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1Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon, Korea
2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
3Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
4Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Korea
Copyright © 2022 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
Study author/design | Mechanism | Intervention/controlduration | Study population | Primary endpoint | Results | Other issues |
---|---|---|---|---|---|---|
REGENERATE trial [12] Phase 3 multicenter, randomized, double-blind, placebo-controlled |
OCA: FXR agonist |
1:1:1 OCA 25 mg OCA 10 mg Placebo 18 months |
NASH (NAS ≥4), F1–F3 | Fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis |
Improved: One stage in liver fibrosis in OCA 25 mg compared to placebo (23% vs. 12%, P=0.0002) Not improved: NASH resolution |
Safety Pruritis (51% of patients; grade 2 or greater in severity in 28% of patients) LDL cholesterol increase (up to 23.8 mg/dL) Increased hepatobiliary events (gallstones or cholecystitis) |
Patel et al. [14] Phase 2 multinational, randomized, double-blind, placebo-controlled |
Cilofexor: FXR agonist (synthetic non-steroidal) |
2:2:1 Cilofexor 100 mg Cilofexor 30 mg Placebo 6 months (24 weeks) |
Noncirrhotic NASH (MRI-PDFF ≥8%), liver stiffness ≥2.5 kPa (MRE) or historical liver biopsy |
The safety and tolerability of cilofexor |
Improved: Hepatic steatosis (median relative decrease in MRI-PDFF of −22.7% in the cilofexor 100 mg group, compared with an increase of 1.9% in the placebo group; P=0.003) Not improved: Fibrosis (ELF, MRE, CK18) |
Safety Pruritis (moderate to severe pruritus in 14% of patients) |
ARGON-1 trial [18] Phase 2 multinational, randomized, double-blind, placebo-controlled |
EDP-305: FXR agonist (synthetic non-steroidal) |
2:2:1 EDP-305 2.5 mg EDP-305 1 mg Placebo 3 months (12 weeks) |
Non-cirrhotic/fibrotic NASH (by historical biopsy or phenotypically, and elevated ALT with LFC by MRI-PDFF >8%) | Mean change from baseline to week 12 for ALT |
Improved: ALT reduction (2.5 mg of EDP-305: −27.9 U/L [P=0.049], compared to −15.4 U/L for those receiving placebo) Absolute liver fat reduction of −7.1% (P=0.0009) with 2.5 mg of EDP-305 |
Safety Pruritus (50.9% in the 2.5 mg of EDP-305 group) |
All (1–3) Resmetirom (MGL-3196): THRβ agonist |
All (1–3) Resmetirom 80 mg or 100 mg, placebo12 months (52 weeks) |
Recruiting | Recruiting | |||
ARMOR trial [28] Phase 3 multinational, multicenter |
Aramchol: SCD-1 inhibitor | Biopsy-proven NASH, F2–F3 (with overweight or obesity, and having prediabetes or type 2 diabetes) | Recruiting | Recruiting | ||
RESOLVE-IT [33] Phase 3 randomized, placebo-controlled |
Elafibranor: dual PPARα/δ agonist |
2:1 Elafibranor Placebo 18 months (72 weeks) |
Biopsy-proven NASH, F2–F3 | NASH resolution without worsening of fibrosis |
Not improved: Primary endpoint: (19.2% in the elafibranor arm, 14.7% in the placebo arm) |
Terminated without significant benefit |
EVIDENCES IV study [34] Phase 2 multicenter, randomized, double-blind, placebo-controlled |
Saroglitazar: dual PPARα/γ agonist |
1:1:1:1 Saroglitazar 4 mg Saroglitazar 2 mg Saroglitazar 1 mg Placebo 4 months (16 weeks) |
NAFLD/NASH patients (by US, CT, MRI, or biopsy) (with BMI over 25 kg/m2) | The percentage change from baseline in ALT levels |
Improved: ALT (in saroglitazar 4 mg, the percentage change from baseline −45.8%) LFC (in saroglitazar 4 mg by MRI-PDFF, −19.7%) |
