etanercept (enbrel ® ) safety review march 4, 2003

Etanercept (Enbrel®) Safety Review

March 4, 2003

Presentation Outline

Introduction Dan Burge, MD

Etanercept Clinical Profile

Pharmacovigilance

General Safety

Malignancy/Lymphoma

Epidemiology of Lymphoma in RA Alan Silman, MD

Lymphoma and Etanercept Dan Burge, MD

Heart Failure Experience

Ongoing Pharmacovigilance

Summary

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Consultants

Jeffrey Borer, MD

Division of Cardiology

The New York Hospital

Cornell University Medical Center

New York, New York

Mary K. Crow, MD

Dept. of Rheumatology

Cornell University

Hospital for Special Surgery

New York, New York

Annette Langer-Gould, MD

Dept. of Health Research and Policy

Stanford University School of Medicine

Palo Alto, California

Alan Silman, MD

Epidemiology Research Unit

University of Manchester Medical School

ARC Professor of Rheumatic Disease

Epidemiology,University of Manchester

Manchester, United Kingdom

Julie Vose, MD

Department of Internal Medicine

Section of Oncology/Hematology

University of Nebraska Medical Center

Omaha, Nebraska

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Etanercept: Distinctive Properties

• Only soluble receptor TNF antagonist

• Fully human protein

• Low immunogenicity

• Does not bind compliment and is not associated with compliment mediated cell lysis

• Dosing schedule maintains stable serum concentrations

• No pharmacokinetic interaction with methotrexate

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Etanercept: Sustained Benefit With Corticosteroid Reduction

4 YearsN=267

10

5

0

P< 0.0001

Pre

dn

iso

ne

(mg

/day

)

0

5

10

15

20

25

30

0 1 2 3 4 5 6

Time on Therapy (years)

Med

ian

Jo

int

Co

un

t

TENDERJOINTS

SWOLLENJOINTS

Reduction in CorticosteroidsLong-Term Efficacy

Median (Interquartile range)

Moreland 2002 ACR abstract 1427 C5

BaselineN=385

72% 75%

59%

71% 70%

ERATrial

Monotherapy2 years

DMARDFailures

MTX Combo6 months

DMARDFailuresPhase 3

Monotherapy6 months

DMARDFailuresPhase 2

Monotherapy3 months

DMARDFailures

Phase 3/EUMonotherapy

6 months

Percentage of Patients Achieving ACR 20

Bathon J. N Engl J Med. 2000:343:1586-1593. Moreland LW, et al. N Engl J Med. 1997;337:141-147. Weinblatt ME, et al. N Engl J Med. 1999;340:253-259. Moreland L, et al. Ann Intern Med. 1999;130:478-486.European Etanercept Investigators Group. EULAR 2000, Nice, France.

Etanercept: Consistent and Substantial Efficacy

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Etanercept: Milestones

1990 P75-TNF receptor cloned

1993 First administration to RA patient

1998 FDA approval for RA (alone or with MTX)

1999 FDA approval for JRA

2000 FDA approval as initial therapy for RA

FDA approval for inhibition of radiographic progression

2001 FDA Arthritis Advisory re: TNF Antagonists Safety

2002 FDA approval for psoriatic arthritis (alone or with MTX)

2002 FDA approval of three year efficacy and safety data in RA

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Etanercept Pharmacovigilance Program

• Ongoing clinical studies (over 3,000 patients) Long-term open label extension studies (n ~1,600)

North America and Europe Safety trial of RA patients with comorbidities (n=1,000) Combination DMARD studies (n ~ 800)

• Observational studies (over 12,000 patients) Juvenile rheumatoid arthritis registry (n=600) RADIUS I and II: observational studies (n=10,000) European RA registries (n ~ 1,600)

GermanySwedenUnited Kingdom

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Etanercept Pharmacovigilance Program (continued)

• Epidemiologic studies Ingenix UnitedHealthcare (n ~ 50,000 rheumatic disease patients): establishing background incidence of adverse events in rheumatic disease populations

• Continued surveillance of facilitated post-marketing adverse event reports 1.2 Million phone contacts in 150,000 patients Each call is an opportunity for reporting 88% adverse event reports are patient initiated Half of health care provider reports are patient initiated

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Over 230,000 Patient-Yearsof Etanercept Experience

Pt-Yrs Pt-YrsPatientsPatientsCommittee DateFDA Advisory

>116,000>111,00033892664August 2001

>230,000>150,00083363839March 2003

----491745May 1998

Commercial ExperienceClinical Trial

Clinical Trials:1084 patients in 5th year of therapy390 patients in 6th year of therapy

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SAE / patient-year in North America

