‘Watershed moment:’ Ocaliva improves NASH in phase 3 trial
VIENNA — Despite missing one of the two primary endpoints set with the FDA, Ocaliva produced antifibrotic effects in a dose-dependent manner in a large, prospective study of patients with nonalcoholic steatohepatitis presented during the International Liver Congress 2019.
“At the moment there is no treatment. This is a watershed moment in this field. This is the first randomized, clinical trial, large study that has shown efficacy,” Zobair M. Younossi, MD, chairman of the department of medicine at Inova Fairfax Medical Center, Fairfax, Virginia, said during a press conference. “We are at the beginning of what this disease is going to be as far as treatment. You’ll see combinations and combinations of combinations over the next few years. This is an exciting time but it’s the beginning of a great journey.”
Younossi presented interim 18-month data from the REGENERATE study, which focused on prespecified endpoints of NASH treatment with Ocaliva (obeticholic acid or OCA, Intercept). The study included 931 participants with biopsy-confirmed NASH and stage F2 or F3 fibrosis. Investigators randomly assigned patients to receive either placebo (n = 311), OCA 10 mg (n = 312) or OCA 25 mg (n = 308).
In looking at the primary endpoints of either fibrosis improvement (1 stage) with no worsening of NASH or NASH resolution with no worsening of liver fibrosis on liver biopsy, Younossi said there was dose-dependent response.
Daily OCA of 25 mg met the primary endpoint of fibrosis improvement without worsening of NASH in 23.1% of patients (P = .0002 vs. placebo). The 10-mg group showed a 17.6% improvement (P = .04 vs. placebo).
“As you can see when you’re looking at the primary endpoint of fibrosis improvement by one stage or higher without worsening of steatohepatitis, there’s a clear-cut improvement,” Younossi said. “The antifibrotic effect of OCA was dose-dependent. It was also consistent across all endpoints.”
NASH resolution as a primary endpoint was not met due to the stringent requirements, but Younossi showed that 35.1% of patients receiving OCA 25 mg did improve in hepatocellular ballooning (P = .0011 vs. placebo). Dose-dependent “rapid improvement” in liver enzymes were also observed, he said.
“Although the primary NASH resolution endpoint was not met, OCA ameliorated steatohepatitis based on pathologist overall assessment and improvement in key disease activity parameters,” Younossi said in his General Session presentation.
He showed that 38% of patients in the 25 mg group had improved fibrosis while 13.1% showed worsening. Comparing that to the placebo group in which those numbers were nearly equal, he said it points to a lot of factors contributing to NASH fibrosis.
“Fibrosis progression in nonalcoholic steatohepatitis is not one-directional. It is very different from other diseases,” Younossi said. “You can have progression and regression of fibrosis in the same individual patients.”
Though adverse events were mostly minor, pruritis was most commonly reported, affecting 51% of the 25-mg group, 28% of the 10-mg group and 19% of the placebo group. More patients in the larger dose group withdrew due to pruritis (9% vs. <1% in the 10 mg and placebo groups).
“REGENERATE is the first successful phase 3 clinical trial in patients with NASH. These results are highly, highly relevant to clinical practice because steatofibrosis is the strongest independent predictor of liver-related mortality in patients with NASH,” Younossi said. – by Katrina Altersitz
Younossi Z. GS-06. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.
Disclosures: Younossi reports receiving consulting fees from Bristol-Myers Squibb, Gilead, Intercept, Novartis, Novo Nordisk and Shinogi.