Genmab A/s · OMXCOP:GMAB
Genmab A/s — 9th International Conference on Malignant Lymphoma 2005
34 slides from Genmab A/s's conference presentation, June 2005
Slide 1: HuMax-CD4 (Zanolimumab): Phase II Trial in Cutaneous T-cell Lymphoma
HuMax -CD4 ((Zanolimumab) HuMax-CD4 Zanolimumab) A Fully Human Anti -CD4 Monoclonal Antibody: Phase II Trial in Anti-CD4 Cutaneous T -cell Lymphoma (CTCL) T-cell 9th International Conference on Malignant Lymphoma Lugano Lugano,, Switzerland - June 88-11, -11, 2005 M Duvic, YY H H Kim, Kim, EE Obitz
Slide 2: Zanolimumab HuMax CD4 MoAb
Zanolimumab HuMax CD4 MoAb • High affinity, fully human monoclonal IgG1κ antibody (Kd = 5 x10-11 M) • Antibody Dependent Cellular Cytotoxicity – Depletion CD4+ T-cells • Blocks signaling, interactions between CD4 and MHC II • Treatment of Cutaneous T-Cell Lymphoma – FDA Fast Track designation – U.S.
Slide 3: Primary Cutaneous T-Cell Lymphomas
Primary Cutaneous T-Cell Lymphomas T-Cell (CTCL) • Extranodal Non-Hodgkin’s peripheral T cell lymphomas presenting in skin are 90% CD4+ Mycosis Fungoides & Sézary Syndrome • US Prevalence MF: 16,000 - 20,000 • EU Prevalence MF: Comparable to US • Anaplastic Large T-cell lymphoma – 8% of primary cuta
Slide 4: Nodal T-Cell Lymphomas
Nodal T -Cell Lymphomas T-Cell – Peripheral T-cell lymphoma, unspecified • 75% CD4+ (3.7% of NHL) – Angioimmunoblastic T-cell lymphoma • 75% CD4+ (1.2% of NHL) – Anaplastic large cell lymphoma • 20% CD4+ (2.4% of NHL) US Prevalence 8,000 - 10,000
Slide 5: Mycosis Fungoides
Mycosis Fungoides APC -dependant stimulation of malignant T APC-dependant -cells T-cells NEJM 2004;350:1978
Slide 6: Mechanisms of action of HuMax-CD4
Mechanisms of action of HuMax-CD4 HuMax-CD4 - yes and no - ADCC yes FcγR CDC Cytokines; - C1q no Inhibition of: surface - proliferation markers CD4+ Classical Signal transduction T cell Cytokine production pathway Surface marker expression Receptor blockade* yes CD4 down-modulation Apoptosis sheddin
Slide 7: Mechanism of Action & Safety
Mechanism of Action & Safety • HuMax-CD4 believed to include both depleting (ADCC) and non-depleting (anti-proliferative) processes. • Toxicity studies in primates at 2- 20 mg/kg twice-weekly (via IV): – Drug was well tolerated. No systemic toxic effects. – Animals could mount humoral and cellular i
Slide 8: Rationale for Targeting CD4
Rationale for Targeting CD4 • CD4 is present on 50% of the malignant cells in T-cell lymphoma • CD4 is present on 90% of CTCL T-cells • CD4 expression is restricted • CD4 expression is stable • CD4 is involved in signaling
Slide 9: Previous Experience With Chimeric Anti-CD4 Mab in MF
Previous Experience With Chimeric Anti-CD4 Mab in MF Anti-CD4 • Non-depleting anti-CD4 (Leu 3a) • 7 pts with persistent, progressive MF • Received graduated doses (10-80 mg) twice weekly for 3 weeks • Results: 2 PR, 1 MR, 3 SD, and 1 PD • Response duration: median 2 weeks, range 9 days to 12 weeks •
Slide 10: Previous Experience With Chimeric Anti-CD4 Mab in MF
Previous Experience With Chimeric Anti-CD4 Mab in MF Anti-CD4 • Depleting anti-CD4 (cM-T412) • 8 patients with persistent or progressive MF • Graded dose (50-200 mg) as a single dose • Results: 5 PR, 2 MR, and 1 PD • Freedom from progression: 6 to 52 weeks • CD4 counts decreased •Knox et al Blood 87
