Introduction Obeticholic acid (OCA), an FXR agonist, improved both fibrosis and histologic features of nonalcoholic steatohepatitis (NASH) in the Ph2 FLINT study. This Month 18 pre-specified interim analysis of the ongoing Ph3 REGENERATE study evaluated the effect of OCA on liver histology in patients (pts) with biopsy-confirmed NASH.
Methods Pts with NASH and fibrosis stages F2–3 (ITT), and an exploratory group of F1 pts with metabolic syndrome, were randomized to placebo (PBO), OCA 10 mg, or OCA 25 mg QD. Primary endpoints were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of liver fibrosis. The safety population included all randomized and dosed pts (F1–3, N=1968). Clinical outcomes will be evaluated at the end-of-study.
Results The ITT population included 931 pts (PBO [n=311], OCA 10 mg [n=312] or OCA 25 mg [n=308]), comprised of 44% F2 and 56% F3. Baseline characteristics were well-balanced across groups. Results in table 1. The primary fibrosis endpoint was met by 11.9% PBO, 17.6% OCA 10 mg (p=0.0446), and 23.1% OCA 25 mg (p=0.0002) pts (ITT). The primary NASH endpoint was not statistically significant (ITT); however, in a pre-specified analysis that included F1-F3 pts (N=1218), more OCA 25 mg pts achieved NASH. Pruritus was the most common AE (19% PBO, 28% OCA 10 mg, 51% OCA 25 mg) and was predominantly mild to moderate in severity (severe: <1% PBO, <1% OCA 10 mg, 5% OCA 25 mg). More OCA 25 mg pts discontinued due to pruritus (<1% PBO, <1% OCA 10 mg, 9% OCA 25 mg. SAEs occurred in 11% PBO, 11% OCA 10 mg and 14% OCA 25 mg pts. Increases in LDLc with OCA were observed by Wk 4, but approached baseline by M18 (OCA 25 mg: LS mean change Wk4 +22.6 mg/dL, M18 +4.0 mg/dL). Three deaths occurred; none were considered treatment-related (PBO n=2; OCA 25 mg n=1).
Conclusion Treatment with OCA 25 mg improved liver fibrosis, key histologic features of steatohepatitis and liver biochemistry, demonstrating consistent efficacy with an overall AE profile similar to previous studies.
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