RA Treatments - Other
- OP0020: Tocilizumab (anti IL-6) in in Patients with Active RA
- OP0021: Tocilizumab (anti IL-6) in Juvenile Idiopathic Athritis
- OP0022: Safety and Efficacy of a Human Monoclonal Antibody to IL-15 (AMG 714) in Patients with RA
- OP0018: Results of Humax-CD20 Fully Human Monoclonal IgG1 Antibody Treatment in RA
- OP0111: Efficacy and Safety of Subcutaneous vs. Oral Methotrexate
OP0020 Efficacy and Safety of Tocilizumab as Monotherapy, an Anti-IL-6 Receptor Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis (RA): Results from a 24 Week Double-Blind Phase III Study
Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, Kishimoto T.
Interleukin-6 (IL-6) is a very potent inflammatory cytokine involved in the pathogenesis of RA. Tocilizumab (TCZ) (previously known as MRA) is an antibody against the IL-6 receptor. This study investigated the safety and efficacy of tocilizumab as monotherapy in patients with active RA who previously had inadequate response to methotrexate (MTX) treatment.
Methods: Patients with active RA despite MTX 8mg/week (the recommended dose in Japan) were randomized to receive either TCA 8mg/kg q 4 weeks + placebo MTX (TCZ group) or placebo TCZ + MTX 8mg/week (MTX group) for 24 weeks. The primary efficacy endpoint was ACR20 improvement rate at 24 weeks. Safety was assessed by adverse events (AEs) and clinical laboratory results.
Results: Of 127 enrolled, 125 patients received at least one dose of study drug (61 in the TCZ group, and 64 in the MTX group). Baseline characteristics were similar between the groups (mean age, 50. 8 yrs; mean disease duration, 8.7 years). At 24 weeks, ACR 20/50/70 responses in the TCZ groups were all statistically significant superior to MTX (see Table below). Similar results were observed using EULAR response criteria./font>
| Treatment | ACR20 | ACR50 | ACR70 |
| TCZ group (n=61) | 80.3% | 49.2% | 29.5% |
| MTX group (n=64) | 25.0% | 10.9% | 6.3% |
| P value | < 0.001 | < 0.001 | < 0.001 |
The most common reported adverse event (AEs) in both groups was nasopharyngitis (TCZ 18.0% and MTX 10.9%). The number of serious AEs was similar between groups (TCZ n=4, MTX n=3). An increases in total and HDL cholesterol, as well as triglycerides, was observed in the TCZ group but became stable at around upper limit of normal. No tuberculosis was reported.
Conclusion: Monotherapy with tocilizumab for 24 weeks improved signs and symptoms in patients with RA who had failed MTX. Tocilizuab and was generally well tolerated.
Editorial Comment: MTX is still considered fairly toxic in Japan, and their regulatory agency has mandated a maximum dose of 8 mg/wk of MTX. One can not conclude, therefore, from this clinical trial that tocilizumab is more efficacious than MTX since this low dose (8 mg/wk) of MTX was employed. The MTX arm may be more rightfully considered a placebo arm. When considered as such, the efficacy of tocilizumab is impressive, equivalent to the anti-TNF agents. These ACR responses are consistent with previous small clinical trials of tocilizumab in RA and JRA. In a previous trial several serious infections were reported. That does not appear to be the case in this clinical trial. Whether IL-6 inhibition will confer any advantage over TNF inhibition remains to be seen.
OP0021 A MULTI-CENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY OF TOCILIZUMAB, AN ANTI-IL-6 RECEPTOR MONOCLONAL ANTIBODY, IN CHILDREN WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS
S. Yokota, T. Imagawa, M. Mori, S. Takei, Y. Kawano, N. Iwata, M. Tomiita, M. Miyoshi, Y. Aihara, T. Murata, D. Abukawa, N. Nishimoto, T. Kishimoto
Open-label studies have suggested that tocilizumab (also known as MRA), a fully humanized monoclonal antibody directed against the IL-6 receptor, is a safe and effective therapy for systemic juvenile idiopathic arthritis (sJIA). Here, Yokota et al report results a double-blind study of maintenance tocilizumab in patients with sJIA with an initial response to the drug.
