Table 1.
Overview of current and pipeline treatments for NAFLD and NASH.
| Target | Drug | Trial ID | BRCT | Cohort Medical Conditions | Ref. | Outcome |
|---|---|---|---|---|---|---|
| PPARα | Gemfibrozil | (Turkey) | Y | NASH | [34] | Decreased serum liver enzymes 1 and triglyceride |
| Fenofibrate | (Spain) | N | NAFLD | [35] | Improved metabolic syndrome, decreased serum liver enzymes and triglycerides | |
| Clofibrate | (US – Pre-1997) | N | NASH | [36] | No improvement | |
| Omega-3 PUFA (Omacor) | Welcome – Phase IV, NCT00760513 | Y | NAFLD | [38] | Decreased liver fat percentage | |
| Omega-3 PUFA (Omacor) | Phase III, NCT01277237 | Y | NAFLD | - | TBD | |
| PPARδ | Seladelpar (MBX-8025)± Atorvastatin | Phase II, NCT00701883 | Y | Hyperlipidaemia | [41] | Decreased liver enzymes and improved serum lipid profile |
| Seladelpar (MBX-8025) | Phase II, NCT03551522 | Y | NASH | - | Trial Suspended – unexplained histological findings | |
| PPARγ | Pioglitazone± vitamin E | PIVENS-Phase III, NCT00063622 | Y | NAFLD, NASH | [46] | Reduced liver steatosis, lobular inflammation and serum ALT/AST |
| Pioglitazone | UTHSCSA NASH-Phase IV, NCT00994682 | Y | Type 2 Diabetes, NAFLD, NASH | [47] | Significant decrease in NAS score by ≥ 2 points in 58% participants; resolution of NASH in 51%. | |
| Lobeglitazone | ELLEGANCE - Phase IV, NCT02285205 | N | Type 2 Diabetes, NAFLD | [48] | Improved liver and serum lipid profiles | |
| PPARα/δ | Elafibranor (GFT505) | Phase IIa, NCT01271777 | Y | Insulin resistance + abdominal obesity | [50] | Improved plasma lipids and hepatic insulin resistance, reduced liver inflammation and ALT |
| Elafibranor (GFT505) | Phase II, NCT01271751 | Y | Athero-genic dyslipidaemia + abdominal obesity | [50] | Decreased serum lipids and liver GGT | |
| Elafibranor (GFT505) | Phase II, NCT01275469 | Y | Impaired glucose tolerance + abdominal obesity | [51] | Improved insulin sensitivity (HOMA-IR), fasting blood glucose and decrease in liver GGT | |
| Elafibranor (GFT505) | Phase IIb, NCT01694849 | Y | NASH | [52] | No significant difference between placebo and elafibranor groups for primary outcome (resolution of NASH) 2 | |
| Elafibranor (GFT505) | RESOLVE-IT – Phase III, NCT02704403 | Y | NASH | - | Ongoing (recruiting) | |
| PPARα/γ | Saroglitazar | EVIDENCES VI – Phase II, NCT03863574 | Y | NASH | - | Ongoing (recruiting) |
| PPAR-pan | lanifibranor (IVA337) | NATIVE – Phase IIb, NCT03459079 | Y | NAFLD, Type 2 Diabetes | - | Ongoing (recruiting) |
| Non-PPAR | Oral insulin (ORMD-0801) | Phase II, NCT02653300 | N | NASH, Type 2 diabetes | - | Ongoing (recruitment) |
| Liraglutide (GLP1 agonist) | LEAN-J | N | NASH | [61] | Decreased liver and visceral fat, liver enzymes and FPG | |
| Semaglutide (GLP1 agonist) | Phase II, NCT02453711 | Y | Obesity, metabolic disorder | [62] | Decreased ALT and hsCRP, significant weight loss at all doses | |
| Semaglutide (GLP1 agonist) | SUSTAIN 6 – Phase III, NCT01720446 | Y | Diabetes, Type 2 diabetes | [62] | Decreased ALT and hsCRP, decreased cardiovascular events (death, infarction or stroke) | |
| Armachol (SCD1 inhibition) | Aramchol003 - Phase II, NCT01094158 | Y | NAFLD, NASH, Metabolic syndrome | [66] | Decrease in liver fat percentage at mid-dose | |
