Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults: a randomized, double-blind, phase 1b study

Abstract

Background: Hepatitis C virus (HCV) entry involves scavenger receptor B1 (SRB1). In vitro, SRB1 inhibition by ITX5061 impedes HCV replication.

Methods: Multicenter study to assess safety/activity of ITX5061 in previously untreated, noncirrhotic, HCV genotype 1 infected adults. Design included sequential cohorts of 10 subjects with ITX5061 (n = 8) or placebo (n = 2) to escalate duration (3 to 14 to 28 days) or deescalate dose (150 to 75 to 25 mg) based on predefined criteria for safety and activity (≥ 4 of 8 subjects with HCV RNA decline ≥ 1 log10 IU/mL).

Results: Thirty subjects enrolled in 3 cohorts: ITX5061 150 mg/day by mouth for 3 (A150), 14 (B150), and 28 (C150) days. Six subjects had grade ≥ 3 adverse events (one in placebo); none were treatment related. One of the 7 C150 subjects (14.3%, 95% confidence interval [CI], .7%-55.4%) had ≥ 1 log10 IU/mL decline in HCV RNA (1.49 log10 IU/mL), whereas none of the 6 placebo, 8 A150 or 8 B150 subjects showed such decline.

Conclusions: Oral ITX5061 150 mg/day for up to 28 days was safe and well tolerated. In the 28-day cohort, 1 of 7 subjects showed antiviral activity; however, predefined criteria for antiviral activity were not met at the doses and durations studied.

Trial registration: ClinicalTrials.gov NCT01560468.

Keywords: HCV; SRB1; entry inhibitors.

Figures

Figure 1.

Study design. Safety and virologic results were reviewed after each cohort was complete and prior to the selection of the next cohort. If predefined safety criteria were met, the next cohort to enroll was based on the observed virologic activity. Each cohort enrolled 10 new subjects: 8 active, 2 placebo. The cohort sequence enrolled in the study was A150, followed by B150, which was followed by C150 which was final cohort. Following cohort C150, enrollment was terminated according to predefined protocolcriteria for observed antiviral activity. V, predefined criteria for virologic activity was observed in the prior cohort. The next cohort enrolled would receive a lower dose of ITX5061. NV, predefined criteria for virologic activity was not observed in the prior cohort. For A150 and B150, the next cohort enrolled would receive the same ITX5061 dose for longer duration. For C150, A75, B75, and C75, the study would end if antiviral activity was not observed.

Figure 2.

Change in serum log10 HCV RNA level during the dosing interval (•represents the single subject with >1 log10 decline). Abbreviation: HCV, hepatitis C virus.

Figure 3.

Change in serum log10HCV RNA and HDL levels over time for the subject dosed with ITX5061 for 28 days (C150) in whom aprotocol-defined HCV RNA response was observed. Abbreviations: HCV, hepatitis C virus; HDL, high-density lipoprotein.

Figure 4.

Plasma concentration vs time curves for ITX5061 after 3 (cohort A150), 14 (cohort B150) and 28 (cohort C150) days of dosing at 150 mg by mouth daily (bars represent interquartile ranges).