Larsucosterol Fails to Improve Outcomes in Severe Alcohol-Associated Hepatitis, But Promises Further Exploration: Study

"There was no significant difference in 90-day mortality or liver transplant rates between patients in the 30-mg or 90-mg larsucosterol groups and the placebo group. The majority of adverse events during treatment were related to hepatic disease, and there was no disproportionate occurrence of adverse events that could not be attributed to liver disease," Mitchell Shiffman, Bon Secours Liver Institute, Richmond, VA, and colleagues reported.

Larsucosterol, a DNA methyltransferase inhibitor, is being developed as a potential treatment for alcohol-associated hepatitis, a condition for which no approved therapy currently exists.

In the phase 2b trial, patients with severe alcohol-associated hepatitis were randomly assigned in a 1:1:1 ratio to receive either 30 mg or 90 mg of larsucosterol, or a placebo. A second dose was administered after 72 hours if the patient remained hospitalized. All participants received supportive care as determined by the investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while those in the larsucosterol groups were given matching placebo capsules. The study's primary endpoint was the 90-day mortality or liver transplant rate, and the key secondary endpoint was 90-day mortality. U.S. results were prespecified for separate reporting.

The following were the key findings of the study:

• Among the 307 enrolled patients, 301 received at least one treatment dose.
• The difference in 90-day mortality or LT rates between the 30-mg or 90-mg larsucosterol groups, and the placebo group did not reach statistical significance.
• The 90-day mortality in the placebo, 30-mg larsucosterol, and 90-mg larsucosterol groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively.
• In U.S. patients (76% of all enrolled patients), 21 deaths and 4 LTs occurred in the placebo group, eight deaths and 5 LTs in the 30-mg larsucosterol group, and 10 deaths and 8 LTs in the 90-mg larsucosterol group.
• Among patients treated within 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients: 17/57), in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients: 4/57), and in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients: 9/66).
• Most adverse events during treatment were attributed to hepatic disease, with no imbalance in adverse events not linked to liver disease.

"The trial did not achieve its primary endpoint of demonstrating a positive effect of larsucosterol on 90-day mortality or liver transplantation (LT) in patients with severe AH. However, the results have established equipoise for conducting a further trial to assess the impact of larsucosterol on survival in AH," the researchers concluded.

Reference: https://evidence.nejm.org/doi/full/10.1056/EVIDoa2400243