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MabThera – the past, present and future impact on the treatment of RA

MabThera – the past, present and future impact on the treatment of RA. 2007. 1995. 1996. 1997. 1998. 1999. 2000. 2001. 2002. 2003. 2004. 2005. 2006. Pre- 1990. 2008. 2009. Professor Paul Emery

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MabThera – the past, present and future impact on the treatment of RA

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  1. MabThera – the past, present and future impact on the treatment of RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009 Professor Paul Emery Professor of Rheumatology and Head of the Academic Section of Musculoskeletal Medicine at the University of Leeds, UK.

  2. B cells: Key players in RA pathophysiology • B cells originally seen as integral to the pathophysiology of RA • But…for the next 20 years, RA was considered a T cell-mediated disease • The important role of B cells in the pathophysiology of RA was then rediscovered • This led to a breakthrough in the management of RA (Dörner & Burmester, 2003)

  3. 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009 Development of MabThera in RA

  4. MabThera: A novel biological agent • MabThera is a novel genetically engineered anti-CD20 therapeutic monoclonal antibody that selectively targets CD20-positive B cells (Shaw et al, 2003; Silverman & Weisman, 2003)

  5. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  6. MabThera in oncology • MabThera was first licensed for use in patients with relapsed indolent Non-Hodgkin’s lymphoma (NHL) in the USA in 1997 and in the rest of the world in 1998 • To date, more than 1.5 million patients have been treated with MabThera worldwide

  7. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  8. B cells: Key players in RA pathophysiology • Recognition that there is an abundance of B cells in the synovium of RA-affected joints • Three critical roles of B cells identified in RA pathogenesis: • Antigen presentation leading to T cell activation • Autoantibody production • Cytokine production (Panayi & Hainsworth, 2005; Silverman & Carson, 2003)

  9. Early indications

  10. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  11. MabThera in RA ― Phase IIa proof-of-concept study (first randomised trial) N Engl J Med 2004;350:2572–2581

  12. Phase IIa ―ACR response at 24 and 48 weeks 24 weeks 48 weeks * * 80 * * 70 60 * * * 50 * Patients (%) * 40 * 30 * 20 10 0 MTX MTX MabThera MabThera MabThera + CTX MabThera + CTX MabThera + MTX MabThera + MTX *p<0.05, Fisher’s exact test comparing the MTX group with each rituximab group. ACR = American College of Rheumatology ACR20 ACR50 ACR70 (Edwards et al. N Engl J Med 2004)

  13. Conclusions from the Phase IIa study • MabThera induced a significant and long lasting response in patients with severe, seropositive, active RA • MabThera in combination with methotrexate was as effective as the combination with cyclophosphamide, but with far better tolerability and, at Week 48 and extended duration of response • Those promising result led to the initiation of a full clinical development program

  14. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  15. Efficacy and Safety from Dose-ranging Assessment: iNternational Clinical Evaluation of Rituximab in RA DANCER Emery et al. EULAR 2005

  16. Phase IIb study – initial results from the DMARD-IR patient population

  17. DANCER — conclusions at 24 weeks • A single course of MabThera 500 mg or 1000 mg, given as two infusions 2 weeks apart, is highly effective over 24 weeks in the treatment of active RA in MTX-inadequate responders (IR) patients • ‘High efficacy’ endpoints showed a trend towards higher efficacy with the higher MabThera dose • Oral glucocorticoids made no significant contribution to efficacy or safety • IV glucocorticoids made no contribution to efficacy, but were required to reduce first-dose reactions (Emery et al, 2006)

  18. Unmet need in patients treated with TNF inhibitors Gold standard therapy TNF inhibitor + MTX Not all patients benefit from treatment UnmetMedical Need TNF inhibitor + MTX TNF inhibitor alone MTX alone ACR 70＝70％ Improvement in: 􀂉 Global disease activity - patient 􀂉 Global disease activity - physician 􀂉 Patient assessment of Pain 􀂉 Physical disability 􀂉 Acute phase reactants – CRP,ESR (Breedveld et al, 2006)

  19. A Randomised Evaluation oFLong-term Efficacy of rituXimab in RA REFLEX Emery et al. EULAR 2005

  20. Phase III study – TNF-IR patient population (Cohen et al, 2006)

  21. REFLEX ― ACR responses at Week 24 p<0.0001 60 MabThera+ MTX (n=298) Placebo + MTX (n=201) 51 50 40 p<0.0001 27 Patients (%) 30 p<0.0001 18 20 12 10 5 1 0 ACR20 ACR50 ACR70 (Cohen et al, 2006)

  22. REFLEX ― Overview of AEs through Week 24 (Cohen et al, 2006)

  23. REFLEX • Identified that MabThera provides a significant and clinically meaningful improvement to patients who have had an inadequate response to TNF inhibitors

  24. REFLEX – radiographic outcomes

  25. REFLEX study: Significant inhibition of radiological progression at 56 weeks* p=0.0046 p=0.0114 Mean change from baseline p=0.0006 *Patients with initial and at least 1 follow-up with linear extrapolation as required (Keystone et al, 2006)

  26. REFLEX • MabThera is the first and only therapy to have demonstrated a reduction in joint structural damage in patients with an inadequate response to TNF inhibitor treatment

