Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis
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ENBREL* (etanercept): A Breakthrough to Sustainable and Repeatable Efficacy in Psoriasis. *trademark. Overview. ENBREL* EU Indications for Psoriatic Diseases Overview of Psoriasis Clinical Evidence for the Role of TNF in Psoriasis Pivotal Phase III Trials

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ENBREL* (etanercept): A Breakthrough to Sustainable and Repeatable Efficacy in Psoriasis

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Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

ENBREL*(etanercept):A Breakthrough to Sustainable and Repeatable Efficacy in Psoriasis

*trademark


Overview

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Enbrel etanercept eu indications for psoriatic diseases

ENBREL*(etanercept)EU Indications for Psoriatic Diseases

ENBREL is the only biologic treatment indicated for both plaque psoriasis and psoriatic arthritis:1

  • ENBREL is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate.

  • ENBREL is indicated for the treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.

Reference 1. ENBREL Summary of Product Characteristics, Wyeth Pharmaceuticals.

*trademark


Overview1

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Overview of psoriasis

Overview of Psoriasis

  • Psoriasis is a chronic, autoimmune, inflammatory skin disease1,2

  • Psoriasis is not contagious and is characterized by skin lesions that can be red, scaly, itchy, painful, and disabling1

  • In Europe, an estimated 5.1 million people are affected by psoriasis3

  • The most common form of psoriasis is plaque psoriasis, which occurs in approximately 80% of all patients with psoriasis4

  • According to a recent review by Brockbank and Gladman, it is estimated that 5% to 42% of patients with psoriasis have psoriatic arthritis5

References 1. Peters BP et al.Am J Health-Syst Pharm 2000;57:645–662. 2. Krueger JG. J Am Acad Dermatol 2002;46:1–23. 3. Christophers E. Clin Exp Dermatol 2001;26:314–320. 4. Lebwohl M. Lancet 2003:361;1197–1204. 5. Brockbank J, Gladman DD. Expert Opin Investig Drugs 2000;9:1511–1522.


The impact of psoriasis

The Impact of Psoriasis

  • Profound reduction in health-related quality of life,1,2 due to

    - Physical symptoms2

    - Psychosocial impairment1,2

    - Compromised activities of daily living1

    • Psychosocial impact includes

      - Embarrassment1,3

      - Helplessness and anger3

      - Feeling unattractive

      - Increased feelings of depression4

    • Annual direct costs for treatment ranging from $US 1400 to $US 67005

    • Disability comparable to heart disease, diabetes, cancer, and depression2

    • Increased risk of malignancy6

References 1. Krueger G et al. Arch Dermatol 2001;137:280284. 2. Choi J, Koo JYM. J Am Acad Dermatol 2003;49:S57S61. 3. Koo JYM. J Dermatol Clin 1996;14:485496. 4. Devrimci-Ozguven H et al. J Eur Acad Dermatol Venereol 2000;14:267271. 5. Sander HM et al. J Am Acad Dermatol 1993;28:422425. 6. Margolis D et al. Arch Dermatol 2001;137:778783.


Overview of psoriasis common symptoms

Overview of Psoriasis: Common Symptoms

Results from the 1998 National Psoriasis Foundation survey.

Reference 1. Krueger G et al.Arch Dermatol 2001;137:280–284.


Overview of psoriasis measuring disease severity

Overview of Psoriasis: Measuring Disease Severity

Traditional Metrics

  • Extent(body surface area; BSA)1,2

  • The Psoriasis Area and Severity Index (PASI)3

  • Dermatology Life Quality Index (DLQI)4

    Proposed Metrics

  • Disease alters the patient’s quality of life

  • Unsatisfactory response to treatments with minimal risk

  • Generally more than 10% of the body surface area is involved

  • Disease is located on the face, hands, fingernails, feet and genitals

  • Joint involvement

References 1.Krueger GG et al. J Am Acad Dermatol 2000;43:281–285. 2. Weinstein GD, Menter MA. In: Weinstein GD, Gottlieb AB et al. Therapy of moderate-to-severe psoriasis. New York, Marcel Dekker, 2003. 3. Fredriksson T, Pettersson U. Dermatologica 1978;157:238–244. 4. Finlay AY, Khan GK. Clin Exp Dermatol 1994;19:210–216.


Traditional therapies 1998 usage pattern

Traditional Therapies: 1998 Usage Pattern

Percentage of Patients Receiving Prescription Treatments for Psoriasis

Topicals

87

Phototherapy or light

Type of Treatment

21

treatment

Oral medication

18

n=502

0

20

40

60

80

100

% of Patients

Reference 1. Krueger G et al. Arch Dermatol 2001;137:280–284.


