1. STN 125011 Tositumomab Therapeutic Regimen (TTR) [tositumomab plus I-131 tositumomab] Oncologic Drugs Advisory Committee December 17, 2002

2. Proposed Indication Treatment of Patients with Relapsed or Refractory, Low- Grade, Follicular, or Transformed Low-Grade Non-Hodgkin’s Lymphoma (NHL) including Patients with Rituximab-Refractory Follicular NHL

3. OVERVIEW OF CLINICAL STUDIES Efficacy Study RIT-II-004 - The primary efficacy trial supporting the request for accelerated approval for the treatment of chemotherapy- refractory patients with low grade and follicular NHL, with or without transformation.

4. OVERVIEW OF CLINICAL STUDIES Efficacy Study CP97-012 : The primary efficacy trial supporting standard approval for the treatment of Rituximab-refractory patients with follicular NHL.

5. OVERVIEW OF CLINICAL STUDIES Efficacy Three additional studies provide supportive anti-tumor activity data for the proposed indications. RIT-II-002 - controlled Phase 2 study RIT-II-000 & 001 are single-arm trials

6. Study RIT-II-004 Trial Design multicenter historically-controlled single-arm patients w/ chemotherapy- refractory low grade or follicular NHL with or without transformation

7. Study RIT-II-004 Analytic Plan (Final) Primary Efficacy Endpoint – –proportion of patients with longer duration of response after TTR vs. proportion with longer duration of response after Last Qualifying Chemotherapy (LQC) regimen –based on MIRROR Panel assessment

8. Study RIT-II-004 Analytic Plan (Final) Secondary Efficacy Endpoints –overall response rate –complete response rate –duration of response –time to progression –survival

9. Study RIT-II-004 Study population consisted of 61 patients enrolled at 8 centers FDA analyses include 1 patient who withdrew consent and did not receive either dosimetric or therapeutic dose

10. RIT-II-004 Among the 61 patients registered: 7 (11%) responded to LQC 1 (2%) achieved CR/CCR to LQC Median duration of response - 4.1 months (range 3.0-5.4 months)

11. Study RIT-II-004 MIRROR-Assessed Response Response to TTR No Response to TTR Total Response to LQC347 No Response to LQC 252954 Total283361

12. Study RIT-II-004 Primary Endpoint Analysis Equivalent duration Longer duration of response after TTR (>30 days longer) than after LQC Longer duration of response after LQC than after TTR

13. Study RIT-II-004 Primary Endpoint Analysis Response to TTR No Response to TTR Total Response to LQC 2 TTR 1 LQC 4 LQC 2 TTR 5 LQC No Response to LQC 25 TTR29 =54 Total 27 TTR 1 LQC 3361

14. Study RIT-II-004 Primary Endpoint Analysis Response Frequency % of 61 ---------------------------------------------------------------------- Equivalent duration 29 48% Longer response w/ TTR27 44% Longer response w/ LQC 5 8% Significant by McNemar’s and by sign-rank test

15. Study RIT-II-004 Secondary Endpoints ORR 46% (28/61) Median Duration ORR in months (95% CI) 11.7 (6.9, NR) CR/CCR 20% (12/61) Median Duration CR/CCR in months (95% CI) NR (12.5, NR)

16. Study CP97-012 Design Single ‑ arm, multicenter Conducted in patients who had relapsed after  1 course(s) of Rituximab Endpoints: ORR, CR+CCR, response duration, time to progression, time to treatment failure, and survival.

17. Study CP97-012 Population/Subpopulations Registered n = 43 Treated n = 40 “Indicated” Population –follicular NHL –Rituximab response duration of < 6 mos n = 30

18. Study CP97-012 Registered (n=43) OutcomeInvestigator Assessment MIRROR Assessment ORR60%63% Median Resp duration 1.9 yrs1.3 yrs CR/CCR33%31%

19. Study CP97-012 “Indicated” subpopulation (n=30) OutcomeInvestigator Assessment MIRROR Assessment ORR60%63% Median Resp Duration NR2.1 yrs CR/CCR37%26%

20. Study CP97-012 Exploratory Analysis of efficacy by responsiveness to Rituximab Outcome Rituximab Responsive (n=18) Rituximab Unresponsive (n= 25) ORR 61% (11/18) 64% (16/25) Median Response Duration 2.1 yrs1.3 yrs