  27. MabThera clinical trial programme as of 2006 at the time of biological license application

  28. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  29. Global approval for MabThera in RA WA17042/IDEC 102-20 RA patients failing anti-TNF therapies 2006Approval in both US and EU Global Filing WA17043/U2644g Phase IIb in active RA

  30. MabThera: A novel biological agent for the treatment of RA • The first and only selective B cell therapy in RA • Provides a fundamentally different treatment approach targeting a key player in the pathogenesis of RA • This approach offers lasting treatment success for RA patients, providing outstanding effects on structural damage, joints and fatigue with an unprecedented dosing interval

  31. Consensus Statement on the Use of Rituximab in Patients with Rheumatoid Arthritis Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N, Burmester GR, Dougados M, Ferraccioli G, Jaeger U, Klareskog L, Kvien TK, Martin-Mola E, Pavelka K. Ann Rheum Dis 2007;66:143–150

  32. Purpose of developing the guidelines • To establish: • Treatment objectives • Potential eligible patients • Contraindications • Screening for initiating rituximab • Dosing and co-medication • Definition of an adequate response • Criteria for repeated courses

  33. The DANCER study MabThera in RA Where are we now? Emery et al. EULAR 2005

  34. MabThera clinical trial programme van Vollenhoven et al. ACR 2008; Poster 361

  35. Extent of exposure with MabThera(all exposure)

  36. Duration of MabThera exposure

  37. Repeated courses of MabThera

  38. MabThera: Efficacy is maintained or further improved with repeat treatment courses Patients (%) (Keystone et al. ACR 2008)

  39. MabThera: Efficacy is maintained or further improved with repeat treatment courses Patients (%) (Keystone et al. ACR 2008)

  40. REFLEX: Significant inhibition of radiological progression at Weeks 56 and 104 p=0.0001 94% receivedMabThera before Wk 104 p=0.0003 Δ59 % p=0.0019 Δ63 % Mean TSS change 84% receivedMabThera before Wk 56 Δ54 % 94% receivedMabThera before Wk 104 Progression TSS=Total Sharp ScorePrimary analysis: radiographs outside time window included, linearextrapolation from Week 24 or 56 for missing values (Cohen et al, 2008; Keystone et al, 2006)

  41. Long-term safety: Serious infections remain stable with repeat courses Serious infections 18 15 12 Serious infections/100 pt-years 9 6 4.48 4.84 3 6.83 3.81 3.79 0 1 2 3 4 5 (n=2578) (n=1890) (n=1043) (n=425) (n=133) Course (van Vollenhoven R et al. ACR 2008; Poster 361)

  42. Incidence of serious infections/100 patient-years 0 2 4 6 8 10 MabThera-treated (n=2578) Biologic-treated (n=7664) (BSR Biologics Register) Biologic-treated (n=928) (German Biologics Register) DMARD-treated (n=1354) (British Biologics Register) DMARD-treated (n=601) (German Biologics Register) Long-term safety : Comparable incidence of serious infections per 100 patient-years Dixon et al. Arthritis Rheum 2005;52(Suppl.):5738Listing et al. Arthritis Rheum 2005;52:3403–3412 (Dixon et al, 2005; Listing et al, 2005; van Vollenhoven et al, 2008)

  43. 150 (81) 25 (13.5) 10 (6.7) Use of biologics after MabThera n=185 Median time from treatment with rituximab to another biologic: 7 months (0.5–37 months) Patients, n (%) * *Anakinra (n=9); Natalizumab (n=1) The median time from last MabThera infusion to another biologic was 7 months (range 0.5–37 months) (Genovese et al, 2008 )

  44. Serious infection rates before and after switch from MabThera to alternative therapy Overall serious infection rate: 4.31/100 pt-yrs (95% CI 3.77–4.92) No opportunistic or fatal infections 6.99 5.49 Serious infections(100 pt-yrs) (186.05 pt-yrs) (182.31 pt-yrs) The median time to SIE after initiating another biologic was 4 months (range 0–23 months) (Genovese et al, 2008)

  45. Development of MabThera in RA 2007 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pre- 1990 2008 2009

  46. The DANCER study Moving forward: DMARD-IR developmentSERENE and MIRROR studies Emery et al. EULAR 2005

  47. Efficacy and Safety of Rituximab (RTX)as First-Line Biologic Therapy in Patients (pts) with Active Rheumatoid Arthritis (RA): Results of a Phase III Randomized Controlled Study (SERENE) P. Emery, W.F. Rigby, B. Combe, K. Latinis, L.J. Szczepański, R.A. Roschmann, A. Chen, G.K. Armstrong, W. Douglass, H. Tyrrell Poster Presentation 364 Sunday 26 October 20089.00 AM – 11.00 AM Hall A

  48. Efficacy and Safety of Various Dosing Regimens of Rituximab in Patients with Active RA: Results of a Phase III Randomized Study (MIRROR)   A. Rubbert-Roth, P.P. Tak, S. Bombardieri,C. Zerbini, J-L. Tremblay, L. Carreño,S. Lacey, N. Collinson, J. Kalsi Poster Presentation 363 Sunday 26 October 2008 9:00 AM–11:00 AM Hall A

  49. Conclusions • MabThera in combination with MTX is an effective and well-tolerated first-line biologic therapy for active RA • MabThera – as a first-line biologic – in combination with methotrexate provided statistically significant and sustained clinically important improvements in physical function, fatigue, and health-related QoL in patients with active RA

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