Potential adverse effects of traditional systemic agents

Potential Adverse Effects of Traditional Systemic Agents

Agent

Potential Adverse Effects

  • Melanoma

  • Non-melanoma skin cancer

  • Skin aging

UVB1

PUVA1

  • Nausea

  • Melanoma

  • Non-melanoma skin cancer

  • Skin aging

Methotrexate2

  • Hepatotoxicity

  • Bone marrow toxicity

  • Teratogenicity

  • Pulmonary toxicity

References 1. Lebwohl M, Ali S. J Am Acad Dermatol 2001;45:487498. 2. Lebwohl M, Ali S. J Am Acad Dermatol 2001;45:649661.

30


Potential adverse effects of currently available systemic agents

Potential Adverse Effects of Currently Available Systemic Agents

Agent

Potential Adverse Effects

Cyclosporine1

  • Nephrotoxicity

  • Hypertension

  • Malignancy

Acitretin1

  • Mucocutaneous side effects

  • Teratogenicity in combination with alcohol

  • Lipid abnormalities

Fumarates2,3

  • Potential skin irritation

  • GI symptoms

References1. Lebwohl M, Ali S. J Am Acad Dermatol 2001;45:649661. 2. Mrowietz U et al. Br J Dermatol 1999;141:424429. 3. Altmeyer PJ et al. J Am Acad Dermatol 1994;30:977981.

31


Potential adverse effects of traditional topical agents 1 2

Potential Adverse Effects of Traditional Topical Agents1,2

References 1. Lebwohl M, Ali S. J Am Acad Dermatol 2001;45:487498. 2. Krueger G et al. Arch Dermatol 2001;137:280–284.


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Psoriasis Management Goals

  • The primary goal of treating psoriasis is to improve the disease to a level where it no longer significantly interferes with the patient’s daily life1

  • Convenient therapy should not in itself impair daily life1

Reference 1. Greaves MW et al. N Engl J Med 1995;332:581–588.


Overview2

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Clinical evidence for the role of tnf in psoriasis

Clinical Evidence for the Role of TNF in Psoriasis

  • Tumor necrosis factor (TNF) production is increased in psoriasis

    • Elevated serum TNF levels1

    • Elevated TNF levels in psoriatic plaque2

  • TNF levels correlate with Psoriasis Area and Severity Index (PASI) score1,2

  • Reduction of TNF levels1,3 correlates with clinical response

References 1. Mussi A et al. J Biol Regul Homeost Agents 1997;11:115–118. 2. Bonifati C et al. Clin Exp Dermatol 1994;19:383–387. 3. Ameglio F et al. Dermatology 1994;189:359–363.


What is enbrel

What Is ENBREL*?

  • ENBREL is a human TNF-receptor fusion protein1

  • It is NOT a monoclonal antibody

  • It has low immunogenicity: no neutralizing antibodies observed in clinical trials

  • ENBREL has been shown not to lyse T cells in vitro2 †

  • ENBREL helps restore a natural balance of TNF by binding to TNF and rendering it biologically inactive, thus reducing inflammation in multiple diseases, including psoriasis

†Clinical significance is unknown

Reference1. ENBREL Summary of Product Characteristics, Wyeth Pharmaceuticals. 2. Data on file, Wyeth Pharmaceuticals.

*trademark


Enbrel proven therapy in chronic immune inflammatory diseases

ENBREL*: Proven Therapy in Chronic Immune Inflammatory Diseases

  • ENBREL is a biologic medication shown to be an effective and generally well-tolerated continuous therapy for several inflammatory diseases1

    – Rheumatoid arthritis

    – Juvenile chronic arthritis

    – Psoriatic arthritis

    – Ankylosing spondylitis

    – Psoriasis

Reference 1. ENBREL Summary of Product Characteristics, Wyeth Pharmaceuticals.

*trademark


Overview3

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Design of pivotal phase iii clinical trials

Design of Pivotal Phase III Clinical Trials

Phase III Global Trial (Dose-reduction Data)1

  • 12-week randomized, placebo-controlled, double-blind; followed by 36-week open label

  • 583 patients at 50 centers

  • 3 arms: placebo plus 2 ENBREL* dose groups (50 mg BIW; 25 mg BIW)

  • Primary end point: percentage of patients achieving PASI 75 at week 12 (≥75% improvement from baseline)

    Phase III U.S. Trial (Re-treatment Data)1,2

  • 24-week double-blind, randomized

  • Placebo-controlled for first 12 weeks

  • 652 patients

  • 47 U.S. centers

  • Placebo-controlled, randomized, double-blind groups

  • 4 arms: placebo plus 3 ENBREL dose groups (50 mg BIW; 25 mg BIW; 25 mg QW)

  • Primary end point: percentage of patients achieving PASI 75 at week 12

  • Responders were discontinued and re-treated for an additional 24 weeks

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Leonardi CL et al. N Engl J Med 2003;349:2014–2022.

