# Presentation: 312228

## Agenda

**Overview**
**Burt Adelman MD**
**Efficacy and Pharmacodynamics**
**Akshay Vaishnaw MD, PhD**
**Safety**
**Gloria Vigliani MD**
**Alefacept Risk Benefit Profile**
**Mark Lebwohl MD**

## Efficacy Overview

**Efficacy**
**Phase 2 overview**
**Phase 3: IM and IV studies**
**Quality of life **
**Efficacy in sub-populations**

## Randomized Placebo-Controlled Studies

**Enrolled**

**229**

**526**

**569**

**Route****of Administration**

**IV**

**IV**

**IM**

**Study**

**Phase 2****(Study 708)**

**Phase 3****(Study 711)**

**Phase 3****(Study 712)**

**0.025, 0.075,****0.15 mg/kg**

**7.5 mg**

**10, 15 mg**

**Dose(s)**

**Randomized Placebo-Controlled Studies**

## Phase 2 Dose-Ranging, Randomized,Placebo-Controlled Study

**Phase 2 Dose-Ranging, Randomized,****Placebo-Controlled Study**

## Phase 2 Summary

**Efficacy**
**Clinically meaningful efficacy**
**Long duration of benefit**
**T-cell effects**
**Selective for memory T cells**
**Correlated with efficacy**
**Dose selection for Phase 3**

## Phase 3 Studies

## Phase 3: Psoriasis Disease Status at Baseline

**BSA = Body surface area**
**PASI = Psoriasis area and severity index**
**PGA = Physician global assessment**

**94**

**85**

**% with PGA of**
**“****moderate” to “severe”**

**Median BSA (%)**

**22**

**21**

**Median duration (yrs)**

**18**

**19**

**15**

**14**

**Median PASI**

**Phase 3****IV**

**Phase 3****IM**

## PASI: Psoriasis Area and Severity Index

**Composite measure of erythema, induration, desquamation and body surface area affected**
**Evaluated for head, trunk, upper and lower limbs**
**Ranges from 0 (clear) to 72 (max severity)**

## Phase 3 Endpoints

**Phase 3 Endpoints**

**PASI 75**
******75% reduction from baseline**
**PASI 50**
******50% reduction from baseline**
**PGA AC/C**
**Physician Global Assessment,****	****“almost clear or clear”**

