BOSTON—Hepatitis used to be the talk of the town at The Liver Meeting, the annual gathering of the American Association for the Study of Liver Diseases. These days, the conversation is turning to nonalcoholic steatohepatitis (NASH), but its cousin alcoholic hepatitis (AH) isn’t getting much attention. Durect is trying to change that.
The California-based company presented data showing that all 19 patients who received its epigenetic regulator, DUR-928, were still alive 28 days after treatment and that it reduced their Maddrey’s Discriminant Function (DF) and Model for End-Stage Liver Disease (MELD)—scores that reflect the likelihood that someone with AH will die within a certain period of time. It also reduced their levels of serum bilirubin, a marker of liver disease.
The study tested three dose levels of the intravenous treatment: 30 mg, 90 mg and 150 mg. All patients were dosed on day one, and, if they were still hospitalized on day four, they received a second dose. Of the 19 patients, 17 responded to the treatment within seven days—a rate of 89%. Nearly three-quarters of them were able to leave hospital within four days of receiving a single dose of DUR-928.
Mortality rates for AH are hard to pin down, but the investigators followed the 19 patients for nearly a month, expecting some of them to die, said Tarek Hassanein, M.D., who presented the results of the phase 2a study. Hassanein is a professor of medicine and director of outreach services for liver transplantation at the University of California San Diego School of Medicine.
“Alcoholic hepatitis is a very specific form of alcohol-induced injury that comes on very quickly. It really kills people, but worse yet, we don’t have any treatments,” Hassanein said.
Today, AH is treated with corticosteroids, but there is debate on just how effective they are. If steroids don’t work, the only option is a liver transplant, which can be difficult to secure.
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“It is challenging to get any patients who are dying from acute alcoholic hepatitis to be accepted by the transplant committee,” Hassanein said. “There are a lot of issues about organ shortage and who should get those organs. Although the data shows that [AH patients] benefit tremendously from transplants, the issue is that they didn’t go through a rehabilitation process that minimizes the chances of recidivism after the transplant.”
Enter DUR-928, a naturally occurring epigenetic regulator Durect CEO Jim Brown likens to antivirus software. If DNA is like hardware, the epigenome is the software. If the software is dysregulated, DUR-928 can be used to fix the software—that is, it stimulates certain genes to get the body to repair itself.
“And like an antivirus software, it doesn’t need to be redone every day—it’s good for the next month, or possibly longer,” Brown said.
The study was open-label, so it didn’t directly compare DUR-928 to corticosteroids. But the investigators carried out a subgroup analysis of eight patients with severe AH against a similar group of patients who received steroids in a separate study. That study, conducted at the University of Louisville, wrapped up recently.
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“We were able to look into every single patient and match their baseline parameters to get the same kinds of patients to compare the response to steroids versus the response to ‘928,” said WeiQi Lin, M.D., Ph.D., Durect’s R&D chief. Both patient groups had similar baseline MELD and Maddrey’s DF scores, but three of the 13 patients who received steroids died within 28 days of treatment whereas all eight DUR-928 patients survived.
Next up, the investigators are working with Durect to design a phase 2b study that will include “a significantly higher number of patients,” Hassanein said. If that study yields similar results, the company will be able to go full steam ahead into phase 3 and, they hope, regulatory approval.