Methods: Subjects 2 19 years of age meeting ILAR classification criteria for sJIA with active disease despite treatment with corticosteroids were enrolled in an initial 6 week, open-label phase in which tocilizumab 8 mg/kg was administered every 2 weeks. Those meeting responder criteria were then randomized to continue at the same dose of tocilizumab or switch to placebo for an additional 12 weeks. Time to loss of response was the primary outcome measure with placebo treated subjects treated with active drug when their initial response was lost.
Results: 56 subjects were enrolled into the initial 6 week open-label phase. 50 subjects completed the run-in phase without an adverse event requiring withdrawal from the study. Of these 50 subjects, 44 entered the double-blind, randomized portion of the study in which 20 subjects were randomized to continue active treatment and 23 subjects were switched in a blinded fashion to placebo. 43 subjects were analyzed (one subject was removed due to unintentional un-blinding)
At baseline, the majority of subjects were female (62.5%) with a mean age of 8.3 years. Subjects had a mean disease duration of 4.5 years and a serum CRP concentration of 5.69 mg/dL at entry. Of the 56 subjects enrolled in the run-in phase, the proportion of subjects meeting JIA 30, 50, and 70 responses was 96%, 90%, and 72%, respectively. Two serious adverse events occurred in the open-label run-in phase: a case of anaphylaxis to the study drug and a GI bleed, both of which resolved with discontinuation of the study drug.
During the 12 week randomized phase, 80% of subjects in the tocilizumab group maintained their initial response, compared to 17.4% of subjects switched to placebo. Two subjects, one in each of the study groups, were withdrawn secondary to adverse events: one subject in the active treatment group with EBV infection and one subject in the placebo group with VZV infection. The remaining subjects (18 in the placebo group and 3 in the active treatment group) were removed secondary to disease flares. Median time to loss of response was > 12 weeks in the active treatment group compared to 4.9 weeks in the placebo group. Other adverse events were mild and included mild infections and asymptomatic elevations of LFTs in approximately one quarter of subjects. No cases of tuberculosis were reported.
Conclusions: Tocilizumab therapy is safe and effective at maintaining treatment response in subjects with active, difficult to manage sJIA with an initial favorable treatment response.
Editorial Comment: These are encouraging findings for a disease that can be difficult to treat in some patients, as the effects of IL-6, a highly inflammatory cytokine, can be intolerant to the effects of corticosteroids, conventional DMARDs, and in some cases, TNF inhibitors. The high proportion of initial responders and the effective maintenance of response are the most important aspects of these reported results. However, longer term studies are needed to fully evaluate whether efficacy can be sustained and, perhaps more importantly, long-term safety of the drug. Other issues, such as the need for concomitant DMARDs, have not been addressed in the literature to date. In addition, head-to-head studies evaluating the safety and efficacy of TNF inhibitor therapies vs. anti-IL-6 therapies have yet to be performed.
OP0022 Safety and Efficacy of a Human Monoclonal Antibody to IL-15 (AMG 714) in Patients with Rheumatoid Arthritis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
McInnes I, Martin R, Zimmermann-Gorska I, et al.
Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is present in the synovium of patients with rheumatoid arthritis (RA). AMG 714 is a human monoclonal IgG1-kappa antibody that binds human IL-15 and inhibits IL-15-induced effector functions. This Phase II study was undertaken to evaluate the safety and efficacy of AMG 714 for the treatment of RA.
Methods: Eligible patients with active RA who had previously failed > 1 DMARD, but were nave to biologic RA therapies, were enrolled. Stable, limited doses of NSAIDs, oral corticosteroids, and MTX were allowed, but other DMARDs were washed out. Patients were randomly assigned to receive one of four doses of AMG 714 (40, 80, 160, or 280 mg) or placebo by SQ infusion every 2 weeks for 12 weeks. The primary outcome was ACR20 response in the 280-mg AMG 714 vs placebo group at week 14. Secondary endpoints included proportions of ACR 20 responders at weeks 12 and 16 and levels of acute phase reactants. Safety reports were also collected.
