEtanercept Time pointN=20 P-Value Week 125 (25)13 (65)<0.05 Week 165 (25)17 (85)<0.05

59. 59 Other Endpoints: Pain Assessment, DSFI, Krupp’s Fatigue Measure at 16 weeks

60. 60 Spinal Mobility (Study 1) Mean Percent Improvement from baseline at 12 weeks * * * *=Nominal p-value <0.05

61. 61 Spinal Mobility (Study 2) Mean Percent Improvement from baseline at 12 weeks * *= Nominal p- value <0.05

62. 62 Spinal Mobility (Study 3) Mean % Improvement from baseline at 12 weeks *= Nominal p- value <0.05

63. 63 Tender and Swollen Peripheral Joints (Study 1) Median Percent Improvement at 12 wks *= Nominal p- value <0.05 *

64. 64 Conclusions: Efficacy Etanercept was demonstrated statistically superior to placebo in 3 trials assessing symptomatic treatment in active Ankylosing Spondylitis (AS). Older age, female gender were associated with lower response rate. –Responses in HLA-B27- negative and concomitant psoriasis patients were also lower but the number of patients with these conditions was small.

65. 65 Conclusions: Methodology Results using ASAS 20 generally demonstrated responses of similar direction and magnitude to previously used measures used in the assessment of therapeutic benefit in AS.

66. 66 Conclusions: Safety Safety profile of etanercept in ankylosing spondylitis similar to that seen in RA and other indications There were more withdrawals for inflammatory bowel disease in etanercept patients compared to placebo recipients in study 1 but numbers were small.