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BackgroundConvenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19.MethodsThis phase 3, randomized, multicenter, open-label study tested non-inferiority of IM to IV administration using a 3.5% absolute non-inferiority margin. From June to August 2021, patients aged ≥12 years with COVID-19, not hospitalized or receiving supplemental oxygen, and at high risk for progression were randomized 1:1:1 to a single 500-mg IV sotrovimab infusion or 500-mg or 250-mg IM sotrovimab injection. The primary composite endpoint was progression to all-cause hospitalization for >24 hours for acute management of illness or all-cause death through day 29.ResultsSotrovimab 500 mg IM was non-inferior to 500 mg IV: 10/376 (2.7%) participants in the sotrovimab 500-mg IM group versus 5/378 (1.3%) in the sotrovimab 500-mg IV group met the primary endpoint (absolute adjusted risk difference: 1.06% [95% confidence interval [CI]: −1.15%, 3.26%]). The CI upper limit was lower than the prespecified non-inferiority margin of 3.5%. 250-mg IM group enrollment was discontinued early because a greater proportion of hospitalizations was seen in that group versus the 500-mg groups. Serious adverse events occurred in ConclusionsSotrovimab 500-mg IM injection was well tolerated and non-inferior to IV administration. IM administration could expand outpatient treatment access for COVID-19.RegistrationClinicalTrials.govIdentifier:NCT04913675Key PointsSotrovimab 500-mg IM was non-inferior to sotrovimab 500-mg IV for treatment of mild/moderate COVID-19 in high-risk patients, measured by all-cause hospitalization >24h or death through day 29, and was well-tolerated. Sotrovimab IM should provide easier outpatient access to COVID-19 treatment.

Background & aimsPatients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR.MethodsPatients with NASH with elevated triglycerides (≥150 and

Background Sotrovimab (VIR-7831) is an engineered human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike protein; it has been shown to have a favorable safety profile and be effective for early treatment of high-risk COVID-19 patients. The COMET-TAIL phase 3 study evaluated sotrovimab administered intravenously (IV) or intramuscularly (IM) for the treatment of participants with mild to moderate COVID-19 who are at high risk of disease progression. Methods Between June to August 2021, 973 participants were randomized and received sotrovimab by 500 mg IV infusion or by 500 or 250 mg IM injection. Deep sequencing of the spike gene was performed on nasopharyngeal samples. Baseline (BL; Day 1 or Day 3), post-BL (Day 5 or later), treatment-emergent (TE) substitutions at sotrovimab epitope positions, and presence of variants of concern/interest (VOC/VOI), were evaluated at a ≥5% allelic frequency. Phenotypic analyses were conducted using a pseudotyped virus assay. Results Sequences were available from 764 participants (500 mg IV: 314/393; 500 mg IM: 302/387; 250 mg IM: 148/193). Consistent with VOC circulation during enrollment, the Delta variant was detected in 88.2% (674/764) of participants. Alpha and Mu variants were also seen at >2% prevalence. Of the 764 participants, 26 met the primary endpoint for clinical progression to hospitalization >24 hours or death due to any cause through day 29 and were infected with Delta (500 mg IV: 4; 500 mg IM: 9; 250 mg IM: 11), Alpha (500 mg IM: 1), or Mu (500 mg IV: 1) variants. Substitutions at sotrovimab epitope positions were similar across arms and were detected in 82/764 (10.7%) participants at any visit (500 mg IV: 42/314; 500 mg IM: 27/302; 250 mg IM: 13/148). Of these, 2 participants experienced clinical progression: 1 participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution at BL; 1 participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions detected at Day 3 and P337L was enriched at Day 8. The predominant TE epitope substitutions included P337L and E340A/K/V, which confer reduced susceptibility to sotrovimab in vitro. Conclusion Overall, TE epitope substitutions were not associated with clinical progression. Funding Vir & GSK (NCT04913675) Disclosures Maria L. Agostini, PhD, Vir Biotechnology, Inc: Employee|Vir Biotechnology, Inc: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Julia di Iulio, PharmD, PhD, MBA, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Anita Kohli, MD, GlaxoSmithKline: Third party funding to Vir|Vir Biotechnology Inc: Support as a trial site paid to my institution and non-financial support for medical writing support Adrienne E. Shapiro, MD, PhD, Vir Biotechnology: Support as a trial site paid to my institution and non-financial support for medical writing GlaxoSmithKline third party funding to Vir support Elias H. Sarkis, MD, Abbvie: Grant/Research Support|Abbvie: Speakers Bureau|Eisai: Grant/Research Support|GlaxoSmithKline: Third party funding to Vir|Ironshore: Grant/Research Support|Janssen: Speakers Bureau|Lilly: Grant/Research Support|Otsuka: Grant/Research Support|Teva: Speakers Bureau|Vir Biotechnology Inc: Support as a trial site paid to my institution and non-financial support for medical writing support Dave Inman, MSc, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Leah A. Gaffney, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Christy M. Hebner, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds.

