Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor

Owens, Christopher M.; Brasher, Bradley; Polemeropoulos, A.; Rhodin, Michael H. J.; McAllister, Nicole; Wong, Kelly A.; Jones, Christopher T.; Jiang, Lijuan; Lin, Kai; Or, Yat Sun

doi:10.1128/aac.00815-16

Cited by 3 publications

(5 citation statements)

References 15 publications

(36 reference statements)

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“…Selection of these resistance-associated mutations in the NS5A gene further supports the hypothesis that EDP-239 interferes with HCV replication by inhibiting NS5A function. Additional analyses concerning RAMs selected in vitro and whether they are predictive of baseline or treatment-emergent mutations in vivo will be reported elsewhere (29). Here, we provide evidence of the compound's potency in numerous in vitro preclinical assays as well as its potential suitability for future development as a therapeutic to be used in combination with existing HCV antivirals.…”

Section: Discussionmentioning

confidence: 79%

“…EDP-239 has no significant activity against the NS3 serine protease or NS5B polymerase (data not shown). Resistance selection studies in vitro identified numerous changes within the first 100 amino acids of NS5A (29). .…”

Section: Discussionmentioning

confidence: 99%

“…The L31V RAM was determined to confer a higher degree of resistance (20-fold) against EDP-239 than against daclatasvir (5-fold). A more detailed analysis of RAMs selected in vitro in GT1a and GT1b replicon cells, as well as an analysis of these data in the context of clinical RAMs identified in the phase I clinical trial, are reported in an accompanying article (29).…”

Section: Edp-239 Inhibits Hcv Replication In Replicon Cellsmentioning

confidence: 99%

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Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

Owens¹,

Brasher²,

Polemeropoulos³

et al. 2016

Antimicrob Agents Chemother

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C hronic infection with the hepatitis C virus (HCV) is a major global health burden, infecting approximately 3.5 million individuals in the United States (1) and up to 150 million worldwide (2). HCV is estimated to infect approximately 3 to 4 million people each year, with a prevalence in the United States estimated at 1.3% (1) and prevalences as high as 22% in Egypt, 4.8% in Pakistan, and 3.2% in China (3). Chronic HCV infection can lead to cirrhosis of the liver and hepatocellular carcinoma, contributing to the deaths of 700,000 individuals each year (3).HCV is an enveloped, single-stranded, positive-sense RNA virus in the family Flaviviridae. The ϳ9.6-kb genome is translated into a single polyprotein that is subsequently processed into at least 10 structural and nonstructural proteins that are necessary for replication of viral RNA and assembly of new virions (4). At least six distinct HCV genotypes (GTs) and more than 50 subtypes have been characterized, with significant variability in their geographic distributions (5).Within the past 5 years, treatment options for HCV infection have improved dramatically, with approvals from the U.S. Food and Drug Administration for sofosbuvir, ledipasvir, daclatasvir, ombitasvir, paritaprevir, dasabuvir, simeprevir, grazoprevir, and elbasvir. However, it is becoming apparent that differences in potency among the existing approved drugs against various HCV genotypes, as well as their associated resistant variants, demonstrate a clear unmet medical need for additional approved therapies. EDP-239, a small-molecule inhibitor targeting the nonstructural protein 5A (NS5A) of HCV, was designed to address this unmet need.NS5A is a nonstructural HCV protein, with no known enzymatic activities, and is an essential component of the HCV replication complex (6). NS5A possesses RNA binding activity and is comprised of an amphipathic ␣-helix (amino acids 5 to 25) that is important for membrane localization, followed by three distinct structural domains (7-9). Domain I (amino acids 37 to 213) is essential for viral replication, possesses a zinc binding motif, and has been crystallized as a homodimer (9, 10). Domains II (amino acids 250 to 342) and III (amino acids 356 to 447) are less well characterized and exist in a natively unfolded conformation (11,12). Current evidence indicates that the NS5A protein is essential not only for genome replication but also for the assembly of infectious virions (13). Given its involvement in multiple stages of the viral life cycle, NS5A is an attractive target for small-molecule inhibition. Clinically, rapid and profound reductions of HCV RNA have been observed following monotherapy with several other NS5A inhibitors, including daclatasvir, ledipasvir, .EDP-239 is a novel NS5A inhibitor with half-maximal effective concentrations (EC 50 s) in vitro of 31 and 7 pM against genotype 1a (GT1a) and GT1b replicons, respectively. In this report, we demonstrate that EDP-239 does not experience a reduction in potency against replicons resistant to other host-tar...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Edp-239 Inhibits Hcv Replication In Replicon Cellsmentioning

confidence: 99%

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Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

Owens¹,

Brasher²,

Polemeropoulos³

et al. 2016

Antimicrob Agents Chemother

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“…Авторы выделяют классы ПППД, действие которых направлено на ингибирование определенных ферментов репликации HCV [21][22][23][24][25]:…”

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“…Продолжительность курсового лечения HCV с использованием ПППД составляет от 8 до 24 нед [22][23][24][25][26][27][28][29][30][31][32][33]. Применение новейших препаратов ПВТ, предлагаемых в последнее время, позволяет сократить курс лечения до 8 нед [25,26,28].…”

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Treatment of chronic viral hepatitis C with direct acting antiviral agent: review

Малов

Ubeeva

Убеева

et al. 2019

Terapevticheskii arkhiv

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Current therapy for chronic hepatitis C: The role of direct-acting antivirals

2017

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One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.

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Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor

Cited by 3 publications

References 15 publications

Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

Treatment of chronic viral hepatitis C with direct acting antiviral agent: review

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

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