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COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib

COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib. Speaker: Ned S. Braunstein, MD Senior Director, Merck Research Labs. Consultants. Marc Hochberg, MD

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COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib

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  1. COX-2 FDA Advisory Committee Meeting 2005Rofecoxib Speaker: Ned S. Braunstein, MD Senior Director, Merck Research Labs

  2. Consultants Marc Hochberg, MD Head, Division of Rheumatology and Clinical Immunology Professor of Medicine, Epidemiology & Preventive Medicine,University of Maryland School of Medicine Marvin A. Konstam, MDChief of Cardiology, Tufts-New England Medical CenterProfessor of Medicine, Tufts University School of Medicine Loren Laine, MDProfessor of Medicine, University of Southern California School of MedicineChief, Gastroenterology Section, L.A. County and U.S.C. Medical Center

  3. Objectives of Merck Presentation: Assessing Risk/Benefit of Rofecoxib/COXIBs • Provide data on risk/benefit assessment of rofecoxib • GI and CV data from NDA through APPROVe • Methods used to acquire and analyze data • Design considerations for rofecoxib study of CV outcomes • New exploratory analyses • Risk/benefit conclusions Feb-2005 for the class and unanswered questions • Next steps

  4. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  5. Overview: Rationale for Development of Selective COX-2 Inhibitors • NSAID gastropathy • Most common cause of drug-related morbidity and mortality • Gastroduodenal perforation • Gastroduodenal ulcers • Upper GI bleeds • Class labeled with bolded Warning

  6. CO2H The COX-2 Hypothesis (1992) Arachidonic Acid COX-1 COX-2 NSAIDs Selective COX-2Inhibitors Prostanoids Prostanoids Protection of Gastric MucosaPlatelet Function Renal Effects Pain, Inflammation, Fever Gastropathy andAntithrombotic Effects Effects on Na+ Balance Anti-inflammatory and Analgesic Effects

  7. Overview: Key GI Observations with Rofecoxib • Demonstrated reduction in clinical upper GI events vs. non-selective NSAIDs • Reduction vs. naproxen in VIGOR (outcomes study) • Only selective COX-2 inhibitor with modification to NSAID-template GI Warning • Consistent reduction vs. each of naproxen, ibuprofen, diclofenac • Pooled analysis of 20 OA/RA studies • More upper GI events with rofecoxib than placebo • Reduced incidence of lower GI events vs. naproxen in VIGOR

  8. Overview: Key Thrombotic CV Safety Observations with Rofecoxib • Clinical data on thrombotic CV events for rofecoxib show: • Increased risk relative to placebo • Seen with long-term use in APPROVe • Rates similar to non-naproxen NSAIDs • Long-term data limited • Increased risk compared to naproxen • Apparent after short-term use

  9. Overview: Key Public Health Questions • What is risk/benefit of selective COX-2 inhibitors? • Relative to placebo • Relative to ibuprofen/diclofenac • Relative to naproxen • Can we identify factors associated with observed increased risk for thrombotic CV events with these drugs? • Is observed increased CV risk a class effect of COX-2 inhibition? • How big is the class? • What are long-term CV effects of traditional NSAIDs?

  10. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • 1998: Data in original NDA • 2000: Data in VIGOR sNDA • 2000-2004: Ongoing assessment post VIGOR until APPROVe findings • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  11. RR (95% CI): 0.45 (0.25, 0.81)p=0.006 NSAIDs Cumulative Incidence (%) with 95% CI Rofecoxib Pts. With Events Month 23 22 Phase IIb/III OA Pooled Analysis: Primary EndpointConfirmed Clinical Upper GI Events (1998) Relative Risk (RR)=Rofecoxib vs. NSAIDs (Ibuprofen, diclofenac, nabumetone).

  12. Rofecoxib N=3357 NSAIDs‡ N=1564 Event Investigator-reported cardiovascular events† 2.0 (34) 2.3 (16) Rofecoxib N=2253 Placebo N=711 Investigator-reported cardiovascular events† 2.7 (14) 2.6 (4) Investigator-Reported Thrombotic CV Events in Phase IIb/III OA Clinical Studies (1998) Rates per 100 Patient-Years (Number of Patients with Events) Clinical Studies of 6 to 86 Weeks Duration † Cardiac, Cerebrovascular, and Peripheral (Arterial and Venous) Events. ‡ Ibuprofen, diclofenac, and nabumetone.