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease −4.8% vs. −2.0% (p = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes., Berberine ursodeoxycholate has been studied for its serum lipid and lipoprotein lowering effects. Here the authors report an 18-week phase 2, randomised, double-blind, placebo-controlled clinical trial that tested the effect of berberine ursodeoxycholate in patients with fatty liver disease and diabetes, and showed that the group taking the higher dose of the drug had reduced liver fat content.

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 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF −22.9% vs −5.7%, HOMA-IR −4.4 vs +0.7, ALT −21.9% vs −7.2%, K-18 M65 −13.6% vs +20.1%, cT1 −69.6 vs +18.3 ms (P < 0.05), and Pro-C3 −13.6% vs −3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF −8.1%, HOMA-IR +8.4, ALT −20.7%, K-18 M65 6.6%, cT1 −34.7 ms, and Pro-C3 −15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

Patient‐reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo‐controlled study of selonsertib, firsocostat, or cilofexor, alone or in two‐drug combinations (NCT03449446). PROs included Short Form 36 (SF‐36), Chronic Liver Disease Questionnaire (CLDQ)‐NASH, EuroQol Five Dimension (EQ‐5D), Work Productivity and Impairment (WPAI), and 5‐D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF‐36 and Fatigue and Worry of CLDQ‐NASH were significantly lower in patients with cirrhosis (total CLDQ‐NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P, As treatment for NASH advances, it is important to know the new treatments improve patients' experiences with their disease. Furthermore, the side effect profile of the new regimens should not add further impairment on PROs. This knowledge can assist healthcare practitioners counsel patients on expectations of treatment when they become available.

Background Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. Methods In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients. Results Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. Conclusions In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

We assessed the performance of machine learning (ML) models in identifying clinically significant NAFLD-associated liver fibrosis and cirrhosis.We implemented ML models including logistic regression (LR), random forest (RF), and artificial neural network to predict histological stages of fibrosis using 17 demographic/clinical features in 1370 patients with NAFLD who underwent liver biopsy, FibroScan, and labs within a 6-month period at multiple U.S.Histological stages of fibrosis (≥F2, ≥F3, and F4) were predicted using ML, FibroScan liver stiffness measurements, and Fibrosis-4 index (FIB-4). NASH with significant fibrosis (NAS ≥ 4 + ≥F2) was assessed using ML, FibroScan-AST (FAST) score, FIB-4, and NAFLD fibrosis score (NFS). We used 80% of the cohort to train and 20% to test the ML models. For ≥F2, ≥F3, F4, and NASH + NAS ≥ 4 + ≥F2, all ML models, especially RF, had primarily higher accuracy and AUC compared with FibroScan, FIB-4, FAST, and NFS. AUC for RF versus FibroScan and FIB-4 for ≥F2, ≥F3, and F4 were (0.86 vs. 0.81, 0.78), (0.89 vs. 0.83, 0.82), and (0.89 vs. 0.86, 0.85), respectively. AUC for RF versus FAST, FIB-4, and NFS for NASH + NAS ≥ 4 + ≥F2 were (0.80 vs. 0.77, 0.66, 0.63). For NASH + NAS ≥ 4 + ≥F2, all ML models had lower/similar percentages within the indeterminate zone compared with FIB-4 and NFS. Overall, ML models performed better in sensitivity, specificity, positive predictive value, and negative predictive value compared with traditional noninvasive tests.ML models performed better overall than FibroScan, FIB-4, FAST, and NFS. ML could be an effective tool for identifying clinically significant liver fibrosis and cirrhosis in patients with NAFLD.

