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

KEYWORDS:

• liver cirrhosis
• metabolic dysfunction-associated steatohepatitis
• compensated cirrhosis
• decompensated cirrhosis
• synthetic drugs

1. Introduction

Cirrhosis is associated with a substantial, and increasing, health and socioeconomic burden worldwide. The leading causes of cirrhosis are steatotic liver diseases (including alcohol-related liver disease and metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis (NASH)) and chronic viral hepatitis. Owing to rising rates of alcohol consumption, an aging general population, and a spiraling prevalence of metabolic risk factors, a dramatic escalation in cirrhosis-related morbidity and mortality is predicted [1]. It currently ranks tenth among the leading causes of death in Africa (compared to thirteenth in 2015), ninth in Southeast Asia and Europe, and fifth in the Eastern Mediterranean [1]. Cirrhosis is associated with huge healthcare costs, with the bulk of this expenditure attributable to inpatient or emergency department care. Furthermore, cirrhosis causes wide-ranging socioeconomic effects including reduced employment and loss of productivity, and impaired health-related quality of life (HRQoL).

In this editorial, we provide an update on our 2021 review of emerging synthetic drugs for cirrhosis [2], consider the setbacks and progress over the past 3 years, and provide some future insights.

2. Current treatment strategies for cirrhosis

The only curative treatment for end-stage cirrhosis remains liver transplantation but there is a global organ supply-demand imbalance (>17,000 patients are on the waiting list in the United States (US) alone), it is a costly (~$878,400 in the US in 2020 [3]) and highly invasive procedure that is complicated by long-term effects of immunosuppression and a variable risk of recurrence of the primary disease. Consequently, there is an urgent requirement for therapies that can reverse or stabilize cirrhosis.

Importantly, ‘compensated’ and ‘decompensated’ cirrhosis represent distinct clinical stages of advanced liver disease with notable differences in terms of physiological function, prognosis, and treatment strategies.

For patients with compensated cirrhosis, the goals of therapy are to slow, halt, or regress fibrosis (to a pre-cirrhotic stage) and to prevent decompensation. Successful etiological treatment remains the only beneficial (and available) antifibrotic therapy; although reversal of cirrhosis may even be possible, studies in chronic viral hepatitis indicate that this is a slow process [4]. To date, despite a detailed understanding of the cellular and molecular features of spontaneous resolution of liver fibrosis, no approved ‘mechanistic’ therapies have emerged [5]. Potential direct antifibrotic approaches include modulating the activity of specific fibrogenic cell types (e.g. myofibroblasts, hepatic macrophage subtypes), targeting the extracellular matrix (scar), inhibiting pro-fibrotic signaling pathways, and modifying inflammation/innate immunity. The possible reasons why effective antifibrotic drugs have proven to be so elusive (particularly characteristics of the extracellular matrix in cirrhosis that confer resistance to remodeling and biological redundancy of therapeutic targets) have been previously discussed in detail [2,6].

In contrast, for patients with decompensated cirrhosis, strategies are aimed at preventing further decompensation or death (e.g. by improving liver function) or treating specific complications such as ascites, hepatic encephalopathy, and sarcopenia. Critically, any new treatment for cirrhosis must not increase the risk of developing hepatocellular carcinoma.

3. Cirrhosis market size and dynamics

Although cirrhosis represents a seemingly recalcitrant pharmacological indication, companies remain undeterred. According to DelveInsight’s’ estimates, in 2022 there were ~3.4 million diagnosed prevalent cases of cirrhosis in the seven major markets (7 MM: US, France, Germany, Italy, Spain, United Kingdom, and Japan) and a market size of approximately USD 3 billion. Furthermore, the anticipated introduction of emerging drug therapies and an increase in cirrhosis prevalence is expected to drive the growth of the cirrhosis market in the 7 MM in the coming years (at a compound annual growth rate of 6.3% by 2032), although this may be tempered by pricing, access, and reimbursement constraints.