21. Supportive studies RIT-II-002 RIT-II-001 RIT-II-000

22. Study RIT-II-002 Design Two-arm Open-label Multi-center Randomized (not stratified) Chemotherapy-relapsed or refractory Low-grade, follicular, or transformed low-grade NHL

23. Study RIT-II-002 Design Treatment Arms –Arm A –TTR (hot arm) –Arm B – unlabeled Tositumomab antibody (cold arm) Endpoints: –1  CR/CCR –2° ORR, response duration, TTP, and toxicity profile

24. Study RIT-II-002 78 patients enrolled –42 in arm A –36 in arm B Prognostic variables similar except for –7% intermed. histology in A vs. 17% B –10% high IPI in Arm A vs. 3% in Arm B –52%  5 cm lesions Arm A vs. 34% Arm B

25. Study RIT-II-002 OutcomeArm A (n=42) Arm B (n=36) P- value CR/CCR33% (14/42) 8% (3/36) ORR55% (23/42) 19% (7/36) Median resp. duration NR2.3 yrs  Median CR duration NR  Median TTP or death 0.52 yrs0.45 yrs

28. Survival in Years RIT-II-002

29. Study RIT-I-000 Single-center, dose escalation study to determine –the optimal biologic dose of cold antibody –MTD for TTR in patients with and without prior BMT 59 patients were enrolled 22 patients without prior BMT were treated at the MTD

30. Study RIT-II-001 Multicenter, single arm study to assess reproducibility of dosimetry methods across clinical sites 47 patients enrolled

31. Overview of Study Results Study 004 (n=61) 012 (n=43) 002 (n=42) 001 (n=47) 000 (n=59) Median # prior chemo (range) 4 (2-13)4 (1-11)2 (1-4)4 (1-8)3 (1-11) ORR 46% (33%, 59%) 63% (47%, 77%) 55% (39%, 70%) 49% (34%, 64%) 48% (34%, 61%) CR/CCR20%30%33%30%27% Median Duration response 1.0 yrs1.3 yrsNR1.0 yrs1.2 yrs

32. Pooled Subset Analyses Long-term responders –Submitted by sponsor to show that TTR provides “a meaningful therapeutic benefit over existing treatments” in support of accelerated approval Low-Grade Transformed NHL –Analyses requested by FDA to assess for differences in activity in transformed vs. non-transformed since results include both types of patients

33. Long-Term Responders Defined as responding patients with TTP  1 year per MIRROR review 76/271 (28%) patients identified by MIRROR 68/271 who rec’d a single dosimetric and any therapeutic dose Patients retrospectively identified across 5 efficacy/activity studies (n=271)

34. Long-term responders (n=68) CR/CCR - 54 of 68 (79%) PR - 14 of 68 (21%) Median response duration 4.9 years (range from 0.9 to 7.8+ years)

35. Study entry variable Long term responders (n= 68) Patients w/o long term response (n=203) LQC end day to study entry day (yrs; 95% CI) 1.0 (0.8, 1.2) 0.4 (0.4, 0.6) Response to LQC CR + CCR PR 23 (34%) 25 (37%) 30 (15%) 62 (31%) Duration of response to LQC (yrs; 95% CI) 0.6 (0.5, 0.9) 0.4 (0.3, 0.5) Tumor Grade: Low Intermediate 58 (85%) 10 (15%) 130 (64%) 68 (33%)

36. Low Grade NHL w/Transformation 71 of 271 (26%) patients across 5 efficacy studies with evidence of transformed histology FDA reviewed and confirmed sufficient info to document transformation in 40 of the 59 (remaining 12 under review)

37. Low Grade NHL w/Transformation ORR 40% (16/40) CR/CCR 26% (11/40) Median response duration 1.6 years (range 0.1+ to 4.9 years)

38. Safety Summary Hematologic-acute –Neutropenia/lymphopenia: Infections –Thrombocytopenia: Hemorrhagic events Infusional reactions Gastrointestinal toxicity Immune responses to murine protein Delayed toxicity due to irradiation –Hypothyroidism –Secondary leukemias, myelodysplasia, other cancers

