876 ACH-3102, A SECOND GENERATION NS5A INHIBITOR, DEMONSTRATES POTENT ANTIVIRAL ACTIVITY IN PATIENTS WITH GENOTYPE 1a HCV INFECTION DESPITE THE PRESENCE OF BASELINE NS5A-RESISTANT VARIANTS

Muir, Andrew J.; Hill, John M.; Läwitz, E.; Marbury, T.; Robarge, L.; Robison, H.; Hui, Jason M.; Huang, M.; Agarwal, Atul; Perelson, A.S.; Deshpande, Milind; Kocinsky, Hetal S.

doi:10.1016/s0168-8278(13)60878-8

Cited by 8 publications

(4 citation statements)

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“…Three- to 5-day monotherapy with next-generation NS5A inhibitors (GS-5816, MK-8742, or TD-6450) resulted in mean or median maximal decreases in HCV RNA levels from baseline ranging from 3.7 to 5.1 log 10 IU/ml ( 29 – 33 ). A single dose of 50 to 300 mg ACH-3102, another next-generation NS5A inhibitor, resulted in mean maximal decreases in HCV RNA levels from baseline ranging from 3.7 to 3.9 log 10 IU/ml, with levels returning to baseline at postdose day 15 ( 34 ). Data reported for these next-generation NS5A inhibitors are comparable to results reported here for ABT-530 ( Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Lawitz

O’Riordan

Asatryan

et al. 2016

Antimicrob Agents Chemother

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ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10 IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)

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Section: Discussionmentioning

confidence: 99%

Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Lawitz

O’Riordan

Asatryan

et al. 2016

Antimicrob Agents Chemother

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“…A phase 1b clinical study with ACH-3102 assessed the effect of the drug on viral load following single oral doses ranging from 25 to 300 mg which were administered to HCV GT-1-infected subjects. , The majority of these subjects harbored NS5A-resistant viral variants at baseline that included Y93C/D/H, M28T/V, and L31M. Nevertheless, the maximum mean decline in plasma HCV RNA was >3.5 log 10 IU/mL in all cohorts and viremia did not return to baseline until day 15 after dosing (Table ).…”

Section: Clinical Trials With Hcv Ns5a Inhibitorsmentioning

confidence: 99%

Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

et al. 2014

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Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.

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“…Multiple targets are being developed for DAA therapy against HCV‐1 but many of these particularly the protease inhibitors have limited activity against HCV‐3 . There are some novel 2nd‐generation NS5A inhibitors such as Achillion ACH‐3102, IdenixIDX‐719 and Gilead GS‐5816 that have potent in vitro activity against HCV‐3 and are moving into early‐phase clinical trials in combination with other DAAs or IFN . The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early‐phase compounds such as Vertex VX‐135.…”

Section: New Direct‐acting Antiviralsmentioning

confidence: 99%

Is 3 the new 1: perspectives on virology, natural history and treatment for hepatitis C genotype 3

Tapper

Afdhal

2013

Journal of Viral Hepatitis

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Affecting 2-3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50-70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, after recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C.

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876 ACH-3102, A SECOND GENERATION NS5A INHIBITOR, DEMONSTRATES POTENT ANTIVIRAL ACTIVITY IN PATIENTS WITH GENOTYPE 1a HCV INFECTION DESPITE THE PRESENCE OF BASELINE NS5A-RESISTANT VARIANTS

Cited by 8 publications

References 0 publications

Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

Is 3 the new 1: perspectives on virology, natural history and treatment for hepatitis C genotype 3

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