U.S. Food and Drug Administration

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1 U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2 BLA ARZERRA TM (ofatumumab) Injection GlaxoSmithKline Presentation Oncologic Drugs Advisory Committee 29 May

3 Presentation Overview Introduction Debasish Roychowdhury, MD GlaxoSmithKline Refractory CLL Susan O Brien, MD U.T. M.D. Anderson Cancer Center Clinical Overview Michael Arning, MD, PhD GlaxoSmithKline Concluding Remarks Debasish Roychowdhury, MD GlaxoSmithKline 2

4 External Participants Susan O Brien, MD Prof. of Medicine, Leukemia Dept., MDACC, Houston Michael Keating, M.B., B.S. Prof. of Medicine, Leukemia Dept., MDACC, Houston Thomas Kipps, MD, PhD Prof. of Medicine, Hematology/Oncology, UCSD, La Jolla Anders Österborg, MD, PhD Prof. of Oncology, Karolinska Institute and Hospital, Stockholm Kanti Rai, MD Chief, Division of Hematology/Oncology, Long Island Jewish Medical Center, New Hyde Park, NY William G. Wierda, MD, PhD Assoc. Prof. of Medicine, Leukemia Dept., MDACC, Houston 3

5 Refractory CLL: Need for New Therapies CLL is the most common leukemia in adults Long lasting remissions common with first line treatments Nearly all patients relapse and require additional treatments Resistance to fludarabine-based therapies heralds a grim prognosis 1,2,3,4 Few treatment options for fludarabine-refractory disease available 1,2,3,4 1 Keating et al 2002; 2 Moreton et al 2005; 3 Fiegl et al 2006; 4 Tam et al

6 Ofatumumab Non-clinical Findings * ADCC: Antibody dependent cell-mediated cytotoxicity CDC: Complement dependent cytotoxicity Human IgG 1 antibody Novel membraneproximal small loop epitope Slow off-rate Induces ADCC* Induces strong and rapid CDC Triggered at low CD20 expression Relatively insensitive to complement regulatory proteins Active against rituximab - resistant cells including CLL 5

7 Ofatumumab Kills Cells with Low CD20 Expression Efficiently by CDC 100 CLL normal B cell % specific lysis ofatumumab rituximab ,000 40,000 60,000 80, , , ,000 CD20 molecules/cell Teeling et al. (2004) Blood 104;

8 Key Regulatory Milestones Date May 2004 April 2008 September 2008 October 2008 January 2009 March 2009 April 2009 Activity IND submitted by Genmab Sponsorship of IND transferred to GSK Clinical Pre-BLA meeting CMC Pre-BLA meeting BLA submitted Orphan drug designation granted Safety update submitted 7

9 Discussions with FDA Regarding Approvability of ARZERRA in the BLA FDA identified durable objective response rate as an acceptable surrogate endpoint reasonably likely to predict clinical benefit in a patient population with unmet medical need Overall response rate of 10-20% unlikely to predict clinical benefit Double refractory (DR) patients have unmet medical need Bulky fludarabine refractory (BFR) population should be analyzed separately Studies to confirm clinical benefit should be ongoing at the time of BLA review 8

10 Proposed Indication ARZERRA (ofatumumab) is a human monoclonal antibody against CD20 for the treatment of patients with chronic lymphocytic leukemia who have received prior therapy. Efficacy in patients who have not previously received fludarabine has not been established. 9

11 Disclosures for Susan M. O Brien, O MD Research Support / P.I. Consultant Genentech, Berlex, Biogen Idec, Eli Lilly, Novartis, Bristol-Myers Squibb, GeminX, Genta, Hana BioSciences Genta, Sanofi-Aventis, Celgene, Genmab, GlaxoSmithKline Scientific Advisory Board GeminX, Biogen Idec, Eli Lilly, GlaxoSmithKline 10

12 11 Refractory Chronic Lymphocytic Leukemia (CLL) Need for New and Better Therapies Susan M. O Brien, MD Professor of Medicine Department of Leukemia The University of Texas M. D. Anderson Cancer Center Houston, Texas

