Jeffrey Siegel

Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial

BACKGROUNDnSystemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis.nnnMETHODSnWe did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years duration from first non-Raynauds sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869.nnnFINDINGSnWe enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3·92 in the tocilizumab group and -1·22 in the placebo group (difference -2·70, 95% CI -5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was -6·33 in the tocilizumab group and -2·77 in the placebo group (treatment difference -3·55, 95% CI -7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.nnnINTERPRETATIONnTocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits.nnnFUNDINGnF Hoffmann-La Roche, Genentech.

The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis.

Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs).

Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

Objectives Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. Methods Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162u2009mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. Results Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95%u2009CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95%u2009CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95%u2009CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10%u2009absolute decline in %pFVC. Serious infection rates/100 patient-years (95%u2009CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. Conclusions Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. Trial registration number NCT01532869; Results.

OP0054 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis: Week 48 Data from the Fasscinate Trial

Background Systemic sclerosis (SSc) is a debilitating disease with limited treatment options. Data indicate a key role for interleukin-6 (IL-6) in the pathogenesis of SSc.1,2 In murine models of SSc, IL-6 receptor (IL-6R) inhibition prevented and reversed skin fibrosis.3,4 Objectives To assess safety and efficacy of the IL-6R inhibitor tocilizumab (TCZ) in pts with SSc. Methods In this first double-blind, placebo-controlled, phase 2, proof-of-concept study, the effect of inhibiting IL-6 in SSc was explored. Pts ≥18 y with active SSc (1980 ACR criteria,5 ≤5 y disease duration, modified Rodnan skin score (mRSS) 15-40, and elevated acute-phase reactants) were randomized 1:1 to TCZ 162 mg or placebo (PBO) subcutaneously (SC) wkly for 48 wks. Primary end point was mean change in mRSS from baseline at wk 24. Mean change in mRSS at wk 48, pt-reported outcomes (PROs), and pulmonary function at wk 48 were secondary/exploratory measures. Results 87 pts (43 TCZ, 44 PBO) were enrolled. Baseline characteristics were similar between arms including mean [SD] mRSS (TCZ 26 [7.2]; PBO 26 [5.9]). At wk 24, a favorable but not statistically significant effect of TCZ over PBO on mRSS was noted (–3.9 vs –1.2; adjusted mean difference, –2.7 [95% CI: –5.85, 0.45], p=0.09; Table). At wk 48, a numerically larger change was noted in the TCZ vs PBO arm (–6.3 vs –2.8; adjusted mean difference, –3.6 [95% CI: –7.23, 0.12], p=0.06). Though not statistically significant, higher proportions of TCZ vs PBO pts had mRSS improvement from baseline of ≥20% (40% vs 27%), ≥40% (21% vs 7%), or ≥60% (12% vs 0). There were numerically greater improvements in the TCZ arm than in the PBO arm for PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48 (Table). The proportion of pts with HAQ-DI improvement ≥0.22 was 28% (12/43) in the TCZ arm and 7% (3/44) in the PBO arm at wk 48 (p=0.01). Fewer TCZ vs PBO pts showed a decline in % predicted forced vital capacity (%FVC <0; 57% vs 84%) and a >10% absolute decrease in %FVC (10% vs 23%; Table) at wk 48. Adverse events (AEs)/serious AEs occurred in 98%/33% of TCZ and 91%/34% of PBO pts by wk 48. One death occurred in the PBO arm and 3 deaths in TCZ pts by wk 48; all were unrelated to study drug except for a fatal lung infection in 1 TCZ pt. Conclusions Treatment with TCZ resulted in consistent, but not statistically significant, improvements in skin sclerosis (mRSS) at wks 24 and 48 and in PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48. A trend toward less FVC decline with TCZ than with PBO noted at wk 24 persisted at wk 48. Observed AEs were consistent with SSc complications and the safety profile of TCZ. Overall, the effect of TCZ on skin sclerosis, PROs, and pulmonary function and the observed safety profile suggest a positive risk/benefit profile for TCZ in SSc and support further evaluation of TCZ in pts with SSc. References J Rheumatol 1998;25:308. Pathobiology 1993;61:239. Am J Pathol 2012;180:165. Arthritis Rheum 2014:66:S1312. Arthritis Rheum 1980;23:581. Disclosure of Interest D. Khanna Grant/research support from: Actelion, Bayer, BMS, EMD Seerono, Gilead, InterMune, NIH/NIAMS, NIH/NIAID, Scleroderma Foundation, Pulmonary Hypertension Association, Consultant for: Actelion, Bayer, BMS, EMD Serono, InterMune, Biogen Idec, Genentech/Roche, Cytori, Lycera, Sanofi-Aventis/Genzyme, GSK, C. Denton Grant/research support from: Roche, Novartis, Consultant for: Roche, Actelion, GlaxoSmithKline, A. Jahreis Shareholder of: Roche, Employee of: Genentech, J. van Laar Consultant for: Pfizer, Tigenix, Novartis, Roche, Eli Lilly, S. Cheng Employee of: Genentech, H. Spotswood Shareholder of: Roche, Employee of: Roche, J. Pope: None declared, Y. Allanore Grant/research support from: Actelion, BMS, Genentech/ Roche, Inventiva, Pfizer, Servier, Consultant for: Actelion, Bayer, Biogen Idec, BMS, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, UCB, U. Müller-Ladner Consultant for: Roche, Chugai, Speakers bureau: Roche, Chugai, J. Siegel Employee of: Roche, D. Furst Grant/research support from: Genentech, Consultant for: Genentech

Patient acceptable symptom state in scleroderma: results from the tocilizumab compared with placebo trial in active diffuse cutaneous systemic sclerosis

ObjectivesnPatient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo.nnnMethodsnData from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR.nnnResultsnThe placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms? showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023).nnnConclusionnPASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis

At present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SSc (dcSSc).

Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis

Objectives Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor. Methods We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains. Results The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways. Conclusions We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases. Trial registration number NCT01532869; Post-results.

The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis: ACR Provisional Composite Index for Scleroderma Clinical Trials

Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs).

Development of a Composite Index for Clinical Trials in Early Diffuse Cutaneous Systemic sclerosis-the Combined Response Index in Systemic Sclerosis.

This free journal suppl. entitled: Special Issue: 2014 ACR/ARHP Annual Meeting Abstract Supplement