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COX-2 CV Safety celecoxib

COX-2 CV Safety celecoxib. James Witter MD, PhD DAAODP/ODE V February 16, 2005. Reasons for Drug Exposure. Acute or chronic pain Patients Placebo-control Short-term - acceptable (rescue) Long-term - not realistic, ? difficult Prevention of disease progression (Alzheimer’s, polyps)

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COX-2 CV Safety celecoxib

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  1. COX-2 CV Safetycelecoxib James Witter MD, PhD DAAODP/ODE V February 16, 2005

  2. Reasons for Drug Exposure • Acute or chronic pain • Patients • Placebo-control • Short-term - acceptable (rescue) • Long-term - not realistic, ? difficult • Prevention of disease progression (Alzheimer’s, polyps) • Subjects • Placebo-control - acceptable

  3. NSAIDs: Rx and OTC • Concomitant medications during trials • Ibuprofen (approved OTC May 1984) • Naproxen (approved OTC January 1994) • Robustness of prior approvals (324 pt yrs) • Diclofenac (approved in 1988) with safety data that included: • OA (pivotal trials): 97 pts (6 weeks) • RA (pivotal trials): 344 pts (6-10-12 weeks) • Phase 1-2 trials: 950 pts/volunteers (most 14 day) • Supportive trials: 111 pts (12 week) • Long-term, open-label trials: 252 pts (38 weeks) • 2 MI, one in double-blind, one in open-label trials

  4. W.H.O. Adverse Reaction Terminology(cardiovascular) • Myocardial infarction • Myocardial ischemia • Cerebrovascular disorder • Embolism pulmonary (continued)

  5. W.H.O. Adverse Reaction Terminology(cardiovascular) • Thrombophlebitis (arm, deep, leg deep, superficial) • Unstable angina • Angina pectoris • Coronary artery disorder

  6. Adverse Event Recording • Adverse Events • Serious • 21 CFR 312.32 • Deaths • “hard endpoint” • Celebrex NDA • Spontaneous investigator reporting • Not pre-specified or adjudicated • CLASS • GI endpoints: pre-specified and adjudicated • CV: not pre-specified and non-adjudicated spontaneous investigator reports

  7. Cardiovascular EndpointVIGOR study 1.9 2.2 2.0 2.4 Anti-platelet Trialist Collaboration (APTC) composite endpoint: CV death, non-fatal myocardial infarction & stroke

  8. Celebrex (celecoxib)www.cder.fda.gov • Original NDA (submitted June 29, 1998) • 51 studies • Phase 1 (PK, drug interaction, etc.): 29 studies • Arthritis (OA/RA): 14 studies • Post-surgical analgesia: 7 studies • Long-term (2 year) safety: 1 open-label study (024) • Patients allowed to increase drug (dose creep) • No control arm, concomitant (OTC) medication use (continued)

  9. Celebrex (celecoxib)www.cder.fda.gov • CLASS trial -2x safety • SUCCESS-1 • Alzheimer’s -IQ5-97-02-001 (Alzheimer’s IND) -ADAPT • Polyp prevention -preSAP -APC

  10. Celebrex NDA Clinical Review Team • Primary Medical Officer (overall efficacy/safety) • Renal/cardiovascular Consultant Medical Officer • General Safety Medical Officer (including CV) • GI Consultant/Secondary Medical Reviewer • Analgesic Trials Medical Officer • Platelet Safety Medical Officer

  11. CelebrexOA and RA Exposure (pt-yrs) Table 3.1.3.2 (12/10/98 Consult)

  12. CelebrexCV Mortality Table 5.1.1.2.4 (12/10/98 Consult)

  13. Celebrex Serious Adverse Events Cardiac & Renal Table 5.1.2.1 (12/10/98 Consult)

  14. Celebrex CV mortality Long-term, Open-label Safety (024) Table 2.1a.1 (12/10/98 and 1/5/01 Consult)

  15. SUCCESS-1Successive Celecoxib Efficacy & Safety StudyStudy I49-98-02-096 • 12 Week Study in Patients with OA - Celebrex 100 mg BID - Celebrex 200 mg BID - Naproxen 500 mg BID - Diclofenac 50 mg BID • 1142 Centers in 39 Countries - Intended to evaluate “homogeneity” of efficacy and safety around world

