# Presentation: 688656

## Agenda

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

## Safety Overview

**Size of database**
**Adverse Events**
**Serious Adverse Events**
**Deaths**
**Infection**
**Malignancy**
**Immunogenicity**

## Safety Database

**Safety Database**

## Comparison of Placebo vs. Alefacept Experience

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**Placebo**

**Alefacept**

**Total**
**Alefacept**

**178 p-y**

**401 p-y**

**1056 p-y**

**n= 413 **

**n= 876**

**n= 1357**

**Placebo-**
**controlled**
**experience**

**Person-years (p-y)**
**exposure **

## Safety Overview Placebo-Controlled Studies

**SAE**

**5**

**5**

**Discontinuations**

**1**

**2**

**Death**

**0**

**<1**

**Placebo**
**(n=413)**

**Alefacept****(n= 876)**

**Any AE**

**79**

**83**

**Event Category**

**%**

**%**

**Safety Overview Placebo-Controlled Studies**

## Safety Overview by Course

**Course 1**
**(n=1357)**

**Course 2**
**(n=756)**

**Course 3**
**(n=199)**

**Course 4**
**(n=81)**

**Course 5**
**(n=46)**

**SAE**

**5**

**4**

**5**

**0**

**2**

**Discontinuations**

**2**

**<1**

**1**

**1**

**0**

**Death**

**<1**

**<1**

**<1**

**0**

**0**

**Any AE**

**83**

**74**

**64**

**72**

**61**

**Event category (%)**

**%**

**%**

**%**

**%**

**%**

## Adverse Events 5% IncidencePlacebo-Controlled Studies

**Placebo**
**(n=413)**

**Alefacept**
**(n=876)**

**Event **
**	****Headache**
**	****Accidental Injury**
**	****Pharyngitis**
**	****Infection**
**	****Pruritis**
**	****Rhinitis**
**	****Flu Syndrome****	**
**	****Viral Infection**
**	****Asthenia**
**	****Chills**
**	****Pain**
**	****Diarrhea**
**	****Dizziness**
**	****Arthralgia**
**	****Nausea**

**	****18**
**	****13**
**	****13**
**	****11**
**	****8**
**	****10**
**	****9**
**	****7**
**	****7**
**1**
**	****5**
**	****5**
**	****3**
**	****6**
**	****3**

**	****17**
**	****15**
**	****15**
**	****11**
**	****11**
**	****11**
**	****9**
**	****6**
**	****6**
**	****6**
**	****6**
**	****5**
**	****5**
**	****5**
**	****5**

**%**
**83**

**Percentage with an event**

**%**
**79**

## Serious Adverse Events

## Most Frequent Serious Adverse Events*

***Events occurring in >1 alefacept patient**

**Alefacept**
**(n=876)**

**2 (<1)**
**4 (<1)**
**3 (<1)**
**3 (<1)**
**2 (<1)**
**2 (<1)**
**2 (<1)**
**2 (<1)**
**2 (<1)**
**2 (<1)**

**42 (5%)**

**Placebo**
**(n=413)**

**6 (1)**
**0**
**0**
**0**
**0**
**0**
**1 (<1)**
**0**
**0**
**1 (<1)**

**19 (5%)**

**	****Psoriasis**
**	****Coronary Artery Disorder**
**	****Cellulitis**
**	****Myocardial Infarction**
**	****Accidental Injury**
**	****Carcinoma**
**	****Chest Pain**
**	****Diabetes Mellitus**
**	****Gastroenteritis**
**	****Pancreatitis****	**

**Any SAE  N (%)**

***Placebo-Controlled First Course Experience***

## Most Frequent Serious Adverse Events*

**Course 1**
**(n=1357)**

**Course 2**
**(n=756)**

**Course 3**
**(n=199)**

**Course 4**
**(n=81)**

**Course 5**
**(n=46)**

**Any SAE N (%)**

**67 ( 5) **

**30 (4)**

**9 (5)**

**0**

**1 (2)**

- 	**Accidental Injury**
**  ****	****Psoriasis**
**	****Cellulitis**
**	****Coronary Artery Disorder**
**	****Skin Carcinoma**
**	****Chest Pain**
**	****Cholelithiasis**
**	****Diabetes Mellitus**
**	****Myocardial Infarct**
**	****Asthma**
**	****Carcinoma**
**	****Gastroenteritis**
**	****Hernia**
**	****Infection**
**	****Infection Bacterial**
**	****Pancreatitis**
**	****Suicide Attempt**

**5 ( <1)**
**5 ( <1)**
**4 ( <1)**
**4 ( <1)**
**4 ( <1)**
**3 ( <1)**
**3 ( <1)**
**3 ( <1)**
**3 ( <1) **
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**
**2 ( <1)**

**5 ( <1)**
**0**
**0**
**0**
**1 ( <1)**
**0**
**4 ( <1)**
**0**
**0 **
**0**
**1 ( <1)**
**1 ( <1)**
**0**
**2 ( <1)**
**0**
**0**
**0****	**

