DURECT Gets FDA Breakthrough Therapy Status for Larsucosterol in Alcoholic Hepatitis

DURECT Corporation, a biopharmaceutical company focused on developing epigenetic therapies, has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation (BTD) to its drug larsucosterol for treating severe alcohol-associated hepatitis (AH). This designation is designed to accelerate the development and review of drugs that show substantial improvement over existing therapies for serious or life-threatening conditions.

James E. Brown, the President and CEO of DURECT, expressed satisfaction with the FDA's decision, highlighting the high mortality rate of AH and the current lack of approved treatments. He mentioned that the company is finalizing the design of a Phase 3 clinical trial for larsucosterol, incorporating feedback from the FDA and positive data from a completed Phase 2b trial named AHFIRM. DURECT aims to release more clinical data on larsucosterol soon, with hopes of making the therapy available to patients as quickly as possible.

The Phase 2b AHFIRM trial was a double-blind, placebo-controlled study conducted internationally across multiple centers. It assessed the safety and efficacy of larsucosterol in treating severe AH. Topline data from the study were announced in 2023, and further details will be presented at the European Association for the Study of the Liver (EASL) Congress 2024 in Milan, Italy.

Breakthrough Therapy designation offers several benefits, including early and frequent communication with the FDA, eligibility for rolling review, and other actions to expedite the review process. Although this designation does not alter the standards required for product approval, it can significantly speed up development.

The AHFIRM trial enrolled 307 patients with severe AH and was structured into three arms: a placebo group receiving standard care with or without methylprednisolone, and two larsucosterol groups receiving either 30 mg or 90 mg of the drug. The primary outcome measured was the 90-day incidence of mortality or liver transplantation, while the key secondary endpoint was 90-day survival. Topline data from the trial were released in November 2023, showing promising results. Reflecting the urgent need for effective AH treatments, the FDA has granted larsucosterol both Fast Track and Breakthrough Therapy designations.

Alcohol-associated hepatitis is a severe inflammation of the liver caused by long-term heavy alcohol consumption, often following a binge. The condition can lead to life-threatening complications, including liver failure and multi-organ failure. There are currently no FDA-approved therapies for AH, and mortality rates are alarmingly high. Studies have shown that stopping alcohol consumption is necessary but often insufficient for recovery, particularly in moderate to severe cases. Current treatments, like corticosteroids, have limited efficacy and come with increased risks of infection. Liver transplantation, although becoming more common, is limited by organ availability and high costs, exceeding $875,000 on average.

Larsucosterol is an endogenous sulfated oxysterol and epigenetic modulator. It inhibits DNA methylation, which can modulate gene expression involved in cell signaling pathways related to stress responses, cell survival, and lipid biosynthesis. This mechanism may improve cell survival, reduce inflammation, and decrease lipotoxicity, making it a promising candidate for treating acute organ injuries and chronic diseases.

DURECT Corporation specializes in developing therapies targeting dysregulated DNA methylation to treat serious conditions like acute organ injury and cancer. Larsucosterol, its lead drug candidate, is in clinical development for AH and is also being explored for treating metabolic dysfunction-associated steatohepatitis (MASH). Additionally, DURECT's non-opioid analgesic, POSIMIR® (bupivacaine solution), is FDA-approved and exclusively licensed to Innocoll Pharmaceuticals for U.S. distribution.