1. COX-2 & 2x: Improved Safety? James Witter, M.D., Ph.D. CLASS/VIGOR-AAC Feb. 7-8, 2001

2. 100 years of NSAIDs “Aspirin” first synthesized - 1899 First endoscopic evidence of gastric mucosal damage by aspirin - 1938 New “safer NSAIDs” developed - 1970’s Cox-2 discovered - 1992 First “COX-2” approved - 1998 First “large and simple” safety trials - 2001

3. NSAIDs/COX-2 and FDA (Arthritis Advisory Committee meetings) Dec. 2, 1986 –“GI paragraph” databases discussed October 11-12, 1995 –Revisions for NSAID class label –Citizen’s Petition-piroxicam March 24, 1998 –NSAID/COX-2 Safety Issues December 1, 1998 (Celebrex approval) April 20, 1999 (Vioxx approval) February 7-8, 2001 (long-term safety)

4. GI paragraph Serious UGI toxicity with/without warning Only one in five (20%) with serious UGI event with warning symptoms Patients “at risk” (i.e. prior ulcer or bleed, older age, medications, poor health…) Trends, and risk, continue Minimize risk by lowest dose, shortest time

5. “Clinically Relevant Events” “It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year”. FDA, GI template warning label NSAID-induced gastropathy may result in 107,000 hospitalizations and 16,500 deaths ARAMIS ‘98

6. NSAIDs: Safety Toxicity, both dose and duration dependent, involve a variety of organ systems as: –adverse events (AEs) mild moderate severe –serious adverse events (SAEs) –death

7. NSAID template General structure for NSAIDs; describes precautions, warnings, adverse reactions: –GI tract –liver –kidney/fluid retention/edema –anaphylactoid reactions –hematological effects –skin...

8. NSAID template: liver Metabolic effects of hepatic insufficiency Elevations in AST or ALT (1%  3x ULN) Rare cases of severe (some fatal) reactions: –jaundice –fulminant hepatitis –liver necrosis –hepatic failure

9. NSAID template: kidney PD effects of renal failure or dehydration Effects on blood pressure (HTN) Fluid retention and edema in some settings Severe reactions such as: renal papillary necrosis interstitial nephritis renal failure

10. NSAID template: skin Adverse events including: –photosensitivity –urticaria –severe (some fatal) reactions such as: Stevens-Johnson syndrome toxic epidermal necrolysis erythema multiforme

11. NSAIDs: Efficacy Osteoarthritis (OA) –signs and symptoms –NOT structure or disability (draft guidance) Rheumatoid arthritis (RA) –signs and symptoms –NOT structure, function, remission (guidance) Acute pain and dysmenorrhea Other indications (AS, gout…)

12. COX-2: Early hopes “Some experts believe they could become the ‘holy grail’ that has eluded arthritis researchers for decades: medicines that not only ease pain, but actually slow the disease’s debilitating progression. ‘These could arrest the course of the disease,’ ” Wall Street Journal May, 1996

13. AAC: March 24, 1998 (Safety/Toxicity Issues: COX-2) Questions to AAC Degree to which endoscopic studies can distinguish between currently available NSAIDs Degree of correlation with clinical outcomes Some comments Endoscopic studies generally under powered The measurable (endoscopic) drives out the important (clinical outcomes) Endoscopy “surrogate” for long-term outcomes

14. GI warning: COX-2 changes? Removal: –Requires “equivalence to placebo”, mutually defined and agreed Major Revision: –Requires substantial, reproducible evidence (endoscopic, clinical endpoints) of superiority over NSAIDs (? three, mutually agreed)

15. Importance of Words Equivalent to placebo Saying two treatments are “similar” does not necessarily mean they are the “same”. Statistically speaking, failing to show a “difference” is not showing “equivalence”. Equivalence requires that the hypothesis “treatment x and y are different” be rejected in a trial designed for this purpose.

16. COX-2: Safety Advantage? (mechanism-based?) COX-2 Absent Platelets Result A (+) Possible Stomach Result B (±) COX-2 Present Kidneys Result C (-)

17. COX-2 agents: Different? Class –How many agents define a class? More potent inhibitors Label –Revise NSAID template or write new? Theory or Drug –In trials, testing the drug, the theory, or both?

