1 ALEFACEPT Biogen, Inc. Dermatologic and Ophthalmic Drugs Advisory Committee Meeting 23 May

2 Proposed Indication for Alefacept Indication  Alefacept is indicated for the treatment of patients with chronic plaque psoriasis who are candidates for systemic or phototherapy Dosing Regimen  Once per week for twelve weeks –7.5 mg intravenous bolus injection –15 mg intramuscular injection  Repeat courses can be given after a twelve week rest period

3 Agenda  Overview Burt Adelman, MD (Biogen Inc.)  Clinical Efficacy and Pharmacodynamics Akshay Vaishnaw, MD, PhD (Biogen Inc.)  Clinical Safety Gloria Vigliani, MD (Biogen Inc.)  Alefacept Risk Benefit Profile Mark Lebwohl, MD (Chairman, Professor of Dermatology, Mount Sinai School of Medicine, NYC)

4 Biogen Consultants  Mark Lebwohl MD Chairman, Professor of Dermatology, Mount Sinai School of Medicine  Richard A. Cooper MD Professor of Medicine and Health Policy Health Policy Institute Medical College of Wisconsin  David J. Margolis MD, PhD Associate Professor of Dermatology Associate Professor of Epidemiology Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  James G. Krueger MD, PhD Associate Professor and Physician Laboratory Head Investigative Dermatology The Rockefeller University

5 Chronic Plaque Psoriasis  T-cell mediated disease  Men and women affected equally  Genetic component  Circumscribed, raised, red plaques –Scaly, itchy, cracking, bleeding –Moderate to severe characterized by > 10% body surface area involvement, but can be up to 98%  Life-long disease with no cure

6 Patient Perspective: Moderate to Severe Psoriasis “They glance at me and glance away, pained. My hands and my face mark me. The name of the disease, spiritually speaking, is Humiliation.” John Updike At War with My Skin

7 Non-Cutaneous Burden of Disease  QOL severely compromised and comparable to other major medical disorders  Increased risk substance abuse, depression, suicide  Common co-morbidities include obesity, heart disease, diabetes, hepatitis  Patients with severe psoriasis surveyed by NPF desired more aggressive therapies

8 Disease – suppressive Disease – remittive Systemic  Methotrexate  Retinoids  Cyclosporine Phototherapy  PUVA  UVB Current Therapies

9 Psoriatic Plaque Immunopathology of Psoriasis  Activated T cells in lesions  >75% T cells memory (CD45RO+) phenotype, derived from circulating memory T cells  Release of inflammatory factors stimulates keratinocyte proliferation and angiogenesis Austin et al., 1999; Friedrich et al., 2000

10 B Cells B Cells Monocytes/ DC Monocytes/ DC NKCells EosinophilsBasophils Neutrophils Naïve CD45RA+ Memory CD45RO+ T Cells (CD4+ or CD8+) Leukocyte Populations

11 Memory T Cells are Derived from Naïve T Cells CD45RO + CD2 CD2 CD2 CD2 CD2 CD2 Memory T Cell CD2 CD2 CD45RA+ CD2 TCR Naïve T Cell CD2 CD2 AntigenPresentingCell MHC LFA3 TCR B7 CD28

12 1st extracellular domain of human LFA-3 Fc portion of human IgG 1 H H LFA-3 CH2CH2 CH2CH2 CH3CH3 CH3CH3 Binds to CD2 Alefacept: A Fully Human Fusion Protein

13 Alefacept Mechanism of Action Memory T Cell CD2 CD2 CD2 CD2 TCR Natural Killer Cell Fc  RIII Granzyme AntigenPresentingCell MHC LFA3 LFA3 Memory T Cell apoptosis CD2 CD2 CD2 CD2 Alefacept

14 Alefacept Targets Memory T Cells Placebo mg/kg mg/kg mg/kg CD4+ memory T cells Mean Count (cells/µL) Time (weeks) Dosing Period CD4+ naïve T cells Dosing Period 0 Mean Count (cells/µL)

15 Toxicology Program  35 toxicology studies in non-human primates  Regimens up to 20 mg/kg IV weekly for 1 year

16 Toxicology Program: Results  Alefacept was well-tolerated  Reversible decreases in lymphocyte counts, blood and lymphoid tissues  No opportunistic infections  No reproductive toxicity  A single non-human primate developed a B cell lymphoma –High dose: 20 mg/kg weekly for 28 weeks –Exposure equivalent to 622 clinical courses

17 Clinical Program  18 Clinical Studies –1357 psoriasis patients –240 healthy volunteers  3 randomized double-blind placebo-controlled studies in psoriasis patients  Safety extension studies –Over 800 patients –Up to 5 treatment courses over 3 years

18 Ongoing Clinical Development Psoriasis Scleroderma Alefacept Rheumatoid Arthritis PsoriaticArthritis

19 Regulatory History August 1996Pre-IND Meeting August 1999End-of-Phase 2 Meeting - Design and size of Phase 3 trials - Study endpoints and statistical analyses - Safety database consistent with ICH Guidance July 2001Pre-BLA Meeting August 2001BLA Filing March 2002Safety Update