Deadly alcoholic hepatitis finds hope in epigenetics

When most people think of someone with severe liver inflammation caused by alcohol consumption, the image that comes to mind is probably of a middle-aged man, perhaps with a chubby belly. But about one-third of people with alcoholic hepatitis in the United States are women, and while most people affected are 40 to 50 years old, the disease is increasing among people in their 20s and 30s ( 1-3).

Alcoholic hepatitis usually occurs in people who have drank heavily for many years, but not always. Some moderate drinkers develop the disease, while some heavy drinkers do not. Although women generally drink less alcohol than men, they are at higher risk of developing alcoholic hepatitis even if they drink moderate amounts (4). Scientists and clinicians don’t know why this risk difference exists.

Because patients typically only develop symptoms in the late stages of the disease, 30% of patients diagnosed with alcoholic hepatitis die within 90 days and 25% within 1 month (5). There is no treatment.

“This is probably the deadliest disease you’ve never heard of,” said James Brown, CEO of DURECT, an epigenetic biopharmaceutical company.

“We try our best to essentially support them through their illness and hope they recover,” said Camille Kezer, a gastroenterology fellow at the Mayo Clinic and an expert in alcohol-related liver disease. Some of them Supportive efforts include placing the patient on a high-protein diet and aggressively treating any infection that occurs. Initially, doctors thought steroids might help treat the disease, but a large multicenter clinical trial showed that steroids did not improve outcomes 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 new cholesterol-derived molecule called larsucosterol. In light of promising results from a Phase 2a clinical trial treating patients with alcoholic hepatitis, researchers have begun a placebo-controlled Phase 2b study to test the drug’s efficacy in more patients, which could lead to a third treatment for the disease. A cure.

Larsucosterol’s path to treating alcoholic hepatitis began with a chance meeting on the campus of Virginia Commonwealth University. There, biochemist Ren Shunlin had been studying metabolism and cholesterol synthesis in the liver for decades, and one day he met his former student Lin Weiqi on the campus shuttle. He told her that he had discovered a new molecule called 5-cholesten-3β, 25-diol 3-sulfate (25HC3S), an oxysterol involved in lipid metabolism (7).

After that shuttle ride, Ren and Lin stayed in touch over the years. Ren’s team learned that this molecule is located in the nucleus of human liver cells and that, in addition to lipid metabolism, it is involved in cell survival and regulating inflammatory responses, but they did not yet know its exact mechanism (8). Lin knew that Brown had previously studied cholesterol molecules at a biopharmaceutical company, so she shared Lin’s publications with him.

If you give lasicosterol, the tissue will look normal. The animals will be fine. If you give them a placebo, 80 to 90 percent will die. This is really amazing.
-James Brown, Durrett

“I saw some of the data they had and I thought, ‘This must be some kind of drug,'” Brown said. “I actually made plans with WeiQi the next day. “We flew out to meet Dr. Ren. “

When 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 affect multiple aspects of cellular function, the research team hypothesized that these molecules act as epigenetic regulators (9). In 2021, they found that 25HC3S indeed modifies the epigenome by inhibiting all three human DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b), which add methyl groups to DNA to inhibit gene expression (10).

“It changes DNA hypermethylation, which changes the inflammatory state, changes apoptosis and autophagy, and stabilizes the mitochondrial membrane. So it does a lot of things to help cells survive and get through difficult times,” Brown said.

Brown and his team at DURECT administered 25HC3S (renamed larsucosterol or DUR-928) to animal models of several different diseases, including sepsis, pancreatitis, acute kidney injury, stroke, and alcoholic hepatitis.

“If you give lasitosterol, the tissue will look normal. The animals will be fine. If you give them a placebo, 80 to 90 percent will die,” Brown said. “It’s really amazing.”

With positive preclinical data, the DURECT team has set its sights on testing larsucosterol in patients with alcoholic hepatitis. For these patients, “if they’re dying, they’re dying,” Brown explained. So we have time to talk to patients, talk to their families, enroll them in studies, and try to change that practice. ” Recent analysis of liver samples from patients with alcoholic hepatitis revealed evidence of hypermethylation and increased expression of DNA methyltransferases, further supporting the use of larsucosterol in treating these patients (11).

