Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial.

Background: The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results.

Methods: ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America.

A trial design to maximize knowledge of the effects of rodatristat ethyl in the treatment of pulmonary arterial hypertension (ELEVATE 2).

Serotonin plays a key role in the development and maintenance of the pathobiology associated with pulmonary arterial hypertension (PAH). Platelet-driven and locally produced serotonin from lung tissue and arterial endothelial cells induce excessive growth of pulmonary artery smooth muscle cells. The unchecked growth of these cells is a major driver of PAH including the remodeling of pulmonary arteries that dramatically reduces the diameter and flexibility of the arterial lumen.

Hepatitis C Virus RNA Persists in Liver Explants of Most Patients Awaiting Liver Transplantation Treated With an Interferon-Free Regimen.

We assessed the presence of hepatitis C virus (HCV) RNA in liver explants from 39 patients awaiting liver transplantation who were treated with an interferon-free regimen and had undetectable serum HCV RNA at the time of liver transplantation. Interestingly, HCV RNA was detected in most liver explants (67%). Patients with HCV RNA-positive explants had received shorter courses of treatment, and HCV RNA was undetectable in serum for shorter periods before transplantation compared to patients with HCV RNA-negative explants (P = .

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.

Background: Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease.

Methods: We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand.

On-treatment HCV RNA in patients with varying degrees of fibrosis and cirrhosis in the SOLAR-1 trial.

Background: In the Phase II SOLAR-1 study, 12 or 24 weeks of ledipasvir/sofosbuvir and ribavirin yielded high sustained virological response rates at 12 weeks (SVR12) in patients with chronic HCV infection and advanced liver disease, including untransplanted patients with decompensated cirrhosis and liver transplant recipients with all stages of liver disease.

Methods: We performed a post hoc analysis using data from this study to investigate associations between baseline characteristics and early on-treatment HCV RNA, and to determine the utility of early virological response (week 2 and 4) to predict SVR12. Serum HCV RNA was quantified using the Roche COBAS Ampliprep/Cobas TaqMan HCV Test, Version 2.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

Background & Aims: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease.

Methods: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation.

Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation.

Unlabelled: Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is associated with accelerated progression of liver disease, frequently leading to graft loss and early death. Existing treatment options for severe recurrent HCV infection are limited by suboptimal efficacy, poor tolerability, and numerous drug interactions. We provided sofosbuvir (SOF) and ribavirin (RBV) on a compassionate-use basis to patients with severe recurrent hepatitis C, including those with fibrosing cholestatic hepatitis (FCH) and decompensated cirrhosis who had a life expectancy of 1 year or less.

Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation.

Background & Aims: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection.

Methods: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation.

Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study.

Background & Aims: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.

Analysis of hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938.

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).

Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection.

We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500.

Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects.

To investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (t(max)) values of 1.