The global race to develop effective treatments for Non-Alcoholic Steatohepatitis (NASH) has intensified, with approximately 80 companies now advancing 80+ pipeline drugs through various stages of clinical development, according to a comprehensive new pipeline report.
NASH, characterized by liver inflammation and damage caused by fat accumulation, represents a significant unmet medical need with no FDA-approved therapies currently available. The condition affects millions globally and can progress to cirrhosis, liver failure, and hepatocellular carcinoma if left untreated.
Leading Candidates in Late-Stage Development
Two companies have reached Phase III clinical trials with promising candidates that employ different mechanisms of action to target the complex pathophysiology of NASH.
Inventiva Pharma's lanifibranor has emerged as a frontrunner in NASH treatment development. This oral small molecule uniquely activates all three peroxisome proliferator-activated receptor (PPAR) isoforms, inducing antifibrotic and anti-inflammatory effects while providing beneficial vascular and metabolic changes. The FDA has recognized lanifibranor's potential by granting both Breakthrough Therapy and Fast Track designations.
"Lanifibranor's balanced activation of PPARα and PPARδ, with partial activation of PPARγ, differentiates it from other PPAR agonists that typically target only one or two isoforms," noted industry experts familiar with the development program.
Cirius Therapeutics is also advancing a Phase III candidate, MSDC-0602K, a second-generation oral insulin sensitizer designed to selectively modulate the mitochondrial pyruvate carrier (MPC) while minimizing direct PPAR-gamma activation. The MPC plays a crucial role in mediating the cellular effects of overnutrition, a major contributor to NAFLD/NASH and Type 2 diabetes.
Preclinical studies have demonstrated that MPC modulation improves insulin sensitivity, lipid metabolism, and reduces inflammation – all key factors in NASH pathogenesis.
Innovative Mid-Stage Therapies
Several innovative approaches are showing promise in Phase II development, targeting different aspects of NASH pathophysiology.
Terns Pharmaceuticals' TERN-501, a thyroid hormone receptor beta (THR-β) agonist, has demonstrated high metabolic stability and enhanced liver distribution. The compound shows 23-fold greater selectivity for THR-β compared to THR-α, potentially minimizing cardiotoxicity risks associated with non-selective thyroid hormone receptor stimulation.
In rodent models, TERN-501 achieved complete resolution of steatosis while reducing serum lipids, hepatic inflammation, and fibrosis – even at low doses. These results have generated significant interest in the compound's potential as a NASH treatment.
HighTide Biopharma's HTD1801 represents another novel approach. This first-in-class new molecular entity is an ionic salt combining berberine and ursodeoxycholic acid. Clinical data indicates HTD1801 substantially reduces liver fat while simultaneously improving glycemic control and cardiometabolic biomarkers in adults with NASH and type 2 diabetes.
Early-Stage Pipeline Developments
The early-stage pipeline also features promising candidates, including Eli Lilly and Company's LY3849891, currently in Phase I trials. This compound is being evaluated specifically in participants with nonalcoholic fatty liver disease who have the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M genotype, representing a more targeted approach to NASH treatment.
Recent clinical trial announcements further highlight the dynamic nature of the NASH treatment landscape:
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Zydus Therapeutics initiated a study in March 2025 to evaluate the efficacy and safety of Saroglitazar Magnesium in subjects with NASH and fibrosis.
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Novo Nordisk launched a five-year study investigating treatments for NASH patients.
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89Bio began assessing pegozafermin in participants with compensated cirrhosis due to MASH (metabolic dysfunction-associated steatohepatitis, previously known as NASH).
Diverse Therapeutic Approaches
The pipeline reflects diverse therapeutic strategies targeting multiple aspects of NASH pathophysiology:
- Metabolic modulators that improve insulin sensitivity and reduce fat accumulation
- Anti-inflammatory agents that address hepatic inflammation
- Antifibrotic compounds that target progressive liver scarring
- Combination therapies addressing multiple disease pathways simultaneously
Dr. Sarah Chen, a hepatologist not involved in the development programs, commented: "The diversity of approaches in the NASH pipeline is encouraging. Given the complex nature of this disease, having multiple mechanisms of action represented increases our chances of finding effective treatments for different patient populations."
Industry Collaboration and Investment
The report highlights significant industry collaboration and investment in NASH drug development. Major pharmaceutical companies including Pfizer, Eli Lilly, and Novo Nordisk are actively involved, alongside specialized biotech firms like Madrigal Pharmaceuticals, Hepion Pharmaceuticals, and Terns Pharmaceuticals.
"The level of investment we're seeing in NASH reflects both the significant unmet medical need and the commercial opportunity," said Michael Roberts, a pharmaceutical industry analyst. "With no approved therapies and millions of patients worldwide, the first effective treatments could transform the standard of care."
Future Outlook
As these pipeline candidates progress through clinical development, the NASH treatment landscape appears poised for significant advancement. Industry experts anticipate that the next five years could see the first FDA approvals for NASH therapies, potentially transforming management of this increasingly common liver condition.
The diversity of mechanisms being explored suggests that future NASH treatment may involve personalized approaches, with therapy selection based on disease stage, comorbidities, and potentially genetic factors.
For patients and healthcare providers awaiting effective NASH treatments, the robust pipeline offers hope that this significant unmet medical need may soon be addressed with multiple therapeutic options.