18. COX-2 agents: Future? Other indications? –structural modification in OA or RA –prophylaxis of colon cancer –prophylaxis of Alzheimer’s disease New “unique” adverse events? Safety and efficacy in children?

19. Celebrex® December 30, 1998 NDA 20-998 (Celecoxib) 452 volumes x 400 pages/volume = 180,800 pages !!!

20. Celebrex-NDA: OA Celebrex: at 100 to 200 mg BID > placebo no obvious efficacy advantage of 200 mg BID 100 mg BID ~ 200 mg QD Comparable to Naproxen 500 mg BID Most patients (~70%) increase dose in open-label experience (dose creep)

21. Celebrex-NDA: RA Celebrex: at 100 to 400 mg BID > placebo no obvious efficacy advantage of 400 mg BID Comparable to Naproxen 500 mg BID Most patients (~70%) increase dose in open-label experience (dose creep)

22. Celebrex-NDA: Pain No labeled indication for acute pain and dysmenorrhea

23. Celecoxib versus COX-2: (Efficacy Characteristics?) Analgesics efficacy < NSAIDs for acute pain ? Is this a problem with: pain models selected? nature of acute vs. chronic pain (COX-2 induction)? related to potency/selectivity of celecoxib? In short-term studies, no efficacy advantage compared to NSAIDs for OA and RA. Will there be any difference in long-term outcomes?

24. Vioxx-NDA: OA Vioxx: at 12.5 and 25 mg QD > placebo no obvious efficacy advantage of 25 mg dose Comparable to: ibuprofen 800 mg TID diclofenac 50 mg TID No open-label experience for dose-creep

25. Vioxx-NDA: RA No data submitted in NDA

26. Vioxx-NDA: Pain Vioxx indicated for acute pain and dysmenorrhea: at 50 mg daily (5-day studies) > placebo

27. COX-2 Efficacy Signs and Symptoms of: –Osteoarthritis (Celebrex, Vioxx) –Rheumatoid arthritis (Celebrex; the ‘x’ dose) Acute pain and dysmenorrhea (Vioxx) FAP (Celebrex; the 2x dose) –Familial Adenomatous Polyposis Adjunctive therapy

28. Long-Term Safety Despite their long history of usage, no NSAID has been tested in a “large and simple” long-term safety trial at doses exceeding the upper limit (i.e. 2x) of approved labeling in arthritis

29. COX-2: 2001+

30. CLASS C elecoxib L ong-term A rthritis S afety S tudy

31. CLASS: basics-1 Two protocols (035 and 102) 035: Ibuprofen-800 mg TID 102: Diclofenac-75 mg BID Celecoxib 400 mg BID 2x upper dose in RA Dose approved for FAP 386 sites (US/Canada) with 7968 patients

32. CLASS: basics-2 Inclusion –Age to give written informed consent –OA or RA for 3 months requiring NSAIDs –Not pregnant Exclusion –Active malignancy, GI disease/ulceration –Significant renal, hepatic or coagulation defect –AST/ALT > 1.5x ULN

33. CLASS-Baseline demographics Mean/median age ~60 years –about 11% age75 years or older Most white females Approximately: – 27% with RA –10% with history of GI bleed or GD ulcer –21% taking ASA

34. Concurrent Medications Prohibited –NSAIDs (RX, OTC) –Anti-ulcer drugs H 2 antagonists, proton pump, sucralfate, misoprostol –Antibiotics for H. pylori Allowed –ASA for CV prophylaxis –Antacids (short-term) including calcium for osteoporosis –MTX < 25 mg/wk, azathioprine, corticosteroids –Analgesics (APAP to oxycodone prn)

35. Aspirin use: CLASS Allowed at  325 mg daily patients at risk for CV events Use was not stratified in the CLASS study Dose and duration of use may have varied No conclusions regarding ASA co-use can be drawn from CLASS, only observations and possible directions for future studies

