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An innovative approach to RA : Efficacy and safety of B cell therapy

An innovative approach to RA : Efficacy and safety of B cell therapy. Professor Patrick DUREZ Royal Belgian Society of Rheumatology Aalst 2007. TNF failure: what options do we have?. Persistent synovitis. B cell. B cell. B cell. Plasma cell. IL-10. IL-6. Dendritic cell. TNF- a.

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An innovative approach to RA : Efficacy and safety of B cell therapy

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  1. An innovative approach to RA :Efficacy and safety of B cell therapy Professor Patrick DUREZ Royal Belgian Society of Rheumatology Aalst 2007

  2. TNF failure: what options do we have? Persistent synovitis

  3. B cell B cell B cell Plasma cell IL-10 IL-6 Dendritic cell TNF-a T cell IgG RF IgM RF IgG RF IgM RF Macrophage TNF-a IgM RF IL-1 IL-6 INFLAMMATORY DAMAGE FIX COMPLEMENT TNF-a INFLAMED SYNOVIA CARTILAGE LOSS Possible role of B cells in RA Edwards JC et al. Immunology. 1999;97:188–196; Takemura S et al. J Immunol. 2001;167:4710–4718; Alberts B et al. Molecular Biology of the Cell. New York: Garland Publishing; 2002; Metlay JP et al. Adv Immunol. 1989;47:45–116; Dorner T, Burmester GR. Curr Opin Rheumatol. 2003;15:246–252; Pistoia V, Corcione A. Stem Cells. 1995;13:487–500.

  4. Rituximab: Mechanism of action B lymphocytes lysis Antibody-Dependant Cell Mediated Cytotoxicity Complement Dependent Cytotoxicity (CDC) Apoptosis Macrophage Complement cascade B cell B cell CD20 Rituximab B-cell lysis Apoptosis Clynes et al, 2000; Reff et al, 1994

  5. WA16291: Design and Treatment Groups MTX (> 10 mg/wk) Rituximab (1 g x 2) Baseline 24 weeks MTX Inadequate Responders R Rituximab (1 g x 2) Cytoxan (750 mg x 2) Rituximab (1 g x 2) R = randomization N = 40/arm MTX (> 10 mg/wk) 17 day corticosteroid regimen in all arms Edwards et al, 2004

  6. Final Results: ACR Responses p-values from Fisher’s Exact test, comparing the MTX group with each rituximab group

  7. DANCER study: design All groups received doses 2 weeks apart + no glucocorticoids Primary endpoint: patients (%) with an ACR20 at Week 24 + i.v. premedication onlya Rituximab 1000 mg x 2 (n=192) + i.v. premedication plus oralb + no glucocorticoids Randomised(n=465) Rituximab 500 mg x 2 (n=124) + i.v. premedication onlya + i.v. premedication plus oralb + no glucocorticoids Follow-upto 2 years Placebo(n=149) + i.v. premedication onlya + i.v. premedication plus oralb Baseline 24 weeks All arms received weekly MTX 10–25 mg (oral or parenteral) aMethylprednisolone 100 mg i.v. on Days 1 and 15; bmethylprednisolone 100 mg i.v.on Days 1 and 15 plus oral prednisone 60 mg/day on Days 2–7 and 30 mg/day on Days 8–14 Emery et al, 2006

  8. DANCER study: ACR response at 24 weeks after the first course ** ** *p=0.029; **p0.001 vs placebo ** ** ** * Patients (%) RF-positive patients, ITT population (n=367) Emery et al, 2006

  9. REFLEX study: design Screen/TNF and/or DMARD withdrawal period Rituximab: 1000 mg or placebo i.v. infusion Methylprednisolone: 100 mg i.v. before rituximab infusion Prednisone: 60 mg p.o. Days 2–7, 30 mg p.o. Days 8–14 Clinic visit Primary efficacy timepoint ¯ · t Screen/TNF Randomisation Treatment period Randomization and/or DMARD ¯ ¯ · · t Long-term follow-up Rituximab + MTX(Group A) n = 308 MTX 3 months Potential for subsequent courses of rituximab in patients with 20% reduction in SJC and TJC from Week 24 Placebo + MTX (Group B) n = 209 Screen Day1 Wk2 Wks 4, 8,12, 16, 20 Wk 24 Wk 56 Rescue (Week 16) Group A: Standard of care Group B: Rituximab + MTX Cohen et al, 2006

  10. REFLEX study:ACR responses at 24 weeks after the first course p<0.0001 p<0.0001 Patients (%) p<0.0001 Cohen et al, 2006

  11. REFLEX study: results at 48 weeks – sustained response after the first course Completing Week 48 Placebo + MTX (n=24) (11%) Rituximab + MTX (n=114) (37%) Patients (%) Observed data Cohen et al, 2006

  12. REFLEX study: significant inhibition of radiological progression at 56 weeks* p=0.0043 p=0.0106 p=0.0007 Mean change from baseline *Patients with initial and at least 1 follow up with linear extrapolation as required Keystone et al, 2006

  13. Events of specific interest Ig counts, protective immunity Infections Infusion reactions Malignancies

  14. Mean (SD) serum Ig levels tend to decrease but remain within the normal range over 24 weeks (REFLEX Study) IgG IgA IgM 4.5 15 2.5 4.0 12 3.5 2.0 3.0 9 2.5 1.5 Mean IgA (mg/mL) Mean IgG (mg/mL) Mean IgM (mg/mL) 2.0 LLN 6 1.0 1.5 LLN 1.0 3 0.5 LLN 0.5 0 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Weeks Weeks Weeks Rituximab 1000 mg x 2 (n=298) Placebo (n=201) SD = standard deviation

  15. Infections, malignancies, infusion reactions Infections Incidence in clinical trials (2.1% vs 0.9%, p=NS) Most common infections were URTIs, nasopharyngitis and other infections commonly found in an RA population No opportunistic infection No cases of tuberculosis (TB) Infusion reactions 23%, mild (headache..) prevented by co-medications Malignancies Unknown Cohen and al Arthritis Rheum. 2006

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