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).In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed.Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups.Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials.NGM Biopharmaceuticals.

Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory.A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis.In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH.NCT03987074.Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Background & aims Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).

BackgroundContinued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV® (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo.MethodsThis final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with ≥1 COVID-19–related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2–positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients.ResultsData from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; PPP=.0003) log10 copies/mL in serum antibody–negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with ≥1 COVID-19–related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with ≥1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups.ConclusionsIn COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19–related MAVs.

Background: AXA1125, an investigational composition of 5 amino acids and n-acetyl-cysteine, targets multiple biologies relevant to NAFLD pathogenesis. Methods: Primary human hepatocytes (PHH) from multiple donors were pretreated with AXA1125 components (LIVRQNac), exposed to lipotoxic insult in the presence of LIVRQNac, incubated in high glucose insulin-free medium, followed by glucose-free medium±insulin. Human safety, tolerability, and biologic activity were evaluated in a 16-week, multicenter, randomized, placebo (Pbo)-controlled study (NCT04073368) in subjects with NAFLD±T2D. Results from Pbo and AXA1125 24 g twice daily dosing in subjects with T2D are reported. Results: In PHH, LIVRQNac reduced glucose output by ~50% (p Conclusions: This concordant multifactorial biologic activity, including the effects on glucose homeostasis, suggests a potential enhanced impact of AXA1125 in NAFLD subjects with diabetes that warrants further investigation. Disclosure S. Baum: Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. J. Zhao: Employee; Self; Axcella Health Inc., Stock/Shareholder; Self; Axcella Health Inc. M. Chakravarthy: None. M. Koziel: None. S. A. Harrison: Consultant; Self; Axcella Health Inc. N. T. Gunn: None. Z. Younes: Research Support; Self; Axcella Health Inc., Novo Nordisk. A. Kohli: Research Support; Self; Axcella Health Inc., Novo Nordisk. R. Patil: Speaker’s Bureau; Self; Intercept Pharmaceuticals, Inc. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. M. Hamill: Employee; Self; Axcella Health Inc. N. Daou: None. Funding Axcella Health Inc.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and diabetes and may lead to progressive liver disease although current treatment options are limited. Berberine ursodeoxycholate is an ionic salt of berberine and ursodeoxycholic acid, representing a new molecular entity that offers the possibility of combination therapy for NASH in a single treatment.Methods: A prospective, randomized, double-blind, placebo-controlled trial of two doses of berberine ursodeoxycholate administered orally was conducted in a cohort of 100 subjects with fatty liver disease and diabetes. Treatment was for 18 weeks and endpoints measured included reduction in liver fat content measured by MRI proton density fat fraction, improvement in glycemic control, changes in liver-associated enzymes, safety and tolerability.Results: Subjects that received 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content compared to placebo (mean absolute decrease -4.8% vs. -2.0% [p=0.011], mean relative decrease -24.1 vs -8.3% [p=0.016]). Also, compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in serum alanine aminotransferase and gamma glutamyl transferase activities. Serum lipid levels decreased modestly during therapy. The higher dose of berberine ursodeoxycholate was associated with an average weight loss (LS Mean) of -3.5kg compared to only -1.1kg with placebo (p=0.012). Diarrhea and abdominal discomfort were the most frequently reported adverse events. Conclusions: Berberine ursodeoxycholate is single molecule with a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and data from this phase 2 randomized controlled trial supportr its further development as a treatment for NASH with diabetes.

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. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. Results At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%−1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. Conclusions In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.