*trademark


Overview4

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Design of phase iii global trial dose reduction data

Design of Phase III Global Trial (Dose-Reduction Data)

Double blind

Open-label

Screen and

Washout

ENBREL* 50 mg twice weekly

(n=203)

ENBREL 25 mg twice weekly

(n=204)

25 mg twice weekly (n=557)

Placebo (n=204)

Week 12

(primary end point)

Day 1

Week 48

N=611 randomized (583 patients received at least one dose of blinded study medication)

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Key patient eligibility criteria phase iii global trial dose reduction data

Key Patient Eligibility CriteriaPhase III Global Trial (Dose-Reduction Data)

  • Exclusion

  • Any previous ENBREL* treatment, or antibody to TNF

  • Investigational drugs, biologics, systemic psoriasis therapy, systemic corticosteroids, or PUVA within 4 weeks of study drug administration

  • UVB within 2 weeks of study drug administration

  • Topical corticosteroids, topical vitamin A or D analogue preparations, UVB, or anthralin within 2 weeks of study drug administration

  • Anti-CD4 or diphtheria IL-2 fusion protein within 6 months

  • Severe infection within 4 weeks, or antibiotics within 1 week of study drug administration

Inclusion

  • Active but clinically stable plaque psoriasis involving 10% of BSA

  • Minimum screening PASI score of 10

  • 1 previous phototherapy or systemic psoriasis therapy, or a candidate for such therapy

  • 18 years of age

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

*trademark


Key efficacy measures phase iii global trial dose reduction data 1 2

Key Efficacy MeasuresPhase III Global Trial (Dose-Reduction Data)1,2

Primary end point:

  • % of patients in each treatment group achieving PASI 75 at week 12

    Secondary end points:

  • % of patients with PASI 50, PASI 75, and PASI 90 at different time points

  • Dermatologist’s Static Global Assessment of Psoriasis (DSGAP) (05)

  • Dermatology Life Quality Index (DLQI) (030)

  • Patient Global Assessment of Psoriasis (PGAP)

  • Short Form-36 Health Survey (SF-36)

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Similar Baseline Demographics/Clinical Characteristics Across Groups1

Phase III Global Trial (Dose-Reduction Data)

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

*trademark


Rapid significant response with enbrel 1

Rapid, Significant Response With ENBREL*1

Phase III Global Trial (Dose-Reduction Data)

Placebo

80

68%

ENBREL 25 mg BIW

70

ENBREL 50 mg BIW

57%

60

50

Mean % Improvement From Baseline PASI score

40

30

20

10

0.2%

0

2

0

4

8

12

Weeks

†P < 0.0001 vs. placebo

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

*trademark


Sustained pasi 75 following dose reduction 1 2

Sustained PASI 75 Following Dose Reduction1,2

Phase III Global Trial (Dose-Reduction Data)

80

Placebo/ENBREL*

25 mg BIW

ENBREL 25 mg BIW

70

ENBREL 50 mg BIW/25 mg BIW

55%

60

46%

50

% of Patients Achieving PASI 75

40

30

20

10

3%

0

0

4

8

12

16

20

24

Weeks

2

†P < 0.001 vs. placebo; ‡P < 0.0001 vs. placebo

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Pasi 75 response improved from week 12 to week 24 despite decrease in dose

PASI 75 Response Improved from Week 12 to Week 24 Despite Decrease in Dose

Overall Response

  • 54% of patients at week 24 (ENBREL* 25 mg BIW after crossover) achieved a PASI 75 response compared to 49% at week 12 (ENBREL 50 mg BIW)1,2

    Responders vs. Non-Responders from Week 12 to Week 24

  • Nearly 80% of patients who achieved PASI 75 at week 12 sustained a PASI 75 at Week 241,2†

  • More than 30% of patients who did not achieve PASI 75 at week 12 achieved a PASI 75 response at week 241,2

†Patients with assessment data available at both week 12 and 24

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Sustained benefit demonstrated through week 48 1

Sustained Benefit Demonstrated Through Week 481

Phase III Global Trial (Dose-Reduction Data)

ENBREL* 25 mg BIW (n=196)

60

Placebo (n=193)

50

40

% of Patients Achieving

PASI 75 Response

30

20

10

0

0

4

8

12

16

20

24

28

32

36

40

44

48

Weeks

†P < 0.001 vs. placebo

ENBREL is indicated for 24 weeks administration

*trademark

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


Efficacy for patients who failed prior systemic or photo therapies

Efficacy for Patients Who Failed Prior Systemic or Photo Therapies

Phase III Global Trial (Dose-Reduction Data)

Did not fail prior therapy (n=184)

60

Failed prior therapy (n=337)

51

All patients in study (n=583)

49

50

40

37

40

34

% Patients With PASI 75 Response at Week 12

28

30

20

10

3

2

2

0

Placebo

25 mg BIW

50 mg BIW

ENBREL* dose

Reference 1. Data on file, Wyeth Pharmaceuticals.