  13. COX-2 Cardiovascular Questions (1998) • What is the clinical importance of inhibiting systemic prostacyclin synthesis without inhibiting platelet thromboxane? • Can some NSAIDs, through their effects on COX-1, decrease the risk of thrombotic CV events? • Is there a clinical benefit to inhibiting COX-2 mediated inflammation in atherosclerotic plaques?

  14. Vascular Events Adjudication SOP Initiated (1998) • Purpose • Standardize the evaluation of cardiovascular events • Predefined criteria • All source documentation collected • Blinded, external adjudication committees • Improve clarity by eliminating questionable events • Pooled analysis of events planned across all studies • Increase precision

  15. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • 1998: Data in original NDA • 2000: Data in VIGOR sNDA • 2000-2004: Ongoing assessment post VIGOR until APPROVe findings • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  16. VIGOR (Jan-1999 to Mar-2000) • 8076 rheumatoid arthritis (RA) patients: • Rofecoxib 50 mg QD • 2 to 4 times recommended chronic dose • Provides rigorous test of GI safety • Naproxen 500 mg BID • Extend GI findings to additional NSAID • Most common NSAID regimen for RA • Exclusion Criteria • Patients using aspirin • Confounds test of COX-2 hypothesis

  17. RR (95% CI): 0.46 (0.33, 0.64) p<0.001 Naproxen1000 mg Cumulative Incidence (%) with 95% CI Rofecoxib50 mg Pts. With Events Month Patients at Risk Rofecoxib 50 mgNaproxen 1000 mg 56 121 VIGOR Primary Endpoint (2000)Time to Confirmed Clinical Upper GI Event

  18. RR (95% CI): 2.38 (1.39, 4.00) p=0.002 Rofecoxib 50 mg Cumulative Incidence (%) with 95% CI Naproxen 1000 mg Pts. with Events Month 45 19 Confirmed Thrombotic CV Events Rofecoxib vs. Naproxen: The VIGOR Study (2000)

  19. Rofecoxib N=40472697 Patient-Years rate‡ (n) Naproxen N=40292698 Patient-Years rate‡ (n) Outcome† Any cardiovascular event CardiacSudden deathMyocardial infarctionUnstable angina CerebrovascularIschemic CVATransient ischemic attack Peripheral events 1.7 1.00.20.70.2 0.40.30.1 0.2 (45) (28)(3)(20)(5) (11)(9)(2) (6) 0.7 0.40.20.20.1 0.30.30.0 0.0 (19) (10)(4)(4)(3) (8)(8)(0) (1) VIGOR Confirmed Thrombotic CV Events (2000) Patients with Events (Rates per 100 Patient-Years) † Patients may be counted in more than one row but are only counted once within a row.‡ Rate per 100 Patient-Years.

  20. VIGOR Additional Exploratory Analyses Thrombotic CV Events (2000) • More hypertension AEs with rofecoxib 50 mg than naproxen 1000 mg • Similar relative risk in patients with or without increases in BP during study • Similar relative risk in patients with or without baseline risk factors for CV events • Merck analyses did not identify significant increases in relative risk over time for rofecoxib vs. naproxen

  21. Alzheimer’s Disease and Mild CognitiveImpairment (MCI) Studies (Sep-2000) • Combined analysis of two large ongoing placebo-controlled studies in patients with MCI and Alzheimer’s Disease • 25 mg rofecoxib vs. placebo • Elderly patient population with increased risk for CV events • As of September, 2000: • 2091 patients • Median duration of therapy: 12.5 months

  22. RR (95% CI): 0.85 (0.53, 1.35)p>0.05 Placebo Cumulative Incidence (%) with 95% CI Rofecoxib 25 mg Month Pts. with Events Patients at Risk Rofecoxib 25 mg 1041 947 879 769 640 359 Placebo 1050 991 930 816 693 376 3240 Investigator-Reported Thrombotic CV Events in the Pooled Alzheimer’s Studies (Sep-2000)

