NDAs 21-389/772Etoricoxib

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

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Efficacy-dose response at 6 weeks

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Efficacy-dose response over 14 weeks

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

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Efficacy-representative plot, Study 077-WOMAC pain

Etoricoxib Safety Program

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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

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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

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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: 5-120– Collected data for all AEs– ASA/GPAs sometimes permitted, sometimes

not

Cardiovascular Safety

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CV Safety-APTC EndpointPooled MEDAL Program

Analysis population

Treatment Rate

(per 100PYR) 95% CI

Relative Risk (95%

CI)

ITT Etoricoxib 0.83 (0.75,0.93)

1.02 (0.87,1.18)

ITT Diclofenac 0.82 (0.73,0.91)

Per Protocol

Etoricoxib 0.84 (0.73,0.95)

0.96 (0.79,1.16)

Per Protocol

Diclofenac 0.87 (0.76,1.00)

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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)

60 0.76 (0.64,0.91)

0.71

(0.59,0.85)

1.07 (0.83,1.37)

90 0.91

(0.74,1.11)

0.70

(0.56,0.88)

1.30 (0.96,1.75)

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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

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Attributable Risk-MEDAL Data-APTC/OA only

Treatment N n/PYR Rate (per 100 PYR) (95% CI)

Relative Risk

Δ in risk (in 100 person-year)

(95% CI)

Etoricoxib 12,533 231/28175 0.82 (0.72,0.93)

1.15 (0.95,1.40)

0.11 (-0.035,0.25)

Diclofenac 12,380 198/27856 0.71 (0.62,0.82)

Etoricoxib

90 mg

5,764 99/10894 0.91 (0.74,1.11)

1.30 (0.96,1.75)

0.20 (-0.034,0.44)

Matched Diclofenac

5,680 76/10789 0.70 (0.56,0.88)

Etoricoxib

60 mg

6,769 132/17280 0.76 (0.64,0.91)

1.07 (0.84,1.37)

0.049 (-0.13,0.23)

Matched Diclofenac

6,700 122/17067 0.71 (0.59,0.85)

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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

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CV safety-non-MEDALTreatment N Cases/PYR* Rate (95% CI)‡ Relative Risk**

(95% CI)

Etoricoxib 3940 7/810 0.86 (0.35,1.78) 1.95 (0.37,19.19)

Placebo 2337 2/450 0.44 (0.05,1.60)

Etoricoxib 2147 11/1817 0.61 (0.30,1.08) 0.80 (0.25,2.59)

Non-Naproxen NSAIDs

1470 4/649 0.62 (0.17,1.58)

Etoricoxib 1960 27/2481 1.09 (0.72,1.58) 2.72 (1.18,6.27)

Naproxen 1497 7/1728 0.41 (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

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GI Event Adjudication

• Categorize– Confirmed vs. unconfirmed– Complicated vs. not complicated

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UGI Safety-MEDAL-Confirmed Cases only

Etoricoxib (N = 17,412-26,388 PYR)

Diclofenac (N = 17,289 – 25,378 PYR)

Definition of event

# of events

Rate 95% CI # of events

Rate 95% CI

Complicated only

78 0.30 0.23, 0.37 82 0.32 0.26, 0.40

Combined 176 0.67 0.57,0.77 246 0.97 0.85,1.10

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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 38 175 32 249

Perforation 5 5 11 11

Obstruction 2 2 2 2

Hemorrhage 70 78 71 76

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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

Rate 95% CI # of events

Rate 95% CI

Complicated only 77 0.29 0.23, 0.36 87 0.34 0.27, 0.42

Combined 84 0.32 0.25,0.39 96 0.38 0.31,0.46

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UGI safety-non-MEDAL, confirmed PUBs only-

Treatment n/N (%) Person-years

Rate* 95% CI for Rate

Relative Risk**

95% CI for RR

Complicated only

Etoricoxib 19/4107 (0.46)

4300 0.44 (0.27,0.69) 0.57 (0.31,1.07)

Nonselective NSAIDs

23/2967 (0.78)

2378 0.97 (0.61,1.45)

Combined

Etoricoxib 40/4107 (0.97)

4294 0.93 (0.67,1.27) 0.47 (0.31,0.72)

Nonselective NSAIDs

55/2967 (1.85)

2373 2.32 (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 0.546.

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UGI safety benefit largely driven by comparison to naproxen

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GI tolerability-MEDAL

Renovascular Safety

27Neaton et al. Arch Inter Med 1992

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

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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

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RV safety - MEDAL - HTN

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RV safety – MEDAL - Edema

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RV safety – MEDAL - CHF

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RV safety - MEDAL – Lab Events

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RV safety-Non-MEDAL (placebo-controlled)

Cohort N HTN-related AE (%) Edema-related AE (%)

Placebo 1035 2.9 1.8

E < 30 231 1.3 3.0

E 30 1014 3.7 3.6

E 60 558 4.8 2.9

E 90 220 5.0 1.8

E 120 288 6.6 3.1

Naproxen 494 4.0 2.8

Ibuprofen 756 6.3 4.6

Celecoxib 200 488 1.2 3.3

Celecoxib 400 107 1.9 2.8

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RV Safety-Non-MEDAL (6 & 12-mo AC)

6-mo AC 12-mo AC

Cohort N Edema-related AE

(%)

HTN-related AE

(%)

Edema-related AE

(%)

HTN-related AE

(%)

E 30 474/55 5.3 5.7 3.6 7.3

E 60 508 5.3 11.8

E 90 112 7.1 9.8

C 200 488 4.9 2.3

N 1000 439 6.4 8.4

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Hepatic Safety

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Hepatic safety-MEDAL

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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.

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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.

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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).

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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.

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Spacer

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Efficacy-representative plot, Study 071-WOMAC pain

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Efficacy-representative plot, Study 019-WOMAC Pain

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Attributable Risk-MEDAL Data-APTC/Pooled data and RA only

Treatment Patient

Population

n/PYR Rate (per 100 PYR) (95% CI)

Relative Risk

Δ in risk (in 100 person-year)

(95% CI)

Etoricoxib MEDAL

Program

332/39894 0.83 (0.73,0.91)

1.02 (0.87,1.18)

0.01 (-0.11,0.14)

Diclofenac 325/39623 0.82 (0.73,0.91)

Etoricoxib

60/90 mg

MEDAL Study

265/31469 0.84 (0.74,0.95)

1.08 (0.91,1.28)

0.06 (-0.08,0.20)

Matched Diclofenac

245/31243 0.78 (0.69,0.89)

Etoricoxib

90 mg

RA Patients

101/11717 0.86 (0.70,1.05)

0.80 (0.62,1.04)

-0.22 (-0.05,0.003)

Matched Diclofenac

127/11767 1.08 (0.90,1.28)

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Mean change in SBP from baseline