39. Safety Database Safety data provided for 620 patients 229 patients enrolled in 5 efficacy/activity studies (RIT ‑ I ‑ 000, RIT-II-001, RIT ‑ II ‑ 002, RIT ‑ II ‑ 004 and CP ‑ 97 ‑ 012) 391 patients treated under expanded access experience in Protocol CP-98- 020 and 4 sponsor-investigator INDs

40. Safety Database Protocol# Enrolled# ISS-A# ISS-B RIT-I-00059220 RIT-II-00147 0 RIT-II-00242+36 (19)42+190 RIT-II-00461590 CP-97-01243400 CP-98-0204640387 Single Pt604 RIT-II-0037700 Total854229391

41. Safety Database Safety profile in 5 efficacy/activity studies (n=229, ISS-A) showed a higher incidence for adverse events in the first 13 weeks vs. expanded access (n=391, ISS-B) Less comprehensive collection of data in expanded access and no monitoring Underreporting of AEs in expanded access confirmed during inspection

42. Incidence of AEs Preferred Term ISS-A Any Grade ISS-B Any Grade ISS-A Gr 3-4 ISS-B Gr 3-4 Asthenia 46%24%2%3% Fever 37%13%2% Nausea 35%19%3%1%  Cough 21%6%< 1% Infection 21%5%< 1%1% Pain 19%11%1%2% Chills 18%9%1%< 1% Rash17%8%< 1%0%

43. Incidence of AEs Preferred Term ISS-A Any Grade ISS-B Any Grade ISS-A Gr 3-4 ISS-B Gr 3-4 Headache16%7%0%< 1% Abdominal Pain 15%6%3%1% Vomiting15%8%1%< 1% Anorexia14%6%0%< 1% Myalgia13%7%< 1% Diarrhea12%7%0%< 1%

44. Incidence of SAE Preferred TermISS-A (n=229) ISS-B (n=391) Myeloproliferative Disorder 17 (7%)1 (<1%) Fever9 (4%)1 (<1%) Sepsis7 (3%)1 (<1%) Pneumonia6 (3%)1 (<1%) Dyspnea5 (2%)1 (<1%) Pleural Effusion5 (2%)1 (<1%)

45. Acute Hematologic Toxicity Complete blood counts were to be collected at least weekly beginning at week 3 until –recovery from nadir –removal from study Patients with missing data during the period of expected nadir (weeks 5-9) or at recovery (week 13) were assigned worst toxicity in “Worst case scenario” analyses

46. Acute Hematologic Toxicity ANC n=229 Platelets n=229 Hgb n=229 Gr 3-4 toxicity51%42%15% Gr 3-4 toxicity worst case 64%54%29% Gr 4 toxicity 21%18%4% Gr 4 toxicity worst case 25%22%4%

47. Acute Hematologic Toxicity ANC n=229 Platelets n=229 Hgb n=229 Median days to nadir (gr 3-4) 433447 Median days of Gr 3-4 (Q1; Q3) 30 (22; 43) 30 (22; 51) 19 (14; 34) 90 th percentile62 days 102 days 40 days Maximum observed 383+21178

48. Lymphopenia in RIT-001 & 003 CD20 (cells/  l) Wk 0 (n=125) Wk 7 (n=111) Wk 13 (n=74) M 6 (n=57) M 12 (n=14) 25 th Quartile 63001942 Median 11821349101 75 th Quartile 1961438100177

49. Infections/Fever Fever 37% (84 patients) 19% (43 pts)  study day 14 7-8% (15 pts/3 missing) fever associated with neutropenia

50. Infectious Events Pooled preferred termsPer-patient incidence # of events Infection pharyngitis Pneumonia bronchitis H. Zoster UTI Sepsis sinusitis H. simplex cellulitis fungal dermatitis periodontal abscess (43%) 98/229 149

51. Hemorrhagic Events Pooled preferred terms Per-patient incidence # of events Epistaxis Ecchymosis Melena GI hemorrhage Hemoptysis Gum hemorrhage Lung hemorrhage 12% (28/229) 31