  23. Cardiovascular Pooled Analysis (Sep-2000) • Phase IIb to V (post-marketing) rofecoxib studies 4 weeks duration • APTC combined endpoint (MI, CVA, vascular death) • Included studies not subject to adjudication • Reports of APTC events had high confirmation rates • Allowed comparison to published reports • Pooled analysis of double-blinded patient-level data stratified by disease • Included data on >28,000 patients and >14,000 patient-years

  24. (Pts. with events) Favors Rofecoxib Favors Comparator PYR Rofecoxib vs. Placebo (65) 3867 0.84 (0.51, 1.38) Rofecoxib vs. Non-Naproxen NSAIDs (35) 2918 0.79 (0.40, 1.55) Rofecoxib vs. Naproxen (84) 8364 1.69 (1.07, 2.69) Relative Risk (Rofecoxib/Comparators) Relative Risk of APTC Events Pooled Analysis: Rofecoxib vs. Placebo or NSAIDs (Sep-2000) Relative Risk with 95% CI PYR = Patient-Years. Konstam et al., Circulation. 2001;104:2280-2288.

  25. Merck’s Conclusions: VIGOR (2000) • Clear evidence for GI benefit of rofecoxib • Data versus placebo and non-naproxen NSAIDs did not suggest increased CV risk with rofecoxib • Thus, weight of evidence most consistent with a cardioprotective effect of naproxen 1000 mg

  26. Arthritis Advisory Committee Conclusions: VIGOR (Feb-2001) • Clear evidence for GI benefit of rofecoxib vs. naproxen • Data on CV risk inconclusive • Both GI and CV data should be described in labeling

  27. Updated VIOXX™ Labeling: GI and CV (Apr-2002) • Modified GI Warning • VIGOR GI results • New CV Precaution • VIGOR and Alzheimer’s Disease CV results • Clinical Significance Unknown • Caution should be exercised when VIOXX™ is used in patients with a medical history of ischemic heart disease • Chronic use of 50 mg not recommended • Increase in NSAID-type AEs at 50 mg • No increased efficacy at 50 mg

  28. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • 1998: Data in original NDA • 2000: Data in VIGOR sNDA • 2000-2004: Ongoing assessment post VIGOR until APPROVe • Study of CV Outcomes • Clinical Trials Data • Assessment of Data • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  29. Considerations in CV Outcomes Study Design • NSAID-controlled studies • OA or RA patients • Placebo control not appropriate in patients needing chronic NSAIDs • Chronic NSAIDs not appropriate for patients without need • Placebo-controlled studies • Precludes study of chronic arthritis patients • Applicability to arthritis population uncertain • Size of studies to exclude 30% increased risk with >95% confidence and with 90% power • More than 600 CV events • Approximately 25,000 patients for 3 years

  30. Considerations for CV Outcomes Study Design Placebo-Controlled Designs • Acute Coronary Syndrome • Known GI and renovascular risks of particular concern in this unstable patient population • All patients on aspirin • Could confound interpretation • Chemoprevention • Known GI and renovascular risks manageable • Patients with broad spectrum of CV risk • Aspirin users and non-users • Not unlike patients with arthritis

  31. Rofecoxib Study of CV Outcomes (Oct-2002) • Prospective combined analysis of 3 studies comparing rofecoxib 25 mg vs. placebo • APPROVe: Recurrent adenomatous colon polyps • VICTOR: Colon cancer mortality (Oxford University Study) • ViP: Incidence of prostate cancer in at-risk patients • Separate protocol, analysis plan and safety monitoring board • Approximately 25,000 patients • Target 20 to 30% patients on aspirin • Discussed with regulatory agencies

  32. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • 1998: Data in original NDA • 2000: Data in VIGOR sNDA • 2000-2004: Ongoing assessment post VIGOR until APPROVe • Study of CV Outcomes • Clinical Trials Data • Assessment of Data • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  33. Favors Rofecoxib Favors Comparator (Pts. With Events) PYR Rofecoxib vs. NSAIDs* (97) (26) Diclofenac Ibuprofen (30) (39) Naproxen* VIGOR: Naproxen (177) Relative Risk (Rofecoxib/Comparators) Final Pooled Analysis Confirms and Broadens GI Safety Benefit for Rofecoxib (2003) Confirmed Clinical Upper GI Events: Relative Risk with 95% CI PYR = Patient-Years. *Excludes VIGOR.

