Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis

Bruce Kirkham, Khaldoun Chaabo, Christopher Hall, Toby Garrood, Timothy Mant, Elizabeth Allen, Alexandra Vincent, Joana C. Vasconcelos, Andrew T. Prevost, Gabriel S. Panayi*, Valerie M. Corrigall

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Objectives. Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. Methods. Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. Results. No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15mg groups, and not patients who received placebo or 1mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. Conclusion. BiP (≤15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study.

Original languageEnglish
Pages (from-to)1993-2000
Number of pages8
JournalRheumatology
Volume55
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • BiP
  • Changes in biomarkers
  • CRP
  • Efficacy
  • First-in-human trial
  • IL-8
  • Prolonged activity
  • Regulatory cells
  • Safety
  • VEGF

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