*trademark


Significant pasi responses at week 12 1 2

Significant PASI Responses at Week 121,2

Phase III Global Trial (Dose-Reduction Data)

77

80

Placebo

ENBREL* 25 mg BIW

70

64

ENBREL 50 mg BIW

60

% of Patients

49

50

40

34

30

21

20

11

9

10

3

1

0

PASI 50

PASI 75

PASI 90

†P < 0.0001 vs. placebo for all comparisons

References1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Patient quality of life significantly improved within 2 weeks 1 2

Patient Quality of Life Significantly Improved Within 2 Weeks1,2

Phase III Global Trial (Dose-Reduction Data)

Placebo

80

70%

ENBREL* 25 mg BIW

70

ENBREL 50 mg BIW

65%

60

50

Mean % Improvement in DLQI From Baseline

40

30

20

6%

10

0

2

0

4

8

12

Weeks

†P = 0.0002 vs. placebo

‡P < 0.0001 vs. placebo

References 1.Data on file, Amgen, Thousand Oaks, Calif. 2. Kreuger G et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p120.

*trademark


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Dermatologist’s Static Global Assessment of Psoriasis:Percent of Patients Achieving Clear or Almost Clear Status1

Phase III Global Trial (Dose-Reduction Data)

80

70

Placebo

57

60

ENBREL* 25 mg BIW

ENBREL 50 mg BIW

50

% of Patients Achieving Clear or Almost-Clear Status

39

40

30

20

10

4

0

12 Weeks

DSGAP significantly improved vs. placebo for both doses by week 4

P < 0.0001 vs. placebo for both ENBREL dose groups at week 12

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

*trademark


Patient s global assessment of psoriasis 1 patients achieving a score of 0 or 1 0 to 5 scale

70

Placebo

55

ENBREL* 25 mg BIW

60

ENBREL 50 mg BIW

50

40

40

% of Patients

30

20

5

10

0

12 Weeks

P < 0.0001 vs. placebo for both dose groups in Patient Global Assessment of Psoriasis

Patient’s Global Assessment of Psoriasis:1Patients Achieving a Score of 0 or 1 (0 to 5 Scale)

Phase III Global Trial (Dose-Reduction Data)

80

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

*trademark


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

ENBREL* Was Generally Well ToleratedWeek 12 Safety: Most common adverse events (% of patients)1,2

Phase III Global Trial (Dose-Reduction Data)

Adverse events occurring in3% in any treatment group

Reference 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Phase iii global trial dose reduction data patient 2365

Phase III Global Trial (Dose-Reduction Data)Patient 2365

6 Months

Baseline

3 Months

5.7

6.0

57.3

PASI score

90

PASI % improvement

89

Patient was initially treated with ENBREL* 50 BIW and crossed over to

25 mg BIW at 3 months.

*trademark

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


Phase iii global trial dose reduction data patient 3066

Phase III Global Trial (Dose-Reduction Data)Patient 3066

1 month

Baseline

3 months

6 months

PASI score

31.6

5.7

1.3

0.6

82

96

PASI % improvement

98

Patient was initially treated with ENBREL* 50 mg BIW and crossed over to

25 mg BIW at 3 months.

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

*trademark


Summary of efficacy data from phase iii global trial dose reduction data 1 3

Summary of Efficacy Data from Phase III Global Trial (Dose-Reduction Data)1–3

ENBREL* can provide rapid, sustained, and clinically meaningful efficacy in plaque psoriasis

  • Significant differences from placebo seen as early as week 2 in % improvement in PASI and DLQI

  • 50 mg BIW and 25 mg BIW were both significantly effective at week 12 in multiple measures

    • PASI 50/75/90

    • DSGAP

    • DLQI

    • PGAP

  • Efficacy was sustained across 24 weeks regardless of dose or regimen

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112. 3. Krueger G et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p120.