Control Etanercept Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Overall

Early RA 0.11 0.09 0.11 0.08 0.08 0.08 0.19 -- 0.09

Advanced RA 0.20 0.13 0.14 0.13 0.16 0.11 0.12 0.25 0.14

Controlled Trials Long-Term Etanercept

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Serious Adverse Event Rates in Etanercept Patients Similar to Placebo and

Stable Over Time

Serious Infection Rates in Etanercept Patients Similar to Placebo and

Stable Over Time

Serious Infections / patient-year in North America


Early RA 0.031 0.024 0.031 0.022 0.030 0.028 0.034 -- 0.028

Advanced RA 0.050 0.043 0.054 0.033 0.048 0.037 0.050 0.00 0.044

Controlled Trials Open-label Etanercept

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Introduction Dan Burge, MD

Etanercept Clinical Profile

Pharmacovigilance

General Safety

MalignancyEpidemiology of Lymphoma in RA Alan Silman, MD


Heart Failure Experience

Ongoing Pharmacovigilance

Summary

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The Surveillance, Epidemiology, and End Results (SEER) Program

• National Cancer Institute’s cancer registry• Data based on 11 population-based cancer

registries and 3 supplemental registries• Covers approximately 14% of US population• Provides incidence, prevalence and mortality

data for cancers

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Standardized Incidence Ratio = Observed/Expected

Total Malignancies Not Increased in Clinical Trials

Controlled Trials All Trials Control Etanercept Etanercept

Observed 5 11 55

Expected* 3.57 8.80 56.2

SIR 1.40 1.25 0.98

*Derived from NCI SEER database, adjusted for age and genderC15

Malignancies Rates are Stable Over Time

All Etanercept Clinical Trials

Malignancies / 100 patient-years

Controlled Trial All Etanercept Experience


1.0 0.9 0.8 0.6 0.6 1.1 0.8 1.4 0.8

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1. Exclude basal cell and squamous cell.

SIR with 95% Confidence Intervals for All Malignancies in Clinical Trials

All Sites

Breast

Digestive

Respiratory

Female Genital

Male Genital

Urinary System

Oropharyngeal

Lymphoma

Endocrine

Skin1

Neurologic

Leukemia

Myeloma

Other

Risk Ratio0 1 2 3 4 5 6 7 8 9 10

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Introduction Dan Burge, MDEtanercept Clinical ProfilePharmacovigilanceGeneral SafetyMalignancy/Lymphoma


Lymphoma and Etanercept Dan Burge, MDHeart Failure ExperienceOngoing PharmacovigilanceSummary

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Background Epidemiology of Lymphoma in RA

Alan Silman, MD Director, Arthritis Research Campaign’s

Epidemiology Research Unit

University of Manchester Medical School

ARC Professor of Rheumatic Disease

Epidemiology,University of Manchester

Manchester, United Kingdom

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• Background population risk• Risk attributable to RA per se• Increased risk attributable to severe RA• Increased risk attributable to prior

exposure to:– Other immunosuppressives

(azathioprine, methotrexate)– Other biologic agents

Components of Lymphoma Risk

in Etanercept Treated Patients

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Measures of Risk

• Standardized Incidence Ratio = ObservedExpected

• Attributable (Absolute) Risk = Observed – Expected

• Attributable Risk Fraction = Observed – Expected

Expected

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Example

• Observed Incidence= 3/1000 pyr

• Expected Incidence= 2/1000 pyr

• SIR = 3/2 = 1.5

• Absolute Risk = 3/1000 – 2/1000 = 1/1000 pyr

• ARF = 3/1000 – 2/1000 = 0.33 (33%) 3/1000

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Considerations in Determination of Risk

• Background incidence in comparable population• Accurate exposure data

Completeness of follow-up Population characterization (age, gender, race, etc.) Disease/treatment characterization

• Accurate and complete detection of incident cases Case ascertainment Case validation

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Other Methodological Issues

• Lymphoma rare and risk estimates have wide confidence intervals

• Surveillance bias – are early lymphomas likely to be due to drug or better detection

• Influence of dose– Ever/never, duration etc

• Influence of length of follow up– Follow up periods may not have equivalent risk

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Variation in Lymphoma Incidence:

RA PopulationsIncidence per 100 Person Years

0.000.020.040.060.080.100.120.140.160.180.20

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Increased Risk of LymphomaIn RA Patients*

Reference SIR Lower CL Upper CL

Isomaki 2.7 1.9 3.7

Gridley 1.9 1.3 2.6

Mellenkjaer 2.4 1.9 2.9

Thomas 2.1 1.7 2.6

All 2.2 2.0 2.5

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*Based on data generated prior to the availability of TNF antagonists

