Etanercept Enbrel Safety Review March 4, 2003

1
Etanercept (Enbrel) Safety ReviewMarch 4,
2003
2
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

C2
3
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

C3
4
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

C4
5
Etanercept Sustained Benefit With Corticosteroid
Reduction
Reduction in Corticosteroids
Long-Term Efficacy
10
30
TENDER
Plt 0.0001
JOINTS
25
Prednisone (mg/day)
SWOLLEN
JOINTS
20
5
Median Joint Count
15
10
5
0
0
4 Years N267
Baseline N385
0
1
2
3
4
5
6
Median (Interquartile range)
Time on Therapy (years)
Moreland 2002 ACR abstract 1427
C5
6
Etanercept Consistent and Substantial Efficacy
Percentage of Patients Achieving ACR 20
Bathon J. N Engl J Med. 20003431586-1593.
Moreland LW, et al. N Engl J Med.
1997337141-147. Weinblatt ME, et al. N Engl
J Med. 1999340253-259. Moreland L, et al. Ann
Intern Med. 1999130478-486. European Etanercept
Investigators Group. EULAR 2000, Nice, France.
C6
7
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

C7
8
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
  (n1,000)
• Combination DMARD studies (n 800)
• Observational studies (over 12,000 patients)
• Juvenile rheumatoid arthritis registry (n600)
• RADIUS I and II observational studies (n10,000)
• European RA registries (n 1,600)
• Germany
• Sweden
• United Kingdom

C8
9
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

C9
10
Over 230,000 Patient-Yearsof Etanercept
Experience
C10
11
Serious Adverse Event Rates in Etanercept
Patients Similar to Placebo and Stable Over Time
SAE / patient-year in North America
Controlled Trials
Long-Term Etanercept
C11
12
Serious Infection Rates in Etanercept Patients
Similar to Placebo and Stable Over Time
Serious Infections / patient-year in North America
Controlled Trials
Open-label Etanercept
C12
13
Presentation Outline

• Introduction Dan Burge, MD
• Etanercept Clinical Profile
• Pharmacovigilance
• General Safety
• Malignancy
• Epidemiology of Lymphoma in RA Alan Silman, MD
• Lymphoma and Etanercept Dan Burge, MD
• Heart Failure Experience
• Ongoing Pharmacovigilance
• Summary

C13
14
The Surveillance, Epidemiology, and End Results
(SEER) Program

• National Cancer Institutes 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

Standardized Incidence Ratio Observed/Expected
C14
15
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

C15
16
Malignancies Rates are Stable Over Time

All Etanercept Clinical Trials Malignancies / 100
patient-years
C16
17
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
0
1
2
3
4
5
6
7
8
9
10
Risk Ratio
1. Exclude basal cell and squamous cell.
C17
18
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

C18
19
Background Epidemiology of Lymphoma in RA

• Alan Silman, MD
• Director, Arthritis Research Campaigns
  Epidemiology Research Unit
• University of Manchester Medical School
• ARC Professor of Rheumatic Disease
• Epidemiology,University of Manchester
• Manchester, United Kingdom

C19
20
Components of Lymphoma Risk in Etanercept
Treated Patients

• 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

C20
21
Measures of Risk

• Standardized Incidence Ratio Observed Expected
  
• Attributable (Absolute) Risk Observed
  Expected
• Attributable Risk Fraction Observed
  Expected Expected

C21
22
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

C22
23
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

C23
24
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

C24
25
Variation in Lymphoma IncidenceRA Populations
C25
26
Increased Risk of LymphomaIn RA Patients
Based on data generated prior to the
availability of TNF antagonists
C26
27
Available Evidence on Lymphoma