  34. Ph IIb/III OA Investigator-Reported Thrombotic CV Events (2003)Rofecoxib vs. Non-Naproxen NSAIDs Kaplan-Meier Estimates (95% CI) RR (95% CI): 0.98 (0.60, 1.62)p>0.05 Rofecoxib Non-Naproxen NSAIDs† Cumulative Incidence (%) with 95% CI Pts. with Events Patients at Risk RofecoxibNon-Naproxen NSAIDs† 50 22 † Ibuprofen, diclofenac, nabumetone.

  35. Alzheimer’s Disease (PN 078 + 091) Confirmed Thrombotic CV Events (2003)Rofecoxib vs. Placebo Kaplan-Meier Estimates (95% CI) RR (95% CI): 1.01 (0.67, 1.53)p>0.05 Rofecoxib 25 mg Placebo Pts. with Events Patients at Risk Rofecoxib 25 mg 1069 878 707 415 318 226 185 Placebo 1074 939 797 463 385 283 243 42 48

  36. Pooled Analysis of APTC Combined Endpoint, Rofecoxib vs. Comparator Agents (2003) Relative Risk with 95% CI (Pts. with events) Favors Rofecoxib Favors Comparator PYR Rofecoxib vs. Placebo 5841 (105) 1.14 (0.77, 1.68) Rofecoxib vs. Non-Naproxen NSAIDs (47) 4222 0.93 (0.51, 1.69) Rofecoxib vs. Naproxen (95) 10318 1.61 (1.04, 2.50) Relative Risk (Rofecoxib/Comparators) PYR = Patient-Years.

  37. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • 1998: Data in original NDA • 2000: Data in VIGOR sNDA • 2000-2004: Ongoing assessment post VIGOR until APPROVe • Study of CV Outcomes • Clinical Trials Data • Assessment of Data • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  38. Updated Safety Assessment(2004 Pre-APPROVe) • Ongoing interest in Thrombotic CV safety of selective COX-2 inhibitors • Observational epidemiology studies (10 presented or published) • Results mixed • Pre-clinical models • Applicability to humans uncertain • TARGET • Thrombotic CV Data from rofecoxib randomized control trials: • CV event rates similar to placebo and non-naproxen NSAIDs • CV event rate higher than naproxen • Similar CV data with other COX-2 selective inhibitors • Overall risk benefit favorable for rofecoxib • CV outcomes study ongoing

  39. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • Implications of the Data

  40. APPROVe Colon Polyp Prevention Study Design • Rofecoxib 25 mg vs. placebo • Approximately 2600 patients • Stratified by baseline aspirin use • 3-Year on-drug treatment period with 1-year off-drug period • Colonoscopies • Screening, 1 year, 3 year • Follow-up at Year 4 after withdrawal of therapy (assess rebound) • Primary endpoint: Cumulative incidence of patients with adenomatous polyps at Year 3 • First patient screened in Dec-1999

  41. APPROVe Inclusion/Exclusion Criteria • Inclusion Criteria • ≥40 years, histologically confirmed large bowel adenoma • Prior History • MI, PTCA, CABG allowed if >1 year prior to randomization • TIA, CVA allowed if >2 years prior to randomization • Exclusion Criteria • Uncontrolled hypertension (>165/95 mm Hg), angina at rest or minimal activity, CHF at rest

  42. RR (95% CI):1.96 (1.20, 3.19)p=0.007 Rofecoxib 25 mg Cumulative Incidence (%) with 95% CI Placebo Pts. with Events Month Patients at Risk Rofecoxib 25 mgPlacebo 1287 1123 1050 986 935 898 4111299 1192 1148 1079 1039 1002 470 45 25 APPROVe Confirmed Thrombotic CV Events (Sep-2004) Kaplan-Meier Estimates (95% CI)

