This article explains the latest experimental treatments for liver scarring (fibrosis) in NASH, a severe form of fatty liver disease. Researchers are testing over 20 drugs targeting fat metabolism, inflammation, and scar formation, with several showing promising results in clinical trials. Key advances include FXR agonists like obeticholic acid (which doubled fibrosis improvement rates to 23.1%) and FGF-21 analogues that reduced liver fat by 5.2-6.8% in studies. While no drugs are yet FDA-approved, many are in late-stage trials and could become available within 3 years.

Emerging Treatments for Liver Scarring in NASH: Latest Research Updates

Table of Contents

• Introduction & Background: Why NASH Fibrosis Matters
• How Doctors Diagnose Fibrosis
• Experimental Treatments in Development
• Metabolism-Targeting Therapies
• Anti-Inflammatory & Anti-Scarring Therapies
• Source Information

Introduction & Background: Why NASH Fibrosis Matters

For decades, hepatitis B (HBV) and C (HCV) were the leading causes of severe liver scarring (cirrhosis) and liver transplants. But with powerful antiviral treatments now available – which either suppress HBV long-term or cure HCV – these viruses are no longer the primary concern. Instead, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of cirrhosis in North America and Europe.

NAFLD affects millions, and a significant portion develop its more severe form called non-alcoholic steatohepatitis (NASH). In NASH, fat accumulation causes liver inflammation and damage that can progress to fibrosis (scarring). When fibrosis worsens, it leads to cirrhosis – where scar tissue replaces healthy liver tissue – increasing risks of liver failure and liver cancer (hepatocellular carcinoma or HCC). Alarmingly, NASH is now the fastest-growing reason for liver transplants.

Fibrosis happens when injured liver cells trigger activation of hepatic stellate cells (HSCs). These specialized cells normally store vitamin A, but when activated, they become the liver's primary scar-producing cells. This scarring process involves complex signals including:

• Transforming growth factor-beta 1 (TGFβ1)
• Platelet-derived growth factor (PDGF)
• Vascular endothelial growth factor (VEGF)

Damaged liver cells (hepatocytes) release inflammatory signals that further activate HSCs. Additional triggers include toxic fats like free cholesterol and high insulin levels. While no anti-fibrotic drugs are yet approved, understanding these pathways has identified over 20 promising drug targets currently being tested.

How Doctors Diagnose Fibrosis

Traditionally, liver biopsy was the "gold standard" for diagnosing fibrosis. However, biopsies have significant limitations:

• Sampling variability: A biopsy examines only 1/50,000th of the liver, potentially missing affected areas
• Invasiveness: Carries risks of pain, bleeding, and rarely death (0.01-0.1% risk)
• Practical constraints: Can't be repeated more than 2-3 times during clinical trials

New non-invasive methods are rapidly replacing biopsies:

1. Blood tests:
   • ELF test (measures specific scar-related proteins)
   • NAFLD Fibrosis Score (uses age, BMI, blood sugar, and liver enzyme levels)
   • FIB-4 Index (calculates risk using age, ALT, AST enzymes, and platelet count) - accurately rules out advanced fibrosis 90% of the time
2. Imaging tests:
   • Transient elastography (FibroScan®): Measures liver stiffness but is less accurate in obese patients
   • MR elastography: More specific than FibroScan®, excellent at ruling out fibrosis
   • MRI-PDFF: Precisely quantifies liver fat percentage

These non-invasive tools are crucial for monitoring treatment response in clinical trials. However, they haven't yet fully replaced biopsies in phase 3 trials seeking FDA approval, as validation studies are ongoing.

Experimental Treatments in Development

Over 30 drugs are currently in clinical trials targeting NASH fibrosis through three main approaches:

• Metabolic agents: Target fat metabolism and insulin resistance (12+ drugs in trials)
• Anti-inflammatories: Reduce liver inflammation (8+ drugs in trials)
• Direct antifibrotics: Block scar-producing cells (10+ drugs in trials)

Promisingly, successful antiviral treatment in hepatitis patients shows fibrosis can reverse when liver injury stops. This suggests NASH treatments that improve underlying metabolic issues may also reduce scarring.

