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A third of patients with type 2 diabetes (T2D) are estimated to have nonalcoholic steatohepatitis (NASH). There is a high unmet need for safe and effective therapies that can address liver health and metabolic comorbidities in NASH patients. Efruxifermin (EFX), a long-acting Fc-FGF21 fusion protein, demonstrated robust reductions in liver fat content, markers of liver injury and fibrosis, and improved lipid and glucose metabolism in patients with NASH and fibrosis stage 1-3.1 Patients (N=80) were randomized to receive placebo or 28, 50, or 70mg EFX for 16 weeks, and continued on their existing antidiabetic medications. The aim of this analysis was to evaluate the effects of EFX on markers of glucose metabolism in patients with NASH and in the subgroup with T2D (N=41). Mean age, BMI and HbA1c at baseline were 52y, 37.6 kg/m2 and 6.3% in the overall study population, and 53y, 38.1 kg/m2, and 7.0% in the T2D subgroup. Clinically meaningful improvements in glycemic control were observed in the T2D subgroup (Table B), consistent with improvements in markers of glucose metabolism in the overall population (Table A), and with the insulin-sensitizing actions of EFX. Considering the prevalence of T2D in NASH, the ability to improve glycemic control over existing medications is a desirable attribute for future NASH therapies. 1Harrison et. al. 2020. Hepatology, 72; 1S; 6A Disclosure: J. 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. S. A. Harrison: Consultant; Self; Axcella Health Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. C. Hu: None. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. [ABSTRACT FROM AUTHOR]

Objective: Severe diarrhea-predominant irritable bowel syndrome (IBS-D) is associated with decreased health-related quality of life (HRQOL) and increased health care costs. Treatment recommendations for IBS-D often start with traditional pharmacotherapy (TP), with escalation to alosetron, rifaximin or eluxadoline if there is no success. There has been no previous head-to-head clinical trial comparing IBS-D treatment outcome for alosetron versus TP. This study, GSK protocol S3B30020, evaluated resource use, work productivity, health-related quality of life and global symptom response in women with IBS-D who were treated with alosetron or TP.Methods: A total of 1956 patients who met criteria for severe IBS-D were randomized to treatment with alosetron 1 mg twice daily (BID) or only TP for up to 24 weeks. Work productivity and resource use were evaluated by standard questionnaires, HRQOL by the IBSQOL instrument and IBS symptoms by the Global Improvement Scale (GIS).Results: Compared to only TP, alosetron-treated patients reported: (1) fewer clinic/office visits for any health problem (p = .0181) or for IBS-D (p = .0004); (2) reduced use of over-the-counter medications for IBS-D (p < .0001); (3) fewer days of lost work productivity (p < .0001); (4) decreased restriction of social and outdoor activities (p < .0001); and (5) greater global improvement in IBS-D symptoms (p < .0001). Alosetron treatment improved HRQOL scores for all domains (p < .0001). Incidence of adverse events during alosetron use was not remarkable and was similar to that previously reported.Conclusions: Alosetron 1 mg BID significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, HRQOL, and participation in outdoor and social activities compared with treatment response to TP. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. NCT02548351 Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy. [Display omitted] • Reduced ALT, AST, GGT, FIB-4, and FibroTest scores were seen with OCA vs. placebo. • Reduced liver stiffness by VCTE was observed in OCA vs. placebo arms at Month 18. • NIT changes in OCA treatment arms were associated with shifts in fibrosis stage. • The antifibrotic effect of OCA might be measurable with commonly used NITs. [ABSTRACT FROM AUTHOR]

FGF21, an endocrine hormone that regulates whole-body metabolism during energy imbalance, is a promising therapeutic target. Efruxifermin (EFX), an Fc-FGF21 analog, is a balanced FGFR1c, 2c, and 3c agonist under investigation as a potential treatment for nonalcoholic steatohepatitis (NASH). In a clinical trial in biopsy-confirmed NASH, EFX significantly reduced liver fat content (LFC), ALT, and AST, and increased adiponectin.1 Activating FGFR1c in adipose tissue increases circulating adiponectin; the aim of this analysis was to evaluate correlations between changes in adiponectin and markers of dyslipidemia, glucose metabolism and liver health following EFX treatment. Patients (N=80) were randomized to placebo or 28, 50, or 70mg EFX. Larger increases in adiponectin correlated with greater improvements in lipid profiles, including decreases in triglycerides and increases in HDL-C, as well as decreases in LFC (Table). Increases in adiponectin also correlated strongly with markers of improved glucose metabolism, and greater reductions in markers of liver injury and fibrosis. These data suggest adipose tissue-mediated effects of EFX contribute substantially to restoration of liver health, healthy lipoprotein profiles, insulin sensitivity and glucose tolerance. 1 Harrison 2020 Hepatol 72 1S; 6A Disclosure: J. 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. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. S. A. Harrison: Consultant; Self; Axcella Health Inc. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐invasive biomarkers are needed for monitoring changes in liver histology in patients with non‐alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non‐invasive fibrosis markers and liver fibrosis improvement. Methods: In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis‐4 (FIB‐4) index and non‐alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks. Results: In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB‐4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB‐4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1‐stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB‐4 (P < 0.0001); NFS (P < 0.05)]. Conclusions: Readily available non‐invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials. See Editorial on Page 812 [ABSTRACT FROM AUTHOR]

Background Rifamycin SV is under development for treatment of travelers' diarrhea ( TD) in a new oral formulation, Rifamycin SV MMX® ( RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug. Methods This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo ( n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool ( TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration ( MIC), and adverse events (AEs). Results TLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections ( p = 0.0035) with nonsignificant activity against invasive bacteria ( p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance ( p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%). Conclusions RIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. ClinicalTrials.gov with the identifier NCT02548351. [ABSTRACT FROM AUTHOR]