POISE (phase 3)68: patients with PBC with insufficient biochemical response or intolerance to UDCA showed improvement of ALP and other liver enzymes when treated with 5–10 mg (uptitration) or 10 mg OCA for 12 months. Total bilirubin concentrations stabilised. Side effects: pruritus, fatigue, increased LDL cholesterol. Long-term data (up to 5 years) confirm phase 3 efficacy and safety data, 4% withdrew treatment.69.

COBALT (NCT02308111): ongoing phase 4 study, evaluates long-term clinical outcomes in patients with PBC.

AESOP (phase 2)241: In patients with PSC, ALP was significantly reduced by 5–10 mg OCA but not by 1.5–3 mg OCA over 24 weeks.

FLINT (phase 2b)77: 25 mg OCA for 18 months improved NAFLD activity score (predefined primary endpoint) and its individual components, but did not result in significantly higher NASH resolution (22 vs 13% compared with placebo); however, a higher proportion of patients (35 vs 19%) showed improved fibrosis (by at least one stage). Side effects: pruritus and hypercholesterolaemia (increased LDL cholesterol, reduced HDL cholesterol).

REGENERATE (phase 3)78: 18-month interim analysis in patients with non-cirrhotic NASH (F2 or F3) showed that 25 mg OCA significantly improved fibrosis by >1 stage (23% vs 12% under placebo) but not NASH (12% vs 8%, n.s.).

REVERSE (NCT03439254): ongoing phase 3 study evaluating whether OCA improves in fibrosis with no worsening of NASH in adults with compensated cirrhosis due to NASH.

PSC (phase 2)103: 12 weeks of cilofexor improved serum ALP, γGT, AST, ALT, bile acid and C4 levels. No pruritus (even trend for improvement).

PRIMIS (NCT03890120): ongoing phase 3 evaluating whether cilofexor reduces the risk of fibrosis progression in non-cirrhotic patients with PSC.

PBC (phase 2)104: improvement of serum ALP, γGT, AST, ALT, bile acid and C4 levels by 12 weeks. Side effects: pruritus.

PBC (phase 2)112: 4 weeks of tropifexor treatment showed dose dependent improvement of γGT and ALT (but not ALP). Side effects: pruritus.

NASH with F1-F3 (phase 2)106: 24 weeks of cilofexor treatment reduced hepatic fat content (MRI-PDFF) and serum γGT (but not ALT and AST). No significant changes in lipid parameters. Side effects: dose-dependent pruritus.

ATLAS (phase 2)107: cilofexor, ASK-1 inhibitor selonsertib and ACC inhibitor firsocostat tested in patients with advanced fibrosis (F3-F4) due to NASH; primary endpoint (≥1 stage improvement in fibrosis without worsening of NASH) was not reached in any of the monotherapy groups; selonsertib monotherapy group was discontinued following termination of the STELLAR trials242. Combination of firsocostat and cilofexor over 48 weeks did not improve fibrosis ≥1 stage without worsening of NASH, but significantly higher proportions had a ≥2-point NAS reduction with improvements in steatosis, lobular inflammation and ballooning; significant improvements in ALT, AST, bilirubin, bile acids, CK18, insulin, eGFR, ELF score, and liver stiffness.

FLIGHT-FXR (phase 2)110: at 12 weeks interim analysis tropexifor reduced ALT and γGT levels as well as liver fat content (MRI-PDFF). After 48 weeks no significant differences in histological improvement of NASH or fibrosis (F2-F3) compared with placebo were seen, but significant reductions of collagen proportional area. Side effects: pruritus; increased serum levels of LDL-cholesterol and decreased HDL-cholesterol.

NASH (phase 1b)113: 12 weeks of MET409 treatment improved hepatic fat content (MRI-PDFF) Side effects: dose-dependent increase in LDL cholesterol, decrease in HDL cholesterol, pruritus.

PBC (phase 2)131: 28 days of aldafermin slightly improved liver enzymes. Side effects: gastrointestinal symptoms (mostly diarrhoea).

