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BLA 125326 ARZERRA TM (ofatumumab) Injection GlaxoSmithKline Presentation Oncologic Drugs Advisory Committee 29 May 2009 1
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
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
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 2007 4
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
Ofatumumab Kills Cells with Low CD20 Expression Efficiently by CDC 100 CLL normal B cell % specific lysis 80 60 40 ofatumumab rituximab 20 0 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 CD20 molecules/cell Teeling et al. (2004) Blood 104; 1793-1800 6
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
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
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
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
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
CLL: Incidence and Survival Most common leukemia in the United States 15,490 estimated new cases in 2009 1 4,390 estimated deaths in 2009 1 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 2009. American Cancer Society, Atlanta. 2009 2. Homer et al. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD. 2009 Available at: http://seer.cancer.gov/csr/1975 2006/ 3. Brenner et al. Blood 2008; 111:4916-4921 4. Mauro et al. Blood 1999;94: 448-454 5. Call et al. Mayo Clin Proc 1994;69:323-328 12
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
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;87:4990-4997 14
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 4 10 9 /L 50% decrease Neutrophils Platelets Hemoglobin Bone Marrow 1.5 10 9 /L > 100 10 9 /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;87:4990-4997 15
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
Survival Outcomes by Line of Therapy Overall survival (%) 100 80 60 40 20 Refractory to alkylating agents Total Died Subgroup 609 129 Initial diagnosis 327 167 1st therapy 794 548 alkylating agent refractory 233 158 fludarabine-refractory 0 Fludarabine-refractory 0 24 48 72 96 120 144 MDACC database Keating et al. Leuk Lymph 2002; 43:1755 Time (months) 17
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; 48:1931-1939 18
Results of Salvage Therapy in Fludarabine-refractory refractory CLL DR N=54 BFR N=39 Median age, years 58 61 Median # Prior Therapies 4 4 Response rate 20% 26% Median TTF, months 2 3 2 3 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; 48:1931-1939 19
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: 2033 20
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 (%) < 2 47 40 2 to 5 29 34 > 5 17 12 Keating et al. Leuk Lymph 2002; 43:1755 Keating et al. Blood 2002; 99:3554 21
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* 66 58 66 3 3 3 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.1.2009 Fiegl et al. Cancer 2006; 107:2408; Moreton et al. J Clin Oncol 2005; 23:2971; Keating et al. Blood 2002; 99:3554 22
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; 48:1931-1939; Perkins et al. Cancer 2002; 94: 2033 23
24 ARZERRA Clinical Overview Study Hx-CD20 CD20-406 Michael Arning, MD PhD GlaxoSmithKline
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
26 ARZERRA Treatment Schedule Planned no. of infusions: 12 over 24 weeks Screening, Baseline characteristics Response evaluation Ofatumumab 300 mg Ofatumumab 2000 mg Week 0 1 2 3 4 5 6 7 12 16 20 24 Pre-medication regimen: acetaminophen 1 gm PO or equivalent cetirizine 10 mg PO or equivalent glucocorticoid (prednisolone) 100 mg IV or equivalent
27 Study Hx-CD20 CD20-406 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
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
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
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
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
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
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
34 Primary Endpoint Analysis: Response Rate Reported by IRC 100 80 58%* 47%* *P<0.0001 versus H 0 (two-sided exact test) RR (%) 60 40 99% CI 20 0 H 0 : RR = 15% DR (n=59) BFR (n=79)
100 IRC Reported Response and Investigator Response 90 Response rate (%) 80 70 60 50 40 30 58 42 99% CI 47 34 99% CI 20 10 H 0 : RR = 15% 0 DR (N=59) BFR (N=79) Overall IRC Assessment of Response Derived Investigator Overall Assessment of Response 35