52. Transfusions Support & Growth Factor Use ISS-A 16% (36/229) rec’d RBC transfusions 15% (35/229) rec’d platelet transfusions 12% (28/229) rec’d G-CSF/GM-CSF –Median duration of use 16 days (Q1=9; Q3=34) 7% (16/229) rec’d Epoetin alfa –Median duration of use 52 days (Q1=32; Q3=123)

53. Infusional Toxicities “Symptom-complex” primarily consisting of fever, asthenia, nausea/vomiting and/or diarrhea, chills, pain & headache, pharyngitis, rhinitis & cough, hypotension, myalgias/arthralgias, and rash

54. Infusional Toxicities Dosimetric dose (day 0-7) –55% (125/229) patients with  1 AE –309 events reported Therapeutic dose (day 8-14) –46% (105/229) patients with  1 AE –222 events reported

55. Gastrointestinal Toxicities Biodistribution studies demonstrated uptake in Waldeyer’s ring & GI tract due to binding to normal CD20+ cells Both acute (per-infusional) and delayed toxicities throughout the GI tract were reported Acute toxicities were also observed with unlabeled antibody (Arm B in RIT-II-002)

56. Gastrointestinal Toxicities Pooled preferred terms Incidence # of events UGI Nausea Vomiting gastrointestinal disorder intestinal obstruction 38% (86/229) 136 LGI Diarrhea abdominal pain abnormal stools Gastroenteritis intestinal perforation ulcerative colitis & colitis 24% (55/229) 78

57. Thyroid (TSH) Evaluation ISS PopulationN = 620 Available TSH value after treatment 362 Elevated TSH after treatment 34 Median Time to TSH Elevation (months) 10.9 95% CI on Median (months) 6.0, 13.6 Range (Months) 1.8, 76.3

58. Percent Elevated TSH by Months Censored at the Last available TSH Value (Cumulative)

59. HAMA Evaluation (Site or Central Assay) ISS PopulationN = 620 HAMA negative at baseline604 At least one f/u assessment515 HAMA positive51 Median time to HAMA + (Days)96 Range (Days)5 - 446

60. Percent HAMA positive (Site or Central) by Months Censored at the Last available HAMA Value (Cumulative)

61. HAMA Evaluation in RIT-II-003 77 patients with previously untreated low grade NHL enrolled At baseline –73 negative, 3 positive, 1 no data After treatment - 54 (70%) patients were HAMA seropositive Median time to seropositivity for HAMA 27 days (95% CI 23; 202 days)

63. MYELODYSPLASIA or ACUTE LEUKEMIA (MDS or AML) StudyN# MDS/ AML % MDS/ AML Median Yrs to MDS/AML RIT-I-00022523%3.9 RIT-II-00147511%1.8 RIT-II-0026134.9%1.2 RIT-II-0045946.8%2.7 CP-97-0124012.5% CP-98-02038710.3% Total620193.1%2.1

64. Percent of MDS/AML Incidence by Year

65. Efficacy Summary Primary efficacy trial in 61 chemo- refractory patients demonstrated significantly higher proportion of patients with longer duration of response following the TTR as compared to last chemotherapy ORR 46% CR/CCR 20% Median response duration 11.7 months

66. Efficacy Summary Primary efficacy trial in 30 Rituximab refractory patients with follicular NHL demonstrated ORR  60% CR/CCR  30% Median response duration 2 yrs

67. Efficacy Summary Supportive studies showed ORR from 48% - 63% Median durations of response from 1.0-1.3 years CR/CCR from 27% - 33%

68. Safety Summary Hematologic toxicity –60-71% incidence of any grade 3-4 hematologic toxicity, median duration 30 days –Profound and prolonged B-cell lymphopenia –43% incidence of infectious events –12% incidence hemorrhagic events

69. Safety Summary Symptom complex of infusional toxicities, comprised of fever, chills, nausea, asthenia, rash in  50% of patients Clinical and serologic immune responses –20% cumulative incidence of HAMA at 18 months in heavily pretreated patients –  70% cumulative incidence of HAMA in chemotherapy -naïve patients at 18 mos –Clinical sequelae (anaphylactoid reactions and serum sickness infrequently observed)

70. Safety Summary Hypothyroidism- –an observed 30% cumulative rate of TSH elevation at 5 years –an observed 45%cumulative rate of TSH elevation at 7 years

