ndas 21 389 772 etoricoxib n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
NDAs 21-389/772 Etoricoxib PowerPoint Presentation
Download Presentation
NDAs 21-389/772 Etoricoxib

Loading in 2 Seconds...

play fullscreen
1 / 46
gabi

NDAs 21-389/772 Etoricoxib - PowerPoint PPT Presentation

1 Views
Download Presentation
NDAs 21-389/772 Etoricoxib
An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. 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

  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

  7. 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: 5-120 • Collected data for all AEs • ASA/GPAs sometimes permitted, sometimes not

  11. Cardiovascular Safety

  12. CV Safety-APTC EndpointPooled MEDAL Program

  13. CV Safety – MEDAL – APTC(by dose, OA only), ITT population

  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

  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 * 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

  18. Gastrointestinal Issues

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

  20. UGI Safety-MEDAL-Confirmed Cases only

  21. UGI Safety-MEDAL-Confirmed Cases only

  22. LGI Safety-MEDAL-Confirmed Cases only

  23. UGI safety-non-MEDAL, confirmed PUBs only- *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.

  24. UGI safety benefit largely driven by comparison to naproxen

  25. GI tolerability-MEDAL

  26. 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)

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

  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

  46. Mean change in SBP from baseline