1. Academic Validation
  2. A randomised, double-blind, placebo-controlled study of the LAG-3-depleting monoclonal antibody GSK2831781 in patients with active ulcerative colitis

A randomised, double-blind, placebo-controlled study of the LAG-3-depleting monoclonal antibody GSK2831781 in patients with active ulcerative colitis

  • Aliment Pharmacol Ther. 2023 Aug;58(3):283-296. doi: 10.1111/apt.17557.
Geert D'Haens 1 Laurent Peyrin-Biroulet 2 Daniel J B Marks 3 Edoardo Lisi 4 Lia Liefaard 5 Andrew Beaton 6 Naren Srinivasan 7 Gerben Bouma 8 Naveen Prasad 9 Raymond Cameron 10 Zeid Kayali 11 Ruth Tarzi 12 Stephen Hanauer 13 William J Sandborn 14
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • 2 Inserm NGERE and Department of Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-les-Nancy, France.
  • 3 GSK, Discovery Medicine, GSK Medicine Research Centre, Stevenage, UK.
  • 4 GSK, Biostatistics, GSK Medicines Research Centre, Stevenage, UK.
  • 5 GSK, Clinical Pharmacology Modelling and Simulation, GSK Medicines Research Centre, Stevenage, UK.
  • 6 GSK, Clinical Sciences, Medicines Research Centre, London, UK.
  • 7 GSK, Immunology Research Unit, Stevenage, UK.
  • 8 GSK, Clinical Pharmacology and Experimental Medicine, GSK Medicines Research Centre, Stevenage, UK.
  • 9 GSK, Computational Biology, Genomic Sciences Group, Stevenage, UK.
  • 10 GSK, Clinical Sciences, GSK, London, UK.
  • 11 ACE Endoscopy, Suite C Inland Empire Liver Foundation, Rialto, California, USA.
  • 12 GSK, Clinical Sciences, Medicines Research Centre, Stevenage, UK.
  • 13 Northwestern University Feinberg School of Medicine, Northwestern Medicine Digestive Health Center, Chicago, Illinois, USA.
  • 14 Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA.
Abstract

Background: Selective depletion of T cells expressing LAG-3, an immune checkpoint receptor that is upregulated on activated T cells, has been investigated in pre-clinical models as a potential therapeutic approach in inflammatory and autoimmune diseases where activated T cells are implicated.

Aims: GSK2831781, a depleting monoclonal antibody that specifically binds LAG-3 proteins, may deplete activated LAG-3+ cells in ulcerative colitis (UC).

Methods: Patients with moderate to severe UC were randomised to GSK2831781 or placebo. Safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GSK2831781 were evaluated.

Results: One hundred four participants across all dose levels were randomised prior to an interim analysis indicating efficacy futility criteria had been met. Efficacy results focus on the double-blind induction phase of the study (GSK2831781 450 mg intravenously [IV], N = 48; placebo, N = 27). Median change from baseline (95% credible interval [CrI]) in complete Mayo score was similar between groups (GSK2831781 450 mg IV: -1.4 [-2.2, -0.7]; placebo: -1.4 [-2.4, -0.5]). Response rates for endoscopic improvement favoured placebo. Clinical remission rates were similar between groups. In the 450-mg IV group, 14 (29%) participants had an adverse event of UC versus 1 (4%) with placebo. LAG-3+ cells were depleted to 51% of baseline in blood; however, there was no reduction in LAG-3+ cells in the colonic mucosa. Transcriptomic analysis of colon biopsies showed no difference between groups.

Conclusion: Despite evidence of target cell depletion in blood, GSK2831781 failed to reduce inflammation in the colonic mucosa suggesting no pharmacological effect. The study was terminated early (NCT03893565).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991300
    CD223/LAG3 Antibody