Maralixibat improves pruritis, reduces total serum bile acids in all PFIC subtypes

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Key takeaways:

  • Treatment with maralixibat led to greater reductions in least-squares mean change from baseline in morning ItchRo score vs. placebo.
  • Treated patients also achieved greater reductions in total serum bile acids.

Maralixibat improved cholestatic pruritis and reduced serum bile acids in pediatric patients with progressive familial intrahepatic cholestasis, regardless of disease genotype, according to data from the MARCH-PFIC trial.

“The accumulation of bile acids in PFIC is an important mediator of pruritus and driver of liver disease progression,” Alexander G. Miethke, MD, of Cincinnati Children’s Hospital, and colleagues wrote in The Lancet Gastroenterology & Hepatology. “More recently, pharmacological agents have been developed to interrupt the enterohepatic circulation via ileal bile acid transporter inhibition in patients with genetic cholestasis, including PFIC.”

Graphic depicting results of mean morning ItchRo score change in PFIC with bile salt export pump deficiencies.

Data derived from: Miethke AG, et al. Lancet Gastroenterol Hepatol. 2024;doi:10.1016/S2468-1253(24)00080-3.

They continued: “The efficacy and safety of ileal bile acid transporter inhibitors, however, remain to be established in the broader PFIC group beyond [bile salt export pump (BSEP)] and [familial intrahepatic cholestasis-associated protein 1 (FIC1)] deficiencies.”

In the multicenter, double-blind, placebo-controlled, phase 3 MARCH-PFIC study, researchers investigated the safety and efficacy of maralixibat in 93 pediatric patients (median age, 3 years; 55% girls) with PFIC and persistent pruritis. Patients were randomly assigned to oral maralixibat at a starting dose of 142.5 µg/kg with escalation to 570 µg/kg twice daily for 26 weeks or placebo, and divided into cohorts of BSEP deficiency (maralixibat, n = 14 vs. placebo, n = 17), all-PFIC subtypes (33 vs. 31) and the full study population (47 vs. 46).

The primary endpoint was mean change from baseline in average morning ItchRO severity score in the BSEP cohort, while the key secondary endpoint was mean change in total serum bile acids between baseline and the average of weeks 18, 22 and 26 in the same cohort.

According to study results, treatment with maralixibat resulted in greater reductions in least-squares mean change from baseline in morning ItchRo score (–1.7; 95% CI, –2.3 to –1.2) compared with placebo (–0.6; 95% CI, –1.1 to –0.1) in the BSEP cohort, with a significant difference between groups of –1.1 (95% CI, –1.8 to –0.3). Researchers noted consistent results in the all-PFIC cohort (mean difference = –1.2; 95% CI, –1.7 to –0.7).

The BSEP cohort also experienced greater reductions in total serum bile acids with maralixibat vs. placebo, with least-squares mean change from baseline of –176 mol/L (95% CI –257 to –94) vs. an increase of 11 mol/L (95% CI, –58 to 80), for a between-group difference of –187 µmol/L (95% CI, –293 to –80). Similar findings were reported in all PFIC cohort (–157 mol/L vs. increase of 3 mol/L)

The most common adverse event was mild or moderate diarrhea, reported in 57% of patients on maralixibat vs. 20% on placebo, while 11% vs. 7% of patients, respectively, experienced serious treatment-emergent adverse events. There were no treatment-related deaths.

“Maralixibat 570 g/kg administered twice daily represents a new nonsurgical, pharmacological option to interrupt the enterohepatic circulation and reduce bile acids in patients with PFIC, showing efficacy beyond BSEP and FIC1 deficiencies,” Miethke and colleagues wrote. “Maralixibat improved cholestatic pruritus and markers of sleep disturbances and has the potential to improve the standard of care in patients with PFIC, regardless of genotype.”

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