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

C27
28
SIR for Lymphoma in Etanercept Clinical Trials
Relative to General Population
Lymphoma during clinical trials
C28
29
SIR for Lymphoma in Etanercept Clinical Trials
Relative to General Population
Lymphoma during clinical trials
Lymphoma SIR by disease duration
Time to onset Median years (range) 2.6
(0.4-4.8)
C29
30
SIR for Lymphoma in Etanercept Clinical Trials
Relative to General Population
Lymphoma during clinical trials
Lymphoma cases during and after clinical trials
completion
C30
31
SIR for Lymphoma in Etanercept Clinical Trials
Relative to RA Population
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
C31
32
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, 2002
C32
33
Lymphoma Reporting Rates from Commercial
Experience are Stable Over Time
200
By report date
160
By diagnosis date
120
Reports per 100,000 pt-yrs
80
40
0
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
Data through November 2,2002. Error bars
represent the upper limit of exact 95 confidence
intervals.
C33
34
Lymphoma Subtypes

• Clinical Trials and Post-marketing Reports
  (Pooled)

Proportions represented in SEER database
C34
35
Histology of Non-Hodgkins 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 Waldenstroms 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
reports 3 Kamel et al. J. Rheum. 1999
C35
36
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
  (SIR2.31)
• 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

C36
37
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

C37
38
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

C38
39
Etanercept CHF Trials Design
Analysis of Combined Data
RENEWAL (n 2048)
Trials discontinued after pre-specified interim
analysis determined study was unlikely to
demonstrate benefit.
C39
40
Etanercept CHF Trials Primary Efficacy Endpoint
All Cause Mortality/CHF Hospitalization
Unadjusted Analysis
Renaissance 25mg vs. placebo (2x/wk) 25mg vs.
placebo (3x/wk) Recover 25mg vs. placebo
(1x/wk) 25mg vs. placebo (2x/wk) Renewal BIW
TIW vs. placebo
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
0.5
1.0
1.5
2.0
Risk Ratio
Results from Cox model. Both analyses include
strata (NYHA class and use of beta-blockers)
C40
41
Renaissance Randomization Imbalances Favor
Placebo Group
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 D
BP - mm Hg (median) 68 66 64 Anti-arrhythmics
() 15 22 21 6-min walk - meters (median)
295 293 288
C41
42
Etanercept CHF Trials Primary Efficacy Endpoint
All Cause Mortality/CHF Hospitalization
Analysis with Covariates
Unadjusted Analysis
Renaissance 25mg vs. placebo (2x/wk) 25mg vs.
placebo (3x/wk) Recover 25mg vs. placebo
(1x/wk) 25mg vs. placebo (2x/wk) Renewal BIW
TIW vs placebo
RR 1.09, p 0.55
RR 1.21, p 0.17
RR 1.11, p 0.43
RR 1.23, p 0.13
RR 0.98, p 0.92
RR 1.01, p 0.97
RR 0.90, p 0.56
RR 0.87, p 0.45
RR 1.01, p 0.90
RR 1.10, p 0.33
0.5
1.0
1.5
2.0
0.5
1.0
1.5
2.0
Risk Ratio
Risk Ratio
Results from Cox model. Both analyses include
strata (NYHA class and use of beta-blockers)
C42
43
Etanercept CHF Trials Analysis of All Cause
Mortality (Secondary Efficacy Endpoint)
Unadjusted Analysis
Analysis with Covariates
Renaissance 25mg vs. placebo (2x/wk) 25mg
vs. placebo (3x/wk) Recover 25mg vs. placebo
(1x/wk) 25mg vs. placebo (2x/wk) Renewal
BIW TIW vs. placebo
RR 1.27, p 0.24
RR 1.13, p 0.55
RR 1.37, p 0.12
RR 1.22, p 0.33
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
0.5
1.0
1.5
2.0
2.5
Risk Ratio
Risk Ratio
Results from Cox model. Both analyses include
strata (NYHA class and use of beta-blockers)
C43
44
New Onset CHF in North American Rheumatic Disease
Trials

• Controlled Trials
• Control 2
• Etanercept 2
• All Trials
• Observed 7
• Expected1 15.2

1. Kannel WB, J Clin Epidemiol 53 (2000)
C44
45
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.

C45
46
Conclusions

• 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

C46
47
Extensive Proactive Pharmacovigilance

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

C47
48
Ongoing and Future Pharmacovigilance
Programs
C48
49
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

C49
50
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

C50