13 CLL: Incidence and Survival Most common leukemia in the United States 15,490 estimated new cases in ,390 estimated deaths in Median age at diagnosis: 72 years 2 5-year survival rate from time of diagnosis: 60% 3 Prognosis at diagnosis dependent on stage of disease, IgVH mutation status, cytogenetics, and serum markers Most patients will die due to complications of CLL, mainly infections 4,5 1. American Cancer Society. Cancer Facts & Figures American Cancer Society, Atlanta Homer et al. SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD Available at: / 3. Brenner et al. Blood 2008; 111: Mauro et al. Blood 1999;94: Call et al. Mayo Clin Proc 1994;69:

14 CLL: Disease Characteristics Lymphocytosis Clonal expansion of mature B lymphocytes that coexpress CD5 and CD19, CD20 (dim), CD23 Clinical features Constitutional symptoms (fever, night sweats, weight loss, extreme fatigue) Lymphadenopathy, splenomegaly, hepatomegaly Cytopenia Increased susceptibility to infections 13

15 Response Evaluation in CLL Based on 1996 NCI-WG CLL guidelines 1 Composite endpoint Response requires improvement of below parameters for at least 2 months duration Disease symptoms Physical findings Laboratory findings (blood counts) CT scan not required for response confirmation Clinical judgment important 1. Cheson et al. Blood. 1996;87:

16 1996 NCI-WG Response Criteria Parameter CR/nPR PR (2 Months Minimum Duration) Lymph Nodes Normal 50% decrease Liver/Spleen Normal 50% decrease Constitutional Symptoms None No improvement required Lymphocytes /L 50% decrease Neutrophils Platelets Hemoglobin Bone Marrow /L > /L > 11.0 g/dl < 30% lymphocytes +/- presence of nodules on bone marrow biopsy 50% improvement* 50% improvement* 50% improvement* (*At least one of the above) No improvement required Cheson et al. Blood. 1996;87:

17 16 CLL Treatment Options First-line CLL Chemotherapy Alkylating agents: chlorambucil, bendamustine, cyclophosphamide Purine analogs: fludarabine Chemoimmunotherapy FCR combination: fludarabine, cyclophosphamide, rituximab Monoclonal antibodies Alemtuzumab Relapsed/refractory CLL Chemotherapy Alkylating agent: bendamustine Monoclonal antibodies Alemtuzumab Treatments have lower responses, shorter duration of response, and greater toxicities when used in subsequent lines of therapy

18 Survival Outcomes by Line of Therapy Overall survival (%) Refractory to alkylating agents Total Died Subgroup Initial diagnosis st therapy alkylating agent refractory fludarabine-refractory 0 Fludarabine-refractory MDACC database Keating et al. Leuk Lymph 2002; 43:1755 Time (months) 17

19 Salvage Therapies in Fludarabine-refractory refractory CLL The MDACC CLL experience Responses categorized by types of salvage therapy Other outcomes reported include major infections, early deaths, and survival Largest dataset available to date for fludarabinerefractory patient population Double-refractory patients (refractory to fludarabine and alemtuzumab: DR) Bulky fludarabine-refractory patients (refractory to fludarabine with bulky nodes: BFR) Tam et al. Leuk Lymph 2007; 48:

20 Results of Salvage Therapy in Fludarabine-refractory refractory CLL DR N=54 BFR N=39 Median age, years Median # Prior Therapies 4 4 Response rate 20% 26% Median TTF, months Major infections 60% 45% Death within 8 weeks 16% 10% Median OS, months 8 14 OS = overall survival; TTF = time to treatment failure Tam et al. Leuk Lymph 2007; 48:

21 Salvage Therapies in Fludarabine-refractory refractory CLL Perkins et al N=27 Median age, years 67 Median # Prior Therapies 2 Response rate 11.4% Median TTF NR Serious infections 89% Fatal infections 48% Median OS 13 months NR = not reported; OS = overall survival; TTF = time to treatment failure Perkins et al. Cancer 2002;94:

22 Alemtuzumab in Fludarabine-refractory refractory CLL Overall response rate 33% (CR 2%, PR 31%) Median time to progression 4.7 months Grade 3-5 infections in 31% Limited activity in patients with bulky lymph nodes Node Size (cm) N Response Rate (%) < to > Keating et al. Leuk Lymph 2002; 43:1755 Keating et al. Blood 2002; 99:

