VIENNA — Obeticholic acid improves liver fibrosis, scarring, and other difficulties of nonalcoholic steatohepatitis (NASH), 18-month results from the phase 3 REGENERATE trial (NCT02548351) show.
"This is a watershed moment," said Zobair Younossi, MD, from Virginia Commonwealth University in Fairfax. "It's the first trial that shows efficacy for NASH."
Interim results for people with biopsy-confirmed NASH and stage F2 or F3 fibrosis treated with the farnesoid X receptor (FXR) agonist were reported here at the International Liver Congress 2019.
Of the 931 study participants, 308 received obeticholic acid 25 mg daily, 312 received obeticholic acid 10 mg daily, and 311 received placebo.
The primary end point of the study was the resolution of NASH with no worsening of fibrosis or an improvement in fibrosis of at least one stage with no worsening of NASH, defined as no worsening of hepatocellular ballooning, no worsening of lobular inflammation, and no worsening of steatosis.
More patients in the 25 mg group than in the placebo group achieved an improvement in fibrosis of at least one stage (23.1% vs 11.9%; P = .0002).
And fibrosis improved by at least two stages in nearly three times as many patients in the 25 mg group as in the placebo group (13.3% vs 4.5%; P = .0008).
Although the end point of NASH resolution was not met, more patients in the 25 mg group than in the placebo group saw improvements in hepatocellular ballooning (35.1% vs 23.2; P = .0011) and in lobular inflammation (44.2% vs 35.7%; P = .0322).
In addition, dose-dependent reductions in liver enzymes were observed.
The results were statistically significant but did not meet the threshold mandated by the US Food and Drug Administration of .0001, said Younossi.
Still, "this constitutes the first promise of efficacy in a phase 3 trial," he added. "The fibrosis data are very interesting."
Because the data are statistically significant, the drug has the "potential to cross the regulatory barrier," said Dimitar Tonev, MD, from IQVIA, a multinational company that serves the health information technologies and clinical research industries.
Pruritus a Prevalent Adverse Effect
Severe itching, the major adverse event in REGENERATE, was dose-dependent, reported by 51% of the patients in the 25 mg group, 28% in the 10 mg group, and 19% in the placebo group.
Withdrawals related to pruritus were also dose-dependant, with 9% of patients in the 25 mg group and less than 1% in the 10 mg and placebo groups discontinuing obeticholic acid.
This is a known risk factor with "the new-generation FXR antigens," said Tonev.
Itching is common in general for these patients, said Younossi, noting that nearly one-fifth of the placebo group reported pruritus. It is likely that many patients in general experience adverse events, "we just don't ask them," he told Medscape Medical News.
But pruritus is not the only adverse event associated with the drug. Once-weekly low-dose obeticholic acid, approved for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid, comes with a black-box warning that describes hepatic decompensation and liver failure, leading in some cases to death, when the recommended dose is not used, as previously reported by Medscape Medical News.
And the drug is expected to be expensive. The current annual price for patients with primary biliary cholangitis is $69,350, but to be cost-effective, the price needs to be below $18,450 per year, one report concludes (Hepatology. 2017;65:920-928).
First Phase 3 Treatment to Emerge
These data on the first potential clinical treatment for NASH are "exciting for patients," said Philip Newsome, PhD, from the University of Birmingham, United Kingdom. "Up until now, trying to lose weight has been the only way to take action."
A therapy that "could reduce scarring is important," he added.
With less inflammation, the patient is more likely to do better. "It seems to reduce the activation of hepatic cells, reducing the buildup that leads to scar tissue," he explained.
Early indications suggest this would translate into clinically relevant effects, because fatigue, malaise, and anxiety are all common morbidities. "If you have an improvement in inflammation, you improve patient-reported outcomes," he said.
Although this is "an encouraging step forward, it's far from being the end of the problem called NASH," said Tonev.
But "right now, we don't have any treatments, so it's an exciting time," Younossi added.
REGENERATE is sponsored by Intercept Pharmaceuticals. Younossi reports receiving consulting fees from Gilead, Intercept, Bristol-Myers Squibb, Novo Nordisk, Shionogi, and Novartis. Tonev is a former Intercept employee and current shareholder. Newsome reports receiving consulting fees from Afimmune, Boehringer Ingelheim, Gilead Sciences, Intercept, Novo Nordisk, Pfizer, and Shire.
International Liver Congress (ILC) 2019. Presented April 11, 2019.
Medscape Medical News © 2019
Cite this: First Drug for Fatty Liver Disease Advances - Medscape - Apr 12, 2019.