**2 weeks after last dose **_***and***_*** *****overall response rate**

## Determination of Response Rate:2 Weeks After Last Dose vs. Overall 

**Placebo**

**Alefacept**

**Weeks 1-12**
**Dosing**

**Weeks 13-24**
**Follow-up**

## PASI 50

**PASI 5.7**
***69% PASI Reduction***

**PASI 50**

## PASI 75

**PASI 34.3**

**PASI 4.2**
***88% PASI Reduction***

## Phase 3 IM Study

## Phase 3 IM study design

**Weeks 1-12**
**Dosing**

**Weeks 13-24**
**Follow-up**

**Placebo (n=168)**

**10 mg (n=173)**

**15 mg (n=166)**

**Phase 3 IM study design**

**Placebo**

**Alefacept**

**Alefacept**

**Screening**

**Randomization**

## Phase 3 IM Primary Endpoint: PASI 75, 2 Weeks After Last Dose

**21%**

**12%**

**5%**

**Phase 3 IM Primary Endpoint: ****PASI 75, 2 Weeks After Last Dose**

********P*****<0.001**

## Phase 3 IMPGA “Almost Clear/Clear”, 2 Weeks After Last Dose

**Phase 3 IM****PGA “Almost Clear/Clear”, 2 Weeks After Last Dose**

- *

**14%**

**10%**

**5%**

********P=*****0.006**

## Phase 3 IMPASI 50, 2 Weeks After Last Dose

** ***** **

** ***** **

**42%**

**36%**

**18%**

********P*****<0.001**

## Phase 3 IM PASI 75, 2 Weeks vs. Overall Response Rate

***2 Weeks After Last Dose***

**5%**

**12%**

**21%**

*****

**Phase 3 IM ****PASI 75, 2 Weeks vs. Overall Response Rate**

********P*****<0.001**

## Phase 3 IV Study

## Phase 3 IV Study Design

**Course 1****24 Weeks**

**Course 2****24 Weeks**

**Cohort 1****(n = 183)**

**Cohort 3****(n = 186)**

**Cohort 2****(n = 184)**

**Alefacept****7.5 mg**

**Alefacept****7.5 mg**

**Alefacept****7.5 mg**

**Placebo**

**Placebo**

**Alefacept****7.5 mg**

**Screening**

**Randomization**

## Phase 3 IV StudyEfficacy, 2 weeks after last dose

**Phase 3 IV Study****Efficacy, 2 weeks after last dose**

**PASI 50**

**38%**

**0**

**10**

**20**

**30**

**40**

**50**

**Proportion Responding (%)**

**PASI 75**

**PGA Almost****Clear or Clear**

**11%**

**14%**

**10%**

**4%**

**4%**

*****

******

*****

*******	*****P*****<0.001**
********	*****P*****=0.004**

**Course 1 Alefacept 7.5 mg (Cohorts 1&2)**

## Phase 3 IV StudyEfficacy, Overall Response Rates

- *

**24%**

**8%**

**6%**

*******	*****P*****<0.001**

**56%**

**28%**

**23%**

**Phase 3 IV Study****Efficacy, Overall Response Rates**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Proportion Responding (%)**

**PASI 50**

**PASI 75**

**PGA Almost****Clear or Clear**

**Course 1 Alefacept 7.5 mg (Cohorts 1&2)**

- *

- *

## Phase 3 IV Duration of Efficacy

**Duration calculated for PASI 75 responders, cohort 2 (alefacept ******** placebo)**
**Duration of remission defined as time spent ********PASI 50**
**Median duration of remission = 7 months**

## Duration of PASI 50 in Those Who Achieved PASI 75 

**0**

**25**

**50**

**75**

**100**

**Response Duration (days)**

**1**

**43**

**85**

**127**

**169**

**211**

**253**

**295**

**337**

**379**

**Proportion responding (%)**

***Phase 3 IV Study, Cohort 2***

## Quality of Life

**  **

**Phase 3 IV Study**

******

**n = 158**

**n = 314**

*****

**p < 0.001**

*****

**Extent of DLQI Change Across Phase 3 Treatment Groups**

**DLQI Score**

**DLQI Score**

**12.1**

**9.1**

**6.7**

**10.7**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**Placebo**

**15 mg IM**

******

**n = 150**

**n = 141**

**Phase 3 IM Study**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**Placebo**

**7.5 mg IV**

**9.9**

**11**

**7.6**

**11**

**Extent of DLQI Change Associated with Efficacy Endpoints in Responders, 2 Weeks After Last Dose**

**Mean DLQI Score**

*** p < 0.001**
**Responder vs. non-responder**

**10.4**

**2.4**

**4.2**

**2.4**

**11**

**11.6**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**PASI 75**

**PASI 50**

**PGA**

**AC/C**

*****

*****

*****

***Phase 3 IV Study, Course 1***

## DLQI Responses in Phase 3 IM Study, 15 mg Group

**	****	****Baseline****	****2 Weeks After**
**	****	****	****Last Dose**
**Embarrassment****	****64%****	****27%**
**Impact on daily activities****	****21%****	****  7%**
**Leisure or social activities****	****34%****	****18%****	**
**Problems with partner, ****	****20%****	****  9%****relatives, friends****	****	****	**
**Sexual difficulties****	****21%****	****15%**

