Larsucosterol Did Not Show Statistical Significance Compared With Placebo in Phase 2b AHFIRM Trial

Key Takeaways

Larsucosterol, an epigenetic modulator, showed trends in reducing 90-day mortality in severe alcohol-associated hepatitis despite not meeting the primary endpoint.
The AHFIRM trial involved 307 patients, with larsucosterol doses of 30-mg and 90-mg showing mortality reductions of 41% and 35%, respectively.
Larsucosterol was safe and well-tolerated, with adverse events similar across treatment and placebo groups, primarily due to hepatic disease.
Regional differences in patient populations and treatment regimens were noted, influencing trial outcomes and highlighting the need for further investigation.

Although larsucosterol did not show statistical significance, it showed clinically meaningful trends in 90-day mortality in patients with severe alcohol-associated hepatitis.

Results published in the New England Journal of Medicine Evidence¹ show that AHFRIM (NCT04563026)², a phase 2b clinical trial evaluating the safety and efficacy of larsucosterol (DUR-928; Durect Crop) in patients with severe alcohol-associated hepatitis (AH), did not meet its primary end point of 90-day mortality or liver transplant.^1,2 Although it did not meet the measure, experts noted that larsucosterol still demonstrated clinically meaningful trends.³

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About the Trial

Trial Name: A Phase 2b Study in Subjects With Alcoholic Hepatitis to Evaluate Safety and Efficacy of DUR-928 Treatment (AHFIRM)

ClinicalTrials.gov ID: NCT04563026

Sponsor: Durect

Completion Date: September 6, 2023

Larsucosterol is an endogenous sulfated oxysterol and an epigenetic modulator—compounds that regulate patterns of gene expression without modifying the DNA sequence—that is currently undergoing investigation as a treatment for severe AH. Larsucosterol can inhibit DNA methylation, which then modulates the expression of genes that are involved in cell signaling pathways associated with stress responses, cell death and survival, and lipid biosynthesis. This mechanism of action may ultimately lead to improved cell survival, reduced inflammation, and decreased lipotoxicity.³

AHFIRM, a randomized, double-blind, placebo-controlled, international, multicenter phase 2b clinical trial, enrolled patients with severe AH, a disease that currently has no approved therapy.¹ The investigators enrolled a total of 307 patients across 62 health care centers who were randomly assigned to receive either 30-mg (n = 102) or 90-mg (n = 102) doses of larsucosterol or placebo (n = 103), all of which were administered intravenously. If the patient was hospitalized and remained so after 72 hours, then a second dose was administered. All patients received supportive care in addition to their treatment as determined by the investigators. The trial’s primary end point was 90-day mortality or liver transplant rate, and the secondary end point was 90-day survival.^1,2

The findings demonstrated that the difference in 90-day mortality or liver transplant between the 30-mg, 90-mg, and placebo groups did not achieve statistical significance; however, both larsucosterol doses showed clinically meaningful trends in reducing 90-day mortality, with mortality reductions of about 41% and 35% in the 30-mg and 90-mg groups, respectively. There were 21 deaths and 4 liver transplants in the placebo group, 8 and 5 in the 30-mg group, and 10 and 8 in the 90-mg group.¹

“Additional analyses in this article highlight regional differences in patient populations and in AH treatment regimens, including time from hospital admission to treatment and the use of liver transplantation,” Norman Sussman, MD, FAASLD, chief medical officer of DURECT, said in a news release.³

Larsucosterol appeared to be safe and well-tolerated in the AHFIRM trial, with the number of treatment-emergent adverse events (AEs) being similar between the karsucosterol groups and placebo. Most AEs that occurred during treatment were a result of hepatic disease, and there was no imbalance in AEs that could not be attributed to liver disease.¹

“We look forward to further demonstrating larsucosterol’s potential in our upcoming phase 3 trial…We plan to initiate the trial in 2025, pending funding,” James E. Brown, DVM, president and CEO of DURECT, said in the news release.³

REFERENCES

1. Shiffman M, Da B, Goel A, et al. Larsucosterol for the Treatment of Alcohol-Associated Hepatitis. NEJM Evid. 2025;4(2). doi: 10.1056/EVIDoa2400243

2. A Phase 2b Study in Subjects With Alcoholic Hepatitis to Evaluate Safety and Efficacy of DUR-928 Treatment (AHFIRM). ClinicalTrials.gov identifier: NCT04563026. Updated September 5, 2024. Accessed February 12, 2025. https://clinicaltrials.gov/study/NCT04563026

3. Durect. DURECT Corporation Announces Publication of Larsucosterol Phase 2b Results in NEJM Evidence. News release. January 28, 2025. Accessed February 12, 2025. https://www.durect.com/2025/01/durect-corporation-announces-publication-of-larsucosterol-phase-2b-results-in-nejm-evidence/