Introduction: Elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are associated with risk of poor clinical outcomes, including hepatic decompensation, liver transplant, or death, in patients (pts) with primary biliary cholangitis (PBC). Obeticholic acid (OCA), a selective, potent farnesoid X receptor (FXR) agonist, received accelerated approval for the treatment of PBC based on improvement in alkaline phosphatase (ALP) and total bilirubin (TB) levels in POISE, a randomized, double-blind, placebo-controlled phase 3 study. Here, we evaluate the impact of OCA on normalization of ALT and AST levels.

Methods: Patients with PBC who could not tolerate or had an incomplete response to first-line ursodeoxycholic acid (UDCA) were randomized 1:1:1 to receive placebo (PBO), OCA titration (5-10 mg), or OCA 10 mg daily for 12 months. Serum ALT and AST levels were assessed at all visits. The study primary endpoint (PE) was ALP ≤1.67× upper limit of normal (ULN) with ≥15% reduction from baseline and TB ≤ULN. The association between OCA treatment and normalization of ALT or AST levels at month 12 was evaluated in the overall population and among pts who achieved or did not achieve the PE using the Cochran–Mantel–Haenszel general association test.

Results: Overall, ≥90% pts had elevated ALT and AST levels at baseline, and significantly greater proportions of pts had normalized each of these at month 12 in both OCA arms vs PBO (Table 1). For ALT, 10% of pts attained normal levels in the PBO arm at month 12 vs 29% and 33% in the OCA titration and OCA 10 mg arms (p<0.05 for both). For AST, the normalization rates at month 12 were 10% in the PBO arm, and 23% and 30% in the OCA titration and OCA 10 mg arms (p<0.05 for both). Among pts who achieved the PE at month 12, 34% and 44% had normal ALT in the OCA titration and OCA 10 mg arms, and 31% and 47% had normal AST, respectively, whereas none of the 7 PBO pts did. Among pts who did not achieve the PE at month 12, the proportion who had normal ALT and AST levels was higher in the OCA-treated arms vs PBO, particularly for ALT, as almost 25% of pts achieved normal levels in both OCA arms.

Conclusions: OCA normalized ALT and AST levels in a high proportion of pts after 12 months of treatment, particularly among pts who achieved the PE (almost half in the OCA 10 mg arm). Even among OCA-treated pts who did not achieve the PE, approximately 1 in 4 and 1 in 6 had normalized ALT and AST levels, respectively, with either OCA regimen. These data suggest that FXR agonism with OCA can reduce ALT and AST levels below thresholds that are prognostic for poor clinical outcomes. Measuring ALT and AST levels with other biomarkers (eg, ALP, TB, gamma-glutamyl transferase) may help clinicians assess the full breadth of OCA treatment response in pts with PBC and minimize the risk of disease progression.

David Victor

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