Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear. METHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. RESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity. CONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).

Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number; ClinicalTrials.gov identifier: NCT05296733. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis. METHODS: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study. Patients with biopsy-confirmed NASH and stage 3 fibrosis (N = 197) received weekly subcutaneous pegbelfermin (10, 20, or 40 mg) or placebo injections for 48 weeks. The week 24 primary endpoint was a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = 0.05). Secondary/exploratory endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: At week 24, the primary endpoint was met by 14% (placebo) vs 24%-31% (pegbelfermin arms); statistical significance was not reached due to lack of pegbelfermin dose response (P = .134). At weeks 24 and 48, more patients who received pegbelfermin had ≥30% relative reductions in hepatic fat fraction (magnetic resonance imaging-proton density fat fraction) vs placebo, although no differences reached statistical significance. In the pegbelfermin arms, improvements in liver fibrosis (magnetic resonance elastography and N-terminal type III collagen propeptide) and liver injury/inflammation (alanine aminotransferase, aspartate aminotransferase) were observed vs placebo. Adverse events occurred at similar frequencies across arms. No treatment-related serious adverse events were observed. CONCLUSIONS: The FALCON 1 study did not meet its primary endpoint; a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening assessed via biopsy. Pegbelfermin was generally well tolerated during 48 weeks of treatment.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis. METHODS: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P = .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). CONCLUSIONS: FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh A cirrhosis detected by an oral cholate challenge test.

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days' treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, -3.2 ± 2.7% for 2 mg twice-daily, and -6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates the use of function testing to measure hepatic improvement in clinical trials and the clinic.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis.

OBJECTIVE: In retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH. DESIGN: We used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3-F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis. RESULTS: Progression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis. CONCLUSION: The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.

Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat.

BACKGROUND & AIMS: Patients 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. METHODS: Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n = 33) or fenofibrate 145 mg daily (n = 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored. RESULTS: All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were -12 mg/dL (IQR, -33 to 7 mg/dL; P = .09) vs -32 mg/dL (IQR, -76 to 6 mg/dL; P = .012) and at 6 weeks were +41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs -2 mg/dL (IQR, -42 to 54 mg/dL; P = .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL). CONCLUSIONS: In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition. CLINICALTRIALS: gov, Number: NCT02781584.

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. The performance of these tests to discriminate advanced fibrosis was evaluated using areas under the receiver operating characteristics curves with 5-fold cross-validation repeated 100 times. RESULTS: Among 3207 patients screened with evaluable liver histology, 2281 were whites and 762 were Asians. Seventy-two percent of whites and 67% of Asians had advanced fibrosis. The areas under the receiver operating characteristics curves of the noninvasive tests for advanced fibrosis were similar in whites and Asians: 0.73 and 0.75 for NFS, 0.78 and 0.80 for FIB-4, 0.79 and 0.81 for ELF, and 0.80 and 0.83 for liver stiffness, respectively. At the published cutoffs, the tests had similar sensitivities and specificities in the 2 groups. However, the sensitivities of NFS, FIB-4, and ELF were low in both white and Asian patients younger than 40 years. CONCLUSIONS: In the global phase III STELLAR trials, the diagnostic performance of routinely available noninvasive tests for the detection of advanced fibrosis due to NASH was acceptable and similar between white and Asian patients.

BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial.

BACKGROUND AND AIMS: Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. We evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis. APPROACH AND RESULTS: NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the United States. Patients with HCV-SVR (for ≥ 1 year) and advanced fibrosis received once-weekly i.v. infusions of placebo or BMS-986263 (45 or 90 mg) for 12 weeks. The primary endpoint was ≥ 1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment, and 2/15 (13%, placebo), 3/18 (17%, 45 mg), and 6/28 (21%, 90 mg) had METAVIR improvements of ≥ 1 stage at Week 12. Five patients in the 90-mg arm had Ishak improvements by ≥ 2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients. CONCLUSIONS: In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.

Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. APPROACH AND RESULTS: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. CONCLUSIONS: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.

Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients.

De novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with metabolic, fibrotic, and imaging markers. We found that hepatic DNL was higher in patients with fibrotic NASH [median (IQR), 40.7% contribution to palmitate (32.1, 47.5), n=103] than has been previously reported in healthy volunteers and remained elevated [median (IQR), 36.8% (31.0, 44.5), n=20] in patients with cirrhosis, despite lower liver fat content. We also showed that turnover of intrahepatic triglyceride pools was slow (t½ >10 days). Furthermore, DNL contribution was determined to be independent of liver stiffness by magnetic resonance imaging but was positively associated with the number of large very low density lipoprotein (VLDL) particles, the size of VLDL, the lipoprotein insulin resistance score, and levels of ApoB100, and trended toward negative associations with the fibrosis markers FIB-4, FibroSure, and APRI. Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH and demonstrate that response to pharmacological agents targeting DNL can be correlated with pretreatment DNL.

