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.

Table 2 Phase 3 trials in non-alcoholic steatohepatitis

Trial name/NCT number	Manufacturer	Drugs	Mechanism of action	Enrollment (targeted)	Study arms	Duration (weeks)	Primary or relevant end point(s)	Results
REGENERATE/NCT02548351	Intercept Pharmaceuticals	Obeticholic acid	Farnesoid X receptor agonist	2480	(1) Obeticholic acid 10 mg QD; (2) Obeticholic acid 25 mg QD; and (3) Placebo	72-378	Fibrosis improvement (≥ 1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis	Fibrosis improvement endpoint-(12%) placebo, (18%) obeticholic acid 10 mg, (23%) obeticholic acid group 25 mg. Safety most common adverse event was pruritus
RESOLVE-IT/NCT02704403	Genfit	Elafibranor	PPAR agonist	2157	(1) Elafibranor 120 mg QD; and (2) Placebo	72-216	Change in fibrosis. Change in histologic score of NASH	ongoing
ARMOR/NCT0410432	Galmed pharmaceuticals	Aramchol	SCD-1 inhibitor	247	(1) Aramchol 600 mg QD; (2) Aramchol 400 mg qd; and (3) Placebo	364	(1) Evaluate the safety and efficacy as measured with % change in the liver triglycerides concentration; and (2) Safety	Ongoing
AURORA/NCT03028740	Tobira Therapeutics	Cenicriviroc	Dual antagonist of CCR types 2 and 5	2000	(1) Cenicriviroc 150 mg; and (2) Placebo	364	(1) Proportion of subjects with ≥ 1-stage improvement in liver fibrosis and no worsening of steatohepatitis at month 12 relative to screening; and (2) Safety	Ongoing
MAESTRO-NASH/ NCT03900429	Madrigal Pharmaceuticals	Resmetirom	Selective thyroid hormone receptor-β agonist	2000	(1) resmetirom 80 mg QD; (2) resmetirom 100 mg QD; and (3) Placebo	364	NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score-biopsy), and with no worsening of fibrosis. Secondary end p. (1) Liver fibrosis improvement of at least one stage, with no worsening of NASH; and (2) Lowering of LDL-cholesterol	Ongoing
NAVIGATE/NCT04365868	Galectin Therapeutics	GR-MD-02 (belapectin)	Inhibitor of galectin 3	1010	(1) Belapectin 2 mg/kg intravenously (IV) every other week; (2) Belapectin 4 mg/kg intravenously (IV) every other week; and (3) Placebo	504	Development of new esophageal varices at 78 weeks in the belapectin group Cumulative incidence rate of decompensations and event-free survival by time to first cirrhosis related clinical event	Ongoing

PPAR: Peroxisome proliferator-activated receptor; SCD-1: Steroyl-CoA desaturase 1; CCR: C-C motif chemokine receptor

