Table 2.

Ongoing phase III clinical trials in NAFLD and NASH

Compound/company	Study design	Mechanism of action	Intervention/control	Key inclusion criteria	Key exclusion criteria	Status
Obeticholic acid (OCA)/Intercept pharmaceuticals	REGENERATE. NASH patients (NCT02548351). Primary outcomes: ≥1 stage fibrosis improvement and no worsening of NASH or NASH resolution without worsening of fibrosis	Farnesoid X (FXR) receptor agonist	– OCA 10 mg/day (N= 330) – OCA 25 mg/day (N= 324) – Placebo (N= 312)	– NASH diagnosed by liver biopsy with 3 key histological features of NASH CRN – F2/F3 or F1 with BMI≥30/type 2 diabetes/ALT>1.5 x ULN – Stable body weight	– Model of end stage liver disease (MELD) score >12 – ALT≥10x ULN – HbA1c>9.5% – Other liver diseases – Liver transplant – Cirrhosis – BMI>45 kg/m2	Ongoing. Current results: – NASH resolution not met (p= 0.18/p= 0.13) (OCA 10 mg/OCA 25 mg) – Fibrosis improvement met (p= 0.045/p= 0.0002)
Aramchol/Galmedresearch and development, Ltd.	ARMOR. NASH (NCT04104321). Primary outcomes: ≥1 stage improvement fibrosis without worsening of NASH or NASH resolution without worsening fibrosis	Staroyl coenzyme A desaturase 1 inhibitor	–Aramchol 300 mg/day – Placebo (N total= 2000)	– NASH diagnosed by liver biopsy – NAS≥4 with at least 1 on each NAS component – F2/F3 – BMI 25–40 kg/m2 – AST>20 IU/L	– Cirrhosis – MELD score>12 – Other liver diseases – Weight loss>5% in last 3 months – Bariatric surgery – Treatment with anti-diabetic medications	Ongoing
Resmetirom (MGL-3196)/Madrigal pharmaceuticals, Inc.	MAESTRO-NAFLD1 NAFLD patients (NCT04197479). Primary outcomes: assess the effect of daily oral admin.	Thyroid hormone receptor-β agonist	–Resmetirom 80 mg/day –Resmetirom open label or double-blinded 100 mg/day – Placebo (N total= 700)	Suspected or confirmed NAFLD or NASH	– Other liver diseases – Cirrhosis – Bariatric surgery – HbA1c≥9% – GLP-1/vit. E/pioglitazone therapy – MELD>12 – ALT>250 U/L – Weight change>5%	Ongoing
Resmetirom (MGL-3196)/Madrigal pharmaceuticals, Inc.	MAESTRO-NASH. NASH patients (NCT03900429). Primary outcomes: NASH resolution with <2 points in NAS and no worsening of fibrosis	Thyroid hormone receptor-β agonist	–Resmetirom 80 mg/day –Resmetirom 100 mg/day – Placebo (N total= 2000)	Biopsy proven NASH with NAS≥4 and at least 1 on each component and F1/F2/F3	– Other liver diseases – Cirrhosis – Bariatric surgery – HbA1c≥9– GLP-1/vit. E/pioglitazone therapy – MELD>12 – ALT>250 U/L	Ongoing
Resmetirom (MGL-3196)/Madrigal pharmaceuticals, Inc.	MAESTRO-NAFLD-OLE. NAFLD patients (NCT04951219). Primary outcomes: assess the effect of daily oral admin.	Thyroid hormone receptor-β agonist	–Resmetirom 80 mg/day first 12 w followed by open-label –Resmetirom 100 mg/day –Resmetirom 100 mg/day first 12 w followed by open-label –Resmetirom 100 mg/day – Open-label Resmetirom 100 mg (N total= 1000)	– Participated in MAESTRO-NAFLD-1 – Liver biopsy with NAS = 3 and F2/F3 or NAS≥4 in all NAS components and F1, PRO-C3≤14	– Other liver diseases – HCC	Ongoing
Lanifibranor (IVA337)/Inventiva Pharma	NATiV3: NASH patients with F2/F3 (NCT04849728). Primary outcomes: resolution of NASH and improvement of fibrosis of ≥1 according to NASH CRN (Part 1). Assess the effect on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death	Pan-PPAR agonist	–Lanifibranor 800 mg/day –Lanifibranor1200 mg/day – Placebo (N total= 2000)	– Liver biopsy with steatosis score ≥1, act. score A3/A4 and F2/F3 according to Steatosis-Activity-Fibrosis (SAF) – Stable dose of GLP-1, vit. E or statins – No weight change ≥5%	– Other chronic liver disease – HCC or cirrhosis – HbA1c>9% – Bariatric surgery	Ongoing
Semaglutide/Novo Nordisk A/S	NASH patients with F2/F3 (NCT04822181). Primary outcomes: resolution of NASH and no worsening of fibrosis or improvement of fibrosis and no worsening of NASH (Part 1). Assess the effect on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death	Glucagon-like peptide-1 receptor agonist (GLP-1 RA)	– Semaglutide 1 subcutaneous admin./week – Placebo (N total= 1200)	– Liver biopsy with NASH – F2/F3 according to NASH CRN System – NAS score≥4 with 1 score in steatosis, inflammation and ballooning	– Other liver diseases – Treatment with pioglitazone, vit. E or other glucose-lowering agents	Ongoing