4. Clinical trials of synthetic drugs for cirrhosis – recent setbacks and ongoing hopes

In the past 3 years, there have been some further notable setbacks in drug development for cirrhosis, particularly in MASH/NASH (Table 1). Following the second rejection of obeticholic acid by the Food and Drug Administration (FDA) for the treatment of pre-cirrhotic NASH-related fibrosis (due to concerns over the drug’s modest efficacy and safety problems), further evaluation in NASH has ceased. As part 1 of the phase 3 trial of the C-C chemokine receptor type 2 and 5 (CCR2/5) antagonist cenicriviroc in patients with NASH and stage F2/3 fibrosis (AURORA; NCT03059446) did not achieve the primary histological endpoint of fibrosis regression [7], the study was terminated early without the part 2 rollover to collect long-term safety and clinical outcome data. Similarly, further development of pegbelfermin, a polyethylene glycol – conjugated analog of human fibroblast growth factor 21 (FGF21), was discontinued after it failed to achieve the primary histological endpoint of improvement in liver fibrosis in patients with compensated NASH-related cirrhosis in the phase 2b FALCON trial (NCT03486912) [8]. Development of the selective small-molecule c-Jun N-terminal Kinase (JNK) inhibitor CC-90001, as a potential antifibrotic agent, has also ceased (at least in NASH) following premature termination of a phase 2 trial (NCT04048876). Finally, the glucagon-like peptide-1 (GLP-1) analog semaglutide did not significantly improve fibrosis or resolve NASH compared to placebo in a phase 2 trial of patients with NASH-related cirrhosis [9]. Nevertheless, there was evidence of improvement in cardiometabolic parameters and noninvasive markers of liver injury with semaglutide treatment and the drug is being evaluated in combination regimens in cirrhosis.

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.

Nevertheless, there are many ongoing clinical trials of both pharmacological agents (including repositioned drugs) and non-pharmacological therapies for cirrhosis that are at various stages of development. Here, we highlight phase 2 and 3 studies of synthetic drugs that specifically target patients with cirrhosis (Table 2) and discuss some of the leading pipeline candidates in more detail below.

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.

4.1. Metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis

4.1.1. Drug monotherapies for MASH-related cirrhosis

Resmetirom is an orally administered, liver-targeted thyroid hormone receptor (THR)-β selective agonist. THR-β agonism increases hepatic fat metabolism and reduces lipotoxicity in MASH. In the pivotal phase 3 randomized placebo-controlled serial biopsy trial in patients with NASH and liver fibrosis (MAESTRO-NASH; NCT03900429), both doses of resmetirom (80 mg and 100 mg) met the primary endpoints of steatohepatitis resolution and no worsening of fibrosis on liver biopsy [10]. The key secondary endpoint of LDL-cholesterol lowering was also achieved, along with improvements in multiple noninvasive biomarker endpoints. Longer-term clinical outcome data from MAESTRO-NASH and the MAESTRO-NASH-OUTCOMES trial (NCT05500222; in patients with compensated cirrhosis) will be critical in the drug’s progression toward full approval.

Efruxifermin is a long-acting Fc-FGF21 fusion protein, engineered to mimic the biological activity profile of native FGF21 which regulates multiple metabolic pathways. A 36-week analysis of SYMMETRY (NCT05039450), a 96-week phase 2b study of efruxifermin in patients with compensated NASH-related cirrhosis, showed that 22% of the 28 mg group and 24% of the 50 mg group achieved the primary endpoint of fibrosis improvement without worsening of NASH, compared with 14% in the placebo group [11]. Although not statistically significant at this relatively early timepoint, results correlated with improvements in noninvasive markers of liver injury and fibrosis and a repeat liver biopsy will be assessed at 96 weeks.

Aldafermin is an engineered analog of fibroblast growth factor 19 (FGF19), which inhibits bile acid synthesis and regulates metabolic homeostasis. Recent data from ALPINE-4 (NCT04210245), a phase 2b trial in patients with compensated NASH-related cirrhosis found that the higher daily dose (3 mg) of aldafermin achieved the primary endpoint of significantly lowering enhanced liver fibrosis (ELF) score from baseline to week 48 [12]. Improvements were also observed in other noninvasive tests. Although there was no associated amelioration of histology, the trial was not statistically powered to detect this.

Belapectin was previously shown, in a subgroup analysis only, to reduce hepatic venous pressure gradient (HVPG) and development of esophageal varices in a phase 2b trial (NCT02462967) in patients with NASH-related cirrhosis and portal hypertension without esophageal varices at baseline [13]. The effect of belapectin on the prevention of varices at 18 months of treatment compared to placebo is currently being assessed in a seamless phase 2b/3 trial in compensated NASH-related cirrhosis (NAVIGATE; NCT04365868),

BMS-986263, a once-weekly intravenously (i.v.)-administered lipid nanoparticle delivering small interfering RNA designed to degrade heat shock protein 47 (HSP47) mRNA, improved histological fibrosis scores after 12 weeks of treatment in some patients with advanced hepatic fibrosis/cirrhosis and cured hepatitis C virus (HCV), in a small phase 2 proof-of-concept trial [14]. A phase 2 study evaluating the antifibrotic effect of BMS‐986263 in compensated NASH-related cirrhosis is ongoing (NCT04267393).

Lanifibranor is an oral pan-peroxisome proliferator-activated receptor (PPAR) agonist that is the only drug in phase 3 that has shown efficacy against the dual histological endpoint of NASH resolution and fibrosis improvement (NATIVE; NCT03008070), albeit in noncirrhotic NASH [15]. A planned phase 3 outcome trial (NATiV3) is expected to randomize ~800 patients with NASH and compensated cirrhosis.

