General Information

Livmarli (maralixibat) is an ileal bile acid transporter (IBAT) inhibitor.

Livmarli is specifically indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older.

Livmarli is supplied as an oral solution. The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before the first meal of the day. Start dosing at 190 mcg/kg administered orally once daily; after one week, increase to 380 mcg/kg once daily, as tolerated. The maximum daily dose volume for patients above 70kg is 3 mL or 28.5 mg per day. If a dose is missed, it should be taken as soon as possible within 12 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed. For patients taking bile acid binding resins, take Livmarli at least 4 hours before or 4 hours after taking a bile acid binding resin.

Mechanism of Action

Livmarli (maralixibat) is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum. Pruritus is a common symptom in patients with ALGS and the pathophysiology of pruritus in patients with ALGS is not completely understood. Although the complete mechanism by which maralixibat improves pruritus in ALGS patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids.

Side Effects

Adverse effects associated with the use of Livmarli may include, but are not limited to, the following:

• diarrhea
• abdominal pain
• vomiting
• fat-soluble vitamin deficiency
• liver test abnormalities
• gastrointestinal bleeding
• bone fractures

Clinical Trial Results

The FDA approval of Livmarli was assessed in Trial 1, which consisted of an 18-week open-label treatment period; a 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; a subsequent 26-week open-label treatment period; and a long-term open-label extension period. Thirty-one pediatric ALGS patients with cholestasis and pruritus were enrolled, with 90.3% of patients receiving at least one medication to treat pruritus at study entry. All patients had JAGGED1 mutation. Patients were administered open-label treatment with Livmarli 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period; two patients discontinued treatment during this first 18 weeks of open-label treatment. The 29 patients who completed the open-label treatment phase were then randomized to continue treatment with Livmarli or receive matching placebo during the 4- week drug withdrawal period at Weeks 19-22 (n=16 placebo, n=13 Livmarli). All 29 patients completed the randomized, blinded drug withdrawal period; subsequently, patients received open label Livmarli at 380 mcg/kg once daily for an additional 26 weeks. Given the patients’ young age, a single-item observer-reported outcome was used to measure patients’ pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]). Pruritus symptoms were assessed on a 5-point ordinal response scale, with scores ranging from 0 (none observed or reported) to 4 (very severe). Patients were included in Trial 1 if their average pruritus score was greater than 2.0 (moderate) in the 2 weeks prior to baseline. Data demonstrated statistically significant reductions in pruritus, one of the most common and arduous symptoms associated with the disease, which was maintained through four years.