The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis.

BACKGROUND & AIM: Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH. METHODS: Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected. RESULTS: A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P < .0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P < .01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P < .05). CONCLUSIONS: Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063).

A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH.

BACKGROUND AND AIMS: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APPROACH AND RESULTS: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression. CONCLUSIONS: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial.

BACKGROUND AND AIMS: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). APPROACH AND RESULTS: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). CONCLUSIONS: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

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). 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.

Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: Pegbelfermin (BMS-986036), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. In this phase 2a study, we aimed to evaluate the safety and efficacy of pegbelfermin in patients with non-alcoholic steatohepatitis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2a study, we recruited adults (aged 21-75 years) with a body-mass index of at least 25 kg/m2, biopsy-confirmed non-alcoholic steatohepatitis (fibrosis stage 1-3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton density fat fraction. These patients were enrolled at 17 medical centres in the USA. Eligible patients were stratified by type 2 diabetes status and they were randomly assigned (1:1:1) by a computer-based system to receive subcutaneous injections of placebo once a day, 10 mg pegbelfermin once a day, or 20 mg pegbelfermin once a week, all for 16 weeks. Participants, the study team administering treatment, and investigators analysing outcomes (who were independent of the study team and had no further involvement) were masked to treatment groups. The primary outcomes were safety and the absolute change in hepatic fat fraction after 16 weeks of treatment. All patients who were randomly assigned to groups and received the study drug or placebo were included in the primary analyses. This trial was registered with ClinicalTrials.gov, number NCT02413372. FINDINGS: Between May 12, 2015, and Aug 4, 2016, 184 overweight or obese patients with non-alcoholic steatohepatitis were screened for study inclusion. Of these, 95 (52%) patients were excluded because they no longer met study criteria and 80 (43%) patients entered the placebo lead-in phase. After further exclusions, 75 (94%) patients were randomly assigned to groups, received at least one dose of treatment (25 patients to receive 10 mg pegbelfermin once a day; 24 patients to receive 20 mg pegbelfermin once a week, and 26 patients to receive placebo), and were included in the primary analysis. A prespecified interim analysis at week 8 showed a greater than expected change in the primary outcome and supported early closing of patient enrolment, since this analysis indicated that the full planned sample size was not needed. We observed a significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (-6·8% vs -1·3%; p=0·0004) and in the group receiving 20 mg pegbelfermin weekly (-5·2% vs -1·3%; p=0·008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events. INTERPRETATION: Treatment with subcutaneously administered pegbelfermin for 16 weeks was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alcoholic steatohepatitis. Further study of pegbelfermin is warranted in patients with non-alcoholic steatohepatitis. Additional studies that use liver biopsies would allow for the assessment of pegbelfermin's effects on liver histology. Moreover, further studies should allow assessments of the safety and effectiveness of pegbelfermin in a larger number of patients. FUNDING: Bristol-Myers Squibb.

Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infections who achieve a sustained virologic response (SVR) to treatment have improved patient-reported outcomes (PROs). We compared post-treatment PRO scores between patients with chronic HCV infection who did and did not achieve an SVR to treatment. METHODS: Patients who completed treatment in clinical trials were enrolled in 2 registries, depending on the treatment outcome (NCT01457755, NCT01457768), from 2016 to 2017 in 17 countries in North America, Europe, and the Asia-Pacific region. PRO scores (scale, 0-100) were collected at pretreatment (baseline); the last day of treatment; the post-treatment week 12 follow-up visit (in patients with SVR only); the registry baseline; and on registry weeks 12, 24, 36, 48, and 96 (the non-SVR registry) or every 24 weeks until week 96 (SVR registry), using the Short Form-36 (SF-36) instrument. RESULTS: Our analysis included 4234 patients with an SVR and 242 without an SVR from whom pretreatment PRO data were available (mean age, 54 ± 10 y; 63% male; 65% enrolled in the United States; 17% with cirrhosis; 12% with human immunodeficiency virus co-infection). Upon registry enrollment, patients with an SVR had significant increases in all PRO scores compared with pretreatment baseline levels (all P < .05). Patients without an SVR had mean reductions of 9.2 points or less in PRO scores while followed up on the registry (P < .05 for 4-8 of 8 PRO domains measured by the SF-36). In contrast, patients with an SVR had sustained increases in PRO scores (mean increase, ≤7.0 points) while on the registry. In multivariate analysis, achieving an SVR was associated independently with superior scores in all SF-36 domains at all registry time points (ß, +4.8 to +15.9 points, all P ≤ .01). CONCLUSIONS: In a follow-up analysis of participants in clinical trials, we found that those with an SVR to treatment for HCV infection had significant increases in well-being, based on PRO scores. Patients without an SVR had decreasing PRO scores over the follow-up period.