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Enbrel in Psoriasis

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					                                      ENBREL® (etanercept) in the Treatment of Psoriasis




        Overview

•   Indications
•   Psoriasis: A Debilitating Disease
•   Psoriasis: An Immune-Mediated Disease
•   ENBREL: A New Approach to Psoriasis Management
•   ENBREL Clinical Trials in Psoriasis
    – Global Phase 3 Study
    – U.S. Phase 3 Study Part 1
    – U.S. Phase 3 Study Part 2: Discontinuation and Retreatment
• ENBREL Support: Access, Enliven® Services and
  Dosing Practicalities
• Indications, Dosing, and Important Treatment
  Considerations

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                    ENBREL® (etanercept) in the Treatment of Psoriasis




Psoriasis: A Debilitating Disease
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis




           Epidemiology: Who Suffers?

• 4.5 million to 7 million people in the US (men, women, and
  children) suffer from psoriasis1-3
     – Between 2.1% and 2.6% of population2,4
     – New cases: between 150,000 and 260,000 per year2
• 30% of sufferers have moderate to severe disease2
     – 1.5 million people2
• Approximately 23% of psoriasis sufferers also have psoriatic
  arthritis2
     – 1 million people2
     – Psoriasis typically precedes development of the arthritic component
       (70% before, 15% concurrent, 15% after)5

 References: 1. Krueger G, et al. Arch Dermatol. 2001;137:280-284. 2. National Psoriasis Foundation
 Web site. Available at: http://www.psoriasis.org/resources/statistics. Accessed November 18, 2003.
 3. National Psoriasis Foundation survey. Available at: http://www.psoriasis.org/files. pdfs/pres/
 npfsurvey.pdf. Accessed November 13, 2003. 4. Koo J. Dermatol Clin. 1996;14:485-496. 5. Tankosic T,
 Sharma D. Psoriasis and Associate Arthropathy. Waltham, ass: Decision Resources, Inc; May 2001
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                                                       ENBREL® (etanercept) in the Treatment of Psoriasis




           Psoriasis

• Chronic, immune-mediated,
  inflammatory skin disease
  characterized by dry, thickened,
  scaling lesions1,2
•   Associated with mild to severe
    disability3
• Associated with increased morbidity3,4
    –   Psoriatic arthritis
    –   Depression
    –   Anxiety
    –   Suicidal ideation
    References: 1. Choi J, et al. J Am Acad Dermatol. 2003;49:S57-S61. 2. Peters BP, et al.
    Am J Health-Syst Pharm. 2000;57:645-659. 3. National Psoriasis Foundation Web site. Available at:
    http://psoriasis.org/resources/statistics. Accessed November 18, 2003. 4. Gupta MA, et al.
    Br J Dermatol. 1998;139:846-850.
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                                                     ENBREL® (etanercept) in the Treatment of Psoriasis




           Psoriasis Can Impair Quality of Life

• Physical symptoms cause
  physical distress1
• Activities of daily life are
  affected1
   –    Sleep
   –    Sexual activities
   –    Using hands
   –    Walking
   –    Sitting/standing long periods

• Job performance is
  affected1


       Reference: 1. Krueger G. Arch Dermatol. 2001;137:280-284.
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                                                      ENBREL® (etanercept) in the Treatment of Psoriasis

          Psoriasis Can Impair Psychosocial
          Well-Being

• Self-consciousness and social
  embarrassment1
• Stigmatization (real or
  perceived)2
• Personal and work
  relationships disturbed2
• Decrease in sexual activity3
• Increased use of psychiatric
  services2
• Increased alcohol
  consumption2
• Suicidal ideation4
    References: 1. Koo J. Dermatol Clin. 1996;14:485-496. 2. Ginsburg IH, et al. Int J Dermatol.
    1993;32:587-591. 3. Gupta MA, et al. Int J Dermatol. 1997;36:259-262. 4. Gupta MA, et al.
    Br J Dermatol. 1998;139:846-50.
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                                               ENBREL® (etanercept) in the Treatment of Psoriasis




    Degrees of Plaque Psoriasis Severity
      Mild                                                      Moderate




                                 Severe




Photographs provided by National Psoriasis Foundation/USA, www.psoriasis.org.
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                                                       ENBREL® (etanercept) in the Treatment of Psoriasis




          Psoriasis Extent and Severity

• Body surface area (BSA) is the physical
  measure of the extent of psoriasis, but may
  be inaccurate in conveying actual disease
  severity1
   – Palm of hand represents approximately
     1% BSA2
• If measured by BSA, ~ 70% of patients
  have mild disease (<3% BSA)3
• If measured by BSA, ~30% of patients have
                                                                             Approximately 1%
  moderate to severe disease (>3% BSA)3                                     of the body’s surface
  Photograph provided by National Psoriasis Foundation/USA, www.psoriasis.org.
  References. 1. Krueger GG, et al. J Am Acad Dermatol. 2000;43:281-285. 2. National Psoriasis
  Foundation Web site. Available at: http://www.psoriasis.org/facts.psoriasis. Accessed March 16, 2004.
  3. National Psoriasis Foundation Web site. Available at: http://psoriasis.org/resources/statistics.
  Accessed November 18, 2003.
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                                                   ENBREL® (etanercept) in the Treatment of Psoriasis




