Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial

Objective Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD). Design Seventy-eight patients (aged >= 18 and <= 75 years) with CD for >= 3 months, Crohn's Disease Activity Index (CDAI) >= 220 and <= 450 and either C-reactive protein >= 10 mg/L or endoscopic evidence of inflammation, were randomised 1: 1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (Delta CDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. Results Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 Delta CDAI=-16); however, there was a significant difference by week 12 (Delta CDAI=-55; p <= 0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n= 28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI >= 330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. Conclusions A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD.