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 EC 50 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 O 6 -alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC 50 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.Potency and selectivity of the novel guanosine nucleotide prodrug, AT-527, against hepatitis C virus PLOS ONE | https://doi.org/10.1371/journal.pone.0227104 January 8, 2020 3 / 25Putative metabolic pathway for AT-527. When dissolved, AT-527 releases its free base AT-511. Sequential hydrolysis, catalyzed by human cathepsin A (CatA) and/or carboxylesterase 1 (CES1) followed by spontaneous cleavage of the then unstable phenolic moiety, produces the L-alanyl intermediate (M1). Removal of the amino acid moiety by histidine triad nucleotide-binding protein 1 (HINT1) results in metabolite M2 which can then be converted to M3 by adenosine deaminase like protein 1 (ADALP1). M3 is further anabolized sequentially by guanylate kinase 1 (GUK1) and nucleoside diphosphate kinase (NDPK) to the pharmacologically active triphosphate, AT-9010. Both M2 and M3 can be dephosphorylated by 5'-nucleotidase (5'-NTase) to their respective nucleosides M4 and AT-273.
IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2-methylguanosine (2-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t 1/2 ) of approximately 1 h, while plasma concentrations of 2-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng ⅐ h/ml. Mean 2-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25-to 100-mg doses. Mean 2-MeG t 1/2 values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.Hepatitis C virus (HCV) infection is a global public health problem. The global prevalence of hepatitis C infection is estimated to average 3%, resulting in approximately 170 million HCV-infected persons worldwide (8).The current standard of care for patients with chronic hepatitis C and compensated liver disease is the combination of parenterally administered pegylated interferon and orally administered ribavirin. However, sustained virologic response rates are less than 50% in treatment-naive patients with genotype 1 infection (2, 4). In addition, many patients are not good candidates for treatment with these agents due to advanced liver disease or concurrent medical conditions, and many patients show poor tolerance of these treatments. Therefore, there is a need for new anti-HCV therapies, particularly for patients with genotype 1 HCV or those who have failed to respond to the available treatment options.While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig. 1) ...
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.
IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50-to 400-mg doses) and then fed (>200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t 1/2 ) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t 1/2 of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 g/ml (range, 0.2 to 2.5 g/ml) and 2.1 g/ml (range, 0.5 to 4.5 g/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.
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