Slide 11: HuMax-CD4 in Open Label Phase II Trials in Refractory CTCL
HuMax -CD4 ((Zanolimumab) HuMax-CD4 Zanolimumab) In Open Label Clinical Phase II Trials in Refractory Early and Advanced Stage CTCL • Once weekly i.v. administration for 17 weeks conducted between April 2003 – June 2004 in 47 CTCL patients • Initial Regimen: 280 mg • High Dose Regimen: - 560 mg in e
Slide 12: Endpoints
Endpoints • Primary Endpoint: Composite Assessment of Index Lesion Disease Activity score (CA score). • PR > 50% reduction; CR = 100% reduction. • Response confirmed after 4 weeks: – no new cutaneous tumors – no new visceral disease – no new pathological lymph nodes – less than 25% increase in size
Slide 13: Composite Assessment of Index Lesion Disease Activity Score
C omposite A Composite ssessment of Assessment Index Lesion Disease Activity Score Component Score Composite Assessment is the Erythema 0-8 sum of scores over components and index lesions* Scaling 0-8 Response confirmed after 4 weeks Elevation 0-8 Pigmentation 0-8 Area 0-18 * J Clin Oncol 19:2456-24
Slide 14: Phase II Demographics
Phase II Demographics • 47 patients with biopsy verified CD4+ CTCL – 38 mycosis fungoides (MF) and 9 Sézary Syndrome (SS) • Age 35 - 81 years Early Stage Advanced Stage IB 23 MF II A 2 MF II B 7 MF III 2 MF 3 SS IV A 4 MF 5 SS IV B 1 SS
Slide 15: Dose Dependent Depletion of Peripheral CD4+ T-Cells
Dose Dependent Depletion of Peripheral CD4+ T-Cells T-Cells Low dose regimens High dose regimens Early Stage MF 14 patients 560mg 1500 Early Stage MF 11 patients 280mg 1500 Advanced Stage MF 9 patients 280mg Advanced Stage MF 4 patients 980mg CD3+CD4+ Count (cells/mm³) CD3+CD4+ Count (cells/mm³) 100
Slide 16: Clinical Responses in Early Stage MF
Clinical Responses in Early Stage MF 280 mg ≥50% CA Reduction in 560 mg ≥50% CA Reduction in 4 of 11 Patients, 1 CR 7 of 14 Patients: 2 CR, 5 PR 50% 50% Early Stage MF 280mg Early Stage MF 560mg 11 patients 14 patients Change in Composite Assessment Score Change in Composite Assessment Score 0% 0% -
Slide 17: Clinical Response in Advanced Stage MF
Clinical Response in Advanced Stage MF 280 mg 980 mg ≥50% CA Reduction in 2 of 9 ≥50% CA Reduction in 3 of 4 Patients, 2 Partial Responses Patients, 3 Partial Responses 50% Advanced Stage MF 280mg 50% 9 Patients Advanced Stage MF 980mg 4 Patients Change in Composite Assessment Score Change in Compos
Slide 18: Clinical Response in Sézary Syndrome
Clinical Response in Sézary Syndrome 280 mg ≥50% CA Reduction in 1 of 980 mg ≥50% CA Reduction in 4 of 5 2 Patients, 1 Partial Response Patients, 1 Partial Response Sézary Syndrome 280mg Sézary Syndrome 980mg 2 patients 5 patients 50% 50% Infusions Infusions Change in Composite Assessment Score Chan
Slide 19: Dose Dependent Clinical Response in MF patients
Dose Dependent Clinical Response in 38 MF patients 80% 3/4 70% 60% Responders 7 / 14 50% 40% 30% 2/9 20% 1 / 11 10% 0% Early Stage MF Advanced Stage MF Early Stage MF Advanced Stage MF 280 mg 280 mg 560 mg 980 mg High dose (560 / 980 mg) compared to low dose (280 mg), p=0.016, Fisher's Exact Test. P
