2. Biologic License Application STN BL 125075/0: Efalizumab for the Treatment of Chronic Plaque Psoriasis Dermatologic and Ophthalmic Drugs Advisory Committee Meeting September 9, 2003 Dermatologic and Ophthalmic Drugs Advisory Committee Meeting September 9, 2003 Center for Drugs Evaluation and Research

3. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 2 Proposed Indication Efalizumab for the treatment of adult patients with moderate to severe plaque psoriasis

4. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 3 Proposed Dose, Route and Mode of Use 1 mg/kg/wk SC Long-term continuous treatment 1 mg/kg/wk SC Long-term continuous treatment

5. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 4 PsoriasisPsoriasis 1-3% US population Polygenic inheritance Infrequent in Native Americans, African Americans, and Japanese Men:women equal ratio Onset bimodal: 16-22 and 57-60 years 1-3% US population Polygenic inheritance Infrequent in Native Americans, African Americans, and Japanese Men:women equal ratio Onset bimodal: 16-22 and 57-60 years

6. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 5 Psoriasis in Children Irregular course, generally more severe disease expression Positive family history (50% first degree relatives) HLA-Cw6 positivity Need for clinical trials in children –Risk-to-benefit considerations Irregular course, generally more severe disease expression Positive family history (50% first degree relatives) HLA-Cw6 positivity Need for clinical trials in children –Risk-to-benefit considerations

7. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 6 Psoriasis: Clinical Significance Usually not life-threatening In 30% of patients moderate to severe disease with significant morbidity Decreased quality of life and increased risk of suicide Usually not life-threatening In 30% of patients moderate to severe disease with significant morbidity Decreased quality of life and increased risk of suicide

8. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 Analysis of Clinical Trials Phase 1 and 2 Studies in Patients with Psoriasis

9. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 8 Phase 1 and 2: Efalizumab in Moderate to Severe Psoriasis Study Dose mg/kg, route Duration treatment Number Treated HU96020.03-10 IV 1 wk 31 HUPS2490.1-1 IV 7 wk 39 HUPS2520.1-0.3 IV 8 wk 97 HUPS2540.5-2 SC 1- 8 wk 52 HUPS256 0.3-1 IV, 1-4 SC 12 wk 68

10. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 9 Phase 1 Studies in Patients with Psoriasis Dose-dependent infusion reactions (meningismus, headache, nausea, vomiting, fever,chills, myalgia and arthralgia) Infusion reactions more common after the first dose  “first dose” effect Dose-dependent infusion reactions (meningismus, headache, nausea, vomiting, fever,chills, myalgia and arthralgia) Infusion reactions more common after the first dose  “first dose” effect

11. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 10 Phase 1 Studies in Patients with Psoriasis The dose-dependent adverse events led to the development of an initial low tolerization dose (0.7 mg/kg SC)

12. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 Analysis of Phase 3 Clinical Trials Four Studies

13. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 12 Phase 3: Efalizumab in Moderate to Severe Psoriasis Study Dose mg/kg, route Treatment Duration (wks) n 2058 (XOMA)1, 2; SC 12-24 498 2059 (XOMA>GNE)1, 2; SC 12-24 597 2390 (GNE)1, SC 12 555 2600 (GNE)1, SC 12 685

14. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 Study 2390 Phase 3 study of to-be-marketed efalizumab Phase 3 study of to-be-marketed efalizumab

15. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 14 Study 2390 Double blind, placebo-controlled, parallel group, multi-center Dose: efalizumab 1 mg/kg/wk SC for 12 weeks Randomization 2:1 (active: placebo) Stratification by baseline PASI and history of systemic anti-psoriatic therapy Double blind, placebo-controlled, parallel group, multi-center Dose: efalizumab 1 mg/kg/wk SC for 12 weeks Randomization 2:1 (active: placebo) Stratification by baseline PASI and history of systemic anti-psoriatic therapy

16. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 15 Efficacy Endpoints Primary endpoint –Proportion of patients achieving >75% improvement in PASI at Day 84 Principal secondary endpoint –Proportion of patients achieving “minimal” or “clear” by static Physician’s global assessment (sPGA) at Day 84 Primary endpoint –Proportion of patients achieving >75% improvement in PASI at Day 84 Principal secondary endpoint –Proportion of patients achieving “minimal” or “clear” by static Physician’s global assessment (sPGA) at Day 84

17. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 16 Study 2390: Key Eligibility Adults (18-70 years) with plaque psoriasis  10% BSA and PASI  12 –Guttate, erythrodermic, pustular psoriasis excluded Psoriasis diagnosed for at least 6 months Clinically stable psoriasis (3 months) Adults (18-70 years) with plaque psoriasis  10% BSA and PASI  12 –Guttate, erythrodermic, pustular psoriasis excluded Psoriasis diagnosed for at least 6 months Clinically stable psoriasis (3 months)

18. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 17 Study 2390: Patient Demographics 556 patients enrolled (placebo: 187 efalizumab: 369) Age: mean 45 years Race: 90% Caucasian Gender distribution: 69% men and 31% women. 556 patients enrolled (placebo: 187 efalizumab: 369) Age: mean 45 years Race: 90% Caucasian Gender distribution: 69% men and 31% women.

19. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 18 Study 2390: Baseline Disease PlaceboEfalizumab Psoriasis duration years (mean) 19 History prior systemic anti-psoriatic therapy 74%77% PASI score (mean)19 BSA affected (mean)27%28% sPGA “moderate” to “very severe” 93%94%

20. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 19 Study 2390: Efficacy Results PlaceboEfalizumab PASI  75 * 4%26% PASI  50 * 14%59% sPGA * “minimal” or “clear” 3%26% *Fisher’s exact p value efalizumab vs. placebo: <0.001

21. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 20 Mean Change in PASI: 2390

22. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 21 Study 2390: Efficacy by Subgroup Treatment effect present in subgroups defined by –gender –age –baseline PASI score –history of systemic therapy Treatment effect present in subgroups defined by –gender –age –baseline PASI score –history of systemic therapy

23. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 22 % PASI Change from Baseline

24. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 23 Summary of Treatment Effect: Initial 12-week treatment StudyPASI 75 (95% CI) 205837% (28%, 46%) 205917% (9%, 27%) 239022% (16%, 29%) 260021% (15%, 27%)

25. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 RetreatmentRetreatment Study 2058

26. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 25 Study Schema: 2058 Placebo (12 wks) Efalizumab (12 wks) PASI  75 PASI<75 PASI  75 E-E (12 wks) PASI<75 E-P (12 wks) E-E (12 wks) P-E (12 wks) E-P (12 wks) P-E (12 wks) SCRN OBSV RT-A

27. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 26 RT-A: Subject Disposition During Retreatment Subject Status E-P (n=27) E-E 1 mg/kg (n=32) E-E 2 mg/kg (n=23) Completed RT 82616 Discontinued RT 1967

28. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 27 Retreatment: PASI Response (% Change from Initial Baseline) PlaceboEfalizumab 1 and 2 mg/kg/wk n=27n=55 >75%017 (31%) >50%5 (19%)37 (67%) 0-50%2 (7%)4 (7%) <0%1 (4%)1 (2%) Missing19 (70%)13 (24%)

29. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 28 Long-term Continuous Treatment

30. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 29 Long-term Continuous Treatment Long term (6 months or greater) continuous treatment: evaluated in a randomized placebo-controlled fashion in Studies 2058 (n=498) and 2059 (n=597) Study 2059: extended treatment for responders as well patients who did not achieve a PASI 75 during the first 12 weeks Long term (6 months or greater) continuous treatment: evaluated in a randomized placebo-controlled fashion in Studies 2058 (n=498) and 2059 (n=597) Study 2059: extended treatment for responders as well patients who did not achieve a PASI 75 during the first 12 weeks

31. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 30 Study Design: 2059

32. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 31 Extended Treatment in Responders (ET-AR): Maintenance of PASI 75 Efalizumab/ Placebo Efalizumab/ Efalizumab * n=40n=79 PASI  75 8 (20%)61 (77%) PASI <7532 (80%)19 (23%) *2 mg/kg weekly or every other week

33. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 32 Extended treatment in Responders (ET-AR): Relapse Efalizumab/ Placebo Efalizumab/ Efalizumab * n=40n=79 Relapsed27 (67%) 6 (8%) Did not relapse 13 (33%) 73 (92%) *2 mg/kg weekly or every other week

34. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 33 Study Design: 2059

35. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 34 Extended Treatment in Non- responders: 2059 Efalizumab/ Placebo Efalizumab/ Efalizumab (4 mg/kg/wk) n=59n=118 PASI  75 1 (1.7%)15 (12.7%) PASI <7558 (98.3%)103 (87.3%)

36. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 35 Efficacy of Extended Treatment Among treatment responders, extended treatment with efalizumab beyond the initial 12 weeks maintained PASI 75 in 77% of patients vs. 20% of patients re- randomized to placebo. In non-responders (Day 84 PASI<50), treatment with an additional 12 weeks of efalizumab 4 mg/kg/wk, captured an additional 11% of PASI 75 responders. Among treatment responders, extended treatment with efalizumab beyond the initial 12 weeks maintained PASI 75 in 77% of patients vs. 20% of patients re- randomized to placebo. In non-responders (Day 84 PASI<50), treatment with an additional 12 weeks of efalizumab 4 mg/kg/wk, captured an additional 11% of PASI 75 responders.

37. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 Integrated Summary of Safety

38. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 37 Safety Database: Efalizumab Exposure in Psoriasis Trials Total exposed: 2762 Approximately 2400 treated weekly for 12 weeks, 939 treated weekly for 24 weeks and 218 for 1 year 1620 received efalizumab in placebo- controlled portion of the four phase 3 studies Total exposed: 2762 Approximately 2400 treated weekly for 12 weeks, 939 treated weekly for 24 weeks and 218 for 1 year 1620 received efalizumab in placebo- controlled portion of the four phase 3 studies

39. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 38 Deaths in Efalizumab-treated Patients No deaths in first 12 weeks of placebo controlled studies 7 deaths in safety database (2762 patients) Two during efalizumab treatment, 5 after treatment Causes: metastatic rectal cancer (1), cardiac (3), accidental (1), cirrhosis (1), unknown (1) None attributed to efalizumab None attributed to infection No deaths in first 12 weeks of placebo controlled studies 7 deaths in safety database (2762 patients) Two during efalizumab treatment, 5 after treatment Causes: metastatic rectal cancer (1), cardiac (3), accidental (1), cirrhosis (1), unknown (1) None attributed to efalizumab None attributed to infection

40. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 39 Serious Infections: First 12 Weeks of Controlled Trials Placebo (n=715) Efalizumab (n=1620) No. with serious infection 1 (0.1%)7 (0.4%) Cellulitis03 Sepsis01 Gastroenteritis12 Pneumonia02

41. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 40 Incidence of Serious Infections Treatment group Events Subject years Incidence per 100 subject years 95% CI efalizumab2716801.61.1, 2.3 placebo21691.20.1, 4.3

42. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 41 Serious Infections: Controlled Clinical Experience Pneumonia in a 74-year-old efalizumab-treated man preceded by a decrease in absolute neutrophil count to 600/mm 3 from normal baseline value

43. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 42 Serious Infection: Opportunistic Infection Legionella pneumonia (one case) –41 year-old woman –History of tobacco use, no concomitant medications –Efalizumab (2 mg/kg/wk for 12 wks) –Multiple complications, survived Legionella pneumonia (one case) –41 year-old woman –History of tobacco use, no concomitant medications –Efalizumab (2 mg/kg/wk for 12 wks) –Multiple complications, survived

44. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 43 Malignancies: First 12 Weeks of Controlled Trials Placebo (n=715) Efalizumab (n=1620) Total2 (0.3%)2 (0.1%) Gastrointestinal1 (0.1%)0 Skin Carcinoma1 (0.1%)2 (0.1%)

45. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 44 Malignancies Efalizumab-treated Patients: Observed vs. Expected Malignancy category Observed (95% CI) Observed subject years External Cohort Expected (95% CI) Solid Tumor 8 (3, 16)1790SH * UHC † SEER ‡ 7 (4, 12) 5 (2, 8) 8 (NA) Melanoma 1 (0, 6)1790SH * SEER ‡ 0.4 (0, 2.3) 0.4 (NA) * Saskatchewan Health, † United Health Care ‡ Surveillance, Epidemiology End Results

46. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 45 Lymphoproliferative Malignancies Two EBV negative malignancies, both in efalizumab-treated patients Hodgkin’s disease (nodular sclerosing type) in a 37 year-old man; efalizumab 29 mg/kg over 5 mo. B cell lymphoma in a 57 year-old man; efalizumab 1 mg/kg/wk for 2 yrs Two EBV negative malignancies, both in efalizumab-treated patients Hodgkin’s disease (nodular sclerosing type) in a 37 year-old man; efalizumab 29 mg/kg over 5 mo. B cell lymphoma in a 57 year-old man; efalizumab 1 mg/kg/wk for 2 yrs

47. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 46 PTLD in Renal Transplant Trial of Efalizumab PTLD: 3 cases in 38 renal transplant patients; all in the 2 mg/kg/wk x 12 dose (n=19) –One resulted in death, judged by the investigator as related to efalizumab –All cases were in patients on concomitant immunosuppressive therapy: cyclosporine, MMF and prednisone. PTLD: 3 cases in 38 renal transplant patients; all in the 2 mg/kg/wk x 12 dose (n=19) –One resulted in death, judged by the investigator as related to efalizumab –All cases were in patients on concomitant immunosuppressive therapy: cyclosporine, MMF and prednisone.

48. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 47 Observed vs. Expected Rates of Lymphomas Efalizumab- Number Observed External Cohort- Number Expected 2 (0.24,7.22)SEER*: 0.9 SH † : 3.7 (1.5, 7.7) UHC ‡ : 2.9 (1.1, 6.2) * Surveillance, Epidemiology End Results † Saskatchewan Health ‡ United Health Care

49. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 48 Observed vs. Expected Rates of Non-melanoma Skin Cancer Efalizumab- observed External Cohort- expected 20 (12,31)SH: 7 (4, 11) UHC: 7 (4, 11)

50. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 49 Psoriasis Flares Requiring Hospitalization 19 patients (0.7%) in safety database experienced serious psoriasis flares 17 of these patients hospitalized for psoriasis Serious psoriasis flares occurred during treatment or after treatment discontinuation 19 patients (0.7%) in safety database experienced serious psoriasis flares 17 of these patients hospitalized for psoriasis Serious psoriasis flares occurred during treatment or after treatment discontinuation

51. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 50 Psoriasis Adverse Events Adverse EventPlacebo (715) Efalizumab (1620) All psoriasis AE’s 10 (1.4%)52 (3.2%) Erythroderma09 Pustular04 Guttate219 Plaque69 Unusual morphology 26 Inverse05 Palmo-plantar04

52. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 51 Arthritis Serious Adverse Events 15 cases: 0.6% of efalizumab-treated patients Other inflammation-associated findings (e.g. peripheral edema, fever, positive ANA) No cases during first 12 weeks of placebo-controlled trials 15 cases: 0.6% of efalizumab-treated patients Other inflammation-associated findings (e.g. peripheral edema, fever, positive ANA) No cases during first 12 weeks of placebo-controlled trials

53. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 52 Arthritis-related Adverse Events All arthritis AEs: 2.8% (45/1607) in efalizumab and 2.2% (16/715) in placebo Severe arthritis AEs: 0.6% (n=9) in efalizumab and 0.3% (n=2) in placebo All arthritis AEs: 2.8% (45/1607) in efalizumab and 2.2% (16/715) in placebo Severe arthritis AEs: 0.6% (n=9) in efalizumab and 0.3% (n=2) in placebo

54. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 53 Other Inflammation Related Serious Adverse Events In 2500 efalizumab-treated patients: –Interstitial pneumonitis (2 patients) –Serum sickness-like reaction (1 patient) –Transverse myelitis (1 patient) –Idiopathic hepatitis (1 patient) In 2500 efalizumab-treated patients: –Interstitial pneumonitis (2 patients) –Serum sickness-like reaction (1 patient) –Transverse myelitis (1 patient) –Idiopathic hepatitis (1 patient)

55. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 54ThrombocytopeniaThrombocytopenia 8 patients with platelets < 52,000 /mm 3 –2 of 8 with platelets  10,000 /mm 3 5 of 8 patients hospitalized (SAE’s) One case identified retrospectively; diagnosed with prostate cancer 8 patients with platelets < 52,000 /mm 3 –2 of 8 with platelets  10,000 /mm 3 5 of 8 patients hospitalized (SAE’s) One case identified retrospectively; diagnosed with prostate cancer

56. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 55 Thrombocytopenia: Patient Characteristics Ages: 29-71 4 men, 4 women Concomitant medical conditions: –Pre-existing ITP (1 patient) –Grave’s disease (2 patients) Ages: 29-71 4 men, 4 women Concomitant medical conditions: –Pre-existing ITP (1 patient) –Grave’s disease (2 patients)

57. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 56 Thrombocytopenia: SAEs All 5 treated with systemic steroids Bone marrow biopsies (n=2): normocellular Events included –40 yr-old woman (plt nadir 10,000/mm 3 ) heavy GU bleeding, antiplatelet antibody positive, remains on prednisone –73 yr-old woman (plt nadir 3,000/mm 3 ) failed prednisone taper; event ongoing All 5 treated with systemic steroids Bone marrow biopsies (n=2): normocellular Events included –40 yr-old woman (plt nadir 10,000/mm 3 ) heavy GU bleeding, antiplatelet antibody positive, remains on prednisone –73 yr-old woman (plt nadir 3,000/mm 3 ) failed prednisone taper; event ongoing

58. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 57 Common Adverse Events With Efalizumab Treatment Placebo (N=455) Efalizumab (N=869) Headache19%32% Chills4%12% Flu syndrome4%9% Pain4%8% Fever2%6% Nausea6%10% Myalgia5%9%

59. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 58 Clinical Laboratory Changes with to-be-marketed Efalizumab

60. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 59 Effects of Efalizumab on WBC Mean WBC increased 30%- 40% from baseline Mean lymphocyte counts doubled Mean eosinophil counts increased 50% Mean neutrophil counts increased slightly Mean WBC increased 30%- 40% from baseline Mean lymphocyte counts doubled Mean eosinophil counts increased 50% Mean neutrophil counts increased slightly

61. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 60 Change in Alkaline Phosphatase (U/L) from Baseline PBOEfalizumab 1 mg/kg Efalizumab 2 mg/kg First 12- weeks/ Controlled Trials n=432n=842n=60 - 1.035.299.57

62. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 61 Alkaline Phosphatase Levels Mean level higher in efalizumab group than placebo Patients with shift to high post baseline values: 4.0% in efalizumab (32/802) vs. 0.5% (2/416) in placebo Liver, intestinal isoenzymes affected Clinical significance not understood Mean level higher in efalizumab group than placebo Patients with shift to high post baseline values: 4.0% in efalizumab (32/802) vs. 0.5% (2/416) in placebo Liver, intestinal isoenzymes affected Clinical significance not understood

63. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 62 Shift to >ULN in Liver Function Tests* No. shifting to high Placebo (n=604) Efalizumab (n=1374) None 93%88% One 5.1%8.7% Two 1.5%3.1% Three 0.3%0.6% * Alkaline phosphatase, SGPT, SGOT, LDH, and total bilirubin

64. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 63 Effect of Efalizumab on Markers of Inflammation Acute phase reactants higher in efalizumab than placebo –C reactive protein –Fibrinogen Thrombocythemia Acute phase reactants higher in efalizumab than placebo –C reactive protein –Fibrinogen Thrombocythemia

65. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 64 C-Reactive Protein Mean Changes from Baseline: Study 2600 Baseline (min-max) Day 84 (min-max) Change (max) Placebo (n=216) 0.6 (0.4-8.9) 0.7 ( 0.4-7.0) 0.09 (6.6) Efalizumab (n=425) 0.6 (0.4-5.4) 1.0 (0.4-22) 0.40 (22)

66. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 65 Anti-efalizumab Antibodies Incidence: 67/1063 (6.3%) patients with post-washout samples Median exposure: 167 days Anti-efalizumab antibody positive patients: 20% achieved a PASI 75 and 53% achieved a PASI 50 Incidence: 67/1063 (6.3%) patients with post-washout samples Median exposure: 167 days Anti-efalizumab antibody positive patients: 20% achieved a PASI 75 and 53% achieved a PASI 50

67. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 ConclusionsConclusions Efficacy and Safety of Efalizumab

68. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 67 Efalizumab Efficacy Treatment Response –PASI 75: 17% - 37% –PASI 50: 36% - 46% –sPGA: 16% - 29% Median time to response in PASI 75 responders: 2 months Median duration of response (loss of 50% improvement post-treatment): 67 days Treatment Response –PASI 75: 17% - 37% –PASI 50: 36% - 46% –sPGA: 16% - 29% Median time to response in PASI 75 responders: 2 months Median duration of response (loss of 50% improvement post-treatment): 67 days

69. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 68 Efalizumab Efficacy PASI 75 maintained in 77% (61/79) of responders randomized to efalizumab compared to 20% (8/40) of responders randomized to placebo. Efalizumab shows relatively limited ability to recapture PASI 75 response upon relapse –31% (17/55) responded with retreatment upon relapse. PASI 75 maintained in 77% (61/79) of responders randomized to efalizumab compared to 20% (8/40) of responders randomized to placebo. Efalizumab shows relatively limited ability to recapture PASI 75 response upon relapse –31% (17/55) responded with retreatment upon relapse.

70. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 69 Efalizumab Safety No deaths in the controlled portion of clinical trials No deaths linked causally to the use of efalizumab in psoriasis trials No deaths in the controlled portion of clinical trials No deaths linked causally to the use of efalizumab in psoriasis trials

71. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 70 MalignanciesMalignancies Solid tumors and melanoma in efalizumab-treated patients comparable to external cohorts Lymphoproliferative malignancies higher than expected by SEER database and lower compared SH and UHC NMSC: higher than expected based on external cohorts Solid tumors and melanoma in efalizumab-treated patients comparable to external cohorts Lymphoproliferative malignancies higher than expected by SEER database and lower compared SH and UHC NMSC: higher than expected based on external cohorts

72. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 71 Efalizumab Safety Serious infections: higher in efalizumab- treated patients than placebo (0.4% vs. 0.1%) –One opportunistic infection, Legionella pneumonia –One infection, pneumonia, associated with new onset decrease in ANC Serious uncommon (19, 0.7%) adverse events of psoriasis (including psoriatic erythroderma and pustular psoriasis) Serious infections: higher in efalizumab- treated patients than placebo (0.4% vs. 0.1%) –One opportunistic infection, Legionella pneumonia –One infection, pneumonia, associated with new onset decrease in ANC Serious uncommon (19, 0.7%) adverse events of psoriasis (including psoriatic erythroderma and pustular psoriasis)

73. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 72 Safety Efalizumab Rare, inflammatory/autoimmune adverse events: transverse myelitis, interstitial pneumonitis, idiopathic hepatitis, serum sickness-like reaction Thrombocytopenia consisting of platelets < 52,000 cells/mm 3 in 8 efalizumab-treated patients resulting in hospitalization in 5 patients Rare, inflammatory/autoimmune adverse events: transverse myelitis, interstitial pneumonitis, idiopathic hepatitis, serum sickness-like reaction Thrombocytopenia consisting of platelets < 52,000 cells/mm 3 in 8 efalizumab-treated patients resulting in hospitalization in 5 patients

74. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 73 Laboratory Abnormalities Elevated: –WBC, lymphocytes, eosinophils –alkaline phosphatase –LFTs –acute phase reactants Elevated: –WBC, lymphocytes, eosinophils –alkaline phosphatase –LFTs –acute phase reactants

75. Dermatologic and Ophthalmic Drugs Advisory Committee September 9, 2003 74 Potential Areas for Further Study Intermittent vs. long-term continuous administration Long-term monitoring of immune function using clinical and laboratory assessments Large scale, long-term studies to assess risk of infection, neoplasms and other adverse events Safety and efficacy in children Intermittent vs. long-term continuous administration Long-term monitoring of immune function using clinical and laboratory assessments Large scale, long-term studies to assess risk of infection, neoplasms and other adverse events Safety and efficacy in children