Larsucosterol for hepatitis proves safety in phase IIa trial

Treatment with larsucosterol is safe and well tolerated in patients with alcohol-associated hepatitis (AH), as shown in a recent study.

“[D]ata from this pilot study showed promising efficacy signals of larsucosterol in [patients] with AH, including [those] with severe AH,” the researchers said. “There is also a strong scientific rationale for further evaluating larsucosterol for severe AH.”

Nineteen clinically diagnosed AH patients were enrolled in this phase IIa, multicentre, open-label, dose-escalation study, which assessed the safety, pharmacokinetics (PK), and efficacy signals of larsucosterol. Of the participants, seven had moderate and 12 had severe AH based on the model for end-stage liver disease (MELD) score.

Patients received one or two intravenous infusions (72 hours apart) of larsucosterol 30, 90, or 150 mg. They were followed up for 28 days. The researchers then compared efficacy signals from a subgroup of patients with severe AH to those from two matched arms of patients with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study.

None of the participants treated with larsucosterol died during the 28-day study. Fourteen (74 percent) of them, including eight (67 percent) with severe AH, were discharged ≤72 hours after receiving a single infusion. [Am J Gastroenterol 2024;119:107-115]

No drug-related serious adverse events or early terminations occurred. Disease severity did not influence PK profiles, and biochemical parameters improved in several AH patients. Serum bilirubin levels significantly reduced from baseline to days 7 and 28, while MELD scores decreased at day 28. In addition, efficacy signals were more favourable in patients from two matched groups treated with SOC.

Lille scores were <0.45 in 16 of 18 (89 percent) patients at day 7. Statistically significantly lower Lille scores (p<0.01) were observed in eight patients with severe AH who received larsucosterol 30 or 90 mg compared to those in severe AH participants treated with SOC from the contemporaneous study.

“Although this study was small and without a control arm, the results were encouraging and compared favourably with 2 matched control arms treated with SOC, including corticosteroids,” the researchers said.

“Most notably, all [patients], seven moderate AH with MELD scores 11–20 and 12 severe with MELD scores 21–30, treated with larsucosterol survived the 28-day study period, with the disease that typically has an overall 1-month mortality rate of approximately 15 percent to 26 percent,” they added. [PLoS One 2018;13:e0192393; Am J Gastroenterol 2021;117:301-310; N Engl J Med 2015;372:1619-1628]

Intracellular signals

“Larsucosterol, endogenously as 25HC3S, was discovered when the mitochondrial membrane STARD1 was overexpressed, suggesting the production of the molecule was induced in response to intracellular signals,” according to the researchers.

A recent study by Wang and colleagues showed that “25HC3S bound to and inhibited DNMT1, 3a, and 3b.” This reduced high glucose-induced DNA hypermethylation and impacted >1,000 genes involved in nearly 80 signalling pathways in cultured hepatocytes. [J Lipid Res 2021;62:100063]

Researchers believed that the endogenous molecule 25HC3S could modulate cellular energy/lipid metabolism, cell proliferation/differentiation, cell death/survival, and tissue regeneration by regulating DNMT activities.

“This trial is a pilot study and uses contemporaneous controls,” the researchers said. “It was not designed to evaluate gender or dose effects or to compare with other agents.”