Advances in novel drug therapy for metabolic dysfunction-associated steatohepatitis cirrhosis

Introduction

Originally linked to alcohol and caloric excess, fatty liver disease has evolved in classification. The redefinition of NAFLD to MASLD reflects its metabolic roots. MASH—marked by inflammation, ballooning degeneration, and fibrosis—leads to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Currently, there are no approved pharmacologic treatments for MASH, particularly for advanced disease stages like cirrhosis. The authors emphasize the urgent need for effective interventions targeting this population.

Evaluating Clinical Efficacy in MASH Cirrhosis

Most clinical trials to date have focused on earlier-stage fibrosis (F2–F3). However, in established cirrhosis (F4), reversing fibrosis is harder due to dense collagen crosslinking and complications like portal hypertension.

• FDA Guidance: For compensated cirrhosis, traditional approval pathways are recommended, requiring hard clinical endpoints (e.g., hepatic decompensation, MELD ≥15, transplantation, or death).

• Surrogate Endpoints: Non-invasive tools like the ELF score and imaging-based elastography (e.g., VCTE, MRI elastography) are being explored as potential surrogate markers of fibrosis improvement.

• Portal Hypertension: HVPG measurements are used to assess treatment effects, though invasive. MELD and Child-Pugh scores remain validated markers for clinical outcomes.

Therapeutic Strategies and Preliminary Outcomes

The review systematically analyzes drugs tested in phase 2/3 trials for MASH cirrhosis:

1. FXR Agonists

   • Obeticholic Acid (OCA) showed modest anti-fibrotic effects in REVERSE trial but failed to meet statistical significance in cirrhotic cohorts.

   • Aldafermin, an FGF19 analog, reduced ELF scores and showed 20% fibrosis reversal in high-dose groups in ALPINE 4 trial.

2. ASK1 Inhibitors

   • Selonsertib, despite early promise, failed to achieve fibrosis reversal in the STELLAR-4 trial in cirrhotic patients.

3. Galectin-3 Inhibitors

   • Belapectin did not reduce HVPG overall but showed benefit in preventing varices in patients without baseline varices, leading to the ongoing NAVIGATE trial.

4. FGF21 Analogues

   • Efruxifermin showed the most promising results, with a 24% placebo-adjusted fibrosis reversal at 96 weeks in the SYMMETRY trial, and up to 63% MASH resolution at 24 weeks. The phase 3 SYNCHRONY trial is underway.

   • Pegozafermin, another FGF21 analog, is currently being tested in ENLIGHTEN-Cirrhosis trial with fibrosis and clinical outcomes as primary endpoints.

5. GLP-1 Receptor Agonists

   • Semaglutide failed to improve fibrosis in cirrhosis but showed benefit in MASH resolution in earlier-stage disease. Combination therapies with cilofexor and firsocostat are under further investigation in WAYFIND.

6. Other Targets

   • Simtuzumab (LOXL2 inhibitor) and Emricasan (pan-caspase inhibitor) failed to meet primary endpoints in cirrhosis.

   • BMS-986263, targeting HSP47 via siRNA, showed modest effects and is under further study.

Ongoing Trials and Future Prospects

Several major trials are currently enrolling:

• NAVIGATE (belapectin) focuses on variceal prevention.

• MAESTRO-NASH-OUTCOMES (resmetirom) assesses clinical outcomes like decompensation.

• ENLIGHTEN-Cirrhosis (pegozafermin) targets fibrosis and disease progression.

• WAYFIND explores combination strategies for fibrosis reversal.

• SYNCHRONY (efruxifermin) evaluates both histologic and clinical endpoints over 5 years.

Conclusion

MASH cirrhosis represents a high-risk population with significant unmet clinical need. While past trials have faced challenges, particularly in fibrosis reversal, promising signals are emerging—especially from FGF21 analogues such as efruxifermin and pegozafermin. Future drug development may hinge on combination therapies that integrate metabolic, anti-inflammatory, and anti-fibrotic effects. To accelerate approvals, further validation of surrogate endpoints (e.g., ELF, LSM) is also crucial. This review serves as a timely summary of current progress, setbacks, and future directions in the evolving therapeutic landscape for MASH cirrhosis.

Full text

https://www.xiahepublishing.com/2994-8754/JTG-2024-00040

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

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