Intercept Pharmaceuticals, Inc., a biopharmaceutical company and wholly owned subsidiary of Alfasigma S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, is presenting two new sub-analyses from its Phase 3 POISE study in primary biliary cholangitis (PBC), at Digestive Disease Week® (DDW) 2024 in Washington, D.C. One analysis evaluated the effect of obeticholic acid (OCA) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver biomarkers associated with poor clinical outcomes; the other evaluated the effect of OCA on aminotransferase to platelet ratio index (APRI) score, a non-invasive test that can predict liver fibrosis progression. The landmark Phase 3 POISE study evaluated the safety and efficacy of once-daily treatment with OCA in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid. Patients were randomized to one of three groups in the trial: placebo, OCA 10 mg, or OCA 5 mg for six months, titrated to 10 mg based on clinical response.

The study included a 12-month double-blind phase, as well as a long-term safety extension phase up to five years. The primary endpoint of the 12-month double-blind portion of the trial is the achievement of both an ALP level <1.67x ULN with a =15% reduction from baseline and a normal bilirubin level, as compared to placebo. OCA Impact on ALT and AST: A retrospective analysis was conducted to evaluate the impact of OCA on serum ALT and AST levels, including the proportion of patients who achieved normalization.

Specifically, this analysis assessed time course of ALT/AST reductions in treatment and placebo arms, as well as normalization of AST/ALT levels in the overall POISE trial population and in patients who achieved or did not achieve the POISE primary endpoint at Month 12. Ultimately, both OCA treatment groups significantly reduced ALT and AST levels as early as Week 2 and normalized ALT and AST levels in a significantly higher proportion of patients after 12 months of treatment compared to placebo. Specific findings include: ALT: OCA 10 mg and OCA 5-10 mg resulted in -25 U/L and -21 U/L least squares (LS) mean change from baseline in ALT, respectively; the placebo arm resulted in -5 U/L during the 12-month time period (p<0.001 for both OCA arms vs placebo at all time periods).

Overall, OCA 10 mg and OCA 5-10 mg normalized ALT levels in 33% and 29% of patients, respectively, as compared to 10% of patients in the placebo group (p<0.05). Among patients who achieved the POISE primary endpoint at Month 12, 44% (p<0.05 vs. placebo) and 34% achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively.

None of the patients who achieved the primary endpoint at Month 12 in the placebo group achieved normal ALT levels. Even among patients who did not achieve the POISE primary endpoint at Month 12, 23% (p<0.05 vs. placebo) and 24% of patients achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively.

This compares to 11% of patients in the placebo group. AST: By Month 12, OCA 10 mg and OCA 5-10 mg resulted in -15 U/L and -13 U/L LS mean change from baseline in AST, respectively; the placebo group induced a +1 U/L over the same time period (p<0.001 for both OCA arms vs. placebo at all time periods).

Overall, OCA 10 mg and OCA 5-10 mg normalized AST levels in 30% and 23% of patients, respectively, as compared to 10% of patients in the placebo group (p<0.05). Among patients who achieved the POISE primary endpoint at Month 12, 47% (p<0.05 vs. placebo) and 31% achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively.

None of the patients who achieved the primary endpoint at Month 12 in the placebo group achieved normal ALT levels. Among patients who did not achieve the POISE primary endpoint at Month 12, 15% (p<0.05 vs. placebo) and 16% of patients achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively.

This compares to 11% of patients in the placebo group. post hoc analysis was conducted to determine the impact of OCA on APRI in patients with PBC from the Phase 3 POISE trial. A subset of patients with higher liver stiffness as measured by transient elastography (TE) at baseline and FIB-4 at Month 3 (to account for rapid OCA reductions in ALT/AST), (i.e., TE >8 kPa at baseline or FIB-4 >1.3 at month 3), suggesting a higher risk of advanced fibrosis, was also analyzed.

Overall, treatment with OCA significantly reduced APRI when compared to the placebo group (p=0.0004), including among those at higher risk for fibrosis.