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ALEFACEPTALEFACEPT

Biogen, Inc.Biogen, Inc.Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs

Advisory Committee MeetingAdvisory Committee Meeting

23 May 200223 May 2002

4000.01

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Proposed Indication for AlefaceptProposed Indication for Alefacept

IndicationIndication Alefacept is indicated for the treatment of patients with Alefacept is indicated for the treatment of patients with

chronic plaque psoriasis who are candidates for chronic plaque psoriasis who are candidates for systemic or phototherapysystemic or phototherapy

Dosing RegimenDosing Regimen Once per week for twelve weeksOnce per week for twelve weeks

– 7.5 mg intravenous bolus injection7.5 mg intravenous bolus injection– 15 mg intramuscular injection15 mg intramuscular injection

Repeat courses can be given after a twelve week rest Repeat courses can be given after a twelve week rest periodperiod

4001.01

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AgendaAgenda

OverviewOverviewBurt Adelman, MD (Biogen Inc.)Burt Adelman, MD (Biogen Inc.)

Clinical Efficacy and Pharmacodynamics Clinical Efficacy and Pharmacodynamics Akshay Vaishnaw, MD, PhD (Biogen Inc.)Akshay Vaishnaw, MD, PhD (Biogen Inc.)

Clinical SafetyClinical SafetyGloria Vigliani, MD (Biogen Inc.)Gloria Vigliani, MD (Biogen Inc.)

Alefacept Risk Benefit ProfileAlefacept Risk Benefit ProfileMark Lebwohl, MD (Chairman, Professor of Dermatology, Mark Lebwohl, MD (Chairman, Professor of Dermatology, Mount Sinai School of Medicine, NYC)Mount Sinai School of Medicine, NYC)

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Biogen ConsultantsBiogen Consultants

Mark Lebwohl MDMark Lebwohl MDChairman, Professor of Dermatology, Chairman, Professor of Dermatology, Mount Sinai School of MedicineMount Sinai School of Medicine

Richard A. Cooper MDRichard A. Cooper MDProfessor of Medicine and Health PolicyProfessor of Medicine and Health PolicyHealth Policy InstituteHealth Policy InstituteMedical College of WisconsinMedical College of Wisconsin

David J. Margolis MD, PhDDavid J. Margolis MD, PhDAssociate Professor of Dermatology Associate Professor of Dermatology Associate Professor of EpidemiologyAssociate Professor of EpidemiologyCenter for Clinical Epidemiology and BiostatisticsCenter for Clinical Epidemiology and BiostatisticsUniversity of PennsylvaniaUniversity of Pennsylvania

James G. Krueger MD, PhDJames G. Krueger MD, PhDAssociate Professor and PhysicianAssociate Professor and PhysicianLaboratory HeadLaboratory HeadInvestigative DermatologyInvestigative DermatologyThe Rockefeller UniversityThe Rockefeller University

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Chronic Plaque PsoriasisChronic Plaque Psoriasis

T-cell mediated diseaseT-cell mediated disease

Men and women affected equallyMen and women affected equally

Genetic componentGenetic component

Circumscribed, raised, red plaquesCircumscribed, raised, red plaques

– Scaly, itchy, cracking, bleedingScaly, itchy, cracking, bleeding

– Moderate to severe characterized by > 10% body Moderate to severe characterized by > 10% body surface area involvement, but can be up to 98%surface area involvement, but can be up to 98%

Life-long disease with no cureLife-long disease with no cure

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Patient Perspective: Moderate to Severe PsoriasisPatient Perspective: Moderate to Severe Psoriasis

““They glance at me and glance They glance at me and glance away, pained. My hands and away, pained. My hands and my face mark me. The name my face mark me. The name of the disease, spiritually of the disease, spiritually speaking, is Humiliation.”speaking, is Humiliation.”

John UpdikeJohn Updike

At War with My SkinAt War with My Skin

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Non-Cutaneous Burden of DiseaseNon-Cutaneous Burden of Disease

QOL severely compromised and comparable to QOL severely compromised and comparable to other major medical disordersother major medical disorders

Increased risk substance abuse, depression, Increased risk substance abuse, depression, suicidesuicide

Common co-morbidities include obesity, heart Common co-morbidities include obesity, heart disease, diabetes, hepatitisdisease, diabetes, hepatitis

Patients with severe psoriasis surveyed by NPF Patients with severe psoriasis surveyed by NPF desired more aggressive therapiesdesired more aggressive therapies

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Disease – suppressiveDisease – suppressive

Disease – remittiveDisease – remittive

SystemicSystemic

MethotrexateMethotrexate

Retinoids Retinoids

Cyclosporine Cyclosporine

PhototherapyPhototherapy

PUVA PUVA

UVBUVB

Current TherapiesCurrent Therapies

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Psoriatic PlaquePsoriatic Plaque