Metabolism-Targeting Therapies

These drugs address the metabolic roots of NASH - insulin resistance and abnormal fat processing:

FXR Agonists: Activate farnesoid X receptors that regulate cholesterol and bile acids. Leading candidate obeticholic acid (OCA) showed significant results in the REGENERATE phase 3 trial (NCT02548351):

• 23.1% of patients had fibrosis improvement vs 11.9% on placebo
• However, it didn't achieve NASH resolution endpoints
• Currently in REVERSE trial (NCT03439254) for NASH cirrhosis patients

Other FXR agonists in development include EDP-305 (Phase 2, NCT03421431) and tropifexor (being tested with cenicriviroc).

Thyroid Hormone Receptor Agonists: Boost fat metabolism. Resmetirom (MGL-3196) is in the MAESTRO-NASH phase 3 trial (NCT03900429) with 2,000 patients. VK2809 showed 12.5% absolute fat reduction on MRI in phase 2 (NCT02927184).

FGF-21 Analogues: Improve insulin sensitivity and may directly reduce scarring. Pegbelfermin produced striking results:

• 10mg dose: -6.8% liver fat reduction vs -1.3% placebo (p=0.0004)
• 20mg dose: -5.2% reduction vs -1.3% placebo (p=0.008)

Two other FGF-21 drugs are in phase 2: BIO89-100 (NCT04048135) and efruxifermin (NCT03976401).

PPAR Agonists: Regulate fat/cholesterol metabolism through different pathways:

• Saroglitazar (PPARα/γ agonist): Phase 2 trial EVIDENCES IV (NCT03061721)
• Lanifibranor (PPARα/γ/δ agonist): Phase 2 trial (NCT03008070)
• Seladelpar (PPARδ agonist): Phase 2 trial (NCT03551522)

GLP-1 Receptor Agonists: Originally diabetes drugs, semaglutide showed impressive NASH resolution in phase 2 (NCT02970942):

• 59% resolution at 0.4mg dose vs 17% placebo (p<0.001)
• However, no significant fibrosis improvement was seen

Other Metabolic Agents:

• Aramchol (fat metabolism modulator): Phase 3 trial (NCT04104321)
• HTD1801 (lipid modulator): Phase 2 trial (NCT03656744)
• Icosabutate (engineered fatty acid): Reduced fibrosis in mice, now in phase 2 (NCT04052516)

Anti-Inflammatory & Anti-Scarring Therapies

These directly target inflammation and HSC activation:

VAP-1 Inhibitors: Block vascular adhesion protein-1 that promotes inflammation. BI 1467335 is being tested in phase 2 (NCT03166735) with ALT reduction as secondary endpoint.

Stem Cell Therapies: Hepastem (liver-derived stem cells) may deactivate HSCs. An open-label safety trial is underway (NCT03963921).

Galectin-3 Inhibitors: Target proteins that drive scarring. Belapectin (GR-MD-02) showed benefit in phase 2:

• 38% fibrosis reduction in non-cirrhotic patients vs 6.39% increase in cirrhotics (p=0.02)
• Phase 3 trial (NAVIGATE, NCT04365868) now recruiting

ASK-1 Inhibitors: Block apoptosis signal-regulating kinase 1 that promotes cell death. Selonsertib showed mixed results in phase 2/3 trials (STELLAR program).

CCR2/5 Antagonists: Cenicriviroc blocks receptors that attract inflammatory cells. When combined with tropifexor, it's being evaluated in phase 2 (NCT03517540).

Source Information

Original Article Title: Experimental and Investigational Targeted Therapies for the Management of Fibrosis in NASH: An Update
Authors: Tsipora M Huisman, Douglas T Dieterich, Scott L Friedman
Publication: Journal of Experimental Pharmacology 2021:13, 329-338
Note: This patient-friendly article preserves all data from the original peer-reviewed research while explaining medical terms and implications for patients.