Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial

Lawitz, Eric; Reau, Nancy; Hinestrosa, Federico; Rabinovitz, Mordechai; Schiff, Eugene R.; Sheikh, Aasim; Younes, Ziad; Herring, Robert; Reddy, K. Rajender; Tran, Tram T.; Bennett, Michael; Nahass, Ronald; Yang, Jenny C.; Lu, Sophia; Dvory‐Sobol, Hadas; Stamm, Luisa M.; Brainard, Diana M.; McHutchison, John G.; Pearlman, Brian L.; Shiffman, Mitchell; Hawkins, Trevor; Curry, Michael P.; Jacobson, Ira M.

doi:10.1053/j.gastro.2016.07.039

Cited by 50 publications

(52 citation statements)

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“…Shortening treatment duration also has the potential to improve treatment uptake, adherence, and tolerability, and thereby improve patient outcomes . Although the new pangenotypic combinations of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir have reduced treatment duration to 8 weeks in some patient populations, attempts to shorten treatment duration to fewer than 8 weeks have generally resulted in high viral relapse rates …”

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confidence: 99%

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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This open‐label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct‐acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6‐12‐week oral regimens of 400‐800 mg once daily (QD) AL‐335 + 50 mg QD/every other day odalasvir ± 75‐150 mg QD simeprevir were evaluated in treatment‐naïve, HCV genotype (GT)1/3‐infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV‐RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment‐emergent adverse events occurred, one of which (a Mobitz type 1 second‐degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1‐infected patients receiving 3‐DAA for 6‐8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1‐infected patients receiving 2‐DAA or GT3‐infected patients receiving 3‐DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance‐associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment‐naïve subjects without cirrhosis, AL‐335 + odalasvir + simeprevir for 6‐8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2‐DAA regimen in GT1‐infected subjects and the 3‐DAA regimen in GT3‐infected subjects.

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confidence: 99%

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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“…The most common AEs observed were headache, diarrhea, nausea, and fatigue. Among all the study subjects, only one patient from Group 4 discontinued the treatment due to increased ALT levels (grade 3) [26]. This study suggested the utility of SOF/VOX/VEL in individuals who had failed other therapies [30,26].…”

Section: Clinical Efficacymentioning

confidence: 98%

“…A total of 120 patients were enrolled in this study to evaluate the safety, PK, and antiviral activity of once-daily administration of VEL at doses ranging from 5 to 150 mg for 3 days in patients with genotypes 1–4 HCV infection [25,26]. …”

Section: Clinical Efficacymentioning

confidence: 99%

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Sofosbuvir + velpatasvir + voxilaprevir for the treatment of hepatitis C infection

Cory

Gong

Kodidela

et al. 2018

Expert Opinion on Pharmacotherapy

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Introduction Hepatitis C is a disease with a significant global impact. Over the last several years, the treatment of the disease has been revolutionized. Therapy has transformed over the last several years with the approval of second generation direct acting antivirals, and currently utilized medications for the treatment of hepatitis C are significantly more efficacious with better safety profiles than previously approved treatments. Treatment for individuals who have failed therapy on direct acting antivirals has, until recently, been complex and difficult to treat, but the approval of sofosbuvir/velpatasvir/voxilaprevir represents a new therapeutic option for these individuals. Areas covered Sofosbuvir/velpatasvir/voxilaprevir is a recently approved therapeutic combination for the treatment of hepatitis C. This article reviews the studies leading to the approval of the combination, and its efficacy and safety profile. Expert opinion Sofosbuvir/velpatasvir/voxilaprevir fills one of the previously unfilled niches for the treatment of hepatitis C, that of the treatment of individuals who have failed therapy with resistant virus. With the filling of this niche, there appears to be a general slowing of the development of new therapeutics. Although understandable, in the long term, there are considerable risks associated with the decreased development of new drugs to treat hepatitis C.

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“…Furthermore, pan-genotypic DAA therapies such as velpatasvir, which has recently demonstrated an SVR12 rate approaching 100% when administered for 12 weeks in combination with sofosbuvir [19], have the potential to eliminate the need for genotyping and thereby greatly simplify treatment. GS-9857 [20, 21] and ravidasvir [22] also show significant promise in this area; the latter has demonstrated a 97% SVR12 rate in 182 non-cirrhotic patients with HCV GT4 in Egypt when given for 12 weeks in combination with sofosbuvir [23]. …”

Section: Introductionmentioning

confidence: 99%

Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response

et al. 2017

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BackgroundHCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12.MethodsThis multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naïve, aged 18–70 years with METAVIR F0–F2 fibrosis. Patients with early virologic response (HCV RNA <25 IU/mL [detectable/undetectable in IL28B CC patients or undetectable in IL28B CT/TT patients] at Week 2 and undetectable at Weeks 4 and 8) were eligible to stop all treatment at the end of Week 12, otherwise PR therapy was continued to Week 24.ResultsOf 67 patients treated, 34 (51%) qualified for 12-week treatment including all but one patient with IL28B CC genotype (14/15). All patients in the 12-week group had undetectable HCV RNA at end of treatment, and 97% (33/34) achieved SVR12. No new safety signals with simeprevir plus PR were identified. The proportion of patients experiencing Grade 3–4 adverse events was lower in the 12-week group than in the 24-week group.ConclusionsOur findings on simeprevir plus PR therapy shortened to 12 weeks in patients with HCV GT4 infection with favourable baseline characteristics and displaying early on-treatment virologic response are encouraging. No new safety signals were associated with simeprevir plus PR in this study.Trial RegistrationNCT01846832

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial

Cited by 50 publications

References 15 publications

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Sofosbuvir + velpatasvir + voxilaprevir for the treatment of hepatitis C infection

Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response

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