NDAs /772 Etoricoxib Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products

2 Efficacy 30 mg dose –Four Phase 3 studies (2 vs. placebo and ibuprofen, 2 vs. placebo and celecoxib) –All positive 60 mg dose –Two Phase 3 studies (both vs. placebo and naproxen) –Both positive

3 Efficacy-dose response at 6 weeks

4 Efficacy-dose response over 14 weeks

5 Cross-study comparison of etoricoxib efficacy at 30 and 60 mg

6 Efficacy-representative plot, Study 077-WOMAC pain

Etoricoxib Safety Program

8 MEDAL Program MEDAL/EDGE/EDGE II Studies R, DB, AC, PG trials of the “large simple” design –MEDAL enrolled OA/RA –EDGE enrolled OA –EDGE II enrolled RA Active control = diclofenac 150 mg/day Etoricoxib dosed at 60 or 90 mg/day

9 MEDAL Program Endpoints –MEDAL = CV –EDGE/EDGE II = GI All used identical adjudication procedures N = 34,701, mean f/u = 20,19, and 9 months EDGE/EDGE II collected data on less severe AEs ASA/GPAs permitted

10 Non-MEDAL database Comprised of 18 conventional Phase 2/3 studies –Populations: OA, RA, AS, CLBP –N = ~4,500 –Duration: 4 to 52 weeks –Controls: Placebo, Ibuprofen, Diclofenac, Naproxen, Celecoxib –Doses of etoricoxib: –Collected data for all AEs –ASA/GPAs sometimes permitted, sometimes not

Cardiovascular Safety

12 CV Safety-APTC Endpoint Pooled MEDAL Program Analysis population TreatmentRate (per 100PYR) 95% CI Relative Risk (95% CI) ITTEtoricoxib0.83 (0.75,0.93) 1.02 (0.87,1.18) ITTDiclofenac0.82 (0.73,0.91) Per Protocol Etoricoxib0.84 (0.73,0.95) 0.96 (0.79,1.16) Per Protocol Diclofenac0.87 (0.76,1.00)

13 CV Safety – MEDAL – APTC (by dose, OA only), ITT population Etoricoxib dose mg Etoricoxib Rate per 100 PYR (95% CI) Matched Diclofenac Rate per 100 PYR (95% CI) Relative Risk (95% CI) (0.64,0.91) 0.71 (0.59,0.85) 1.07 (0.83,1.37) (0.74,1.11) 0.70 (0.56,0.88) 1.30 (0.96,1.75)

14 Relative vs. Attributable Risk Relative Risk = Quotient of the rate in Group A and the rate in Group B (estimated by Cox Proportional Hazards Model) Attributable Risk = Arithmetic difference in rates between Groups A & B

15 Attributable Risk-MEDAL Data- APTC/OA only TreatmentNn/PYRRate (per 100 PYR) (95% CI) Relative Risk Δ in risk (in 100 person-year) (95% CI) Etoricoxib12,533231/ (0.72,0.93) 1.15 (0.95,1.40) 0.11 (-0.035,0.25) Diclofenac12,380198/ (0.62,0.82) Etoricoxib 90 mg 5,76499/ (0.74,1.11) 1.30 (0.96,1.75) 0.20 (-0.034,0.44) Matched Diclofenac 5,68076/ (0.56,0.88) Etoricoxib 60 mg 6,769132/ (0.64,0.91) 1.07 (0.84,1.37) (-0.13,0.23) Matched Diclofenac 6,700122/ (0.59,0.85)

16 Mortality/Morbidity based on Attributable Risk Subgroup Analysis Based on the point estimate, if etoricoxib were prescribed to 1,000,000 patients: –490 excess patients would experience an APTC event on etoricoxib 60 mg than if they had taken diclofenac. –High estimate (upper limit of the 95% CI) - 2,300 excess events could occur compared to diclofenac treatment –Low estimate (lower limit of the 95% CI) – 1,300 fewer events could occur compared to diclofenac treatment

17 CV safety-non-MEDAL TreatmentNCases/PYR*Rate (95% CI)‡Relative Risk** (95% CI) Etoricoxib39407/ (0.35,1.78)1.95 (0.37,19.19) Placebo23372/ (0.05,1.60) Etoricoxib214711/ (0.30,1.08)0.80 (0.25,2.59) Non-Naproxen NSAIDs 14704/ (0.17,1.58) Etoricoxib196027/ (0.72,1.58)2.72 (1.18,6.27) Naproxen14977/ (0.16,0.83) * Patient-years at risk ‡ Per 100 PYR ** Relative risk using Cox model stratified by therapeutic block where the number of cases is at least 11, otherwise relative risk is ratio of rates

Gastrointestinal Issues

19 GI Event Adjudication Categorize –Confirmed vs. unconfirmed –Complicated vs. not complicated

20 UGI Safety-MEDAL-Confirmed Cases only Etoricoxib (N = 17, ,388 PYR) Diclofenac (N = 17,289 – 25,378 PYR) Definition of event # of events Rate95% CI# of events Rate95% CI Complicated only , , 0.40 Combined , ,1.10