**1 ( <1)**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**1 ( <1)**
**1 ( <1)**
**0**
**0**
**0**
**1 ( <1)**
**0**
**0**
**0****	**

**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**

**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**1 (2)**
**0**
**0**
**0**
**0**
**0**
**0**
**0**
**0****	**

***Events occurring in more than 1 patient included.**

***Multiple Course Experience***

## Deaths

## Deaths

**Cause****of Death**

**Age/**
**gender**

**Underlying****factors**

**Alefacept**
**Received**

**Suicide**

**34M**

**Psoriasis, family history of suicide**

**Yes**

**Myocardial **
**infarction**

**47M**

**CAD, HT,**
**obesity, smoker**

**Yes**

**Esophageal**
**carcinoma**

**53M**

**Diaphragmatic hernia,**
**Barrett’s esophagus**

**Yes**

**Myocardial **
**infarction**

**52M**

**CAD, HT**

**No**

**Lung **
**carcinoma**

**46M**

**Smoker**

**Yes**

**Seizure**

**43M**

**Life-long**
**history of seizures**

**Yes**

## Infections

## Infections 5% Incidence

**Event**** ****	**
**	****Pharyngitis**
**	****Nasopharyngitis**
**	****Flu syndrome**
**	****Viral infection**

**Percentage with an infection**

**10%**
**  ****7%**
**  ****5%**
**  ****7%**

**Placebo**
**n=413**

**43%**

**Alefacept**
**n=876**

**10%**
**  ****8%**
**  ****7%**
**  ****6%**

**45%**

***Placebo-Controlled First Course Experience***

## Infections by CD4+ T Cell Counts*

**Alefacept**

**Number with an infection n (%)**
**Event n (%)****	**
**	****Pharyngitis**
**	****Nasopharyngitis**
**	****Flu syndrome**
**	****Viral infection**
**	****Infection fungal**
**	****Sinusitis**
**	****Urinary tract infection**
**	****Accidental injury**
**	****Bronchitis**
**	****Conjunctivitis**
**	****Fungal dermatitis**
**	****Skin infection**
**	****Periodontal abscess**

**174 (42)**
**  **
**  ****40 (10)**
**  ****28   (7)**
**  ****21   (5)**
**  ****27   (7)**
**    ****5   (1)**
**  ****15   (4)**
**    ****5   (1)**
**    ****1 (<1)**
**    ****9   (2)**
**    ****5   (1)**
**    ****0**
**    ****5   (1)**
**    ****4 (<1)**
**  **

**CD4********250**
**(n=411)**

**22 (24)**
**	****8 (9)**
**	****5 (6)**
**	****4 (4)**
**	****3 (3)**
**	****2 (2)**
**	****2 (2)**
**	****2 (2)**
**	****1 (1)**
**	****1 (1)**
**	****1 (1)**
**	****1 (1)**
**  ****1 (1)**
**	****1 (1)**

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

**359 (46)**
**  ****80 (10)**
**  ****57 (7)**
**  ****58 (7)**
**  ****47 (6)**
**  ****10 (1)**
**  ****26 (3) **
**    ****6 (<1)**
**    ****1 (<1)**
**  ****18 (2)**
**  ****10 (1)**
**    ****6 (<1)**
**    ****6 (<1)**
**  ****14 (2)**

**CD4 ******** 250**
**(n=786)**

**Placebo**

***Placebo-Controlled First Course Experience***

- * Only infections which occurred after the onset of CD4+ T cell count < 250 cells/uL are included

## Serious Infections

***Placebo-Controlled First Course Experience***

## Serious Skin Infections - All Studies

**Skin Infections:**
**Facial cellultis****	****12****	****50 M****	****Obesity, DM, recurrent ****	****	****343****	****Cont. Rx**
**	****	****	****otitis externa****	**
**Pre-septal cellulitis****	****10****	****44 F****	****Sty manipulation****	****	****600****	****(placebo)**
**Leg cellulitis****	****1****	****52 M****	****DM, CAD, COPD, edema, ****	****	****312****	****Withdrew**
**	****	****	****erythema around plaque**
**Finger abscess****	****8****	****43 M****	****Olecranon bursitis****	****	****720****	****Cont. Rx**
**Peri-orbital infection****	****23****	****50 M****	****Herpes simplex superinfection****	****868****	****N.A.**
**Burn infection****	****5****	****55 M****	****Obesity, 18x24 cm burn, DM****	****1014****	****Cont. Rx**
**Toxic shock****	****6****	****56 F****	****Cellulitis, renal and respiratory****	****673****	****Withdrew**
**	****	****	****failure - full recovery**
**Post-surgical Wound Infections:**
**Post-op infection****	****17****	****58 M****	****DM, rotator cuff repair****	****	****616****	****Cont. Rx**
**Post-op infection****	****11****	****26 M****	****Open tibial fracture repair****	****	****289****	****Cont. Rx**
**Post-op infection ****	****12****	****32 M****	****Post-appendiceal rupture****	****	****491****	****Cont. Rx**

