11111 COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib Speaker: Ned S. Braunstein, MD Senior...

11111

COX-2 FDA Advisory Committee Meeting 2005Rofecoxib

Speaker: Ned S. Braunstein, MD

Senior Director, Merck Research Labs

22222

Consultants

Marc Hochberg, MDHead, 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

33333

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

44444

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

55555

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

66666

The COX-2 Hypothesis (1992)Arachidonic Acid

ProstanoidsProstanoidsProstanoidsProstanoids

Protection of Gastric MucosaProtection of Gastric MucosaPlatelet FunctionPlatelet Function

Pain, Inflammation, FeverPain, Inflammation, FeverRenal EffectsRenal Effects

Gastropathy andAntithrombotic Effects

Effects on Na+ Balance

Anti-inflammatory and Analgesic Effects

NSAIDsCOX-2COX-2COX-1COX-1

CO2H

Selective COX-2Inhibitors

77777

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

88888

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

99999

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?

1010101010


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




1111111111

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

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

Cu

mu

lativ

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cid

en

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%)

w

ith 9

5% C

I

Month

Rofecoxib

NSAIDs

RR (95% CI): 0.45 (0.25, 0.81)p=0.006

0 2 4 6 8 10 12

0

1

2

3

4

843 580

3357 1919 1606 975 874

0 6 16 18 19 19 23

1564 822 654 415 382 366 238

0 12 15 20 21 22 22

Patients at Risk

Cases

Rofecoxib

Rofecoxib

NSAIDs

NSAIDscrry0f07cox2metaPostVIOXXCOXIBreqstACM_Feb05ACM86kmplotout_graphicskmsld_tempkmsld.cfmupgi.acm86.ci.ptrisk.ys.sgr -S.Kh(RY) Jan. 6, 2005 4:54:09 PM

Pts. With Events

23

22

1212121212

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.

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

Investigator-reportedcardiovascular events†

EventRofecoxibN=3357

2.0 (34)

NSAIDs‡

N=1564

2.3 (16)

PlaceboN=711

2.6 (4)

RofecoxibN=2253

2.7 (14)Investigator-reportedcardiovascular events†

1313131313

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?

1414141414

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

1515151515


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




1616161616

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

1717171717

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

Cu

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cid

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%)

w

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5% C

I

Month

RR (95% CI): 0.46 (0.33, 0.64) p<0.001

56

121

0 2 4 6 8 10

0

1

2

3

4

5

1073

4047 3641 3402 3180 2806

0 18 30 37 45 55

4029 3644 3389 3163 2796 1071

0 39 57 87 105 117

Patients at Risk

Cumulative Events

Rofecoxib

Rofecoxib

Naproxen

NaproxenC:km_rofe_gi_010405out_graphicskmsld_tempkmsld.rofepub.ci.rofe.gi.pubs.ww.sgr -S.Kh(RY) Jan. 7, 2005 8:47:29 AM

Rofecoxib50 mg

Naproxen1000 mg

Pts. With EventsPatients at Risk

Rofecoxib 50 mg

Naproxen 1000 mg

1818181818

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

0 2 4 6 8 10

0.0

0.5

1.0

1.5

2.0

2.5

1067

4047 3643 3405 3177 2806

0 9 17 27 29 42

4029 3647 3395 3172 2798 1073

0 6 9 11 15 19

Patients at Risk

Cumulative Events

Rofecoxib 50 mg

Rofecoxib 50 mg

Naproxen 1000 mg

Naproxen 1000 mgC:km_rofe_thro_VIOGR_010505out_graphicskmsld_tempkmsld.rofethrovigor.ci.rofe.thro.vigor.ww.sgr -S.Kh(RY) Jan. 7, 2005 9:35:11 AM

Cu

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%)

w

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5% C

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Month

Rofecoxib50 mg

Naproxen 1000 mg

RR (95% CI): 2.38 (1.39, 4.00)p=0.002

Pts. with Events

4519

1919191919

(45)

(28)(3)

(20)(5)

(11)(9)(2)

(6)

1.7

1.00.20.70.2

0.40.30.1

0.2

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

(19)

(10)(4)(4)(3)

(8)(8)(0)

(1)

0.7

0.40.20.20.1

0.30.30.0

0.0

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.

2020202020

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

2121212121

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

2222222222

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

0 3 6 9 12 15

0

2

4

6

8

359

1041 947 879 769 640

0 6 13 20 24 27

1050 991 930 816 693 376

0 11 18 27 32 37

Patients at Risk

Cumulative Events

Rofecoxib

Rofecoxib

Placebo

Placebo

C:KM_VIGORTIME_ALZ_010605out_graphicskmsld_tempkmsld.cvunadjud.ci.alz.scale8.ww.sgr -S.Kh(RY) Jan. 24, 2005 10:37:23 AM

Cu

mu

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cid

en

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%)

w

ith 9

5% C

I

Month

Rofecoxib 25 mg

Placebo

RR (95% CI): 0.85 (0.53, 1.35)p>0.05

Pts. with Events

3240

Patients at RiskRofecoxib 25 mg 1041 947 879 769 640 359 Placebo 1050 991 930 816 693 376

2323232323

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

2424242424

Relative Risk of APTC Events Pooled Analysis: Rofecoxib vs. Placebo or NSAIDs (Sep-2000)

Relative Risk with 95% CI

Relative Risk (Etoricoxib/Diclofenac Sodium)

0.84 (0.51, 1.38) 3867Rofecoxbi vs.

