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

Abstract

BACKGROUND & AIMS:

The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection.

METHODS:

We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12).

RESULTS:

Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events.

CONCLUSIONS:

In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.

• Authors: Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr, K Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M Stamm, Diana M Brainard, John G McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
• Journal: Gastroenterology (Gastroenterology) Vol. 151 Issue 5 Pg. 893-901.e1 (11 2016) ISSN: 1528-0012 [Electronic] United States
• PMID: 27486034 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)
• Copyright: Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aminoisobutyric Acids
• Antiviral Agents
• Carbamates
• Cyclopropanes
• Drug Combinations
• Heterocyclic Compounds, 4 or More Rings
• Lactams, Macrocyclic
• Macrocyclic Compounds
• Quinoxalines
• Sulfonamides
• Viral Nonstructural Proteins
• voxilaprevir
• Ribavirin
• Proline
• NS3-4A serine protease, Hepatitis C virus
• Serine Proteases
• Leucine
• velpatasvir
• Sofosbuvir

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aminoisobutyric Acids
• Antiviral Agents (therapeutic use)
• Carbamates (therapeutic use)
• Cyclopropanes
• Drug Administration Schedule
• Drug Combinations
• Drug Therapy, Combination
• Female
• Genotype
• Hepacivirus (genetics)
• Hepatitis C, Chronic (drug therapy, virology)
• Heterocyclic Compounds, 4 or More Rings (therapeutic use)
• Humans
• Lactams, Macrocyclic
• Leucine (analogs & derivatives)
• Macrocyclic Compounds (therapeutic use)
• Male
• Middle Aged
• Proline (analogs & derivatives)
• Quinoxalines
• Ribavirin (therapeutic use)
• Serine Proteases
• Sofosbuvir (therapeutic use)
• Sulfonamides (therapeutic use)
• Treatment Outcome
• Viral Nonstructural Proteins (antagonists & inhibitors)
• Young Adult