When most people think of a person with severe liver inflammation caused by drinking alcohol, the image of a middle-aged man, perhaps with a rotund belly is probably what comes to mind. But about one third of alcoholic hepatitis patients in the United States are women, and while the majority of people affected are 40 to 50 years old, incidence of the disease is rising in people in their 20s and 30s (1-3).
Alcoholic hepatitis typically occurs in people who drink heavily over the course of many years, but not always. Some moderate drinkers develop the disease, while some heavy drinkers don’t. Although women typically drink less than men, they have a higher risk for developing alcoholic hepatitis, even from moderate amounts of alcohol consumption (4). Scientists and clinicians don’t know why this variation in risk exists.
Because patients typically only show symptoms at advanced stages of the disease, 30 percent of those who get diagnosed with alcoholic hepatitis die within 90 days, and 25 percent die within one month (5). There is no treatment.
“It's probably the most deadly disease you've never heard of,” said James Brown, the chief executive officer of the epigenetics biopharmaceutical company DURECT.
“We do our best to essentially support them through the illness and hope that they recover,” said Camille Kezer, a gastroenterology fellow at the Mayo Clinic with expertise in alcohol-associated liver disease. Some of those supportive efforts include getting patients on a high protein diet and aggressively treating any infections that occur. Initially, doctors thought that steroids might help treat this condition, but a large multicenter clinical trial revealed that steroids did not improve outcomes at 90 days or one year after diagnosis (6).
Now, Brown and his colleagues may have found a way to help these patients by using a novel cholesterol-derived molecule called larsucosterol. With promising results from a Phase 2a clinical trial treating alcoholic hepatitis patients, the researchers have embarked on a placebo-controlled Phase 2b study to test the drug’s efficacy in more patients, potentially leading to the very first therapy for this disease.
Larsucosterol’s path to alcoholic hepatitis treatment started with a serendipitous reunion on the Virginia Commonwealth University campus. There, biochemist Shunlin Ren had been investigating metabolism and cholesterol synthesis in the context of the liver for decades when one day he ran into his former student, WeiQi Lin, on a campus shuttle. He told her about a new molecule he had discovered called 5-cholesten-3β, 25-diol 3-sulfate (25HC3S), an oxysterol that was involved in lipid metabolism (7).
After that shuttle ride, Ren and Lin stayed in touch over the years. Ren’s team learned that the molecule is located in the nuclei of human liver cells and that in addition to lipid metabolism, it’s involved in cell survival and modulating inflammatory responses, but they didn’t know its exact mechanism yet (8). Lin knew that Brown had worked on cholesterol-based molecules at biopharmaceutical companies before, so she shared Ren’s publications with him.
If you'd give larsucosterol, the tissues would look normal. The animals would be fine. If you gave them a placebo, they would die at 80 to 90 percent. It was pretty remarkable.
- James Brown, DURECT
“I saw some of the data they had, and I thought, ‘this has got to be a drug somewhere,’” said Brown. “I actually got on a plane the next day with WeiQi. We flew out and met with Dr. Ren.”
As they began working together, Ren and the DURECT researchers noticed that this molecule and other related oxysterols always seemed to end up in the cell nucleus. Because these oxysterols influenced multiple aspects of cellular function, the research team hypothesized that these molecules act as epigenetic regulators (9). In 2021, they found that indeed, 25HC3S modifies the epigenome by inhibiting all three of the human DNA methyltransferases: DNMT1, DNMT3a, and DNMT3b, which add methyl groups to DNA to repress gene expression (10).
“It changes DNA hypermethylation and then in turn, changes inflammatory states, changes apoptosis and autophagy, and stabilizes the mitochondrial membrane. So, it does a whole bunch of things that help cells live and get through tough times,” said Brown.
Brown and his team at DURECT administered 25HC3S — renamed larsucosterol or DUR-928 — to multiple animal models of different diseases including sepsis, pancreatitis, acute kidney injury, stroke, and alcoholic hepatitis.
“If you'd give larsucosterol, the tissues would look normal. The animals would be fine. If you gave them a placebo, they would die at 80 to 90 percent,” said Brown. “It was pretty remarkable.”
With positive preclinical data, the DURECT team set their sights on testing larsucosterol in alcoholic hepatitis patients. With these patients, Brown explained, “if they're on the course to die, that is it. So, we have time to talk to the patients, to talk to their families, to enroll them in the study, and to try and change that course.” Recent analysis of liver samples from people with alcoholic hepatitis revealed evidence of hypermethylation and increased expression of DNA methyltransferases, further supporting treatment of these patients with larsucosterol (11).
