1. 1 Agenda  Overview –Burt Adelman MD  Efficacy and Pharmacodynamics –Akshay Vaishnaw MD, PhD  Safety –Gloria Vigliani MD  Alefacept Risk Benefit Profile –Mark Lebwohl MD

2. 2 Efficacy Overview  Efficacy –Phase 2 overview –Phase 3: IM and IV studies  Quality of life  Efficacy in sub-populations

3. 3 NumberEnrolled 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

4. 4 Ellis and Krueger, NEJM, 2001 Phase 2 Dose-Ranging, Randomized, Placebo-Controlled Study

5. 5 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

6. 6 Phase 3 Studies

7. 7 Phase 3: Psoriasis Disease Status at Baseline BSA = Body surface area PASI = Psoriasis area and severity index PGA = Physician global assessment 9485 % with PGA of “moderate” to “severe” Median BSA (%) 2221 Median duration (yrs) 1819 1514 Median PASI Phase 3 IV Phase 3 IM

8. 8 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)

9. 9 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

10. 10 Determination of Response Rate: 2 Weeks After Last Dose vs. Overall Placebo Alefacept Other efficacy endpoints Overall response rate Weeks 1-12 Dosing Weeks 13-24 Follow-up Primary efficacy endpoint 2 weeks after last dose

11. 11 PASI 18.7 PASI 5.7 69% PASI Reduction PASI 50

12. 12 PASI 75 PASI 34.3 PASI 4.2 88% PASI Reduction

13. 13 Phase 3 IM Study

14. 14 Primary endpoint PASI 75, 2 weeks after last dose without use of disqualifying medications 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 Screening Randomization

15. 15 * 21% 12% 5% Phase 3 IM Primary Endpoint: PASI 75, 2 Weeks After Last Dose *P<0.001

16. 16 Phase 3 IM PGA “Almost Clear/Clear”, 2 Weeks After Last Dose * 14% 10% 5% *P=0.006

17. 17 Phase 3 IM PASI 50, 2 Weeks After Last Dose * * 42% 36% 18% *P<0.001

18. 18 2 Weeks After Last Dose 5% 12% 21% * Phase 3 IM PASI 75, 2 Weeks vs. Overall Response Rate *P<0.001 Overall Response Rate 13% 28% 33% * *

19. 19 Phase 3 IV Study

20. 20 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 Placebo Alefacept 7.5 mg Screening Randomization Primary endpoint PASI 75, 2 weeks after last dose without use of disqualifying medications

21. 21 Course 2 Alefacept 7.5 mg (Cohort 1) 48% 20% 23% Phase 3 IV Study Efficacy, 2 weeks after last dose PASI 50 38% 0 10 20 30 40 50 Proportion Responding (%) PASI 75PGA Almost Clear or Clear 11% 14% 10% 4% * ** * *P<0.001 **P=0.004 Course 1 Alefacept 7.5 mg (Cohorts 1&2) Course 1 Placebo

22. 22 64% 37% 30% Course 2 Alefacept 7.5 mg (Cohort 1) * 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 50PASI 75PGA Almost Clear or Clear Course 1 Alefacept 7.5 mg (Cohorts 1&2) Course 1 Placebo * *

23. 23 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

24. 24 Duration of PASI 50 in Those Who Achieved PASI 75 0 25 50 75 100 Response Duration (days) 14385127169211253295337379 Proportion responding (%) Phase 3 IV Study, Cohort 2

25. 25 Quality of Life

26. 26 *DLQI = Dermatology Life Quality Index, Finlay and Khan, 1994 Phase 3 IV Study ** n = 158n = 314 Baseline 2 weeks after last dose * p < 0.001 * Extent of DLQI Change Across Phase 3 Treatment Groups DLQI Score 12.1 9.1 6.7 10.7 0 2 4 6 8 10 12 14 Placebo15 mg IM ** n = 150n = 141 Phase 3 IM Study 0 2 4 6 8 10 12 14 Placebo7.5 mg IV 9.9 11 7.6 11

27. 27 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 75PASI 50PGA AC/C * * * Phase 3 IV Study, Course 1

28. 28 Baseline2 Weeks After Last Dose  Embarrassment64%27%  Impact on daily activities21% 7%  Leisure or social activities34%18%  Problems with partner, 20% 9% relatives, friends  Sexual difficulties21%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

29. 29 Efficacy in Sub-populations

30. 30 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=246n=108n=481n=225 Proportion Responding (%) * ** p < 0.001 p = 0.026 * **

31. 31 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=109n=213n=434 n=76 n=163 No prior Rx No change/worsened on prior Rx p = 0.027

32. 32 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

33. 33 Pharmacodynamics

34. 34 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

35. 35 B Cells B Cells Monocytes/ DC Monocytes/ DC NKCells Naïve Memory CD4+ T Cells Lymphocyte Populations Naïve Memory CD8+ T Cells

36. 36 100 400 200 300 500 600 48202416 Dosing Period Mean Count (cells/µL) CD4+ naïve T cells Study Week 12 100 400 200 300 500 600 Dosing Period 48202416 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

37. 37 Mean CD4+ T Cell Count Course 1 of Phase 3 IV Study 04590135180 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)

38. 38 Alefacept (n=366) Placebo (n=185) 04590135180 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

39. 39 Mean CD4+ T Cell Count Courses 1 and 2 of Phase 3 IV Study 090180090180 400 500 600 700 800 1000 1100 900 Dosing period Mean Count (cells/µL) Days Lower limit of normal 200 300 Dosing period

40. 40 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) 5 (3)

41. 41 0100200300 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

42. 42 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

43. 43 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?

44. 44 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)

45. 45 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)  X174 (neo-antigen) (naïve → memory) Tetanus toxoid (recall antigen) (memory)Tetanus toxoid (recall antigen) (memory) –Alefacept treatment did not abrogate anti-  X174 and anti-tetanus antibody responses

46. 46 1 10 100 1000 06 Time After Primary Immunization (wk) Mean Antibody Titer Alefacept (n=23) Control (n=23) PrimarySecondary Total Anti-  x174 Antibody Titers Primary and Secondary Antibody Responses to Neoantigen (  X174) Dosing Interval 12

47. 47 Relationship Between CD4+ Memory T Cell Effects and PASI 75, Overall Response Rate 13% 23% 33% 41% 0 10 20 30 40 50 LowHigh Proportion Responding (%) Reduction in CD4 + Memory T Cells (by Quartiles) Phase 3 IV Study, Cohort 1 Course 1

48. 48 300 200 100 0 0600 T-Cell Number in Epidermis Epidermal Thickness (µm) r = 0.87 100200300400500 Relationship Between T-Cell Counts in Skin Lesions and Disease Activity* * J. Krueger, Rockefeller University

49. 49 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