NI‐0801, an anti‐chemokine (C‐X‐C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid

Abstract

NI‐0801 is a fully human monoclonal antibody against chemokine (C‐X‐C motif) ligand 10 (CXCL10), which is involved in the recruitment of inflammatory T cells into the liver. The safety and efficacy of NI‐0801 was assessed in patients with primary biliary cholangitis. In this open‐label phase 2a study, patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid received six consecutive intravenous administrations of NI‐0801 (10 mg/kg) every 2 weeks. Patients were followed up for 3 months after the last infusion. Liver function tests, safety assessments, as well as pharmacokinetic and pharmacodynamic parameters were evaluated at different time points throughout the dosing period and the safety follow‐up period. Twenty‐nine patients were enrolled in the study and were treated with NI‐0801. The most frequently reported adverse events included headaches (52%), pruritus (34%), fatigue (24%), and diarrhea (21%). No study drug‐related serious adverse events were reported. NI‐0801 administration did not lead to a significant reduction in any of the liver function tests assessed at the end of the treatment period (i.e., 2 weeks after final NI‐0801 administration) compared to baseline. Conclusion: Despite clear pharmacologic responses in the blood, no therapeutic benefit of multiple administrations of NI‐0801 could be demonstrated. The high production rate of CXCL10 makes it difficult to achieve drug levels that lead to sustained neutralization of the chemokine, thus limiting its targetability. (Hepatology Communications 2018;2:492‐503)

Novel Targets in the Immune Microenvironment of the Hepatic Sinusoids for Treating Liver Diseases

“…NI-0801 is a human monoclonal antibody against the CXCR3 ligand, CXCL10, which was studied in the context of primary biliary cholangitis. 106 Investigators completed a phase 2a study in patients with PBC with inadequate response to ursodeoxycholic acid with the aim of assessing the safety and efficacy of NI-0801. The study demonstrated that the drug was safely tolerated and led to pharmacological responses in the blood but there was no therapeutic benefit identified with repeated infusions.…”

Reply to: “A spotlight on natural killer cells in primary biliary cholangitis”

“…PBC will not be cured until we deeply understand its complex, multifaceted pathogenesis. Approaches targeting interleukin-12 (IL-12) 6 and CXCL10, 7 identified as relevant signalling pathways in genome-wide association studies (GWAS) in PBC, 8 have not reached the proposed primary endpoints. This reinforces the idea that the immune system works like an orchestra with different instruments working together to make the music.…”

Primary biliary cholangitis: a multifaceted pathogenesis with potential therapeutic targets

“…Biological drugs targeting the 'upstream' immune response have conferred dismal results so far. 9,10 Promising results have come from specific modifiers of hepatobiliary secretory mechanisms against bile acid-mediated cytotoxicity which target the 'downstream' biliary and fibrotic injury, e.g. agonists of nuclear receptors (FXR and PPAR).…”