     PASI Score Calculation1
 Region             Area         Involvement*             Severity†
                                                Redness      Thickness          Scale

                     0.1   x         3   x        2               0               1          (0.9)



                     0.2   x         3   x        2               1               2          (3.0)


                     0.3   x         2   x        2                2              2          (3.6)



                     0.4   x         3   x        3                2              3          (9.6)
                            *0   = None         †0-None
                     1.0                                                                     17.1
                               1 = <10%          1-Slight
                               2 = 10-<30%       2-Moderate
                               3 = 30-<50%       3-Exceptional
                               4 = 50-<70%
                               5 = 70-<90%
                               6 = 90-100%
Reference: 1. Fredricksson T, et al. Dermatologica. 1978;157:238-244.
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                  ENBREL® (etanercept) in the Treatment of Psoriasis




Psoriasis:
A Chronic Immune-Mediated
Inflammatory Disease
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis

        Evidence for the Role of TNF
        in Psoriasis

• TNF production is increased in psoriasis
  – Elevated serum TNF levels1
  – Elevated TNF levels in psoriatic
    plaque2,3
• TNF levels correlate strongly with
  disease severity (PASI score)1,2
• TNF levels decrease with effective treatment1,3
  – Extent of reduction correlates with clinical response


   References. 1. Mussi A, et al. J Biol Regul Homeost Agents. 1997;11:115-118. 2. Bonifati C, et al. Cl
   Exp Dermatol. 1994;19:383-387. 3. Ameglio F, et al. Dermatology. 1994;189:359-363.
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                                                        ENBREL® (etanercept) in the Treatment of Psoriasis




          Effects of TNF in Psoriasis1-4
               1. TNF can facilitate T cell     T cell
                  interactions with
                                                activation
                  antigen-presenting cells




                                                T cells
               2. Adhesion molecules in
TNF               the endothelium enable
                                                infiltrate the
                  T cell infiltration           dermis and
                                                epidermis



                                                                           Cross section of
                                                Inflammation               psoriatic skin
              3. T cells and keratinocytes
                 release proinflammatory        and keratinocyte
                 cytokines                      hyperproliferation



      References: 1. Girolomoni G, et al. Curr Opin Invest Drug. 2002;3:1590-1595. 2.
      Bonifati C, et al. Int J Dermatol.1999;38:241-251. 3. Krueger JG, et al. J Am Acad
      Dermatol. 2002;46:1-23. 4. Nickoloff BJ. Arch Dermatol. 1999;135:1104-1110.
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                  ENBREL® (etanercept) in the Treatment of Psoriasis




Etanercept: A New Approach to
Psoriasis Management
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

        ENBREL: Indications for Psoriatic
        Disease1,2

• ENBREL is the only treatment indicated for both plaque
  psoriasis and psoriatic arthritis
• ENBREL is indicated for the treatment of adult patients
  (18 years or older) with chronic moderate to severe
  plaque psoriasis who are candidates for systemic
  therapy or phototherapy
• ENBREL is indicated for reducing signs and symptoms
  and inhibiting the progression of structural damage of
  active arthritis in patients with psoriatic arthritis.
  ENBREL can be used in combination with methotrexate
  in patients who do not respond adequately to
  methotrexate alone
   Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
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                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

        ENBREL is the Only Fully Human
        TNF Receptor1

• ENBREL is not a
  monoclonal antibody                                        TNF


• Low immunogenicity:                               Extracellular
                                                        domains
  no neutralizing antibodies                       of human p75
                                                   TNF receptors
• ENBREL binds specifically
                                                     Fc region of
  to TNF and blocks its                             Human IgG1

  interaction with cell surface
  TNF receptors



   Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
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                                                          ENBREL® (etanercept) in the Treatment of Psoriasis

        ENBREL Mimics Natural TNF
        Inhibition to Control Inflammation1

• ENBREL is a soluble TNF receptor that
  competitively binds to soluble TNF to prevent
  activation of cell-surface receptors




  TNF initiates                   ENBREL bound to                   Cell-surface receptors
  inflammation                     circulating TNF                    are not activated
                                                                            by TNF
   Reference: 1. Data on file, Amgen/Wyeth, Thousand Oaks, CA.
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                   ENBREL® (etanercept) in the Treatment of Psoriasis




ENBREL Clinical Trials
in Psoriasis
                                                ENBREL® (etanercept) in the Treatment of Psoriasis

    Baseline Disease Characteristics
    Across Global and US Study Groups1

                                                N = 1283
   Psoriasis BSA involvement                     21.3%
   (median %)
   Baseline PASI Score (median)                    15.9
   DSGA of Psoriasis*
   Moderate – Severe (3-5)                         84%
   Prior Systemic Therapies
   Systemic Agent                                  67%
   Phototherapy                                    59%
   Systemic or Phototherapy                        82%


* Dermatologist Static Global Assessment of Psoriasis
Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
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                   ENBREL® (etanercept) in the Treatment of Psoriasis




Global Phase 3 Study
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis




        Global Phase 3 Study Design1

• Subjects and site personnel remained blinded
  to original treatment group through 3 months
• No analysis was performed until all subjects
  completed 6 months
Screen and      50 mg twice weekly
Washout

                50 mg weekly (25 mg BIW)                50 mg weekly (25 mg BIW)


