المؤلفون: Feld, Jordan J, Lawitz, Eric, Nguyen, Tuan, Lalezari, Jacob, Hassanein, Tarek, Martin, Paul, Han, Steven-Huy, Dieterich, Douglas, Giard, Jeanne-Marie, De La Rosa, Guy, Ahmad, Alaa, Luo, Ed, Conery, Annie L, Adda, Nathalie

المساهمون: Enanta Pharmaceuticals, Inc.

المصدر: Antiviral Therapy ; volume 27, issue 6, page 135965352211278 ; ISSN 1359-6535 2040-2058

الوصف: Background Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. Methods In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50–800 mg and multiple ascending doses of 200–800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200–800 mg or placebo for 28 days. Results EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (C trough ) approximately 20-fold above the protein-adjusted 50% effective concentration (EC 50 ) for the dose range. Mean change in HBV RNA from baseline to Day 28 was −2.03, −1.67, −1.87, and −0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. Conclusions EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.

الإتاحة: https://doi.org/10.1177/13596535221127848Test

المؤلفون: Lawitz, Eric, Yang, Jenny C, Stamm, Luisa M, Taylor, James G, Cheng, Guofeng, Brainard, Diana M, Miller, Michael D, Mo, Hongmei, Dvory-Sobol, Hadas

المصدر: Antiviral Therapy ; volume 23, issue 4, page 325-334 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background Voxilaprevir (VOX; GS-9857) is a pangenotypic HCV NS3/4A protease inhibitor (PI) with potent antiviral activity against HCV genotypes (GTs) 1–6 and improved coverage of GT1 NS3 resistance-associated substitutions (RAS) associated with other HCV PIs. In a 3-day Phase Ib monotherapy study in patients infected with HCV GT1a, 1b, 2, 3 and 4, VOX was well-tolerated and resulted in maximal mean viral load reduction >3 log 10 IU/ml at the 100 mg dose across all genotypes evaluated. This report characterizes the HCV NS3 RAS in the study. Methods The NS3 gene was amplified and successfully deep sequenced using MiSeq for 66 patients at baseline and 61 patients post-baseline using 15% and 1% assay cutoffs. Results With a 15% assay cutoff, pretreatment HCV NS3 RAS were present in the HCV of 38% (9/24) of patients with GT1a and 5% (1/19) with GT3a; there were no pre-treatment NS3 RAS present in patients with GT1b ( n=6), GT2 ( n=7) or GT4 ( n=4). In patients with and without pretreatment NS3 RAS, ≥3.4 log 10 mean maximal viral load reductions over 3 days of VOX administration were observed. The majority of patients did not have detectable treatment-emergent NS3 RAS and only 12% (7/53) and 26% (14/53) had emergent NS3 RAS using 15% and 1% cutoffs, respectively. No NS3 RAS were detected in patients with GT2 or GT4. A156T or A156V were the most prevalent emergent NS3 RAS in patients with GT1a or GT1b infection, but were not observed in patients with GT3 infection. Conclusions The lack of selection of NS3 RAS in the majority of patients demonstrates a high resistance barrier for VOX. ClinicalTrails.gov identifier NCT02185794.

الإتاحة: https://doi.org/10.3851/imp3202Test

المؤلفون: Lawitz, Eric, Poordad, Fred, Hyland, Robert H, Wang, Jing, Liu, Lin, Dvory-Sobol, Hadas, Brainard, Diana M, McHutchison, John G, Gutierrez, Julio A

المصدر: Antiviral Therapy ; volume 21, issue 8, page 679-687 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis. Methods In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRIL-OGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety. Results In both studies, most patients were male (each 65%) and white (92–96%), infected with HCV genotype-1a (62–70%) and had IL28B non-CC genotypes (82–87%). In total, 37–39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRIL-OGY-1 (82–91%) and TRILOGY-2 (88–95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent. Conclusions All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.

