TNF Antagonists Safety Review Focus on Etanercept Enbrel and

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TNF Antagonists Safety Review Focus on Etanercept Enbrel and Powered By Docstoc
					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                        Alan Silman, MD
Division of Cardiology                   Epidemiology Research Unit
The New York Hospital                    University of Manchester Medical School
Cornell University Medical Center        ARC Professor of Rheumatic Disease
New York, New York                       Epidemiology,University of Manchester
                                         Manchester, United Kingdom
Mary K. Crow, MD
Dept. of Rheumatology                    Julie Vose, MD
Cornell University                       Department of Internal Medicine
Hospital for Special Surgery             Section of Oncology/Hematology
New York, New York                       University of Nebraska Medical Center
                                         Omaha, Nebraska
Annette Langer-Gould, MD
Dept. of Health Research and Policy
Stanford University School of Medicine
Palo Alto, California
                                                                                   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
                      Long-Term Efficacy                                               Reduction in Corticosteroids
                     30                                                        10
                                             TENDER
                                             JOINTS                                                        P< 0.0001
                     25




                                                             Prednisone (mg/day)
Median Joint Count




                                             SWOLLEN
                     20                      JOINTS

                     15                                                            5

                     10

                     5

                     0                                                             0
                                                                                            Baseline        4 Years
                          0    1    2    3    4    5     6
                                                                                             N=385           N=267
                               Time on Therapy (years)                                     Median (Interquartile range)

Moreland 2002 ACR abstract 1427                                                                                           C5
                    Etanercept: Consistent and
                       Substantial Efficacy
                        Percentage of Patients Achieving ACR 20
                 72%               75%
                                                                        71%                70%
                                                      59%




                ERA             DMARD              DMARD            DMARD     DMARD
                Trial           Failures           Failures         Failures  Failures
             Monotherapy        Phase 2            Phase 3         MTX Combo Phase 3/EU
               2 years         Monotherapy        Monotherapy          6 months        Monotherapy
                                3 months           6 months                             6 months

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.
                                                                                                            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)
     Germany
     Sweden
     United 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-Years
        of Etanercept Experience

                      Clinical Trial     Commercial Experience
FDA Advisory
Committee Date     Patients     Pt-Yrs   Patients     Pt-Yrs
May 1998              745         491       --          --

August 2001          2664       3389     >111,000    >116,000

March 2003           3839       8336     >150,000    >230,000


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

                                                                 C10
     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

              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




                                                                                          C11
           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

                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




                                                                                                C12
               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
  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

Standardized Incidence Ratio = Observed/Expected



                                                   C14
  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 gender
                                                                            C15
    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
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
               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
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
    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
              Measures of Risk

• Standardized Incidence Ratio = Observed
                                 Expected

• 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 Populations
                   Incidence per 100 Person Years

0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00




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                                                                 C25
       Increased Risk of Lymphoma
              In 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


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


                                                                        C26
Available Evidence on Lymphoma

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




                                         C27
 SIR for Lymphoma in Etanercept Clinical
   Trials Relative to General Population
Lymphoma during clinical trials
Cases   Patient-years   Expected   SIR    95% Confidence Intervals
  6         8336          2.59     2.31         0.85 – 5.03




                                                                     C28
    SIR for Lymphoma in Etanercept Clinical
      Trials Relative to General Population
  Lymphoma during clinical trials
   Cases    Patient-years     Expected        SIR       95% Confidence Intervals
     6          8336               2.59       2.31              0.85 – 5.03

Lymphoma SIR by disease duration
 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



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




                                                                                   C29
 SIR for Lymphoma in Etanercept Clinical
   Trials Relative to General Population

Lymphoma during clinical trials
Cases   Patient-years   Expected    SIR     95% Confidence Intervals
  6         8336          2.59     2.31           0.85 – 5.03




Lymphoma cases during and after clinical trials completion
Cases   Patient-years   Expected    SIR     95% Confidence Intervals
  9        > 8336        > 2.59    < 3.47         1.59 – 6.59




                                                                       C30
  SIR for Lymphoma in Etanercept Clinical
      Trials Relative to RA Population


Lymphoma during clinical trials (relative to general population)
Cases    Patient-years     Expected          SIR    95% Confidence Intervals
  6          8336             2.59           2.31         0.85 – 5.03




