Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), a progressive condition involving inflammation and liver cell damage. This can lead to scarring, known as fibrosis, potentially advancing to cirrhosis or liver failure. With over 115 million adults affected worldwide, the global prevalence of NASH is rising. Currently, no approved pharmacological treatments exist, highlighting a significant need for new therapeutic options.
Understanding NASH and Treatment Gaps
NASH represents a more advanced stage of NAFLD, characterized by fat in the liver, inflammation, and liver cell damage. This inflammation can trigger fibrosis, where scar tissue replaces healthy liver tissue, eventually leading to cirrhosis. Cirrhosis is a life-threatening condition that impairs liver function and can progress to liver failure, necessitating a liver transplant, or even liver cancer.
Current management strategies for NASH involve lifestyle modifications, including dietary changes and increased physical activity. While 5% to 7% weight loss can improve liver fat, over 10% is often needed to resolve NASH and improve fibrosis. These lifestyle changes can be challenging for patients to sustain, leaving a substantial gap in effective treatment options. The lack of approved drugs highlights the limitations of existing approaches and the demand for new pharmacological solutions to address disease progression.
Promising New Drug Candidates
Several new drug classes are in development to target the complex pathways involved in NASH progression. Farnesoid X Receptor (FXR) agonists activate FXR, a nuclear receptor in liver cells that regulates bile acid synthesis and lipid metabolism. By activating FXR, these drugs aim to reduce liver fat, inflammation, and fibrosis. Obeticholic acid is a leading FXR agonist studied for NASH treatment.
Another class is Glucagon-Like Peptide-1 (GLP-1) receptor agonists, already used for diabetes and weight management. Drugs like semaglutide improve blood sugar control, reduce appetite, and promote weight loss, indirectly alleviating liver fat and inflammation. Thyroid Hormone Receptor-beta (THR-β) agonists, such as resmetirom, selectively activate the THR-β receptor in the liver. This activation reduces liver fat accumulation, improves cholesterol levels, and may directly impact inflammation and fibrosis by increasing the liver’s metabolic rate.
Fibroblast Growth Factor 21 (FGF21) analogues mimic FGF21, a hormone regulating glucose and lipid metabolism. These analogues lead to reduced liver fat, improved insulin sensitivity, and anti-inflammatory actions.
Acetyl-CoA Carboxylase (ACC) inhibitors, like firsocostat, block the ACC enzyme involved in fatty acid synthesis. By inhibiting ACC, these drugs reduce new fat production in the liver, decreasing steatosis.
Pan-PPAR agonists, such as lanifibranor, activate multiple peroxisome proliferator-activated receptors (PPARs). These nuclear receptors regulate gene expression in metabolism and inflammation, helping to reduce liver fat, inflammation, and fibrosis.
Clinical Trial Progress and Safety
Clinical trials for these drug candidates provide important insights into their effectiveness and safety profiles. Obeticholic acid, an FXR agonist, demonstrated an ability to improve liver fibrosis without worsening NASH in a Phase 3 trial. Side effects included pruritus (itching) and increased low-density lipoprotein (LDL) cholesterol levels.
Resmetirom, a THR-β agonist, has shown promising results in Phase 3 trials, leading to significant reductions in liver fat and improvements in markers of liver damage. Studies indicated a notable percentage of patients achieved NASH resolution or fibrosis improvement without worsening NASH. Common side effects included gastrointestinal issues like diarrhea and nausea.
Semaglutide, a GLP-1 receptor agonist, has also been investigated in NASH trials, showing a high rate of NASH resolution without worsening of fibrosis. In one study, nearly 60% of patients receiving a higher dose achieved NASH resolution. While effective for weight loss and metabolic improvement, semaglutide’s side effects often involve gastrointestinal disturbances such as nausea, vomiting, and diarrhea.
Lanifibranor, a pan-PPAR agonist, achieved a statistically significant improvement in NASH resolution and fibrosis regression in its Phase 2b trial. This drug’s mechanism targeting multiple pathways suggests a comprehensive approach to treatment. Reported side effects included gastrointestinal issues and weight gain. Ongoing clinical trials continue to gather additional safety data for these and other emerging treatments, as understanding both efficacy and potential risks is essential.
Regulatory Status and Patient Access
The regulatory landscape for NASH drugs is evolving, with several candidates currently under review by regulatory bodies such as the U.S. Food and Drug Administration (FDA). Resmetirom, for instance, has been under FDA review, with an approval decision anticipated. Regulatory approval signifies that a drug has met the agency’s standards for safety and effectiveness, making it available for prescription to patients.
Once approved, these new drugs could become accessible to patients through prescription, likely with specific eligibility criteria based on the severity of their NASH and other co-existing conditions. The timeline for widespread patient access depends on various factors, including the speed of regulatory review, manufacturing scale-up, and subsequent commercialization efforts. Initial access might be limited to specialized liver centers or through specific patient programs.
Anticipated challenges to patient access may include the cost of these novel therapies, as specialty drugs often carry a high price tag. Insurance coverage and reimbursement policies will play a significant role in determining how widely these treatments can be adopted. Additionally, guidelines from medical societies will help define which patient populations are most suitable for these new pharmacological interventions, impacting their broader availability.