Immunopathology of PsoriasisImmunopathology of Psoriasis

Activated T cells in lesionsActivated T cells in lesions

>75% T cells memory >75% T cells memory (CD45RO+) phenotype, (CD45RO+) phenotype, derived from circulating derived from circulating memory T cellsmemory T cells

Release of inflammatory Release of inflammatory factors stimulates factors stimulates keratinocyte proliferation and keratinocyte proliferation and angiogenesisangiogenesis

Austin et al., 1999; Friedrich et al., 2000

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B Cells

B Cells

Monocytes/DC

Monocytes/DC

NK NK CellsCells

EosinophilsEosinophilsBasophilsBasophils

NeutrophilsNeutrophils NaNaïïveveCD45RA+CD45RA+

NaNaïïveveCD45RA+CD45RA+

MemoryMemoryCD45RO+CD45RO+

T Cells(CD4+ or CD8+)

Leukocyte PopulationsLeukocyte Populations

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Memory T Cells are Derived from Naïve T CellsMemory T Cells are Derived from Naïve T Cells

CD45ROCD45RO++

CD2CD2

CD2CD2

CD

2C

D2

CD2CD2

CD2CD2

CD2CD2

Memory T Cell

CD2CD2

CD2CD2

CD45RA+CD45RA+CD2CD2

TCRTCR

Naïve T Cell

CD2CD2

CD

2C

D2

AntigenAntigenPresenting Presenting

CellCell

MHCMHC

LFA3LFA3

TCRTCRB7B7 CD28CD28

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1st extracellular1st extracellulardomain ofdomain ofhuman LFA-3human LFA-3

Fc portion ofFc portion ofhuman IgGhuman IgG11

H H

LFA-3 LFA-3

CH2

CH2

CH3

CH3

Bindsto CD2

Alefacept: A Fully Human Fusion ProteinAlefacept: A Fully Human Fusion Protein

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Alefacept Mechanism of ActionAlefacept Mechanism of Action

Memory Memory T CellT Cell

CD2CD2

CD2CD2

CD2CD2

CD2CD2

TCRTCR

NaturalNaturalKiller CellKiller Cell FcFcRIII

RIII

GranzymeGranzyme

AntigenAntigenPresentingPresenting

CellCellMHCMHC

LFA3LFA3

LFA3LFA3 MemoryMemoryT CellT Cell

apoptosisapoptosis

CD2CD2

CD2CD2

CD2CD2

CD2CD2

AlefaceptAlefacept

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Alefacept Targets Memory T CellsAlefacept Targets Memory T Cells

Placebo

0.025 mg/kg

0.075 mg/kg

0.150 mg/kg

CD4+ memory T cells

700

500

300

100Mea

n C

ou

nt

(cel

ls/µ

L)

0 6 12 18 24

Time (weeks)

Dosing Period

700

500

300

100

0

CD4+ naïve T cells

0 6 12 18 24

Dosing Period0

Mea

n C

ou

nt

(cel

ls/µ

L)

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Toxicology ProgramToxicology Program

35 toxicology studies in non-human primates35 toxicology studies in non-human primates

Regimens up to 20 mg/kg IV weekly for 1 yearRegimens up to 20 mg/kg IV weekly for 1 year

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Toxicology Program: ResultsToxicology Program: Results

Alefacept was well-tolerated Alefacept was well-tolerated

Reversible decreases in lymphocyte counts, Reversible decreases in lymphocyte counts, blood and lymphoid tissuesblood and lymphoid tissues

No opportunistic infectionsNo opportunistic infections

No reproductive toxicityNo reproductive toxicity

A single non-human primate developed aA single non-human primate developed aB cell lymphomaB cell lymphoma

– High dose: 20 mg/kg weekly for 28 weeksHigh dose: 20 mg/kg weekly for 28 weeks

– Exposure equivalent to 622 clinical coursesExposure equivalent to 622 clinical courses

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Clinical ProgramClinical Program

18 Clinical Studies18 Clinical Studies– 1357 psoriasis patients1357 psoriasis patients– 240 healthy volunteers240 healthy volunteers

3 randomized double-blind placebo-controlled studies in 3 randomized double-blind placebo-controlled studies in psoriasis patientspsoriasis patients

Safety extension studies Safety extension studies – Over 800 patientsOver 800 patients– Up to 5 treatment courses over 3 yearsUp to 5 treatment courses over 3 years

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Ongoing Clinical DevelopmentOngoing Clinical Development

PsoriasisPsoriasis SclerodermaScleroderma

AlefaceptAlefacept

Rheumatoid Rheumatoid ArthritisArthritis

PsoriaticPsoriaticArthritisArthritis

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Regulatory HistoryRegulatory History

August 1996 Pre-IND Meeting August 1999 End-of-Phase 2 Meeting

- Design and size of Phase 3 trials- Study endpoints and statistical

analyses- Safety database consistent with

ICH Guidance

July 2001 Pre-BLA Meeting

August 2001 BLA Filing

March 2002 Safety Update