23 Alemtuzumab in Bulky Fludarabine-refractory refractory CLL Fiegl 2006 n=37 Moreton 2005 n=11 Keating 2002 n=17 Median age*, years Median # prior therapies* Response rate 8% 9% 12% Median OS 10 months 9 months NR OS = overall survival; NR = not reported *For all patients in the study Alemtuzumab less effective for bulky (>5 cm) lymphadenopathy NCCN practice guidelines in oncology v Fiegl et al. Cancer 2006; 107:2408; Moreton et al. J Clin Oncol 2005; 23:2971; Keating et al. Blood 2002; 99:

24 Need for New Agents in Fludarabine-refractory refractory CLL No effective treatment option if also refractory to alemtuzumab (DR), or with bulky lymph nodes (BFR) Response with salvage regimens ORR 11-26%; median TTF 2-3 months Median overall survival 8-14 months Major/serious infections: 45-89% Poor prognosis for fludarabine-refractory CLL Keating et al. Leuk Lymph 2002; 43:1755; Tam et al. Leuk Lymph 2007; 48: ; Perkins et al. Cancer 2002; 94:

25 24 ARZERRA Clinical Overview Study Hx-CD20 CD Michael Arning, MD PhD GlaxoSmithKline

26 25 ARZERRA Study in Refractory CLL (Study Hx-CD20 CD20-406) Single-arm, international, multi-center study Primary endpoint: response rate Planned interim analysis to determine efficacy or futility 2 refractory populations with active CLL Double Refractory (DR) group Refractory to fludarabine-containing regimen ( 2 cycles) and to alemtuzumab-containing regimen ( 12 doses) Bulky Fludarabine Refractory (BFR) group Refractory to fludarabine-containing regimen ( 2 cycles) and considered inappropriate for alemtuzumab treatment due to at least one lymph node >5 cm No upper age limit No exclusions for severe cytopenia at baseline

27 26 ARZERRA Treatment Schedule Planned no. of infusions: 12 over 24 weeks Screening, Baseline characteristics Response evaluation Ofatumumab 300 mg Ofatumumab 2000 mg Week Pre-medication regimen: acetaminophen 1 gm PO or equivalent cetirizine 10 mg PO or equivalent glucocorticoid (prednisolone) 100 mg IV or equivalent

28 27 Study Hx-CD20 CD Dose Regimen Selection Based on Phase I/II study (Hx-CD20-402) in CLL Doses studied: 500, 1000, and 2000 mg for 4 weekly treatments No responses >2 months with 500 or 1000 mg dose 48% (13/27) response rate with 2000 mg dose Median response duration 16 weeks No dose-related safety issues Increased number of weekly doses from 4 to 8 To increase probability of response Added 4 monthly infusions To maximize duration of response Initial dose 300 mg To minimize infusion reactions

29 28 Study Endpoints Primary endpoint Response rate Measured over 24 weeks from start of treatment Assessed by Independent endpoints Review Committee (IRC) Based upon NCIWG CLL 1996 guidelines Key secondary endpoints Response duration Progression-free survival Overall survival Safety

30 IRC Response Evaluation NCIWG CLL 1996 criteria Composite endpoint Patient symptoms, physical findings, laboratory values; analyzed over time 5 CLL experts, including 2 authors of 1996 NCIWG CLL guidelines IRC determined from investigators assessments and laboratory data Eligibility Onset of response Date of progression Overall response 29

31 Primary Endpoint Interim Analysis Triggered when primary endpoint data available for 66 DR patients (as categorized by sponsor) Performed on strict significance level: 1% If lower limit of the exact two-sided 99% CI >15% for either of the 2 populations, DMC* was to notify the sponsor that criteria for primary efficacy were met *DMC = Data Monitoring Committee 30