Available Evidence on Lymphoma

• Clinical Trials• Post-Marketing Safety Surveillance• Histology• Conclusions

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SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population

8336

Patient-years

0.85 – 5.032.312.596

95% Confidence IntervalsSIRExpectedCases

Lymphoma during clinical trials

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8336

Patient-years

0.85 – 5.032.312.596



Time to onset: Median years (range): 2.6 (0.4-4.8)

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Population Cases Patient-years Expected SIR 95% Confidence Intervals

Early 2 1942 0.582 3.44 0.42 – 12.41

Advanced 4 6394 2.012 1.99 0.54 – 5.09

Lymphoma SIR by disease duration


8336

Patient-years

0.85 – 5.032.312.596


> 8336

Patient-years

1.59 – 6.59< 3.47> 2.59 9



Lymphoma cases during and after clinical trials completion

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SIR for Lymphoma in Etanercept Clinical Trials Relative to RA Population

8336

Patient-years

0.85 – 5.032.312.596


8336

Patient-years

0.39 – 2.291.055.70 6


Lymphoma during clinical trials (relative to general population)

Lymphoma cases in clinical trials (relative to RA population)*

*Benchmark factor of 2.2 for RA population

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Post-Marketing Lymphoma Reports

Reported cases*: 70 / 140,000 pts

Reporting rate: 0.3 / 1000 pt-yrs

Demographic characteristics of patients

Female 69%

Mean age 61 years

Past or concurrent MTX 60%

*Data through November 2, 2002C32

0

40

80

120

160

200

11/98-4/99 5/99-10/99 11/99-4/00 5/00-10/00 11/00-4/01 5/01-10/01 11/01-4/02 5/02-10/02

Re

po

rts

pe

r 1

00

,00

0 p

t-y

rs

By report date

By diagnosis date

Data through November 2,2002. Error bars represent the upper limit of exact 95% confidence intervals.

Lymphoma Reporting Rates from Commercial Experience are

Stable Over Time

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Lymphoma Subtypes

Clinical Trials and Post-marketing Reports (Pooled)

Hodgkins(%)

NHL(%)

Observed 14 86

Expected* 13 87

*Proportions represented in SEER databaseC34

Histology of Non-Hodgkin’s Lymphomas Similar to RA Population1

Histology Etanercept Reports2 RA3 Non-RA Controls3

Diffuse large cell 43% 38% 43%

Mantle cell 5% 0% 2%

Peripheral T cell 8% 2% 4%

Follicular 16% 33% 27%

Small lymphocytic

lymphoma/B-cell CLL 22% 14% 12%

Waldenstrom’s Macro. 5% NA NA

Marginal zone 0% 7% 0%

Other NA 2% 2%

1 Histopathology report available in 67% of lymphoma reports 2 Data through November 2, 2002, combined clinical trials and post-marketing reports3 Kamel et al. J. Rheum. 1999 C35

ConclusionsLymphoma Incidence Consistent with Background RA

• Lymphoma reports with etanercept are rare • Comprehensive pharmacovigilance program has

been in place for 4-1/2 years• The rate observed in clinical trials is consistent with

the expected rate observed for RA (SIR=2.31)• Post-marketing experience is compatible with clinical

trial experience• The proportion of histologic subtypes comparable

with background• Six years of sustained therapy has revealed no

increase in incidence

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Amgen Initiatives• Update label to describe experience

Submitted October 2002 (Adverse Reactions) Describes lymphoproliferative disorders from post-marketing and clinical studies

• Lymphoproliferative disorders, including lymphoma, have been reported from patients on etanercept

• Rates similar to RA population

• Presentations at scientific meetings ACR, Sabath et al, Arth.Rheum., 2002 EULAR, Sabath et al, Ann Rheum Dis., 2002

• Large, long-term clinical trials• Observational studies / registries in over 12,000 patients• Epidemiologic studies• Safety surveillance of post-marketing reports

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Introduction Dan Burge, MDEtanercept Clinical ProfilePharmacovigilanceGeneral SafetyMalignancy/Lymphoma



Heart Failure ExperienceOngoing PharmacovigilanceSummary

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Etanercept CHF Trials Design

RENEWAL (n = 2048)

Trials discontinued after pre-specified interim analysis determined study was unlikely to demonstrate benefit.

