Overview
This lecture reviews new drugs under investigation for non-alcoholic steatohepatitis (NASH), focusing on their mechanisms, clinical trial results, and future directions in NASH therapy.
Background & Unmet Needs
- NASH is a progressive liver disease with increasing prevalence and risk of cirrhosis and hepatocellular carcinoma.
- No drugs are currently approved for NASH treatment, despite many ongoing clinical trials.
- Effective therapy should target both liver inflammation (steatohepatitis), fibrosis, and cardiometabolic risk factors.
Drugs Targeting Metabolic Pathways
FXR Agonists
- Obeticholic acid (OCA) is a potent FXR agonist improving liver histology but with frequent pruritus; long-term clinical impact still under study.
- Tropifexor is another FXR agonist in phase 2 trials, often being tested in combination therapies.
PPAR Agonists
- Elafibranor and saroglitazar are dual PPAR agonists; elafibranor showed variable histological benefits, saroglitazar reduced ALT levels and liver fat in trials.
- Aramchol inhibits SCD1 and reduces de novo fat synthesis; phase 3 trials are ongoing.
Incretins & FGF Analogues
- Semaglutide (GLP-1 analogue) resolved NASH in 59% but did not improve fibrosis significantly.
- Tirzepatide and cotadutide (combination incretins) are being evaluated in phase 2/3 trials.
- NGM282 (FGF19 analogue) significantly reduced liver fat and improved multiple liver histology parameters but with GI side effects.
Other Metabolic Agents
- MSDC-0602K (insulin sensitizer) improved non-invasive liver injury markers but not histology endpoints.
- Resmetirom (THR-β agonist) reduced liver fat and improved steatohepatitis, with mild GI side effects.
Drugs Targeting Oxidative Stress & Inflammation
- Cenicriviroc (CCR2/5 antagonist) improved fibrosis in phase 2 but not NASH activity; phase 3 data awaited.
- Selonsertib (ASK1 inhibitor) and emricasan (caspase inhibitor) failed to meet primary endpoints; development halted.
Anti-Fibrotic Agents
- Simtuzumab (lysyl oxidase inhibitor) and GR-MD-02 (galectin-3 inhibitor) showed limited efficacy and did not meet primary clinical endpoints in trials.
Intestinal Targeted Approaches
- Gut-focused therapies (e.g., orlistat, microbiota transplantation) have not yet advanced beyond early-phase trials for NASH.
Combination Therapy
- Combining different drug classes (e.g., FXR agonist, ACC inhibitor, ASK1 inhibitor) is being explored for synergistic anti-fibrotic/anti-steatotic effects.
Key Terms & Definitions
- NASH — Non-alcoholic steatohepatitis, a liver disease combining fat accumulation and inflammation.
- FXR — Farnesoid X receptor, a nuclear receptor regulating bile acid and lipid metabolism.
- PPAR — Peroxisome proliferator activated receptor, regulates lipid/glucose metabolism.
- GLP-1 — Glucagon-like peptide 1, an incretin hormone affecting insulin secretion and appetite.
- FGF19 — Fibroblast growth factor 19, regulates bile acid and glucose homeostasis.
- Cirrhosis — Advanced liver scarring from chronic liver damage.
- Pruritus — Itching, a common side effect of FXR agonists.
Action Items / Next Steps
- Review ongoing phase 3 clinical trials for newly developed anti-NASH drugs.
- Monitor release of long-term clinical outcomes from current studies (e.g., OCA REGENERATE, NGM282, cenicriviroc).
- Stay updated on developments in combination therapy approaches for NASH.