DURECT Corporation is advancing its lead drug candidate, larsucosterol, for the treatment of alcohol-associated hepatitis (AH). The company will present additional data from its Phase 2b AHFIRM trial at The Liver Meeting 2024, showcasing the potential of larsucosterol and supporting the design of the upcoming Phase 3 trial.
The FDA has granted larsucosterol Fast Track and Breakthrough Therapy designations for AH, underscoring the urgent need for effective therapies. The company held a Type B meeting with the FDA, reaching an agreement on key aspects of the Phase 3 trial design.
Phase 3 Trial Design
The Phase 3 trial is designed as a randomized, double-blind, placebo-controlled, multi-center study in the U.S. It will enroll approximately 200 patients with severe AH, randomized 1:1 to receive either larsucosterol (30 mg) or placebo, in addition to standard of care, with or without methylprednisolone at the investigator's discretion. The primary outcome measure is 90-day survival, with topline results expected within two years of trial initiation.
James E. Brown, D.V.M., President and CEO of DURECT, stated, "We believe the primary endpoint of 90-day survival is clinically meaningful and provides the greatest probability of success based on the AHFIRM data."
AHFIRM Trial Data
Data from the Phase 2b AHFIRM trial demonstrated a compelling efficacy signal for larsucosterol. In U.S. patients, both the 30 mg and 90 mg doses of larsucosterol reduced mortality at 90 days by 57% (p=0.014) and 58% (p=0.008), respectively, compared to placebo.
Norman Sussman, M.D., FAASLD, Chief Medical Officer of DURECT, noted, "Based on our Phase 2b AHFIRM data, we believe larsucosterol has the potential to save the lives of tens of thousands of patients yearly who currently have very limited options."
About Larsucosterol
Larsucosterol is an endogenous sulfated oxysterol and an epigenetic modulator. It inhibits DNA methyltransferases (DNMT1, DNMT3a, and 3b), which are elevated and associated with hypermethylation in AH patients. By inhibiting DNA methylation, larsucosterol modulates the expression of genes involved in cell signaling pathways, potentially improving cell survival, reducing inflammation, and decreasing lipotoxicity.
The Need for New AH Treatments
AH is an acute form of alcohol-associated liver disease characterized by severe inflammation and liver cell damage. There are no FDA-approved therapies for AH, and mortality rates remain high. A retrospective analysis showed overall mortality from AH was 26% at 28 days, 29% at 90 days, and 44% at 180 days. While liver transplantation is an option, it is limited by organ availability and high costs, averaging over $875,000 per transplant.