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Analysis ofCombined

Data

RENAISSANCE (n = 925)

Placebo (n = 309)

Etanercept 25mg x biw (n = 308)

Etanercept 25mg x tiw (n = 308)

RECOVER (n = 1123)

Placebo (n = 373)

Etanercept 25mg x q wk (n = 375)

Etanercept 25mg x biw (n = 375)

*Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers)

Etanercept CHF Trials Primary Efficacy Endpoint: All Cause Mortality/CHF Hospitalization

Unadjusted Analysis*

Renaissance

25mg vs. placebo (2x/wk)


Recover



Renewal

BIW + TIW vs. placebo

0.5 1.0 1.5 2.0

Risk Ratio

RR = 1.21, p = 0.17

RR = 1.23, p = 0.13

RR = 1.01, p = 0.97

RR = 0.87, p = 0.45

RR = 1.10, p = 0.33

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Etanercept

Placebo 25 mg biw 25 mg tiw (n = 309) (n = 308) (n = 308)

Afib/flutter(%) 29 36 36

CABG (%) 33 42 41

SBP - mm Hg (median) 110 108 105

DBP - mm Hg (median) 68 66 64

Anti-arrhythmics (%) 15 22 21

6-min walk - meters (median) 295 293 288

Renaissance: Randomization Imbalances Favor Placebo Group

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Etanercept CHF Trials Primary Efficacy Endpoint: All Cause Mortality/CHF Hospitalization

0.5 1.0 1.5 2.0

Risk Ratio

RR = 1.09, p = 0.55

RR = 1.11, p = 0.43

RR = 0.98, p = 0.92

RR = 0.90, p = 0.56

RR = 1.01, p = 0.90

Analysis with Covariates*



Renaissance



Recover



Renewal

BIW + TIW vs placebo

0.5 1.0 1.5 2.0

Risk Ratio

RR = 1.21, p = 0.17

RR = 1.23, p = 0.13

RR = 1.01, p = 0.97

RR = 0.87, p = 0.45

RR = 1.10, p = 0.33

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Etanercept CHF Trials: Analysis of All Cause Mortality (Secondary Efficacy Endpoint)


Renaissance



Recover



Renewal BIW + TIW

vs. placebo

Risk Ratio Risk Ratio

Analysis with Covariates*

0.5 1.0 1.5 2.0 2.50.0

RR = 1.27, p = 0.24 RR = 1.13, p = 0.55

RR = 1.37, p = 0.12 RR = 1.22, p = 0.33

0.5 1.0 1.5 2.0 2.50.0

RR = 0.68, p = 0.16 RR = 0.66, p = 0.13

RR = 0.83, p = 0.47 RR = 0.85, p = 0.55

RR = 1.13, p = 0.39 RR = 0.96, p = 0.79

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New Onset CHF in North American Rheumatic Disease Trials

Controlled TrialsControl 2

Etanercept 2

All TrialsObserved 7

Expected1 15.2

1. Kannel WB, J Clin Epidemiol 53 (2000)

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Etanercept Label

Precaution: Patients with Heart Failure

Two large clinical trials evaluating the use of ENBREL in the treatment of heart failure were terminated early due to lack of efficacy. Although the studies did not demonstrate harm, there was a suggestion of worse heart failure outcomes with ENBREL treatment in one of the two trials. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL. Physicians should exercise caution when using ENBREL in patients who also have heart failure.

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• Two large heart failure studies were discontinued due to lack of efficacy

• One of two studies showed a trend toward worse heart failure outcomes that diminishes with adjustment for covariates

• No evidence from rheumatic disease trials that etanercept increases risk for CHF

• Proactive communication in product label and at scientific meetings

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Conclusions

• Large, long term clinical trials• Epidemiologic studies• Observational studies and registries• Safety surveillance and post-marketing reports• Proactive risk communication

Extensive Proactive Pharmacovigilance

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Ongoing and Future Pharmacovigilance Programs

Prospective Program

Status

Planned Duration

(yrs.)

Current or Planned

Enrollment

North American long term clinical trials

5 years experience

10 1100

EU long term clinical trials 4 years experience

4 549

RADIUS I (all DMARDS) Fully enrolled 5 5000

RADIUS II (etanercept) 80% enrolled 5 5000

JRA Registry > 50% enrolled 3 600

EU Registries Enrolling 5-8 1600 (approx.)

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Nearing Completion of Post-Marketing Commitment for Long Term Follow-up

• Submitted 3 year data: currently labeled• Submitted 4 year data: January 2003• Plan to submit 5 year data: August 2003

Ongoing Amgen commitment: continued follow-up for additional 5 years for a total of 10 years

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Etanercept Summary

• Unique mechanism of action

• Established track record Over 9 years experience treating rheumatic

disease patients Over 4 years of clinical practice experience

• Robust pharmacovigilance program

• Safety profile well established

• Benefit / risk highly favorable

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etanercept (enbrel ® ) safety review march 4, 2003

Documents

years n

ra fda approval

observational studies

comorbidities n

n engl j

combination dmard studies

ra c7 slide

md lymphoma