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Expanded Horizons: Long-Term Treatment with Selective B Cell Therapy

Expanded Horizons: Long-Term Treatment with Selective B Cell Therapy. Paul Emery arc Professor of Rheumatology, Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK. Rituximab. Efficacy demonstrated in Phase II/III trials

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Expanded Horizons: Long-Term Treatment with Selective B Cell Therapy

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  1. Expanded Horizons: Long-Term Treatment with Selective B Cell Therapy Paul Emery arc Professor of Rheumatology, Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK

  2. Rituximab • Efficacy demonstrated in Phase II/III trials • Long-term efficacy and safety are being explored in an ongoing extension study • As of September 2006, a total of 1053 RA patients had been exposed to rituximab in the clinical programme

  3. Questions • Can B cell targeted therapy be safe long-term? • Will there be tachyphylaxis? • What happens to B cell depleted non-responders? • Why do some patients not respond? • What determines time of relapse?

  4. Protocol Design for Open-Label Extension Study of Rituximab in RA Open-label extension study of rituximab treatment Phase II/III Course 3 Repeated courses Course 1 of rituximab Course 2 Rituximab 2 x 1000 mg Placebo Rituximab 2 x 1000 mg The timing of repeat treatment courses were variable, depending on clinical need Phase IIa Rituximab 2 x 1000 mg + cyclophosphamide Rituximab 2 x 1000 mg + methotrexate Rituximab 2 x 1000 mg Long-term follow-up Placebo Rituximab 2 x 500 mg + methotrexate Phase IIb DANCER Rituximab 2 x 1000 mg + methotrexate Placebo Phase III REFLEX Rituximab 2 x 1000 mg + methotrexate All patients in the open-label extension study received weekly methotrexate (10–25 mg) and methylprednisolone100 mg on Days 1 and 15 plus oral prednisone 60 mg/day on Days 2–7 and 30 mg/day on Days 8–14

  5. Repeated Treatment Courses With Rituximab (as of September 2006) 101 228 235 92 28 C1 n=1053 C2 n=684 C3 n=400 C4 n=142 C5 n=41 C6 n=11 C7 n=1 235 42 20 8 2 35 14 3 1 0 Treatment course number n=no. of treated patients Patients awaiting next course Withdrawal due to AE or illness Withdrawal due to Other cause C, treatment course

  6. Duration of Rituximab Exposure

  7. Subset Analysis for Efficacy ≥3 courses of RTX (1 g x 2) + MTX with an IR to TNF inhibitors* 2 or more courses of RTX 1 or more courses of RTX No. patients with>24 weeks FU post 3rd course 3 or more courses of RTX 210 97 400 1053 684 94 57 Patients receiving ≥3 courses of rituximab (1 g x 2) + MTX with an IR to DMARDs* *Patients who had initially received rituximab (0.5 g x 2) + MTX or Rituximab monotherapy were excluded from the efficacy analyses

  8. How Effective are Repeated Courses of Rituximab in Patients with an Inadequate Response or Intolerance to DMARDs?

  9. Patients With Prior TNF inhibitors: Disease Activity Over Time Observed data; n=73 at baseline and n=16 at Week 24 Only patients with 4 treatment courses at each visit included

  10. Patients With Prior TNF inhibitors: ACR Response at Week 24 Patients (%) Versus original baseline Versus course baseline Week 24, n=96 Keystone, et al. Ann Rheum Dis 2007;66(Suppl. II):432

  11. Patients With Prior TNF Inhibitors: Patients Achieving Good Response, Low Disease or Remission at Week 24 Patients (%) Week 24, n=97 Keystone, et al. Ann Rheum Dis 2007;66(Suppl. II):432

  12. DMARD Inadequate Responder Population: Patients Achieving Good Response, Low Disease Activity and Remission Patients (%) Week 24, n=57 Emery, et al. Ann Rheum Dis 2007;66(Suppl. II):430

  13. Median Time Between Courses of Treatment Median time between courses (weeks)

  14. Long-Term Efficacy Summary • Comparable or improved degree of sustained efficacy with repeat treatment courses

  15. What is the Safety Profile of Rituximab Over Repeated Courses?

  16. Rates of Adverse Events by Treatment Course

  17. Incidence of Acute Infusion Reactionsa Over Repeated Courses Patients (%) aDefined as pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema,throat irritation, cough, bronchospasm, hypotension, or hypertension van Vollenhoven, et al. Ann Rheum Dis 2007;66(Suppl. II):88

  18. Incidence of Infections • 702 patients (67%) experienced ≥1 infection • The most common infections were upper respiratory tract infections, including nasopharyngitis (32%), and urinary tract infections (11%) • No opportunistic infections, viral reactivations or tuberculosis were observed

  19. Infection Rates by Treatment Course 101 97 85 80 Infections/100 patient-years 5.4 6.3 5.4 4.6

  20. Patients With IgM <LLN by Treatment Course a a Insufficient data beyond Week 24 LLN = lower limit of normal

  21. IgM RF Levels Over Time by Treatment Course RF = rheumatoid factor

  22. Proportions of Patients With IgG <LLN by Treatment Course a a Insufficient data beyond Week 24

  23. Serious Infection Rate by Ig Concentration *Defined as a serious AE and/or requiring iv antibiotics

  24. Tetanus Ab Titre: Change Over Time and by Treatment Course (n = 622) (n = 394) PriorTNF inhibitor (n = 431) (n = 290) No prior TNF inhibitor