| Armachol (SCD1 inhibition) | ARMOR - Phase III/IV, NCT04104321 | Y | NASH | - | Ongoing (recruiting) | |
| Dapagliflozin (SGLT2 inhibitor) | Dokkyo Medical University (Japan) - UMIN000022155 | Y | NAFLD | [72] | Decreased liver fibrosis, visceral fat mass and liver enzymes | |
| Dapagliflozin (SGLT2 inhibitor) + omega-3 carboxylic acid | EFFECTII – Phase II, NCT02279407 | Y | NAFLD, Type 2 diabetes | [73] | Significant reduction in liver fat and liver enzymes | |
| Dapagliflozin (SGLT2 inhibitor) | DEAN – Phase III, NCT03723252 | Y | NASH | - | Ongoing (recruitment) | |
| Pentoxifylline (TNFα inhibitor) | Phase II, NCT00590161 | Y | NASH | [78] | Improved liver steatosis, fibrosis and lobular inflammation | |
| Pentoxifylline (TNFα inhibitor) | (Sri Lanka) -SLCTR/2014/016 | N | NASH | [79] | Lifestyle intervention+pentoxifyllin improved NAS | |
| Pentoxifylline (TNFα inhibitor) | Phase II/III, NCT00267670 | Y | NASH | - | No difference between placebo and pentoxifylline groups | |
| Vitamin D3 | Phase II, NCT01571063 | Y | NASH | [87] | Decreased serum ALT | |
| Obeticholic acid (FXR1 ligand) | FLINT – Phase IIb, NCT01265498 | Y | NASH, NAFLD | [98] | Improved liver NAS in 45% of patients, elevated pruritis | |
| Obeticholic acid (FXR1 ligand) | REGENERATE – Phase III, NCT02548351 | Y | NASH | [100] | Improved fibrosis in 23% of patients, elevated pruritis | |
| NGM282 (FGF19 signalling) | Phase II, NCT02443116 | Y | NASH | [104] | Reduction in liver fat content | |
| ND-L02-s0201 (Vitamin A-coupled siRNA to HSP47 – hepatic stellate cell fibrosis target) | METAVIR F3-4 - Phase Ib/II, NCT02227459 | Y | Hepatic fibrosis | - | TBD | |
| Selonsertib (inhibitor of ASK1) | Multi-center Phase 2 | N | NASH | [111] | Improved liver fibrosis | |
| Selonsertib (inhibitor of ASK1) | STELLAR 3 and 4 - Phase 3, NCT03053050 and NCT03053063 | Y | NASH | [112] | No improvement in fibrosis, trial terminated | |
| Rifaximin (antibiotic) | Phase I, NCT02884037 | Y | NAFLD, NASH | [123] | Reduction in proinflammatory cytokines, liver enzymes and NAFLD-liver fat score; improved insulin sensitivity (HOMA-IR) | |
| Rifaximin (antibiotic) | Phase II, EudraCT 2010–021515-17 | N | NASH | [124] | Trial prematurely ended - no improvement | |
| VSL#3 (Probiotic) | VAIIO – Phase II, NCT01650025 | Y | Obesity | [133] | Significant improvement in NAFLD |
Trial ID, patient group and main outcomes are depicted. ALT: alanine aminotransferase; ASK1: apoptosis signal-regulating kinase 1; AST: alanine transaminase; BRCT: blinded, randomized, placebo-controlled trial; GGT: γ glutamyl transferase; hsCRP: high-sensitivity C-reactive protein; FXR: Farnesoid X receptor; HOMA-IR: homeostasis model assessment of insulin resistance; NAS: NASH activity score; stearoyl co-A desaturase: SCD1; TBD; results yet to be disclosed. 1 liver enzymes refer to hepatocyte injury biomarkers detected in the serum (for, e.g., ALT, AST, GGT, fibroblast growth factor 21, cytokeratin) 2 elafibranor resolved NASH in a greater proportion of patients with NAS score ≥ 4 than the placebo group, when a post-hoc analysis of the study was performed using a modified definition of NASH.