PSC (phase 2)135: at 12 weeks improved non-invasive markers of hepatic fibrosis, but not ALP. Side effects: gastrointestinal symptoms.

NASH with F2/F3 (phase 2): improved hepatic fat content (MRI-PDFF), serum aminotransferase levels and non-invasive fibrosis markers (pro-C3) after 24 weeks (1 mg)136 in line with a 12-week study testing higher doses (3 and 6 mg)138; histological improvement of fibrosis or NASH did not reach statistical significance136 despite encouraging signals of a 12-week open label study243. Side effects: dose-dependent diarrhoea, abdominal pain, nausea, increases in LDL-cholesterol which could be managed with statins136 138 139.

BEZURSO (phase 3)70: bezafibrate 400 mg/day over 24 months resulted in complete biochemical response (defined as normalisation of hepatic serum biochemistry including ALP, aminotransferases, albumin, bilirubin and prothrombin index) in 31% of patients with PBC with an incomplete response to UDCA vs 0% on placebo; 67% normalised ALP; also improved pruritus and liver stiffness. Side effects: increases in serum creatinine, myalgia and hepatotoxicity (ALT>5 x ULN).

FITCH146: bezafibrate was superior to placebo in improving moderate-to-severe pruritus in patients with PSC and PBC.

PIVENS (phase 3)79; non-diabetics with NASH; 96 weeks of treatment with pioglitazone improved serum transaminases, hepatic steatosis and inflammation, while no significant improvement of fibrosis and NASH was observed. Side effects: weight gain.

In NASH patients with T2DM 36 months treatment was associated with resolution of NASH and improvement in individual histological scores, including fibrosis; improved hepatic fat content (MR-PDFF) and adipose tissue, hepatic and muscle insulin sensitivity. Side effects: weight gain80.

PBC (phase 2)160: 12 weeks of seladelpar treatment improved ALP in patients with PBC with inadequate response to UDCA (normalisation in five patients treated for full 12 weeks), but three patients developed fully reversible, asymptomatic grade 3 ALT increases (one on 50 mg, two on 200 mg), study was terminated after 41 patients were randomised.

ENHANCE (NCT03602560): Ongoing phase 3 study evaluating the safety and efficacy of lower doses (5 or 10 mg) of seladelpar in patients with PBC with inadequate response or intolerant to UDCA. By 3 months (interim analysis) 10 mg seladelpar normalised ALP levels in 27% of patients. Improvement of pruritus244.

PSC (phase 2; NCT04024813)—ongoing.

NASH (phase 2)162: 52 weeks of seladelpar treatment in patients with NASH (NAS ≥4; F1‐F3) improved liver enzymes, but changes in liver fat content by MRI-PDFF were not significant from placebo.

PBC (Phase 2a)171: at 12 weeks elafibranor improved serum ALP, ALT, γGT, bilirubin, cholesterol, triglycerides and CRP in patients with PBC without adequate response or intolerance to UCDA. A potential antipruritic effect was also observed.

ELATIVE (NCT04526665), phase 3 study evaluating the effect of 80 mg elafibranor in patients with PBC not responding to UDCA.

GOLDEN (phase 2)169: resolution of NASH (F0-F3) without fibrosis worsening, based on a modified definition, while the predefined end point was not met; improved cardiometabolic risk profile.

RESOLVE-IT170: phase 3 study in biopsy-proven NASH patients (NAS ≥4; F1–F3); 72 weeks of elafibranor did not achieve the primary endpoint NASH resolution without worsening fibrosis (19% of patients in the treatment arm compared with 15% of patients in the placebo group; n.s.).

PBC (phase 3, open label)168: 16 weeks of saroglitazar (in addition to UDCA) improved serum ALP (primary endpoint) and γGT levels.

NASH (phase 2)165: improved ALT, liver fat content (MRI-PDFF), insulin resistance and atherogenic disorders over 16 weeks. Side effects: weight gain (mild and not significant compared with placebo).