Slide 20: Dose-Dependent Increase in Maximal Trough Serum Values
Dose -Dependent Increase in Dose-Dependent Maximal Trough Serum Values of Zanolimumab in MF Patients Dose N Geometric Mean Range (µg/ml) (µg/ml) 280mg1 11 0.5 <0.02-33.8 280mg2 9 0.1 <0.02-13.5 560mg1 14 59.9 2.68-176 980mg2 4 231.0 132-459 1: Early stage MF, 2: Advanced stage MF
Slide 21: Correlation between Maximal Trough Values and Clinical Response
Correlation between Maximal Trough Values and Clinical Response in MF Patients 100.00 1000.00 Maximal Trough Serum Concentration (µg/mL) OR: 55% 12/22 10.00 1.00 OR: 6% 1/16 0.10 0.01 Early Stage Advanced Stage Early Stage Advanced Stage 280mg 280mg 560mg 980mg n=11 n=9 n=14 n=4 Clinical Response No
Slide 22: Time To Response and Response Duration in MF patients
Time To Response and Response Duration in MF patients Time To Response Number of responders weeks (percentage of 13 responders) 0-4 7 (54%) 0-8 11 (85%) 0 - 12 12 (93%) 0 - 16 13 (100%) The median response duration was > 45 weeks
Slide 23: Response in Stage IB Patient 280 mg
Response in Stage IB Patient 280 mg Baseline Week 2
Slide 24: Response in Stage IB Patient 280 mg
Response in Stage IB Patient 280 mg Baseline Week 2
Slide 25: Response in Stage IB Patient 280 mg
Response in Stage IB Patient 280 mg Baseline Week 2
Slide 26: Response in Stage IB Patient 560 mg
Response in Stage IB Patient 560 mg Baseline Week 4
Slide 27: Response in Stage IB Patient 560 mg
Response in Stage IB Patient 560 mg Baseline Week 4
Slide 28: Response in Stage IVA Tumor Patient – 980mg
Response in Stage IVA Tumor Patient – 980mg Baseline Week 8
Slide 29: Number of Patients with AEs/SAEs
Number of Patients with AEs/SAEs CTCL Early and Advanced Stage Early Stage Advanced Early Advanced Stage Stage Stage 280 mg 280 mg 560 mg 980 mg Number of Patients 11 13 14 9 Number of Patients with 11 13 14 9 AE Number of Patients with 8 10 13 8 related AE - Grade 1-2 7 10 8 6 - Grade 3 1 0 4 2 - G
Slide 30: Most common AE in CTCL
Most common AE in CTCL – Flu-like symptoms – Pruritus – Infections reflecting co-morbidity of disease – Eczema (dermatitis) – Fatigue – Headache
Slide 31: Safety of HuMax-CD4
Safety of HuMax HuMax-- CD4 SAEs: 41 SAEs in 465 patients have been reported (as of 17-Jan-2005) • Nine SAEs in 465 patients were judged as related: All recovered except 1(see below) - Pneumonia due to haemophilus - Psoriasis aggravated - Hypoglycaemia (two cases) - Febrile Reaction - Bronchitis - P
Slide 32: Pivotal Trial SPA approved
Pivotal Trial SPA approved • Open-label, Dose escalation, followed by Double-blind, Randomized, Two-dose, Parallel Group, Multi-center Clinical Trial of HuMax-CD4, a Fully Human Monoclonal Anti-CD4 Antibody, in Patients with Mycosis Fungoides type CTCL (stage IB-IVB) who are Refractory or Intolerant
Slide 33: Summary and Conclusions
Summary and Conclusions • Higher dose led to higher Zanolimumab antibody concentrations. • Higher Zanolimumab antibody concentrations are correlated with higher response rates. • Responses seen in early and advanced stage CTCL patients including patients with Sézary Syndrome. • Zanolimumab treatment
Slide 34: Genmab
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