*trademark


Summary of tolerability from phase iii global trial dose reduction data 1 2

Summary of Tolerability from Phase III Global Trial (Dose-Reduction Data)1,2

ENBREL* was well tolerated

  • Frequency of injection-site reactions in both groups receiving ENBREL was higher than placebo at week 12

  • Incidence of infections in both ENBREL groups was comparable to placebo at week 12

  • No increased incidence of adverse events was seen in patients receiving 50 mg BIW versus 25 mg BIW

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

*trademark


Overview5

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

*trademark


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Design of Phase III U.S. Trial (Re-treatment Data)1–3

Discontinuation and Re-treatment

Double Blind

E* 50 mg twice weekly

PASI

50

E 25 mg twice weekly

Discontinue drug

E50 mg twice weekly (n=168)

E 25 mg once weekly

E 25 mg twice weekly (n=167)

Blinded re-treatment with

week 24 dose at time of relapse

E 25 mg once weekly (n=169)

25 mg

twice weekly

Placebo (n=168)

PASI <50

25 mg twice weekly

Day 1

Week 12

Week 24

Primary Time Point

Assess Responder Status

E = ENBREL

*trademark

References 1. Leonardi CL et al. N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oak, Calif. 3. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110.


Key patient eligibility criteria phase iii u s trial re treatment data 1 2

Key Patient Eligibility CriteriaPhase III U.S. Trial (Re-treatment Data)1,2

  • Exclusion

  • Any previous treatment with ENBREL* or antibody to TNF treatment

  • Investigational drugs, biologics, systemic psoriasis therapy, systemic corticosteroids, or PUVA within 4 weeks of study drug administration

  • Topical corticosteroids, topical vitamin A or D analogue preparations, UVB, or anthralin within 2 weeks of study drug administration

  • Anti-CD4 or diphtheria IL-2 fusion protein within 6 months of study drug administration

  • Severe infection within 4 weeks, or antibiotics within 1 week of study drug administration

Inclusion

  • Active but clinically stable plaque psoriasis involving  10% BSA

  • Minimum screening PASI score of 10

  • At least one previous phototherapy or systemic psoriasis therapy, or a candidate for such therapy

  • At least 18 years of age

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on file, Amgen, Thousand Oaks, Calif.

*trademark


Key efficacy measures phase iii u s trial re treatment data

Key Efficacy MeasuresPhase III U.S. Trial (Re-treatment Data)

Primary end point1

  • % of patients in each treatment group achieving PASI 75 at week 12

    Secondary end points1,2

  • % of patients with PASI 50, PASI 75, and PASI 90 at different time points

  • Dermatologist’s Static Global Assessment of Psoriasis (DSGAP) (05)

  • Dermatology Life Quality Index (DLQI) (030)

  • Patient Global Assessment of Psoriasis (PGAP)

  • Health status “feeling thermometer” (0100)

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.


Similar baseline demographics clinical characteristics across groups 1 2

Similar Baseline Demographics/Clinical Characteristics Across Groups1,2

Phase III U.S. Trial (Re-treatment Data)

References 1. Leonardi CL et al.N Engl J Med 2003;349: 2014–2022. 2. Data on file, Amgen, Thousand Oaks, Calif.

*trademark


Significant improvement in pasi score as early as week 2 1 2

Significant Improvement in PASI Score as Early as Week 21,2

Phase III U.S. Trial (Re-treatment Data)

80

Placebo

71.1%

ENBREL* 25 mg QW

70

ENBREL 25 mg BIW

ENBREL 50 mg BIW

62.1%

60

50

50.3%

40

Mean% Improvement from Baseline PASI Score

30

†P≤ 0.003 vs. placebo

‡P < 0.0001 vs. placebo

20

10

0

0

4

8

12

16

20

24

2

Weeks

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.

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Pasi 75 response significant at week 12 and sustained at week 24 1 2

25

PASI 75 Response Significant at Week 12 and Sustained at Week 241,2

Phase III U.S. Trial (Re-treatment Data)

Placebo

80

ENBREL* 25 mg QW

70

ENBREL 25 mg BIW

59

ENBREL 50 mg BIW

60

49

50

44

% of Patients with PASI 75

Response

40

34

†P < 0.05 vs. placebo

‡P < 0.0001 vs. placebo

30

20

14

10

4

0

12 Weeks

24 Weeks

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.

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Pasi 50 and 90 response rates improved during treatment 1 2

PASI 50 and 90 Response Rates Improved During Treatment1,2

Phase III U.S. Trial (Re-treatment Data)

77

80

74

Placebo

70

ENBREL* 25 mg QW

70

ENBREL 25 mg BIW

58

58

ENBREL 50 mg BIW

60

% of Patients

50

41

40

30

30

†P < 0.0001 vs. placebo

22

20

20

14

12

6

10

3

1

0

12 Weeks

24 Weeks

12 Weeks

24 Weeks

(PASI 50)

(PASI 50)

(PASI 90)

(PASI 90)

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.

