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Agenda

Agenda. Overview Burt Adelman MD Efficacy and Pharmacodynamics Akshay Vaishnaw MD, PhD Safety Gloria Vigliani MD Alefacept Risk Benefit Profile Mark Lebwohl MD. Psoriasis. Psoriasis. Psoriasis. Psoriasis. Psoriasis. Alefacept Clinical Trial Patients – Baseline. Impact of Psoriasis.

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Agenda

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

  2. Psoriasis

  3. Psoriasis

  4. Psoriasis

  5. Psoriasis

  6. Psoriasis

  7. Alefacept Clinical Trial Patients – Baseline

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

  9. Light Therapy Unit

  10. 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)

  11. 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)

  12. Limitations of Methotrexate

  13. 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

  14. Retinoid Side Effects

  15. Retinoid Side Effects

  16. 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

  17. 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

  18. 131-201 PASI 50 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

  19. 151-206 PASI 50 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

  20. 153-205 PASI 50 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

  21. 123-217 PASI 75 After Primary Endpoint 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

  22. 142-203 PASI 75 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

  23. 154-202 Duration Baseline PASI 22.2 2 Weeks After Last Dose PASI 2 91% PASI Reduction 12 Weeks After Last Dose PASI 0 100% PASI Reduction

  24. Page 2; 154-202 Duration 23 Weeks After Last Dose PASI 3.6 84% PASI Reduction 37 Weeks After Last Dose PASI 8.7 61% PASI Reduction

  25. Who Should Receive Alefacept? • Patients with challenging disease • Not candidate for topical monotherapy • UVB is impractical • Candidate for PUVA, Methotrexate, or Cyclosporine

  26. Managing the Alefacept – Treated Patient • Select dosing route – IM and IV • IV offers single needlestick • Patient 90% BSA can’t 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

  27. 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

  28. 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

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