36. CLASS-Statistical Issues Null hypothesis: Celecoxib = NSAIDs for primary outcome of complicated ulcers... –Estimated 40 events total: 8 events in 4000 celecoxib patients 32 events in 4000 NSAID patients Withdrawal rate of 35% Power = 90% Significance = 0.05 (two-sided)

37. Patient disposition-CLASS

38. Efficacy in OA/RA: CLASS Not more effective than NSAIDs based on: –Patient global –Patient assessment of pain (VAS) –HAQ and SF-36 scores –Patient withdrawals rate but less than rates in NDA (? dose effect)

39. CLASS GI outcomes-1 Complicated ulcers (Primary Endpoint) –Total of 38 uncensored events in ALL groups –Celecoxib was not statistically significantly different than individual or pooled NSAIDs Celecoxib did NOT meet primary endpoint of trial

40. CLASS GI outcomes-2 However, when primary endpoint restricted to include those not taking ASA: –Total of 22 uncensored events in ALL groups –Celecoxib was different (p=0.03) than ibuprofen, but NOT diclofenac

41. CLASS GI outcomes-3 When endpoints expanded to complicated and symptomatic ulcers: –Total of 105 events in ALL groups –Celecoxib > ibuprofen but NOT diclofenac When restricted to non-ASA patients, the complicated and symptomatic ulcers show: –Total of 59 events in ALL groups –Celecoxib > ibuprofen but NOT diclofenac

42. GI Adverse Events

43. Adverse Events (%): CLASS

44. Deaths (%) Overall, 36 deaths for all causes Celecoxib 19 (0.5 %) Diclofenac 9 (0.5 %) Ibuprofen 8 (0.4 %) Most (69%) in patients  65 years Most cardiovascular in nature Celecoxib (58 %) Diclofenac (56 %) Ibuprofen (63 %)

45. Deaths (pt-yrs)

46. Renal Adverse Events(%)

47. CV (combined) AEs (%)

48. Serious CV Events (%)

49. Hepatic Adverse Events (%)

50. Skin Adverse Events (%)

51. ASA and GI: CLASS (some observations)

52. ASA and CV: CLASS (some observations)

53. Overall Safety-GI Celecoxib was unable to demonstrate statistical superiority to either ibuprofen or diclofenac when considering the primary endpoint of the CLASS trial However, celecoxib was able to demonstrate a trend in superiority to ibuprofen (only) in patients not taking ASA and with broader endpoints (complicated and symptomatic)

54. Overall Safety-Renal Celecoxib does not effect acid-base balance more than diclofenac or ibuprofen (phase 4) No large effect on renal adverse events relative to ibuprofen or diclofenac Although not seen in the CLASS trial, serious renal disease such as acute failure and interstitial nephritis are in the label

55. Overall Safety-Cardiovascular In CLASS, no apparent adverse effect on CV mortality or SAEs related to thrombosis relative to ibuprofen or diclofenac Does not exclude a lesser CV effect Events such as MI, CHF, VF, PE, CVA, vasculitis and other events are in the label

56. Overall Safety-Hepatobiliary Adverse events are not more frequent than seen with ibuprofen or diclofenac Although not seen in the CLASS trial, events such as hepatitis, jaundice and liver failure are in the label

57. Overall Safety-Skin Rash and pruritis (mild, moderate) are important adverse events that frequently lead to withdrawal Serious adverse events such as Stevens- Johnson syndrome, toxic epidermal necrolysis or erythema multiforme are in the label

58. Overall Safety-Deaths There were no deaths from hepatobiliary, renal, dermatologic or GI causes Deaths from CV causes appear to reflect the population studied rather than any new adverse effect of celecoxib Deaths from CV causes are not more common in the celecoxib group as compared to the controls

59. Overall Safety: Celecoxib From all data to date (NDA to CLASS), celecoxib appears more like NSAIDs than placebo

60. COX-2 versus NSAID: Safety With regards to any safety endpoint: –Is “beating” one NSAID the same as beating them all? –Is “losing” to one NSAID the same as losing to them all?