                Placebo

          Day 1                                 3 Months                                 6 Months
                                           (Primary Endpoint)
                                                                                         N = 611
   Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
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                                                        ENBREL® (etanercept) in the Treatment of Psoriasis




             Inclusion and Exclusion Criteria1
Global Phase 3 Study
Inclusion                                    Exclusion
• Active but clinically stable plaque        • Patients with guttate, erythrodermic, or pustular
  psoriasis involving >10% BSA                 psoriasis or other active skin conditions at
                                               screening that would interfere with evaluation
• Minimal screening PASI score of 10
  (moderate to severe psoriasis)             • Previous use of ENBREL or antibodies to TNF
• Must have received previous                • Antibiotics within the previous week
  phototherapy or systemic therapy           • Topical steroids, topical vitamin A or D
  at least once or have been an                analog preparations, anthralin, or UVB within
  appropriate candidate for therapy            previous 2 weeks of study drug initiation
• At least 18 years of age                   • Treatment with biologic or investigational
                                               drugs, PUVA phototherapy, systemic
                                               corticosteroids, or systemic psoriasis therapy
                                               within 4 weeks of study drug initiation
                                             • Anti-CD4 or diphtheria IL-2 fusion protein
                                               within previous 6 months
        Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
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                                                        ENBREL® (etanercept) in the Treatment of Psoriasis

            Similar Baseline Demographics/
            Clinical Characteristics Across Groups1

Global Phase 3 Study: Part #1

                                                        Placebo           50 Mg Twice Weekly
Patient number                                            193                    194
Age (mean, yrs)                                             45                         45
Male                                                      64%                        67%
Caucasian                                                 91%                        89%
Weight (mean, kg)                                           91                         86
BSA involvement                                           27%                        29%
Psoriasis duration (yrs)                                    19                         20
PASI                                                      18.6                       19.5
Patient global score of 4 or 5 (0–5 scale)                71%                        70%


       Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.

                                                                                                             22
                                                     ENBREL® (etanercept) in the Treatment of Psoriasis

         Patients with PASI Response
         at 3 months1
Global Phase 3 Study

                             *




                                               *

                                                                       *P<0.0001 vs placebo

                                                                   *




     ENBREL 50 mg weekly (25 mg BIW) was also studied in this trial.
     Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
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                                                            ENBREL® (etanercept) in the Treatment of Psoriasis

                     PASI 75 Response Was Maintained
                     Following Step-Down Dosing1
                                                       Placebo
Global Phase 3 Study                                   ENBREL 50 mg twice weekly
                                                       ENBREL 50 mg weekly (25 mg BIW)
                                                       *P<0.001 vs placebo
                                                        †P<0.0001 vs placebo


                                                                50 mg weekly                50%
                                                                (25 mg BIW)
     % of Patients




                                                   †

                                         †                                                  25%




                             *
                              1              2         3            4             5             6
                                                    Months
           Modified ITT analysis
           ENBREL 50 mg weekly (25 mg BIW) was also studied in this trial.
           Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                                                                                                                 24
                                                  ENBREL® (etanercept) in the Treatment of Psoriasis

       Global Phase 3 Summary: ENBREL
       Step-Down Dosing Maintained Response1,2

• In patients treated with 50 mg twice weekly
  for 3 months, followed by step-down dosing to
  50 mg weekly:
  – PASI 75 response rate continued to increase,
    reaching 50% by 6 months
  – 77% of week 12 PASI 75 responders maintained
    their response through 6 months
  – An additional 32% of week 12 nonresponders
    achieved a PASI 75 by 6 months
• ENBREL was generally well tolerated
   References: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks,
   Calif. 2. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                       25
                                                         ENBREL® (etanercept) in the Treatment of Psoriasis




              Global Phase 3 Study—Patient 23651
        Baseline                Week 2                 3 months                    6 months




PASI      57.3                      15.5                    6.0                             5.7
Score
PASI %                                73                     89                             90
Improvement
           Patient was initially treated with ENBREL 50 mg twice weekly and was stepped
           down to 50 mg weekly (25 mg BIW) at 3 months.
           Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                              26
                                                ENBREL® (etanercept) in the Treatment of Psoriasis




    Global Phase 3 Study—Patient 23651




   Baseline                                                          1 month




   3 months                                                         6 months
Patient was initially treated with ENBREL 50 mg twice weekly and was stepped down to 50 mg
weekly (25 mg BIW) at 3 months.
Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                     27
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis




          Global Phase 3 Study—Patient 30661
    Baseline                1 month                 3 months                    6 months




PASI     31.6                      5.7                    1.3                         0.6
Score
PASI %                             82                     96                          98
Improvement
    Patient was initially treated with ENBREL 50 mg twice weekly and was stepped down to 50 mg
    weekly (25 mg BIW) at 3 months.
    Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                           28
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis




          Global Phase 3 Study—Patient 30551
     Baseline                           3 months                               6 months




PASI   11.2                                  1.2                                     0.0
Score
PASI %                                       89                                     100
Improvement
    Patient was initially treated with ENBREL 50 mg twice weekly and was stepped
    down to 50 mg weekly (25 mg BIW) at 3 months.
    Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
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                  ENBREL® (etanercept) in the Treatment of Psoriasis




U.S. Phase 3 Study of ENBREL
in Psoriasis
                                                         ENBREL® (etanercept) in the Treatment of Psoriasis




