AHFIRM: Phase 2b Data Shows Promise for Larsucosterol in Alcohol-Associated Hepatitis

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Despite missing the primary endpoint among the global study population, additional analyses of participants from the US revealed significant impacts on mortality reduction with larsucosterol.

Mitchel Shiffman, MD | Credit: Bon Secours

Mitchel Shiffman, MD

Credit: Bon Secours

Findings from a phase 2b trial of larsucosterol in patients with severe alcohol-associated hepatitis are highlighting the agent’s impact on 90-day mortality and liver transplantation, especially among US-based participants.1

Although the AHFIRM trial did not meet its primary endpoint for 90-day mortality or liver transplant in the global study population, statistical significance was reached in analyses focusing solely on participants from the US, who comprised 75% of the total study population.1

“There are currently no effective treatments for severe alcohol-associated hepatitis. Although many of us have utilized corticosteroids to treat this disease for decades, the results of the STOPAH trial do not appear to support this,” Mitchell Shiffman, MD, director of the Liver Institute of Virginia at the Bon Secours Virginia Health System, explained during a late-breaking presentation at the 2024 European Association for the Study of the Liver (EASL) Congress.

Abstinence, along with adequate nutritional support, remains the cornerstone of the management of patients with alcohol-associated hepatitis, although corticosteroids are frequently used in patients with severe alcohol-associated hepatitis. However, in the absence of a US Food and Drug Administration (FDA)-approved therapeutic and with uncertainty regarding the use of corticosteroids in these patients, treatment is limited and outcomes are generally poor.2

An endogenous sulfated oxysterol, larsucosterol inhibits DNA methyltransferases and has been shown to reduce inflammation, lipotoxicity, oxidative stress, and cell death while promoting liver regeneration. It was granted Breakthrough Therapy Designation by the FDA for patients with severe alcohol-associated hepatitis on May 21, 2024, based on clinical evidence from AHFIRM.1,3

A phase 2b randomized, double-blind, placebo-controlled, international, multicenter study, AHFIRM evaluated the safety and efficacy of larsucosterol in 307 patients from the US, France/Belgium, the United Kingdom, and Australia with severe alcohol-associated hepatitis, defined as Maddrey's discriminant function > 32 and a Model for End-Stage Liver Disease score between 21-30. For inclusion, patients were also required to have onset of jaundice within 8 weeks of screening; average daily alcohol consumption > 40 g for women and > 60 g for men; less than 8 weeks of abstinence; bilirubin > 3.0 mg/dL; AST 50-400 IU/L; ALT < 400 IU/L; and AST/ALT > 1.5. Of note, liver biopsy was not required for entry.1

Participants were randomly assigned in a 1:1:1 ratio to receive larsucosterol 30 mg (n = 102), larsucosterol 90 mg (n = 102), or placebo (n = 103), along with local standard of care at the investigators’ discretion. Investigators noted the groups were well-balanced across most characteristics, except for the larsucosterol 30 mg group, which contained twice as many male participants as female participants.1

The primary endpoint was death or liver transplant at 90 days, measured by win-ratio. The key secondary endpoint was death at 90 days.1

In total, 90-day outcome data was available for 102 participants in the placebo group, 99 participants in the larsucosterol 30 mg group, and 101 participants in the larsucosterol 90 mg group. Of note, 77, 73, and 77 of these patients, respectively, were from the US.1

Although fewer deaths occurred in the larsucosterol 30 mg (n = 15) and larsucosterol 90 mg (n = 17) groups, a similar number of liver transplants were performed across both groups (n = 6 and n = 9, respectively) compared to placebo (n = 4). The study therefore missed the primary endpoint, with win probability differences of 0.078 (P = .196) in the 30 mg larsucosterol arm and 0.039 (P = .533) in the 90 mg larsucosterol arm against placebo.1

Investigators noted the number of patients alive and transplant-free was similar across all 3 groups. Mortality at 90 days was reduced by 41% in the larsucosterol 30 mg arm (P = .068) and 35% in the larsucosterol 90 mg arm (P = .124).1

Investigators pointed out significant regional differences, noting US participants comprised 75% of the study population. Looking at results for US participants only, the win rato primary endpoint analysis in the larsucosterol 30 mg group was statistically significant against placebo (28.1% vs 12.7%; P = .0265). Although reductions in mortality did not reach statistical significance in either larsucosterol group in the global study population, investigators observed significant reductions across both larsucosterol groups in the US-only analysis (30 mg, 57%; P = .014 and 90 mg, 58%; P = .008).1

“Significant regional differences in clinical practice, sample size, and randomization were seen—these should be addressed when designing future multinational alcohol-associated hepatitis trials,” investigators wrote.1

Both doses of larsucosterol were well tolerated with numerically fewer treatment-emergent adverse events in the active arms than in the placebo arm. There were no meaningful differences in serious adverse events between the groups, and none were attributed to larsucosterol.1

References:

  1. Shiffman ML, Da B, Stein L, et al. Results of a Phase 2b multicenter randomized trial of larsucosterol for the treatment of severe alcohol-associated hepatitis (AHFIRM Trial). Durect. Accessed June 13, 2024. https://www.durect.com/wp-content/uploads/2024/06/Shiffman-EASL-AHFIRM-060824-SHOW.pdf
  2. Shah NJ, Royer A, John S. Alcoholic Hepatitis. StatPearls. June 5, 2023. Accessed June 14, 2024. https://www.ncbi.nlm.nih.gov/books/NBK470217/
  3. Durect. DURECT Corporation Receives FDA Breakthrough Therapy Designation for Larsucosterol in Alcohol-Associated Hepatitis. May 21, 2024. Accessed June 13, 2024. https://www.durect.com/2024/05/durect-corporation-receives-fda-breakthrough-therapy-designation-for-larsucosterol-in-alcohol-associated-hepatitis/
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