Long-Term Safety and Tolerability of Obeticholic Acid and Bezafibrate in Primary Biliary Cholangitis: A Phase 3 Open-Label Extension Study

The primary objective of this study is to evaluate the long-term **safety** and **tolerability** of the fixed-dose combination tablet of obeticholic acid (OCA) and bezafibrate (BZF) in subjects with **Primary Biliary Cholangitis (PBC)**. This will be assessed through biochemical disease markers, including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total and conjugated bilirubin. Additionally, biomarkers of bile acid synthesis and homeostasis, such as 7α-hydroxy-4-cholesten-3-one (C4) and bile acids, will be evaluated. The clinical relevance of this objective lies in ensuring the therapeutic regimen's safety profile for long-term use in managing PBC, a chronic liver disease.

Secondary objectives include assessing the effects of the OCA + BZF fixed-dose combination tablet on liver elastography, Model for End-Stage Liver Disease (MELD) scores, Visual Analogue Scale (VAS), EQ-5D-5L, Numerical Rating Scale (NRS), Fatigue Impact Scale (FIS), pharmacokinetics (PK), pharmacodynamics (PD), and the occurrence of all-cause mortality and liver-related clinical outcomes. These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on various clinical and patient-reported outcomes, further informing its potential benefits and risks in the management of PBC.

The clinical trial involves a total of **69 participants** diagnosed with **Primary Biliary Cholangitis (PBC)**. 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 from those who have previously participated and are actively taking the investigational product in Study 747-213 or Study 747-214. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and ethical treatment. The health status of participants is characterized by their ongoing management of PBC, and the trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria focus on individuals already engaged in related studies, ensuring a consistent and relevant participant group for assessing the long-term safety and tolerability of the investigational treatment.

The clinical trial is a **Phase 3, open-label, long-term safety extension study** designed to evaluate the safety and tolerability of a fixed-dose combination tablet containing **obeticholic acid** and **bezafibrate** in subjects with **Primary Biliary Cholangitis (PBC)**. The trial aims to assess long-term safety through biochemical disease markers such as ALP, GGT, ALT, AST, and bilirubin levels, as well as biomarkers of bile acid synthesis and homeostasis. The study is not categorized as low intervention and is expected to conclude by November 2029, with recruitment starting in November 2024.

Participants eligible for this study are those who have previously participated in Study 747-213 or Study 747-214 and are actively taking the investigational product. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to collect data on the primary and secondary endpoints. These endpoints include changes in liver function tests and non-invasive markers of liver fibrosis, as well as the percentage of subjects achieving specific biochemical targets.

The expected duration of participant involvement is up to 60 months, with regular assessments to ensure safety and efficacy. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment. The study is conducted under the sponsorship of Intercept Pharmaceuticals Inc., with the investigational product administered orally in tablet form.

The clinical trial involves the administration of an **experimental medication** known as OCA+BZF FDC, which is a fixed-dose combination tablet containing **obeticholic acid** (OCA) at a dosage of 5 mg and **bezafibrate** (BZF) at a dosage of 400 mg. The pharmaceutical form of this medication is a tablet, and it is intended for **oral use**. The trial aims to evaluate the long-term safety and tolerability of this combination in subjects diagnosed with **primary biliary cholangitis** (PBC). The maximum treatment period for participants is set at 60 days. The medication is manufactured by Intercept Pharmaceuticals Inc., and it is classified as a chemical substance. The trial does not specify a maximum daily dose amount, indicating that dosing will be determined based on the study protocol and participant response.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial is designed to assess various biochemical disease markers and biomarkers of bile acid synthesis and homeostasis, which are critical in evaluating the safety and efficacy of the treatment in the target population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the response rates of reduction from baseline and normalization rates of biochemical disease markers, including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and both total and conjugated bilirubin. Additionally, changes from baseline in these markers, as well as in 7α-hydroxy-4-cholesten-3-one (C4) and bile acids, will be evaluated to assess the efficacy of the treatment in subjects with **Primary Biliary Cholangitis** (PBC).

Secondary endpoints will include changes from baseline in non-invasive markers of liver fibrosis and various patient-reported outcomes, such as the GLOBE score, UK-PBC score, Numerical Rating Scale (NRS), PBC-40, pruritus Visual Analogue Scale (VAS), EQ-5D-5L, Fatigue Impact Scale (FIS), and Aspartate Aminotransferase to Platelet Ratio Index (APRI). The trial will also measure the percentage of subjects achieving specific biochemical targets, such as ALP levels less than 1.67 times the upper limit of normal (ULN), total bilirubin levels at or below ULN, and an ALP decrease of at least 15% from baseline. Furthermore, the time to first occurrence of significant clinical events, including death (all-cause), liver transplant, a Model for End-Stage Liver Disease (MELD) score of 15 or higher, hospitalization, or hepatocellular carcinoma (HCC), will be tracked.