COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib

1
COX-2 FDA Advisory Committee Meeting
2005Rofecoxib

• Speaker Ned S. Braunstein, MD
• Senior Director, Merck Research Labs

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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

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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

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

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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

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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?

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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

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Phase IIb/III OA Pooled Analysis Primary
EndpointConfirmed Clinical Upper GI Events
(1998)
Relative Risk (RR)Rofecoxib vs. NSAIDs
(Ibuprofen, diclofenac, nabumetone).
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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.
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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?

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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

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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

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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

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VIGOR Primary Endpoint (2000)Time to Confirmed
Clinical Upper GI Event
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Confirmed Thrombotic CV Events Rofecoxib vs.
Naproxen The VIGOR Study (2000)
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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.
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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

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Alzheimers Disease and Mild CognitiveImpairment
(MCI) Studies (Sep-2000)

• Combined analysis of two large ongoing
  placebo-controlled studies in patients with MCI
  and Alzheimers 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

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Investigator-Reported Thrombotic CV Events in the
Pooled Alzheimers Studies (Sep-2000)
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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 gt28,000 patients and gt14,000
  patient-years

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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.
20011042280-2288.
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Mercks 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

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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

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Updated VIOXX Labeling GI and CV (Apr-2002)

• Modified GI Warning
• VIGOR GI results
• New CV Precaution
• VIGOR and Alzheimers 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

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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

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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 gt95 confidence and with 90 power
• More than 600 CV events
• Approximately 25,000 patients for 3 years

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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

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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

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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

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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.
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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)pgt0.05
Rofecoxib
Non-Naproxen NSAIDs
Cumulative Incidence () with 95 CI
Pts. with Events
Patients at Risk RofecoxibNon-Naproxen NSAIDs
50 22
Ibuprofen, diclofenac, nabumetone.
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Alzheimers 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)pgt0.05
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
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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.
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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

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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

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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

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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

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APPROVe Inclusion/Exclusion Criteria

• Inclusion Criteria
• 40 years, histologically confirmed large bowel
  adenoma
• Prior History
• MI, PTCA, CABG allowed if gt1 year prior to
  randomization
• TIA, CVA allowed if gt2 years prior to
  randomization
• Exclusion Criteria
• Uncontrolled hypertension (gt165/95 mm Hg), angina
  at rest or minimal activity, CHF at rest

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APPROVe Confirmed Thrombotic CV Events (Sep-2004)
Kaplan-Meier Estimates (95 CI)
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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.
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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

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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

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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 (gt10 factors)
• (e.g., age, gender, individual CV risk factors,
  etc.)
• Concomitant aspirin use
• Blood pressure (gt40 analyses)
• Statistical approach Tests for
  treatment-by-subgroup factor interaction, one
  subgroup factor at a time
• Multiple subgroup testing
• Results considered hypothesis generating

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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).
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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

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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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Rofecoxib 25 mg Reduces Cumulative Incidence of
Colorectal Adenomas in APPROVe (Dec 2004)
plt0.0001 Primary endpoint evaluated over the
entire 3-year study in patients with increased
risk of colorectal cancer.
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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

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Pooled Analysis of Confirmed Thrombotic CV Events
CV Outcomes Study (Interim Data Feb-2005)
Relative Risk with 95 CI
Pts with Events
Favors Rofecoxib Favors Placebo
PYR
CV Outcomes Pooled Analysis
(116)
(72)
APPROVe
(28)
ViP
(16)
VICTOR
Relative Risk (Rofecoxib/Placebo)
Interim data as of Feb 2005.
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All-Cause Mortality in Rofecoxib Clinical
Program(Updated Feb-2005)
Rates per 100 Patient-Years with 95 CI
NSAIDs controlled
Placebo
Controlled OA IIb/III VIGOR RA
IIb/III ADVANTAGE ALZHEIMER
APPROVe VIP ? VICTOR ?
Rate per 100 Patient-Years
? Rofecoxib 12.5-50 mg ? Rofecoxib 25 mg
? Rofecoxib 50 mg ? Diclofenac
Ibuprofen ? Naproxen ?
Placebo
On-drug population ?Interim data as of Feb 2005
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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

56
Implications Key Public Health Questions

• What is risk/benefit of selective COX-2
  inhibitors for established indications?
• Relative to ibuprofen/diclofenac
• Relative to naproxen
• Can we identify factors associated with observed
  increased risk for thrombotic CV events with
  these drugs?
• Duration
• Patient demographics
• Dose
• 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?

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Next Steps (Feb-2005)

• Ongoing assessment of rofecoxib thrombotic CV
  data
• Examine additional factors for relationship in
  APPROVe
• Patients in APPROVe being followed off-drug
• Scientific hypotheses for thrombotic CV findings
  being explored
• Efforts underway to analyze thrombotic CV data
  across drugs
• Comparative outcome studies needed to determine
  relative risk among agents in relevant
  populations
• Etoricoxib vs. diclofenac MEDAL study in gt23,000
  patients targeted to complete 2006