4.1.2. Combination drug regimens for MASH-related cirrhosis

There is growing evidence suggesting that the combined use of drugs with distinct mechanisms of action may exhibit higher efficacy in treating MASH compared to individual drugs. Semaglutide, and a fixed-dose combination of the nonsteroidal farnesoid X receptor (FXR) agonist cilofexor and the liver-directed acetyl-CoA carboxylase (ACC) inhibitor firsocostat, alone and in combination, is being evaluated in a phase 2 trial in patients with compensated NASH-related cirrhosis (WAYFIND; NCT04971785). In addition, a phase 2 trial in patients with NASH and fibrosis stage 2, 3 or 4 (NCT05016882) will investigate whether the combination of semaglutide and a drug that mimics FGF21 activity (NNC0194 0499) is effective in decreasing fibrosis.

4.2. Non-MASH drug development for cirrhosis

A reduction in liver stiffness (but not histological fibrosis) in an exploratory-phase 1/2a study in patients with HCV- and hepatitis B virus (HBV)-associated cirrhosis after 12 weeks of twice-weekly i.v. treatment (NCT03620474), suggested that the CREB-binding protein (CBP)/✓ catenin inhibitor foscenvivint might have potential as an antifibrotic agent [16]. A phase 2 study in patients with decompensated cirrhosis induced by HCV, HBV, or NASH has been announced.

Seladelpar is a selective PPAR-δ agonist that acts on multiple hepatic cell types to modulate cholestasis, hepatocellular injury, inflammation, fibrosis, and lipid metabolism. Development of seladelpar in NASH was terminated due to reports of interface hepatitis in some patients in a phase 2b trial (NCT03551522), but the drug has been resurrected in primary biliary cholangitis (PBC) and recently showed positive long-term safety and efficacy data (ASSURE; NCT03301506) [17]. A phase 3b/4 trial to evaluate its effect on clinical outcomes in patients with PBC and compensated cirrhosis (AFFIRM; NCT06051617) is ongoing.

LPCN 1148 is an oral prodrug of bioidentical testosterone that is being evaluated for decompensated cirrhosis with sarcopenia. Sarcopenia in cirrhosis is common (prevalence 30–70%) and multifactorial (including protein catabolism, hyperammonemia, insulin resistance, and reduced testosterone in males) and is associated with adverse outcomes (impaired HRQoL, increased decompensation events, hospital admissions, and mortality). A small phase 2 trial of LPCN 1148 in male patients with decompensated cirrhosis and sarcopenia who are on the liver transplant waiting list (NCT04874350) showed increased L3 skeletal muscle index and fewer clinical events relative to placebo after 24 weeks of blinded study treatment [18]; results from the open-label extension stage are awaited.

5. Expert opinion

To date, drug development in cirrhosis has been an uphill struggle, yet various companies are evaluating a diverse assortment of synthetic drugs. Disease complexity and patient heterogeneity remain ongoing challenges in identifying effective anti-fibrotic therapies that will require advances in precision medicine (including leveraging ‘big data’ resources and relevant human samples), further exploration of combination drug regimens, and innovations in clinical trial design to overcome [19]. Most agents are being tested in patients with compensated MASH-related cirrhosis and resmetirom has emerged as the first approved drug in pre-cirrhotic disease; efficacy data for resmetirom in compensated MASH-related cirrhosis are therefore keenly awaited. Interestingly, a recent ‘master regulator’ gene analysis in a large multimodal MASLD database identified THR-β as a critical suppressor of disease progression and clinical outcomes (including in patients with cirrhosis) [20]. Nevertheless, in MAESTRO-NASH resmetirom improved key readouts of liver histopathology in only 25–30% of patients, highlighting the ongoing need to develop new (and more effective) drugs. For decompensated cirrhosis, advanced therapy medicinal products (ATMPs) – rather than synthetic drugs – could be particularly impactful, by promoting both tissue repair and the restoration of liver function. Human allogeneic liver-derived progenitor cells (HepaStem®) [21], adipose-derived mesenchymal stem cells (ADR-001), and macrophage cell therapy [22] represent promising pipeline ATMPs for decompensated cirrhosis. Meanwhile, albumin-human injection (Albutein) and continuous infusion terlipressin (BIV201) might advance as future ‘bridge therapies’ to increase survival time for end-stage cirrhosis patients awaiting a liver transplant.

Declaration of interests

J A Fallowfield serves as a consultant or advisory board member for Resolution Therapeutics, Kynos Therapeutics, Ipsen, River 2 Renal Corp., Stimuliver, Galecto Biotech, Global Clinical Trial Partners and Guidepoint and has received research grant funding from GlaxoSmithKline, Intercept Pharmaceuticals and Genentech.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.