              ENBREL in Psoriasis: Study Design1,2
• No analysis was performed until all subjects completed 15 months
Efficacy Evaluation                                               Safety Evaluation
U.S. Phase 3 Study: Part 1                                        U.S. Phase 3 Study: Part 2
                                                                           Discontinuation &
                                                                              Retreatment
            Double Blind

         50 mg           Twice Weekly                                     50 mg twice weekly

                            Weekly        PASI    Discontinue         50 mg weekly (25 mg BIW)
         50 mg           (25 mg B/W)      50        Drug
                                                                          25 mg once weekly
         25 mg           Once Weekly
                                                                   Blinded retreatment with 6 month
                         50 mgWeekly                               dose at time of loss of response
         Placebo         (125 mg B/W)     PASI
                                          <50                          50 mg weekly (25 mg BIW)
 Day 1        3 months        6 months

     Primary Endpoint         Assess responder status
          References: 1. Leonardi CL, et al. N Engl J Med. 2003;349:2012-2020.
          2. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                              31
                                                        ENBREL® (etanercept) in the Treatment of Psoriasis

            Similar Baseline Demographics/
            Clinical Characteristics Across Groups1

US Phase 3 Study

                                                        Placebo           50 Mg Twice Weekly
Patient number                                            166                    164
Age (mean, yrs)                                             46                         45
Male                                                      63%                        65%
Caucasian                                                 90%                        87%
Weight (mean, kg)                                           96                         95
BSA involvement                                          28.8%                      29.9%
Psoriasis duration (yrs)                                    18                         19
PASI                                                      18.3                       18.5
Patient global score of 4 or 5 (0–5 scale)                76%                        76%



         Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                             32
                                                                 ENBREL® (etanercept) in the Treatment of Psoriasis

                     PASI 75 Responses Were Similar at
                     6 Months in Both Phase 3 Studies1
                                                                              Placebo
                                                                              ENBREL 50 mg twice weekly
                                                                              ENBREL 50 mg weekly (25 mg BIW)

                     *P<0.001 vs. placebo;                      *P<0.05 vs. placebo
                     †P<0.001 vs. placebo.                      †P<0.0001 vs. placebo




                             Dose decreased                                Dose maintained            54%
                                                       50%
                                       †                                              †
% of Patients




                               †                                                                      33%
                                                                             †
                                                       25%



                         *
                                                                     *


                         1         2       3   4   5     6           1        2      3      4     5       6
                         Global Study (N = 611)                            U.S. Study (N = 672)
                Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                                      33
                                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

                                       Response May Be Seen As Early As
                                       1 Month1,2
                                                                       Placebo
U.S. Phase 3 Study:                                                    ENBREL 50 mg twice weekly
                                                                       ENBREL 50 mg weekly (25 mg BIW)
                                                                       *P<0.0001 vs. placebo
    Mean % improvement in PASI score




                                                                                                71%
                                                                *
                                                      *                                         53%



                                              *


                                          *


                                                  1       2     3          4          5          6
                                                              Months

                 ENBREL 50 mg weekly (25 mg BIW) and Enbrel 25 mg once weekly were also studied in this trial.
                 Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                 2. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                                         34
                                                       ENBREL® (etanercept) in the Treatment of Psoriasis

           Only Injection Site Reactions were
           Significant Through Week 241
U.S. Phase 3 Study: Part 1
Adverse events and infections occurring in 5% of patients
                                   Placebo/ENBREL             ENBREL
                                 week 1-12 week 12-24         week 1-24
                                          25 mg twice 25 mg twice 50 mg twice
                                Placebo     weekly      weekly        weekly
Injection site reaction            7          7           33            26
Headache                           7          5           12             9
Upper respiratory Infection         11             6                   14                  12
Asthenia                            3              1                   7                    3
Myalgia                             2              2                   7                    4
Accidental injury                   4              4                   7                    7
Sinusitis                           1              1                   6                    5
Nausea                              1              1                   3                    3
Injection site bruising             4              2                   3                    5
Rash                                2              0                   4                    6
      Reference: 1. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy
      in patients with psoriasis. N Engl J Med. 2003;349:2012-2020.
                                                                                                            35
                                                          ENBREL® (etanercept) in the Treatment of Psoriasis




            Week 24 Tolerability
U.S. Phase 3 Study: Part 1

 • Grade 3 serious adverse events (SAEs) and infections
   were well balanced across active treatment groups1
 • Serious adverse events and serious infections were
   minimal1,2
 • No cases of TB or opportunistic infections reported1,2
                           Placebo/25 mg          25 mg               25 mg                50 mg
                               twice               once               twice                 twice
                               weekly             weekly              weekly               weekly
Noninfectious SAEs                 5                  6                   6                    5

Infectious SAEs                    3                  2                   0                    1


   References: 1. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients
   with psoriasis. N Engl J Med. 2003;349:2012-2020. 2. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                               36
                                                        ENBREL® (etanercept) in the Treatment of Psoriasis

            ENBREL U.S. Phase 3 Study—
            Patient 16611
        Baseline                            3 months                               6 months




PASI       22.7                                 6.3                                     3.8
Score
PASI %                                           72                                      83
Improvement
        Patient was treated with Enbrel 25 mg once weekly through 6 months.
        Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                             37
                                                                   ENBREL® (etanercept) in the Treatment of Psoriasis