الإتاحة: https://doi.org/10.3851/imp3062Test

المؤلفون: Lawitz, Eric, Gruener, Daniel, Marbury, Thomas, Hill, John, Webster, Lynn, Hassman, David, Nguyen, Anh-Hoa, Pflanz, Stefan, Mogalian, Erik, Gaggar, Anuj, Massetto, Benedetta, Subramanian, G Mani, McHutchison, John G, Jacobson, Ira M, Freilich, Bradley, Rodriguez-Torres, Maribel

المصدر: Antiviral Therapy ; volume 20, issue 7, page 699-708 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4 and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-α and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics and pharmacodynamics of GS-9620 in treatment-naive patients chronically infected with HCV genotype 1. Methods In this double-blind, placebo-controlled study, 51 patients were randomized 5:1 (active:placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2 and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-α and interferon-γ-inducible protein (IP)-10 levels and HCV RNA quantification. Results GS-9620 was well-tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 h. Transient, dose-dependent ISG15 induction was observed at 1, 2 and 4 mg, with peak mean fold change within 48 h followed by a decline to baseline levels within 7 days of dosing. Serum interferon-α induction post-baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed. Conclusions GS-9620 was safe, well-tolerated and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-α or systemic AEs in most patients, supporting a pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.

الإتاحة: https://doi.org/10.3851/imp2845Test

المؤلفون: Guedj, Jeremie, Pang, Phillip S, Denning, Jill, Rodriguez-Torres, Maribel, Lawitz, Eric, Symonds, William, Perelson, Alan S

المصدر: Antiviral Therapy ; volume 19, issue 2, page 211-220 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background Sofosbuvir (GS-7977) and GS-0938 are nucleotide analogue HCV polymerase inhibitors, with sofosbuvir being a pyrimidine and GS-0938 being a purine. Mathematical modelling has provided important insights for characterizing HCV RNA decline and for estimating the in vivo effectiveness of single direct-acting antiviral agents (DAAs); however it has not been used to characterize viral kinetics with combination DAA therapy. Methods We evaluated the antiviral activity of sofosbuvir and GS-0938 given alone and in combination for 14 days in 32 HCV genotype 1 treatment-naive patients (P2938-0212; NUCLEAR study). Results Viral load declined rapidly in a biphasic manner in all subjects and could be well fitted by assuming that both drugs had a similar and additive level of effectiveness in reducing viral production equal to 99.96%, on average. The model predicted that this level of effectiveness was not reached until 0.6 and 2 days for GS-0938 and sofosbuvir, respectively, and likely represents the time needed to accumulate intracellular triphosphates. Subsequently, both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d -1 . No effect of IL28B-polymorphism was found on viral kinetic parameters. Conclusions Both sofosbuvir and GS-0938 are highly effective at blocking viral production from HCV-infected cells. Both drugs led to a rapid and consistent second phase viral decline and exhibited no breakthroughs or other signs of resistance. From a kinetics perspective, because both drugs were of the same class there was little benefit in combining them, suggesting that future DAA combinations should consider utilizing drugs with different modes of action.

الإتاحة: https://doi.org/10.3851/imp2733Test

المؤلفون: Nelson, David, Yoshida, Eric M, Paulson, Matthew S, Hengen, Paul N, Ge, Dongliang, Kanwar, Bittoo, McNally, John, Pang, Phillip S, Subramanian, G Mani, McHutchison, John G, Urbanek, Petr, Lawitz, Eric, Urban, Thomas J

المصدر: Antiviral Therapy ; volume 19, issue 7, page 679-686 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial. Methods Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0–1) versus high (grade 2–4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed. Results A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed. Conclusions These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.

