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Efficacy in pivotal trials for MabThera® in RA

The Phase IIa proof of concept study provided strong early evidence in support of the efficacy of MabThera® against signs and symptoms of RA.1

  • At Week 24 the American College of Rheumatology 50% (ACR50) response rate following a single course of MabThera® plus methotrexate (MTX) combination therapy was 43% compared with 13% in patients treated with MTX alone (p=0.005).
  • Respective rates for the secondary ACR20 endpoint were 73% and 38% (p=0.003).
  • Good to moderate European League Against Rheumatism (EULAR) response rates were significantly higher in patients treated with MabThera® plus MTX compared with patients receiving MTX alone (83% vs. 50%, respectively; p=0.004).

MabThera® was subsequently investigated for the treatment of RA in two large controlled trials.

DANCER (Dose-ranging Assessment iNternational Clinical Evaluation of Rituximab in RA)

Further supporting evidence for the efficacy of MabThera® against RA signs and symptoms was provided by data from the Phase IIb DANCER trial:2

  • 54% of patients receiving MabThera® 2 x 1000 mg achieved an ACR20 response at Week 24, compared with only 28% of patients in the placebo arm (p<0.0001).
  • Of the patients receiving MabThera® 2 x 1000 mg, 34% achieved an ACR50 response compared with only 13% in the placebo group (p<0.001).
  • The highest response level (ACR70) was attained by 20% of patients who received MabThera® 2 x 1000 mg compared with only 5% of patients in the placebo arm (p≤0.001).
  • Although no dose-response relationship was established, there was an overall trend towards a higher proportion of patients achieving ‘high efficacy’ endpoints (ACR70, EULAR good response) in the MabThera® 2 x 1000 mg group compared with patients receiving MabThera® 2 x 500 mg.

REFLEX (Randomised Evaluation of Long-term Efficacy of rituXimab in RA)

Results from the Phase III REFLEX trial indicate that MabThera® is highly effective at relieving the signs and symptoms of RA in patients who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitors:3

  • The primary endpoint ACR20 measure was achieved by a significantly higher proportion of patients receiving MabThera® 2 x 1000 mg plus MTX compared with those in the placebo plus MTX group (p<0.0001) (Figure 1a).
  • The proportion of patients achieving the secondary endpoints ACR50 and ACR70 was significantly higher for MabThera® plus MTX-treated patients than for placebo plus MTX-treated patients (27% vs. 5% and 12% vs. 1% respectively; p<0.0001) (Figure 1a).
  • MabThera®-treated patients had a significantly greater reduction in disease activity score (DAS28) than patients treated with MTX alone (mean change in DAS28 from baseline: –1.9 vs.  –0.4 respectively; p<0.0001).
  • EULAR moderate and good responses were significantly better for MabThera®-treated patients compared with those on placebo (50% and 15%, respectively, vs. 20% and 2%; p<0.0001) (Figure 1b).
  • MabThera® also provided impressive benefits in terms of clinically significant reductions in swollen and tender joint counts at Week 24 (p<0.0001 for both measures); placebo-treated patients reported little or no improvement in these parameters.

In summary, the data from these trials provide strong evidence in support of the efficacy of MabThera® for alleviating the signs and symptoms of RA in patients who did not benefit from a TNF inhibitor therapy.

Figure 1: Responses to treatment in the REFLEX trial: (A) American College of Rheumatology (ACR) 20%, 50% and 70% improvement criteria; (B) European League Against Rheumatism (EULAR) treatment response criteria. EULAR moderate and good responses were significantly better in the MabThera® group compared to the placebo group (p<0.0001)3

Responses to treatment in the REFLEX trial

MabThera® leads the way as a targeted therapy in RA

Biomarkers predictive of treatment response offer the possibility of targeted therapy and personalised healthcare to ensure that patients receive the best care possible. Data from studies of MabThera® therapy in patients with an inadequate response to TNF inhibitors suggest that seropositivity for the autoantibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) may confer improved clinical benefit compared with patients negative for both.

