1186 Safety and Antiviral Activity of Abt-267, a Novel Ns5a Inhibitor, During 3-Day Monotherapy: First Study in HCV Genotype-1 (Gt1)-Infected Treatment-Naive Subjects

Lawitz, Eric; Marbury, T.; Campbell, Andrew; Dumas, Emily O.; Kapoor, Mudra; Pilot‐Matias, Tami; Krishnan, Preethi; Setze, Carolyn M.; Xie, Wenhui; Podsadecki, Thomas; Bernstein, Barry; Williams, Lauren

doi:10.1016/s0168-8278(12)61198-2

Cited by 22 publications

(20 citation statements)

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“…There was no dose-responsive pattern to the adverse events. No deaths or serious adverse events were reported (40).…”

Section: Resultsmentioning

confidence: 95%

“…On day 3, ombitasvir dose-normalized maximum concentration (C max ) and area under the concentration-time curve (AUC) values were similar across all doses. The C max ranged from 5.7 to 442 ng/ml, and the half-life ranged from 25.5 to 32.0 h (40). Figure 3 shows the individual HCV RNA viral load declines for the 12 HCV-infected patients who were administered ombitasvir.…”

Section: Resultsmentioning

confidence: 99%

“…HCV RNA was measured using the Roche COBAS TaqMan HCV Test v2.0 real-time reverse transcriptase PCR assay (with a lower limit of quantification of 25 IU/ml and a lower limit of detection of 10 IU/ml). The virologic response was assessed as HCV RNA decrease from baseline in log 10 IU/ml (40).…”

Section: Compoundmentioning

confidence: 99%

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In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Krishnan

Beyer

Mistry

et al. 2015

Antimicrob Agents Chemother

128

136

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Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC 50 s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log 10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. HCV genotype 1, predominant in North America, Europe, and Japan, accounts for 60% of the global infections (4-6). Genotype 2 infections are most prevalent in North America, Europe, and Japan, while genotype 3, 6, and 7 infections are predominant within various parts of Southeast Asia (3, 7-9). In Egypt, HCV infections are almost exclusively genotype 4, while genotype 5 is common in South Africa (10, 11). The levels of nucleotide sequence diversity between genotypes and between subtypes are 30 to 35% and 20 to 25%, respectively (12). The viral dynamics are rapid for HCV, with 10 12 virions being produced daily with a half-life of 45 min (13). Moreover, the RNA-dependent RNA polymerase of HCV is intrinsically error prone, and its lack of a proofreading function allows for introduction of approximately one nucleotide change per genome per replication cycle, which under drug pressure results in the expansion of preexisting drug resistant variants (13). These factors have created challenges in developing pan-genotypic HCV inhibitors with high genetic barriers to the development of resistance.HCV replication can be inhibited at various points in the replication cycle by targeting viral or host cell functions (14,15). For the treatment of HCV genotype 1, three HCV NS3/4A protease inhibitors (telaprevir, boceprevir, and simeprevir) and one nucleoside NS5B polymerase inhibitor (sofosbuvir), each in combination with pegylated interferon (pegIFN) and ribavirin (RBV), have received marketing approval in the United States and Europe. The sustained virologic response (SVR) rate increased from 40 to 52% with pegIFN and RBV regimens to 67...

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“…There was no dose-responsive pattern to the adverse events. No deaths or serious adverse events were reported (40).…”

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Krishnan

Beyer

Mistry

et al. 2015

Antimicrob Agents Chemother

128

136

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“…Ombitasvir (formerly ABT-267) is a NS5A inhibitor; 3 days of ombitasvir monotherapy decreased mean HCV RNA levels by approximately 3 log 10 IU/mL [16]. Ombitasvir, paritaprevir, and ritonavir have been co-formulated into a single fixed-dose tablet (ombitasvir/paritaprevir/r).…”

Section: Background and Aimsmentioning

confidence: 99%

Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine

Lalezari¹,

Sullivan²,

Varunok³

et al. 2015

Journal of Hepatology

120

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“…Ombitasvir exhibited picomolar activities against HCV genotype 1a and 1b subgenomic replicons in vitro, with EC 50 values of 14 and 5 pM, respectively. Ombitasvir also demonstrated robust in vivo responses with mean maximum decreases in HCV RNA up to 3.10 log10 IU/ml following 3-day monotherapy in treatment-naïve HCV genotype-1-infected subjects (Lawitz et al, 2012).…”

Section: Introductionmentioning

confidence: 93%

Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS5A Ombitasvir in Humans

Shen

Serby

Surber

et al. 2016

Drug Metabolism and Disposition

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Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [ 14 C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [ 14 C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steadystate concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug.

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1186 Safety and Antiviral Activity of Abt-267, a Novel Ns5a Inhibitor, During 3-Day Monotherapy: First Study in HCV Genotype-1 (Gt1)-Infected Treatment-Naive Subjects

Cited by 22 publications

References 0 publications

In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine

Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS5A Ombitasvir in Humans

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