Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

Abstract

f BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC 50 ], 3 nM) and 1b (EC 50 , 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of Ϸ2.5 log 10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC 90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log 10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once-or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.)

Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

“…To evaluate the ability of the compound to eradicate HCV RNA from GT3 to -6 chimeric replicon cells, replicon clearance studies were performed using BMS-791325 at a 300 nM concentration for up to 10 days. Since BMS-791325 has demonstrated substantial antiviral effect against GT1 patients in the clinic (28), GT1a replicon cells were used as a control, and a 300 nM concentration was chosen as it is the average minimum concentration of drug (C min ) observed at 24 h after a single 100-mg dose of BMS-791325 which resulted in a mean HCV RNA decline of approximately 1.3 log 10 copies/ml in HCV GT1-infected patients (28). Consistent with the EC 50 results, replicon clearance occurred efficiently in GT3a, -4a, and -5a chimeric replicons, similar to that observed in the GT1a replicon (Fig.…”

“…BMS-791325 was synthesized at Bristol-Myers Squibb. Daclatasvir (DCV; NS5A replication complex inhibitor) and asunaprevir (ASV; NS3 protease inhibitor) were previously described (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

“…The correlation between replicon and clinical resistance development in GT1 (27,28) helps to validate the replicon system and provide guidance for clinical resistance emerging in other genotypes. We also show that replicons resistant to BMS-791325 remain fully sensitive to other DAAs, such as NS3 protease or NS5A replication complex inhibitors, further supporting the use of BMS-791325 in combination therapy.…”

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

“…The activity of the P495L variant is ϳ2-fold lower than WT and is highly resistant to BMS-791325 inhibition (EC 50 Ͼ500 nM and IC 50 431 Ϯ 110 nM; Table 2) (10, 11). It was observed in replicons after selection in vitro and in clinical specimens of GT-1 patients treated with BMS-791325 (7,11). The P495L and L30S variants were used in this study to confirm that the inhibition and binding observed with WT NS5B is specific and to probe the impact of the weakened interaction between the thumb and finger on the inhibitor-enzyme interactions.…”

“…The two-step binding mode and long residence time for BMS-791325 and WT NS5B may contribute to the efficacy that has been observed in vivo (7,46,47).…”