A Randomized, Double-Blind, Placebo-Controlled Study of the PD-1 Inhibitor Cetrelimab in Chronic Hepatitis B

Hepatitis B virus (HBV)-induced T-cell exhaustion may be reversed using a programmed death receptor 1 (PD-1) inhibitor such as cetrelimab, an investigational fully human monoclonal antibody targeting PD-1. To evaluate the safety, activity and pharmacokinetics of low-dose (i.e., a dose lower than that used in oncology) cetrelimab in participants with chronic hepatitis B (CHB) virologically suppressed (VS) on a stable nucleos(t)ide analog (NA). Randomized, double-blind, placebo-controlled, multi-cohort, single-dose escalation study of cetrelimab administered subcutaneously or intravenously. Due to a strategic decision, and not to any safety concern, only one cohort (45 mg subcutaneous) was executed. Participants maintained their NA treatment to avoid HBV reactivation. Serum cetrelimab concentrations, HBV biomarkers, PD-1 receptor occupancy (RO) and safety were collected over 24 weeks. Eleven participants were enrolled and randomized, eight to cetrelimab and three to placebo and all 11 completed the study. Mean cetrelimab half-life was 16.3 days with median time to maximum cetrelimab concentration 10.4 days post-dose. Near-maximal RO was achieved 6 h post-dose which waned over time. There were no clinically relevant changes in HBV biomarkers or laboratory values including liver function tests and thyroid-stimulating hormone. No clinically relevant adverse events were reported. A single 45 mg dose of cetrelimab administered subcutaneously in VS participants with CHB was safe and well tolerated. There was no change in HBV biomarkers and further development of cetrelimab for HBV was abandoned. Clinical Trial Registration: ClinicalTrials.gov: NCT05242445; EudraCT Number: 2021-004857-21.