Table 3 Multidrug regimens for the treatment of non-alcoholic steatohepatitis

Trial name/NCT number	Phase	Manufacturer	Drugs	Mechanism of action	Enrollment (targeted)	Study arms	Duration (weeks)	Primary or relevant end point(s)
NCT02781584 (Proof of Concept)	1	Gilead Sciences	Selonsertib, firsocostat, cilofexor, fenofibrate, icosapent ethyl	(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; (3) Cilofexor-FXR agonist; (4) Fenofibrate-PPAR agonist; and (5) Icosapent ethyl-under investigation	220	(1) Selonsertib; (2) Firsocostat; (3) Cilofexor; (4) Selonsertib + cilofexor; (5) Selonsertib + firsocostat; (6) Firsocostat + cilofexor; (7) Firsocostat (cirrhotic patients); (8) Cilofexor (cirrhotic patients); (9) Selonsertib + firsocostat + cilofexor; (10) Firsocostat + fenofibrate 48 mg; (11) Firsocostat + fenofibrate 145 mg; and (12) Icosapent ethyl + firsocostat + cilofexor	12	(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ATLAS/NCT03449446	2	Gilead Sciences	Selonsertib, firsocostat, cilofexor	(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist	395	(1) Selonsertib + firsocostat + placebo; (2) Selonsertib + cilofexor + placebo; (3) Firsocostat + cilofexor + placebo; (4) Selonsertib + placebo + placebo; (5) Firsocostat + placebo + placebo; (6) Cilofexor + placebo + placebo; and (7) 3 placebos	48	(1) Adverse events; (2) Lab abnormalities; and (3) Improvement of ≥ 1-stage in fibrosis without worsening of NASH
NCT03987074	2	Gilead Sciences, Novo Nordisk	Cilofexor, semaglutide, firsocostat	(1) Semaglutide-GLP-1 agonist; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist	109	(1) Semaglutide; (2) Firsocostat + semaglutide; (3) Semaglutide + cilofexor 30 mg; (4) Semaglutide + cilofexor 100 mg; and (5) Semaglutide + firsocostat + cilofexor	24	(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ELIVATE/NCT04065841	2	Novartis	Tropifexor, licogliflozin	(1) Tropifexor-FXR agonist; and (2) Licogliflozin-SGLT1/2 inhibitor	380	(1) Tropifexor + licogliflozin; (2) Tropifexor + placebo; (3) Licogliflozin + placebo; and (4) 2 placebos	48	(1) Improvement of ≥ 1-stage in fibrosis without worsening of NASH; and (2) Resolution of NASH without worsening fibrosis
NCT03776175	2A	Pfizer	PF-05221304, PF-06865571	(1) PF-05221304-ACC inhibitor; and (2) PF-06865571 - DGAT 2 inhibitor	99	(1) ACC inhibitor + placebo; (2) DGAT2 inhibitor + placebo; (3) ACC inhibitor + DGAT2 inhibitor; and (4) 2 placebos	6	Improvement in fat fraction
TANDEM/NCT03517540	2	Novartis, Allergan	Tropifexor, cenicriviroc	(1) Tropifexor-FXR agonist; and (2) Cenicriviroc-CCR2/CCR5 inhibitor	193	(1) Tropifexor; (2) Cenicriviroc; (3) Tropifexor dose 1 + cenicriviroc; and (4) Tropifexor dose 2 + cenicriviroc	48	(1) improvement in fibrosis; and (2) Resolution of steatohepatitis
CONTROL/NCT02633956	2	Intercept Pharmaceuticals	Obeticholic acid, atorvastatin	(1) Obeticholic acid-FXR agonist; and (2) Atorvastatin-HMG-CoA reductase inhibitor	84	(1) Obeticholic acid 5 mg/10 mg/25 mg + atorvastatin 10 mg/20 mg; and (2) Placebo + atorvastatin 10 mg/20 mg	16	(1) Change in LDL concentration; (2) Change in LDL particle size; and (3) Change in LDL particle concentration
NCT04235205	2	Albireo Pharma	Elobixibat, cholestyramine	(1) Elobixibat-IBAT inhibitor; and (2) Cholestyramine-bile acid binding resin	100	(1) Elobixibat + cholestyramine; (2) Elobixibat + placebo; (3) Placebo + cholestyramine; and (4) 2 placebos	16	(1) Change in liver fat fraction measured by MRI-PDFF; and (2) Change in fibrosis measured by MRE
PUVENAFLD/NCT04198805	2	DSM Nutritional Products	Vitamin E, omega-3 fatty acid	(1) Vitamin E-scavenging reactive oxidation species; and (2) Omega 3 FA-competing with omega 6 for cyclooxgenase and lipoxygenase-mediated inflammatory eicosanoid production, forming anti-inflammatory compounds	200	(1) Vitamin E + placebo; (2) Omega-3 fatty acid + placebo; (3) Omega 3-fatty acid + vitamin E; and (4) 2 placebos	24	(1) Change in liver fat fraction measured by MRI-PDFF; (2) Change in liver enzymes; and (3) FIB-4 scores
NEXSCOT/NCT04147195	2	Novartis	LYS006, tropifexor	(1) Tropifexor-FXR agonist; and (2) LYS006-leukotriene A4 hydrolase inhibitor	250	(1) LYS006; and (2) LYS006 + tropifexor	21	(1) Change in ELF score; and (2) Change in liver fat fraction measured by MRI-PDFF
NCT02466516	2	Gilead Sciences	Selonsertib, simtuzumab	(1) Selonsertib-selective ASK1 inhibitor; and (2) Simtuzumab-lysyl oxidase-like 2 inhibitor	72	(1) Selonsertib 6 mg; (2) Selonsertib 18 mg; (3) Selonsertib 6 mg + simtuzumab; (4) Selonsertib 18 mg + simtuzumab; and (5) Simtuzumab	24	(1) Adverse events; (2) Serious adverse events; (3) Lab abnormalities; and (4) Number of participants who prematurely discontinued study due to adverse events
NCT01703260	2	AstraZeneca	Roflumilast, pioglitazone	(1) Roflumilast-phosphodiesterase 4 inhibitor; and (2) Pioglitazone-PPAR agonist	16	(1) Roflumilast + pioglitazone; (2) Roflumilast + placebo; and (3) Pioglitazone + placebo	20	(1) Change in liver enzymes; and (2) Change in liver fat fraction measured by MRI-PDFF

ASK1: Apoptosis signal-regulating kinase-1; ACC: Acetyl-coenzyme A carboxylase; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; GLP-1: Glucagon-like peptide-1; SGLT: Sodium/glucose transport protein; DGAT: Diacylglycerol acyltransferase; CCR: C-C motif chemokine receptor; IBAT: Ileal bile acid transporter.