Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis

Table 1 Phase 2 trials in non-alcoholic steatohepatitis

Trial name/NCT number	Manufacturer	Drugs	Mechanism of action	Enrollment (targeted)	Study arms	Duration	Primary or relevant end point(s)	Results/SE
NCT03976401	Akero Therapeutics	AKR-001	FGF 21 receptor agonist	80	(1) AKR-001 50 mg QD; and (2) Placebo	112	Change in liver fat fraction measured by MRI-PDFF	Ongoing
NCT04541186	89bio	BIO89-100	FGF 21 receptor agonist	90	(1) BIO89-100 (QW or every 2 wk); and (2) Placebo	112	Change in various lab parameters TG, LDL, HDL, fasting glucose. Change in liver fat fraction measured by MRI-PDFF	Ongoing
NCT02097277	Bristol-Myers Squibb	Pegbelfermin (BMS-986036)	FGF 21 receptor agonist	120	(1) Pegbelfermin 1 mg QD; (2) Pegbelfermin 5 mg QD; (3) Pegbelfermin 20 mg QD; (4) Pegbelfermin 20 mg weekly; and (5) Placebo	84	Safety, tolerability, and change in HbA1c. Change in insulin sensitivity, lipids, adiponectin, and disease progression biomarkers	No significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol and triglycerides. Most frequent adverse events were injection-site bruising and diarrhea
NCT01237119	Novo Nordisk	Liraglutide	GLP-1analogue	52	(1) Liraglutide 1.8 mg SC QD; and (2) Placebo	336	Resolution of NASH without worsening fibrosis	39% who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with 9% in placebo (P = 0·019). Side efffects diarrhea and loss of appetite
NCT02970942	Novo Nordisk	Semaglutide	GLP-1 analogue	320	(1) Semaglutide 0.1 mg SC QD; (2) Semaglutide 0.2 mg SC QD; (3) Semaglutide 0.4 mg SC QD; and (4) Placebo	504	Resolution of NASH without worsening fibrosis. Improvement in fibrosis, LFTs, A1c level	NASH resolution was achieved in 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P < 0.001 for semaglutide 0.4 mg vs placebo). Side effects including nausea, constipation, and vomiting which was higher in the 0.4-mg group
2013-004605-38	Dr Falk Pharma GmbH	Norursodeoxycholic acid	homologue of ursodeoxycholic acid, undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity	198	(1) 500 mg norursodeoxycholic acid QD; (2) 1500 mg norursodeoxycholic acid QD; and (3) Placebo	112	Change in ALT levels	Dose-dependent reduction in ALT with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (P < 0.0001). Side effects included headache, gastrointestinal disorders, and infections
COHORT 4/NCT02443116	NGM Biopharmaceuticals	Aldafermin	Analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis	78	(1) aldafermin 1 mg QD; and (2) Placebo	168	Improvement in liver fibrosis of greater or equal to one stage with no worsening of NASH	Aldafermin group with higher rate of liver fat content reduction compared to placebo (7.7% vs 2.7%, P = 0.02). Aldafermin produced significantly greater decrease in bile acids, liver enzymes. Fibrosis improvement without worsening NASH higher in aldafermin group (38% vs 18%, P = 0.10). NASH resolution without worsening fibrosis higher in aldafermin group (24% vs 9%, P = 0.20). Side effects include diarrhea, headache, abdominal distation and peripheral edema
ALPINE 4/NCT04210245	NGM Biopharmaceuticals	Aldafermin	Analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis	72	(1) Aldafermin 0.3 mg QD; (2) Aldafermin 1 mg QD; (3) Aldafermin 3 mg; and (4) Placebo	168	Improvement in liver fibrosis of greater or equal to one stage with no worsening of NASH	Ongoing
