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

Summary 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). Median change from baseline (95% CrI) in complete Mayo score at Week 10 was −1.4 (−2.2, −0.7) with 450 mg IV vs −1.4 (−2.4, −0.5) for placebo (treatment difference, 0.0 [−1.2, 1.3]). Despite evidence of target cell depletion in blood, there was no reduction of CD3+ LAG‐3+ cells in colon.