Olivier Harari

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial

Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). Methods This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. Results In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: −0.21; 95% CI −0.35 to −0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). Conclusions Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. Trial registration number: NCT00988221.

Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials

Objectives BUILDER-1 and BUILDER-2 aimed to assess the efficacy and safety of tocilizumab (TCZ) in patients with ankylosing spondylitis (AS). Methods BUILDER-1 was a two part, phase II–III parallel-group trial in patients with AS naive to antitumour necrosis factor (aTNF) treatment. Patients in part 1 received TCZ 8 mg/kg or placebo for 12 weeks. In part 2 (beginning after part 1 enrolment ended), newly enrolled patients received TCZ 4 or 8 mg/kg or placebo for 24 weeks. The same treatment arms were used in BUILDER-2, a phase III study in aTNF-inadequate responders. The primary endpoint for both studies was the proportion of patients achieving 20% improvement in the Assessments in Axial SpondyloArthritis international Society (ASAS). Secondary and exploratory endpoints included ASAS40 response rates, Bath Ankylosing Spondylitis Disease Activity Index improvement, changes in joint counts, enthesitis score and C reactive protein (CRP). Results 102 patients were randomised in BUILDER-1 part 1; 99 (48 TCZ, 51 placebo) completed 12 weeks. Week 12 ASAS20 response rates were 37.3% and 27.5% in the TCZ and placebo arms, respectively (p=0.2823). Secondary and exploratory endpoints did not differ between treatment arms. CRP levels declined with TCZ treatment, suggesting adequate IL-6 receptor blockade. As a result, BUILDER-1 part 2 and BUILDER-2 were terminated. TCZ safety results were consistent with previous observations in rheumatoid arthritis, except for a cluster of anaphylactic and hypersensitivity events at Bulgarian study sites. No apparent explanation for this clustering could be found. Conclusions BUILDER-1 failed to demonstrate TCZ efficacy in treating aTNF-naive patients with AS. Clinical trial registration numbers: NCT01209702 and NCT01209689 (www.clinicaltrials.gov).

Design of the Tocilizumab in Giant Cell Arteritis Trial

Overview. The GiACTA trial is a multicenter, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA). Design. Approximately 100 centers will enroll 250 patients with active disease. The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension. Patients will be randomized into one of four groups. Group A (TCZ 162 mg weekly plus a 6-month prednisone-taper); group B (TCZ 162 mg every other week plus a 6-month prednisone-taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper). We hypothesize that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy endpoint of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids. Conclusion. GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA. The objective of this paper is to describe the design of the trial and address major issues related to its development.

IL-6 Receptor Inhibition Positively Modulates Bone Balance in Rheumatoid Arthritis Patients with an Inadequate Response to Anti-Tumor Necrosis Factor Therapy: Biochemical Marker Analysis of Bone Metabolism in the Tocilizumab RADIATE Study (NCT00106522)

OBJECTIVE To evaluate changes in biochemical markers of bone metabolism in response to tocilizumab in patients with anti-tumor necrosis factor-refractory rheumatoid arthritis (RA). METHODS RADIATE was a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. C-reactive protein, osteocalcin (OC), C-terminal telopeptides of type-I collagen (C-terminal telopeptides of type-1 collagen (CTX-I) and type-I collagen degradation product), and matrix metalloproteinase-3 (MMP-3) serum levels were analyzed from 299 RA patients. Patients were randomly assigned to either tocilizumab (4 or 8 mg/kg) or placebo intravenously every 4 weeks, along with concomitant stable methotrexate (10 to 25 mg weekly) in all treatment arms. The change in biochemical markers CTX-I and OC in combination was evaluated as a measure of net bone balance, a reflection of the change in equilibrium between resorption and formation. RESULTS Both tocilizumab doses decreased C-reactive protein levels and significantly inhibited cathepsin K-mediated bone resorption in RADIATE subjects, as measured by a decrease in CTX-I. There was a significant overall improvement in net bone balance at week 16 as measured by a decrease in the CTX-I:OC ratio (-25%, P < 0.01). Furthermore, a significant reduction in MMP-3 (43%, P < 0.001) and type-I collagen degradation product levels (18%, P < 0.001) were observed following treatment, both consistent with decreased MMP-mediated type-I collagen catabolism in joint tissue. CONCLUSIONS In anti-tumor necrosis factor-refractory patients, tocilizumab significantly reduced the levels of biochemical markers of cathepsin K-mediated bone resorption and MMP-mediated tissue degradation and remodeling. These observations suggest that tocilizumab has a positive effect on bone balance, which could in part explain the retardation of progressive structural damage observed with tocilizumab. Clinical trial registry number: NCT00106522.

IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis

Objectives To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab. Design Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response. Results Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response. Conclusions Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.

Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.

OP0166 Tocilizumab (TCZ) is not effective for the treatment of ankylosing spondylitis (AS): Results of a phase 2, international, multicentre, randomised, double-blind, placebo-controlled trial

Background Interleukin-6 (IL-6) has been shown to be elevated in patients (pts) with AS and correlates with disease activity.1 Case reports concerning the use of TCZ in pts with AS have been published.2-5 The efficacy and safety of TCZ, an inhibitor of IL-6 receptor signalling, as a treatment for AS have not been evaluated in a placebo-controlled trial. Objectives To examine the efficacy and safety of TCZ for the treatment of AS. Methods Study Design: Phase 2, multicentre, randomised, double-blind, placebo-controlled study, 12-week (wk) duration. Patients: Definite diagnoses of AS by the modified New York criteria and Bath AS Disease Activity Index (BASDAI) score ≥4.0; adults who were NSAID inadequate responders (IR) and anti-TNF naive. Study Drugs: TCZ 8 mg/kg or placebo (PBO) IV every 4 wks. Primary Endpoints: 20% improvement in assessment of AS (ASAS20) response and safety at wk 12. Results Of 102 pts enrolled, 99 (48 TCZ, 51 PBO) completed 12 wks. Pt demographics and disease status were in keeping with the target population (Table). The proportion of pts achieving ASAS20 and ASAS40 at wk 12 was not significantly different for TCZ vs PBO (37% vs 28%, p=0.2823; 12% vs 20%, p=0.2694) (Table). No differences between TCZ and PBO were observed for (1) higher percentage ASAS responses, (2) change in individual ASAS components, (3) BASDAI endpoints. These findings were independent of baseline CRP level. There was a reduction in CRP and in AS Disease Activity Score (ASDAS)–CRP with TCZ but not PBO (difference in median CRP change between arms, –1.2 mg/dl, p<0.0001; difference in mean ASDAS-CRP change between arms, –0.9, p<0.0001). Rates/100 patient-years of adverse events (AEs) for TCZ and PBO were 262.4 and 226.9; rates of serious AEs were 17.5 and 0. No AEs led to withdrawal during this 12-wk study. TCZ 8 mg/kg (N=51) PBO (N=51) Demographics, n (%)  Age, mean (range) 41.6 (23-69) y 42.7 (19-84) y  Sex M 36 (71)/F 15 (29) M 40 (78)/F 11 (22)  HLA-B27 status Positive 43 (84.3) Positive 45 (88.2) Negative 8 (15.7) Negative 6 (11.8)  Disease duration ≤10 y 39 (76.5) ≤10 y 34 (66.7) >10 y 12 (23.5) >10 y 17 (33.3)  Baseline BASDAI, mean (range) 6.62 (2.9-9.5) 6.77 (4.2-9.7) Efficacy Endpoint, n (%)  ASAS20 19 (37.3) 14 (27.5)  ASAS20 (baseline CRP <3× ULN) 6 (23.1) 6 (27.3)  ASAS20 (baseline CRP ≥3× ULN) 13 (52.0) (27.6)  ASAS40 6 (11.8) 10 (19.6)  BASDAI (<4) 1 (2.0) 0 (0.0)  BASDAI50 3 (5.9) 5 (9.8)  ASDAS-CRP (mean change) –1.40 –0.44 Conclusions The study failed to demonstrate the efficacy of TCZ over placebo for the treatment of symptoms of AS, irrespective of baseline CRP level. CRP levels declined with TCZ, suggesting adequate IL-6R blockade. The change in ASDAS-CRP was driven by the decrease in CRP. The safety profile of TCZ in this study was consistent with that seen in RA pts. References Gratacόs J et al. Br J Rheumatol 1994;33:927-31. Brulhart L et al. Joint Bone Spine 2010;77;625-6. Henes JC et al. Ann Rheum Dis 2010;69:2217-8. Shima Y et al. Mod Rheumatol 2011;21:436-9. Cohen JD et al. J Rheumatol 2011;38:1527. Disclosure of Interest J. Sieper Grant/Research support from: Abbott, Merck, Pfizer, Consultant for: Abbott, Merck, Pfizer, UCB, Roche, Sanofi, Speakers Bureau: Abbott, Merck, Pfizer, B. Porter-Brown Shareholder of: Roche, Employee of: Roche, L. Thompson Shareholder of: Roche, Employee of: Roche, O. Harari Employee of: Roche, M. Dougados Grant/Research support from: Roche, Consultant for: Roche, Speakers Bureau: Roche