**Serious Skin Infections - All Studies**

## Infection: Conclusions

**Similar incidence alefacept vs. placebo**
**Low CD4+ T cell counts not a risk factor**
**No increase by course **
**Uncomplicated clinical course and outcome**
**No opportunistic infections**
**No TB**
**No deaths due to infections**

## Functional Integrity of Immune System

**Preservation of naïve T cells**
**Partial effect against memory T cells, preservation of antibody responses**
**Redundancy of immune system**

## Malignancy 

## Incidence of Malignancies

**Event N (%)****	**
**	****Non-melanoma skin cancer**
**	****Carcinoma***
**	****Prostatic carcinoma**
**	****Skin melanoma**

**	****	****2 (<1)**
**	**
**	****	****1 (<1)**
**	****	****0**
**	****	****1 (<1)**
**	****	****0**

**Placebo**
**(n=413)**

**Alefacept**
**(n=876)**

**	****10 (1)**
**	****	**
**	****	****	****6 (<1)**
**	****	****	****2 (<1)**
**	****	****	****1 (<1)**
**	****	****	****1 (<1)**

**Incidence of Malignancies**

***One case each of testicular and renal cell cancer**

***Placebo-Controlled First Course Experience***

## Incidence of Malignancies

**Number With a Malignancy n (%)**
**Event n (%)**
**	****Skin Carcinoma**
**	****Carcinoma**
**	****Skin Melanoma**
**	****Prostatic Carcinoma**
**	****Carcinoma of Lung**
**	****Gastrointestinal ****	****	****Carcinoma***
**	****GI Neoplasia****

**Course 1**
**n=1357**

**Course 2**
**n=756**

**Course 3**
**n=199**

**	****16 (  1)**
**	****11 (<1)**
**	****	****	****2 (<1)**
**	****	****	****2 (<1)**
**	****	****	****1 (<1)**
**	****	****	****0**
**	****	****	****0**
**	****	****	****	****	****	****0**

**Course 4**
**n=81**

**Course 5**
**n=46**

**	****	****	****4 (<1)**
**	****	****	****2 (<1)**
**	****	****	****1 (<1)**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****1 (<1)**
**	****	****	****	****	****	****0**

**	****	****	****4 (  2)**
**	****	****	****2 (  1)**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****1 (<1)**
**	****	****	****1 (<1)**
**	****	****	****	****	****	****1 (<1)**

**	****	****	****1 (  1)**
**	****	****	****1 (  1)**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****	****	****	****0**

**	****	****	****1 (  2)**
**	****	****	****1 (  2)**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****0**
**	****	****	****	****	****	****0**

*** One case each of adenocarcinoma of colon and esophagus**

**** Benign colonic polyp**

***Multiple Course Experience***

## 68 yr old female
Long-standing psoriasis, previous MTX and PUVA
During third course of alefacept (total 20 injections)
Isolated 2 cm node
Follicular B cell Non-Hodgkin’s lymphoma
No other lymphoid/bone marrow involvement
Features consistent with sporadic B cell NHL and not with immunotherapy-related lesion

**Long-standing psoriasis, previous MTX and PUVA**
**During third course of alefacept (total 20 injections)**
**Isolated 2 cm node**
**Follicular B cell Non-Hodgkin’s lymphoma**
**No other lymphoid/bone marrow involvement**
**Features consistent with sporadic B cell NHL and not with immunotherapy-related lesion**

**Single case of B cell lymphoma**

## Overall Malignancy Rates

***Incidence Rate Per 1000 Person Years (p-y) Exposure***

**Alefacept**
**(Overall)**
**22/1056 p-y**

**Expected Rate**
**(Psoriasis population)***

**32.1**

**13**

**20.8**

- *Margolis (2001)

**29**

**36**

**23**

## Malignancy Conclusions

**No evidence of increase in malignancy**
**Majority skin cancers**
**Observed rates for skin and total malignancies within expected rates **

## Percentage Testing Positivefor Anti-Alefacept Antibodies

**Course of Alefacept**

**First**

**Second**

**Third**

**Fourth**

**Fifth**

**Baseline**

**During course**

**<1**

**2**

**<1**

**2**

**2**

**<1**

**         ****0**

**         ****0**

**          ****0**

**          ****0**

**Number of****patients dosed**

**1357**

**756**

**199**

**81**

**46**

## Safety Conclusions

**Alefacept has a favorable safety profile**
**Similar incidence of adverse events alefacept vs. placebo**
**No convincing evidence of increased risk of infection or malignancy **
**No correlation between rates of malignancy, infections and CD4+ T cell counts**
**Low immunogenicity**

## Plans for Extended Long-Term Safety Evaluation

**Approximately 800 patients in ongoing safety-extension studies**
**Alefacept safety registry**
**powered to specifically evaluate increase in risk of adverse events of interest**

## 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 **

## Agenda

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