NASH (phase 2)166: very small study demonstrating improved serum lipid and lipoprotein profiles; improvement of NAS score (primary endpoint) was not significant, but improvements in hepatocyte ballooning and steatosis; NASH resolution and fibrosis improvement were observed

NASH with F1-3 (phase 2a)176: reduced hepatic fat content (MRI-PDFF) and liver transaminases after 16 weeks; increased serum levels of adiponectin and improved lipid profile (reduction in LDL cholesterol and triglycerides, increase in HDL cholesterol). Side effects: diarrhoea, nausea.

NASH with F1-F3 (phase 2a)177: Over 16 weeks improved hepatic fat content (MRI-PDFF), serum triglycerides with increase in HDL cholesterol and no increase in LDL cholesterol. In patients ≥30% reduction in hepatic fat undergoing end-of-treatment biopsies, 85% had a ≥2-point reduction in NAS, 78% had a ≥2-point reduction in NAS without worsening of fibrosis, 48% had ≥1 stage improvement in fibrosis without NASH worsening, 28% had both NASH resolution and fibrosis improvement (no placebo control group with histology). Gastrointestinal side effects.

NASH with F4 (phase 2a)178: 16 weeks of EFX improved markers of liver fibrosis, glucose and lipid metabolism.

NASH with F1-F3 (phase 2)185: reduced hepatic fat content (MRI-PDFF) after 36 weeks; histological improvement (>2 point NAS reduction, NASH resolution); significant reduction of liver enzymes, LDL cholesterol, triglycerides and lipoprotein(a). N-terminal type III collagen propeptide (non-invasive fibrosis marker) was reduced. Side effects: diarrhoea, nausea.

Open label extension study for additional 36 weeks demonstrated further improvement of liver fat and liver enzymes245.

MAESTRO-NASH (NCT03900429): ongoing phase 3 study to evaluate the efficacy and safety of resmetirom in patients with NASH and fibrosis (F1-3); primary endpoint: resolution of NASH without worsening of fibrosis and prevention of progression to cirrhosis and/or advanced liver disease.

NASH (phase 2a)246: VK2809 therapy for 12 weeks improved liver fat content (MRI-PDFF).

VOYAGE (NCT04173065) ongoing phase 2 evaluating the impact on liver fat content (MRI-PDFF; primary outcome) at week 12 and NASH CRN fibrosis score (secondary outcome) at week 52.

PSC (phase 2)212: dose-dependent improvement of serum ALP levels and other liver enzymes over 12 weeks, independent of previous response to UDCA; good safety profile without aggravation of pruritus.

Phase 3 study (NCT03872921) in PSC with biochemical, histological and clinical endpoints ongoing

NAFLD (phase 2a)215: significant reduction of serum ALT at 12 weeks compared with placebo. norUDCA was safe and well tolerated.

OASIS (phase 2b; EudraCT: 2018-003443-31) assessing histological efficacy in NASH ongoing.

 PERSEUS (phase 2)247: 24 weeks of CVC treatment in patients with PSC achieved a modest (but not significant) reduction in ALP. CVC was well tolerated.

CENTAUR (phase 2): after 1 year twice as many patients with NASH (NAS ≥4, F1-3) receiving CVC had an improvement in fibrosis by ≥1 NAS stage without worsening of NASH; resolution rates of NASH were similar in the CVC and the placebo group219. However, final analysis after 2 years revealed that a similar proportion on CVC or placebo achieved ≥1-stage fibrosis improvement and no worsening of NASH220.

AURORA (NCT03028740): phase 3 study evaluating CVC for the treatment of liver fibrosis (improvement by at least one stage and no worsening of NASH) in adults with NASH (F2-F3) was terminated early due to lack of efficacy.

PSC (phase 2)228: treatment for 96 weeks did not improve fibrosis (hepatic collagen content, Ishak fibrosis stage) or frequency of PSC-related clinical events compared with placebo.

NASH with F3 or F4 (phase 2b)227: treatment for 96 weeks did not improve hepatic collagen content (predefined primary endpoint in patients with bridging fibrosis) or hepatic venous pressure gradient (predefined primary endpoint in patients with cirrhosis) compared with placebo.