21 UGI Safety-MEDAL-Confirmed Cases only Etoricoxib (N = 17,412 – 26,388 PYR) Diclofenac (N = 17,289 – 25, 378 PYR) Specific Event# events complicated only # events combined # events complicated only # events combined Ulceration Perforation5511 Obstruction2222 Hemorrhage

22 LGI Safety-MEDAL-Confirmed Cases only Etoricoxib (N = 17,412-26,382 PYR) Diclofenac (N = 17,289 – 25,386 PYR) Definition of event# of events Rate95% CI# of events Rate95% CI Complicated only , , 0.42 Combined , ,0.46

23 UGI safety-non-MEDAL, confirmed PUBs only- Treatmentn/N (%)Person- years Rate*95% CI for Rate Relative Risk** 95% CI for RR Complicated only Etoricoxib19/4107 (0.46) (0.27,0.69)0.57(0.31,1.07) Nonselective NSAIDs 23/2967 (0.78) (0.61,1.45) Combined Etoricoxib40/4107 (0.97) (0.67,1.27)0.47(0.31,0.72) Nonselective NSAIDs 55/2967 (1.85) (1.75,3.02) *Number of events per 100 person-years **Relative risk was calculated using a Cox model stratified by protocol and with terms for treatment and the 3 risk factors. The p-value for testing the proportionality assumption is

24 UGI safety benefit largely driven by comparison to naproxen

25 GI tolerability-MEDAL

Renovascular Safety

27 Neaton et al. Arch Inter Med 1992

28 Prospective Studies Collaboration Lancet 2002 (Stroke mortality, left panel, IHD mortality, right panel)

29 Renovascular Safety Program Effects on Blood Pressure –Discontinuations for HTN-related AEs –HTN-related AEs –Mean difference in baseline for systolic and diastolic BP –Proportions meeting prespecified increases in systolic and diastolic BP Congestive Heart Failure Edema Pertinent laboratory abnormalities

30 RV safety - MEDAL - HTN

31 RV safety – MEDAL - Edema

32 RV safety – MEDAL - CHF

33 RV safety - MEDAL – Lab Events

34 RV safety-Non-MEDAL (placebo-controlled) CohortNHTN-related AE (%)Edema-related AE (%) Placebo E < E E E E Naproxen Ibuprofen Celecoxib Celecoxib

35 RV Safety-Non-MEDAL (6 & 12-mo AC) 6-mo AC12-mo AC CohortNEdema- related AE (%) HTN- related AE (%) Edema- related AE (%) HTN- related AE (%) E 30474/ E E C N

36 Hepatic Safety

37 Hepatic safety-MEDAL

38 Summary of Efficacy Findings Etoricoxib is effective at doses of 30 and 60 mg/day. One Phase 2 clinical trial shows some evidence of dose response between 5 and 60 mg with wide confidence intervals after 6 weeks of treatment. The differences between doses diminish as the study progressed beyond 6 weeks. Cross-study comparisons do not show evidence of added benefit for the 60 mg dose.

39 Summary of Safety Findings Cardiovascular thromboembolic events –As assessed by relative risk, the pooled MEDAL data show comparable CV risk versus diclofenac. –However, given the 95% CI, the attributable risk for etoricoxib compared to diclofenac could be as high as 2,300 excess events per million patient-years. –The non-MEDAL database suggests that etoricoxib is inferior to naproxen.

40 Summary of Safety Findings Renovascular Safety –Etoricoxib 90 mg causes more hypertension, edema, and congestive heart failure than diclofenac. –Etoricoxib 60 mg causes more hypertension and slightly more edema and CHF than diclofenac. –Compared to other NSAIDs (celecoxib, ibuprofen, and naproxen), 30 and 60 mg of etoricoxib appears mixed for renovascular safety (conclusions less robust due to relatively low exposures compared to diclofenac).

41 Summary of Safety Findings Gastrointestinal events –For medically significant upper GI events, etoricoxib approximates diclofenac and appears to be superior to naproxen. –For nonserious GI-related symptoms, etoricoxib is superior to diclofenac and naproxen.

42 Spacer

43 Efficacy-representative plot, Study 071-WOMAC pain

44 Efficacy-representative plot, Study 019- WOMAC Pain

45 Attributable Risk-MEDAL Data- APTC/Pooled data and RA only TreatmentPatient Population n/PYRRate (per 100 PYR) (95% CI) Relative Risk Δ in risk (in 100 person-year) (95% CI) EtoricoxibMEDAL Program 332/ (0.73,0.91) 1.02 (0.87,1.18) 0.01 (-0.11,0.14) Diclofenac325/ (0.73,0.91) Etoricoxib 60/90 mg MEDAL Study 265/ (0.74,0.95) 1.08 (0.91,1.28) 0.06 (-0.08,0.20) Matched Diclofenac 245/ (0.69,0.89) Etoricoxib 90 mg RA Patients 101/ (0.70,1.05) 0.80 (0.62,1.04) (-0.05,0.003) Matched Diclofenac 127/ (0.90,1.28)

46 Mean change in SBP from baseline