***Proportion responding “Very Much” or “A Lot”****

***Scale:  1=Very Much;  2= A Lot;  3= A Little;  4=Not At All;  5= Not Relevant**

**DLQI Responses in Phase 3 IM Study, 15 mg Group**

## Efficacy in Sub-populations

**16.2**

**13.8**

**4.1**

**5.6**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**BSA ********30%**

**BSA >30%**

**Placebo**

**Alefacept**

**PASI 75: Primary Efficacy Endpoint in Phase 3 Patients with Severe Disease**

**n=246**

**n=108**

**n=481**

**n=225**

**Proportion Responding (%)**

*****

*****

*****

**p < 0.001**

**p = 0.026**

*****

*****

*****

**PASI 75: Primary Efficacy Endpoint in Phase 3 Patients Based on Response to Prior Therapy**

**Proportion Responding (%)**

*****

*******

*****

*****

*****

*******

**p = 0.001**

**p < 0.001**

**Improved on**
**prior Rx**

******

**n=65**

**n=109**

**n=213**

**n=434**

**n=76**

**n=163**

**No**
**prior Rx**

**No change/worsened**
**on prior Rx**

**p = 0.027**

## Efficacy Conclusions

**Effective in reducing psoriasis disease activity**
**3 independent trials including IV and****IM routes**
**Data consistent and robust across all endpoints and sub-populations**
**Greater response with second course **
**Extended duration of remission **
**Significant QOL benefit**

## Pharmacodynamics

## Overview of Pharmacodynamics

**Range of alefacept-mediated lymphocyte effects**
**focus on Phase 3 IV study**
**similar data for Phase 3 IM study**
**Mean counts and individual patient experience**
**Implications**
**Role of memory T cells**
**Evidence for integrity of immune function in ****alefacept-treated patients**

## Lymphocyte Populations

**B **
**Cells**

**Monocytes/**
**DC**

**NK **
**Cells**

**Na****ï****ve**

**  ****CD4+ T Cells**

**Lymphocyte Populations**

**Na****ï****ve**

**  ****CD8+ T Cells**

## Mean Memory and Naïve T Cells, Course 1 of Phase 3 IV Study

**100**

**400**

**200**

**300**

**500**

**600**

**4**

**8**

**20**

**24**

**16**

**Dosing Period**

**Mean Count (cells/μL)**

***CD4+ naïve T cells***

**Study Week**

**12**

**100**

**400**

**200**

**300**

**500**

**600**

**Dosing Period**

**4**

**8**

**20**

**24**

**16**

**Mean Count (cells/μL)**

***CD4+ memory T cells***

**Study Week**

**12**

**Mean Memory and Naïve T Cells, ****Course 1 of Phase 3 IV Study**

**Alefacept**

**Placebo**

## Mean CD4+ T Cell CountCourse 1 of Phase 3 IV Study

**0**

**45**

**90**

**135**

**180**

**400**

**500**

**600**

**700**

**800**

**1000**

**1100**

**900**

**Dosing Period**

**Mean Count (cells/μL)**

**Days**

**200**

**300**

**Lower limit **
**of normal**

**Alefacept (n=366)**

**Placebo (n=185)**

## Mean Total Lymphocyte Count from Course 1 of Phase 3 IV study

**Alefacept (n=366)**

**Placebo (n=185)**

**0**

**45**

**90**

**135**

**180**

**700**

**1000**

**1300**

**1600**

**1900**

**2500**

**2200**

**Dosing Period**

**Mean Count (cells/μL)**

**Days**

**Lower limit **
**of normal**

**Mean Total Lymphocyte Count from ****Course 1 of Phase 3 IV study**

## Mean CD4+ T Cell CountCourses 1 and 2 of Phase 3 IV Study

**0**

**90**

**180**

**0**

**90**

**180**

**400**

**500**

**600**

**700**

**800**

**1000**

**1100**

**900**

- Dosing period

**Mean Count (cells/μL)**

**Days**

**Lower limit **
**of normal**

**200**

**300**

- Dosing period

**Number of patients with:****	**
**Total lymphocyte count <910 cells/********L (LLN)**
**Total lymphocyte count <500 cells/********L**
**CD4+ count <404 cells/********L (LLN)**
**CD4+ count <200 cells/********L**
**CD8+ count <220 cells/********L (LLN)**
**CD8+ count <50 cells/********L**