71. Safety Summary Leukemias and myelodysplasia observed with increasing cumulative incidence (23% in study with longest follow-up) Across all studies, incidence is 3% with median time to MDS/AML of 2.1 yrs

74. Response–RIT-II-004 (n=61) Response Category LQC Investigator LQC MIRROR I-131 MIRROR Complete Response (CR)117 Complete Clinical Response (CCR) 105 Partial Response (PR)15616 Stable Disease (SD)2354 Progressive Disease (PD)214929

75. RIT-004 Subset Analysis Transformed vs Non-transformed Response Category Response Rate in Subset without Transformation Response Rates in Subset with Transformation CR 13% (5/38) 13% (3/23) CCR 11% (4/38) 0 % (0/23) PR 37% (14/38) 8% (2/23) ORR 61% (23/38) 21% (5/23) SD 8% (3/38) 4% (1/23) PD 32% (11/38) 74% (17/23)

76. Study CP97 ‑ 012 Analyses of time to progression, time to treatment failure, and survival are not provided by FDA, because these data cannot be interpreted in a study that does not contain an internal control population.

77. Response Rates & Duration CP-97-012 IIT- Inves N=43 IIT- MIR. N=43 Treat Inves N=40 Treat MIR N=40 Indic- Inves N=30 Indic- MIR N=30 ORR (%) 606365686063 Median Duration (Years) 1.91.31.01.3NR2.1

78. Response Rates CP-97-012 IIT- Inves N=43 IIT- MIR. N=43 Treat Inves N=40 Treat MIR N=40 Indic- Inves N=30 Indic- MIR N=30 CR (%) 142615281723 CCR (%) 195205 3 PR (%) 283330352337

79. Response rate to I-131 in subsets of based on prior response to rituximab Prior response to most recent Rituximab regimen Response to the I- 131 regimen Median Duration of response to I- 131 Rituximab-responsive (CR, CCR, or PR) 11/18 (61%) 2.1 years Rituximab non- responsive (PD OR SD) 16/25 (64%) 1.3 years

80. Efficacy Results - RIT ‑ II ‑ 002 -- MIRROR Panel–Assessed Outcomes Efficacy Endpoint Arm A (N = 42) Arm B (N = 36) P ‑ value Complete response (CR+CCR) 14/42 (33%) 3/36 (8%) 0.01 Secondary endpoints Overall Response23/42 (55%) 7/36 (19%) 0.001 Median duration (yrs) of response (95% CI) NR (0.5–NR) 2.3 (0.4, NR ) 0.9 Median duration (yrs) of CR (95% CI) NR (NR, NR) NR (2.3, NR) 0.4 Median time to progression or death (yrs) (95% CI) 0.52 (0.35, NR) 0.45 (0.24, 0.5) 0.031

81. Duration of durable response over years

82. ISS Population Protocol# Enrolled# ISE# ISS-A# ISS-B RIT-I-00059 220 RIT-II-00147 0 RIT-II-00242+36+1942+19 0 RIT-II-00377000 RIT-II-00461 590 CP-97-01243 400 CP-98-02046400387 Single Pt6004 Total854271229391

83. Grade 3-4 Hematologic Toxicity Neutropenia ISS-A (n=229) ISS-B (n=391) % Documented Grade 3-4 toxicity 51%37% Median days to nadir (95% CI) 43 (42, 46) 42 (42, 43) 25 th and 75 th percentiles for days to nadir 39 ; 4937; 50 Median duration of documented Grade 3-4 toxicity 30 (22, 43) 30 (24, 36) 25 th and 75 th percentiles for duration of toxicity (days) 21; 4919; 54

84. Grade 3-4 Hematologic Toxicity Thrombocytopenia ISS-A (n=229) ISS-B (n=391) % Documented Grade 3-4 toxicity 42%33% Median days to nadir (95% CI) 34 (33, 35) 33 (31, 34) 25 th and 75 th percentiles for days to nadir 29; 4028, 36 Median duration of documented Grade 3-4 toxicity 30 (28, 36) 29 (24, 29) 25 th and 75 th percentiles for duration of toxicity (days) 22; 5122; 47

