The protocol has been amended to implement an open label extension (OLE).

Based on feedback from regulatory authorities, the stopping criteria and subsequent regulatory action has been clarified and defined.

Based on feedback from regulatory authorities, acceptable methods of contraception have been clarified and defined. Additionally, exclusion criteria for females of child-bearing potential has been added.

Protocol 2 has been prepared to: Change the terminology of the OCA drug formulation that will be used for the younger and smaller children from “oral suspension” to “pediatric formulation” since an oral suspension will not be used. The pediatric formulation is currently under development and therefore a generic term is more appropriate at this time; Clarify the timing and process for initiating enrollment of the younger group of children (<2 years); Clarify that standard of care medications for the treatment of biliary atresia (eg, UDCA) need to be stable for at least 1 month prior to Day 1; Clarify that the collection of a blood sample is intended for all participants at each visit per Table 1 and Table 2 who meet the minimum enrollment weight restriction on Day 0 of ≥20 kilograms (kg). Initially, the protocol indicated that blood would only be drawn for participants who weighed ≥20 kg at the time of each visit. participants who have slight weight loss resulting in a weight <20 kg should still provide a blood sample at each respective visit. Originally, the minimum weight requirement was defined based on the ability to dose the participants appropriately without having a pediatric formulation available, and was not based on any safety concerns for participants who weighed <20 kg; Updated the Table of Procedures (Table 2 and Table 3) for the OLE phase to include the procedures required for participants who enroll into the OLE phase at a time other than the end of the SD MD phase (Day 64); Clarify that participants who enroll in the OLE phase ≥3 weeks to ≤3 months and >3 months will be dispensed OCA on Day 1, but will be instructed to wait for a telephone contact by the principle investigator (PI) or designee before starting dosing; Clarify in the Procedure Section the list of procedures required for participants who enroll in the OLE phase at a time other than the end of the SD MD phase (Day 64); Delete dose charts in Appendix B as it is not necessary to include.

OCA 0.1 mg mini-tablet formulation has become available for dosing of participants aged <2 years. Protocol Version 3 includes details regarding this formulation and dosing instructions. Further, the weight restrictions on participant enrollment have been clarified. Other major changes include addition of exploratory objectives: (1) accessibility and swallowability and (2) palatability.

The pathophysiology of biliary atresia is known to include portal hypertension, cholestasis, and/or hepatic impairment (cirrhosis). The presence and magnitude of these disease features are likely to have a substantial impact on the plasma and/or liver concentrations of OCA. Although there are no safety concerns, as a precautionary measure, additional time has been added to receive single-dose pharmacokinetics (PK) data for all participants being treated with OCA prior to the start of the MD phase. This additional time is intended to allow for a decision regarding whether each participant should proceed into the MD phase or be discontinued from the study. Exclusion criteria for participants with aspartate aminotransferase (AST) to platelet ratio index Aspartate aminotransferase to platelet ratio index (APRI) >0.95 was added to make sure participants are unnecessarily exposed to high levels of OCA. Participants would be allowed to rescreen. Based on PK data from the initial participants enrolled into the low dose arm of this protocol, which showed a positive relationship between single-dose total OCA area under the concentration-time curve from time 0 to 24 hours (AUC0-24h) exposure and the APRI calculated at the screening visit, APRI will also be used as a preliminary predictor of exposure. Visit window extensions for Days 7 and 14 have been incorporated to receive and evaluate single-dose PK data for participants prior to entering the MD phase due to disease features (ie, portal hypertension) playing a significant role in OCA PK exposure. Additional visits have been added for Control participants enrolling into the OLE, to evaluate baseline characteristics prior to assigning participants to an appropriate dose group.

There are not known or accepted clinical parameters to evaluate the efficacy of therapies such as OCA in participants with post-hepatoportoenterostomy (HPE) biliary atresia. There is a mechanistic rationale for OCA as a candidate for the treatment of post-HPE biliary atresia based on its farnesoid X receptor (FXR) mediated hepatoprotective properties including improvement in choleresis, inhibition of the progression to fibrosis, reversal of established fibrosis, and the ability of OCA to counteract hepatic inflammation. Modifications have been made to transition the intent of the 747-206 trial from proof of concept to a clinical pharmacology and proof of mechanism study that assesses safety, PK, and pharmacodynamics (PD). Efficacy will be evaluated in subsequent studies. Additionally, based on participant PK data received to date, there has been difficulty in predicting OCA exposure due to varying levels of disease manifestations, including portal hypertension, and therefore OCA exposure has shown to be higher than anticipated in certain participants. No adverse events or safety concerns existed with the higher exposures seen, in fact some measurements of transaminases improved with OCA dosing. However, this finding required a re-assessment of the study design to minimize the potential risk of high OCA exposure.

Previous iterations of the study protocol allowed the use of contraceptives that did not meet the criteria of a failure rate of less than 1% per year. The current protocol revision updates the entry criteria to limit the acceptable methods of contraceptives to be compliant with a failure rate of less than 1% per year. Additionally, protocol version 5 lacked clarity on the combination of tablets to achieve the most appropriate weight adjusted dose. The current protocol revision includes dosing charts describing the combination of tablets to achieve the most accurate target dose as well as an alternate dose minimizing the number of tablets while remaining accurate to maximize participant compliance.

The three most important modifications to the protocol include a reduction of the sample size by elimination of several dose cohorts in both the Single-Dose (SD) and Multiple-Dose (MD) Phases, a reduction in the duration of the MD Phase from 8 to 4 weeks, and a reintroduction of an OLE Phase following the MD Phase. Other changes include updating the Introduction, including the literature review and clinical history with OCA, changing the eligibility criteria (inclusion and exclusion criteria) to enroll more stable participants, and updating the Drug-induced Liver Injury (DILI) Algorithm and safety tables according to advisory board suggestions.