A New Step in Treating Itching in Rare Liver Diseases: Livmarli Meets Phase 3 Trial Endpoint

For children with rare cholestatic liver diseases, persistent itching can become a burden that is difficult to escape in daily life. The rarity of these diseases also makes it difficult to gather sufficient drug trial evidence for each condition. Mirum Pharmaceuticals announced on October 12 that its Livmarli (maralixibat) met the primary efficacy endpoint in the Phase 3 EXPAND trial, raising the possibility of expanded treatment options for more patients, including those with biliary atresia.

Livmarli is an oral ileal bile acid transporter (IBAT) inhibitor currently approved in the United States to treat itching associated with Alagille syndrome and progressive familial intrahepatic cholestasis. This study focused on extending the efficacy assessment to other ultra-rare liver diseases outside its approved indications, rather than demonstrating that the drug can cure these diseases.

EXPAND enrolled 52 participants, including 46 children and 6 adults, who were randomly assigned to receive maralixibat or placebo in a 20-week double-blind comparison. According to a transcript of the results briefing published by Stock Analysis, Mirum’s chief medical officer said this design spanning multiple diseases was developed at the FDA’s request and in coordination with the agency. It allowed patients who share problems with cholestasis and itching, but whose individual conditions make large trials difficult to conduct, to be evaluated in the same study.

The primary efficacy analysis focused on the 46 children, with caregivers recording the worst daily itching severity on a scale from zero to four. Compared with pretreatment levels, the average score during weeks 13 to 20 fell by 1.81 points in the drug group and 0.83 points in the placebo group. The difference between the groups was 0.98 points and was statistically significant (p = 0.0004). This difference provides evidence of symptom improvement, but a decrease in scores does not mean that all children stopped experiencing itching.

The company also announced that all five prespecified secondary endpoints were met, covering days with improvement in itching, serum bile acids, and an analysis of patients with biliary atresia who still had their native liver. In this subgroup of 25 participants, the improvement in itching scores was 1.15 points greater than with placebo. Across the overall study, serum bile acids fell by 70.1% from baseline in the drug group and by 3.5% in the placebo group. The changes in symptoms and biochemical measures moved in the same direction, providing additional support for the results.

The safety findings present a tradeoff that requires consideration: diarrhea occurred in 64% of the drug group and 11.1% of the placebo group, while serious treatment-emergent adverse events occurred in 20% and 18.5%, respectively. Management said during the briefing that no patients discontinued treatment because of diarrhea, but one participant in the drug group did withdraw from the study early because of an adverse event. “No discontinuations due to diarrhea” therefore cannot be interpreted as meaning that gastrointestinal side effects imposed no burden.

The information currently available consists of the company’s announced topline results and briefing materials. The limited sample size and inclusion of different diseases are not sufficient to establish that patients with every disease type, or adult patients, can obtain the same benefits. The 20-week comparison also cannot answer how long efficacy may last or whether the drug can reduce the need for liver transplantation. Mirum plans to submit a supplemental new drug application in the United States in the first half of 2027. Whether the indications can be expanded remains subject to regulatory review of the full evidence.