85. Grade 3-4 Hematologic Toxicity Anemia ISS-A (n=229) ISS-B (n=391) % Documented Grade 3-4 toxicity 15%9% Median days to nadir (95% CI) 47 (45, 49) 46 (43, 48) 25 th and 75 th percentiles for days to nadir 39; 6035, 57 Median duration of documented Grade 3-4 toxicity 19 (15, 22) 17 (15, 31) 25 th and 75 th percentiles for duration of toxicity (days) 14; 3415; 35

86. Grade 3-4 Hematologic Toxicity Neutropenia &/or Thrombocytopenia ISS-A (n=229) ISS-B (n=391) % Documented Grade 3-4 toxicity 59%47% % Grade 3-4 toxicity (worst case scenario accounting for missing values) 70%61% % Documented Grade 4 toxicity26% % Grade 4 toxicity (worst case scenario accounting for missing values) 30%

87. Study CP97-012 Treated/mITT (n=40) OutcomeInvestigator Assessment MIRROR Assessment ORR65%68% Median Resp duration 1.0 yrs1.3 yrs CR/CCR35%33%

88. Long-term Responders Logistic regression analysis in 271 patients Variables correlated with achieving a long- term response: –Low grade histology at study entry –Objective response to LQC –Longer duration of response to LQC –Longer time between LQC & Study entry –Fewer prior prior chemotherapy regimens

89. Low Grade NHL w/Transformation Logistic regression analysis in 271 patients Variables correlated with confirmed histologic dx of transformation –Intermediate/high tumor grade at study entry –Shorter time between LQC and Study entry –Greater number of prior chemotherapy regimens –Higher Ann Arbor Stage at study entry

90. Grade 3-4 Hematologic Toxicity Neutropenia, Anemia &/or Thrombocytopenia ISS-A (n=229) ISS-B (n=391) % Grade 3-4 toxicity60%48% % Grade 3-4 toxicity (worst case scenario) 71%62% % Grade 4 toxicity26%23% % Grade 4 toxicity (worst case scenario) 30%26%

91. Timeline Sept 14, 2000- Original BLA –RIT-II-004- interim study report dated 5/31/2000 –RIT-II-000 and 001- final study reports –RIT-II-002 and 003-interim study reports –ISS - 286 subjects Dec 14, 2000 –CP98-020 interim study report –ISS - 308 subjects

92. Timeline August 27, 2001 –RIT-II-003 second interim report through 12/20/2000 –ISS update – 309 patients Sept 7, 2001 –Final study report CP97-012 –Amended study report RIT-II-002 - MIRROR panel review, data cut-off Jan. 2001

93. Timeline Dec 11, 2001 –RIT-II-004- amended final study report, data cutoff Jan 2001, MIRROR panel review Sept 2001 –ISS update – 620 patients (includes 387 from expanded access) –Long-term responders- various studies- MIRROR panel review –Additional info for CP98-020

94. Timeline March 5, 2002 –ISS update – 620 patients – additional hematology data collected from audit at clinical study sites July 2, 2002 –Case report forms and report tabulations for long-term responder subpopulation

95. Timeline July 11, 2002 –Revised proposed indication –Requested accelerated approval for chemo-refractory and standard approval for Rituximab-refractory pts –Amendment 1 to final study report for CP97-012

96. Timeline October 4, 2002 –Amendment 2 to final study report for CP97- 012 October 30, 2002 –Independent review for additional patients with transformed histology in CP 97-012 December 10, 2002 –Responses to BiMo inspectional findings

97. Study RIT-II-002 - Duration of Response

98. Study RIT-II-002 – Time to Progression or Death

99. Study RIT-II-002 – Overall Survival

100. Study RIT-II-004 Exploratory subset analysis Outcomewithout transformation (n=38) with transformation (n=23) ORR60% (23/38) 22% (5/23) CR/CCR24% (9/38) 13% (3/23)

101. Incidence of AEs Preferred Term AE ISS-A Any Grade (n=229) ISS-A Grade 3-4 (n=229) ISS-B Any Grade (n=391) ISS-B Grade 3- 4 (n=391) Headache16%0%7%< 1% Abdominal Pain 15%3%6%1% Vomiting15%1%8%< 1% Anorexia14%0%6%< 1% Myalgia13%< 1%7%< 1% Diarrhea12%0%7%< 1%