  25. Malignancies • A total of 36 high- and low-grade malignancies (18 in C1, 13 in C2, 4 in C3 and 1 in C4) occurred in 32 pts (3%), of which 4 had a fatal outcome (duodenal cancer, adenocarcinoma, pancreatic cancer, myelodysplastic syndrome) • No lymphoproliferative malignancies and no increased risk of malignancy with additional courses of treatment were observed

  26. Subsequent TNF Inhibitors After Rituximab Therapy • 78 patients received subsequent TNF inhibitor therapy • Etanercept (n=23) • Infliximab (n=23) • Adalimumab (n=26) • Multiple TNF inhibitors (n=7) Breedveld, et al. Ann Rheum Dis 2006;65(Suppl. II):178; Roche, data on file

  27. Serious Infection Rate in Patients who Received TNF Inhibitors Subsequent to Rituximab (n=78) BSR biological register: serious infection rate with de novo TNF inhibitors = 6.4 per 100 patient-years Serious infections/100 patient-years (n, 95% CI) 7.62 5.23 Total exposure:57.4 Pt -years Total exposure:52.5 Pt-years CI = confidence interval * n= 4 infections (cellulitis, bacterial arthritis, erysipeles, viral meningitis)

  28. Serious Infection Rate in Patients Treated with TNF inhibitors Artis registry (n=4167) 12 10 8 7.0 Infections leading to hospitalisation / 100 patient-years (n, 95% CI) 6 4.5 4 2 0 First TNF inhibitor Second TNF inhibitor CI = confidence interval Askling J. Arthritis Rheum Dis 2007;66:1339-1344

  29. TNF Inhibitors Subsequent to Rituximab Therapy (n=78) • Median time to switch: 181 days (23–695) • Type of infections and clinical course typical for RA patients • No opportunistic infections, TB, or viral reactivation • Patients in whom a switch to another biological therapy is considered within 4 months (time of response assessment) of the last rituximab infusion should be closely observed for signs of infection

  30. Loss of Response and Return of B Cells Emery et al Ann Rheum Dis 2007;66(Suppl.II):124

  31. Multivariate Analysis • The risk of losing EULAR response doubled when peripheral CD19+ B-cell depletion ended independently of other significant factors: • Weekly MTX (Y/N), whether response began at Wk 12 or later, extent of reduction in DAS28 at onset of response, and HAQ-DI at baseline • Age, sex, RA duration, peripheral B-cell count at baseline, and use of CTX were non significant factors for duration of response.

  32. Temporal Sequence of Peripheral CD19+ B Cell Return Relative to Loss of EULAR Response (LOR)

  33. Time to Loss of EULAR Response by Study Regimen • The use of MTX, as compared with cyclophosphamide or RTX monotherapy, enhanced duration of response.

  34. Time to Peripheral CD19+ B Cell Return Among Patients with EULAR Response • In patients in whom peripheral CD19+ B cell depletion ended prior to LOR, • end of depletion occurred a median of 32 weeks (95% CI 24-40) before LOR.

  35. Limitations • LoR taken at 104 weeks, different earlier • Conventional assay used Questions • If depletion of B cells necessary, how come relapse before repletion? • If return of B cells is not always associated with relapse, which other factors relevent?

  36. B cell Response to Rituximab Therapy Absolute Count (109/L) B cells Pre Plasma Cells 1 Standard-sensitivity flow cytometry 0.1 0.01 0.005 Before Treatment Before 2nd Dose After Treatment Before Treatment Before 2nd Dose After Treatment

  37. B cell Response to Rituximab Therapy Absolute Count (109/L) B cells Pre Plasma Cells 1 High-sensitivity 6-Colour flow cytometry 0.1 0.01 0.001 0.0001 Before Treatment Before 2nd Dose After Treatment Before Treatment Before 2nd Dose After Treatment

  38. High Sensitivity Flow Detects B Cells in Patients Considered Depleted by Standard Methods Median baseline level of B cells 0.07 x 109/L (0.023 –0.21 x 109/L) At week 2, 50% of detectable cells were PPC Dass, et al. Ann Rheum Dis 2006;65(Suppl. II):185

  39. B Cell Depletion at 2 Weeks Predicts Depth of Clinical Response Dass, et al. Arth Rheum 2006;54(Suppl.):S832

  40. Peripheral Blood B Cell Status at 6 Months:No Effect on Later Clinical Response Dass, et al. Arth Rheum 2006;54(Suppl.):S832

  41. Level of Initial B Cell Depletion (Day 15) in PB Correlates with Later Synovial B Cell Expression Dass, et al. Ann Rheum Dis 2007;66(Suppl. II):90

  42. Safety Summary This further update on the long-term follow-up of patients with RA receiving rituximab showed a safety profile consistent with that reported previously • Reduced incidence and severity of infusion reactions • No increase in the rate of serious infections • No opportunistic, viral reactivation or tuberculosis • Respectively 25% and 6% of patients had low IgM and low IgG at some point post rituximab • Rates of serious infections were all consistent with those expected with biologic RA therapy

  43. Conclusions • B cell targeting has emerged as a rational interventional approach to the treatment of RA • Rituximab, the first and only B cell-targeted therapy approved for the treatment of RA, provides long-term efficacy with a consistent safety profile over repeated courses • Understanding of the mechanism action of response is ongoing

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