**Phase 3 Treatment Group**

**Course 1**
**7.5 mg IV**

**N = 154**

**Course 2**
**7.5 mg IV**

**N = 154**

**26 (17)**
**1  (1)**
**68 (44)**
**4  (3)**
**86 (56)**
**5   (3)**

**28 (18)**
**1   (1)**
**67 (44)**
**0       **

**Number of Patients with Counts <LLN****Phase 3 IV Study, Course 1 vs. 2 **

**78 (51)**
**  ****5   (3)**

## Return of CD4+ T Cell Counts to Normal RangePhase 3 IV Study, Cohort 2

**0**

**100**

**200**

**300**

**Percentage of Patients**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Days After Alefacept Treatment**

**Patients lost to follow-up or had counts between 300-400 cells/uL**

**Return of CD4+ T Cell Counts to Normal Range****Phase 3 IV Study, Cohort 2**

## Monitoring Alefacept Therapy

**Dosing initiated in those with CD4+ T cell counts in normal range**
**Dose omission for CD4+ T cell count <250 cells/uL**
**CD4+ T cell monitoring every 2 weeks****during therapy**

## Lymphocyte PD: Implications

**Physiologically**
**Prevent infections**
**Antibody responses to recall antigens**
**Potential role in immune surveillance**** **
**Pathologically**
**Induce disease in a variety of autoimmune disorders, including psoriasis**

**What are the functions of memory T cells?**

## Infections and CD4+ T Cell Counts in Placebo-Controlled Studies

**Alefacept**

**Number with an infection, n (%)**

**22 (24%)**

**CD4<250**
**(n=90)**

**359 (46%)**

**CD4********250**
**(n=786)**

## Immune Function Tests in Alefacept-treated Patients

**Cell-mediated responses:**
**Phase 2, delayed-type hypersensitivity (DTH) skin tests**
**Minor trends towards loss of response to some antigens**
**Humoral responses:**
**Clinical study of alefacept vs placebo in 46 pts**
**Two T cell-dependent antigens used**
******X174 (neo-antigen) (naïve → memory)**
**Tetanus toxoid (recall antigen) (memory)**
**Alefacept treatment did not abrogate anti-********X174 and   anti-tetanus antibody responses**

## Primary and Secondary AntibodyResponses to Neoantigen (X174)

**1**

**10**

**100**

**1000**

**0**

**6**

**Time After Primary Immunization (wk)**

**Mean Antibody Titer**

**Alefacept (n=23)**

**Control (n=23)**

**Primary**

**Secondary**

**Total Anti-********x174 Antibody Titers**

**Primary and Secondary Antibody****Responses to Neoantigen (********X174)**

**Dosing Interval**

**12**

## Relationship Between CD4+ Memory T Cell Effects and PASI 75, Overall Response Rate

**13%**

**23%**

**33%**

**41%**

**0**

**10**

**20**

**30**

**40**

**50**

**Low**

**High**

**Proportion Responding**** (%)**

**Reduction in CD4 + Memory T Cells**
**(by Quartiles)**

***Phase 3 IV Study, Cohort 1 Course 1***

## Relationship Between T-Cell Counts in Skin Lesions and Disease Activity*

**Relationship Between T-Cell Counts in Skin Lesions and Disease Activity***

*** J. Krueger, Rockefeller University **

## Lymphocyte PD: Conclusions

**Alefacept treatment associated with selective reduction of memory T cells**
**Dose-dependent, gradual and predictable changes during therapy**
**Increase in counts following cessation of therapy **
**Reductions do not predispose to infections**