The DURECT team initiated a Phase 2a clinical trial testing the safety, efficacy, and pharmacokinetics of larsucosterol in 19 alcoholic hepatitis patients compared to two groups of patients with similar disease severity receiving the standard of care, supportive care with corticosteroid treatment (12). Each patient got an infusion of one dose of 30, 90, or 150 mg of larsucosterol on day one of the trial, and if they were still in the hospital three days later, they received a second dose.
“The half-life of the drug is two hours, but it goes to the nucleus. Then, its effect lasts for a long time because you're literally up and down regulating more than 1000 genes. So, you're changing cells from going towards death to going towards life,” said Brown. “If you can get that liver over that acute hepatitis, the liver has great capacity to repair itself, as do a number of other organ systems.”
The researchers found that larsocusterol was safe at all three doses and that 14 out of the 19 patients in the trial were discharged from the hospital less than 72 hours after receiving their first dose. This group of discharged patients included eight of 12 patients with severe alcoholic hepatitis. Additionally, they saw a significant improvement in the level of serum bilirubin, which is a marker of the liver’s capacity to clear out toxins, and improvements in their MELD and Lille scores, which are used to predict a patient’s chance of surviving alcoholic hepatitis.
Most importantly for Brown, all of the patients in the trial survived the entire 28-day study period. He recalled one of the first patients who enrolled in the trial who had already been in the hospital for one month before his doctors sent him home on hospice care.
“There was nothing they could do for him. He was going to die. And he enrolled in our study, was dosed, and the study coordinator told us when she saw him two weeks later, she cried because she couldn't believe how good he looked. And it turns out, he was still alive two years later,” said Brown.
With these exciting results, the DURECT team is already evaluating the efficacy of larsucosterol in the Phase 2b multicenter, randomized, double-blinded, placebo-controlled AHFIRM trial (13). They enrolled the last patient in the trial at the beginning of June, and they expect to have data to share by the end of the year.
Kezer, who is not associated with DURECT, is eager to see the results of this Phase 2b study. “It's a promising drug,” she said. “This Phase 2b study will be important to see if it indeed does have a benefit. Even a different mechanism of action in and of itself is exciting for alcohol associated hepatitis.”
The DURECT team recently released topline data from the Phase 2b study demonstrating that while larsucosterol reduced mortality at 90 days, that reduction was not statistically significant compared to the standard of care. The mortality reduction was, however, more pronounced in a subset of patients, so the team hopes to meet with the FDA to discuss the next steps for advancing larsucosterol in a future clinical trial.
If larsucosterol proves effective for alcoholic hepatitis, Brown wants to explore its potential for other acute conditions with promising preclinical data such as acute kidney injury and stroke as well as chronic conditions including nonalcoholic steatohepatitis. But for now, he is focused squarely on alcoholic hepatitis, and he’s hopeful for the future of larsucosterol for treating this disease.
“I've been doing this for a long time, developing drugs,” he said. “And I've never had a drug like this.”
This story was updated on November 15, 2023 to include newly released clinical trial results.
References
- McElroy, L.M. et al. Gender Disparities in Patients With Alcoholic Liver Disease Evaluated for Liver Transplantation. Transplantation 104, 293-298 (2020).
- Cohen, S.M. and Ahn, J. Review article: the diagnosis and management of alcoholic hepatitis. Alimentary Pharmacology & Therapeutics 30, 3-13 (2009).
- Tapper E.B. and Parikh, N.D. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. BMJ 362, k2817 (2018).
- Kezer, C.A., Simonetto, D.A., Shah, V.H. Sex Differences in Alcohol Consumption and Alcohol-Associated Liver Disease. Mayo Clinic Proceedings 96, 1006-1016 (2021).
- Hughes, E., Hopkins, L.J., Parker, R. Survival from alcoholic hepatitis has not improved over time. PLoS ONE 13, e0192393 (2018).
- Thursz, M.R. et al. Prednisolone or Pentoxifylline for Alcoholic Hepatitis. N Engl J Med 372, 1619-1628 (2015).
- Ren, S. et al. Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes. Biochem Biophys Res Commun 360, 802-808 (2007).
- Ren, S. and Ning, Y. Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation. Am J Physiol Endocrinol Metab 306, E123-E130 (2014).
- Wang, Y. et al. High Glucose Induces Lipid Accumulation via 25-Hydroxycholesterol DNA-CpG Methylation. iScience 23, 101102 (2020).
- Wang, Y. et al. 25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes. J Lipid Res 62, 100063 (2021).
- Argemi, J. et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun 10, 3126 (2019).
- Hassanein, T. et al. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis. Am J Gastroenterol 00, 1-9 (2023).
- A Phase 2b Study in Subjects With Alcoholic Hepatitis to Evaluate Safety and Efficacy of DUR-928 Treatment (AHFIRM). https://classic.clinicaltrials.gov/ct2/show/NCT04563026