Rheumatoid Arthritis - Anti B-Cell Therapies
Rituximab, a monoclonal antibody that targets B lymphocytes, has been approved for the treatment of RA in patients who fail to respond to TNF antagonists. Several questions remain regarding the optimal dose, frequency of administration, and effects on immune responses. We have selected 2 studies from the ACR meeting highlighting dosing of rituximab.
Abstract 363 - Efficacy and Safety of Various Dosing Regimens of Rituximab in Patients with Active RA: Results of a Phase III Randomized Study (MIRROR)
Authors
Andrea Rubbert-Roth, PP Tak, S Bombardieri, C Zerbini, J-L Tremblay, L Carreño, S Lacey, N Collinson, J Kalsi.
Purpose:
To evaluate the efficacy and safety of 3 dosing regimens of rituximab (RTX) in combination with methotrexate (MTX) in patients (pts) with active RA.
Methods:
Patients with active RA in spite of background MTX were randomized to 1 of 3 treatment regimens comprising two courses of RTX given 24 wks apart: reduced dose (RD; 2 x 500 mg, 2 x 500 mg), dose escalation (DE; 2 x 500 mg, 2 x 1000 mg), and standard dose (SD; 2 x 1000 mg, 2 x 1000 mg). The primary endpoint was proportion of patients achieving ACR20 at Week 48. Secondary endpoints included ACR50, ACR70, and EULAR responses.
Results:
378 patients were randomized with 346 receiving per-protocol treatment (134 RD, 119 DE, 93 SD). There was no difference in ACR response rates between any of the 3 regimens at week 48; however, significantly more standard dose patients achieved EULAR Good/Moderate responses (p=0.0297). In patients who had received a prior biologic, the standard dose regimen was associated with endpoint outcomes that were numerically higher than those for the reduced dose regimen. Only the ACR50 achieved statistical significance (Table), with p-values derived from exploratory analyses and without adjustment for multiple significance testing. Through 48 weeks all 3 RTX regimens were well tolerated and demonstrated comparable safety. The fixed re-treatment at Week 24 did not lead to an increase in infusion-related reactions. Rates of serious infections were 3.36, 4.73, and 2.36 events/100 pt-yr for RD, DE, and SD, respectively.
|
All patients (modified ITT) |
|||
Week 48 endpoints, % pts |
RD |
DE |
SD |
|
ACR20 |
62 |
64 |
71 |
|
ACR50 |
37 |
39 |
48 |
|
ACR70 |
19 |
19 |
23 |
|
EULAR moderate/good response |
72 |
72 |
88* |
|
*p<0.05 vs RD (Cochran–Mantel–Haenszel test). |
||||
Conclusions:
At 48 weeks a 2 course regimen using RTX at a reduced dose of 2 x 500 mg for each course was not shown to be different from the standard dose (2 courses of 2 x 1000 mg) or dose escalation (2 x 500 mg; 2 x 1000 mg) regimens.
Editorial Comment:
The data from this study and from the SERENE Study below both indicate that lower doses of 500 mg per infusion are associated with similar efficacy to higher doses of 1000 mg per infusion. This study raises questions as to the optimal dose needed. Based on the available data, we still do not know if even lower doses of RTX may have efficacy in RA. It is hoped that additional studies will be performed to evaluate the lowest effective dose of the drug for most patients with RA. With additional compounds in development that target CD20, ocrelizumab and ofatumumab and TRU015, these questions may be answered to some extent, but additional study of even lower doses of Rituximab, which is currently available, seems warranted. In this study there was no difference in AEs between the groups but whether total or specific immunoglobulin depletion, infection risk, etc. could be decreased further with an even lower dose is also an important question.
Editor: Clifton Bingham, M.D.
