Mitchell Shiffman, MD: Phase 2b AHFIRM Data for Larsucosterol in Alcohol-Associated Hepatitis

In the absence of a US Food and Drug Administration (FDA)-approved therapeutic for alcohol-associated hepatitis, abstinence and adequate nutritional support serve as the cornerstone of treatment. However, larsucosterol may be poised to reshape this approach.

Boasting a recent FDA Breakthrough Therapy designation, new phase 2b data for the endogenous sulfated oxysterol and epigenetic modulator Mitchell Shiffman, MD, director of the Liver Institute of Virginia at the Bon Secours Virginia Health System, described as a “very interesting drug” in a previous interview with HCPLive are providing further evidence of its potential benefit in alcohol-associated hepatitis.

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. 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.

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

Although the total number of patients who met the primary endpoint with larsucosterol was not statistically significant, Schiffman called attention to the greater number of transplants these patients received and suggested this may have been because they were able to survive longer to become liver transplant candidates versus patients on placebo.

Additionally, Shiffman pointed out notable regional differences in the study population, pointing out that 75% of patients were from the US and adding that looking at the US data separately from the global data was prespecified in the study.

“If you look at just the United States patients, the larsucosterol 30 mg group had a 57% reduction in mortality compared to placebo, and this was highly statistically significant,” Shiffman explained. “The larsucosterol 90 mg group had a 58% reduction in mortality, also highly statistically significant.”

Although adverse events were prevalent across patients in all 3 study groups, Shiffman noted the specific complications of end-stage liver disease and treatment effects directly related to liver failure were less in the larsucosterol arms compared to placebo, again pointing to the lack of complications in these patients potentially serving as a reason why more of them were able to get a liver transplant.

Taking a closer look at why patients outside of the US did not appear to do well in the study, Shiffman called attention to potential differences in treatment, specifically the time to randomization and the impact of early treatment on outcomes. He also cited differences in alcohol consumption in the US versus other study regions.

“Based on the US data, the US Food and Drug Administration has granted Breakthrough Therapy designation to larsucosterol for the treatment of severe autoimmune hepatitis, and a phase 3 trial is planned, and I think that's going to be very exciting,” Shiffman concluded.

Reference

^{Brooks, A. AHFIRM: Phase 2b Data Shows Promise for Larsucosterol in Alcohol-Associated Hepatitis. HCPLive. June 14, 2024. Accessed June 28, 2024. https://www.hcplive.com/view/ahfirm-phase-2b-data-shows-promise-for-larsucosterol-in-alcohol-associated-hepatitis}