  • After 24 weeks of MabThera® treatment in combination with MTX, patients who were seropositive to RF and/or anti CCP at baseline had a significantly higher probability of achieving an ACR20 and ACR50 response compared with seronegative patients (p<0.05 for both responses; Table 1).4
  • These findings were replicated at Week 48, where autoantibody seropositivity also significantly increased the probability of achieving an ACR70 response. At Week 48, seropositive patients were 2–3 times more likely to achieve ACR responses compared with seronegative patients.4
  • Seropositive patients had a significantly greater decrease in DAS28(ESR) over time compared with seropositive patients (Figure 2).4
  • Importantly, seronegative patients still derived a benefit from MabThera® therapy, with 62.9% and 72.3% achieving a good or moderate EULAR response at Weeks 24 and 48.4

Table 1: Summary of efficacy by baseline autoantibody status4

Change from baseline of DAS28-ESR by baseline autoantibody status

Figure 2: Change from baseline of DAS28-ESR by baseline autoantibody status4

Change from baseline of DAS28-ESR by baseline autoantibody status

Further insight into the use of baseline parameters to predict the response to MabThera® is provided by data from the SMART study:5

  • Data from the SMART study were analysed to identify biological parameters predictive of response to first course of MabThera® treatment in patients who had an inadequate response (n=194) or were intolerant to TNF inhibitor therapy (n=14).
  • Univariate analysis was performed to identify predictive factors of good or partial EULAR response in comparison with non-response at Week 24. Results with p-value <0.15 in this analysis were then included in a multivariate analysis adjusted on DAS28 level.
  • Multivariate analyses indicated that RF and anti-CCP positivity and serum IgG level above normal are predictive of response to MabThera® (Figure 3). Combining these predictive factors further increases the probability of response (Figure 4).

Figure 3: Predictive factors to good or partial response in multivariate analysis adjusted on DAS285

Figure 3: Predictive factors to good or partial response in multivariate analysis adjusted on DAS28

Figure 4: Response according to the presence of the number of independent predictive factors

Response according to the presence of the number of independent predictive factors

Registry data further support the efficacy of MabThera® in patients seropositive for RF and anti-CCP:6

  • Pooled data from 10 European registries including patients treated with MabThera® were analysed for predictors of treatment response and improvements in DAS28 (CERERRA).
  • MabThera® was associated with significant improvements in DAS28 at 6 months in seropositive patients compared with seronegative patients (Figure 5).
  • At 12 months, retreated patients had a significantly greater mean reduction in DAS28 compared with the same patients at 6 months (Figure 6). Retreated patients who were seropositive for both RF and anti-CCP achieved significantly greater reductions in DAS28 at 12 months compared with patients receiving a single course (–2.8 vs. –1.3; p<0.005).
  • Predictors of EULAR good response at 6 months were anti-CCP positivity (p=0.02), lower number of previous disease-modifying anti-rheumatic drugs (DMARDs) (p=0.0003) and lower number of previous biologics (p=0.001). Predictors of EULAR good response at 12 months were lower number of prior biologics (p=0.02) and lower HAQ score at baseline (p=0.01).

Figure 5: Mean change in DAS28 at 6 months by baseline autoantibody status6 

Mean change in DAS28 at 6 months by baseline autoantibody status

Figure 6: Mean reduction in DAS28 at 12 months compared to the same patients at 6 months6 

Figure 6: Mean reduction in DAS28 at 12 months compared to the same patients at 6 months

Six months clinical response following a single course

MabThera® provides 6 months of clinical response following a single course of therapy3

  • In the REFLEX trial, patients receiving a single course of MabThera® (2 x 1000 mg at Weeks 1 and 15) plus MTX continued to experience significant and clinically meaningful improvements in disease activity at Week 24.
  • ACR response rates at Week 24 were significantly higher in patients receiving MabThera® plus MTX compared with those receiving MTX alone (p<0.0001).
  • Improvements in DAS28 were maintained to Week 24 in MabThera®-treated patients and were significantly greater than patients on MTX alone from Week 8 through to the end of the study (Week 24) (Figure 7).
  • These results are particularly impressive given that patients had longstanding disease (~12 years) and previously had an inadequate response to an average of 1.5 TNF inhibitors.