|
NATIVE trial [35] Phase 2b double-blind, randomized, placebo-controlled |
Lanifibranor: pan-PPAR agonist |
1:1:1 Lanifibranor 1,200 mg Lanifibranor 800 mg Placebo 6 months (24 weeks) |
Noncirrhotic, highly active NASH (biopsy-proven) | Decrease of at least 2 points in the SAF-A score without worsening of fibrosis |
Improved: Achieved primary endpoint (1,200 mg vs. placebo, 55% vs. 33%, P=0.007) |
|
AURORA trial [39] Phase 3 two-part international, randomized, double-blind, placebo-controlled |
Cenicriviroc: C motif chemokine receptor type 2 and 5 antagonist |
Cenicriviroc 150 mg Placebo 12 months |
Biopsy-proven NASH (NAS ≥4), F2–F3 | Improvement of fibrosis by ≥1 grade without exacerbation of steatohepatitis | Terminated early due to lack of efficacy based on the results of part I of the AURORA study | Terminated without significant benefit |
EMMINENCE trial [40] Phase 2b randomized, double-blind, placebo-controlled |
MSDC-0602K: Second-generation thiazolidinediones – minimize direct binding to PPARγ and preferentially target the mitochondrial pyruvate transporter |
1:1:1:1 MSDC-0602K 250 mg MSDC-0602K 125 mg MSDC-0602K 62.5 mg Placebo 12 months (52 weeks) |
Biopsy-proven NASH, F1–F3 | ≥2-point histological improvement of the liver on the NAS, ≥1-point decrease in balloon or lobular inflammation, no increase in the fibrosis stage |
Improved: Fasting glucose, insulin, glycated hemoglobin, and markers of liver injury Not improved: Primary endpoint (29.7%, 29.8 %, 32.9%, and 39.5% of patients in the placebo group, MSDC-0602K 62.5, 125, and 250 mg) Secondary liver histology endpoints |
The incidence of PPARγ agonist-related events such as hypoglycemia, edema and fractures was not increased. |
NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; FXR, farnesoid X receptor; NAS, nonalcoholic fatty liver disease activity score; LDL, low-density lipoprotein; MRI-PDFF, magnetic resonance imaging proton density fat fraction; MRE, magnetic resonance elastography; ELF, enhanced liver fibrosis; CK, cytokeratin; LFC, liver fat content; ALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease; THR, thyroid hormone receptor; SCD, stearoyl-CoA desaturase; PPAR, peroxisome proliferator activated receptor; US, ultrasonography; CT, computed tomography; BMI, body mass index.
Study author/design | Mechanism | Intervention/control duration | Study population | Primary endpoint | Results/Other issues |
---|---|---|---|---|---|
Cusi et al. [59] Phase 4 single-center, randomized, double-blind, placebo-controlled |
Pioglitazone: thiazolidinedione - PPARγ agonist |
1:1 (low-calorie diet) Pioglitazone 45 mg Placebo 18 months |
Biopsy-proven NASH (prediabetes or T2DM) | Reduction of at least 2 points in the NAS in 2 histologic categories without worsening of fibrosis |
Improved: 58% achieved the primary outcome (treatment difference, 41 percentage points) 51% had resolution of NASH (treatment difference, 32 percentage points) (P<0.001 for each)’ Individual histologic scores Safety: Weight gain was greater with pioglitazone (2.5 kg vs. placebo). |
LEAN trial [61] Phase 2 multicenter, randomized, double-blind, placebo-controlled |
Liraglutide: GLP1RA |
1:1 Liraglutide 1.8 mg Placebo 12 months (48 weeks) |
Clinical evidence of NASH (overweight) | Resolution of NASH without worsening of fibrosis as a pathological outcome |
Improved: Resolution of NASH (39% in the liraglutide group vs. 9% in the placebo group, relative risk 4.3, P=0.019) Progression of fibrosis (9% in the liraglutide group vs. 36% in the placebo, relative risk 0.2, P=0.04) |
Newsome et al. [62] Phase 2 multinational, randomized, double-blind, placebo-controlled |
Semaglutide: GLP1RA |
1:1:1:1 Semaglutide 0.4 mg Semaglutide 0.2 mg Semaglutide 0.1 mg Placebo 18 months (72 weeks) |
Biopsy-proven NASH, F1–3 (with or without T2DM, with BMI over 25 kg/m2) | Histologic resolution of NASH and no worsening of fibrosis |
Improved: Primary endpoint (59% in the 0.4 mg group vs. 17% in the placebo group, P<0.001) Not improved: Fibrosis stage Marked/Safety: The mean percent weight loss was 13% in the 0.4 mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4 mg group than in the placebo group. |
D-LIFT trial [63] Single-center, randomized, open-label, placebo-controlled |
Dulaglutide: GLP1RA |
1:1 Dulaglutide weekly 0.75 mg for 4 weeks, then 1.5 mg weekly Placebo 6 months (24 weeks) |
MRI-PDFF ≥6.0% (with T2DM) | The difference of the change in LFC from 0 to 24 weeks between groups |
Improved: MRI-PDFF (control-corrected absolute change in LFC of −3.5%, P=0.025; relative change of −26.4%, P=0.004) |
EFFECTII study [67] Phase 2 randomized, double-blind, placebo-controlled |
Dapagliflozin: SGLT2i |
1:1:1:1 Dapagliflozin 10 mg 4 g omega-3 (n-3) carboxylic acids Combination of both 3 months (12 weeks) Placebo |
MRI-PDFF >5.5% (with T2DM, aged 40–75 years, BMI 25–40 kg/m2) | The change in liver fat measured by MRI-PDFF |
Improved: Only the combination treatment significantly reduced LFC (MRI-PDFF (P=0.046) and total liver fat volume (relative change, −24%, P=0.037) |
E-LIFT trial [69] Single-center, randomized, open-label |
Empagliflozin: SGLT2i |
1:1 Empagliflozin 10 mg Standard diabetes treatment without empagliflozin 5 months (20 weeks) |
MRI-PDFF >6% (with T2DM) | The change in liver fat measured by MRI-PDFF |
Improved: Reducing liver fat (MRI-PDFF difference between groups −4.0%, P<0.0001) |
Kahl et al. [70] Phase 4 randomized, double-blind, placebo-controlled |
Empagliflozin: SGLT2i |
1:1 Empagliflozin 25 mg Placebo 6 months (24 weeks) |
Type 2 diabetes (BMI <45 kg/m2, known T2DM duration ≤7 years, HbA1c of 6%–8%, and no previous antihyperglycemic treatment) | The change in liver fat measured by MRS |
Improved: Reducing liver fat (placebo-corrected absolute change of −1.8%, P=0.02; and relative change in LFC of −22%, P=0.009) |
Cusi et al. [71] Phase 1 multicenter, randomized, double-blind, placebo-controlled |
Canagliflozin: SGLT2i |
1:1 Canagliflozin 300 mg Placebo 6 months |
Inadequately controlled T2DM (HbA1c ≥7.0% to ≤9.5%) | The difference in the change for intrahepatic triglyceride content by MRS, insulin sensitivity, and beta-cell function |
Improved: Canagliflozin significantly improved hepatic insulin sensitivity Not improved: Only a numerically larger absolute decrease in intrahepatic triglyceride content (−4.6% vs. placebo −2.4%, P=0.09) |
NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator activated receptor; T2DM, type 2 diabetes mellitus; NAS, nonalcoholic fatty liver disease activity score; GLP1RA, glucagon-like peptide 1 receptor agonist; BMI, body mass index; MRI-PDFF, magnetic resonance imaging proton density fat fraction; LFC, liver fat content; SGLT2i, sodium glucose co transporter 2 inhibitor; HbA1c, glycated hemoglobin; MRS, magnetic resonance spectroscopy.