By Lynda Williams, medwireNews Reporter
medwireNews: Treatment with the ileal bile acid transporter inhibitor maralixibat relieves morning itch for children with different types of progressive familial intrahepatic cholestasis (PFIC), show phase 3 study findings published in The Lancet Gastroenterology and Hepatology.
“Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC”, report Alexander Miethke (Cincinnati Children’s Hospital, Ohio, USA) and co-authors.
The MARCH-PFIC trial included patients aged 1–17 years (median 3 years) who had PFIC and persistent pruritus with an average morning Itch-Reported Outcome (ItchRO) score of 1.5 points or higher over the previous 4 weeks accompanied by biochemical abnormalities and/or pathological evidence of progressive liver disease.
The primary endpoint of mean change in the average ItchRO score between baseline and the last 12 weeks of treatment (weeks 15–26) was reported for 31 patients with the non-truncated bile salt export pump (BSEP) form of PFIC without prior biliary surgery or low or fluctuating serum bile acids. Fourteen patients were given oral maralixibat at a starting dose of 142.5 μg/kg, rising to 570.0 μg/kg twice daily for 26 weeks, while 17 instead received placebo.
Maralixibat was associated with a significantly greater least squares mean reduction in ItchRO score compared with placebo (–1.7 vs –0.6), and this was “consistent for the highest daily and evening ItchRO scores”, the investigators say.
Patients given maralixibat also experienced a significantly greater reduction in total serum bile acid concentration than placebo-treated controls, with a least squares mean decrease from baseline of 176 μmol/L versus an increase of 11 μmol/L.
Miethke et al report that similar benefits in pruritus severity were also found with maralixibat versus placebo among an all-PFIC cohort of 64 children who had not previously undergone surgery but had any bile acid profile. This included patients with FIC-associated protein (F1C)1 deficiency, multi-drug resistance protein-3 deficiency, tight junction protein 2 deficiency and unconventional myosin-Vb deficiency, as well as those with non-truncated BSEP. And this was again accompanied by a greater change in serum bile acid concentration, with a least squares mean reduction of 157 μmol/L versus a 3 μmol/L increase with placebo.
“Overall, maralixibat was well tolerated, with no unexpected treatment-emergent adverse events observed”, the researchers comment, noting that maralixibat was associated with a higher rate of diarrhoea than placebo (57 vs 20%) but that the symptoms were “mild or moderate” and “mostly transient”.
Recognising that serum bile acid concentration reductions have been shown to predict improved native liver survival in children with BSEP or FIC1 deficiencies, the authors now hypothesize that “improvements in liver health could occur after pharmacological interruption of the enterohepatic circulation with maralixibat without the clinical burden associated with surgery.”
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Lancet Gastroenterol Hepatol 2024; doi:10.1016/S2468-1253(24)00080-3