الإتاحة: https://doi.org/10.3851/imp2747Test

المؤلفون: Lawitz, Eric J, Hill, John M, Marbury, Thomas, DeMicco, Michael P, Delaney, William, Yang, Jenny, Moorehead, Lisa, Mathias, Anita, Mo, Hongmei, McHutchison, John G, Rodriguez-Torres, Maribel, Gordon, Stuart C

المصدر: Antiviral Therapy ; volume 18, issue 3, page 311-319 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background GS-9451 is a novel inhibitor of the HCV NS3/4A protease and demonstrates potent in vitro suppression of HCV genotype 1 replicons. Methods The safety, pharmacokinetics and antiviral efficacy of GS-9451 were evaluated in a Phase I study in treatment-naive, HCV genotype-1-infected patients. Patients were randomized to 3 days of once-daily dosing with placebo ( n=8) or GS-9451 60 mg ( n=8 genotype 1a), 200 mg ( n=8 genotype 1a; n=8 genotype 1b) or 400 mg ( n=9 genotype 1a). Plasma samples were collected up to and on day 14 for pharmacokinetic evaluation, serum HCV RNA quantitation and NS3 sequencing. Results No patients interrupted or discontinued dosing because of an adverse event. The median (range) maximal HCV RNA reductions from baseline were -0.88 (-1.24– -0.64), -3.19 (-3.31– -2.94) and -3.64 (-4.08– -3.54) log 10 IU/ml in genotype 1a patients receiving 60, 200 and 400 mg/day GS-9451, respectively, and -3.48 (-3.54– -3.03) log 10 IU/ml in genotype 1b patients receiving GS-9451 200 mg/day. Median half-life ranged from 14 to 17 h. Day 3 mean concentration at the end of dosing interval was 5.5- and 17-fold above protein-binding adjusted mean 50% effective inhibitory concentration in 200 mg and 400 mg cohorts, respectively. No resistance mutations were detected with GS-9451 60 mg/day. In the 200 mg/day or 400 mg/day groups, predominant mutations were NS3 R155 (R155K) in genotype 1a patients and D168 (D168E, D168V and D168G) in genotype 1b patients. Conclusions GS-9451 was well-tolerated. During 3 days of monotherapy, GS-9451 200 mg/day or 400 mg/day demonstrated potent antiviral activity in both HCV genotype 1a- and 1b-infected patients. GS-9451 is currently being evaluated in combination regimens with and without pegylated interferon-α.

الإتاحة: https://doi.org/10.3851/imp2415Test

المؤلفون: Patel, Keyur, Lim, Seng G, Cheng, Chow W, Lawitz, Eric, Tillmann, Hans L, Chopra, Narinder, Altmeyer, Ralf, Randle, John CR, McHutchison, John G

المصدر: Antiviral Therapy ; volume 16, issue 8, page 1341-1346 ; ISSN 1359-6535 2040-2058

مصطلحات موضوعية: Infectious Diseases, Pharmacology (medical), Pharmacology

الوصف: Background 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors inhibit HCV replication in vitro. The combination of sertraline and simvastatin has synergistic antiviral activity in vitro, but there are no prior in vivo studies. Our aims were to prospectively assess the antiviral efficacy and safety of this drug combination in chronic hepatitis C (CHC) patients. Methods A total of 15 CHC adults (including 1 control subject) that were treatment-naive or prior partial responders/relapsers to standard-of-care therapy were enrolled at four centres (2 in Singapore and 2 in the US). Patients received simvastatin 40 mg once daily and sertraline 50 mg once daily for 7 days, and then 80 mg once daily and 100 mg once daily, respectively, for another 21 days with a 14-day follow-up. Results Of the 15 CHC patients, 13 completed the study. Subjects were mostly Caucasian (8/15), mean age 49.1 ±9 years and the genotype distribution was 1=10, 2=2 and 3=3. No subject discontinued dosing due to adverse events. Mean HCV RNA change from baseline was from -0.005 to -0.236 log 10 IU/ml across study intervals. Three subjects had transient >1 log 10 HCV RNA declines. No subject achieved >2 log 10 HCV RNA decline. Conclusions The combination of sertraline and simvastatin is well-tolerated over the short-term, but has no significant antiviral or anti-inflammatory response in CHC patients. This may reflect in vivo differences in synergy between statin and/or selective serotonin reuptake inhibitors and incomplete inhibition of membrane protein prenylation with statin therapy.

الإتاحة: https://doi.org/10.3851/imp1898Test