# Presentation: 305323

## Display 4-1: Therapies that Disqualified Patients as Responders

**Display 4-1: ****Therapies that Disqualified Patients as Responders**

**Phototherapy (PUVA, UVB)**
**Systemic retinoids**
**High potency topical corticosteroids**
**Systemic corticosteroids**
**Fumarates**
**Methotrexate, cyclosporine, azathioprine, or other systemic immunosuppressant and immunomodulatory agents**
**Another investigational drug or approved therapy for investigational use**
**Inappropriate use of moderate potency topical corticosteroids, keratolytics, coal tar, or vitamin D analogs**

**Notes:**
As discussed in your briefing doc, 3 RCT, studies 708, 711, and 712 have been
conducted. Study 708 was a phase 2 IV study enrolling 229 patients, 712 was a phase 3
IM study enrolling 569 patients, and 711 was a phase 3 IV study enrolling 526 patients.
The doses used are shown and note that between phase 2 and 3 there was a transition
from weight based to use of a fixed dose.

Here onwards, I will refer to these studies as the phase 2 IV, phase 3 IM and phase 3
IV studies.  The3 studies had a number of common features in terms of pt 
dispo, demog, baseline dz severity and past Rx hx.

## Display 4-14: Proportions of Patients Responding in Courses 1 and 2 of Study 711

**3779.01**

**NOTE: Numbers in parentheses are percentages.**
**P-values for comparisons with placebo.**
**(a)  From Display 4-5.**** **

**	****Placebo IV****	****7.5 mg****	****Placebo IV****	****7.5 mg****	****	****Alefacept IV****	****	****Alefacept IV****	****(Cohort 3)****	****(Cohorts 1 and 2)****	****(Cohort 2)****	****(Cohort 1) **

**	****Study 711 Course 1 (a)****	****Study 711 Course 2**

## Display 4-15: Study 711 – Proportion of Patients Achieving PASI 75 by Course 

**3780.01**

**Placebo IV (Cohort 3)**

**Alefacept 7.5 mg IV (Cohorts 1 and 2)**

**0**

**10**

**0**

**2**

**4**

**6**

**8**

**10**

**14**

**16**

**18**

**20**

**24**

**Proportion responding (%) **

**Dosing Period**

**20**

**30**

**0**

**10**

**20**

**30**

**0**

**2**

**4**

**6**

**8**

**10**

**14**

**16**

**18**

**20**

**24**

**Proportion responding (%) **

**Alefacept/placebo (Cohort 2)**

**Alefacept/alefacept (Cohort 1)**

**Dosing Period**

**Study Week**

**Study Week**

**Course 1**

**Course 2**

## Immunizations Coincided With MaximalCD4+ Memory T-Cell Reduction

**Alefacept 7.5 mg IV Weekly x12**

**Follow-Up 16 Weeks**

**600**

**550**

**500**

**450**

**400**

**350**

**300**

**250**

**Mean Count (cells/μL)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**22**

**24**

**26**

**28**

**Weeks**

**T**

****

******X174**

**Tetanus****Toxoid**

**CD4+ Naive**

**CD4+ Memory**

****

****

****

****

**T**

**Day 43**

**Day 1**

**Day 99**

**Day 106**

**Day 141**

**Immunizations Coincided With Maximal****CD4+ Memory T-Cell Reduction**

**3444.01**

## Percentage of Patients WithAnti-X174 IgG 30% of Total Anti-X174 Response*

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**% of Patients**

**Control**

**Alefacept**

**†**

**Immunization**

**2nd**

**3rd**

**4th**

- *2 weeks after each immunization.†*P*=0.7299 for overall treatment difference (logistic regression model).

**Percentage of Patients With****Anti-********X174 IgG ********30% of Total Anti-********X174 Response***

**3446.01**

## Squamous Cell Carcinoma of Skin by Course of Alefacept

***  Patient also diagnosed with BCC**

**3846.01**

**Baseline History**

**Patient ID**

**Course 1**

**Course 2**

**Course 3**

**Course 4**

**Course 5**

**Total SCC**

**SCC**

**PUVA**

**UVB**

**MTX**

**CyA**

**106-008**
**111-101**
**114-204***
**111-104**
**111-114**
**139-209**
**128-004**
**145-209**
**Total: 8**

**2**
**1**
**2**
**1**
**0**
**1**
**1**
**1**
**9**

**0**
**3**
**0**
**0**
**0**
**0**
**-**
**-**
**3**

**1**
**-**
**0**
**0**
**1**
**-**
**-**
**-**
**2**

**2**
**-**
**-**
**0**
**0**
**-**
**-**
**-**
**2**

**1**
**-**
**-**
**-**
**-**
**-**
**-**
**-**
**1**

**6**
**4**
**2**
**1**
**1**
**1**
**1**
**1**
**17**

**X**
**X**

**X**
**X**
**X**
**X**
**X**

**X**
**X**
**X**
**X**

**X**
**X**
**X**
**X**
**X**
**X**

**X**

**X**

**BCC**

## Incidence of Injection Site Reactions

**3853.01**

***Phase 3 IM Study***

**No. of Patients Dosed**
**No. with an injection****site reaction**
**No. of injections ****associated with an ****injection site reaction**
**	****1**
**	****2**
**	****3**
**	****4**
**	****5**

