TY - JOUR
T1 - Safety, pharmacokinetics, and antiviral activity of AT-527, a novel purine nucleotide prodrug, in hepatitis C virus-infected subjects with or without cirrhosis
AU - Berliba, Elina
AU - Bogus, Maxim
AU - Vanhoutte, Frédéric
AU - Berghmans, Pieter Jan
AU - Good, Steven S.
AU - Moussa, Adel
AU - Pietropaolo, Keith
AU - Murphy, Robert L.
AU - Zhou, Xiao Jian
AU - Sommadossi, Jean Pierre
N1 - Funding Information:
We thank the subjects who participated in this study. In addition, we also thank the dedicated staff at the clinical study sites. E.B., M.B., F.V., and P.-J.B. are clinical investigators/subinvestigators contracted by Atea Pharmaceuticals, Inc., to conduct the reported study. S.S.G., A.M., K.P., X.-J.Z., and J.-P.S. are employees and shareholders of Atea Pharmaceuticals, Inc. R.L.M. is a shareholder of and consultant to Atea Pharmaceuticals, Inc. This study was sponsored and funded by Atea Pharmaceuticals, Inc. The sponsor protocol number is AT-01B-001.
Funding Information:
This study was sponsored and funded by Atea Pharmaceuticals, Inc. The sponsor protocol number is AT-01B-001.
Publisher Copyright:
Copyright © 2019 Berliba et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2019
Y1 - 2019
N2 - AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity 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 7 days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naive, noncirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open-label cohorts of (i) noncirrhotic, genotype 3, HCV-infected subjects and (ii) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for 7 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 h of dosing. Mean maximum reductions observed with 7 days of dosing were 4.4, 4.5, and 4.6 log10 IU/ml in noncirrhotic subjects with HCV genotype 1b, noncirrhotic 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 h, supporting once-daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related, and pangenotypic 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. (This study has been registered in the European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] under number 2017-002148-34 and at ClinicalTrials.gov under identifier NCT03219957.)
AB - AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity 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 7 days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naive, noncirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open-label cohorts of (i) noncirrhotic, genotype 3, HCV-infected subjects and (ii) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for 7 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 h of dosing. Mean maximum reductions observed with 7 days of dosing were 4.4, 4.5, and 4.6 log10 IU/ml in noncirrhotic subjects with HCV genotype 1b, noncirrhotic 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 h, supporting once-daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related, and pangenotypic 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. (This study has been registered in the European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] under number 2017-002148-34 and at ClinicalTrials.gov under identifier NCT03219957.)
KW - Chronic hepatitis C virus infection
KW - Cirrhosis
KW - Direct-acting antiviral
KW - NS5B
KW - Nucleotide
KW - Pangenotypic
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UR - http://www.scopus.com/inward/citedby.url?scp=85075558274&partnerID=8YFLogxK
U2 - 10.1128/AAC.01201-19
DO - 10.1128/AAC.01201-19
M3 - Article
C2 - 31570394
AN - SCOPUS:85075558274
SN - 0066-4804
VL - 63
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 12
M1 - e01201-19
ER -