0.79 (0.40, 1.55) 2918Rofecoxbi vs.

1.69 (1.07, 2.69) 8364Rofecoxbi vs.

0.1 0.2 0.5 1 2 5 10

C:slide29_meta_rofe_aptc_011705out_graphicsmet2sld_tempslide29s.rofe.aptc.slide.ww.sgr -S.Kh(RY) Jan. 17, 2005 1:40:59 PM

Favors Rofecoxib Favors Comparator

Rofecoxib vs. Non-Naproxen NSAIDs

Relative Risk (Rofecoxib/Comparators)

Rofecoxib vs.Naproxen

Rofecoxib vs.Placebo

0.84 (0.51, 1.38) 3867

8364

2918

1.69 (1.07, 2.69)

0.79 (0.40, 1.55)

(65)

(35)

(84)

(Pts. with events)PYR

PYR = Patient-Years.Konstam et al., Circulation. 2001;104:2280-2288.

2525252525

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

2626262626

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

2727272727

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

2828282828


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

2929292929

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

3030303030

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

3131313131

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

3232323232









3333333333

Final Pooled Analysis Confirms and Broadens GI Safety Benefit for Rofecoxib (2003)

Confirmed Clinical Upper GI Events: Relative Risk with 95% CI


0.36 (0.24, 0.54) 8738Rofecoxbi vs.

0.52 (0.24, 1.12) 2700Rofecoxbi vs.

0.32 (0.15, 0.66) 889Rofecoxbi vs.

0.27 (0.14, 0.53) 4707Rofecoxbi vs.

0.46 (0.33, 0.64) 5391Rofecoxbi vs.

0.1 0.2 0.5 1 2 5 10

C:slide40_meta_rofe_gi_011705out_graphicsmet2sld_tempslide40s.rofe.gi.slide.ww.sgr -S.Kh(RY) Feb. 7, 2005 3:23:41 PM


Ibuprofen

PYR


Naproxen*

NSAIDs*

Diclofenac

VIGOR:Naproxen

(97)

(26)

(30)

(39)

(Pts. With Events)

(177)

Rofecoxib vs.

PYR = Patient-Years.*Excludes VIGOR.

3434343434

Ph IIb/III OA Investigator-Reported Thrombotic CV Events (2003)

Rofecoxib vs. Non-Naproxen NSAIDs

0 6 12 18 24 30

0

2

4

6

8

3358 1245 849 534 448 2611565 541 368 237 184 105

Patients at RiskRofecoxib

Non-Naproxen NSAIDs

C:km_120804out_graphicskm_tempkm.cvnnp069ci.pyars.skh.sgr -S.Kh(RY) Jan. 17, 2005 3:11:25 PM

Kaplan-Meier Estimates (95% CI)RR (95% CI): 0.98 (0.60, 1.62)p>0.05

Rofecoxib

Non-Naproxen NSAIDs†

Cum

ulat

ive

Inci

denc

e (%

)w

ith 9

5% C

I

Patients at RiskRofecoxib

Non-Naproxen NSAIDs†

† Ibuprofen, diclofenac, nabumetone.

Pts. with Events

5022

3535353535

Alzheimer’s Disease (PN 078 + 091) Confirmed Thrombotic CV Events (2003)

Rofecoxib vs. Placebo

m966combThrombAcol Jan. 4, 2005

Rofecoxib 25 mgPlacebo

1069 878 707 415 318 226 1851074 939 797 463 385 283 243

0 6 12 18 24 30 36Month

0

5

10

15

20C

umul

ativ

e In

cide

nce

(%)

with

95%

CI

Patients at Risk

Kaplan-Meier Estimates (95% CI)

RR (95% CI): 1.01 (0.67, 1.53)p>0.05

Rofecoxib 25 mg

Placebo

Pts. with Events

4248

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

3636363636

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



Rofecoxib vs.Non-Naproxen NSAIDs


Rofecoxib vs.Naproxen

Rofecoxib vs.Placebo


1.14 (0.77, 1.68) 5841Rofecoxbi vs. Placebo

0.93 (0.51, 1.69) 4222Rofecoxbi vs. Non-Naproxen NSAIDs

1.61 (1.04, 2.50) 10318Rofecoxbi vs. Naproxen

0.1 0.2 0.5 1 2 5 10

C:slide44_meta_rofe_aptc_03updt_011705out_graphicsmet2sld_tempslide44s.rofe.aptc.03updt.slide.ww.sgr -S.Kh(RY) Jan. 17, 2005 1:49:36 PM

1.14 (0.77, 1.68) 5841

10318

42220.93 (0.51, 1.69)

1.61 (1.04, 2.50)

PYR = Patient-Years.

