Maralixibat improves pruritus across all PFIC types

Treatment with maralixibat significantly reduced the severity of pruritus in children with progressive familial intrahepatic cholestasis (PFIC) in the MARCH-PFIC* study presented at The Liver Meeting 2022.

PFIC is a heterogeneous group of autosomal recessive cholestatic liver diseases. An important symptom of PFIC is debilitating pruritus, which compromises quality of life and often interferes with sleep.

In the MARCH-PFIC study, pruritus severity improved as shown by a ≥1-point reduction in ItchRO(Obs)** score from baseline to week 26 among children with PFIC treated with maralixibat. In those with BSEP*** deficiency, mean change in ItchRO(Obs) score was -1.7 with maralixibat vs -0.6 with placebo (p=0.0098). Change from baseline in serum bile acid level was -176 vs 11 μmol/L (p=0.0013), respectively. [The Liver Meeting 2022, abstract LO1]

In patients with other PFIC types (deficiencies of FIC1⁺, MDR3⁺⁺, TJP2⁺⁺⁺, and MYO5B^#) treated with maralixibat, improvement in ItchRO(Obs) score was also greater than with placebo (mean change from baseline, -1.9 vs -0.5; p=0.0029). Maralixibat also resulted in a statistically significant improvement in serum bile acid level (-132 vs -6 μmol/L; p=0.0007, respectively).

“The study represents a significant step forward in the evaluation of therapies for PFIC. The sustained and clinically significant reduction in itching scores in the maralixibat treatment arm is an important topline result,” said principal trial investigator Dr Alexander Miethke from the PFIC Research Center at Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio, US. [https://ir.mirumpharma.com/news-events/News/news-details/2022/Positive-Topline-Data-Announced-from-Mirums-LIVMARLI-Phase-3-MARCH-Study-in-Progressive-Familial-Intrahepatic-Cholestasis-PFIC/default.aspx]

“Lowered serum bile acids are a prognostic marker for native liver survival, and it is encouraging to see such an impressive response,” Miethke added. “These data improved upon the compelling results seen in the maralixibat phase II study and underscored the strong effect IBAT^## inhibitor can have on patients with all PFIC subtypes when optimally dosed.”

Largest trial of an IBAT inhibitor

MARCH-PFIC is the largest interventional trial of an IBAT inhibitor in children with PFIC, including PFIC types that have not been studied before, said presenting author Dr Richard Thompson from the Institute of Liver Studies at King’s College London, London, UK.

The full-study cohort included 93 patients (aged ≥12 months to <18 years) with PFIC and cholestatic pruritus. Thirty-one patients had BSEP deficiency and 33 had either deficiency in FIC1, MDR3, TJP2, or MYO5B8. Both formed part of the all-PFIC cohort.

Participants were randomized in a 1:1 ratio to receive maralixibat 570 µg/kg twice daily or placebo for 26 weeks. Mean ItchRO(Obs) scores at baseline were 2.8 and 2.9 in the maralixibat and placebo arms, respectively.

The primary efficacy endpoint was mean change from baseline to week 28 in pruritus in the BSEP cohort. The secondary endpoints included additional pruritus and serum bile acid assessments in the BSEP and all-PFIC cohorts.

In the all-PFIC cohort, assessed for secondary endpoints, significantly more maralixibat-treated patients met the response thresholds for pruritus (63.6 percent vs 25.8 percent; p=0.0023) and serum bile acid at week 26 (51.5 percent vs 6.5 percent; p<0.0001) than the placebo-treated patients. Mean change in ItchRO(Obs) score was -1.8 with maralixibat vs -0.6 with placebo (p<0.0001). Change from baseline in serum bile acids was -157 vs 3 μmol/L (p<0.0001), respectively.

In an exploratory analysis in the all-PFIC cohort, significant improvements in total bilirubin (-1.1 vs 0.9 mg/dL; p=0.0471) and weight Z-score (0.35 vs 0.12; p=0.0391) were observed at week 26 with maralixibat compared with placebo.

Treatment-emergent adverse events (TEAEs) were similar between the maralixibat and placebo arms (100.0 percent vs 93.5 percent), as were the rates of severe TEAEs (6.4 percent and 6.5 percent, respectively).

The most common AE reported was diarrhoea, which occurred in 57.4 percent of patients on maralixibat and 19.6 percent of patients on placebo. Nonetheless, the event was predominantly mild and transient, with a median duration of 5.5 days.

 

*MARCH-PFIC: A study to evaluate the efficacy and safety of maralixibat in subjects with progressive familial intrahepatic cholestasis

**ItchRO(Obs): Itch-Reported Outcome (Observer)

***BSEP: Bile salt export pump

⁺FIC1: Familial intrahepatic cholestasis-associated protein 1

⁺⁺MDR3: Multidrug resistant 3 protein

⁺⁺⁺TJP2: Tight junction protein 2

^#MYO5B: Myosin VB 

^##IBAT: ileal bile acid transporter