Effect of scavenger receptor B-I antagonist, ITX5061, on early hepatitis C virus kinetics in liver transplantation: results of a phase 1b clinical trial

Abstract Background Prevention of recurrent hepatitis C virus (HCV) infection after liver transplantation is a major unmet clinical need. ITX5061 is a small molecule antagonist of scavenger receptor B-I that prevents HCV entry and infection in vitro. The aim of this phase 1 study was to determine safety and efficacy of ITX5061 to prevent HCV allograft infection. Methods In this phase 1b single-centre, prospective, open-label study, we included 23 consecutive patients with HCV infection (21 male) undergoing liver transplantation. The first 13 patients did not receive study drug (controls). The subsequent ten patients received ITX5061 150 mg orally immediately before liver transplantation, after transplantation, and daily for 1 week. Plasma HCV RNA was measured at 13 predefined time-points during the first week and weekly thereafter for the first month, allowing detailed viral kinetic monitoring. Plasma samples were collected to determine ITX5061 before and after transplantation and measured with liquid chromatography and mass spectrometry. This trial is registered with ClinicalTrials.gov, number NCT01292824. Findings 13 recipients were infected with HCV genotype 1. There was no significant difference between untreated and treated patients at baseline and all patients survived 1 month after liver transplantation. ITX5061 treatment was well tolerated with no difference in the nature or frequency of adverse events between the treated and untreated patients. Oral absorption of ITX5061 was demonstrated, with measurable plasma concentrations before transplatation and daily for 1 week after transplantation. HCV RNA concentrations decreased during the first 24 h but remained detectable for all patients at all times during treatment and follow-up. Compared with values measured during the anhepatic phase of surgery, the median reduction in HCV RNA was greater for treated patients at all timepoints (∼ 1 log 10 difference during 7 days' treatment). The maximum decline in HCV RNA was greater than 2 log 10 in eight of ten treated patients compared with six of 13 untreated patients. In patients with genotype 1 disease (n=6), treatment was associated with a sustained reduction in HCV RNA titre (all >2 log 10 ) during 7 days compared with the control group (n=7), none of whom achieved a 2 log 10 reduction at any time. After withdrawal of treatment, HCV RNA increased in all patients. Interpretation Our findings show that treatment with ITX5061, an inhibitor of HCV entry, is safe and well tolerated in liver transplantation. ITX5061 affects plasma HCV RNA kinetics, and a substantial reduction in plasma HCV RNA during treatment was recorded. These findings support further investigation into the efficacy of ITX5061 in HCV- infected patients undergoing liver transplantation. Funding iTherX, Inc., NIHR Birmingham Liver Biomedical Research Unit.