DURECT Unveils Phase 3 Trial Design for Larsucosterol in Alcohol-associated Hepatitis

DURECT Corporation, a biopharmaceutical company focused on developing epigenetic therapies, has announced critical details regarding its upcoming Phase 3 trial for larsucosterol in treating severe alcohol-associated hepatitis (AH). The company had a productive Type B meeting with the U.S. Food and Drug Administration (FDA) under the Breakthrough Therapy designation, leading to an agreement on significant elements of the Phase 3 trial protocol.

James E. Brown, President and CEO of DURECT, expressed satisfaction with the FDA's collaborative approach. He highlighted the importance of the 90-day survival primary endpoint, which he believes offers the highest likelihood of success, given the data from the AHFIRM Phase 2b trial. In this trial, larsucosterol demonstrated a significant reduction in 90-day mortality for AH patients in the U.S., with nearly 60% lower mortality rates for both the 30 mg and 90 mg doses compared to placebo. DURECT aims to initiate the Phase 3 trial promptly, pending sufficient funding, and expects to report topline results within two years of starting the trial. The FDA has also indicated that a single Phase 3 trial will be adequate to support a New Drug Application (NDA), allowing for a rolling submission under the Breakthrough Therapy designation.

Norman Sussman, Chief Medical Officer of DURECT, emphasized the urgent need for effective AH therapies due to the rising incidence of the condition and high mortality rates, approximately 30% at 90 days. Based on Phase 2b data, larsucosterol shows promise in potentially saving many lives annually, offering hope where current options are limited. Discussions with various U.S. clinical sites and hepatologists are ongoing to expedite the Phase 3 trial's initiation.

The Phase 3 trial will be a randomized, double-blind, placebo-controlled, multi-center study in the U.S., evaluating larsucosterol's safety and efficacy in severe AH patients. About 200 patients will be enrolled and randomized in a 1:1 ratio into two groups: one receiving 30 mg of larsucosterol and the other a placebo, both added to standard care. The trial includes an optional use of methylprednisolone capsules at the investigators' discretion. Patients will be monitored for up to 180 days to gather additional safety and outcomes data.

Data from the AHFIRM trial indicated a strong efficacy signal for larsucosterol in reducing 90-day mortality. The 30 mg and 90 mg doses showed a 41% and 35% reduction in mortality, respectively, compared to placebo. These reductions were notably more significant in U.S. patients, with 57% and 58% lower mortality rates for the 30 mg and 90 mg doses, respectively. Although the primary endpoint of mortality or liver transplant at 90 days did not achieve statistical significance, the results underscore the potential of larsucosterol as a life-saving treatment for AH.

Alcohol-associated hepatitis (AH) is a severe form of alcohol-associated liver disease resulting from chronic heavy drinking, often exacerbated by recent binge drinking. AH is marked by significant liver inflammation and cell damage, potentially leading to life-threatening complications like liver failure and multi-organ dysfunction. There are currently no FDA-approved therapies for AH, and studies have shown high mortality rates, underscoring the need for effective treatments. Corticosteroids have limited effectiveness and carry increased infection risks, while liver transplants are constrained by donor availability and high costs, averaging over $875,000.

The AHFIRM Phase 2b trial was an international study assessing the safety and efficacy of larsucosterol in severe AH patients. Conducted in the U.S., EU, U.K., and Australia, the trial enrolled 307 patients across three arms: placebo, 30 mg larsucosterol, and 90 mg larsucosterol. The primary outcome was the 90-day incidence of mortality or liver transplantation, and the key secondary endpoint was 90-day survival. The study results led to the FDA granting larsucosterol Fast Track and Breakthrough Therapy designations for AH treatment.

Larsucosterol acts as an epigenetic modulator by inhibiting DNA methyltransferases, which are involved in DNA methylation and gene expression regulation. This mechanism could improve cell survival, reduce inflammation, and decrease lipotoxicity, making larsucosterol a promising candidate for treating acute organ injury and chronic conditions. DURECT Corporation continues to explore larsucosterol's potential in treating AH and other diseases, aiming to transform the therapeutic landscape for life-threatening conditions.