# Presentation: 249211

## COX-2 FDA Advisory Committee Meeting 2005Rofecoxib

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

## 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

## 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

## Outline of Merck Rofecoxib Presentation

- Overview
- Chronology of Rofecoxib GI and CV Safety Prior to APPROVe
- APPROVe and the Voluntary Withdrawal of VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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

## The COX-2 Hypothesis (1992)

- Arachidonic Acid

- Prostanoids

- Prostanoids

**Protection of Gastric Mucosa****Platelet Function**

**Pain, Inflammation, Fever**

**Renal Effects**

- Gastropathy andAntithrombotic Effects

- Effects on Na+ Balance

- Anti-inflammatory and Analgesic Effects

**NSAIDs**

- COX-2

- COX-1

**Selective COX-2****Inhibitors**

## 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

## 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

## 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?

## 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 VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## Phase IIb/III OA Pooled Analysis: Primary EndpointConfirmed Clinical Upper GI Events (1998) 

- Relative Risk (RR)=Rofecoxib vs. NSAIDs (Ibuprofen, diclofenac, nabumetone).

## Investigator-Reported Thrombotic CV Events in Phase IIb/III OA Clinical Studies (1998)

- Clinical Studies of 6 to 86 Weeks Duration

- † Cardiac, Cerebrovascular, and Peripheral (Arterial and Venous) Events.
- ‡ Ibuprofen, diclofenac, and nabumetone.

## 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?

## 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

## 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 VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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

## VIGOR Primary Endpoint (2000)Time to Confirmed Clinical Upper GI Event

## Confirmed Thrombotic CV Events Rofecoxib vs. Naproxen: The VIGOR Study (2000)

## 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.

## 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

## Alzheimer’s Disease and Mild CognitiveImpairment (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

## Investigator-Reported Thrombotic CV Events in the Pooled Alzheimer’s Studies (Sep-2000)

## 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

##  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.

## 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

## 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

## Updated VIOXXTM 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 VIOXXTM 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

## 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 VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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

## 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

## 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

## 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 VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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.

## 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

- Patients at Risk
- RofecoxibNon-Naproxen NSAIDs†

- † Ibuprofen, diclofenac, nabumetone.

- Pts. with Events

- 50
- 22

## 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

- 42
- 48

-   Patients at Risk
- Rofecoxib 25 mg	1069  	  878	    707	     415	      318	        226	         185              Placebo	1074	  939           797         463         385           283         243

## Pooled Analysis of APTC Combined Endpoint, Rofecoxib vs. Comparator Agents (2003)

- Relative Risk with 95% CI

- Favors Rofecoxib        Favors Comparator

- Rofecoxib vs.
- Non-Naproxen NSAIDs

- Relative Risk (Rofecoxib/Comparators)

- Rofecoxib vs.
- Naproxen

- Rofecoxib vs.
- Placebo

- 1.14 (0.77, 1.68)

- 5841

- 10318

- 4222

- 0.93 (0.51, 1.69)

- 1.61 (1.04, 2.50)

- PYR = Patient-Years.

- (Pts. with
- events)

- PYR

- (105)

- (47)

- (95)

## 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 VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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

## Outline of Merck Rofecoxib Presentation

- Overview
- Chronology of Rofecoxib GI and CV Safety Prior to APPROVe
- APPROVe and the Voluntary Withdrawal of VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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

## 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

##  APPROVe Confirmed Thrombotic CV Events (Sep-2004)

- Kaplan-Meier Estimates (95% CI)

## 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.

## 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

## Reasons for VIOXXTM 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 VIOXXTM 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

## Outline of Merck Rofecoxib Presentation

- Overview
- Chronology of Rofecoxib GI and CV Safety Prior to APPROVe
- APPROVe and the Voluntary Withdrawal of VIOXXTM
- Data Since Withdrawal
- APPROVe Final Data and Exploratory Analyses of Risk Factors
- Thrombotic CV Events from CV Outcomes Study
- Implications of the Data

## 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

## APPROVe Confirmed Thrombotic Events: Exploratory Post Hoc Analyses of CV Risk Factors (Dec-2004 Data)

- APPROVe Confirmed Thrombotic Events: Exploratory Post Hoc Analyses of CV Risk Factors (Dec-2004 Data)

- Relative Risk with 95% CI

- Favors Rofecoxib   Favors Placebo

- Total Cohort

- (Pts. with
- events)

- Relative Risk (Rofecoxib/Placebo)

- Incr. CV Risk†

- ASA User

- Hx Diabetes

- No Hx Diabetes

- Hx Sympt. ASCVD

- Not Incr. CV Risk

- Non ASA User

- No Hx Sympt. ASCVD

- (72)

- (38)
- (34)

- (16)
- (56)

- (14)
- (58)

- (11)
- (61)

- PYR

- PYR = Patient-Years.
- † 2 or More Risk Factors for CV Disease or a History of Symptomatic Atherosclerotic CV Disease (ASCVD).

## 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

## 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.

## Rofecoxib 25 mg Reduces Cumulative Incidence of Colorectal Adenomas in APPROVe (Dec 2004)

- *p<0.0001
- † Primary endpoint evaluated over the entire 3-year study in patients with increased risk of colorectal cancer.

**Notes:**
p<0.0001

## Outline of Merck Rofecoxib Presentation

- Overview
- Chronology of Rofecoxib GI and CV Safety Prior to APPROVe
- APPROVe and the Voluntary Withdrawal of VIOXXTM
- Data Since Withdrawal
- APPROVe Final Data and Exploratory Analyses of Risk Factors
- Thrombotic CV Events from CV Outcomes Study
- Implications of the Data

## Pooled Analysis of Confirmed Thrombotic CV Events CV Outcomes Study (Interim Data Feb-2005)

-             Relative Risk with 95% CI

- Relative Risk (Rofecoxib/Placebo)

-   APPROVe

*VICTOR**

- Favors Rofecoxib        Favors Placebo

- PYR

**CV Outcomes Pooled Analysis**

*ViP**

- *Interim data as of Feb 2005.

- Pts with
- Events

- (116)

-   (72)

-   (28)

-   (16)

## All-Cause Mortality in Rofecoxib Clinical Program:(Updated Feb-2005)

-  OA IIb/III        VIGOR            RA IIb/III          ADVANTAGE    ALZHEIMER*   APPROVe      VIP       VICTOR 

- All-Cause Mortality in Rofecoxib Clinical Program:(Updated Feb-2005)

- Rates per 100 Patient-Years with 95% CI

-   Rofecoxib 12.5-50 mg          Rofecoxib 25 mg         Rofecoxib 50 mg
-     Diclofenac + Ibuprofen       Naproxen                      Placebo

-         Rate per
- 100 Patient-Years

- * On-drug population: Interim data as of Feb 2005

## Outline of Merck Rofecoxib Presentation

- Overview
- Chronology of Rofecoxib GI and CV Safety Prior to APPROVe
- APPROVe and the Voluntary Withdrawal of VIOXXTM
- Data Since Withdrawal
- Implications of the Data

## 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?

## 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 >23,000 patients targeted to complete 2006