FRI0132 Insulin resistance is improved by tocilizumab therapy in rheumatoid arthritis: results from the toward study

Background Insulin resistance is increased in rheumatoid arthritis (RA). Reductions in inflammation, glucocorticoid therapy and disease-modifying anti-rheumatic drugs (DMARDs) have been associated with improvement in insulin resistance in patients with RA. Objectives To study whether tocilizumab (TCZ) therapy, an IL-6 receptor-inhibiting monoclonal antibody, improves insulin resistance in patients with RA. Methods TOWARD was a phase 3 study in patients with moderate to severe active RA on stable oral DMARDs that compared TCZ 8 mg/kg to placebo with 2:1 randomisation. Insulin resistance was calculated using the homeostatic model (HOMA-IR). Insulin resistance was classified as a HOMA-IR ≥2.2. Associations of baseline HOMA-IR against variables were analysed using linear regression. We examined associations between baseline HOMA-IR and baseline demographics, cardiovascular disease risk factors and disease-related factors using linear regression. Associations between change in HOMA-IR and change in RA disease parameters were also analysed using regression. Results Of the 1123 patients in the study, HOMA-IR could be calculated in 893 (79.5%). Median (IQR) age, glucose, insulin and HOMA-IR were 54 (46-62) years, 5.1 (4.6-5.6) mmol/l, 7.6 (4.6-12.6) µU/ml and 1.7 (1.0-2.9), respectively. 328 patients (37%) had insulin resistance. In an age- and gender-adjusted analysis, baseline HOMA-IR was associated with older age, higher BMI, SBP and DBP as well as IL-6 level (β-coefficient [95% CI]; 0.01 [0.01, 0.02] per pg/dl), RF positivity (0.25 [0.12, 0.38]) and lower IL-6 receptor levels (–0.02 [–0.02,–0.01] per ng/dl). HOMA-IR was reduced over 24 weeks in patients with insulin resistance who received TCZ but not in those who received placebo (Table). Image/graph Conclusions Insulin resistance is common in RA patients with inadequate response to DMARDs and is associated with RF positivity and IL-6 levels. In patients with pre-existing insulin resistance, HOMA-IR was significantly improved by TCZ therapy while unchanged by placebo. Understanding the mechanistic links between IL-6 and insulin regulation may provide an additional rationale for a stratified approach to using biologics to reduce cardiovascular disease risk in patients with RA. Disclosure of Interest H. Mirjafari Employee of: Roche Products Ltd, J. Wang Employee of: Roche Products Ltd, M. Klearman Employee of: Genentech, a member of the Roche group, O. Harari Employee of: Roche, I. Bruce Grant/research support from: UCB, Roche, GSK, Genzyme/Sanofi, Consultant for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Paid instructor for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Speakers bureau: Pfizer, UCB, GSK, Human Genome Sciences, Roche

A54: Insulin Sensitivity Is Improved in sJIA Children With Insulin Resistance After Tocilizumab Treatment: Results From the TENDER Study

In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin‐6 (IL‐6) is postulated to play a mechanistic role in IR. The aim of this study was to evaluate the degree of IR among children with systemic juvenile idiopathic arthritis (sJIA) and to determine whether treatment with tocilizumab (TCZ) results in attenuation of IR in sJIA.

PReS-FINAL-2188: Insulin sensitivity is improved in sjia children with insulin resistance after tocilizumab treatment: results from the tender study.

In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin-6 (IL-6) is postulated to play a mechanistic role in IR.