Mitchell Shiffman, MD: Current Alcohol-Associated Hepatitis Care, Larsucosterol’s Potential

Although there are currently no US Food and Drug Administration (FDA)-approved therapeutics for alcohol-associated hepatitis, larsucosterol may be on its way to becoming the first, boasting FDA Breakthrough Therapy designation and with additional phase 2b data supporting its impact on mortality reduction.

In the absence of an FDA-approved therapeutic for the treatment of alcohol-associated hepatitis, abstinence and adequate nutritional support serve as the cornerstone of treatment for affected patients. Patients with severe alcohol-associated hepatitis are also candidates for treatment with corticosteroids, although their use is controversial due to a potential lack of long-term benefits.

“Currently, the only accepted therapy, although the data for this becomes weaker and weaker over time, is the use of corticosteroids,” Mitchell Shiffman, MD, director of the Liver Institute of Virginia at the Bon Secours Virginia Health System, explained to HCPLive, describing himself as a “steroid nihilist” because he tends to use them selectively in his patients who are getting worse because he has nothing else to treat them with.

“If I have people with severe alcoholic hepatitis that are stable or look like they're getting better, then I usually don't give them any treatment. Many of them do slowly come around, but if they get worse, I throw in steroids,” he said.

However, a new treatment option may be on the horizon for patients with severe alcohol-associated hepatitis: larsucosterol. 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 the phase 2b AHFIRM trial.

“Larsucosterol is a very interesting drug in that it interacts with a protein called DNA methyltransferase,” explaining how DNA methyltransferase activity prevents downstream genes from being produced to assist alcohol-associated hepatitis recovery, also called gene silencing. “[Larsucosterol] binds to DNA methyltransferase and modulates DNA methylation, promoting the downstream transcription of these necessary proteins to help prepare the cell and thereby improves cellular function to recover from alcohol-induced hepatitis and potentially, down the road, maybe other cellular toxic hepatocellular toxins as well.”

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}