Phase 2, open-label, rollover study of cenicriviroc for liver fibrosis associated with metabolic dysfunction-associated steatohepatitis.

Background: Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0-4 liver fibrosis.

Methods: Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily.

A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis.

Background And Aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

Approach And Results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.

Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19).

Performance of Noninvasive Tests of Fibrosis Among Asians, Hispanic, and non-Hispanic Whites in the STELLAR Trials.

Background & Aims: The effect of race on routinely available noninvasive tests of fibrosis is incompletely understood. This study evaluated the performance of noninvasive tests among white and Asian patients in the STELLAR trials (NCT03053050 and NCT03053063), which evaluated selonsertib in patients with advanced (F3-F4) fibrosis due to nonalcoholic steatohepatitis (NASH).

Methods: Baseline liver biopsies were centrally read using the NASH Clinical Research Network system, and 4 noninvasive tests (Nonalcoholic fatty liver disease fibrosis score [NFS], Fibrosis-4 index [FIB-4], Enhanced Liver Fibrosis test [ELF], and liver stiffness by vibration-controlled transient elastography) were measured.

Quality of Care Program Reduces Unplanned Health Care Utilization in Patients With Inflammatory Bowel Disease.

Introduction: There is significant variation in processes and outcomes of care for patients with inflammatory bowel disease (IBD), suggesting opportunities to improve quality of care. We aimed to determine whether a structured quality of care program can improve IBD outcomes, including the need for unplanned health care utilization.

Methods: We used a structured approach to improve adult IBD care in 27 community-based gastroenterology practices and academic medical centers.

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.

Introduction: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD.

Methods: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.

Role of Noninvasive Tests in Clinical Gastroenterology Practices to Identify Patients With Nonalcoholic Steatohepatitis at High Risk of Adverse Outcomes: Expert Panel Recommendations.

Nonalcoholic fatty liver disease (NAFLD) is generally considered a silent and potentially reversible condition. The subtype of NAFLD that can be classified as nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis. Because of the metabolic nature of the pathogenic mechanism underlying NAFLD and NASH, it is often accompanied by common comorbidities such as obesity, insulin resistance, and type 2 diabetes mellitus.

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.

Background And Aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease.

Approach And Results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review.

A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of nonalcoholic fatty liver disease, is characterized by hepatocellular injury and inflammation. Patients with NASH are at higher risk of progression to cirrhosis and it is therefore targeted for drug development efforts. Lifestyle modifications and weight loss are the only recommended modalities and no drug is yet approved for the treatment of patients with NASH.

Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis.

Background & Aims: Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH).

Methods: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States.

Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials.

Background & Aims: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.

Methods: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4).

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1β and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in patients with NASH.

Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.

Background & Aims: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis.

Methods: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks.

Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR Trials.

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification.

Not Achieving Sustained Viral Eradication of Hepatitis C Virus After Treatment Leads to Worsening Patient-reported Outcomes.

Background: The causative relationship between the clearance of infections and long-term, health-related quality-of-life (HRQL) improvements in patients with hepatitis C virus (HCV) has been generally accepted. The aim of this study was to assess long-term HRQL trends in HCV patients who did not achieve sustained virologic responses (SVRs) after treatment with direct-acting antivirals.

Methods: HCV patients who completed treatment in clinical trials and did not achieve SVRs were enrolled in a long-term registry (#NCT01457768).

Ombitasvir/paritaprevir/ritonavir and dasabuvir with or without sofosbuvir for patients with hepatitis C virus genotype 1 infection who failed a prior course of direct-acting antiviral therapy.

Introduction: Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection.

Materials And Methods: Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2).

A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn's Disease.

Background And Aims: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of Crohn's disease and may serve as a potential biomarker. A phase 2 trial was conducted to examine the efficacy and safety of the anti-MMP9 antibody andecaliximab [GS-5745] in patients with moderately to severely active Crohn's disease.

Methods: Patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo weekly [QW], andecaliximab 150 mg every 2 weeks [Q2W], andecaliximab 150 mg QW, or andecaliximab 300 mg QW.

Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease.

Background And Aims: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC.

Methods: Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration.

The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment.

S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF-based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF-based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff).

Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.

Background & Aims: Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.

Methods: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

Background: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

Methods: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks.