Maralixibat may benefit certain subgroups of children with PFIC

Maralixibat may have a role in treating a broader profile of children with progressive familial intrahepatic cholestasis (PFIC), including those who have had biliary diversion (BD) surgery and those with MDR3 deficiency, suggest subgroup analyses from the phase III MARCH/MARCH-ON trials.

The full MARCH study population consisted of 93 children with PFIC who had persistent, moderate-to-severe pruritus. The all-PFIC cohort accounted for 68.8 percent of the population. Maralixibat was dosed ranging from 142.5 to 570 µg/kg BID, in a double-blind manner. [Lancet Gastroenterol Hepatol 2024;doi:10.1016/S2468-1253(24)00080-3]

Surgical BD subgroup

“For some patients who undergo surgical BD, pruritis is not improved or improvements are transient,” said lead author Dr Lorenzo D'Antiga from the Department of Paediatric Hepatology, Gastroenterology, and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy, at ESPGHAN 2024.

Hence, the team evaluated children with a history of internal or external BD within the exploratory cohort (n=8). In this subgroup, 3 out of 4 children who were randomized to receive maralixibat showed improvements in pruritus, as indicated by their changes from baseline to weeks 15-26 in Itch-Reported Outcome (Observer; ItchRO[Obs]) morning score (−1.9, −1.5, and −0.7, respectively). On the other hand, those randomized to receive placebo showed no improvements in pruritus (change from baseline in ItchRO[Obs], 0.0 and 0.2). [ESPGHAN 2024, poster H‐PW004]

The improvement in the ItchRO(Obs) morning score was sustained until the last assessment in MARCH-ON, the open-label, long-term extension study of MARCH, in the current 2-year analysis.

MDR3-deficient subgroup

In the subgroup of children with MDR3 (multidrug resistance protein 3) deficiency (n=9), “all participants who received maralixibat showed improvements in pruritus,” said presenting author Professor Richard Thompson from the Institute of Liver Studies, King’s College London in UK, at ESPGHAN 2024.

Treatment with maralixibat resulted in a median change of −1.7 in the ItchRO(Obs) morning average score, which is considered clinically meaningful (≥1-point reduction). [ESPGHAN 2024, poster EPP019]

Children who received maralixibat in MARCH and MARCH-ON had sustained reductions in pruritus for up to 102 weeks. Children who switched from placebo to maralixibat generally had either sustained or further improved reductions in pruritus.

Taken together with previous data on PFIC children who were FIC1-, TJP2-, or MYO5B-deficient, the data now solidly demonstrate the efficacy of maralixibat across disease-causing mutations in PFIC. [ESPGHAN 2023, abstract H-O029; AASLD 2023, poster 4604-C]

Rationales behind the analyses

A defect in encoding MDR3 results in PFIC3, which exhibits biochemical features that differ from those of PFIC1/2. Together with TJP2- and MYO5B-related PFIC, they contribute to all known established genotypes of PFIC, in addition to PFIC1 and PFIC2. These groups of interest were studied for the first time in a placebo-controlled manner, according to Thompson.

In a previous trial of another ileal bile acid transport inhibitor, enrolment was limited to only those with PFIC1 or PFIC2. Participants who had BD surgery within 6 months prior to screening were also excluded. [Lancet Gastroenterol Hepatol 2022;7:830-842]

“The robustness of the results across all studied groups … indicate[s] a true drug effect across the PFIC types studied,” concluded Thompson and colleagues.