麻豆传媒

VIENNA – An interim analysis of an ongoing phase III study appears to show that treatment of non-alcoholic steatohepatitis (NASH) with the agent obeticholic acid (Ocaliva) significantly improved liver fibrosis without worsening NASH, researchers reported here.

That co-primary endpoint was achieved by 11.9% of patients on placebo, compared with 17.6% of patients on the 10-mg low dose of obeticholic acid (P=0.0446) and 23.1% of patients on the 25-mg high dose of obeticholic acid (P=0.0002), said Zobair Younossi, MD, of Inova Fairfax Medical Campus/Virginia Commonwealth University in Falls Church.

Under the stringent trial protocol, only outcomes that generated a P-value of less than 0.01 were deemed to be statistically significant; hence only the high dose of obeticholic acid was characterized as having a significant difference.

"There is an urgent need for effective treatment regimens for NASH, a common liver disease which can lead to cirrhosis, liver failure, and need for transplant," Younossi said at a press conference at the , sponsored by the European Association for the Study of the Liver. "Halting or reversing fibrosis is a central therapeutic objective for patients with NASH, so the results from the 18-month interim analysis of REGENERATE are highly meaningful and clinically important."

In that 18-month analysis, however, the second co-primary endpoint – resolution of NASH – was not significantly different for either dose of obeticholic acid compared with placebo, he said. Resolution of NASH without worsening of fibrosis was observed in 8% of placebo patients and 11.2% of the patients on the low dose of the active agent (P=0.1814) and 11.7% of the patients treated with the high dose (P=0.1268).

The FDA mandated that in order for the primary objective to be met, the study had to achieve one of the two primary endpoints, according to a statement from Intercept Pharmaceuticals, the drug's manufacturer.

'Important Step Forward'

Press conference moderator Philip Newsome, PhD, of the University of Birmingham in England, commented: "I would view this information about obeticholic acid as the start of what I would hope would be one of many effective therapies. It you recall that when we started with hepatitis C treatment we had a 7% cure rate, but that didn't stop us from using those agents because 7% is better than nothing."

"This is an important step forward," he told 麻豆传媒. "It is the first study that shows effectiveness in treating NASH; there is a signal there that shows effect against fibrosis, which is the most important thing. It will be interesting to see how that evolves further with more prolonged treatment," he continued. "I think I would use it now in patients with Stage F3 fibrosis. I would hope and expect that the benefits will increase with this treatment and future treatments."

For the study, Younossi and colleagues enrolled patients with biopsy-proven NASH with fibrosis, diagnosed in stages F2-F3. The intention-to-treat population included 311 patients assigned to the placebo group, 312 patients given low-dose obeticholic acid, and 308 patients who received the high-dose of the drug. A repeat biopsy was performed at 18 months.

"The new REGENERATE data indicate that obeticholic acid also improves other important measures of liver health, including the key underlying drivers of NASH and biochemical tests that clinicians routinely monitor when managing patients in the real world," Younossi said.

He noted that about 13.3% of patients on the high dose of obeticholic acid achieved an improvement in fibrosis of at least two stages compared with 4.5% of patients on placebo (P=0.0008). In addition, more patients on obeticholic acid improved by at least one fibrosis grade compared with those on the drug who had worsening fibrosis, whereas in the placebo group the difference between those who improved and those who worsened was not appreciably different.

Younossi explained that a clinical feature of NASH is that the disease has a tendency to improve and worsen within patients over the course of time.

"This is a watershed moment in the field, because this is the first randomized trial that has shown efficacy," he said. "We are at the very beginning of what the disease will be in terms of treatment. I think we will see combinations and combination over the next few years. It is the beginning of a great journey."

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