Emerging synthetic drugs for the treatment of hepatic cirrhosis: a 2024 update

Figures & data

Table 1. Recent drug failures for cirrhosis.

Compound (company)	Target/mechanism	Phase	Study description	Result	Status
Obeticholic acid (INT-747; Intercept Pharmaceuticals, Inc.)	Steroidal FXR agonist	3	Compensated NASH cirrhosis (NCT03439254); Primary outcome: histological improvement in fibrosis with no worsening of NASH	No significant difference in primary endpoint of histological improvement	Completed (failed primary).Company to discontinue NASH program
Cenicriviroc (TAK-652, TBR-652; Tobira Therapeutics, Inc.)	CCR2 and CCR5 antagonist	2	NASH cirrhosis (NCT03059446); Primary outcome: number of participants with treatment-emergent adverse events	Lack of efficacy based on data from planned interim analysis of Part 1 of the AURORA study (NCT03028740; no improvement of histological fibrosis)	Terminated
Pegbelfermin (BMS-986036; Bristol-Myers Squibb)	Polyethylene glycol-conjugated analog of human FGF21	2	Compensated NASH cirrhosis (FALCON 2; NCT03486912 Primary outcome: histological improvement in fibrosis with no worsening of NASH	No significant difference in primary endpoint of histological improvement	Completed (failed primary).Development discontinued
Semaglutide (Novo Nordisk A/S)	GLP-1 receptor agonist	2	Compensated NASH cirrhosis (NCT03987451); Primary outcome: histological improvement in fibrosis with no worsening of NASH	No significant difference in primary endpoint of histological improvement. Note: improvement in cardio-metabolic risk parameters was observed	Completed (failed primary)
CC-90001 (BMS-986360; Bristol-Myers Squibb)	JNK inhibitor	2	NASH with bridging fibrosis or compensated cirrhosis (NCT04048876); Primary outcome: histological improvement in fibrosis	n/a	Terminated (Company business objectives have changed)
Ambrisentan (Noorik Biopharmaceuticals AG)	Selective ETA receptor antagonist	2	Decompensated cirrhosis with moderate or severe ascites (NCT03827200); Primary outcome: mean change in HVPG from baseline to day 14	Lack of recruitment, result of COVID-19 pandemic	Terminated
G-CSF	Mobilization of bone marrow stem cells	2/3	Decompensated cirrhosis of any etiology (NCT03911037); Primary outcome: overall survival at 1 year	No significant difference in survival between G-CSF and placebo groups. Note: reduction in liver related events was observed	Completed (Failed primary)

NASH, nonalcoholic steatohepatitis; FXR, farnesoid X receptor; CCR2/5, C-C chemokine receptor type 2/5; FGF21, fibroblast growth factor 21; GLP-1, glucagon-like peptide 1; JNK, c-Jun N-terminal kinase; ET_A, endothelin receptor subtype A; HVPG, hepatic venous pressure gradient; G-CSF, granulocyte colony stimulating factor.

Table 2. Current phase 2 and phase 3 drugs in development for cirrhosis.

