Maralixibat relieves pruritus, reduces serum bile acid

WASHINGTON — Maralixibat, a minimally absorbed inhibitor of the ileal apical sodium-dependent bile acid transporter, provided long-term relief of pruritus and reduced serum bile acid levels in children with Alagille syndrome, according to a presentation at The Liver Meeting 2017.

“The aim of the study was an extension of a previous, randomized study in Alagille syndrome, which as many of you will know is characterized by severe cholestasis in particular and intractable pruritus in a number of patients — the object of this exercise was to look at effects of maralixibat,” Richard J. Thompson, MRCP, MRCPCH, said in his presentation.

Thompson and colleagues enrolled 19 pediatric patients with Alagille syndrome from the IMAGO 13-week randomized, placebo-controlled study into the IMAGINE phase 2 extension study. Median patient age was 5 years (range, 1-7 years) and 10 were boys.

Fourteen patients had received maralixibat in the previous study and five had received placebo. Maralixibat dosage was either continued from the IMAGO study or escalated from placebo in weeks 1 to 4 from 35 µg/kg per day up to 280 µg/kg per day at week 12. The maximum dosage was continued up to 2 years.

Seventeen patients continued treatment to week 48 and six reached end of treatment at week 96. Patients discontinued because they did not consent to the optional extension after week 72 (n = 9), their caregiver withdrew consent (n = 3) or an adverse event (n = 1).

Regarding pruritus, patients who previously received placebo had greater reductions in their itch-reported outcomes scores (median, –2.571; range, –2.86 to –0.71) compared with those who previously received maralixibat (median, –0.857; range, –2.14 to 0.00). Median change in serum bile acid levels at week 48 of the IMAGINE study was –36% (range, –87.3 to 88.2) compared with –19.79% (range, –79.9 to 95.6) in the IMAGO study.

At 96 weeks, the researchers considered four patients to be responders based on a 70% or more reduction in serum bile acid levels and more than 1-point reduction of their itch-reported outcome scores.

Most patients (n = 13) had treatment-emergent events potentially related to maralixibat, including abdominal pain, mild to moderate diarrhea, increased International Normalized Ratio and vitamin D deficiency. One patient discontinued due to increased alanine transaminase.

“These results suggest that maralixibat does provide long-term pruritus relief and reduction of serum bile acid, but unfortunately there will remain a subset of patients with Alagille syndrome and it remains entirely unclear to us what determines that subset. Although we can obviously postulate ideas, it would obviously be ideal if we could predict who was going to respond,” Thompson concluded. “We think these studies are enough to justify further studies of this drug in the treatment of pruritus in patients with Alagille syndrome.” – by Talitha Bennett

Reference:

Thompson RJ, et al. Abstract LB-3. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Thompson reports he received speaking and teaching fees and grants or research support from Shire; and is a consultant to Alberio, Alexion, Arcturus, GlaxoSmithKline and Retrophin.