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
37 Consistent Response Rate by Prior Therapies Subgroup DR BFR Response Rate 58 % 47 % 5 prior therapies < 5 prior therapies N RR, % N RR, % 37 22 65 45 39 40 38 55 Prior rituximab-containing regimen No prior rituximab-containing regimen 35 24 54 63 43 36 44 50 Prior FCR* No prior FCR 16 43 50 60 16 63 44 48 *Fludarabine + cyclophosphamide + rituximab (FCR), with or without other drugs as qualifying therapy for inclusion in the study
38 Consistent Response Rate by Baseline Characteristics Subgroup* DR BFR Response Rate 58 % 47 % N RR, % N RR, % Age 65 yrs 27 52 33 45 Rai stage III-IV Rai stage I-II 32 26 56 60 55 24 44 54 17p del No 17p del 17 40 41 65 14 62 14 55 11q del No 11q del 24 33 63 55 22 56 64 41 *In patients for whom data are available
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
Key Secondary Efficacy Endpoints 40
Duration of Response* Estimated probability (%) 100 90 80 70 60 50 40 30 20 10 5.6 mo 7.1 mo DR (n=34) BFR (n=37) 0 0 2 4 6 8 10 12 14 16 Months from onset of response Number of patients DR 34 28 14 10 5 3 1 0 0 BFR 37 31 21 10 5 2 1 1 1 0 0 * Time from initial response to progression (assessed by IRC) or last assessment 41
Progression-free Survival* Estimated probability (%) 100 90 80 70 60 50 40 30 20 10 5.9 mo 5.7 mo DR (n=59) BFR (n=79) 0 0 2 4 6 8 10 12 14 16 18 Months from start of treatment Number of patients DR 59 49 38 19 11 5 2 1 0 0 BFR 79 62 47 31 13 8 1 1 1 0 * Time from start of treatment to progression (assessed by IRC) or last assessment 42
Estimated probability (%) 100 90 80 70 60 50 40 30 20 10 0 Overall Survival* 15.4 mo 13.7 mo DR (n=59) BFR (n=79) 0 2 4 6 8 10 12 14 16 18 20 Months from start of treatment Number of patients DR 59 54 47 39 32 24 19 15 11 4 0 0 BFR 79 77 73 65 46 33 27 29 10 4 2 0 * Time from start of treatment to last assessment 43
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
Overall Survival by Response Landmark analysis 1 at Week 12* DR (n = 53) BFR (n=75) Estimated probability (%) 100 90 80 70 60 50 40 30 20 10 0 log-rank p=0.0424 100 90 80 70 60 50 40 30 20 10 0 log-rank p<0.0001 2 4 6 8 10 12 14 16 18 20 Months from start of treatment 2 4 6 8 10 12 14 16 18 20 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
Analysis of Individual Components of the CLL Response Criteria Clinical Symptoms Physical Findings Hematologic Parameters 46
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
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%
Complete Resolution of All Constitutional Symptoms* Over Time Percent of Patients with Constitutional Symptoms 100 90 80 70 60 50 40 30 20 10 0 Screening Treatment Period Follow-up -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks from start of treatment DR BFR Number of patients DR 31 31 27 25 22 21 20 18 13 6 4 BFR 46 46 42 43 38 32 27 28 21 5 5 * In patients who had constitutional symptoms at baseline (n=77) and resolution was maintained for 2 months 49
50 Median Lymphocyte Count Over Time Median Lymphocyte Count (10 9 /L) 40 35 30 25 20 15 10 5 0 Screening Treatment Period Follow-up -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks from start of treatment DR BFR Number of patients DR 58 59 54 49 52 47 46 40 40 34 24 10 5 BFR 76 79 73 71 71 73 63 55 50 46 36 9 7
Maximum Decrease in Palpable Lymph Node SPD* by Response Status 50 Maximum Decrease from Baseline (cm 2 ) 0-100 -200-300 -700 Partial Remission (n=63) Stable Disease (n=47) Progressive Disease (n=10) Not Evaluable (n=1) 0 10 20 30 40 50 60 70 80 90 100 110 120 *SPD Sum of product of greatest diameters Number of patients 51
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
53 Safety Results Study Hx-CD20 CD20-406
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
Pivotal Study in Refractory CLL Exposure Percent of Patients with Infusion 100 90 80 70 60 50 40 30 20 10 0 Weekly regimen (over 8 weeks) 1 2 3 4 5 Monthly regimen (over 16 weeks) 6 7 8 9 10 11 12 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