Abstract 364: Efficacy and Safety of Rituximab as First-Line Biologic Therapy in Patients with Active Rheumatoid Arthritis: Results of a Phase III Randomized Controlled Study (SERENE)
Authors:
P Emery, WF Rigby, B Combe, K Latinis, L J Szczepański, RA Roschmann, A Chen, GK Armstrong, W Douglass, H Tyrrell
Purpose:
To evaluate the efficacy and safety of RTX combined with methotrexate (MTX) in patients with active RA with an inadequate response to MTX and naïve to prior biologic therapy.
Methods:
Patients with active RA on background MTX (10-25 mg/wk) were randomized to infusions of either RTX 500 mg, RTX 1000 mg, or placebo (PL), infused on day 1 and 15, with each infusion preceded by methylprednisolone (100 mg IV). From Weeks 16 to 23, patients could receive rescue therapy with 1 additional nonbiologic DMARD; rescue patients were considered nonresponders in the primary analysis. From Week 24, patients not in DAS28 remission (DAS ≥2.6) received a second course of RTX, with patients initially randomized to PL switched to RTX 500 mg. The primary endpoint was the proportion of pts achieving an ACR20 response at Wk 24. Secondary endpoints included changes in DAS28 and EULAR responses at both Weeks 24 and 48.
Results:
Of 512 patients randomized, 509 (167 RTX 500 mg, 170 RTX 1000 mg, 172 PL) comprised the primary ITT efficacy population. Rescue therapy was given to 8% PL, 4% RTX 500 mg, and 2% RTX 1000 mg pts. Less than 1% of patients withdrew due to lack of efficacy in the RTX groups vs 4% in the PL group. At Week 24, both doses of RTX showed superior efficacy to PL (Table). Responses to both RTX doses generally improved from Week 24 to 48. RTX was well tolerated, demonstrating comparable safety to PL through Week 24, and between RTX doses through Week 48. The most common AEs were infusion-related reactions (IRRs). The incidence of IRRs for the first infusion (D 1) was numerically higher in the RTX 1000 mg vs the 500 mg group (25% vs 19%, respectively). There were no serious IRRs with either RTX dose. The rate of serious infection was 2.62 and 1.95 events/100 pt-yr in the RTX 500 mg and 1000 mg groups, respectively, vs 8.81 events/100 pt-yr in the PL group.
Endpoints, % patients |
Placebo |
RTX 1000 mg |
RTX 500 mg |
|||
|
Wk24 |
Wk48 |
Wk24 |
Wk48 |
Wk24 |
Wk48 |
ACR20 |
23 |
- |
55*** |
57 |
51*** |
59 |
ACR50 |
9 |
- |
26*** |
33 |
26*** |
36 |
ACR70 |
5 |
- |
9 |
13 |
10 |
14 |
EULAR Moderate/Good |
34 |
- |
67*** |
75 |
64*** |
71 |
Low Disease Activity (DAS28 ≤ 3.2) |
5 |
- |
17** |
20 |
12* |
24 |
DAS28 Remission (< 2.6) |
2 |
- |
10** |
9 |
9** |
11 |
Wk 24 comparisons vs PL ***p<0.0001, **p<0.01, *p <0.05 |
||||||
Conclusion:
These results show that RTX in combination with MTX is an effective and well-tolerated agent for active RA in patients who have not yet received a TNF antagonist.
Editorial Comment:
Rituximab is currently approved for the treatment of patients who have not responded to TNF antagonists. In the prior Phase IIB dose-ranging study of RTX evaluating the efficacy of RTX in DMARD inadequate responders (DANCER) almost 30% of the patients had previously received TNF antagonists. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM; DANCER Study Group. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006 May;54(5):1390-400. ) There are limited data on dosing or efficacy in a population of patients who are naïve to other biological DMARDS. The results from the SERENE study are remarkably similar to the ACR 20/50/70 results reported for DANCER. As in the earlier study, there was little difference in efficacy between the two doses of RTX. It remains to be seen whether there will be any changes in recommended starting doses based on the results of now three studies evaluating lower doses of RTX at 500 mg per infusion (DANCER, MIRROR reviewed above, and SERENE) showing similar efficacy to 1000 mg per infusion.
Editor: Clifton Bingham, M.D.