             ENBREL U.S. Phase 3 Study—
             Patient 16671
        Baseline                                  3 months                                    6 months




PASI        28.4                                     22.0                                          1.2
Score
PASI %                                                 23                                           96
Improvement
        Patient initially received placebo, and was then switched to ENBREL 50 mg weekly (25 mg BIW) at
        3 months.
        Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                                        38
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

         U.S. Phase 3 Study: Clinical Response Was
         Rapid, Consistent, and Sustained1

• A statistically significant improvement in the percentage
  of patients achieving a PASI 75 response was seen as
  early as 1 month with the 50 mg twice-weekly dose
• Continued improvement was seen through 6 months
   – PASI 75 reached 47% at 12 weeks and 54% at 6 months in the
     50 mg twice-weekly group
• Week 24 PASI 75 response rates in the global study
  were similar to those reported in the U.S. study, in
  which patients were treated with 50 mg twice weekly
  throughout the 6-month period


    Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                                                                                                         39
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

        U.S. Phase 3 Study: ENBREL Was
        Generally Well Tolerated1

• ENBREL had similar rates of adverse events and
  infections in all treatment groups
   – Adverse events and infections comparable to placebo
     at 3 months
   – Injection site reactions slightly higher in active dose groups
     at 3 months
• Safety and adverse event profile was unremarkable
  over 6 months of dosing
• Safety and adverse event profile was similar among all
  treatment arms and comparable to the global study


    Reference: 1. Leonardi CL, et al. N Engl J Med. 2003;349:2012-2020.
                                                                                                         40
                            ENBREL® (etanercept) in the Treatment of Psoriasis




Discontinuation and Retreatment
Safety Evaluation
U.S. Phase 3 Study Part 2
        Etanercept US Phase 3 Study              ENBREL® (etanercept) in the Treatment of Psoriasis




        Time-to-Loss of Response Analysis

 Double Blind Period                         Drug Discontinuation Period

                                                         Discontinue drug and
                                                      follow monthly until loss of
                                                              response
 50 mg twice    weekly
                                      PASI            Loss of response = Loss of
50 mg weekly    (25 mg BIW)           50                   half of the PASI
                                                        improvement achieved
 25 mg once    weekly               N = 409              between baseline and
                                                                week 24
 Placebo        50 mg
                weekly
                                                     Example :
Day 1      3 months      6 months                    Baseline PASI             20
    Primary Endpoint                                 Week 24 PASI              5
                                                     Improvement               15 (75%)
                                                     Relapse PASI              12.5
                                                                                                      42
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis


           Time to Loss of Response* Following ENBREL
           Discontinuation Was Approximately 3 Months1

U.S. Phase 3 Study: Part 2


                                               Median Time to
                                             Loss of Response
  Dose During                               After Discontinuation
  Double-Blind Period                               (Days)                                  N
  Placebo/50 mg weekly
                                                            85                             95
  (25 mg BIW)
  50 mg BIW                                                 91                            122
  Total                                                     85                            409

      *Defined as loss of >50% of improvement in PASI score in patients who had
      previously achieved a PASI 50 response.
      Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                           43
                                                   ENBREL® (etanercept) in the Treatment of Psoriasis

       Rebound: NPF Medical Advisory
       Board Definition1




“We operationally define rebound as a PASI of 125%
or greater of baseline or new generalized pustular,
erythrodermic, or more inflammatory psoriasis
occurring within 3 months of stopping therapy.”




  Reference: 1. Gordon KB, et al. NPF Psoriasis Forum. 2002;8(3):1-3.
                                                                                                        44
                                                       ENBREL® (etanercept) in the Treatment of Psoriasis

           No Rebound Occurred at 50 mg
           Twice Weekly or 25 mg Twice Weekly1

U.S. Phase 3 Study: Part 2
 In 409 patients observed during the discontinuation period
 • No conversion of morphology
 • No SAEs or hospitalization due to psoriasis
 • No study discontinuation due to psoriasis AEs
 • One case of rebound (0.2%) was reported in the 25 mg
    once-weekly dosing arm.



      ENBREL 25 mg once weekly dosing and twice weekly dosing were also studied
      in this trial.
      Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                            45
                                                   ENBREL® (etanercept) in the Treatment of Psoriasis


        Initial Treatment and Retreatment With ENBREL
        Resulted in Similar PASI 75 Response Rates1,2


• After 3 months of retreatment after
  discontinuation, 93% of the PASI 75 responders at
  month 3 achieved a PASI ≥50 response




   References: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks,
   Calif. 2. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                        46
                                                  ENBREL® (etanercept) in the Treatment of Psoriasis




               US Phase 3 Study: Part 2—Patient 1610
   Baseline           Week 12           Week 24            Week 48                Week 60




        21.4             3.6              3.6                14.4                   10.4
PASI
Score
PASI %                  83.2             83.2                32.7                   51.4
Improvement

        Patient 1610 on 50 mg twice-weekly dosing treatment arm.
                                                                                                       47
                                                ENBREL® (etanercept) in the Treatment of Psoriasis




            US Phase 3 Study: Part 2—Patient 1665

   Baseline         Week 12          Week 24             Week 48                Week 60




PASI 14.4             2.4               5.1                 4.2                  3.5
Score

