Etanercept (Enbrel ® ) Safety Review March 4, 2003.
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Transcript of 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
C2
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
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
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
C6
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
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
C8
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
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
C10
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
C11
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
Control Etanercept Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Overall
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
C12
Presentation Outline
Introduction Dan Burge, MD
Etanercept Clinical Profile
Pharmacovigilance
General Safety
MalignancyEpidemiology of Lymphoma in RA Alan Silman, MD
Lymphoma and Etanercept Dan Burge, MD
Heart Failure Experience
Ongoing Pharmacovigilance
Summary
C13
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
C14
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
Control Etanercept Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Overall
1.0 0.9 0.8 0.6 0.6 1.1 0.8 1.4 0.8
C16
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
C17
Presentation Outline
Introduction Dan Burge, MDEtanercept Clinical ProfilePharmacovigilanceGeneral SafetyMalignancy/Lymphoma
Epidemiology of Lymphoma in RA Alan Silman, MD
Lymphoma and Etanercept Dan Burge, MDHeart Failure ExperienceOngoing PharmacovigilanceSummary
C18
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
C19
• 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
C20
Measures of Risk
• Standardized Incidence Ratio = ObservedExpected
• Attributable (Absolute) Risk = Observed – Expected
• Attributable Risk Fraction = Observed – Expected
Expected
C21
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
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
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
Variation in Lymphoma Incidence:
RA PopulationsIncidence per 100 Person Years
0.000.020.040.060.080.100.120.140.160.180.20
C25
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
C26
*Based on data generated prior to the availability of TNF antagonists
Available Evidence on Lymphoma
• Clinical Trials• Post-Marketing Safety Surveillance• Histology• Conclusions
C27
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
C28
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
Time to onset: Median years (range): 2.6 (0.4-4.8)
C29
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
SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population
8336
Patient-years
0.85 – 5.032.312.596
95% Confidence IntervalsSIRExpectedCases
> 8336
Patient-years
1.59 – 6.59< 3.47> 2.59 9
95% Confidence IntervalsSIRExpectedCases
Lymphoma during clinical trials
Lymphoma cases during and after clinical trials completion
C30
SIR for Lymphoma in Etanercept Clinical Trials Relative to RA Population
8336
Patient-years
0.85 – 5.032.312.596
95% Confidence IntervalsSIRExpectedCases
8336
Patient-years
0.39 – 2.291.055.70 6
95% Confidence IntervalsSIRExpectedCases
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
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
C33
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
C36
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
Presentation Outline
Introduction Dan Burge, MDEtanercept Clinical ProfilePharmacovigilanceGeneral SafetyMalignancy/Lymphoma
Epidemiology of Lymphoma in RA Alan Silman, MD
Lymphoma and Etanercept Dan Burge, MD
Heart Failure ExperienceOngoing PharmacovigilanceSummary
C38
Etanercept CHF Trials Design
RENEWAL (n = 2048)
Trials discontinued after pre-specified interim analysis determined study was unlikely to demonstrate benefit.
C39
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)
25mg vs. placebo (3x/wk)
Recover
25mg vs. placebo (1x/wk)
25mg vs. placebo (2x/wk)
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
C40
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
C41
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*
*Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers)
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
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
C42
*Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers)
Etanercept CHF Trials: Analysis of All Cause Mortality (Secondary Efficacy Endpoint)
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
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
C43
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)
C44
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
• 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
Conclusions
• Large, long term clinical trials• Epidemiologic studies• Observational studies and registries• Safety surveillance and post-marketing reports• Proactive risk communication
Extensive Proactive Pharmacovigilance
C47
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.)
C48
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
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