Abstract L15: IL-6 Receptor Inhibition with Tocilizumab Reduces Disease Activity in Patients with Rheumatoid Arthritis with Inadequate Response to a Range of DMARDs: The TOWARD Study
Alan N. Baer, M.D.
Authors:
M. Genovese, J. McKay, E. Nasonov, E. Mysler, N. da Silva, E. Alecock, T. Woodworth, J. Gomez-Reino.
Background:
Interleukin-6 (IL-6) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and is a novel therapeutic target in this disease. TOWARD is a large multinational study that examined the efficacy and safety of tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, in patients with moderate to severe active RA with an inadequate response to a range of disease-modifying antirheumatic drugs (DMARDs).
Methods:
Patients with active RA despite treatment with one or more traditional DMARDs were eligible to participate in this 24 week phase III, randomized (2:1), placebo-controlled study. The 1216 study participants continued stable doses of DMARDs and received TCZ 8 mg/kg or placebo (PBO) intravenously, every 4 weeks for 24 weeks.
Results:
At week 24, the composite ACR20, ACR50, and ACR70 responses were significantly higher in the TCZ group vs. placebo (Table). At week 2, there was already a measurably higher ACR20 response rate and improvement in CRP and hemoglobin levels in the TCZ arm. The incidence of adverse events (AEs) was 72.8% in the TCZ group and 61.1% in the placebo group. Serious AEs were reported in 6.7% of the TCZ and 4.3% of the placebo group. AE leading to withdrawal were low in both groups (TCZ: 3.9% and placebo: 1.9%). Overall infection rate (per 100 patient years) was 1.2 in the TCZ group and 0.95 in the placebo group. Serious infections were reported in 2.7% of the TCZ group and 1.9% of the placebo group. Among the more frequent AEs, hypertension was noted among 5.0% of the TCZ group and 2.7%of the placebo group. One percent of patients in the TCZ group and none in the placebo group had transient elevation > 3xULN, with only 1 patient withdrawing. These patients had an elevated baseline ALT. Elevated total cholesterol was observed in 22.9% of the TCZ group and 5.6% of the placebo group, with increased LDL in 16.1% and 3.4% of patients, respectively. Improvement in HDL was observed in 15.0% of the TCZ group and 6% of the placebo group. The ApoB/ApoA atherogenic index was unchanged.
Week 24 results |
Tocilizumab |
Placebo |
p-value |
ACR 20 response (%) |
60.8 |
24.5 |
p<0.0001 |
ACR 50 response (%) |
37.6 |
9.0 |
p<0.0001 |
ACR 70 response (%) |
20.5 |
2.9 |
p<0.0001 |
Patients with DAS28 <2.6 (%) |
30.2 |
3.4 |
p<0.0001 |
Mean change in DAS28 |
-3.17 |
-1.16 |
p<0.0001 |
Mean change in HAQ-DI |
-0.47 |
-0.20 |
p<0.0001 |
Mean change CRP (mg/dL) |
-2.19 |
-0.27 |
p<0.0001 |
Mean change ESR (mg/dL) |
-35.6 |
-4.7 |
p<0.0001 |
Conclusions:
The study confirms that TCZ is highly effective in reducing articular and systemic symptoms and has a favorable risk/benefit profile when combined with background DMARDs.
Editorial Comment:
The TOWARD and OPTION studies, both presented at this meeting, examined the therapeutic efficacy and safety of toclizumab in patients with rheumatoid arthritis. Patients who had inadequate responses to methotrexate were eligible for the OPTION study and patients who had failed to respond to one or more traditional DMARDs were eligible for the TOWARD study. Both studies demonstrated substantial clinical benefit of tocilizumab when compared to placebo. These studies thus demonstrate that inhibition of IL-6 signaling is an effective therapy for RA and that IL-6 is important in the pathogenesis of RA. It will be important to determine whether tocilizumab retards radiographic progression of RA.
The most important safety concerns related to the use of tocilizumab have been significant elevations of the serum hepatic transaminases and lipid levels. In earlier clinical trials of tocilizumab, dose-related increases in the mean serum transaminase levels were observed during tocilizumab treatment, with a sawtooth pattern of rise and fall between infusions. In the TOWARD study reported here, elevations of the serum ALT to levels 3-times the upper limit of normal were observed in a small number of tocilizumab-treated patients with baseline ALT elevations. These elevations proved transient and prompted only one patient to be withdrawn from the study. Similarly, elevations of the serum cholesterol and of the LDL occurred in a significant proportion of the tocilizumab-treated patients. However, the ApoB/ApoA ratio remained unchanged as a result of concomitant elevations of serum HDL levels. The ApoB/ApoA ratio is a much better indicator for heart attack risk than standard cholesterol measurements. Thus this study suggests that the two safety signals related to tocilizumab therapy may not be associated with short-term morbidity. However, additonal studies will be needed to assess the long-term hepatic and cardiovascular risks of tocilizumab therapy.
