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

Abstract

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 162 mg 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% CI)) 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% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) 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.

Keywords: DMARDs (biologic); interleukin-6; scleroderma; systemic sclerosis (SSc); tocilizumab; treatment.

Conflict of interest statement

Competing interests: DK reports personal fees from Actelion, Boehringer-Ingelheim, Covis, CSL Behring, Corbus, Cytori, EMD Serono, Genentech/Roche, GSK, Inventiva, Medac, Sanofi-Aventis and UCB; grants from BMS, Bayer and Pfizer; stocks in Eicos Sciences, Inc, during the conduct of the study; and personal fees from Astra Zeneca outside the submitted work. CPD reports personal fees from Roche, Actelion, EMD Serono, Sanofi and Boehringer Ingelheim; grants and personal fees from GSK and Inventiva; and grants from CSL Behring during the conduct of the study. CJFL is an employee of Genentech. JMvL reports grants and personal fees from MSD and Genentech and personal fees from BMS, Eli Lilly and Pfizer outside the submitted work. MEA reports funding to Hospital Trust from Roche during the conduct of the study and personal fees from Actelion Pharmaceuticals outside the submitted work. YA has received research support and grants related to the submitted work from BMS, Roche/Genentech, Inventiva, Pfizer and Sanofi; consulting honoraria and personal fees related to the current work from Actelion, Bayer, Boehringer, Roche/Genentech, Galapagos, Inventiva, Medac, Pfizer, Sanofi, Servier and UCB; and personal fees outside the submitted work from Sandoz. JEP reports funding for the current trial by Roche. GR has received lecturer’s fees from Roche and Chugai outside the submitted work. UM-L is a speaker and advisor to Roche and Chugai related to the submitted work. HS is an employee of and has non-voting shares in Roche Products Limited. LB is an employee of Roche. JS is an employee of Genentech. AJ is an employee of Genentech, owns stock and options in Roche and owns a patent for subcutaneous tocilizumab. All other authors have no conflicts of interest to disclose.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Patient disposition (intent-to-treat population). *Methotrexate, n=5; hydroxychloroquine, n=2; mycophenolate mofetil, n=5. †Methotrexate, n=2; hydroxychloroquine, n=2; mycophenolate mofetil, n=1. ‡One patient who continued as an escape patient at week 48 was later removed by the site and was not included at week 96. §Methotrexate, n=1; hydroxychloroquine, n=1; mycophenolate mofetil, n=4 (1 patient who received mycophenolate mofetil in the double-blind period and received it again in the open-label period was not counted in the open-label period). ¶Hydroxychloroquine, n=2; mycophenolate mofetil, n=2. OL, open-label; QW, every week; SC, subcutaneously; TCZ, tocilizumab.

Figure 2

Mean change (95% CI) in mRSS from baseline to week 96 (intent-to-treat population; observed data). Negative values denote improvement. Patients randomly assigned to PBO 162 mg QW SC received OL TCZ 162 mg QW SC from week 48. BL, baseline; DB, double-blind; mRSS, modified Rodnan Skin Score; OL, open-label; PBO, placebo; %pFVC, per cent predicted forced vital capacity; QW, every week; SC, subcutaneously; TCZ, tocilizumab.

Figure 3

Cumulative distribution plot of change from baseline in %pFVC (completers analysis). Data for TCZ 162 mg QW SC and PBO 162 mg QW SC treatment groups show change from baseline to week 48. Patients receiving PBO-TCZ 162 mg QW SC and continuous-TCZ 162 mg QW SC started OL TCZ from week 48 (mean (SD) %pFVC at week 48 was 0.78 (0.14) for the PBO group and 0.80 (0.11) for the TCZ group), and change from week 48 to week 96 is shown. Only patients with data at week 96 are included in any arm (completers); one completer had a missing FVC assessment at week 96 and was excluded from the completers analysis. DB, double-blind; OL, open-label; PBO, placebo; %pFVC, per cent predicted forced vital capacity; QW, every week; SC subcutaneously; TCZ, tocilizumab.