1191 Gs-5816, a Second Generation HCV Ns5a Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage and a High Resistance Barrier

Cheng, Guofeng; Yu, Minshu; Peng, Betty; Lee, Y.-J.; Trejo‐Martin, Alejandra; Gong, Ruoyu; Bush, Caroline O.; Worth, Angela; Nash, Michelle C; Chan, Kcw; Yang, Haojie; Beran, Rudolf K. F.; Yang, Tian; Perry, Jason K.; Taylor, James G.; Yang, Ching‐Fen; Paulson, Matthew; Delaney, William E.; Link, John O.

doi:10.1016/s0168-8278(13)61192-7

Cited by 42 publications

(38 citation statements)

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“…In vitro solubility data suggest that gastrointestinal (GI) concentrations could reach solubility saturation at VEL doses of Ͼ50 mg (50-mg dose in a 250-ml GI fluid volume ϭ ϳ0.2 mg/ml), assuming the solubility determined in FeSSIF (0.18 mg/ml); however, this assumption is complicated by the potential for extensive solubilization in the stomach under fasting conditions followed by precipitation in the small intestine (22) and the nature of the drug product, an amorphous solid dispersion of VEL, which could enhance the physiological behavior of VEL (23). Following multiple once-daily doses of VEL, modest accumulation was observed (Յ64% by any exposure metric) across the dose range of 5 mg to 450 mg, consistent with the observed elimination half-life of approximately 16 h. After multiple once-daily doses of VEL at doses greater than 5 mg, mean plasma VEL concentrations at 24 h postdosing were well above the protein-adjusted half-maximal (50%) effective concentration (EC 50 ) for genotype 1 to 6 HCV replicons (17).…”

Section: Discussionsupporting

confidence: 66%

“…As the volume of distribution and plasma protein binding were similar across species (Tables 1 and 2), the estimated volume of distribution in humans was projected to be similar to that in other species (approximately 1.5 liters/kg). At a dose of 50 mg, the steady-state trough concentration was estimated to be approximately 23 ng/ml, which, on the basis of in vitro potency data (17), would be sufficient to provide significant antiviral activity in human subjects.…”

Section: Resultsmentioning

confidence: 99%

“…However, the antiviral potencies of these agents vary considerably across HCV genotypes (15,16). Velpatasvir (VEL; GS-5816) is an HCV NS5A inhibitor with potent activity against HCV genotypes 1 to 6 (Table 1) (17). A short-duration, welltolerated, and highly effective pangenotypic treatment for HCV could have a major impact on the global prevalence and burden of HCV infection, particularly for individuals with HCV genotype 3 infection, and, more broadly, would eliminate the diagnostic burden of genotyping that is currently necessary for proper regimen selection and, thus, a barrier to the implementation of treatment in resource-limited regions.…”

mentioning

confidence: 99%

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Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

Mogalian

German

Kearney

et al. 2017

Antimicrob Agents Chemother

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Preclinical characterization of velpatasvir (VEL; , an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n ϭ 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection.

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Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

Mogalian

German

Kearney

et al. 2017

Antimicrob Agents Chemother

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“…VEL (GS-5816) is a potent pan-genotypic HCV NS5A inhibitor with activity across HCV GT1 to GT6 that has better in vitro activity against GT2 and GT3 than the NS5A inhibitors LDV and DCV (14,36). A phase 1b monotherapy study was con- ducted in which GT1a, GT1b, GT2, GT3, and GT4 HCV chronically infected, treatment-naive patients were treated once daily with VEL for 3 days.…”

Section: Discussionmentioning

confidence: 99%

“…It is a selective inhibitor of HCV RNA replication with mean 50% effective concentrations (EC 50 s) against GT1 to GT6 of 6 to 130 pM (14). VEL showed potent activity against some of the clinically significant GT1 NS5A inhibitor resistance-associated substitutions (RASs), as well as clinically prevalent GT2a and GT2b polymorphism M31 and GT3a poly-morphism A30K that confer high-level resistance to NS5A inhibitors (e.g., daclatasvir and ledipasvir) (14).…”

mentioning

confidence: 99%

Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein

Lawitz

Dvory‐Sobol

Doehle

et al. 2016

Antimicrob Agents Chemother

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a; Gilead Sciences, Foster City, California, USA b Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of >3.3 log 10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. NCT01740791.) H epatitis C virus (HCV) infects an estimated 180 million people worldwide (1). Infection can lead to cirrhosis, hepatocellular carcinoma, and other complications. Novel direct-acting antiviral agents (DAAs) are being developed in combination with pegylated interferon (PegIFN)/ribavirin (RBV) and are also being pursued as components of IFN-free and IFN/RBV-free regimens to improve efficacy and shorten treatment duration. Recently, new DAAs that are well tolerated and highly effective have been approved for the treatment of chronic HCV infection. In December 2013, the FDA approved Sovaldi (sofosbuvir [SOF]; Gilead Sciences), a once-daily pan-genotypic oral nucleotide analog polymerase inhibitor (NI) for the treatment of HCV infection as a component of a combination antiviral treatment regimen for patients with genotype 1 (GT1), GT2, GT3, or GT4 infection (2, 3). The protease inhibitor (PI) Olysio (simeprevir; Janssen Pharmaceutica), in combination with PegIFN/RBV, also received FDA approval in December 2013. Simeprevir has better activity against multiple genotypes than the PIs boceprevir and telaprevir but weak activity against GT2 and no activity against GT3 (4). Another recently approved treatment of GT1 HCV infection in the United States and Europe is Harvoni (Gilead Scien...

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Study on fluorescence properties of HCV antiviral (velpatasvir) and its fluorimetric determination in presence of sofosbuvir; application to stability study and human plasma

et al. 2018

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Velpatasvir (VLP) is a new, oral, direct-acting antiviral with potent inhibitory activity against all hepatitis C virus (HCV) genotypes. A highly sensitive, simple, fast and specific one fluorometric method for determination of VLP in the presence of sofosbuvir was developed and validated. The fluorescence behavior of VLP in different organic solvents was examined and explained. Methanol was concluded to be the best sensitizing reagent. The native fluorescence intensity of VLP was accomplished at 383 nm with 339 nm for excitation wavelength. The impacts of experimental variables included pH, various organized media, and time of stability were examined and optimized. A linear relationship was achieved between the VLP concentration and the fluorescence intensity in a range of 5 to 5 × 10 ng mL with 0.70 and 0.23 ng mL , for quantitation and detection limits respectively. The proposed method was utilized for analyzing of VLP in human plasma and additionally expanded to examine the stability of VLP after its exposure to various stress conditions, like oxidative, alkaline, acidic, UV, daylight and sunlight conditions, according to ICH guidelines. Furthermore, the kinetics of acidic and oxidative degradations of VLP was examined. Moreover, the half-life times of the reaction (t ) and the first-order reaction rate constants were estimated. Finally, a suggestion for the degradation pathway was presented.

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1191 Gs-5816, a Second Generation HCV Ns5a Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage and a High Resistance Barrier

Cited by 42 publications

References 0 publications

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein

Study on fluorescence properties of HCV antiviral (velpatasvir) and its fluorimetric determination in presence of sofosbuvir; application to stability study and human plasma

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