(Pts. with events)PYR

(105)

(47)

(95)

3737373737









3838383838

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

3939393939


Overview





4040404040

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

4141414141

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

4242424242

APPROVe Confirmed Thrombotic CV Events (Sep-2004)

Kaplan-Meier Estimates (95% CI)

0 6 12 18 24 30 36

0

2

4

6

8

1287 1123 1050 986 935 898 411 1299 1192 1148 1079 1039 1002 470

1287 1123 1050 986 935 898 411 1299 1192 1148 1079 1039 1002 470

Patients at Risk

Rofecoxib 25mgPlacebo

Cumulative EventsRofecoxib 25mg

Placebo

C:APPROVe_111504km_4_g_PP_slideskm_4bout_graphicskmplot020305_tempkmplot020305.kmxcvx1111.2tbl.skh.sgr S.Kh(RY) Feb. 3, 2005 11:30:11 AM

RR (95% CI): 1.96 (1.20, 3.19)p=0.007

Placebo

Rofecoxib 25 mg

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%)

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MonthPatients at Risk Rofecoxib 25 mg

Placebo1287 1123 1050 986 935 898 4111299 1192 1148 1079 1039 1002 470

Pts. with Events

4525

4343434343

APPROVe Confirmed Thrombotic CV Events (Sep-2004)

Any Confirmed Thrombotic CV event‡

Cardiac EventsAcute myocardial infarctionFatal acute myocardial infarctionSudden cardiac deathUnstable angina pectoris

Cerebrovascular EventsFatal ischemic cerebrovascular strokeIschemic cerebrovascular strokeTransient ischemic attack

Peripheral Vascular Events

Placebo (N=1299)3315 Patient-Years

(25)(11)

(8)(3)(1)(4)(7)(0)(6)(2)(7)

0.750.330.240.090.030.120.210.000.180.060.21

(n)Rate†

Rofecoxib (N=1287)3041 Patient-Years

(n)Rate†

(45)

(30)

(20)

(1)(3)(7)(15

)(0)(11

)(5)(3)

1.480.990.660.030.100.230.490.000.360.160.10

† Rate per 100 Patient-Years.‡ Patients may be counted in more than one row but are only counted once within a row.

4444444444

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

4545454545

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

4646464646


Overview



Data Since Withdrawal– APPROVe Final Data and Exploratory Analyses of Risk

Factors– Thrombotic CV Events from CV Outcomes Study


4747474747

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

4848484848


1.92 (1.19, 3.11) 6386Total Cohort

2.71 (1.28, 6.24) 1687Increased Risk1.28 (0.65, 2.51) 4699Not Increased Risk

3.25 (0.98, 13.81) 1226Concomitant ASA User1.68 (0.99, 2.88) 5159Not Concomitant ASA User

9.59 (1.36, 416.36) 513History of Symtomatic ASCVD1.58 (0.95, 2.64) 5872No History of Symtomatic ASCVD

6.10 (1.36, 56.11) 539History of Diabetic1.55 (0.92, 2.61) 5847No History of Diabetic

0.1 0.2 0.5 1 2 5 10

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

Relative Risk with 95% CIFavors Rofecoxib Favors Placebo

Total Cohort

(Pts. with events)

Relative Risk (Rofecoxib/Placebo)

Incr. CV Risk†

ASA User

Hx DiabetesNo 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).

4949494949

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

5050505050

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.

5151515151

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.

Endpoint

Primary endpoint†

(ITT Analysis)

Relative Risk(95% CI)

0.76*(0.69, 0.83)

Cumulative Incidence (%) (Number of Pts. with Adenomas)

Rofecoxib 25 mgN=929

42 (376)

PlaceboN=956

56 (515)

5252525252


Overview



Data Since Withdrawal– APPROVe Final Data and Exploratory Analyses of Risk

Factors– Thrombotic CV Events from CV Outcomes Study


5353535353

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


Relative Risk (Rofecoxib/Placebo)

APPROVe

VICTOR*


1.67 (1.15, 2.43) 10563Pooled

1.92 (1.19, 3.11) 6385APPROVe

0.87 (0.41, 1.83) 2201VIP

3.14 (1.01, 9.75) 1976VICTOR

0.1 0.2 0.5 1 2 5 10

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Favors Rofecoxib Favors Placebo PYR

CV Outcomes Pooled Analysis

ViP*

*Interim data as of Feb 2005.

Pts withEvents

(116)

(72)

(28)

(16)

5454545454

NSAIDs controlled Placebo Controlled

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

Ra

te p

er

100

Pat

ient

-Ye

ars

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Pt. Years

Events

2390

5

1032

8

4047

22

4029

15

1665

5

183

1

512

2

640

5

630

4

1677

36

1891

19

3088

10

3346

10

1100

2

1105

4

963

12

1016

13

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

5555555555


Overview





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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 >23,000 patients targeted to complete 2006

11111 COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib Speaker: Ned S. Braunstein, MD Senior...

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Transcript of 11111 COX-2 FDA Advisory Committee Meeting 2005 Rofecoxib Speaker: Ned S. Braunstein, MD Senior...