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Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Patient Quality of Life Significantly Improved Within 2 Weeks1,2DLQI Percentage Improvement in Total Score

Phase III U.S. Trial (Re-treatment Data)

Placebo

80

ENBREL* 25 mg QW

74%

ENBREL 25 mg BIW

70

ENBREL 50 mg BIW

59%

60

54%

50

40

Mean % Improvement in DLQI From Baseline

30

20

10

0

0

2

4

6

8

10

12

14

16

18

20

22

24

Weeks

†P = 0.01 vs. placebo

‡P = 0.0001 vs. placebo

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.

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Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Dermatologist’s Static Global Assessment of Psoriasis: Percentage of Patients Achieving Clear or Almost Clear Status1,2

Phase III U.S. Trial (Re-treatment Data)

Placebo

80

ENBREL* 25 mg QW

ENBREL 25 mg BIW

70

ENBREL 50 mg BIW

55

60

49

50

39

% of Patients Achieving Clear or Almost-Clear Status

34

40

26

30

23

20

5

10

0

12 Weeks

24 Weeks

† P<0.0001 vs. placebo

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on File, Amgen, Thousand Oaks, Calif.

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Patient s global assessment of psoriasis patients achieving a score of 0 or 1 0 to 5 scale 1 2

Patient’s Global Assessment of Psoriasis:Patients Achieving a Score of 0 or 1 (0 to 5 Scale)1,2

Phase III U.S. Trial (Re-treatment Data)

Placebo

80

ENBREL* 25 mg QW

66

70

ENBREL 25 mg BIW

ENBREL 50 mg BIW

60

50

46

50

% of Patients Achieving Score of 0 or 1

35

40

31

30

17

20

5

10

0

12 Weeks

24 Weeks

†P < 0.0001 vs. placebo

References 1. Leonardi CL et al.N Engl J Med 2003;349:2014–2022. 2. Data on file, Amgen, Thousand Oaks, Calif.

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Tolerability data for dose ranging period

Tolerability Data for Dose-Ranging Period

Placebo

ENBREL*

ENBREL

Weeks 1–12

Weeks 12–24

Weeks 1–24

Placebo

25 mg BIW

25 mg QW

25 mg BIW

50 mg BIW

Injection-site reaction

7%

7%

14%

20%

16%

Upper respiratory infection

11%

6%

14%

14%

12%

Headache

7%

5%

5%

12%

9%

Asthenia

3%

1%

6%

7%

3%

Myalgia

2%

2%

5%

7%

4%

Sinusitis

1%

1%

6%

6%

5%

Rash

2%

0%

2%

4%

6%

Nausea

1%

1%

5%

3%

3%

Injection-site ecchymosis

4%

2%

7%

3%

5%

Adverse events and infections occurring in  5% of patients in any dose group

Reference 1. Leonardi CL et al. N Engl J Med 2003;349:2014–2022.

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Clearing of skin lesions through 6 months phase iii u s trial re treatment data

Clearing of Skin Lesions Through 6 MonthsPhase III U.S. Trial (Re-treatment Data)

Week 12

Week 0

Week 24

PASI

22.7

6.3

3.8

BSA

18.5

23

4.5

Patient was treated with ENBREL* 25 mg once weekly.

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Summary of efficacy data from first period of u s phase iii study

Summary of Efficacy Data From First Period of U.S. Phase III Study

ENBREL* can provide rapid, sustained and clinically meaningful efficacy in plaque psoriasis

  • Significant differences from placebo seen as early as week 2 in % improvement in PASI and DLQI

  • 50 mg BIW and 25 mg BIW were both significantly effective at week 12 in multiple measures

    - PASI 50/75/90

    - DSGAP

    - DLQI

    - PGAP

    • Efficacy was sustained across 24 weeks for both 25 mg BIW and 50 mg BIW

References 1. Leonardi CL et al. N Engl J Med 2003;349:2014–2022. 2. Data on file, Amgen, Thousand Oaks, Calif.


Phase iii u s trial re treatment data 1 2 time to relapse

Phase III U.S. Trial (Re-treatment Data)1,2Time to Relapse

Efficacy Evaluation

Safety Evaluation

Double-Blind Period

Drug Discontinuation Period

Discontinue drug and follow up monthly until loss of response

Loss of response = Loss of at least

half of the PASI improvement

achieved between baseline

and 6 months

Example:

Baseline PASI 20

6-month PASI 5

Improvement 15 (75%)

Loss of Response PASI 12.5

N=652

N=409

E* 50 mg twice weekly

E 25 mg twice weekly

PASI 50

E 25 mg once weekly

25 mg twice

weekly

Placebo

Day 1

Week 12

Week 24

Primary End point

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110.


Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

Time to relapse following ENBREL* withdrawal1,2

Phase III U.S. Trial (Re-treatment Data)

†Defined as loss of 50% of improvement in PASI score in patients who had previously achieved a PASI 50 response.

References 1. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110. 2. Data on file, Amgen, Thousand Oaks, Calif.

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Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

ENBREL* Was Not Associated With Rebound1,2

Phase III U.S. Trial (Re-treatment Data)

  • “Rebound” was defined as a PASI of 150% or greater of baseline value

  • 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

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110.

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Re treatment period design 1 2

Re-treatment Period Design1,2

  • Study ended after all patients completed at least 60 weeks (15 months) total on study: 24 weeks treatment, 12 weeks withdrawal, 24 weeks re-treatment

  • 297 patients completed 3 months of re-treatment with ENBREL*

Blinded re-treatment with same dose patients were receiving at end of double-blind period (week 24)

E* 50 mg twice weekly

Week 24 PASI

50

Discontinuation

E 25 mg twice weekly

E 25 mg once weekly

E = ENBREL

References 1.van de Kerkhof PCM, et al. European Society of Dermatological Research abstract; September 2004; Vienna, Austria.2. Data on file, Amgen, Thousand Oaks, Calif.

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Enbrel etanercept a breakthrough to sustainable and repeatable efficacy in psoriasis

PASI 75 Responses After Initial Therapy and Re-treatment with ENBREL*1,2

Phase III U.S. Trial (Re-treatment Data)

Re-treatment

Double Blind

Week 24

Week 24

70

58

59

60

49

50

44

Discontinuation

40

% of Patients Achieving PASI 75

30

25

19

20

10

0

ENBREL 25 mg QW

ENBREL 25 mg BIW

ENBREL 50 mg BIW

References 1. Leonardi CL et al. N Engl J Med 2003;349:2014–2022. 2. Data on file, Amgen, Thousand Oaks, Calif.

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Phase iii u s trial re treatment phase conclusions 1 2

Phase III U.S. Trial Re-treatment Phase Conclusions1,2

  • ENBREL* remained efficacious upon re-treatment of responders

    • Re-treatment with ENBREL resulted in re-establishment of disease control

  • ENBREL can be discontinued without significant adverse effects:

    • After discontinuing treatment with ENBREL, psoriasis gradually relapsed over approximately 12 weeks

    • ENBREL discontinuation was well tolerated and was not associated with rebound of disease or conversion of psoriasis morphology

    • Re-treatment with ENBREL was not associated with increased antigenicity or formation of neutralizing antibodies

References 1.Data on file, Amgen, Thousand Oaks, Calif. 2. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110.

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Overview6

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

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Pooled safety data from 3 clinical trials

Pooled Safety Data from 3 Clinical Trials

There were no reports of opportunistic infections or tuberculosis during 662 patient exposure years.

23 malignancies were reported in patients with plaque psoriasis treated with ENBREL in double-blind and open-label studies of up to 15 months involving 1,261 patients treated with ENBREL.

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


Overview7

Overview

  • ENBREL* EU Indications for Psoriatic Diseases

  • Overview of Psoriasis

  • Clinical Evidence for the Role of TNF in Psoriasis

  • Pivotal Phase III Trials

    - Phase III Global Trial (Dose-reduction Data)

    - Phase III U.S. Trial (Re-treatment Data)

    - Discontinuation and Re-treatment

    - Pooled Safety Data

    5. Conclusions and Important Treatment Considerations

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Pasi 75 response was comparable for both phase iii enbrel trials at 12 and 24 weeks 1 3

PASI 75 Response Was Comparable for both Phase III ENBREL* Trials at 12 and 24 Weeks1–3

% of Patients Achieving PASI 75

Phase III U.S. Trial (n = 652)

Phase III Global Trial (n = 583)

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112. 3. Leonardi CL et al. N Engl J Med 2003;349:2014–2022.

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Pasi 75 response was comparable for both phase iii enbrel trials at 12 and 24 weeks 1

PASI 75 Response Was Comparable for Both Phase III ENBREL* Trials at 12 and 24 Weeks1

Response rates for the two phase III trials were nearly identical at 12 weeks

  • In the global phase III study, PASI 75 response was maintained at 6 months in patients whose dose was reduced from ENBREL 50 mg BIW to 25 mg BIW1

  • In the U.S. phase III study, a similar response was observed at 6 months in patients who continued on the same 50 mg BIW dose over the full 6 months1

References 1. Data on file, Amgen, Thousand Oaks, Calif.