  43. Rofecoxib (N=1287) 3041 Patient-Years Placebo (N=1299) 3315 Patient-Years Rate† (n) Rate† (n) Any Confirmed Thrombotic CV event‡ Cardiac Events Acute myocardial infarction Fatal acute myocardial infarction Sudden cardiac death Unstable angina pectoris Cerebrovascular Events Fatal ischemic cerebrovascular stroke Ischemic cerebrovascular stroke Transient ischemic attack Peripheral Vascular Events 1.48 0.99 0.66 0.03 0.10 0.23 0.49 0.00 0.36 0.16 0.10 (45) (30) (20) (1) (3) (7) (15) (0) (11) (5) (3) 0.75 0.33 0.24 0.09 0.03 0.12 0.21 0.00 0.18 0.06 0.21 (25) (11) (8) (3) (1) (4) (7) (0) (6) (2) (7) APPROVe Confirmed Thrombotic CV Events (Sep-2004) † Rate per 100 Patient-Years. ‡ Patients may be counted in more than one row but are only counted once within a row.

  44. Rofecoxib Assessment CV Thrombotic Events (Post-APPROVe Sep-2004) • Increased thrombotic CV risk rofecoxib 25 mg relative to placebo • Non-constant relative risk in APPROVe • Risk similar to placebo over first approximately 18 months • Risk relative to placebo began to increase starting after approximately 18 months • Potentially molecule specific • Mechanism uncertain • At the time, no placebo-controlled data available on other agents to support class effect

  45. Reasons for VIOXX™ Voluntary Withdrawal (30-Sep 2004) • Administrative committee communicated recommendation for termination of study treatment September 23, 2004 • On the basis of the data, Merck voluntarily withdrew VIOXX™ from the market on September 30, 2004 • APPROVe was first clinical trial with rofecoxib that showed an increased cardiovascular risk versus placebo • Alternative therapies were available without evidence of a similar cardiovascular risk • Merck believed voluntary withdrawal best served interest of patients

  46. Outline of Merck Rofecoxib Presentation • Overview • Chronology of Rofecoxib GI and CV Safety Prior to APPROVe • APPROVe and the Voluntary Withdrawal of VIOXX™ • Data Since Withdrawal • APPROVe Final Data and Exploratory Analyses of Risk Factors • Thrombotic CV Events from CV Outcomes Study • Implications of the Data

  47. Post-Hoc Exploratory Analyses of APPROVe (Dec-2004 Data) • Many factors assessed in multiple analyses • Baseline factors (>10 factors) • (e.g., age, gender, individual CV risk factors, etc.) • Concomitant aspirin use • Blood pressure (>40 analyses) • Statistical approach: Tests for treatment-by-subgroup factor interaction, one subgroup factor at a time • Multiple subgroup testing • Results considered hypothesis generating

  48. APPROVe Confirmed Thrombotic Events:Exploratory Post Hoc Analyses of CV Risk Factors (Dec-2004 Data) Relative Risk with 95% CI (Pts. with events) Favors Rofecoxib Favors Placebo PYR (72) Total Cohort Incr. CV Risk† (38) (34) Not Incr. CV Risk ASA User (16) (56) Non ASA User Hx Sympt. ASCVD (11) (61) No Hx Sympt. ASCVD Hx Diabetes (14) (58) No Hx Diabetes Relative Risk (Rofecoxib/Placebo) PYR = Patient-Years. † 2 or More Risk Factors for CV Disease or a History of Symptomatic Atherosclerotic CV Disease (ASCVD).

  49. Blood Pressure Measurement Methodology in APPROVe • BP measured once per visit • Every 4 months • BP measurements not standardized across sites • Time of day and measurement technique varied • Between-group difference in change from baseline in mean systolic and diastolic BP values (rofecoxib – placebo) • 4 mm Hg systolic • 2 mm Hg diastolic

  50. APPROVe Exploratory Post-Hoc Analyses of Blood Pressure (Dec-2004 Data) • Multiple BP analyses did not identify consistent patient subgroups or covariates associated with increased relative risk • Baseline BP • Change from baseline BP • On treatment BP • Hypertension reported as adverse experience • One subgroup with increased relative risk • SBP ≥160 mm Hg DBP = diastolic blood pressure.SBP = systolic blood pressure.

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