Lymphoma cases in clinical trials (relative to RA population)*
Cases    Patient-years     Expected          SIR    95% Confidence Intervals
  6          8336             5.70           1.05         0.39 – 2.29

*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, 2002
                                                      C32
                                     Lymphoma Reporting Rates from
                                       Commercial Experience are
                                           Stable Over Time
                             200


                                                                                                            By report date
                             160                                                                            By diagnosis date
Reports per 100,000 pt-yrs




                             120



                             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
          Lymphoma Subtypes


 Clinical Trials and Post-marketing Reports (Pooled)

                             Hodgkins       NHL
                               (%)          (%)
  Observed                      14           86
  Expected*                     13           87




*Proportions represented in SEER database
                                                       C34
 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 reports
3 Kamel et al. J. Rheum. 1999
                                                                                                C35
                   Conclusions
 Lymphoma 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, 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
     Etanercept CHF Trials Design

                       Placebo (n = 309)
RENAISSANCE            Etanercept 25mg x biw (n = 308)
    (n = 925)          Etanercept 25mg x tiw (n = 308)    Analysis of
                                                          Combined
                                                             Data
                       Placebo (n = 373)
    RECOVER                                               RENEWAL
                       Etanercept 25mg x q wk (n = 375)   (n = 2048)
    (n = 1123)
                       Etanercept 25mg x biw (n = 375)




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


                                                                        C39
Etanercept CHF Trials Primary Efficacy Endpoint:
All Cause Mortality/CHF Hospitalization
                                          Unadjusted Analysis*


            Renaissance
              25mg vs. placebo (2x/wk)                      RR = 1.21, p = 0.17

              25mg vs. placebo (3x/wk)                      RR = 1.23, p = 0.13

            Recover
              25mg vs. placebo (1x/wk)                      RR = 1.01, p = 0.97

              25mg vs. placebo (2x/wk)                      RR = 0.87, p = 0.45

            Renewal
             BIW + TIW vs. placebo                          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
  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

DBP - mm Hg (median)             68           66             64

Anti-arrhythmics (%)             15           22             21

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



                                                                      C41
Etanercept CHF Trials Primary Efficacy Endpoint:
All Cause Mortality/CHF Hospitalization
                             Unadjusted Analysis*                     Analysis with Covariates*


 Renaissance
 25mg vs. placebo (2x/wk)                      RR = 1.21, p = 0.17                  RR = 1.09, p = 0.55

 25mg vs. placebo (3x/wk)                      RR = 1.23, p = 0.13                  RR = 1.11, p = 0.43

 Recover
 25mg vs. placebo (1x/wk)                      RR = 1.01, p = 0.97                 RR = 0.98, p = 0.92

 25mg vs. placebo (2x/wk)                      RR = 0.87, p = 0.45                 RR = 0.90, p = 0.56

 Renewal
 BIW + TIW vs placebo                          RR = 1.10, p = 0.33                RR = 1.01, p = 0.90


                            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
    Etanercept CHF Trials: Analysis of All Cause
      Mortality (Secondary Efficacy Endpoint)
                          Unadjusted Analysis*                            Analysis with Covariates*

  Renaissance
    25mg vs. placebo
                                                 RR = 1.27, p = 0.24                          RR = 1.13, p = 0.55
   (2x/wk)
    25mg vs. placebo
                                                 RR = 1.37, p = 0.12                          RR = 1.22, p = 0.33
   (3x/wk)

  Recover
    25mg vs. placebo
                                                 RR = 0.68, p = 0.16                          RR = 0.66, p = 0.13
   (1x/wk)
    25mg vs. placebo
   (2x/wk)                                       RR = 0.83, p = 0.47                          RR = 0.85, p = 0.55

  Renewal
   BIW + TIW
   vs. placebo                              RR = 1.13, p = 0.39                             RR = 0.96, p = 0.79

                  0.0   0.5   1.0   1.5    2.0      2.5            0.0   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
  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
                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
                 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
Extensive Proactive Pharmacovigilance

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




                                                     C47
               Ongoing and Future
           Pharmacovigilance Programs

 Prospective Program                            Planned     Current or
                                  Status        Duration     Planned
                                                 (yrs.)     Enrollment
North American long term          5 years         10           1100
clinical trials                 experience

EU long term clinical trials      4 years          4            549
                                experience
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

				
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