1. Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia, and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Overview of Presentation Cardiovascular findings from COX-2 development FDA conclusions about CV Risk and NSAIDs

3. 3 February 2005 Joint advisory committee meeting with arthritis and drug safety committees Data presented on rofecoxib, celecoxib, lumiracoxib, etoricoxib

4. 4 Vioxx May 20, 1999 Approval of New Drug Application for Vioxx (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and osteoarthritis ~ 5000 subjects ~ 5000 subjects - 700+ at least 1 year (12.5 and 25 mg) - 700+ at least 1 year (12.5 and 25 mg) No cardiovascular signal – small number of events, no dose response No cardiovascular signal – small number of events, no dose response

5. 5 Vioxx - VIGOR Rofecoxib 50 mg daily vs. naproxen 500 mg BID Rofecoxib 50 mg daily vs. naproxen 500 mg BID 8,000 RA patients, no ASA 8,000 RA patients, no ASA Median exposure - 9 months Median exposure - 9 months Endpoints Endpoints –serious GI events –serious CV/thrombotic events

6. 6 Vioxx - VIGOR Cardiovascular risk identified for rofecoxib vs. naproxen  All CV events - RR 2.37  MI - RR 5.0 (20 vs. 4)  Incidence increased over time  Results taken to AC February, 2001

7. 7 Vioxx - Alzheimer’s Disease To slow progression or prevent onset To slow progression or prevent onset 3 placebo-controlled, double-blind, multicenter studies 3 placebo-controlled, double-blind, multicenter studies Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 15-24 months 15-24 months N=~2800 patients N=~2800 patients No consistent cardiovascular signal No consistent cardiovascular signal

8. 8 Vioxx - APPROVe Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas Randomized, placebo-controlled, double-blind, 3 years + 1 year Randomized, placebo-controlled, double-blind, 3 years + 1 year Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 2586 patients 2586 patients

9. 9 Vioxx - APPROVe September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe  All CV events – RR 1.8  MI – RR 2.5  Ischemic CVA – RR 1.8 September 30, 2004 – Merck withdraws Vioxx from the market

10. 10 Vioxx – APPROVe Effect of ASA on APTC Vioxx 25 mgPlacebo All patientsN=1287 3053 pt-yrs N=1300 3322 pt-yrs n Rate/100 pt-yrs 59 1.9 34 1.0 Non-ASA UsersN=1074N=1096 n Rate/100 pt-yrs 43 1.7220.8 ASA UsersN=213N=204 n Rate/100 pt-yrs 15 3.1 12 2.3

11. 11 Celebrex December 31, 1998 Approval of New Drug Application for Celebrex (celecoxib) for the signs and symptoms of osteoarthritis (200 mg/day) and rheumatoid arthritis 200- 400 mg/day) N= 9600 patients N= 9600 patients No CV signal with initial application No CV signal with initial application

12. 12 Celebrex - CLASS CLASS Double-blind, active-controlled, 1 year Double-blind, active-controlled, 1 year ~ 8,000 patients with OA or RA, ASA if indicated ~ 8,000 patients with OA or RA, ASA if indicated Celecoxib 400 mg twice daily Celecoxib 400 mg twice daily Endpoint – serious GI events Endpoint – serious GI events No cardiovascular signal vs. ibuprofen 800 mg TID or diclofenac 75 mg BID No cardiovascular signal vs. ibuprofen 800 mg TID or diclofenac 75 mg BID

13. 13 CLASS Myocardial Infarction CelecoxibDiclofenacIbuprofen All patientsN=3987 2340 pt-yrs N=1996 1080 pt-yrs N=1985 1122 pt-yrs n Rate/100 pt-yrs 19 0.8 4 0.4 9 0.8 Non-ASA UsersN=3105N=15511573 n Rate/100 pt-yrs 6 0.320.220.2 ASA UsersN=882N=445N=412 n Rate/100 pt-yrs 13 2.5 2 0.8 7 2.8

14. 14 Celebrex - APC APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib) Double-blind, placebo-controlled, 3 years, over 1900 patients, ASA use by ~30% Double-blind, placebo-controlled, 3 years, over 1900 patients, ASA use by ~30% –Celebrex 400 mg twice daily (N=671) –Celebrex 200 mg twice daily (N=685) –Placebo (N=679)

15. 15 Celebrex - APC December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo Death from CV causes, MI, or stroke – –celecoxib 200 mg bid vs. placebo RR 2.5 – –celecoxib 400 mg bid vs. placebo RR 3.4

16. 16 Incidence of Hierarchical Cardiovascular Composite Endpoints in the APC Trial EndpointNumber of patients (%)Rate/100 pt-yrs Placebo 200 mg BID 400 mg BID Placeb o 200 mg BID 400 mg BID Death from CV causes1 (0.1)3 (0.4)6 (0.9)0.050.140.29 Death from CV causes or MI 4 (0.6)12 (1.8)15 (2.2)0.190.580.74 Death from CV causes, MI, or stroke 6 (0.9)15 (2.2)20 (3.0)0.290.730.99 Death from CV causes, MI, stroke, or heart failure 7 (1.0)16 (2.3)23 (3.4)0.340.780.11 Solomon SD, et al: N Engl J Med 352, 2005

