Updates in Nonalcoholic Steatohepatitis (NASH) Diagnosis and Pipeline Drugs
Introduction
Nonalcoholic steatohepatitis (NASH) lies on the more aggressive end of the NAFLD spectrum. It is characterized histologically by hepatocellular ballooning, inflammation, and varying degrees of fibrosis. With rising global rates of obesity, type 2 diabetes, and metabolic syndrome, NASH is now poised to surpass hepatitis C as the leading indication for liver transplantation in many countries. Yet, no FDA-approved pharmacotherapy exists as of mid-2025.
Epidemiology at a Glance:
- Global NAFLD prevalence: ~25–30%
- Estimated global NASH prevalence: ~3–6%
- 20–30% of patients with NAFLD progress to NASH
- Annual progression to cirrhosis in NASH: ~10–15%
Pathophysiology: Beyond the Two-Hit Hypothesis
The once-dominant "two-hit" model (steatosis → oxidative stress/inflammation) has been replaced by a multi-hit paradigm, integrating:
- Insulin resistance and adipokine imbalance
- Gut-liver axis disruption (microbiome dysbiosis)
- Lipotoxicity from free fatty acids and ceramides
- Genetic polymorphisms: PNPLA3, TM6SF2, HSD17B13
- Mitochondrial dysfunction and ER stress
Advances in Diagnosis
1. Limitations of Liver Biopsy
While liver biopsy remains the gold standard, it's invasive, expensive, and prone to sampling error. This has driven the development of non-invasive diagnostic modalities, especially for fibrosis staging.
2. Non-Invasive Biomarkers & Scores
| Biomarker/Test | Clinical Use |
|---|---|
| FIB-4 | Widely used for ruling out advanced fibrosis |
| NAFLD Fibrosis Score (NFS) | High NPV in primary care settings |
| FAST Score (FibroScan-AST) | Combines LSM with AST for NASH detection |
| NIS4™ (Genfit) | Proprietary biomarker panel for clinical trials |
| Pro-C3, ELF Score | Collagen turnover markers gaining traction |
3. Imaging Advances
- Transient Elastography (FibroScan): Most accessible fibrosis assessment tool
- MRI-PDFF (Proton Density Fat Fraction): Accurate quantification of steatosis
- MR Elastography (MRE): Highly sensitive for fibrosis staging
- Multiparametric MRI (e.g., LiverMultiScan): Emerging as trial endpoints
Therapeutic Landscape: 2025 Pipeline Overview
While lifestyle intervention (≥10% weight loss) remains cornerstone therapy, several drug classes are showing promise in phase 2/3 trials:
1. FXR Agonists
Obeticholic Acid (OCA) – Intercept Pharmaceuticals
- MOA: Farnesoid X receptor activation reduces bile acid synthesis, inflammation, and fibrosis.
- REGENERATE Trial (2023 update): Met fibrosis endpoint but with pruritus and LDL elevation as key AEs.
- FDA Status: Rejected in 2023; resubmission expected pending long-term data.
2. PPAR Agonists
Lanifibranor – Inventiva
- Pan-PPAR agonist (α, δ, γ) showing dual effect on inflammation and fibrosis.
- NATIVE trial: Significant resolution of NASH with fibrosis improvement.
- Phase 3 NATiV3 ongoing
Saroglitazar – Dual PPARα/γ agonist approved in India for NASH/NAFLD.
3. GLP-1 Receptor Agonists
Semaglutide (Ozempic/Wegovy) – Novo Nordisk
- Promotes weight loss and insulin sensitivity
- Phase 2 trial: Resolution of NASH in ~59% vs. 17% in placebo
- Fibrosis improvement less significant; trials ongoing with higher doses
4. Thyroid Hormone Receptor-β (THR-β) Agonists
Resmetirom (MGL-3196) – Madrigal Pharmaceuticals
- Liver-specific THR-β agonist improves lipid metabolism
- MAESTRO-NASH: Met both NASH resolution and fibrosis improvement endpoints
- FDA Priority Review: Approval expected late 2025
5. FGF Analogues
Pegbelfermin (FGF21 analogue) – Bristol Myers Squibb
- Improves insulin resistance, inflammation, and liver histology
- Phase 2b results encouraging; phase 3 trials ongoing
Aldafermin (FGF19 analogue) – Early promise but discontinued due to suboptimal efficacy in fibrosis
6. CCR2/5 Antagonists
Cenicriviroc – Allergan
- Anti-inflammatory and antifibrotic
- Mixed results in AURORA trial; development discontinued
7. Combination Therapies
Given NASH's multifactorial nature, dual or triple therapies are being explored:
- GLP-1 RA + FXR agonists
- PPAR + THR-β agonists
- Semaglutide + Cenicriviroc (early trials)
Ongoing Challenges
- Lack of a universally accepted surrogate endpoint for accelerated drug approval
- Inter-patient variability in disease progression
- Limited real-world application of trial results (strict inclusion criteria)
- Cost and access to advanced diagnostics and therapeutics
Future Directions
- Artificial Intelligence in Histopathology: Digital biopsy interpretation to improve objectivity and interobserver agreement.
- Multi-omics Integration: Genomic, metabolomic, and proteomic signatures for personalized NASH care.
- Microbiome Modulation: Fecal microbiota transplantation and probiotics as adjuvant therapies under investigation.
- Regulatory Evolution: Surrogate endpoints like liver stiffness and serum biomarkers may accelerate drug approval by 2026.
Conclusion
NASH is a growing silent epidemic with a complex pathophysiological basis. While lifestyle modification remains the only established intervention, the emergence of promising pharmacological agents — particularly FXR, THR-β, and PPAR agonists — offers a glimpse of hope. Advances in non-invasive diagnostics are reshaping patient stratification and clinical trial design. A multipronged approach, combining early detection, lifestyle support, and targeted therapies, will be essential to alter the course of this progressive disease.
References
- Younossi ZM, et al. (2023). Nonalcoholic steatohepatitis: Emerging perspectives. Lancet Gastroenterol Hepatol.
- Rinella ME, et al. (2024). Current and emerging pharmacotherapy for NASH. Gastroenterology.
- Sanyal AJ, et al. (2023). Obeticholic acid in NASH: REGENERATE trial update. Hepatology.
- Francque SM, et al. (2024). Lanifibranor for NASH: New evidence. J Hepatol.
- Harrison SA, et al. (2025). MAESTRO-NASH: Resmetirom phase 3 results. New England Journal of Medicine.
- Ratziu V, et al. (2023). MRI-based assessment of NASH fibrosis. J Clin Gastroenterol.
- EASL Clinical Practice Guidelines (2024). NAFLD management. Journal of Hepatology.