  16. SUCCESS-1 Summary Results Data presented to AAC, Dec. 7, 2001 Updated 1/12/05: MI 8 (0.2%) for Celebrex 100 mg; 2 (< 0.1) for Celebrex 200 mg; 1 (< 0.1) for NSAIDs

  17. CLASS • Celecoxib • Long-term • Arthritis • Safety • Study

  18. CLASS • Unique Trial • Intended to mimic “real world” setting • ASA Use if Indicated • Patients with OA or RA • RA doubles risk of heart failure • Arthritis Rheum: Feb. 2005 • Designed as GI Safety Study • Intended to change NSAID template regarding GI • Not powered or designed as CV study

  19. COX-2 & 2x Improved Safety? CLASS/VIGOR-AAC February 7-8, 2001

  20. “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 1998)

  21. CLASS - Baseline demographics • Mean/median age ~60 years • about 11% age 75 years or older • Most white females • Approximately: • 27% with RA • 10% with history of GI bleed or GD ulcer • 21% taking ASA

  22. CLASS - Patients • 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

  23. 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

  24. CLASS - Exposure Table 2.0a.1 (1/5/01Consult)

  25. CLASS - Exposure Table 2.0a.2 (1/05/01 Consult)

  26. Deaths (pt-yrs) • Overall, 36 deaths for all causes • Celecoxib 19 (0.8 %) • Diclofenac 9 (0.8%) • Ibuprofen 8 (0.7 %) • Most (69%) in patients  65 years • Most cardiovascular in nature • Celecoxib (11 /19 = 58 %) • Diclofenac (5/9 = 56 %) • Ibuprofen (5/8 = 63 %)

  27. CLASS: Mortality-ASA Use (pt-yrs)

  28. CLASS - Serious CV Events (pt-yrs) Table 2.1b.2 (1/5/01 Consult)

  29. CLASS - APTC-like Events

  30. 2.4 2.0 1.6 1.2 0.8 0.4 0 CLASS: Non-Aspirin Users KM: Serious Thromboembolic CV Events • Fitzgerald: Nature Reviews/Drugs Discovery (2) 2003 • Strand & Hochberg: Arthritis Rheum 47, 349-355 (2002) Rates Crude Pt-yr Diclofenac 0.97% 1.78% Celebrex 0.77% 1.33% Ibuprofen 0.45% 0.80% Diclofenac 75 mg BID (n=1551) ● ● Celecoxib 400 mg BID (n=3105) ● ● ● ● Cumulative Incidence (%) ● ● ● ● ● ● ● ● ● ● Ibuprofen 800 mg TID (n=1573) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 40 80 120 160 200 240 280 320 360 Days

  31. Alzheimer’s (IND)Division of Neuropharmacological Drug Products • Study IQ5-97-02-001 (April 1997) • DB, PC, 52-week comparative study of Celecoxib for the Inhibition of Alzheimer’s Disease • Celecoxib 200 mg BID did not limit progression • Study IQ5-01-06-004 • OL for long-term safety • Terminated due to 001 (continued)

  32. Alzheimer’s (IND)Division of Neuropharmacological Drug Products • Study EQ5-00-06-002 • PC, long-term with vitamin E to evaluate MRI (brain size) and Alzheimer’s disease-associated proteins and inflammatory mediators • Terminated due to 001 • IND inactivated July 2001

  33. Alzheimer’s 001 - DSMB LetterDecember 24, 2004 • Trial conducted 1997-1999 with DSMB • No adverse events to support stopping trial • Final review: excess of CV-related and other risk but difficult to interpret due to: • Small sample size (relative risks and odds ratios unreliable) • Frail, fragile population • Substantial co-morbidity and concomitant medications • Indications of failure of randomization in baseline CV disease and CV medications • Celecoxib more than placebo (continued)

  34. Alzheimer’s 001 - DSMB LetterDecember 24, 2004 (continued) • Concerned that this data only presented in abstract • May be only medically ill elderly population with placebo control

  35. Alzheimer’s - CV Events (IQ5-97-02-001)# patients (crude rates) From Table T5 and Table 1 (12/22/04 submission, SN 1149)

  36. Study 001 – CV Randomization Table 9: Cardiovascular-related medical history terms that differ by > 2% (Dec. 22, 2004 submission)

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