COX-2 & 2x: Improved Safety?

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 Present Kidneys Result C (-) COX-2 Absent Platelets Result A (+) Possible Stomach Result B (±)

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 • Celecoxib • Long-term • Arthritis • Safety • Study

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 • H2 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 (%)