**Placebo**

**10 mg**

**15 mg**

**	****168****	****(100)**
**	****14****	****(8)**
**	****10****	**** (6)**
**	****4****	**** (2)**
**	****0**
**	****0**
**	**** ****0**

**	****173****	****(100)**
**	****22****	****(13)**
**	****14****	**** (8)**
**	****6****	**** (3)**
**	****2****	**** (1)**
**	****0**
**	****0**

**	****166****	****(100)**
**	****31****	****(19)**
**	****20****	**** (12)**
**	****8****	**** (5)**
**	****0**
**	****0**
**	****3****	**** (2)**

## Injection Site Reactions by Severity

**3854.01**

**No. with an injection****site reaction**
**Maximum severity**
**	****Mild**
**	****Moderate**
**	****Severe**

**Placebo**

**10 mg**

**15 mg**

**	****14****	****(100)**
**	**
**	****13****	**** (93)**
**	****1****	**** (7)**
**	****0**

**	****22****	****(100)**
**	****18****	**** (82)**
**	****4****	**** (18)**
**	****0**

**	****31****	****(100)**
**	****26****	**** (84)**
**	****5****	**** (16)**
**	****0**

***Phase 3 IM Study***

## Malignancy Rates: Invasive Squamous Cell Cancers

**3855.01**

**Malignancy Rates: Invasive Squamous Cell Cancers**

***Number of tumors per 1000 person years (p-y) exposure***

**Placebo**
**0/178 p-y**

**Alefacept**
**(Placebo-Controlled**
**Studies)**
**5/401 p-y**

**Alefacept**
**(Overall)**
**14/1056 p-y**

**Expected Rates**

**21**

**0**

**0**

**29**

**4**

**12.5**

**22**

**7**

**13.3**

**20 - 76**

**10 - 38**

*****

******

- * R. Stern (PUVA registry data, adjusted rates)
- **Estimated current rates, R. Stern (Personal communication)

## PASI 75 at 2 Weeks After Last Doseby Quartiles of Weight

**PASI 75 at 2 Weeks After Last Dose****by Quartiles of Weight**

**3889.01**

**2**

**9**

**7**

**3**

**22**

**21**

**19**

**22**

**0**

**5**

**10**

**15**

**20**

**25**

**40-75**

**76-87**

**88-102**

**103-206**

**Weight (kg)**

**Proportion Responding (%)**

**Placebo**

**15 mg IM**

**Quartiles of weight are calculated using baseline weights**

**n=46**

**n=55**

**n=47**

**n=44**

**n=37**

**n=45**

**n=27**

**n=33**

## Baseline Characteristics of Patients Who Developed SCC or BCC

**No. of Patients**
**Male**
**Age (years)**
**	****Median**
**Caucasian**
**History of Prior****SCC or BCC**
**	****SCC****	****BCC**
**Prior Treatment of:**
**	****PUVA****	****UVB****	****Methotrexate****	****Cyclosporine**

**Baseline****Characteristics**

**4093.01**

## Mean EAUC  CD4+ Memory by Weight Quartile

***Phase 3 IV Study***

**593**

**716**

**540**

**657**

**4825**

**4803**

**4188**

**5093**

**40-75**

**75-87**

**87-12**

**102-206**

**Weight (kg)**

**Mean EAUC**

**placebo**

**7.5 mg IV**

**4210.01**

## Efficacy Summary: IV vs IM

**Alefacept 7.5 mg IV**

**Alefacept 15 mg IM**

**2 Weeks After Last Dose**

**Overall Response Rate**

*** *****P<*****0.001**
**†**** *****P*****=0.004**
**‡**** *****P*****=0.006**

**Efficacy Summary: IV vs IM**

***Phase 3 Studies***

**Alefacept 7.5 mg IV**

**Alefacept 15 mg IM**

**PASI 75**

**PGA AC/C**

**PASI 50**

**Proportion Responding (%)**

**14%**

**21%**

**11%**

**14%**

**38%**

**42%**

*****

*****

*****

*****

**†**

**‡**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**PASI 75**

**PGA AC/C**

**PASI 50**

**Proportion Responding (%)**

**28%**

**33%**

**23%**

**24%**

**56%**

**57%**

*****

*****

*****

*****

*****

*****

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**4218.01**

## DTH Response Converting from Positive to Negative

**Antigen**

**Placebo**

**0.025 mg/kg**

**0.075 mg/kg**

**0.15 mg/kg**

- Tetanus

- 15/32 (47)

- 13/26 (50)

- 18/28 (64)

- 9/14 (64)

