Safety and tolerability of anti-toll-like receptor 3, monoclonal antibody PRV-300 in patients with moderate-to-severe ulcerative colitis: a randomized phase 1B clinical trial (PULSE)

Abstract

Abstract Background & Aims PRV-300 is a fully human IgG4κ monoclonal antibody that binds the extracellular domain of human toll-like receptor 3, which is overexpressed in the inflamed colonic epithelium in patients with inflammatory bowel disease. This study aimed at proving its safety and efficacy in patients with ulcerative colitis (UC). Methods Patients with moderate-to-severe UC (Mayo Clinical Score [MCS] 6-12) were randomized to receive 7 doses of PRV-300 intravenously or matched placebo (PBO). After a 12-week treatment period, participants underwent an 8-week follow-up. The primary endpoint was to assess the safety and tolerability of PRV-300. Secondary endpoints included assessment of pharmacodynamics, pharmacokinetics, immunogenicity, and endoscopic disease activity. Results In total, 38 patients were randomized (28 in PRV-300 arm, 9 in placebo arm), of whom 32 completed the trial (24 and 8, respectively). Although TEAEs and TE-SAEs were numerically higher with PRV-300 than placebo (50.0% vs 11.1% and 39.3% vs 0.0%, respectively), the drug was well-tolerated, with only 7.1% (2/28) discontinuing therapy due to AEs and most events being mild, non-specific, or related to underlying disease. In colonic biopsies, PRV-300 had a greater, albeit not statistically significant, effect on the downregulation of TLR3 expression, but not on a UC gene expression signature. No differences in MCS and endoscopic severity were observed. Conclusions While PRV-300 demonstrated an acceptable safety profile, TLR3 blockade did not translate into clinical benefit despite exploratory evidence of target engagement. Our results are challenging a pivotal role of the mode-of-action for the pathogenesis of UC (funded by Provention Bio) Clinical trial registration number ClinicalTrials.gov (NCT03849599).