56 Overview of Adverse Events* % of Patients DR (N=59) BFR (N=79) Other (N=16) Total (N=154) Any AE 92 96 100 95 AEs Grade 3 64 48 75 57 AEs leading to withdrawal from treatment 20 10 13 14 All SAEs 54 48 75 53 Fatal (Grade 5 SAEs) 20 13 13 16 * During reporting period per protocol 5 additional patients had disease progression listed as AE leading to discontinuation
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 16 12 Pneumonia 16 10 Anemia 16 5 Fatigue 15 0 * During per protocol reporting period, regardless of causality (MedDRA preferred terms)
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)
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
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
Infusion Reactions Percent of patients with infusion reactions 100 90 80 70 60 50 40 30 20 10 0 Infusion No. Weekly regimen (over 8 weeks) 1 2 3 4 5 Monthly regimen (over 16 weeks) 6 7 8 9 10 11 12 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
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
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%)
64 Laboratory Abnormalities Laboratory abnormalities Biochemical Uric Acid Alkaline Phosphatase Hyperglycemia ALT Hyponatremia Total Bilirubin Hyperkalemia Hypokalemia Hematologic Hemoglobin Platelets Neutrophils All Grade (%) 41 34 27 25 21 19 16 13 97 88 81 Grade 3/4 (%) 5 1 2 1 2 1 3 1 18 29 54
Median Neutrophil Counts Over Time 16% of patients had neutropenia as AEs (12% Grade 3 AEs) Median Neutrophil Count (10 9 /L) 5 4 3 2 1 Screening Treatment Period Follow-up -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks from start of treatment DR BFR Number of patients DR 56 57 50 45 46 40 37 31 31 28 20 9 5 BFR 76 79 67 62 64 64 58 51 46 42 33 9 7 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
Median Hemoglobin (g/dl) Median Hemoglobin Levels Over Time 15 14 13 12 11 10 Screening 16% of patients had anemia as AEs (5% Grade 3 AEs) Treatment Period Follow-up -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks from start of treatment DR BFR Number of patients DR 56 56 43 40 40 38 37 33 32 29 22 10 5 BFR 73 75 53 48 47 48 41 38 34 31 27 7 6 Median Hemoglobin level increased during the observation period 66
Median Platelet Counts Over Time 2 patients had thrombocytopenia as AEs (1 had Grade 3 AE) Median Platelet Count (10 9 /L) 200 180 160 140 120 100 Screening Treatment Period Follow-up -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks from start of treatment DR BFR Number of patients DR 59 59 51 47 47 44 42 38 35 32 24 10 5 BFR 74 78 67 64 66 68 60 51 48 43 35 9 7 Median Platelet Count increased from baseline (< 100x10 9 /L) during the observation period 67
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
69 Concluding Remarks Debasish Roychowdhury, MD GlaxoSmithKline
Results of Salvage Therapy in Fludarabine-refractory refractory CLL: DR Tam et al DR (N=54) Hx-CD20-406 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; 48:1931-1939 8 Median OS, months OS = overall survival 13.7 70
Results of Salvage Therapy in Fludarabine-refractory refractory CLL: BFR Published data BFR Hx-CD20-406 BFR (N=79) Median age, yrs 58-67 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;48:1931-1939 (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
Ofatumumab: Clinical Development Plan in CLL Phase I Studies Phase II Studies Phase III Studies First Line Hx-CD20-407 ofatumumab + FC (N=61, enrollment completed) OMB110911 ofatumumab + chlorambucil vs. chlorambucil (N=444, ongoing) Second Line Hx-CD20-402 ofatumumab doseranging (N=33, completed) OMB110913 ofatumumab + FC vs. FC (N=328, ongoing) Third Line Hx-CD20-406 ofatumumab monotherapy (n=225 planned, 154 in current interim analysis) GEN416 ofatumumab monotherapy continuation study (N=25, ongoing) 72
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
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
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
A 54 Adjudication Process DR group Patient ID Reader 1 Reader 2 Adj. Trigger # Adjudicator Consensus IRC (sponsor) IRC (FDA) 406118 PR PR 2 PR Y PR SD 406147 SD PR 1,2,3 PR Y PR SD 406158 PR PR 3 PR PR PD 406195 PR PR 3 PR PR SD 406199 PR PR NA NA PR SD 406203 PR PR 2 PR PR PD 406210 CR SD 1,2 PR Y PR SD 406218 PR PR 3 PR Y PR SD
Patient Profiles EFP 24 406218 (DR) 60 SPD Lymphocyte count 35 50 30 SPD (cm^2) 40 30 20 10 PR (IRC) 25 20 15 10 5 Lymphocyte count (x10^9/l) WEEK 0 BL 4 8 12 16 20 24 28 36 Inv. Response SD PR SD SD PR 0