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A randomized, double-blind, placebo-controlled, parallel group study on the effects of a cathepsin S inhibitor in primary Sjögren's syndrome.

Authors
  • Bentley, Darren1
  • Fisher, Benjamin A2, 3
  • Barone, Francesca4
  • Kolb, Fabrice A5
  • Attley, Gemma6
  • 1 Certara UK Ltd, Sheffield, UK.
  • 2 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • 3 National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
  • 4 Candel Therapeutics, Needham, MA, USA.
  • 5 Galapagos GmbH, Basel, Switzerland. , (Switzerland)
  • 6 Roche Pharma Research and Early Development, Little Falls, NJ, USA.
Type
Published Article
Journal
Rheumatology (Oxford, England)
Publication Date
Nov 02, 2023
Volume
62
Issue
11
Pages
3644–3653
Identifiers
DOI: 10.1093/rheumatology/kead092
PMID: 36864622
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Primary SS (pSS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSS. This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily; 200 mg per day). Seventy-five patients with pSS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in EULAR SS Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to SS, and safety and tolerability. The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favour of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B cells and T cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated. There was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favour of RO5459072 in any of the secondary clinical endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSS. ClinicalTrials.gov; NCT02701985. © The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected].

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