32 31 Patient Population Interim Results Efficacy data presented for 138 patients (categorized by IRC) 59 patients in DR group 79 patients in BFR group Safety data presented for 154 patients 59 patients in DR group 79 patients in BFR group 16 patients did not meet IRC criteria for DR or BFR in Other group Main reason: Patients did not receive a minimum of 2 cycles of fludarabine or received < 12 doses of alemtuzumab

33 Baseline Characteristics Characteristics Median age, yrs (range) DR (n = 59) 64 (41-86) BFR (n = 79) 62 (43-84) Age 65 yrs (%) Median no. of prior CLL regimens (range) Rai stage III/IV at screening, n (%) 27 (46) 33 (42) 5 (1-14) 4 (1-16) 32 (54) 55 (70) Largest lymph node/ct lesion >5 cm, n (%) 55 (93) 79 (100) Chromosomal Abnormalities, n (%) 17p deletion (%) 49 (86) 17 (30) 59 (75) 14 (18) 11q deletion (%) 24 (42) 22 (28) Baseline anemia (%) 44 (75) 67 (85) Baseline thrombocytopenia (%) 43 (73) 57 (72) Baseline neutropenia (%) 21 (36) 20 (25) 32

34 Prior Therapy All patients in the DR group were refractory to fludarabine and alemtuzumab All patients in the BFR group were refractory to fludarabine In addition: DR Group (N=59) BFR Group (N=79) Prior alkylator * therapy 93% 92% Refractory to latest alkylator therapy 78% 82% Refractory to latest therapy 95% 90% Refractory to latest rituximabcontaining therapy * Alkylators include chlorambucil, cyclophosphamide, bendamustine, melphalan 53% 42% 33

35 34 Primary Endpoint Analysis: Response Rate Reported by IRC %* 47%* *P< versus H 0 (two-sided exact test) RR (%) % CI 20 0 H 0 : RR = 15% DR (n=59) BFR (n=79)

36 100 IRC Reported Response and Investigator Response 90 Response rate (%) % CI % CI H 0 : RR = 15% 0 DR (N=59) BFR (N=79) Overall IRC Assessment of Response Derived Investigator Overall Assessment of Response 35

37 36 Primary Causes for Differences in Response Rates between IRC and Investigator Clinical judgment of Changes in response parameters at single visits / transient Lymphocyte counts Lymph node size Organomegaly Small new lymph nodes at single visits/transient IRC assesses overall response (longitudinal) Investigators assess response at individual visit

38 37 Consistent Response Rate by Prior Therapies Subgroup DR BFR Response Rate 58 % 47 % 5 prior therapies < 5 prior therapies N RR, % N RR, % Prior rituximab-containing regimen No prior rituximab-containing regimen Prior FCR* No prior FCR *Fludarabine + cyclophosphamide + rituximab (FCR), with or without other drugs as qualifying therapy for inclusion in the study

39 38 Consistent Response Rate by Baseline Characteristics Subgroup* DR BFR Response Rate 58 % 47 % N RR, % N RR, % Age 65 yrs Rai stage III-IV Rai stage I-II p del No 17p del q del No 11q del *In patients for whom data are available

40 39 Primary Endpoint Summary Clinically meaningful results Regardless of method of assessment (IRC, investigator) Consistent results across important subgroups Rai stage Number of prior therapies Prior rituximab-containing therapy

41 Key Secondary Efficacy Endpoints 40

42 Duration of Response* Estimated probability (%) mo 7.1 mo DR (n=34) BFR (n=37) Months from onset of response Number of patients DR BFR * Time from initial response to progression (assessed by IRC) or last assessment 41

43 Progression-free Survival* Estimated probability (%) mo 5.7 mo DR (n=59) BFR (n=79) Months from start of treatment Number of patients DR BFR * Time from start of treatment to progression (assessed by IRC) or last assessment 42

44 Estimated probability (%) Overall Survival* 15.4 mo 13.7 mo DR (n=59) BFR (n=79) Months from start of treatment Number of patients DR BFR * Time from start of treatment to last assessment 43

45 44 Landmark Analysis Post-hoc analysis to determine if response to ARZERRA is predictive of longer survival in the study populations Week 12 for the analysis was selected as earliest time-point at which a response at week 4 can be confirmed

