The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.
For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.
The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.
Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.
Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.
REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.
Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.
REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.