Figure 7: DAS28 scores over 6 months following a single course of treatment in the REFLEX trial3

DAS28 scores over 6 months following a single course of treatment in the REFLEX trial

Treatment of patients with an inadequate response to TNF inhibitors

Results from large observational studies suggest that efficacy of TNF inhibitors may decline following cycling to a second or third TNF inhibitor. This is apparent in terms of both the proportion of patients responding to treatment and the ‘drug survival’ time (i.e. the length of response in those who initially responded).7,8

A longitudinal study of Swiss registry (SCQM-RA) data compared the effectiveness of MabThera® therapy with a TNF inhibitor cycling strategy in the management of patients with RA who had an inadequate response to one or more prior TNF inhibitors:

  • MabThera® therapy offered significantly greater improvements in DAS28 compared with an alternative TNF inhibitor, and significantly more MabThera®-treated patients experienced a clinically meaningful improvement in DAS28 (>1.2 units; p=0.001) (Figure 8).9
  • Further analyses demonstrated that in patients who discontinued a TNF inhibitor for lack of efficacy, the longitudinal improvement in DAS28 was significantly greater for MabThera® than for an alternative TNF inhibitor (p=0.03).10
  • The authors concluded that switching to a biologic agent of a different class, such as MabThera®, after an inadequate response to a TNF inhibitor may be more effective than switching to an alternative TNF inhibitor.10

Figure 8: Change in DAS28 for patients with an inadequate response to one or more TNF inhibitors switching to MabThera® therapy vs. switching to an alternative TNF inhibitor10

Change in DAS28 for patients with an inadequate response

MabThera® slows the rate of progression of structural joint damage

In the REFLEX study, patients originally randomised to MabThera® plus MTX demonstrated significantly less radiographic progression at 56 weeks than patients originally randomised to MTX alone (Figure 9).11 Of the patients originally randomised to MTX alone, 81% received MabThera® either as rescue between Weeks 16–24 or, in the extension trial, before Week 56.11 A clear separation of the treatment groups was apparent by 24 weeks, when changes in the joint space narrowing score had already reached significance (mean change in joint space narrowing score: 0.5 in the placebo group vs. 0.2 in the MabThera®-treated group; p=0.016).3 A higher proportion of patients originally randomised to MabThera® plus MTX had no erosive progression over 56 weeks versus the placebo plus MTX group (61% vs. 52%, respectively; p=0.0494).

Figure 9: Mean change in structural joint damage from baseline to 1 year for patients with an inadequate response to TNF inhibitors in the REFLEX study11

Mean change in structural joint damage

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years demonstrated significantly reduced progression of structural joint damage in patients receiving MabThera® in combination with MTX compared with MTX alone as well as a significantly higher proportion of patients with no progression of joint damage over the 2 year period.12

Efficacy is maintained or further improved with repeat treatment courses13,14

MabThera® offers the opportunity for further improvement with a repeat treatment course, thereby maximising patient response. Following completion of the 24-week double-blind comparative study period of the three trials of MabThera® in RA described above, patients were permitted to enrol into an open-label long-term follow-up study. Patients received subsequent courses of MabThera® as needed according to the treating clinician's assessment of disease activity and irrespective of the peripheral B lymphocyte count. The time interval between courses was variable, with the majority of patients receiving further therapy 6–12 months after the previous course. Some patients required even less-frequent retreatment.

  • Higher responses were seen after a second MabThera® treatment course compared with the initial course and efficacy was sustained over multiple courses of treatment. The proportion of patients achieving DAS28 low disease activity or remission doubled over four treatment courses (Figure 10).
  • Repeat courses of MabThera® showed consistent and sustained efficacy relative to baseline, with no clinically significant safety concerns in patients who had previously had an inadequate response to one or more TNF inhibitors.

Figure 10: Treatment responses to multiple courses of MabThera®14

Treatment responses to multiple courses of MabThera
 

References

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  2. Emery P, et al. Arthritis Rheum 2006; 54: 1390–1400.
  3. Cohen SB, et al. Arthritis Rheum 2006; 54: 2793–2806.
  4. MabThera® (rituximab) Summary of Product Characteristics. Roche Registration Limited.
  5. Sellam J, et al. Ann Rheum Dis 2010; 69(Suppl. 3): 68.
  6. Chatzidionysiou, K et al. Ann Rheum Dis 2010; 69(Suppl. 3): 380.
  7. Gomez-Reino JJ & Carmona L. Arthritis Res Ther 2006; 8: R29.
  8. Karlsson JA, et al. Rheumatology 2008; 47: 507–513.
  9. Finckh A, et al. Arthritis Rheum 2007; 56: 1417–1423.
  10. Finckh A, et al. Ann Rheum Dis 2010; 69: 387–393.
  11. Keystone E, et al. Ann Rheum Dis 2009; 68: 216–221.
  12. Cohen S, et al. Ann Rheum Dis 2010; 69:1158–1161.
  13. Keystone E, et al. Arthritis Rheum 2007; 56: 3896–3908.
  14. Keystone E, et al. ACR 2009; Abstract 1683.