Maralixibat, an ileal bile acid transporter inhibitor, has shown significant efficacy in improving pruritus and reducing serum bile acid concentrations in children with progressive familial intrahepatic cholestasis (PFIC), according to results from the Phase 3 MARCH-PFIC trial. The study, a multicenter, randomized, double-blind, placebo-controlled trial, was conducted across 29 sites in 16 countries and included patients aged 1-17 years with various types of PFIC.
The findings, published in The Lancet Gastroenterology & Hepatology, highlight maralixibat's potential as a non-surgical, pharmacological option to improve the standard of care for patients with PFIC.
Key Findings from the MARCH-PFIC Trial
The MARCH-PFIC trial enrolled 93 patients who were randomized to receive either oral maralixibat (starting dose 142.5 μg/kg, escalated to 570 μg/kg twice daily) or placebo for 26 weeks. The primary endpoint was the mean change in average morning Itch Reported Outcome (Observer; ItchRO(Obs)) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort.
In the BSEP cohort, the least-squares mean change from baseline in morning ItchRO(Obs) was -1.7 (95% CI -2.3 to -1.2) with maralixibat versus -0.6 (-1.1 to -0.1) with placebo, resulting in a significant between-group difference of -1.1 (95% CI -1.8 to -0.3; p=0.0063). The least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0.0013).
The most common adverse event was diarrhea, reported in 57% of patients on maralixibat versus 20% on placebo. All cases were mild or moderate and mostly transient. Serious treatment-emergent adverse events occurred in 11% of participants in the maralixibat group and 7% in the placebo group. No treatment-related deaths were reported.
Clinical Implications and Expert Commentary
"Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids)," the researchers stated. "Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC."
About Progressive Familial Intrahepatic Cholestasis (PFIC)
PFIC is a group of rare autosomal recessive liver disorders characterized by disrupted bile formation, cholestasis, and pruritus. The most prevalent types include BSEP deficiency (PFIC2), MDR3 deficiency (PFIC3), and FIC1 deficiency (PFIC1). Severe pruritus is a common symptom, significantly impacting quality of life and potentially leading to liver transplantation. Accumulation of bile acids is a key mediator of pruritus and contributes to liver disease progression.
The study was funded by Mirum Pharmaceuticals.