17. 17 Hazard Ratios for Hierarchical CV Composite Endpoints in the APC Trial Solomon SD, et al: N Engl J Med 352, 2005 EndpointHazard Ratio with 95% CI* 200 mg BID400 mg BID Death from CV causes3.0 (0.3-28.6)6.1 (0.7-50.3) Death from CV causes or MI3.0 (1.0-9.3)3.8 (1.3-11.5) Death from CV causes, MI, or stroke2.5 (1.0-6.4)3.4 (1.4-8.5) Death from CV causes, MI, stroke, or heart failure 2.3 (0.9-5.5)3.4 (1.4-7.8) *Relative to placebo

18. 18 Celebrex - APC Solomon SD, et al: N Engl J Med 352, 2005 *In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure 671

19. 19 Celebrex - PreSAP Celecoxib in Adenoma Prevention Double-blind, placebo-controlled, 3 years, over 1900 patients Double-blind, placebo-controlled, 3 years, over 1900 patients –Celebrex 400 mg once daily –Placebo ASA use by ~16% ASA use by ~16%

20. 20 Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial EndpointPlacebo n (%) 400 mg n (%) Hazard Ratio with 95% CI* Death from CV causes4 (0.6)2 (0.2)0.3 (0.1, 1.8) Death from CV causes or MI7 (1.1)11 (1.2)1.1 (0.4, 2.7) Death from CV causes, MI, or stroke 12 (1.9)19 (2.0)1.1 (0.5, 2.2) Death from CV causes, MI, stroke, or heart failure 12 (1.9)20 (2.1)1.1 (0.6, 2.3) *Relative to placebo

21. 21 Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial EndpointPlacebo N = 628 n (%) 400 mg N = 933 n (%) Hazard Ratio with 95% CI* Death from CV causes4 (0.6)2 (0.2)0.3 (0.1, 1.8) Death from CV causes or MI7 (1.1)11 (1.2)1.1 (0.4, 2.7) MI3 (0.4)9 (1.0) *Relative to placebo

22. 22 Celebrex - ADAPT Alzheimer’s prevention study December 17, 2004 – ADAPT trial halted December 17, 2004 – ADAPT trial halted Celecoxib 200 mg bid, naproxen 220 mg bid, placebo N=~2500 patients Cardiovascular risk not found for celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo was suggested.

23. 23 TARGET Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial 52 weeks 52 weeks 18,000 patients with osteoarthritis 18,000 patients with osteoarthritis Two sub-studies: Two sub-studies: –0117: lumiracoxib 400 mg, naproxen 500 mg bid –2332: lumiracoxib 400 mg, ibuprofen 800 mg tid 25% of patients on low dose aspirin (ASA) 25% of patients on low dose aspirin (ASA)

24. 24 TARGET Confirmed & Probable APTC Events LUMNaprLUMIbu N4741473043764397 Pt-yr at risk 3639353432423090 APTC40 27 271921 CV Death 118810 All MI Rate/100 pt-yr 18 (0.49) 10(0.28) 5 (0.15) 7 (0.22) All Ischemic/hem stroke 161289

25. 25 TARGET Confirmed /Probable APTC Endpoint KM plot (%) TARGET Confirmed /Probable APTC Endpoint KM plot (%) Study 0117 Study 2332

26. 26 Epidemiological Studies Consistent risk associated with high dose rofecoxib Variable findings of risk associated with other selective and nonselective NSAIDs

27. 27 FDA Conclusions April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk” April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk” http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf

28. 28 FDA Conclusions “The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with an increased risk of serious adverse CV events compared to placebo. The available data do not permit a rank ordering of these drugs with regard to CV risk.”

29. 29 FDA Conclusions “Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs. ”

30. 30 FDA Regulatory Actions April 7, 2005 Boxed warning all Rx NSAIDs Boxed warning all Rx NSAIDs – Potential increased risk serious CV events – May be higher with prior history of CV disease/risk – Added GI warnings to box – Contraindication perioperative CABG

31. 31 FDA Regulatory Actions Class Medication Guide for all Rx NSAIDs Class Medication Guide for all Rx NSAIDs Revised warnings for OTC NSAIDs Revised warnings for OTC NSAIDs

32. 32 Information Request Review of all clinical trial data from controlled studies Review of all clinical trial data from controlled studies Unable to draw conclusions Unable to draw conclusions –Small sample size, even with pooling –Very small number of CV events –Short duration of treatment

33. 33

34. 34 Additional slides

35. 35 TARGET Confirmed & Probable MI by ASA Use LUMNapLUMIbu Overall Population N 4741473043764397 All MI n All MI n Rate/100 pt-yr 180.49100.2850.1570.23 Non-ASA Users N 3549353734013431 All MI n Rate/100 pt-yr 100.3640.1540.1650.21 ASA Users N 11921193975966 All MI n Rate/100 pt-yr 80.9160.6710.1420.30

36. 36 TARGET New Analysis -2007 Farkouh et. al. Annals of Rheumatic Disease, 2007 Apr 5; [Epub ahead of print] Post hoc analysis stratified by BL CV risk, treatment assignment and low-dose ASA use Primary composite endpoint – CV mortality, nonfatal MI, stroke at 1 year Secondary – congestive heart failure

37. 37 TARGET New Analysis -2007 Composite endpoint – CV mortality, nonfatal MI, stroke LUMNapLUMIbu High Risk/ASA Usersn=541n=505n=394n=373 %1.481.580.252.14 High Risk/No ASA n=318n=335n=326n=250 %1.5700.920.80 Low Risk/ASA Users n=651n=688 n= 581 n= 593 %1.540.730.860.34 Low Risk/No ASA n=3231n=3202 n= 3075 n= 3181 %0.530.440.330.35