Endocrinology and Metabolism (original) (raw)

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)

MAESTRO-NASH study [22]

MAESTRO-NAFLD1 study [23]

MAESTRO-NAFLD-Open-Label-Extension (MAESTRO-NAFLD-OLE) study [24]

All (1–3)
Resmetirom (MGL-3196): THRβ agonist

All (1–3)
Resmetirom 80 mg or 100 mg, placebo12 months (52 weeks)

Biopsy-proven NASH (F2–F3)

NASH or NAFLD (on fibroscan/MRE and MRI-PDFF/liver biopsy)

Same as 2

NASH resolution at repeated biopsy

The incidence of adverse events

The incidence of adverse events

Recruiting

Phase 3, multinational, randomized, double-blind, placebo-controlled

Phase 3, randomized, double-blind, placebo-controlled/Some, open-label

Phase 3, open-label extension, single-blind lead-in

Recruiting

ARMOR trial [28]
Phase 3 multinational, multicenter

Double-blind, part-randomized

Open label part

Aramchol: SCD-1 inhibitor

2:1

Aramchol 600 mg

Placebo

18 months (72 weeks)

Aramchol 600 mg

18 or 30 months (72 or 120 weeks)

Biopsy-proven NASH, F2–F3 (with overweight or obesity, and having prediabetes or type 2 diabetes)

Resolution of NASH and no worsening of liver fibrosis

Improvement in fibrosis and no worsening of steatohepatitis

Resolution of NASH and improvement of fibrosis

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.