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. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have higher levels of immune activation, impaired antigen-specific responses, and accelerated fibrogenesis compared to patients monoinfected with HCV. Whether different direct-acting antiviral (DAA) combinations have differential effects on immunophenotypes and functions following successful HCV therapy remain unknown. Therefore, we aimed to assess the peripheral T-cell immunophenotypes and functions in patients coinfected with HIV/HCV who were successfully treated with combination DAA treatment regimens. We analyzed peripheral blood mononuclear cells (PBMCs) at baseline and at the time of sustained viral response (SVR) from subjects treated with three different combination DAA regimens: daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks (CONQUER 2-DAA), DCV/ASV/beclabuvir (BCV) for 12 weeks (CONQUER 3-DAA), and sofosbuvir (SOF) and ledipasvir (LDV) for 12 weeks (ERADICATE study). We used flow cytometry to assess T-cell phenotypes (activation and exhaustion) and HCV-specific T-cell functions (cytokine secretion and cytotoxicity). Statistical analyses were conducted using the Wilcoxon matched-pairs signed-rank test with P < 0.05 considered significant. Overall, there was an improvement in T-cell exhaustion markers, a decrease in T-cell activation, an increase in the effector memory population, and improved T-cell function after achieving SVR, with the largest effects noted with CONQUER 3-DAA treatment. Conclusion: Treatment with DCV/ASV/BCV in patients coinfected with HIV/HCV resulted in greater restoration of the T-cell impairments and perturbations associated with HIV/HCV coinfection to an extent that was greater than that observed in either two-drug regimens. We showed that different DAA-based therapies have different immunologic outcomes after successful HCV treatment in patients coinfected with HIV/HCV. This information will be beneficial for providers when selecting the regimens for patients coinfected with HIV/HCV.

High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.

Treatment of chronic hepatitis C virus (HCV) infection with direct‐acting antivirals results in a rapid decline in viral load and markers of hepatic inflammation, including serum chemokine (C‐X‐C motif) ligand 10 (CXCL10) concentration, which is followed in most cases by a sustained virologic response. Whether parallel changes of significance occur in the cellular composition of peripheral blood is relatively unknown. We hypothesized that longitudinal characterization of peripheral blood during treatment would provide insight into cellular migration and immune activation, which would have implications for understanding host immunity both before and after HCV treatment and may relate to HCV clearance. We analyzed longitudinal peripheral innate and adaptive immune cell populations by flow cytometry from 95 subjects enrolled in two direct‐acting antiviral clinical trials and examined chemokine receptor expression on T lymphocytes in 43 patients. Within 1‐2 weeks of initiating treatment, significant increases were observed in the concentration of peripheral cluster of differentiation 4–positive (CD4+) and CD8+ T lymphocytes but not monocyte or natural killer cells. In tandem with these changes, the percent of both CD4+ and CD8+ T lymphocytes with an activated phenotype (human leukocyte antigen [HLA] DR+ and CD38+) decreased, and T‐lymphocyte surface expression of chemokine (C‐X‐C motif) receptor 3, the chemokine receptor for CXCL10, increased. Conclusion: Rapid changes in peripheral cellular populations occur during direct‐acting antiviral treatment of HCV infection, which could potentially relate to hepatic efflux of tissue lymphocytes due to altered inflammation and chemokine receptor signaling, providing critical insight into the relationship between host immunity and viral clearance during HCV infection. (Hepatology Communications 2017;1:586–594)

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. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis‐4 (FIB‐4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration‐controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5‐fold cross‐validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0‐F2 fibrosis and 2,262 with F3‐F4 fibrosis. Significant differences between median values of NITs for patients with F0‐F2 versus F3‐F4 fibrosis were observed: −0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB‐4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB‐4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB‐4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real‐world population.

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). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. Results Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. Conclusions Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. Lay summary Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. Trial registration details Clinicaltrials.gov numbers NCT03053050 and NCT03053063.