PASI %                83.3             64.6                70.8                 75.7
Improvement



     Patient 1610 on 50 mg BIW-dosing treatment arm and over discontinuation period.
                                                                                                     48
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis
        Phase 3 Study Part 2 Summary:
        ENBREL Was Effective and Generally Well Tolerated
        Over the Discontinuation and Retreatment Period1


• No increase in adverse events despite increased dose
• No increase in adverse events over 15 months of therapy
• Rebound did not occur in the 50 mg weekly or 50 mg
  twice-weekly treatment arms
   – In 409 patients observed during the discontinuation period
        • No conversion of morphology
        • No SAEs or hospitalization due to psoriasis
        • No study discontinuation due to psoriasis AEs
• After 3 months of retreatment after discontinuation,
  93% of PASI 75 responders at month 3 achieved a
  PASI ≥50 response

   Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                         49
                  ENBREL® (etanercept) in the Treatment of Psoriasis




ENBREL in Psoriasis:
Conclusions
                                                    ENBREL® (etanercept) in the Treatment of Psoriasis

        In Two Phase 3 Psoriasis Studies, ENBREL
        Was Shown To Be Generally Well Tolerated1


• ENBREL has exhibited a consistent safety profile
  – No increase in adverse events despite increased dose
    or step-down in dose
  – No increase in adverse events over 15 months
    (60 weeks) of therapy
  – ENBREL was generally well tolerated during
    discontinuation and retreatment
       • No rebound seen in the 50 mg weekly or 50 mg BIW
         treatment arms




   Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                         51
                                                   ENBREL® (etanercept) in the Treatment of Psoriasis

       In Two Phase 3 Psoriasis Studies, ENBREL
       Demonstrated Rapid and Consistent Efficacy1


• ENBREL has shown consistent and
  sustainable efficacy
  – Efficacy consistent across all endpoints in both
    psoriasis studies
  – At 6 months, efficacy with step-down dosing
    was similar to that reported with 50 mg twice-weekly
    dosing
  – ENBREL can be stopped and restarted with
    comparable efficacy reestablished



  Reference: 1. Data on file, Amgen, Thousand Oaks, Calif.
                                                                                                        52
                    ENBREL® (etanercept) in the Treatment of Psoriasis




ENBREL Support: Access, Enliven®
Services, and Dosing Practicalities
                                                 ENBREL® (etanercept) in the Treatment of Psoriasis




          Dermatology Access Options for Enbrel
Dermatologist decides to Rx ENBREL® (etanercept) and has 3 options


                                                                  Amgen PSR/DSR
                                                                provides messages,
                                                                 collateral, options,
                                                                      follow-up



      Rx to Patient                                                 Office/Patient calls
   (business as usual)                                               1-888-4ENBREL
                                                                       for questions
                                   Physician
                                   calls/faxes
                                  Specialty Rx
                                    directly

    • Simple options will help ENBREL prescriptions to be filled promptly
    • Your office will receive a call only if additional documentation is needed

                                                                                                      54
                                    ENBREL® (etanercept) in the Treatment of Psoriasis

       Enliven ® Services: Support for Health
       Care Professionals Who Use ENBREL
Authorization Form                           Enliven® Services is the
  and Insurance                              centralized resource for:
    Assistance
                                             • Physician/office staff
                     Teaching Kits for
                       Dosing and
                                             • Pharmacists
                      Administration         • One number for health
                                               care professionals:
                                               1-888-4ENBREL
                                               (1-888-436-2735)
                                             • www.enbrel.com also
                                               offers access to
                                               Enliven® services




                                                                                         55
                    ENBREL® (etanercept) in the Treatment of Psoriasis

Teaching Kit:
A Resource for Health Care Professionals


                Components Include:
                • Guide for teaching
                  patients how to use
                  ENBREL
                • Getting Patients Started
                  on ENBREL Brochure
                • Cap removal tool
                • Instructional video



                                                                         56
                                                  ENBREL® (etanercept) in the Treatment of Psoriasis

              Enliven® Services: Extensive
              Resources for Patients
                                                                          Patient
Enliven® Services support includes:                                       Resource Kits
                                              Patient
• Free educational resources for patients     Brochures
• Newsletters, free sharps containers, free
  travel coolers, and more for patients
    – Patients enrolled in Enliven® have
      shown a higher persistency with
      therapy than those not enrolled and                              Sharp’s            Travel
      compliance may be improved                                       Containers         Coolers

• Registered Nurses
    – 8 am to 11 pm EST, 7 days a week
                                                           Psoriasis
• Insurance Specialists
                                                                        Newsletters
• Spanish-speaking representatives
One number for patients:
1-888-4ENBREL (I-888-436-2735)
  or www.enbrel.com


                                                                                                       57
                    ENBREL® (etanercept) in the Treatment of Psoriasis

Resource Kit:
for Patients Using Etanercept

                 Components include:
                 • Instruction video
                 • Handbook with step-by-
                   step instruction guide
                 • Sharps container
                 • Cap removal tool
                 • Table mat



                                                                         58
                             ENBREL® (etanercept) in the Treatment of Psoriasis




      Mixing Station

• Developed to help prepare a dose of etanercept
• Helps patient remove vial cap, remove needle
  cover, reconstitute etanercept, and fill syringe
  for injection




