Genmab A/s · OMXCOP:GMAB
Genmab A/s — Technical Presentation (2006)
22 slides from Genmab A/s's technical presentation, Oct 21, 2006
Slide 1: First Clinical Results of HuMax-CD20 Treatment in Rheumatoid Arthritis
First Clinical Results of HuMax-CD20 fully human monoclonal IgG1 antibody Treatment in Rheumatoid Arthritis M Østergaard1, C Wiell1, PT Dawes2, W Rigby3, J Petersen4, H Kastberg4, S Sierakowski5 1Copenhagen University Hospital at Hvidovre, Denmark; 2The Haywood Hospital, Stoke on Trent, UK; 3Dartmou
Slide 2: The roles of B cells in the pathophysiology of RA
The roles of B cells in the pathophysiology of RA •Secretion of pro-inflammatory cytokines •Antigen presentation •T-cell activation •Auto-antibody production
Slide 3: HuMax-CD20
HuMax-CD20 HuMax-CD20 (fully human) compared to rituximab (chimeric): Different epitope Better binding; slower off rate (Dissociation from surface CD20: T½: 180 min vs 90 min) Stronger complement activation (Complement dependent cytotoxicity higher in tested tumor cell lines) More efficient
Slide 4: Patient population
Patient population • A diagnosis of RA of at least 6 months duration • Active disease ≥ 6 swollen joints (of 28 joints) ≥ 6 tender joints (of 28 joints) ESR ≥ 22 mm/h or CRP ≥ 10mg/L • Failure to at least one DMARD • Previous exposure to biological agents allowed except for anti-CD20 antibodie
Slide 5: Study design
Study design Double blind, randomized, placebo controlled, dose escalation, multi center, 24 week, phase I/II clinical trial 300mg 700mg 1000mg/placebo 1000mg 700mg/placebo placebo 300mg/placebo Part A (39 patients) Part B (200 patients)
Slide 6: Study design
Study design • 2 infusions of either HuMax-CD20 (300, 700 or 1000 mg) or placebo 2 weeks apart • Premedication with paracetamol and antihistaminics; corticosteroids by amendment • Allowed continuation of ongoing therapy with stable doses of methotrexate and low dose corticosteroid • Patients followe
Slide 7: Primary objective, part A
Primary objective, part A • To evaluate the safety of HuMax-CD20 in patients with active RA Endpoints Adverse events and ACR20, ACR50 and ACR70 response rates EULAR response CD19+ and CD20+ B cell depletion
Slide 8: Demographics, part A
Demographics, part A Placebo 300 mg 700 mg 1000 mg No of patients 7 12 10 10 Age, median 60 53 50 57 Duration of RA, years, median 7 6 14 12 Sex male/female 0/7 1/11 1/9 2/8 Concomitant methotrexate no of patients 7 12 7 6 weekly dose, mg, median 20 13 18 15 Concomitant glucocorticoids no of patient
Slide 9: Patient disposition, part A
Patient disposition, part A Randomised 300 mg: 15 4 withdrawn (AE) Randomised 700 mg: 12 1 withdrawn (AE) Randomised 1000 mg: 12 1 withdrawn (AE) 26 active treatment Completed dosing: 33 7 placebo
Slide 10: B cell depletion
B cell depletion Indicates infusion Placebo 700 300 mg 700 CD19+ / mm3 600 600 500 500 400 400 300 300 200 200 100 100 109 0 0 -2 2 CD20-403 fig05.0x.sas 13JUN2006 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 Figure 05.01.01 CD19+, placebo CD20-403 fig05.0x.sas 13JUN2006 -2 2 6 10 14 18 22 26 30 3
Slide 11: Adverse events
Adverse events Reported in ≥ 4 patients No of patients with event / No of events Active treatment Placebo N = 32 N=7 Urticaria NOS 5/5 1/1 Rash NOS 5/7 Nausea 5/5 4/6 Dyspnoea 4/5 Fatigue 4/7 4/4 Pyrexia 5/5 1/1 Hypotension NOS 7/7 Flushing 4/7
Slide 12: Adverse events
Adverse events The majority occurred at the first infusion 100 92 90 80 Grade 4 80 Grade 3 % of patients Grade 2 70 Grade 1 57 60 60 50 43 40 30 20 20 17 10 0 0 Placebo 300 700 1000 Placebo 300 700 1000 Dose group, mg 1st infusion 2nd infusion
Slide 13: Infusion related events, part A
Infusion related events, part A ≥ CTC grade 3 and SAE Dose group Event Premedication by amendment 300 mg Bronchospasm (grade 3 non-serious) Anaphylactoid reaction (SAE) Corticosteroids 50 mg i.v. on infusion day Urticaria (SAE) 1 mg Antihistamine p.o. on day before infusion Corticosteroids 100 mg i.
