DURECT Corporation's investigational drug larsucosterol has demonstrated significant promise in treating severe alcohol-associated hepatitis (AH), according to Phase 2b trial results recently published in NEJM Evidence. The AHFIRM trial findings reveal meaningful reductions in mortality rates, particularly among U.S. patients.
Key Efficacy Findings
The double-blind, placebo-controlled study evaluated two dosing regimens of larsucosterol across 307 patients. The 30mg dose showed a 41% reduction in 90-day mortality (p=0.068), while the 90mg dose demonstrated a 35% reduction (p=0.124) compared to placebo. These results were particularly pronounced in the U.S. patient population, where mortality reductions reached 57% (p=0.014) and 58% (p=0.008) for the 30mg and 90mg doses, respectively.
Safety and Tolerability Profile
Larsucosterol exhibited a favorable safety profile throughout the trial. The frequency of treatment-emergent adverse events (TEAEs) and liver disease complications in both treatment groups was comparable to the placebo arm, suggesting good tolerability among this critically ill patient population.
Clinical Significance and Unmet Need
Alcohol-associated hepatitis represents a severe form of alcohol-associated liver disease with dire outcomes. Current statistics paint a grim picture, with 90-day mortality rates reaching approximately 31% in severe cases. No FDA-approved therapies exist for AH, and while corticosteroids are sometimes used, they have not demonstrated improved survival at 90 days and carry an increased infection risk.
Mechanism of Action
Larsucosterol functions as an epigenetic modulator, specifically targeting DNA methyltransferases (DNMT1, DNMT3a and 3b). This novel mechanism helps regulate gene expression patterns without modifying DNA sequences, potentially reducing inflammation and improving cell survival in damaged liver tissue.
Regulatory Status and Future Directions
The FDA has granted both Fast Track Designation and Breakthrough Therapy Designation to larsucosterol for AH treatment, acknowledging the critical need for effective therapies in this space. While the primary endpoint of mortality or liver transplant at 90 days did not achieve statistical significance, the strong mortality reduction signals, particularly in U.S. patients, suggest promising therapeutic potential.
Trial Design Details
The AHFIRM trial enrolled patients across multiple international sites, including the U.S., EU, U.K., and Australia. The study comprised three arms: placebo (standard of care with or without methylprednisolone), larsucosterol 30mg, and larsucosterol 90mg. Timing of treatment initiation emerged as a crucial factor, highlighting the importance of early intervention in severe AH cases.
