1. 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. 2 Psoriasis

3. 3 Psoriasis

4. 4 Psoriasis

5. 5 Psoriasis

6. 6 Psoriasis

7. 7 Alefacept Clinical Trial Patients – Baseline

8. 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. 9 Light Therapy Unit

10. 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. 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. 12 Limitations of Methotrexate

13. 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. 14 Retinoid Side Effects

15. 15 Retinoid Side Effects

16. 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. 17 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 What Does Alefacept Offer?

18. 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. 19 PASI 50 151-206Baseline 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. 20 153-205Baseline 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 PASI 50

21. 21 123-217Baseline 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 PASI 75 After Primary Endpoint

22. 22 142-203Baseline PASI 30 2 Weeks After Last Dose PASI 6.1 80% PASI Reduction 12 Weeks After Last Dose PASI 3.5 88% PASI Reduction PASI 75

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

24. 24 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 Duration

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

26. 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. 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. 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