Slide 14: Infusion related events, part B
Infusion related events, part B ≥ CTC grade 3 and SAE (preliminary, blinded data from 119 patients dosed) Event Premedication by amendment Fatigue (grade 3, non-serious) Infusion related reaction (SAE) Corticosteroids : 100 mg on day before 1st infusion 30 mg on day before 2nd infusion Bronchospasm
Slide 15: ACR responses at 24 weeks
ACR responses at 24 weeks Intention-to-treat population 90 80 70 70 % of patients 70 63 60 50 50 40 40 40 34 30 25 20 20 17 16 10 10 000 N=7 N=12 N=10 N=10 N=32 Placebo 300mg 700mg 1000mg Total Active ACR20 ACR50 ACR70
Slide 16: ACR20 responses at 24 weeks, patients previously treated with TNFα inhibitors
ACR20 responses at 24 weeks patients previously treated with TNFα inhibitors 26 patients were previously exposed to TNFα inhibitors but were refractory, intolerant or stopped treatment for other reasons No of patients Placebo 300 mg 700 mg 1000 mg Total Active previously treated with TNFα inhibitor
Slide 17: EULAR response at 24 weeks
EULAR response at 24 weeks Intention-to-treat population Improvement Placebo 300 mg 700 mg 1000 mg Total Active No of patients 7 12 10 10 32 Good 0 3 2 2 7 Moderate 2 6 5 6 17 None 5 3 3 2 8 Good / Moderate 29 % 75 % 70 % 80 % 75 %
Slide 18: Conclusions
Conclusions • Satisfactory safety profile; AEs predominantly infusion related reported at first infusion • Immediate, profound and long lasting B-cell depletion at all dose levels • ACR20 responses achieved in all groups treated with HuMax- CD20 (50 – 70 %) vs 0 % in placebo group (ITT) • Overall AC
Slide 19: Investigators
Investigators Denmark, Poland M Østergaard Copenhagen University Hospital at Hvidovre, Denmark B Baslund Rigshospitalet, Copenhagen, Denmark MS Hansen Copenhagen University Hospital at Herlev , Denmark A Filipowicz-Sosnowska Instytut Reumatologii im. Prof. Dr. hab.med. Eleonory Reicher, Warszawa, Po
Slide 20: Investigators
Investigators UK, US PT Dawes The Haywood Hospital, Stoke on Trent, UK BL Hazleman Addenbrooke’s Hospital, Cambridge, UK T Sheeran Cannock Chase Hospital, Staffordshire, UK I McInnes University of Glasgow, Glasgow, UK JD Isaacs Royal Victoria Infirmary, Newcastle upon Tyne, UK W Rigby Dartmouth - Hi
Slide 21: backups
backups
Slide 22: B cell depletion
B cell depletion 7 patients 12 patients CD20+ (/mm3) Placebo CD20+ (/mm3) 300 mg infusion infusion CD20+ / mm3 1515 700 700 600 600 500 108 500 400 400 300 114 206 300 309 200 200 301 203 115 104 100 103 100 111 107 106 105101 110 113 109 112 102 0 0 -2 2 6 10 14 18 22 26 30 34 38 -2 2 6 10 14 18 22