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In three psoriasis studies enbrel was shown to be generally well tolerated 1 4

In Three Psoriasis Studies, ENBREL* Was Shown To Be Generally Well Tolerated14

  • No change in adverse event frequencies despite increase or decrease in dose

  • Adverse events were monitored up to 15 months of continuous therapy

  • ENBREL was not associated with rebound following discontinuation

  • Re-treatment with ENBREL was not associated with increased antigenicity or formation of neutralizing antibodies

  • No routine laboratory monitoring specific to ENBREL is required

References 1.ENBREL Summary of Product Characteristics. Wyeth Pharmaceuticals. 2. Gottlieb AB et al. Arch Dermatology 2003; 139: 1627-1632. 3. Leonardi CL et al. N Engl J Med 2003;349:2014–2022. 4. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112.

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In three psoriasis studies enbrel demonstrated rapid and consistent efficacy 1 5

In Three Psoriasis Studies, ENBREL* Demonstrated Rapid and Consistent Efficacy15

  • Significant improvements in PASI score and DLQI were observed as early as 2 weeks

  • Similar proportions of patients achieved a PASI 75 response in all three studies at week 12

  • Similar proportions of patients (58%70%) achieved a PASI 50 response in all three studies at week 12

  • PASI responses at 12 weeks were generally sustained at 24 weeks

  • At 24 weeks, efficacy after reduction of dose was similar to that reported with maintenance of dose

  • The sustained efficacy of initial therapy with ENBREL was repeatable when re-treating responders who had relapsed

References 1. Data on file, Amgen, Thousand Oaks, Calif. 2. Kreuger G et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p120. 3. Leonardi CL et al. N Engl J Med 2003;349:20142022. 4. Papp K et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p112. 5. Gottlieb AB et al. Poster presented at 10th International Psoriasis Symposium, June 10–13, 2004, Toronto. Abstracts, p110.

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Enbrel prescribing information 1

ENBREL* Prescribing Information1

Posology and method of administration

ENBREL treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or psoriasis.

Each vial of ENBREL 25 mg must be reconstituted with 1 ml of water for injections before use and administered by subcutaneous injection.

Adults (18-64 years)

Plaque psoriasis

The recommended dose of ENBREL is 25 mg administered twice weekly. Alternatively, 50 mg given twice weekly may beused for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly. Treatment with ENBREL should continue until remission is achieved, for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.

If re-treatment with ENBREL is indicated, the above guidance on treatment duration should be followed. The dose should be 25 mg twice weekly.

Psoriatic arthritis

25 mg ENBREL administered twice weekly is the recommended dose. Doses other than 25 mg administered twice weekly have not been studied.

Elderly patients ( 65 years)

No dose adjustment is required. Posology and administration are the same as for adults 18-64 years of age.

Children and adolescents ( 4 to <18 years)

0.4 mg/kg (up to a maximum of 25 mg per dose) after reconstitution of 25 mg ENBREL in 1 ml of water for injections, give twice weekly as a subcutaneous injection with an interval of 3-4 days between doses.

Renal and hepatic impairment

No dose adjustment is required.

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Reference 1. ENBREL Summary of Product Characteristics, Wyeth Pharmaceuticals.


Important treatment considerations 1

Important Treatment Considerations (1)

In postmarketing use, serious infections and sepsis, including fatalities, have been reported. Discontinue ENBREL in patients with serious infections or sepsis. 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.

Cases of CNS demyelinating disorders have been reported, although the causal relationship to ENBREL remains unclear. Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported in patients with rheumatoid arthritis (RA). Exercise caution in patients who have a previous history of significant hematologic abnormalities. Although the causal relationship to ENBREL remains unclear, advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. If significant hematologic abnormalities are confirmed, discontinue ENBREL. Long-term effects of ENBREL therapy on the development or course of infection and malignancy are unknown.


Important treatment considerations 2

Important Treatment Considerations (2)

The most frequent adverse events in five double-blind, controlledclinical trials in patients with RA were infections (49% of patients), injection-site reactions (31%), headaches (12%), and respiratory disorders (10%). Malignancies were rare.

The types of adverse events observed in the psoriatic arthritis and ankylosing spondylitis trials were similar to those reported in RA clinical trials.

The most common adverse events observed during the double-blind, placebo-controlled portions of three clinical trials in patients with psoriasis were infections (27%–29% of patients), injection-site reactions (14%–16%), headaches (9%–12%), and injection-site ecchymoses (6%– 8%). There were no reports of opportunistic infections or tuberculosis during 662 patient exposure years.

Twenty-three malignancies were reported in patients with plaque psoriasis treated with ENBREL in double-blind and open-label studies of up to 15 months involving 1,261 patients treated with ENBREL.


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