The protocol was amended to reflect the following key changes, which were incorporated in the protocol and protocol summary where applicable: 1. Based on FDA requests, changes were made to the PRO measures used in the study and Key Secondary Endpoints. 2. The 2 errors that had been identified and described in the protocol clarification letter dated 05 July 2021 were corrected (IMP was not to be dispensed at the Week 104/Year 2 Visit, and for PBC 40, addition that 3 additional questions related to general health and well-being were part of the questionnaire). 3. Changes implemented in the local UK, Spanish, Austrian, and German revised protocols were incorporated in the global amendment. This includes an added on-site visit at Week 4. 4. Language on product complaint reporting was added. 5. Changes to the Concomitant Medication and Procedures Section 6.7 based on a request from the Belgian Regulatory Authority. In addition, the following non-substantial revisions and corrections have been incorporated in the protocol and protocol summary where applicable: 1. Genkyotex Suisse SA has been renamed Calliditas Therapeutics Suisse SA effective 01 April 2022. 2. Clarification of Inclusion Criterion #10b 3. The exclusion criteria numbering has been revised to ensure alignment and consistency across all versions of the protocol. 4. Background Section 1.1 includes minor revisions to align with the Investigator Brochure, Edition 12.0.

The protocol has been amended to reflect the following key changes, which have been incorporated in the protocol and protocol summary where applicable: 1. If futility is not met for the setanaxib 1200 mg/day and 1600 mg/day doses, the Independent Data Monitoring Committee (IDMC) will select one dose for Stage 2. Ongoing patients who are receiving the selected dose will continue the study at the same dose. Ongoing patients who are receiving a dose that is discontinued will have their dose escalated/de-escalated to the selected dose. Patients enrolled after the interim analysis will be randomized to setanaxib (dose selected by the IDMC), or placebo, according to a 1:1 randomization ratio, up to full enrollment. 2. An analysis of the proportion of patients with alkaline phosphatase (ALP) reduction of ≥70% reduction from Baseline at Week 52 and changes in markers of cholestasis as assessed by proportion of patients at Week 52 with ALP reduction to <1.5×upper limit of normal (ULN) and total bilirubin ≤1×ULN and with a ≥40% ALP reduction from Baseline have been added following recommendations from the FDA and the European Medicines Agency, respectively. 3. Inclusion criterion 5 was updated to allow patients with liver stiffness of ≥8.0 kPa (previously ≥8.8 kPa). 4. The exploratory endpoint of changes in markers of cholestasis has been upgraded to secondary endpoint (as abovementioned). 5. The list of prohibited medications was updated with regards to corticosteroid use and removal of biologics.

The study design was revised to a Phase 2b study with the following key changes: 1a. Revision of primary and secondary objectives, ie, the decrease in ALP from Baseline at 24 weeks as primary objective and no further selection of a key secondary parameter. b. Regarding the new primary endpoint: bi. A new sample size calculation was performed that resulted in 60 to 70 patients instead of 318, and a reduced number of sites (80 to 130). bii. The statistical methods planned to be applied were revised. c. Reduction of the Double-blind Treatment Period from 1 year to 24 weeks. d. The rationale for a 52-week Extension Phase Treatment Period was no longer applicable; therefore, this period as well as the 12-week Follow up Period were removed. e. With the reduction of the Double-blind Treatment Period to 24 weeks, the optional liver biopsy at Week 52 was removed; it was not expected to find effects at an earlier time point. f. The rationale for an interim analysis, ie, the assessment of futility and dose selection, was no longer applicable; therefore, the interim analysis was removed. The study design was no longer adaptive. g. Corresponding to changes to the overall study design, the statistical methods planned to be applied were revised, including the definition of the FAS, handling of missing data values, the plans for sensitivity and supplementary analyses. 2. Exclusion criterion 18 was removed. 3. The criterion for premature discontinuation of the IMP was amended for patients with a severe cardiac condition or QT prolongation or an increase in QTc greater than 60 milliseconds from Baseline. Patients who were following the previous protocol schedule (protocol version 4) and were already beyond Week 24 were to permanently discontinue IMP as soon as possible and have an End-of-Treatment Visit 30 days after their last dose.