46 Overall Survival by Response Landmark analysis 1 at Week 12* DR (n = 53) BFR (n=75) Estimated probability (%) log-rank p= log-rank p< Months from start of treatment Responder (n=29) Non-responder (n=22) Responder (n=28) Non-responder (n=45) 1. Based on Anderson et al. J Clin Oncol 2008;26:3913 * Analysis included patients who were alive at the Week 12 time point 45

47 Analysis of Individual Components of the CLL Response Criteria Clinical Symptoms Physical Findings Hematologic Parameters 46

48 47 Clinical Improvements for At Least 2 Months Efficacy Endpoint DR (N=59) BFR (N=79) Complete Resolution of Constitutional Symptoms a 48% 63% 50% Reduction in Lymphadenopathy b 62% 49% Complete Resolution of Lymphadenopathy 16% 11% 50% Reduction in Splenomegaly 53% 57% Complete Resolution of Splenomegaly 47% 35% 50% Reduction in Hepatomegaly 61% 62% Complete Resolution of Hepatomegaly 50% 52% a. Complete resolution of constitutional symptoms (fever, night sweats, fatigue, and weight loss) defined as the presence of any symptoms at baseline, followed by no symptoms present b. Lymphadenopathy measured by sum of the products of greatest diameters (SPD) as assessed by physical examination

49 48 Clinical Improvements for At Least 2 Months Efficacy Endpoint DR (N=59) BFR (N=79) Hemoglobin 11 g/dl to >11 g/dl post-baseline 31% 26% Platelet counts 100x10 9 /L to >50% increase or >100x10 9 /L post-baseline 41% 39% Neutrophils < 1.5x10 9 /L to 1.5x10 9 /L post-baseline 10% 28%

50 Complete Resolution of All Constitutional Symptoms* Over Time Percent of Patients with Constitutional Symptoms Screening Treatment Period Follow-up Weeks from start of treatment DR BFR Number of patients DR BFR * In patients who had constitutional symptoms at baseline (n=77) and resolution was maintained for 2 months 49

51 50 Median Lymphocyte Count Over Time Median Lymphocyte Count (10 9 /L) Screening Treatment Period Follow-up Weeks from start of treatment DR BFR Number of patients DR BFR

52 Maximum Decrease in Palpable Lymph Node SPD* by Response Status 50 Maximum Decrease from Baseline (cm 2 ) Partial Remission (n=63) Stable Disease (n=47) Progressive Disease (n=10) Not Evaluable (n=1) *SPD Sum of product of greatest diameters Number of patients 51

53 52 ARZERRA Efficacy Conclusions Remarkable response rates in both populations (DR and BFR) Consistent responses across important subgroups Clinically meaningful duration of responses Improvement or resolution of clinical symptoms and hematologic parameters frequently observed Longer median survival for responders in landmark analysis

54 53 Safety Results Study Hx-CD20 CD20-406

55 54 Safety Database for BLA 648 patients across 12 studies 154 patients with safety data in ongoing study in refractory CLL Other studies included in safety analysis: Oncology indications (6 studies, N=212): CLL dose escalation monotherapy and combination studies Follicular lymphoma - monotherapy and combination studies Diffuse large B-cell lymphoma Non-oncology indications (5 studies, N=282): Rheumatoid arthritis Chronic obstructive pulmonary disease

56 Pivotal Study in Refractory CLL Exposure Percent of Patients with Infusion Weekly regimen (over 8 weeks) Monthly regimen (over 16 weeks) Infusion Number 90% patients completed the 8 weekly infusions 55% completed all 12 infusions over 24 week course Primary reasons for withdrawal of treatment were progressive disease and infections 55

57 56 Overview of Adverse Events* % of Patients DR (N=59) BFR (N=79) Other (N=16) Total (N=154) Any AE AEs Grade AEs leading to withdrawal from treatment All SAEs Fatal (Grade 5 SAEs) * During reporting period per protocol 5 additional patients had disease progression listed as AE leading to discontinuation

58 57 Adverse Events* 15% Frequency (by Type and Grade) % of Patients All Grades (N=154) Grade 3 (N=154) Pyrexia 20 3 Cough 19 0 Diarrhea 18 0 Neutropenia Pneumonia Anemia 16 5 Fatigue 15 0 * During per protocol reporting period, regardless of causality (MedDRA preferred terms)

