Safety, pharmacokinetics and antiviral activity of AT-527, a novel purine nucleotide prodrug, in HCV-infected subjects with and without cirrhosis

Abstract

AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity as compared to sofosbuvir and a highly differentiated favorable preclinical profile compared to other anti-HCV nucleoside/nucleotide analogs. This was a multiple part clinical study where multiple ascending doses of AT-527 up to 600 mg (expressed as AT-527 salt form; equivalent to 553 mg free base) once daily for seven days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naïve, non-cirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open label cohorts of a) non-cirrhotic, genotype 3, HCV-infected subjects and b) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for seven days in all cohorts. At the highest dose tested, mean HCV RNA reductions of up to 2.4 log10 IU/mL occurred within the first 24 hours of dosing. Mean maximum reductions observed with seven days of dosing were 4.4, 4.5 and 4.6 log10 IU/mL in non-cirrhotic subjects with HCV genotype 1b, non-cirrhotic subjects with HCV genotype 3, and subjects with compensated cirrhosis, respectively. The systemic half-life of AT-273, the nucleoside metabolite considered a surrogate of intracellular phosphates including the active triphosphate, exceeded 20 hours, supporting once daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related and pan-genotypic antiviral activity with similar responses between subjects with and without cirrhosis. Exposure-antiviral response analysis identified 550 mg (free base equivalent) as the optimal dose of AT-527. Safety and antiviral activity data from this study warrant continued clinical development of AT-527 dosed once daily.

Copyright © 2019 Berliba et al.

Figures

FIG 1

AT-527 chemical structure.

FIG 2

Mean (+SD) steady-state plasma concentration-time profiles of AT-511 and AT-273 on day 7. (A) Ascending doses of 150, 300, and 600 mg QD (6 subjects per dose) in noncirrhotic (NC) GT1b subjects. (B) AT-527 600 mg QD in NC GT1b (n = 6), NC GT3 (n = 6), and cirrhotic (GT1, -2, or -3; n = 6) subjects.

FIG 3

Antiviral activity. (A) Mean (+SD) HCV RNA change from baseline with ascending doses (6 subjects per dose) in noncirrhotic (NC) GT1b subjects and with 600 mg QD in NC GT1b (n = 6), NC GT3 (n = 6), and cirrhotic (GT1, -2, or -3; n = 6) subjects. (B) HCV RNA changes from baseline in individual subjects receiving 600 mg QD.

FIG 4

Relationship determined by Emax modeling between steady-state plasma exposure (AUCτ) of AT-273 and plasma HCV RNA reduction on day 7 from baseline in GT1, -2, or -3 subjects with or without (NC) cirrhosis.