Compound	Company/Sponsor	Indication	Stage of development	Mechanism of action (target)
Monotherapies
Resmetirom (MGL-3196)	Madrigal Pharmaceuticals, Inc.	Compensated NASH cirrhosis	Phase 3; NCT05500222 (MAESTRO-NASH-OUTCOMES); Recruiting	Increased hepatic fat metabolism and reduced lipotoxicity (THR-β agonist)
Belapectin (GR MD 02)	Galectin Therapeutics, Inc.	Compensated NASH cirrhosis with portal hypertension	Phase 2/3; NCT04365868; (NAVIGATE); Active not recruiting	Macrophage activation/fibrogenesis (Gal-3 inhibitor)
Efruxifermin (AKR-001)	Akero Therapeutics, Inc.	Compensated NASH cirrhosis	Phase 2; NCT05039450 (SYMMETRY); Active, not recruiting	Decreased lipogenesis and oxidative stress; improved glycemic control (FGF21 analog)
BMS-986263 (ND-L02-s0201)	Bristol-Myers Squibb	Compensated NASH cirrhosis	Phase 2; NCT04267393; Active, not recruiting	Collagen synthesis (HSP47 inhibitor)
BI 685,509	Boehringer Ingelheim	Compensated cirrhosis (non-cholestatic etiologies) and first hepatic decompensation event	Phase 2; NCT0608284; Not yet recruiting	Sinusoidal vasodilation, reduced oxidative stress (soluble sGC activator)
Rosuvastatin	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	Compensated cirrhosis (NASH, ArLD, HBV, HCV, cryptogenic etiology)	Phase 2; NCT05832229 (LCN RESCU); Recruiting	Reduced endothelial dysfunction, intrahepatic vasoconstriction, inflammation and fibrosis (HMG-CoA reductase inhibitor)
Simvastatin	Veterans Affairs (VA) Office of Research and Development	Compensated cirrhosis due to chronic viral hepatitis, ArLD, NAFLD (and at high risk of decompensation)	Phase 3; NCT03654053 (SACRED); Active, not recruiting	Reduced endothelial dysfunction, intrahepatic vasoconstriction, inflammation and fibrosis (HMG-CoA reductase inhibitor)
Growth hormone	Postgraduate Institute of Medical Education and Research, India	Decompensated cirrhosis (any etiology)	Phase 2/3; NCT05253287; Ongoing, recruiting	Improved nitrogen economy, growth hormone resistance, sarcopenia, immune function and liver regeneration
Foscenvivint (PRI-724, OP-724)	Ohara Pharmaceutical Co Ltd.	Cirrhosis caused by HIV/HCV co-infection with hemophilia	Phase 2/3; NCT06144086; Recruiting	Anti-inflammatory and antifibrotic effects (CREB-binding protein/β-catenin inhibitor)
Seladelpar (MBX-8025)	CymaBay Therapeutics, Inc.	Compensated cirrhosis and PBC	Phase 3; NCT06051617 (AFFIRM); Recruiting	Decreased bile acid synthesis and anti-inflammatory effects (PPARδ agonist)
Pirfenidone	University of Guadalajara, Mexico	HCV (with SVR) and residual advanced fibrosis or cirrhosis	Phase 2; NCT05542615 (MINERVA); Recruiting	Anti-inflammatory and antifibrotic effects (suppression of TGFβ activity)
Fenofibrate	Xijing Hospital of Digestive Diseases, China	Compensated cirrhosis and PBC	Phase 2/3; NCT05749822; Recruiting	Anti-inflammatory and hypolipidemic effects (PPARα agonist)
Albutein	Grifols Therapeutics LLC	Decompensated cirrhosis and ascites	Phase 3; NCT03451292 (PRECIOSA); Active, not recruiting	Plasma volume expansion, immuno-modulation, endothelial stabilization (human albumin)
LPCN 1148	Lipocine Inc.	Male subjects with decompensated cirrhosis and sarcopenia	Phase 2; NCT05895136; Active, not recruiting	Myo-augmentation, anti-catabolic, anti-inflammatory (prodrug of bioidentical testosterone)
Allopurinol versus atorvastatin	University of Tanta, Egypt	Compensated NASH cirrhosis	Phase 2/3; NCT05511766; Ongoing, recruiting	Reduced oxidative stress (xanthine oxidase inhibitor); reduced endothelial dysfunction, intrahepatic vasoconstriction, inflammation and fibrosis (HMG-CoA reductase inhibitor)
Drug combinations
Albutein and enoxaparin	European Foundation for Study of Chronic Liver Failure	Decompensated cirrhosis at high risk of poor outcome	Phase 2; NCT05895136 (COMBAT); Not yet recruiting	Plasma volume expansion (human albumin) and potentiation of antithrombin (anticoagulant)
Pioglitazone and metformin	The Affiliated Hospital of Hangzhou Normal University, China	NASH cirrhosis and bridging fibrosis	Phase 1–2; NCT06135584 (SMART); Not yet recruiting	Insulin sensitizing, antifibrotic effects (PPAR-γ agonist) and non-genomic mechanisms (thiazolidinedione); anti-hyperglycemic effects (biguanide)
Zibotentan (ZD4054) and dapagliflozin	AstraZeneca	Cirrhosis and portal hypertension (non-cholestatic etiologies)	Phase 2; NCT05516498 (ZEAL); Recruiting	Hemodynamic improvements, reduced inflammation and fibrosis (ETA receptor antagonist); improved diuresis, renoprotection (SGLT2 inhibitor)
Semaglutide, Cilofexor (GS-9674) and Firsocostat GS-0976)	Gilead Sciences and Novo Nordisk A/S	Compensated NASH cirrhosis	Phase 2; NCT04971785 (WAYFIND); Active, not recruiting	Stimulating insulin secretion (GLP-1 receptor agonist); reduced lipogenesis/oxidative stress (non-steroidal FXR agonist); reduced hepatic de novo lipogenesis (ACC inhibitor)

NASH, nonalcoholic steatohepatitis; THRβ, thyroid hormone receptor beta; Gal-3, galectin-3; FGF21, fibroblast growth factor 21; HSP47, heat shock protein 47; HBV, hepatitis B virus; HCV, hepatitis C virus; ArLD, alcohol-related liver disease; NAFLD, nonalcoholic fatty liver disease; SGLT2, sodium-glucose cotransporter-2; FXR, farnesoid X receptor; HMG coA reductase, 3-hydroxy-3-methylglutaryl-coenzyme a reductase; HIV, human immunodeficiency virus; PPAR (-α/-δ/-γ), peroxisome proliferator-activated receptor; TGFβ, transforming growth factor beta; ET_A, endothelin receptor subtype A; GLP-1, glucagon-like peptide 1; ACC, acetyl-CoA carboxylase.