59 58 Serious Adverse Events* 5% % of Patients All Grades (N=154) Pneumonia 12 Neutropenia 6 Disease progression 6 Pyrexia 5 Sepsis 5 *During per protocol reporting period, regardless of causality (MedDRA preferred terms)

60 59 Mortality During Treatment or Follow-up 24 patients died 18 did not achieve at least a PR 11 infections 5 disease progression 2 cardiac events (both with history of cardiac disease; events were considered unrelated by investigator) 6 were responders at some time: 4 died after disease progression 2 died during response 1 peritoneal infection secondary to complication of GI cancer surgery 1 with baseline grade 3 neutropenia due to septic shock after 10 th dose, considered unrelated by investigator

61 60 Mortality During Extended Follow-up 37 deaths, none considered drug-related 32 occurred after new CLL therapy Of the remaining 5 patients: 3 did not achieve at least a PR (1 sepsis, 1 pneumonia, 1 cause of death not reported) 1 disease progression after PR 1 fatal pneumonia (BFR), > 9 months after last ofatumumab infusion

62 Infusion Reactions Percent of patients with infusion reactions Infusion No. Weekly regimen (over 8 weeks) Monthly regimen (over 16 weeks) All Grades Grade 3 Mostly mild to moderate, declined after 1 st infusion 1 withdrawal No grade 4 or fatal infusion reactions * Broadly defined as any signs and symptoms that could be infusion-related, occurred on infusion days, and started after the beginning of infusion 61

63 Infections Incidence, types, and severity of infections were as expected in this heavily pretreated refractory CLL population 108/154 patients (70%) had 250 events, mainly grade 1 or 2 51/154 (35%) had grade 3 infections 32/154 (21%) had infections considered drug-related 43/154 (28%) had major infections* Respiratory infections and septic complications most common * Major infections defined as infections leading to hospitalization for > 48 hours during or within 4 weeks of completing treatment 62

64 63 Underlying Disease as Risk Factor for Infections Infections were more frequent in patients with poor prognostic indicators >2 prior therapies Infections (76% vs. 59%) and Grade 3 infections (31% vs. 18%) Advanced Rai Stage III-IV Grade 3 infections (24% vs. 5%) Baseline grade 3 or 4 neutropenia Infections Grade 3 (53% vs. 37%), including fatal infections (24% vs. 16%)

65 64 Laboratory Abnormalities Laboratory abnormalities Biochemical Uric Acid Alkaline Phosphatase Hyperglycemia ALT Hyponatremia Total Bilirubin Hyperkalemia Hypokalemia Hematologic Hemoglobin Platelets Neutrophils All Grade (%) Grade 3/4 (%)

66 Median Neutrophil Counts Over Time 16% of patients had neutropenia as AEs (12% Grade 3 AEs) Median Neutrophil Count (10 9 /L) Screening Treatment Period Follow-up Weeks from start of treatment DR BFR Number of patients DR BFR Median Neutrophil Counts decreased from baseline within the first t few weeks, but remained at or above the lower limit of normal during the observation period 65

67 Median Hemoglobin (g/dl) Median Hemoglobin Levels Over Time Screening 16% of patients had anemia as AEs (5% Grade 3 AEs) Treatment Period Follow-up Weeks from start of treatment DR BFR Number of patients DR BFR Median Hemoglobin level increased during the observation period 66

68 Median Platelet Counts Over Time 2 patients had thrombocytopenia as AEs (1 had Grade 3 AE) Median Platelet Count (10 9 /L) Screening Treatment Period Follow-up Weeks from start of treatment DR BFR Number of patients DR BFR Median Platelet Count increased from baseline (< 100x10 9 /L) during the observation period 67

69 68 ARZERRA Safety Conclusions Interpreted in the context of these heavily pre-treated refractory patient populations ARZERRA was well-tolerated No unexpected safety findings AEs mostly mild to moderate Most common AEs were infusion reactions, infections, and hematologic AEs Safety profile acceptable

