Agenda

1
Agenda

• Overview
• Burt Adelman MD
• Efficacy and Pharmacodynamics
• Akshay Vaishnaw MD, PhD
• Safety
• Gloria Vigliani MD
• Alefacept Risk Benefit Profile
• Mark Lebwohl MD

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Psoriasis
3
Psoriasis
4
Psoriasis
5
Psoriasis
6
Psoriasis
7
Alefacept Clinical Trial Patients Baseline
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Impact of Psoriasis

• Psoriasis causes as much disability as other
  major medical diseases (Rapp, Feldman, et. al.,
  Journal of the American Academy of Dermatology)

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Light Therapy Unit
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Limitations of PUVA

• Non-melanoma skin cancer occurring in patients
  treated with PUVA five to ten years after first
  treatment (Stern et al., J Invest Dermatol ,
  1988)
• Malignant melanoma in patients treated for
  psoriasis with methoxsalen (psoralen) and
  ultraviolet A radiation (PUVA). The PUVA
  Follow-Up Study (Stern et al. N Engl J Med 1997)

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Limitations of Methotrexate

• Complications in methotrexate treatment of
  psoriasis with particular reference to liver
  fibrosis (Ashton et al., Invest Dermatol, 1982)
• Methotrexate in psoriasis consensus conference
  (Roenigk HH Jr, Auerbach R, Maibach H, Weinstein
  G, Lebwohl M, (J Am Acad Dermatol, 1998)
• A 21-year experience with major hemorrhage after
  percutaneous liver biopsy (McGill et al.,
  Gastroenterology, 1990)
• Methotrexate for rheumatoid arthritis. Suggested
  guidelines for monitoring liver toxicity.
  American College of Rheumatology (Kremer et al.,
  Arthritis Rheum 1994)

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Limitations of Methotrexate
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Methotrexate

• Pancytopenia associated with low dose
  methotrexate therapy. A regional survey.
  (al-Awadhi, et al., Journal of Rheumatology,
  1993)
• 15 cases from Ottawa physician survey and 2
  teaching hospitals
• 2 deaths, 1 attributed to methotrexate

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Retinoid Side Effects
15
Retinoid Side Effects
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Limitations of Cyclosporine A

• Renal biopsy findings in long-term cyclosporin
  treatment of psoriasis (Zachariae et al., Br J
  Dermatol 1997)
• 30 psoriatics, 6months - 8 years, 2.5 - 6 mg/kg/d
• after 2 years, all showed features of CsA
  nephropathy
• arteriolar hyalinosis, focal interstitial
  fibrosis, sclerotic glomeruli

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What Does Alefacept Offer?
Baseline PASI 14.2
2 Weeks After Last Dose PASI 9.5 33 PASI
Reduction
12 Weeks After Last Dose PASI 4.8 66 PASI
Reduction
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PASI 50
131-201
Baseline PASI 21.3
2 Weeks After Last Dose PASI 5.8 73 PASI
Reduction
12 Weeks After Last Dose PASI 6.5 69 PASI
Reduction
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PASI 50
151-206
Baseline PASI 28.7
2 Weeks After Last Dose PASI 9.6 67 PASI
Reduction
12 Weeks After Last Dose PASI 11.4 60 PASI
Reduction
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PASI 50
153-205
Baseline PASI 18.7
2 Weeks After Last Dose PASI 5.7 70 PASI
Reduction
12 Weeks After Last Dose PASI 9.6 49 PASI
Reduction
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PASI 75 After Primary Endpoint
123-217
Baseline PASI 17.8
2 Weeks After Last Dose PASI 9.8 45 PASI
Reduction
12 Weeks After Last Dose PASI 3.9 78 PASI
Reduction
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PASI 75
142-203
Baseline PASI 30
2 Weeks After Last Dose PASI 6.1 80 PASI
Reduction
12 Weeks After Last Dose PASI 3.5 88 PASI
Reduction
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Duration
154-202
Baseline PASI 22.2
2 Weeks After Last Dose PASI 2 91 PASI Reduction
12 Weeks After Last Dose PASI 0 100 PASI
Reduction
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Duration
Page 2 154-202
23 Weeks After Last Dose PASI 3.6 84 PASI
Reduction
37 Weeks After Last Dose PASI 8.7 61 PASI
Reduction
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Who Should Receive Alefacept?

• Patients with challenging disease
• Not candidate for topical monotherapy
• UVB is impractical
• Candidate for PUVA, Methotrexate, or Cyclosporine

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Managing the Alefacept Treated Patient

• Select dosing route IM and IV
• IV offers single needlestick
• Patient 90 BSA cant get IM
• Routine monitoring (lymphocyte counts) and
  evaluation during therapy
• Future courses administered to previous
  responders
• Continued observation of patients for as yet
  undetected long term issues

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Overall Benefit / Risk Ratio

• Long term exposure will be limited to those
  patients that respond to therapy
• Majority of patients benefit from therapy
• Lymphocyte counts are monitorable
• Duration superior to current therapy
• No hepatotoxicity, no nephrotoxicity

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Alefacept Conclusions

• Selective and novel approach targeting memory T
  cells
• T-cell effects correlate with efficacy but not
  with adverse safety outcomes
• Clinically meaningful benefit in the majority of
  patients
• Significant duration of remission
• Improvements in disease activity associated with
  QOL benefit
• Well-tolerated
• First systemic disease-remittive agent