Background Treatment for chronic hepatitis C virus (HCV) has rapidly evolved to simple, well-tolerated, all-oral regimens of direct-acting antivirals (DAAs). There are few data on the epidemiology of HCV in American Indians/Alaska Natives (AI/ANs), a population disproportionately affected by HCV. Methods In this retrospective cohort study, all HCV-infected AI/AN patients treated with DAA therapies between January 1, 2014, and February 24, 2016, in specialty clinics or by primary care clinicians participating in Extension for Community Healthcare Outcomes (ECHO) were included. Demographic, clinical, and virologic data on all patients treated for HCV from pretreatment through sustained virologic response at 12 weeks (SVR12) were collected. Results Two hundred eighty patients were included; 71.1% of patients (n = 199) were infected with genotype 1 (GT1), 18.2% (n = 51) with GT2, and 10.7% with (n = 30) GT3. At baseline, 26.1% (n = 73) patients had cirrhosis and 22.6% (n = 56) had active substance use disorder; eighty-eight percent (n = 232) of patients achieved SVR12. Among the 165 GT1 patients treated with sofosbuvir (SOF)/ledipasvir for 8, 12, and 24 weeks, SVR12 was achieved by 91.5% (n = 54), 92.2% (n = 71), and 100% (n = 13), respectively. Among GT2 patients, 87.2% (n = 34) and 71.4% (n = 5) treated with 12 and 16 weeks of SOF/ribavirin (RBV) achieved SVR12, respectively. Among GT3 patients, 100% (n = 2) and 83.3% (n = 20) treated with 12 and 24 weeks of SOF/RBV achieved SVR12, respectively. SVR12 rates remained high among patients with active substance use disorder. Conclusions DAA therapies are highly efficacious in HCV-infected AI/ANs. SVR12 rates remained high among patients with active substance use disorder. More steps must be taken to increase access to treatment for this underserved, vulnerable population.

Background There is a major unmet need for accurate, readily available, noninvasive tests (NITs) to identify patients with advanced fibrosis due to NASH. Our goal was to evaluate sequential NIT algorithms to minimize the requirement for biopsy and improve accuracy overuse of single tests. Methods The STELLAR studies (NCT03053050, NCT03053063) enrolled NASH patients with bridging fibrosis (F3) or compensated cirrhosis (F4). Baseline liver biopsies were read using the NASH CRN fibrosis classification and noninvasive fibrosis markers: FIB-4 index, ELF test, and FibroScan® (FS). The performance of these tests to discriminate advanced fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Thresholds were obtained by maximizing specificity given ≥85% sensitivity. The cohort was divided (80%/20%) into evaluation/validation sets. The evaluation set was further stratified 250x into training and test sets (66%/33%). Optimal thresholds were derived as the average across training sets, and applied sequentially (FIB-4 followed by ELF and/or FS) to the validation set. Data are from an interim analysis on 26 July 2018. Results All patients with available liver histology (N=3202, 71% F3-F4) and NIT results were included. While single tests were able to discriminate advanced fibrosis (AUROCs of 0.78, 0.80, and 0.80 for FIB-4, ELF, and FS in validation cohort), up to 32% of patients had an indeterminate result. Using thresholds derived from STELLAR data, FIB-4 followed by FS or ELF in those with indeterminate FIB-4 values (1.23 to 2.1) reduced indeterminate results to as low as 13% (table 1). Published NIT thresholds yielded similar results (data not shown). Adding a third test (FIB-4 then ELF then FS) reduced the rate of indeterminate results to 8%. Misclassification occurred at rates similar to biopsy (15–21%). The majority of misclassifications (63–81%) were false negatives; among false positive cases (19–27% of misclassifications) up to 70% had F2 fibrosis. Conclusions FIB-4 followed by ELF and/or FS nearly eliminated the need for liver biopsy and accurately identified patients with advanced fibrosis due to NASH with misclassification rates similar to liver biopsy.

Background Liver biopsy is currently the reference standard for fibrosis staging, but is an invasive procedure with limitations. There are a major unmet need for accurate, readily available noninvasive tests (NITs) to identify patients with advanced fibrosis due to NASH. Our aim is to describe the performance of NITs using the baseline data from the Phase 3 STELLAR studies of the ASK1 inhibitor selonsertib (SEL). Methods The STELLAR studies (NCT03053050 and NCT03053063) enrolled patients with bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH (NAFLD Activity Score [NAS] ≥3). Baseline liver biopsies were centrally read according to the NASH CRN fibrosis classification and noninvasive markers of fibrosis, including the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness (LS) by transient elastography (TE; FibroScan®) were measured. The performance of these tests to discriminate advanced (F3-F4) fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Optimal thresholds for F3-F4 fibrosis were selected based on the literature. Data presented are from an interim analysis on 1 May 2018. Results A total of 4467 patients (median age 58 years, 55% women, 72% Caucasian, 59% with diabetes) were screened. In the 3220 with evaluable histology, median biopsy length was 2.0 cm, 8% F0, 9% F1, 13% F2, 31% F3, 40% F4, 59% with NAS ≥5. Median values of NFS, FIB-4, ELF, and LS by TE increased with worsening fibrosis (-0.962/1.19/9.21/8.8 kPa in F0-F2 vs 0.342/2.20/10.39/16.5 kPa in F3-F4 respectively). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis (table 1). When tests were combined, performance characteristics improved and PPVs ≥98% were possible. Conclusions In these large, global phase 3 trials of SEL, routinely available NITs demonstrated acceptable diagnostic performance for the discrimination of advanced fibrosis due to NASH.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