70 69 Concluding Remarks Debasish Roychowdhury, MD GlaxoSmithKline

71 Results of Salvage Therapy in Fludarabine-refractory refractory CLL: DR Tam et al DR (N=54) Hx-CD DR (N=59) Median age, yrs 58 Median age, yrs 64 Median # prior therapies 4 Median # prior therapies 5 Response rate 20% Response rate 58% Major infections 60% Major infections 32% Death within 8 weeks 16% Death within 8 weeks 7% Median OS, months Tam et al. Leuk Lymph 2007; 48: Median OS, months OS = overall survival

72 Results of Salvage Therapy in Fludarabine-refractory refractory CLL: BFR Published data BFR Hx-CD BFR (N=79) Median age, yrs Median age, yrs 62 Median # prior therapies 2 4 Median # prior therapies 4 Response rate 8 26% Response rate 47% Major infections 45% Major Infections 23% Death within 8 weeks 10% Death within 8 weeks 3% Median OS, months 9 14 Median OS, months Tam et al. Leuk Lymph 2007;48: (n=39); Fiegl et al. Cancer 2006;107:2408 (n=37); Moreton et al. J Clin Oncol 2005; 23:2971 (n=11); Keating et al. Blood 2002; 99:3554 (n=17) 15.4 OS = overall survival 71

73 Ofatumumab: Clinical Development Plan in CLL Phase I Studies Phase II Studies Phase III Studies First Line Hx-CD ofatumumab + FC (N=61, enrollment completed) OMB ofatumumab + chlorambucil vs. chlorambucil (N=444, ongoing) Second Line Hx-CD ofatumumab doseranging (N=33, completed) OMB ofatumumab + FC vs. FC (N=328, ongoing) Third Line Hx-CD ofatumumab monotherapy (n=225 planned, 154 in current interim analysis) GEN416 ofatumumab monotherapy continuation study (N=25, ongoing) 72

74 73 Overall Conclusions Treatment-refractory CLL is a serious illness that requires effective therapies Efficacy demonstrated with ARZERRA monotherapy in DR and BFR CLL patients and this is reasonably likely to predict clinical benefit Acceptable safety profile in the context of current salvage therapies Randomized trials to confirm clinical benefit are ongoing ARZERRA should be made available for these patients

75 Opportunistic Infections Pivotal Study in Refractory CLL Number of patients, n (%) Opportunistic infection Opportunistic infection SAE DR (N=59) BFR (N=79) Other (N=16) Total (N=154) 15 (25) 8 (10) 1 (6) 24 (16) 6 (10) 2 (3) 0 8 (5) Higher number of opportunistic infections in DR group Serious opportunistic infections included herpes zoster (3 patients), aspergilloma, fusarium infection, pneumocystis jiroveci pneumonia, fungal pneumonia, PML (1 patient each) None of the patients had a PR at the time of the serious opportunistic infection Infections considered opportunistic (based on clinical judgment) included fungal and viral infections i.e. HSV, CMV, pneumocystis jiroveci S 35

76 EF 66 IRC- Response Rate Assignment Independent review of ecrf data displays of visit response assessments and CRF data for each subject To assign IRC response, two readers need to agree on three variables: response onset of response date of progression Lack of agreement on any of 3 variables for first 2 readers triggers automated independent and blinded third read (adjudication) Lack of agreement between at least 2 of the 3 reads on any of the 3 variable leads to live consensus read (Webex or face to face) between 2 IRC members to reach consensus

77 A 54 Adjudication Process DR group Patient ID Reader 1 Reader 2 Adj. Trigger # Adjudicator Consensus IRC (sponsor) IRC (FDA) PR PR 2 PR Y PR SD SD PR 1,2,3 PR Y PR SD PR PR 3 PR PR PD PR PR 3 PR PR SD PR PR NA NA PR SD PR PR 2 PR PR PD CR SD 1,2 PR Y PR SD PR PR 3 PR Y PR SD

78 Patient Profiles EFP (DR) 60 SPD Lymphocyte count SPD (cm^2) PR (IRC) Lymphocyte count (x10^9/l) WEEK 0 BL Inv. Response SD PR SD SD PR 0