Results: 180 patients were enrolled: 110 with the original protocol, and 70 following protocol amendment. Efficacy was evaluated in 114 patients (280-mg AMG 714, N = 56; placebo, N = 58), and safety was evaluated in 179 patients. The primary outcome at 14 wks was not met, but ACR20 responses in the AMG 714 were superior to placebo at the secondary time points (wks 12 and 16). [See table below.]
| Proportion of Subjects Achieving an ACR 20 Response | |||
| Treatment | Wk 12 | Wk 14 | Wk 16 |
| 280-mg AMG714 | 64% | 54% | 66% |
| Placebo | 34% | 38% | 38% |
| P value | 0.003 | NS (0.10) | 0.003 |
Levels of acute phase reactants decreased more with 280-mg AMG 714 than placebo beginning at week 4 (CRP, p < 0.0001; ESR, p = 0.005). AMG 714 was well tolerated. 4% of AMG 714 treated patients had serious AEs compared to 3% in the placebo group. Serious infections were reported in 2 patients: 1 in the placebo group (viral bronchitis) and 1 in the 80-mg AMG 714 group (sepsis). No deaths occurred.
Conclusion: Although the primary efficacy endpoint was not met (14 wks), the overall clinical results suggest efficacy of AMG 714 in the treatment of DMARD-refractory RA. The safety profile of AMG 714 was similar to that of placebo, with doses up to 280 mg being well tolerated.
Editorial Comment: These ACR20 responses are fairly modest. Furthermore, the investigators did not provide ACR50 and 70 responses; these likely would not have been different between the two groups. Unless there is a chance that a higher dose of anti-IL-15 mAb would be more efficacious, further development of this drug would not seem prudent given the very competitive market in RA. As for proof of concept, the mild ACR responses and the marked decreases in inflammatory markers in response to IL-15 inhibition does support a contribution of IL-15 to the pathophysiology of rheumatoid arthritis.
P0018 First Clinical Results of Humax-CD20 Fully Human Monoclonal IgG1 Antibody Treatment in Rheumatoid Arthritis (RA)
Ostergaard M, Wiell C, Dawes PT, Rigby W, Petersen J, Kastberg H, Sierakowski S.
B cells, via their role in producing antoantibodies, are believed to be important in the pathogenesis of RA. There is currently one FDA approved therapy to target and deplete B cells that is, rituximab, a chimeric murine-human anti-CD20 monoclonal antibody. A new anti-CD20 antibody in development, HuMax-CD20, differs from rituximab in that it targets a novel epitope on the CD20 molecule and is a fully human (rather than chimeric) molecule. The results presented here are from an ongoing double-blind, randomized, placebo-controlled multicenter phase I/II safety study in RA.
Methods: Patients with active RA, who have previously failed >1 DMARDs, received two infusions of either HuMax-CD20 (300, 700 or 1000 mg) or placebo 2 weeks apart. Stable doses of methotrexate and low dose corticosteroid were continued. Endpoints were adverse events (AE) and efficacy including ACR and EULAR responses at wk 24.
Results: Of the 39 patients treated (mean age 53, mean duration of RA 12 years), 36 were RF positive, 26 patients were previously received TNFainhibitors, and median tender and swollen joint counts were 16 and 12, respectively. Blinded safety data were presented for all doses, and unblinded data for the 300 mg cohort (12 HuMax and 3 placebo). In the 300 mg cohort, 2 patients had serious infusion related AEs (anaphylactoid reaction and urticaria), and 3 had bronchospasm. As a result, corticosteroid prophylaxis was intensified. In the 700 and 1000 mg dose group no treatment-related SAEs were reported. Most non-serious AEs where observed on the first infusion day: 13 of 15 (87%) patients in the 300 mg group, 9 of 12 (75%) patients in the 700 mg group and 7 of 12 (58%) patients in the 1000 mg group. These included rash, nausea, pyrexia and hypotension. Correspondingly, 3, 4 and 0 patients reported adverse events on the second infusion day. ACR responses from the 300 mg cohort were presented but the number of patients treated was very small (only 3 placebo).
Conclusion: The authors concluded that these are encouraging results.
