Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy, of Vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase 2a study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, Vonafexor 100 mg twice daily (VONA-100BID), Vonafexor 200 mg once daily (VONA-200QD), or 400 mg Vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, Vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. Efficacy endpoints were reduction in liver fat content (LFC) from baseline to Week 12 by magnetic resonance imaging proton density fat fraction (MRI-PDFF, primary), imaging biomarker of fibrotic steatohepatitis (corrected T1 signal), and liver enzymes. RESULTS: One hundred and twenty patients were randomised (Part A, n=24; Part B, n=96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD, (-6.3% [0.9]), VONA-200QD (-5.4% [0.9]), versus placebo (-2.3% [0.9], p=0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with Vonafexor. Creatinine based glomerular filtration rate (eGFR) improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of subjects in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, Vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: NASH has become a leading cause for chronic liver disease and patients are also at higher risk for the development of chronic kidney disease. There are no approved therapies and only few options to treat this population. LIVIFY Phase 2a trial results show that single daily administration of oral Vonafexor, a FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-Cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials to ultimately provide therapies for the unmet medical need in NASH.

Randomized placebo-controlled trial of losartan for pediatric NAFLD.

BACKGROUND AND AIMS: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. APPROACH AND RESULTS: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. CONCLUSIONS: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

Fibrosis-4 Predicts the Need for Mechanical Ventilation in a National Multiethnic Cohort of Corona Virus Disease 2019.

Simple tests of routine data are needed for those with severe acute respiratory syndrome coronavirus 2, which causes corona virus disease 2019 (COVID-19), to help identify those who may need mechanical ventilation (MV). In this study, we aimed to determine if fibrosis-4 (FIB-4) is associated with the need for MV in patients with COVID-19 and if there is an association to determine the optimal FIB-4 cutoff. This was a retrospective, national, multiethnic cohort study of adults seen in an ambulatory or emergency department setting who were diagnosed with COVID-19. We used the TriNetX platform for analysis. Measures included demographics, comorbid diseases, and routine laboratory tests. A total of 4,901 patients with COVID-19 were included. Patients had a mean age of 56, 48% were women, 42% were obese, 38% were white, 40% were black, 15% had cardiac disease, 39% had diabetes mellitus, 20% had liver disease, and 50% had respiratory disease. The need for MV was 6%. The optimal FIB-4 cutoff for the need for MV was 3.04 (area under the curve, 0.735), which had sensitivity, specificity, and positive and negative predictive values of 42%, 77%, 11%, and 95%, respectively, with 93% accuracy. When stratified by race, increased FIB-4 remained associated with the need for MV in both white and black patients. Conclusion: FIB-4 can be used by frontline providers to identify patients that may require MV.

Hepatic Steatosis, Rather Than Underlying Obesity, Increases the Risk of Infection and Hospitalization for COVID-19.

Objective: Obesity is a risk factor for SARS-COV2 infection and is often associated with hepatic steatosis. The aim of this study was to determine if pre-existing hepatic steatosis affects the risk of infection and severity for COVID-19. Design: Prospective cohort study (UK Biobank). Univariate and stepwise multivariate logistic regression analyses were performed on liver phenotypic biomarkers to determine if these variables increased risk of testing positive and being hospitalized for COVID-19; then compared to previously described risk factors associated with COVID-19, including age, ethnicity, gender, obesity, socio-economic status. Setting: UK biobank study. Participants: 502,506 participants (healthy at baseline) in the UK Biobank, of whom 41,791 underwent MRI (aged 50-83) for assessment of liver fat, liver fibro-inflammatory disease, and liver iron. Positive COVID-19 test was determined from UK testing data, starting in March 2020 and censored in January 2021. Primary and Secondary Outcome Measures: Liver fat measured as proton density fat fraction (PDFF%) MRI and body mass index (BMI, Kg/m2) to assess prior to February 2020 using MRI of the liver to assess hepatic steatosis. Results: Within the imaged cohort (n = 41, 791), 4,458 had been tested and 1,043 (2.49% of the imaged population) tested positive for COVID-19. Individuals with fatty liver (≥10%) were at increased risk of testing positive (OR: 1.35, p = 0.007) and those participants with obesity and fatty liver, were at increased risk of hospitalization with a positive test result by 5.14 times (p = 0.0006). Conclusions: UK Biobank data revealed obese individuals with fatty liver disease were at increased risk of infection and hospitalization for COVID-19. Public policy measures and personalized medicine should be considered in order to protect these high-risk individuals.

The Fibrosis-4 Index Is Associated With Need for Mechanical Ventilation and 30-Day Mortality in Patients Admitted With Coronavirus Disease 2019.

The Fibrosis-4 Index (FIB-4), developed to predict fibrosis in liver disease, was used to identify patients with coronavirus disease 2019 who will require ventilator support as well as those associated with 30-day mortality. Multivariate analysis found obesity (odds ratio [OR], 4.5), diabetes mellitus (OR, 2.55), and FIB-4 ≥2.67 (OR, 3.09) independently associated with need for mechanical ventilation. When controlling for ventilator use, sex, and comorbid conditions, FIB-4 ≥2.67 was also associated with increased 30-day mortality (OR, 8.4 [95% confidence interval, 2.23-31.7]). Although it may not be measuring hepatic fibrosis, its components suggest that increases in FIB-4 may be reflecting systemic inflammation associated with poor outcomes.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.