Evaluation of Long-Term Safety and Tolerability of Seladelpar in Patients with Primary Biliary Cholangitis

The primary objective of this study is to evaluate the long-term **safety** and tolerability of **seladelpar** in subjects with **Primary Biliary Cholangitis** (PBC). This is clinically relevant as it aims to ensure that seladelpar can be safely administered over an extended period, which is crucial for chronic conditions like PBC that require long-term management.

Secondary objectives include:

• Evaluating the long-term efficacy of seladelpar.
• Assessing the effect of seladelpar on patient-reported outcomes, specifically pruritus.

These secondary objectives are important for understanding the comprehensive benefits of seladelpar, including its impact on symptoms that significantly affect the quality of life in patients with PBC.

The clinical trial involves a total of **272 participants** diagnosed with **Primary Biliary Cholangitis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on their prior involvement in studies related to seladelpar for Primary Biliary Cholangitis, ensuring they meet the eligibility criteria for the current study. The trial includes a vulnerable population, indicating that special considerations are in place to protect these individuals. Participants are required to adhere to specific contraceptive measures if they are of reproductive potential, highlighting the importance of lifestyle considerations related to reproductive health during the study. The trial aims to evaluate the long-term safety and tolerability of seladelpar in this population.

The clinical trial is designed to evaluate the long-term safety and tolerability of **seladelpar** in subjects with **Primary Biliary Cholangitis** (PBC). This study is structured as an open-label, long-term investigation, allowing for the assessment of treatment-emergent adverse events (AEs) and various biochemical markers. The trial is expected to run until February 28, 2026, with recruitment having commenced on March 8, 2021. Participants will be administered **seladelpar** in capsule form, with dosages of either 50 mg or 100 mg, taken orally. The maximum daily dose is 10 mg, and the treatment period is capped at 60 days.

Participants eligible for this study must have previously participated in a PBC study involving **seladelpar** and meet the current study's eligibility criteria. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation. The primary endpoint focuses on the collection of treatment-emergent AEs, while secondary endpoints include the occurrence of specific PBC clinical outcomes and changes in biochemical markers such as alkaline phosphatase (ALP) and bilirubin levels.

The expected duration of participant involvement is contingent upon the individual's response to treatment and adherence to study protocols. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or non-compliance with study requirements. Participants are required to use effective contraception during the study and for at least 90 days after the last dose to prevent pregnancy. The trial is not classified as low intervention and is categorized as a Phase III trial, emphasizing its importance in the development of treatments for PBC.

The clinical trial involves the administration of **seladelpar**, a chemical compound, as the experimental medication. Seladelpar is provided in two pharmaceutical forms: a 100 mg capsule and a 50 mg capsule, both manufactured by Cymabay Therapeutics Inc. The medication is administered orally. The maximum daily dose for each formulation is 10 mg, with a total treatment period not exceeding 60 days. The primary objective of the trial is to evaluate the long-term safety and tolerability of seladelpar in subjects with Primary Biliary Cholangitis (PBC). The trial does not include a pediatric formulation, and seladelpar has been designated as an orphan drug under the designation number EU/3/17/1930.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of seladelpar. Participants' compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen. The trial is designed to assess the safety profile of seladelpar over an extended period, providing valuable data on its tolerability in the target population.

The efficacy of the investigational product, **seladelpar**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the evaluation of treatment-emergent adverse events (AEs) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, alongside biochemistry and hematology results. These parameters will be systematically collected and analyzed to determine the safety profile of seladelpar.

Secondary endpoints include the occurrence of specific adjudicated clinical outcomes related to Primary Biliary Cholangitis (PBC), such as overall death, liver transplantation, and a Model for End-Stage Liver Disease (MELD) score of 15 or higher for at least two consecutive visits. Additional secondary measures involve the assessment of biochemical markers, including the response on a composite of alkaline phosphatase (ALP) and total bilirubin, the proportion of subjects achieving normalization of ALP, and the relative and absolute changes in ALP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and bilirubin levels (total, direct, indirect). Furthermore, changes from baseline in pruritus as measured by the Numerical Rating Scale (NRS) will be evaluated.