- Diphtheria

- 4/10 (40)

- 3/6 (50)

- 8/11 (73)

- 8/11 (73)

- Streptococcus

- 5/7 (71)

- 3/3 (100)

- 3/4 (75)

- 5/5 (100)

- Tuberculin

- 7/9 (78)

- 7/7 (100)

- 12/14 (86)

- 9/11 (82)

- Candida

- 3/5 (60)

- 6/8 (75)

- 7/8 (88)

- 3/4 (75)

- Trycophyton

- 3/3 (100)

- 5/7 (71)

- 4/6 (67)

- 2/2 (100)

- Proteus

- 4/11 (36)

- 8/15 (53)

- 6/13 (46)

- 9/13 (69)

***Study 708***

**4269.02**

**Less than 30% of patients were reactive at baseline**

## DTH Response Converting from Positive to Negative

**Antigen**

**Placebo**

**0.025 mg/kg**

**0.075 mg/kg**

**0.15 mg/kg**

- Tetanus

- 10/32 (31)

- 9/26 (35)

- 13/28 (46)

- 4/14 (29)

- Diphtheria

- 1/10 (10)

- 2/6 (33)

- 5/11 (45)

- 5/11 (45)

- Streptococcus

- 4/7 (57)

- 2/3 (67)

- 2/4 (50)

- 4/5 (80)

- Tuberculin

- 5/9 (56)

- 3/7 (43)

- 9/14 (64)

- 7/11 (64)

- Candida

- 2/5 (40)

- 4/8 (50)

- 6/8 (75)

- 2/4 (50)

- Trycophyton

- 0/3

- 3/7 (43)

- 3/6 (50)

- 1/2 (50)

- Proteus

- 2/11 (18)

- 4/15 (27)

- 3/13 (23)

- 5/13 (38)

***Study 708***

**4270.02**

**Less than 30% of patients were reactive at baseline**

## Influence of Concomitant Medications on the Primary Endpoint

**PASI 75 responders n (%)**
***irrespective***** of use of disqualifying **
**meds**

**PASI 75 responders n (%)**
**without the use of phototherapy or other systemic therapies **
**(pre-specified)**

**PASI 75 responders n (%)**
**without the use of phototherapy or other systemic therapies **
**(Table 28)**

**Placebo **
**(n=186)**

**7.5 mg**
**(n=367)**

**Placebo**
**(n=168) **

**15 mg**
**(n=166)**

**7 (4%) **

**55 (15%)**

**12 (7%)**

**37 (22%)**

**53 (14%)**

**9 (5%)**

**35 (21%)**

**53 (14%)**

**8 (5%)**

**33 (20%)**

**P< 0.001**

**P< 0.001**

**P< 0.001**

**P< 0.001**

**P< 0.001**

**P< 0.001**

**4370.01**

**7 (4%) **

**7 (4%) **

***Phase 3 Studies***

**IV Study**

**IM Study**

## Range of Memory and Naïve T-Cell Counts at Baseline

**CD4+ Memory Cells (cells/********L)**
**CD4+ Naïve Cells (cells/********L)**
**CD8+ Memory Cells (cells/********L)**
**CD8+ Naïve Cells (cells/********L)**

**Phase 2 IV Study **

**Phase 3 IV Study **

**Phase 3 IM Study**

**  ****81 to 1233**
**   **
**    ****8 to 1084**
**   **
**    ****3 to 575**
**  ****24 to 700**

**159 to 3233**
**   **
**    ****8 to 985**
**   **
**  ****15 to 981**
**    ****2 to 1000**

**143 to 1415**
**   **
**  ****11 to 1351**
**   **
**    ****9 to 707**
**  ****25 to 1237**

## Estimated Incidence of Serious Adverse Events

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

**Course 2**
**(n=790*)**

**Course 3**
**(n=422*)**

**Course 4**
**(n=152*)**

**Course 5**
**(n=116*)**

**Any SAE**  n (%)**

**67 ( 5) **

**33 (4)**

**15 (4)**

**3 (2)**

**2 (2)**

***Multiple Course Experience***

*** ****	****Number of patients in the 2nd through 5th course is estimated.  **
********	****The serious adverse events represent all events reported to Biogen through May 20, 2002 **

**Estimated Incidence of Serious Adverse Events**

## Changes in Lesional Skin: Histologic Responders vs Nonresponders

**NL = non-lesional skin at baseline.**
**B = baseline.**

## Effect of Alefacept on Circulating CD4+ T-Cell Subsets*

**Na****ï****ve**

**Memory**

**CD4**

**CD4**

***Primary Response***

***Expansion of effector CD4+ cells during active immune response***

**Central Memory**
**–****16%**

***Long-term memory***

**Effector **
**Memory**
** –****50%**

***at week 13; N=21**

***P*****=0.0007**

**Effect of Alefacept on Circulating CD4+ T-Cell Subsets***

## Incidence of B Cell Lymphomain Nonhuman Primates