Editorial Comment: It is ironic that this compound, being a fully human monoclonal antibody, might be expected to be less immunogenic than rituximab, which has murine components. However, in this small preliminary study, there seemed to be more significant infusion reactions than with the chimeric antibody. The protocol had to be amended twice such that patients would receive corticosteroids the day before and the day of the HuMax infusion. This will clearly be a limiting feature of this compound. Interestingly, the higher doses of HuMax appeared to be less immunogenic; this is true for most proteins wherein low concentrations are more immunogenic than higher concentrations. A similar trend was observed in the original studies of infliximab by Maini et al.
OP0111 THE CLINICAL EFFICACY AND SAFETY OF SUBCUTANEOUS (S.C.) VERSUS ORAL APPLICATION OF METHOTREXATE (MTX) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (RA) - RESULTS OF A RANDOMIZED, CONTROLLED, DOUBLE-BLIND, MULTI-CENTER STUDY
J. Braun, P. Kaestner, P. Flaxenberg, J. Waehrisch, P. Hanke, W. Demary, U. Von Hinueber, K. Rockwitz, W. Heitz, C. Guimbal-Schmolck, U. Pichlmeier, A. Brandt.
Oral vs. subcutaneous (sq) administration of methotrexate is generally considered equivalent in rheumatoid arthritis (RA) treatment. However, the enhanced bioavailability of sq methotrexate may make this route of administration preferable to the oral route in certain patients. Here, Braun et al report the findings of the first multi-center, prospective, randomized, blinded trial of oral vs. sq methotrexate in methotrexate nave patients with RA.
Methods: Methotrexate and biologic-DMARD nave RA patients with high disease activity (defined as a DAS28 > 4) were blindly randomized to one of two groups:
- oral methotrexate (po MTX) 15 mg weekly oral methotrexate + placebo injection
- sq methotrexate (sq MTX) 15 mg weekly sq methotrexate + oral placebo
A rescue arm was utilized, such that subjects in the po MTX group who had not achieved an ACR20 response by week 16 were blindly crossed over to the sq MTX group. Subjects in the sq MTX group not achieving an ACR20 response at 16 weeks had their sq MTX dosage increased to 20 mg per week.
Results: 187 and 188 subjects (384 total) were randomized to the po MTX and sq MTX groups, respectively. Subjects were primarily female (74 79%) with a mean age of 59 years. RA disease characteristics included a mean disease duration of 2.1 2.5 months and high baseline disease activity (mean DAS28 > 6.0). Baseline characteristics were balanced between the two treatment groups. Eighty-nine percent of enrolled subjects completed the 24 weeks of the study with the proportion of completers balanced between the two treatment allocations. Twenty subjects in the po MTX group were rescued at 16 weeks and were crossed over to sq MTX, while 22 subjects in the sq MTX group had their sq MTX dosage increased to 20 mg per week at that time.
Efficacy endpoints tended to favor the sq MTX group:
| po MTX n=187 |
sq MTX n=188 |
p | |
| ACR20 | 70% | 78% | 0.04 |
| ACR50 | 54% | 62% | ns |
| ACR70 | 33% | 41% | ns |
| EULAR remission | 24% | 34% | <0.05 |
There was no difference in safety or toxicity between the two groups.
Conclusions: The clinical efficacy of subcutaneous methotrexate is superior to the orally administered form without an increase in adverse events.
Editorial Comment: This is the first placebo-controlled, double-blind study to evaluate the efficacy of oral vs. sq methotrexate in early RA. One aspect of this study that may be missed are the overall excellent responses achieved with only a moderate dose of methotrexate, highlighting the potency of methotrexate as a DMARD which can often be overlooked in clinical trials that typically enroll only subjects with inadequate responses to methotrexate. While these results seem to suggest that sq methotrexate should be chosen first choice over oral, one issue with the study design may compromise these conclusions. The methodologic design of the rescue arm favors the sq methotrexate group, in that, on average, approximately 10% of the subjects in this group received a 25% higher dose of methotrexate than did those in the oral group (who could never receive a dose higher than 15 mg as part of the protocol). This difference could be responsible for the observed differences in the two groups. A sub-analysis excluding the rescue subjects would help to answer this discrepancy.