Aliment Pharmacol Ther. 2023 Aug;58(3):283-296.doi: 10.1111/apt.17557. Epub 2023 Jun 16.

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

Author information

¹Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

²Inserm NGERE and Department of Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-les-Nancy, France.

³GSK, Discovery Medicine, GSK Medicine Research Centre, Stevenage, UK.

⁴GSK, Biostatistics, GSK Medicines Research Centre, Stevenage, UK.

⁵GSK, Clinical Pharmacology Modelling and Simulation, GSK Medicines Research Centre, Stevenage, UK.

⁶GSK, Clinical Sciences, Medicines Research Centre, London, UK.

⁷GSK, Immunology Research Unit, Stevenage, UK.

⁸GSK, Clinical Pharmacology and Experimental Medicine, GSK Medicines Research Centre, Stevenage, UK.

⁹GSK, Computational Biology, Genomic Sciences Group, Stevenage, UK.

¹⁰GSK, Clinical Sciences, GSK, London, UK.

¹¹ACE Endoscopy, Suite C Inland Empire Liver Foundation, Rialto, California, USA.

¹²GSK, Clinical Sciences, Medicines Research Centre, Stevenage, UK.

¹³Northwestern University Feinberg School of Medicine, Northwestern Medicine Digestive Health Center, Chicago, Illinois, USA.

¹⁴Division 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).