This is an exciting program. Here is the abstract from the 2005 meeting followed by some interesting Editorial Comments from JHMC which may now have been superceded. I have also read somewhere that characterizing the safety profile and anti-IL6r Mab will need a lot of work, and that Roche/Chugai are likely to spend the money to get it done. (Some other interesting comments by JHMC on other results, like Blys. hopkins-arthritis.som.jhmi.edu )
Abstract L27 Blocking Interleukin-6 (IL-6) By Tocilizumab (A Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody) Monotherapy Reduces Joint Damage In Active Rheumatoid Arthritis (RA): Evidence From A X-Ray Reader -Blinded Randomised Controlled Trial
N Nishimoto, Jun Hashimoto, N Miyasaka, K Yamamoto, S Kawai, T Takeuchi, N Murata, D van der Heijde, T Kishimoto
Summarized by Clifton Bingham, M.D.
Background: IL-6 has been implicated as an important cytokine in the pathogenesis of RA. The cytokine is a potent inducer of acute phase reactants and is a multifunctional cytokine with affects on many other immunological and inflammatory cells including T cells, B cells, and osteoclasts. Previous studies (Arthritis Rheum 2004; 50(6): 1761) have reported the efficacy of a monoclonal antibody, tocilizumab, (also called MRA) directed against the IL6-receptor in patients with RA (see study summary), though these studies have not evaluated a radiographic endpoint. This study was designed to assess the ability of tocilizumab monotherapy to inhibit progression of structural joint damage, clinical efficacy and tolerability, in patients with active RA.
Methods: 306 patients with active early RA of <5 years’ duration were randomly allocated to receive either tocilizumab at 8 mg/kg IV every 4 weeks or conventional DMARDs for 52 weeks. In the control group, the dose, type and combination of DMARDs could be varied according to disease activity, but anti-TNF agents and leflunomide were not permitted. The efficacy endpoints included change from baseline to week 52 in van der Heijde modified Sharp score, evaluated by 2 readers blinded for treatment and order of films, and ACR response rates. Adverse events (AEs) and laboratory values were monitored for safety.
Results: A total of 302 patients (157 on tocilizumab and 145 on DMARDs) received study drugs. MTX was the most common treatment (80%) in the DMARDs group at study start. All baseline characteristics were similar in the two groups. Patients had a mean disease duration of 2.3 years, DAS28 score of 6.9 and CRP of 4.8 mg/dL at baseline, indicating very active disease. Mean Total Sharp Score (TSS) at baseline was 30.0, which was very high despite relatively short disease duration. At week 52, patients in the tocilizumab group showed statistically significantly less radiographic progression, as measured by change in TSS, than those receiving DMARDs (2.3 + 5.6 versus 6.1 + 11.4; p=0.001). Tocilizumab was superior to DMARDs in preventing both erosion and joint space narrowing (p<0.001 and p=0.018 respectively). The percentages of patients who achieved ACR20, 50 and 70 were 89%, 70% and 47% in the tocilizumab group and 35%, 14% and 6% in the DMARDs group (LOCF data; p<0.001, p<0.001, p<0.001 respectively). The overall incidences of AEs including laboratory abnormalities were 96% and 87% (serious AEs: 19% and 13%) in the tocilizumab and DMARDs groups, respectively. Nasopharyngitis, and mild, transient increases in LFTs were frequently observed in both groups. Lipid increases were predominantly reported in the tocilizumab group but the mean cholesterol level became stable (217 + 39.3 mg/dL) at around the normal upper limit. No tuberculosis was observed.
Conclusion: This study demonstrates an apparent slowing of radiographic progression with tocilizumab blocking IL6 compared to ad libitum administration of traditional DMARD therapy.
Editorial Comment: While the study suggests an effect of tocilzumab on slowing radiographic progression, the results of this study, concerning drug efficacy on signs and symptoms and X-ray endpoints, are to be interpreted with caution. This was not a traditional double-blind placebo-controlled study, but rather was open label in allocation with an unclear randomization strategy. The treatment in the traditional DMARD group was not standardized but could be varied or changed according to disease activity. This confounds interpretation of any treatment response on signs and symptoms. The baseline characteristics of the study population were notable for extremely high acute phase reactants and relatively early disease. The low efficacy responses noted in the DMARD group (far less than has been seen in other studies of effectively dosed MTX in other studies of early RA) and the lack of detail provided concerning drug dosages and details in the DMARD group make interpretation of differences between tocilizumab and a comparator group difficult to assess as the differences may reflect underdosing or less than aggressive clinical care in the comparator group. As in prior clinical trials, an effect of IL6 inhibition with tocilizumab has been an elevation in cholesterol measurements and LFTs. The clinical significance of these changes with long term administration needs to be determined. Additional studies are needed that use traditional randomized double-blind placebo-controlled study designs to better understand the efficacy of tocilizumab alone and in combination with other DMARDS on clinical and radiographic endpoints. |
