# Presentation: 098979

## ALEFACEPT

**ALEFACEPT**

***Biogen, Inc.***
***Dermatologic and Ophthalmic Drugs  Advisory Committee Meeting***
***23 May 2002***

**4000.01**

## Proposed Indication for Alefacept

**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**

**4001.01**

## 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)**

## 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**

## 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**

## 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***

## 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**

## Current Therapies

**Disease – remittive**

***Systemic******	*****	****	**
**Methotrexate**
**Retinoids **
**Cyclosporine **
***Phototherapy***
**PUVA **
**UVB**

**Current Therapies**

## Immunopathology of Psoriasis

**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**

## Leukocyte Populations

**B **
**Cells**

**NK **
**Cells**

**Eosinophils**
**Basophils**

**Neutrophils**

**Na****ï****ve****CD45RA+**

**  ****T Cells**
**(CD4+ or CD8+)**

**Leukocyte Populations**

## Memory T Cells are Derived from Naïve T Cells

**Memory T Cells are Derived from Naïve T Cells**

**CD45RO****+**

**CD2**

**CD2**

**CD2**

**CD2**

**CD2**

**CD2**

***Memory T Cell ***

**CD2**

**CD2**

**CD45RA+**

**CD2**

**TCR**

***Na******ï******ve T Cell****** ***

**CD2**

**CD2**

**Antigen**
**Presenting **
**Cell**

**MHC**

**LFA3**

**TCR**

**B7**

**CD28**

## Alefacept: A Fully Human Fusion Protein

**Fc portion of****human IgG****1**

**H**

**H**

**LFA-3**

**LFA-3**

**C**
**H**
**2**

**C**
**H**
**2**

**C**
**H**
**3**

**C**
**H**
**3**

**Binds**
**to CD2**

**Alefacept: A Fully Human Fusion Protein**

## Alefacept Mechanism of Action

**Memory **
**T Cell**

**CD2**

**CD2**

**CD2**

**CD2**

**TCR**

**Antigen**
**Presenting**
**Cell**

**MHC**

**LFA3**

**LFA3**

**CD2**

**CD2**

**CD2**

**CD2**

## Alefacept Targets Memory T Cells

- Placebo

- 0.025 mg/kg

- 0.075 mg/kg

- 0.150 mg/kg

***CD4+ memory T cells***

- 700

- 500

- 300

- 100

**Mean Count (cells/μL)**

- 0

- 6

- 12

- 18

- 24

**Time (weeks)**

- Dosing Period

- 700

- 500

- 300

- 100

- 0

***CD4+ naïve T cells***

- 0

- 6

- 12

- 18

- 24

- Dosing Period

- 0

**Mean Count (cells/μL)**

## Toxicology Program

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

## 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**

## 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**

## Ongoing Clinical Development

**Psoriasis**

## Regulatory 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**