Long-Term Safety and Efficacy Evaluation of Maralixibat in Patients with Alagille Syndrome in the European Union

The primary objective of this clinical study is to evaluate the **tolerability**, long-term safety, including potential liver toxicity, and long-term efficacy of Livmarli in patients diagnosed with **Alagille syndrome** (ALGS) within the European Union. This study is significant as it aims to provide insights into the sustained use of Livmarli, a treatment option for ALGS, a rare genetic disorder that affects the liver and other organs. Understanding the long-term safety and efficacy of Livmarli is crucial for optimizing patient management and improving clinical outcomes in this patient population.

The clinical trial involves participants diagnosed with **Alagille syndrome** (ALGS), a rare genetic disorder. The study population includes both male and female subjects, with an age range spanning from early childhood to adolescence. Participants are selected based on a clinically and/or genetically confirmed diagnosis of ALGS, with pruritus secondary to chronic cholestasis. The trial includes individuals who have been prescribed Livmarli, either at the time of study entry or prior. The study population is considered vulnerable, given the age and health condition of the participants. The sponsor has not provided information regarding the total number of participants involved in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **tolerability**, long-term safety, and efficacy of Livmarli in patients diagnosed with **Alagille syndrome**. This study is a low-intervention trial, reflecting minimal additional risk compared to standard clinical practice. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends until April 19, 2035, with recruitment anticipated to commence on April 19, 2025. Participants will be involved in the study for a maximum treatment period of 119 weeks, during which they will receive Livmarli, an oral solution containing the active substance **maralixibat**.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as informed consent and a clinically or genetically confirmed diagnosis of Alagille syndrome with pruritus secondary to chronic cholestasis. Participants are divided into a primary cohort, prescribed Livmarli at study entry, and a supplemental cohort, prescribed Livmarli prior to study entry. Follow-up visits are scheduled to monitor safety, efficacy, and tolerability, with assessments including adverse events, liver function tests, and changes in pruritus severity. The end-of-study visit marks the conclusion of the participant's involvement, where final evaluations are conducted.

Participants may be subject to early termination from the study if they experience adverse events that necessitate discontinuation, or if they fail to adhere to the study protocol. The primary endpoints focus on safety, efficacy, and tolerability, with secondary endpoints not specified. The trial aims to provide comprehensive data on the long-term use of Livmarli in managing Alagille syndrome, contributing valuable insights into its clinical application.

The clinical trial involves the administration of **Livmarli 9.5 mg/mL oral solution**, an experimental medication containing the active substance **maralixibat**. This pharmaceutical product is formulated as an **oral solution** and is intended for **oral use**. The maximum daily dose is specified as 380 µg/kg, with the same amount being the maximum total dose. The treatment period is capped at 119 days. The medication is a chemical drug developed by Mirum Pharmaceuticals International B.V. and is designated as an orphan drug for the treatment of Alagille Syndrome (ALGS). The study aims to evaluate the long-term safety, including potential liver toxicity, tolerability, and efficacy of Livmarli in patients with ALGS.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Livmarli. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial is designed to assess the outcomes of Livmarli administration over an extended period, providing valuable data on its safety and efficacy in the target patient population.

Efficacy in the clinical trial titled "Long-Term Low-Intervention SafEty and Clinical Outcomes Clinical Study of LivmArli in Patients with Alagille Syndrome in the European Union (LEAP-EU)" will be assessed through several primary endpoints. The primary efficacy endpoint involves evaluating the change in **pruritus** severity from baseline, which will be measured using the Clinician Scratch Scale (CSS) score. Additionally, changes in serum bile acid (sBA) levels from baseline will be monitored. The frequency of use of concomitant medications for the treatment of underlying liver disease, pruritus, or cholestasis will also be assessed as part of the efficacy evaluation.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the study. The CSS score and sBA levels will be measured at baseline and compared to subsequent measurements to determine any changes. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The study aims to provide comprehensive insights into the long-term efficacy of Livmarli in patients with Alagille Syndrome, focusing on symptom improvement and the management of associated conditions.