FLIGHT-FXR/NCT02855164	Novartis Pharmaceutical	Tropifexor	FXR agonist	152	(1) TXR 140 g QD; (2) TXR 200gr QD; and (3) Placebo	84	Changes in liver fat fraction, liver enzymes, body weight	End point achieved in TXR 800 mg vs 1200 mg vs Placebo (51% vs 55% vs 34%, P = 0.001). Side effects include mild pruritus and increase in LDL
NATIVE/NCT03008070	Inventiva	Lanifibranor	PPAR agonist	247	(1) Lanifibranor 800 mg QD; (2) Lanifibranor 1200 mg QD; and (3) Placebo	168	Responder analysis based on the improvement of the SAF activity score	L800 mg vs 1200 mg vs Placebo (51% vs 55% vs 34%) P = 0.0015. SE weight gain, peripheral edema
FASCINATE-1/NCT03938246	Sagimet Biosciences Inc	TVB-2640	FASN inhibitor	99	(1) TVB2640 25 mg QD; (2) TVB2640 50 mg; and (3) Placebo	84	Change in hepatic fat fraction from baseline in subjects with NASH by proton-density fat fraction by magnetic resonance imaging	Dose-dependent relative changes in liver fat by MRI-PDFF were -28.2% with 50 mg (P < 0.005 vs placebo), -9.6% with 25 mg, and +4.5% with placebo. 30% relative reduction in liver fat at week 12 were 61% (P < 0.001 vs placebo)
NCT02856555	Gilead Sciences	Firsocostat	Acetyl-coenzyme A carboxylase Inhibitor	126	(1) Firsocostat 20 mg QD; (2) Firsocostat 5 mg QD; and (3) Placebo	84	Safety and tolerability. Secondary end point efficacy (NASH improvement without fibrosis)	Decrease of at least 30% from baseline in MRI-PDFF occurred in 48% of patients with 20 mg (P = 0.004), 23% given 5 mg (P = 0.43), and 15% given placebo. SE cause, abdominal pain, diarrhea
VOYAG/LBP20	Viking therapeutics	VK2809	Thyroid beta receptor agonist, selectively cleaved in hepatic tissue	45	(1) VK2809 5 mg QD; (2) VK2809 10 mg QOD; (3) VK280910 mg QD; and (4) Placebo	84	Safety, tolerability and efficacy in reducing liver fat content and LDL	< Liver fat content was 8.7% for 5 mg QD (P = 0.0014) vs 8.9% 10 mg QOD (P = 0.013) vs 10.6% for 10 mg QD (P = 0.0030), vs 1.1% for placebo. 70% in VK2809 therapy showed a ≥ 50%. Reduction in MRI-PDFF (P = 0.014)
NCT02912260	Madrigal Pharmaceuticals	Resmetirom (MGL-3196)	Selective thyroid hormone receptor-β agonist	125	(1) Resmetirom 80 mg QD; and (2) Placebo	252	Change in liver fat fraction measured by MRI-PDFF	80 mg vs placebo reduction of hepatic fat at week 12 (-32.9% vs -10.4%; P < 0·0001) and week 36 (-37.3% vs -8.5%; P < 0·0001)
NCT02784444	Cirius Therapeutics	MSDC-0602K	Insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier with direct binding to the transcriptional factor PPARγ	392	(1) MSDC-0602K 62.5 mg QD; (2) MSDC-0602K 125 mg QD; (3) MSDC-0602K 250 mg QD; and (4) Placebo	364	Hepatic histological and activity score improvement in either ballooning or lobular inflammationNo increase in fibrosis stage at 12 mo	Primary end point placebo 29.7%, vs 62.5 mg 29.8%, vs 125 mg 32.9% vs 250 mg 39.5% (95%CI: 0.44–1.81) (95%CI: 0.60–2.48), (95%CI: 0.83–3.27)

FGF: Fibroblast growth factor; MRI-PDFF: Magnetic resonance imaging with proton density fat fraction; GLP-1: Glucagon-like peptide-1; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; FASN: Fatty acid synthase.