Another IBAT inhibitor makes its case in large PFIC trial

The ileal bile acid transporter (IBAT) inhibitor maralixibat appears to quell itching and reduce serum bile acid concentration in children with progressive familial intrahepatic cholestasis (PFIC), while having a tolerable safety profile, according to data from the phase III MARCH-PFIC trial said to be the largest to date.

“Primary and secondary endpoints were met,” reported principal investigator Dr Richard Thompson of King’s College London, London, UK. “Maralixibat demonstrated significant and rapid improvements in pruritus and serum bile acid consistently across all PFIC types.”

MARCH-PFIC included 93 children (1–18 years of age) with PFIC, among whom 47 received maralixibat 570 µg/kg twice daily and 46 received placebo for 26 weeks.

Thompson and his team evaluated the primary and secondary endpoints of mean change from baseline in pruritus and serum bile acid levels, respectively, in the subgroup of patients with nontruncating bile salt export pump (BSEP) deficiency (BSEP cohort, n=31) and across all PFIC cohort (BSEP cohort plus other PFIC types, n=64). The mean age, serum bile acid levels, pruritus, and liver biochemistries were balanced between groups. 

After 26 weeks of treatment, maralixibat yielded a significantly greater reduction in pruritus compared with placebo. The mean change from baseline in the Itch Reported Outcome (ItchRO) scores was –1.7 vs –0.6 (p=0.0098) in the BSEP cohort and –1.8 vs –0.6 (p<0.0001) in all-PFIC cohort. [ESPGHAN 2023, abstract H-O027]

In terms of serum bile acid levels at week 26, treatment with maralixibat likewise led to a significantly greater decrease compared with placebo. The mean change from baseline in serum bile acid levels was –176 vs 11 µmol/L (p=0.0013) in the BSEP cohort and –157.5 vs 2.9 µmol/L (p<0.0001) in the all-PFIC cohort.

Significantly more maralixibat-treated patients met the response thresholds for pruritus (≥1-point reduction or ItchRO score ≤1.0; 64 percent vs 26 percent with placebo; p=0.0023) and serum bile acid (≥75-percent reduction or serum bile acid levels <102 µmol/L; 51.5 percent vs 6.5 percent; p<0.0001), Thompson noted.

Additionally, treatment with maralixibat resulted in statistically significant improvements in direct bilirubin (–0.8 vs 0.8 mg/dL; p=0.048) and in weight Z-score (0.35 vs 1.12; p=0.039), he continued.

“As you know, these drugs do have side effects, and the majority of the side effects are related to the fact that we are moving bile acids into the colon and [included] gastrointestinal disturbance, abdominal discomfort, and diarrhoea,” according to Thompson.

Diarrhoea was the most frequent treatment-emergent adverse event (57.4 percent with maralixibat vs 19.6 percent with placebo) and was mostly mild and transient (median duration 5.5 days). There were neither severe adverse events nor deaths reported. One patient who had a mild diarrhoea discontinued treatment.

In a separate presentation, Thompson reported that maralixibat also proved to be well-tolerated and beneficial in the subgroup of patients with familial intrahepatic cholestasis type 1 disease (n=13). Significant improvements in the efficacy endpoints of pruritus and serum bile acid occurred with the drug, whereas no significant changes were observed with placebo. [ESPGHAN 2023, abstract H-O029]