IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab.

The combination of synthetic diseasemodifying anti-rheumatic drugs (sDMARDs) such as methotrexate (MTX) and biologic DMARDs (bDMARDs) targeting inflammatory cytokines such as tumour necrosis factor (TNF) has enabled markedly efficient control of disease activity in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR). Although TNF inhibitors have offered pivotal strategies for rheumatologists in daily practice and 20–50% of RA patients treated with TNF inhibitors achieve clinical remission within 6 months, the remaining patients still have active disease and progressive disability. IL-6 is also a pleiotropic cytokine with diverse activities and plays a central role in the pathogenesis of RA by contributing to T cell activation, B cell activation, synoviocyte stimulation, endothelial activation, osteoclast maturation and production of acute-phase proteins. Serum levels of IL-6 and soluble IL-6 receptor (IL-6R) are elevated and correlate with disease activity in RA patients and so blocking IL-6/IL-6R has been considered beneficial for the treatment of RA. In accordance with this, accumulated evidence has shown the clinical efficacy as well as the adequate safety of tocilizumab, a humanised anti-IL-6R monoclonal antibody (mAb), as monotherapy or in combination with sDMARDs such as MTX in patients who are sDMARD naive and have an inadequate response to TNF inhibitors (TNF-IR). Tocilizumab was, therefore, approved as a first-line bDMARD in patients responding insufficiently to MTX or other sDMARDs in Japan and Europe. Also, in the 2013 EULAR recommendations for the management of RA, tocilizumab was listed as a first-line TNF inhibitor in patients with sDMARD-IR. The successful treatment of RA by tocilizumab has encouraged the development of novel bDMARDs targeting IL-6 or IL-6R. In addition to tocilizumab, the phase II clinical trials of olokizumab, sarilumab and sirukumab, three new bDMARDs targeting IL-6, are reported. Olokizumab is a humanised anti-IL-6 mAb. Genovese et al report the findings of a 12-week phase IIb study to assess the safety and efficacy of subcutaneous olokizumab in RA patients with moderate-to-severe disease activity despite TNF inhibitors. A total of 221 patients were randomised to one of nine treatment arms receiving placebo or olokizumab (60, 120 or 240 mg) every 4 weeks (q4w) or every 2 weeks (q2w), or 8 mg/kg tocilizumab q4w. All patients received background MTX. Treatment with olokizumab met the primary endpoint (change from baseline in DAS28 C-reactive protein (CRP)) as compared to placebo at week 12 at all olokizumab doses tested (60 mg, p=0.0001; 120 mg and 240 mg olokizumab, p<0.0001). Olokizumab at various doses demonstrated similar efficacy to tocilizumab across multiple endpoints. The greatest improvement in DAS28-CRP scores was observed in the olokizumab 240 mg q2w group. In addition, pharmacokinetic modelling demonstrated a shallow dose–exposure response relationship in terms of the percentage of patients with DAS28<2.6. Olokizumab was also superior to placebo according to American College of Rheumatology (ACR) responses. Most treatment emergent adverse events (TEAEs) were comparable between the olokizumab and tocilizumab treatment groups, the incidence of serious TEAEs (SAEs) was similar between treatment groups, and no serious SAEs were reported by more than one patient. There was one recorded SAE of increased blood triglycerides in the tocilizumab group. Sarilumab is a human anti-IL-6Ra mAb. The results of a 12-week phase II study to assess the safety and efficacy of subcutaneous sarilumab are reported by Huizinga et al. A total of 306 patients with active RA despite MTX were randomised to one of six treatment arms receiving placebo or sarilumab (100 mg q2w, 150 mg q2w, 100 mg qw, 200 mg q2w or 150 mg qw for 12 weeks) with background MTX. The proportion of patients achieving the primary endpoint, an ACR20 response at week 12, compared to placebo was significantly higher for sarilumab 150 mg qw (72.0% vs 46.2%, multiplicity adjusted p=0.0203) and higher ACR20 responses were also attained with 150 mg q2w (67%; unadjusted (nominal) p=0.0363) and 200 mg q2w (65%; unadjusted p=0.0426) versus placebo. Infections were the most common TEAEs, although no serious infections were reported. At week 12, mean total cholesterol was higher in the four highest dose groups; the increase from baseline was 9.4%, 10%, 16.4% and 21.1%, respectively, in the 150 mg q2w, 100 mg qw, 200 mg q2w and 150 mg qw groups, compared to 4.9% in the placebo group. Sirukumab is a human anti-IL-6 mAb. Smolen et al report the findings of two parts of a phase II study to assess the safety and efficacy of subcutaneous sirukumab in patients with active RA despite MTX. In part A, the proof of concept study, 36 patients were randomised to placebo or sirukumab 100 mg q2w through week 10, with crossover treatment during weeks 12–22. In part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w. The primary endpoint (ACR50 at week 12 in part B) was achieved only with sirukumab 100 mg q2w (26.7% vs 3.3% with placebo; p=0.026). Greater improvements in the mean DAS28-CRP score at week 12 were observed with sirukumab 100 mg q2w versus placebo in parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). Through week 12 in parts A and B, the incidence of TEAEs was similar among the sirukumab and placebo groups. There were no reports of opportunistic infections, tuberculosis or gastrointestinal perforations. Changes in laboratory values, including neutropenia, liver transaminases and total cholesterol, were consistent with reports for tocilizumab. Promising findings in a phase IIb study using clazakizumab, a humanised anti-IL-6 mAb, for RA patients have also been previously reported. 19 The combination of MTX and clazakizumab (80, 160 and 320 mg intravenously at day 1 and week 8) was associated with rapid and The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan; Servicio de Reumatología, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Paseo de la Castellana 261, Madrid, Spain