ndas 21-389/772 etoricoxib robert b. shibuya, m.d. medical officer division of anesthesia,...
TRANSCRIPT
NDAs 21-389/772Etoricoxib
Robert B. Shibuya, M.D.Medical Officer
Division of Anesthesia, Analgesia, and Rheumatology Products
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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