In this review we critically assess the literature to evaluate the level of risk posed by alcohol as both a primary etiology of hepatocellular carcinoma (HCC) and as a cofactor in its development. Although there have been conflicting findings, based on the body of evidence to date, it appears that the linkage between compensated alcoholic liver disease-associated cirrhosis and HCC is best characterized as medium-high risk, with the risk increasing with age and with quantity and duration of alcohol consumption and is more pronounced in females. While abstinence is the most effective way to reduce HCC risk, its effect seems largely dependent on the severity of liver damage at the point of cessation. Alcohol clearly interacts with other etiologies and conditions including viral hepatitis B and C, hereditary hemochromatosis, diabetes, and obesity to increase the risk for developing HCC, either synergistically or additively. Continued progress in genetics, especially through mechanistic-based and genome-wide association studies may ultimately identify which single nucleotide polymorphisms are risk factors for the onset of alcoholic liver disease and its progression to HCC and lead to the development of targeted therapeutics which may help providers better manage at-risk patients.

Historically, chronic hepatitis C virus (HCV) treatment was response-guided. Clinical trials with sofosbuvir indicated on-treatment virologic response was not predictive of sustained virologic response (SVR) and hence response-guided therapy (RGT) was abandoned. The purpose of this study is to examine the association between on-treatment 4-week HCV RNA and SVR in patients treated in real-world practice. The study is a retrospective analysis of consecutive patients started on treatment with a sofosbuvir-containing regimen, January 1, 2014 through August 20, 2014, for HCV genotype 1–6 infection. Patients were treated by HCV specialists at 6 centers in the Project ECHO (Extension for Community Healthcare Outcomes) HCV Collaborative or in the community by primary care clinicians mentored by HCV specialists through Project ECHO. Patients were included if they were over 18 years, had evidence of chronic HCV, and were started on a sofosbuvir-containing regimen. The aspartate aminotransferase:platelet ratio index (APRI) was used to estimate fibrosis. The main outcome measures were 4-week HCV RNA and SVR. Overall SVR was 82.5 %. At week 4, HCV RNA was detected in 27.4 % of patients. Stepwise multivariable logistic-regression analyses identified APRI > 1.0, male sex, genotype 3, and detectable on treatment 4-week HCV RNA as independent predictors of failure to achieve SVR. In a real-world setting, a significant proportion of sofosbuvir treated patients have detectable on-treatment 4-week HCV RNA. Detectable on-treatment 4-week HCV RNA is associated with virologic failure. More data are needed to formulate guidance for RGT with newly available HCV therapies.

This review summarizes published data on sofosbuvir-based regimens for patients infected with HCV GT1 with a focus on evaluating the optimal and possible durations of treatment. Methods: PubMed and conference abstract books published between 2011–2015 were searched. Results: HCV treatment has decreased from 24 week regimens to studies done as short as 4 weeks. History of prior treatment or cirrhosis have consistently shown lower SVR12 rates with shorter duration therapies. Low cure rates have been seen in patients within 4 week trials, however, select patients with low fibrosis scores, low HCV VL and HCV GT-1b have moderate cure rates. Conclusion: Most patients will require 12–24 weeks of therapy. Further studies are needed to elucidate the predictors of treatment response to short duration therapies and optimal combination of DAAs.

Background As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described. Methods Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report. Results Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report. Conclusions Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence. Electronic supplementary material The online version of this article (doi:10.1007/s12072-015-9680-7) contains supplementary material, which is available to authorized users.