The DURECT team initiated a Phase 2a clinical trial testing the safety, efficacy and pharmacokinetics of larsucosterol in 19 patients with alcoholic hepatitis compared with two groups receiving standard care, supportive care and corticosteroids Compare (12). Each patient received an infusion of 30, 90 or 150 mg of larsucosterol on the first day of the trial, and received a second dose if they were still in the hospital three days later.

“The half-life of the drug is two hours, but it gets into the nucleus of the cell. And then its effect lasts a long time because you’re actually regulating more than 1,000 genes up and down. So, you’re switching the cell from going toward death to going toward death.” life,” Brown said. “If you can get the liver out of acute hepatitis, then the liver has a strong ability to repair itself, as do many other organ systems.”

Researchers found that larsocusterol was safe at all three doses, with 14 of 19 patients in the trial discharged from hospital less than 72 hours after receiving the first dose. Among this group of discharged patients, 8 of the 12 patients with severe alcoholic hepatitis were patients with severe alcoholic hepatitis. Additionally, they found significant improvements in serum bilirubin levels, a marker of the liver’s ability to clear toxins, and improvements in MELD and Lille scores, which are used to predict patients’ chances of survival with alcoholic hepatitis.

Most importantly to Brown, all patients in the trial survived the entire 28-day study period. He recalled one of the first patients in the trial, who was hospitalized for a month before doctors sent him home for hospice care.

“There was nothing they could do. He was dying. He was in our study, he took the medication, and the study coordinator told us that when she saw him two weeks later, she cried because she couldn’t believe how good he looked. Well. It turns out, two years later he’s still alive,” Brown said.

With these exciting results, the DURECT team has evaluated the efficacy of larsucosterol in the Phase 2b multicenter, randomized, double-blind, placebo-controlled AHFIRM trial (13). They enrolled the last patient into the trial in early June and expect to share data by the end of the year.

Kezer is not affiliated with DURECT, but he is eager to see the results of the Phase 2b study. “This is a very promising drug,” she said. “This phase 2b study is very important to see if it actually has a benefit. Even the different mechanism of action itself is exciting for alcohol-related hepatitis.”

The DURECT team recently released topline data from the Phase 2b study, showing that while larsucosterol reduced 90-day mortality, the reduction was not statistically significant compared with standard treatment. However, the mortality reduction was more pronounced in some patients, so the team hopes to meet with the FDA to discuss next steps for advancing larsucosterol in future clinical trials.

If larsucosterol proves effective against alcoholic hepatitis, Brown hopes to explore its potential to treat other acute conditions for which it has good preclinical data, such as acute kidney injury and stroke, as well as chronic conditions including nonalcoholic steatohepatitis. But for now, he’s focused on alcoholic hepatitis and is hopeful about the future of larsucosterol in treating the disease.

“I’ve been doing this for a long time, developing drugs,” he said. “I’ve never taken medicine like this.”

This article was updated on November 15, 2023, to include newly released clinical trial results.

refer to

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3. Tapper EB and Parikh, ND Cirrhosis and liver cancer mortality in the United States, 1999-2016: an observational study. BMJ Chapter 362K2817 (2018).
4. Kezer, CA, Simonetto, DA, Shah, VH Sex differences in alcohol consumption and alcohol-related liver disease. mayo clinic surgery 961006-1016 (2021).
5. Hughes, E., Hopkins, LJ, Parker, R. Survival in alcoholic hepatitis does not improve over time. PLOS One 13e0192393 (2018).
6. Seuss, MR et al. Prednisolone or pentoxifylline is used to treat alcoholic hepatitis. New England Journal of Medicine Chapter 3721619-1628 (2015).
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11. Aljemi, J. et al. Defects in HNF4α-dependent gene expression are drivers of hepatocellular failure in alcoholic hepatitis. Nat Comb 103126 (2019).
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13. A Phase 2b study to evaluate the safety and efficacy of DUR-928 treatment in subjects with alcoholic hepatitis (AHFIRM). https://classic.clinicaltrials.gov/ct2/show/NCT04563026