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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.

SUBMITTER: Berliba E

PROVIDER: S-EPMC6879261 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Berliba Elina E Bogus Maxim M Vanhoutte Frédéric F Berghmans Pieter-Jan PJ Good Steven S SS Moussa Adel A Pietropaolo Keith K Murphy Robert L RL Zhou Xiao-Jian XJ Sommadossi Jean-Pierre JP

Antimicrobial agents and chemotherapy 20190930 12

AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased <i>in vitro</i> 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 evalu ...[more]

PMID: 31570394

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Project description:Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC50 of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1-5, ranged from 5-28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1-5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 μM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O6-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC50 values ≥25 μM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.

Dataset Information

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

Publications

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

Similar Datasets

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