Larsucosteral shows ‘promising efficacy signals’ for alcohol-associated hepatitis
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Key takeaways:
- Larsucosterol was safe and well-tolerated at 30 mg, 90 mg and 150 mg in patients with alcohol-associated hepatitis.
- Serum bilirubin levels and MELD scores declined from baseline to days 7 and 28.
Larsucosteral was well-tolerated and improved short-term biomarkers of liver injury or disease in a subset of patients with moderate to severe alcohol-associated hepatitis, according to research in The American Journal of Gastroenterology.
“Alcohol-associated hepatitis (AH) is a severe form of liver disease with very high morbidity and mortality,” Craig J. McClain, MD, FACN, AGAF, FACG, FAASLD, director of the University of Louisville Alcohol Research Center and Hepatobiliary and Toxicology Center and professor of medicine, pharmacology and toxicology, told Healio. “Deaths from alcohol-associated liver disease are on the rise and alcohol misuse increased dramatically during COVID.”
He added, “The only widely used form of therapy for severe AH is prednisone, which improves 1-month but not long-term survival. Thus, new forms of therapy are desperately needed. Larsucosterol is an endogenous oxysterol that decreases inflammation, improves cell survival and appears to have a great safety profile.”
To evaluate the safety and pharmacokinetics of larsucosteral in patients with AH, McClain and colleagues conducted a phase 2a, multicenter, open-label, dose-escalation study in 19 individuals (median age, 41 years; 58% men). Seven patients with moderate AH (MELD score = 11-20) received a 90 mg dose and 12 patients with severe AH (MELD score = 21-30) underwent dose escalation of 30 mg, 90 mg and 150 mg (four patients/group). All patients received larsucosterol by IV infusion over approximately 2 hours for 1 or 2 infusions, with the second infusion on day 4 if the patient remained in the hospital.
Researchers monitored participants for 28 days and compared efficacy signals from a subgroup of patients with severe AH who were treated with standard of care in a concurrent study. Fourteen patients, including eight with severe AH, were discharged less than 72 hours after the single infusion, but no treatment-emergent adverse events led to study discontinuation.
According to study results, there were “rapid and significant reductions” in serum total bilirubin levels, as well as reductions in MELD scores, from baseline to days 7 and 28. Disease severity did not affect pharmacokinetic profiles.
“Patients tolerated the drug very well with no serious adverse effects; there was no mortality at 28 days,” McClain said. “There were also efficacy signals to suggest that it improved short-term biomarkers of liver injury/disease. The drug only had to be given once or twice intravenously, and thus, no long-term therapy was required.”
Researchers also reported that most patients (89%) were considered treatment responders (Lille score < 0.45 at day 7), and eight patients with severe AH who received 30 mg or 90 mg doses had Lille scores that were “significantly lower” (P < .01) compared with similar patients treated with standard of care in the concurrent study.
“Large randomized confirmatory studies are needed,” McClain told Healio. “There is a large, randomized trial (AHFIRM) that is nearing completion. If the AHFIRM trial is positive and larsucosterol is FDA-approved, this will be a new form of therapy for severe AH.”
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