                       New
                                                                                  59
                               ENBREL® (etanercept) in the Treatment of Psoriasis




      Etanercept Drug Preparation


• Reconstitute aseptically with 1 mL of supplied
  Sterile Bacteriostatic Water for Injection, USP
  (0.9% benzyl alcohol)
• Do not reconstitute ENBREL with other diluents
• A vial adapter is supplied for use when
  reconstituting ENBREL
  – 25-gauge needle should not be used if multiple
    doses are going to be withdrawn from the vial



                                                                                    60
                           ENBREL® (etanercept) in the Treatment of Psoriasis




Etanercept Drug Preparation

    • Inject diluent slowly
    • DON’T SHAKE
     Some normal foaming will occur
     Swirl gently to dissolve
     Dissolution time <10 minutes




                                                                                61
                                ENBREL® (etanercept) in the Treatment of Psoriasis




      Etanercept Drug Preparation

• Visually inspect for particulate matter and
  discoloration before administration
• Reconstituted solution should be clear and colorless
• Do not use if discolored or cloudy
• Do not use if particulate
  matter remains
• Use within 6 hours
  unless refrigerated



                                                                                     62
                                  ENBREL® (etanercept) in the Treatment of Psoriasis




      Etanercept Storage

• Do not use beyond date stamped on carton or
  labels
• Reconstituted etanercept can be stored up to
  14 days between 2°C and 8°C (36°F - 46°F)
  – Maintains protein stability
  – Do not freeze




                                                                                       63
                              ENBREL® (etanercept) in the Treatment of Psoriasis




      Etanercept Administration: Injection

• Rotate injection sites (thigh, abdomen,
  upper arm) after each injection
• New injections at least 1 inch from old site
• Never inject where skin is tender, bruised, red,
  or hard




                                                                                   64
                                ENBREL® (etanercept) in the Treatment of Psoriasis




      Injection Site Reactions

• Rare
  – Occur in approximately 14% of psoriasis patients
• Mild to moderate in intensity
  – Occur early in therapy and usually last about 3 days
  – Incidence decreases with
    continued administration
    past 1 month




                                                                                     65
                                   ENBREL® (etanercept) in the Treatment of Psoriasis




       Managing Injection Site Reactions

• How to minimize
  –   Prepare site properly
  –   Inject into fatty areas of legs and arms
  –   Rotate sites
  –   Avoid injecting in swollen, hard, or red areas
• Treatment is generally not necessary
• Other supportive treatments
  – Cold compress
  – Oral antihistamines
  – Topical corticosteroid creams

                                                                                        66
                                    ENBREL® (etanercept) in the Treatment of Psoriasis




        Role of the Dermatology Staff

• Management of patient apprehension and concerns
   – Encouragement provided by nurse education and support
   – Involvement of caregivers, family members
• Take time for demonstration or discussion
• Confirm patient comfort level
• Provide ongoing support
   –   Physician, staff
   –   Company
   –   Materials
   –   Caregivers, family members


                                                                                         67
                   ENBREL® (etanercept) in the Treatment of Psoriasis




ENBREL: Indications and Important
Treatment Considerations
                                                            ENBREL® (etanercept) in the Treatment of Psoriasis




          ENBREL: Indications

• ENBREL is indicated for the treatment of adult
  patients (18 years or older) with chronic moderate
  to severe plaque psoriasis who are candidates for
  systemic therapy or phototherapy1
• ENBREL is indicated for reducing signs and
  symptoms and inhibiting the progression of
  structural damage of active arthritis in patients with
  psoriatic arthritis. ENBREL can be used in
  combination with methotrexate in patients who do
  not respond adequately to methotrexate alone1

   References: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                                                                                                                 69
                                                             ENBREL® (etanercept) in the Treatment of Psoriasis




          ENBREL: Indications1

• ENBREL is indicated for reducing signs and symptoms of
  moderately to severely active polyarticular-course juvenile
  rheumatoid arthritis in patients 4 years of age and older who
  have had an inadequate response to one or more DMARDs
• ENBREL is indicated for reducing signs and symptoms,
  inhibiting the progression of structural damage, and
  improving physical function in patients with moderately to
  severely active rheumatoid arthritis. ENBREL can be used
  in combination with methotrexate in patients who do not
  respond adequately to methotrexate alone
• ENBREL is indicated for reducing signs and symptoms in
  patients with active ankylosing spondylitis

   Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                                                                                                                  70
                                                      ENBREL® (etanercept) in the Treatment of Psoriasis




           ENBREL: Administration1

• The recommended starting dose of ENBREL for
  adult patients with psoriasis is a 50-mg
  subcutaneous (SC) dose given twice weekly
  (administered 3 to 4 days apart) for 12 weeks
  followed by a reduction to a maintenance dose of
  50 mg weekly
• For adult patients with psoriatic arthritis, the
  dosing of ENBREL is as follows:
     –   Once weekly: two SC injections of 25-mg each on
         the same day, or
     –   Twice weekly: 25-mg SC injection, administered
         3 or 4 days apart
• SC injection can be easy to learn and allows
  convenient at-home self-administration after
  proper instruction
• ENBREL is supplied in 25-mg vials for
  reconstitution


     Reference: 1. Enbrel Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
                                                                                                           71
                           ENBREL® (etanercept) in the Treatment of Psoriasis




