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, mg/kg/d –after 2 years, all showed features of CsA nephropathy –arteriolar hyalinosis, focal interstitial fibrosis, sclerotic glomeruli

17 Baseline PASI Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction What Does Alefacept Offer?

PASI 50 Baseline PASI Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction

19 PASI Baseline PASI Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction

Baseline PASI Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction PASI 50

Baseline PASI Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction PASI 75 After Primary Endpoint

Baseline PASI 30 2 Weeks After Last Dose PASI % PASI Reduction 12 Weeks After Last Dose PASI % PASI Reduction PASI 75

Baseline PASI Weeks After Last Dose PASI 2 91% PASI Reduction 12 Weeks After Last Dose PASI 0 100% PASI Reduction Duration

24 Page 2; Weeks After Last Dose PASI % PASI Reduction 37 Weeks After Last Dose PASI % PASI Reduction Duration

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