     Important Treatment Considerations

• IN POSTMARKETING USE, THE FOLLOWING
  SERIOUS ADVERSE
• EVENTS HAVE BEEN REPORTED
• SERIOUS INFECTIONS AND SEPSIS, INCLUDING
  FATALITIES
  – MANY OF THESE INFECTIONS OCCURRED IN PATIENTS
    PREDISPOSED TO INFECTIONS BECAUSE OF
    CONCOMITANT IMMUNOSUPPRESSIVE THERAPY AND/OR
    THEIR UNDERLYING DISEASE
  – RARE CASES OF TB HAVE BEEN OBSERVED
  – DISCONTINUE ENBREL IN PATIENTS WITH SERIOUS
    INFECTIONS OR SEPSIS


                                                                                72
                                     ENBREL® (etanercept) in the Treatment of Psoriasis

       Important Treatment Considerations
       (cont’d)

   – DO NOT START ENBREL IN THE PRESENCE OF SEPSIS,
     INFECTION (INCLUDING CHRONIC OR LOCALIZED), OR
     ALLERGY TO ENBREL OR ITS COMPONENTS
   – USE CAUTION IN PATIENTS PREDISPOSED TO INFECTION,
     SUCH AS THOSE WITH ADVANCED OR POORLY
     CONTROLLED DIABETES
• Cases of CNS demyelinating disorders (some presenting
  with mental status changes and some associated with
  permanent disability), transverse myelitis, optic neuritis,
  multiple sclerosis, and new onset or exacerbation of
  seizure disorder
   – The causal relationship to ENBREL therapy is unclear
   – Exercise caution when considering ENBREL for patients with
     these disorders
                                                                                          73
                                            ENBREL® (etanercept) in the Treatment of Psoriasis

         Important Treatment Considerations
         (cont’d)

• Rare cases of pancytopenia, including aplastic anemia, some fatal
    – The causal relationship to ENBREL® (etanercept) therapy is unclear
    – Exercise caution in patients who have a previous history of significant
      hematologic abnormalities
    – Advise patients to seek immediate medical attention if they develop
      signs or symptoms of blood dyscrasias or infection
    – Consider discontinuing ENBREL if significant hematologic
      abnormalities are confirmed
• In clinical trials of all TNF inhibitors, a higher rate of lymphoma was
  seen compared to the general population; however, the risk of
  lymphoma may be up to several-fold higher in RA patients
    – The role of TNF inhibitors in the development of lymphoma is unknown
• In clinical trials, the incidence of malignancies other than
  lymphoma has not increased with exposure to ENBREL and is
  similar to the projected background rate


                                                                                                 74
                                                                         ENBREL® (etanercept) in the Treatment of Psoriasis


                  Important Treatment Considerations
                  (cont’d)


 Most Frequently Reported Adverse Events in RA Clinical Trials*
                                                                  Percentage of Patients
                                             Placebo Controlled                             Active Controlled
                                         Placebo†               ENBREL                  MTX‡                 ENBREL
  Event
                                         (n = 152)              (n = 349)             (n = 217)              (n = 415)
  Injection site reactions                   10                     37                     7                     34
  Infection§ (total)                         32                     35                    72                     64
    Nonupper respiratory                     32                     38                    60                     51
    Upper respiratory                        16                     29                    39                     31
  Headache                                   13                     17                    27                     24
* The 3 most commonly reported adverse events; includes data from a 6-month study in which patients received concurrent
  MTX therapy.
† The duration of exposure for patients receiving placebo was less than that for the patients treated with ENBREL ®

  (etanercept).
‡ MTX patients received concomitant placebo injections.
§ Infection (total) includes data from 3 placebo-controlled trials. Nonupper respiratory and upper respiratory include data only

  from the 2 placebo-controlled trials where infections were collected separately from adverse events (placebo n = 110,
  ENBREL n = 213).

                                                                                                                                   75
                            ENBREL® (etanercept) in the Treatment of Psoriasis


      Important Treatment Considerations
      (cont’d)


• Adverse events in the AS and psoriatic arthritis
  trials were similar to those reported in RA
  clinical trials
• No increased incidence of tuberculosis (TB)
  observed in clinical trials; however, rare cases
  of TB have been observed in postmarketing use
• Routine laboratory monitoring specific for
  ENBREL® (etanercept) therapy not required;
  careful medical management and supervision
  of patients recommended

                                                                                 76
                                   ENBREL® (etanercept) in the Treatment of Psoriasis

       Important Treatment Considerations
       (cont’d)

• In a JRA study (n = 69), infections (62%), headache (19%),
  abdominal pain (19%), vomiting (13%), and nausea (9%)
  occurred more frequently than in adults. The types of
  infections reported in JRA patients were generally mild and
  consistent with those commonly seen in outpatient pediatric
  populations
• Serious adverse reactions reported rarely in a JRA study
  were varicella (3%), gastroenteritis (3%),
  depression/personality disorder (1%), cutaneous ulcer (1%),
  esophagitis/gastritis (1%), group A streptococcal septic
  shock (1%), type I diabetes mellitus (1%), and soft tissue
  and postoperative wound infection (1%)
• Please see full Prescribing Information

                                                                                        77
                   ENBREL® (etanercept) in the Treatment of Psoriasis




ENBREL in the Treatment of Psoriasis