A Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Liver Stiffness

Inclusion Criteria:

• Male or female participant aged ≥18 years, inclusive at the time of informedconsent.

• Willing and able to give written informed consent and to comply with therequirements of the study.

• Definite or probable PBC diagnosis as demonstrated by the presence of ≥2 of thefollowing 3 diagnostic factors:

• Documented history of elevated ALP levels ≥1.67×ULN of the local referencerange.

• Documented history of positive antimitochondrial antibodies (AMA) titer orpositive PBC-specific antibodies (anti-GP210 or anti-SP100 or antibodiesagainst the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenasecomplex]).

• Historical liver biopsy consistent with PBC.

• Serum ALP ≥1.67×ULN at Screening.

• Liver stiffness measured by transient elastography (FibroScan®) of ≥8.8 kilopascals (kPa) and an interquartile range over median ratio (IQR/med) of ≤30% at Screening,are taken with the results expressed in kilopascals).

• Ursodeoxycholic acid (UDCA) prescriptional dose use for the past 6 months (at astable dose for >3 months prior to Screening) OR intolerant to UDCA (last dose ofUDCA >3 months prior to Screening). Intolerance to UDCA is defined as participantsunable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due tofrequently reported gastrointestinal symptoms such as diarrhea and abdominal pain.

• For participants receiving obeticholic acid (OCA), fenofibrate, or bezafibratetreatment for at least 6 months and stable dose for >3 months prior to Screening.

• For participants intolerant to OCA, OCA must have been discontinued >3 months priorto Screening.

• For participants previously treated with bezafibrate or fenofibrate, and theseagents were discontinued prior to screening, they must have been discontinued >3months prior to Screening.

• Female participants of childbearing potential must use a highly effective method ofcontraception to prevent pregnancy for ≥4 weeks before Randomization and must agreeto continue strict contraception up to 90 days after the last dose ofinvestigational medicinal product (IMP).

• For the purposes of this trial, women of childbearing potential are defined as "Fertile, following menarche and until becoming postmenopausal unlesspermanently sterile. Permanent sterilization methods include hysterectomy,bilateral salpingectomy and bilateral oophorectomy."

• Postmenopausal state is defined as no menses for 12 months without analternative medical cause. In female participants who are not using hormonalcontraception or hormonal replacement therapy but with suspected menopause andless than 12 months of amenorrhea, a high follicle stimulating hormone (FSH)level in the postmenopausal range will be required at Screening to confirm apostmenopausal state. Confirmation with more than one FSH measurement isrequired.

• Highly effective contraception is defined as methods that can achieve a failurerate of less than 1% per year when used consistently and correctly. Thesemethods are:

• Combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation (oral, intravaginal, ortransdermal)

• Progestogen-only hormonal contraception associated with inhibition ofovulation (oral, injectable, or implantable)

• Intrauterine device

• Intrauterine hormone-releasing system

• Bilateral tubal occlusion

• Vasectomized partner

• Sexual abstinence (refraining from heterosexual intercourse during theentire period of risk associate with the study treatments). Thereliability of sexual abstinence needs to be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle ofthe participant. Periodic abstinence (calendar, symptothermal,post-ovulation methods), withdrawal (coitus interruptus), spermicidesonly, and lactational amenorrhea method are not acceptable methods ofcontraception. Female condom and male condom should not be used together.

• Female participants of childbearing potential must have a negative serum pregnancytest at Screening and a negative urine pregnancy test at Baseline/Randomizationbefore dosing.

• Male participants with female partners of childbearing potential must be willing touse a condom and require their partner to use a highly effective contraceptivemethod. This requirement begins at the time of informed consent and ends 90 daysafter receiving the last dose of IMP.

• Male participants must be willing not to donate sperm, and female study participantsmust be willing not to donate eggs, from Baseline until 90 days after the last doseof IMP.

Exclusion Criteria:

• A positive pregnancy test or breastfeeding for female participants.

• Any historical or current hepatic decompensation event defined as variceal/portalhypertension bleed and/or hepatic encephalopathy, spontaneous bacterial peritonitis,ascites requiring treatment, or liver transplantation list inclusion.

• History of liver transplantation, current placement on a liver transplant list orcurrent model for end stage liver disease (MELD) score of ≥12 unless the participantis on anticoagulant therapy, or a Child-Pugh Score of ≥6.

• Cirrhosis with complications, including history or presence of hepatocellularcarcinoma.

• Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screeningserum albumin must be within the reference range.

• Plasma alanine aminotransferase (ALT) >3×ULN and/or aspartate aminotransferase (AST) >3×ULN.

• International normalized ratio (INR) >1.2 unless participant is on anticoagulanttherapy. One repeat blood sampling (with analysis by the central laboratory) can beperformed at the discretion of the Investigator at Screening Visit 2 forparticipants who meet this exclusion criterion at Screening Visit 1. If thisexclusion criterion is not met at Screening Visit 2, the participant may be eligiblefor the study.

• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2, as calculated bythe central laboratory using the chronic kidney disease-epidemiology collaboration (CKD- EPI) equation.

• Thyroid-stimulating hormone >ULN at Screening. One repeat blood sampling (withanalysis by the central laboratory) can be performed at the discretion of theInvestigator at Screening Visit 2 for participants who meet this exclusion criterionat Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2,the participant may be eligible for the study.

• Competing etiology for liver disease (eg, hepatitis C [unless effectively cured ofhepatitis C, with a sustained virologic response for at least 6 months prior toScreening], active hepatitis B [HBsAg positive], nonalcoholic steatohepatitis [NASH], alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis-PBCoverlap syndrome, primary sclerosing cholangitis, Gilbert's Syndrome).

• Medical conditions that could cause nonhepatic increases in ALP (eg, Paget'sdisease).

• Known history of human immunodeficiency virus (HIV) infection.

• Surgery (eg, stomach bypass) or medical condition that might significantly affectabsorption of medicines (as judged by the Investigator).

• Positive urine drug screen (if not due to prescriptional use of a concomitantmedication, as confirmed by the Investigator) at Screening. Participants on stablemethadone or buprenorphine maintenance treatment for at least 6 months prior toScreening Visit 1 may be included in the study. Medicinal cannabis and cannabidiolproducts are not exclusionary and may be allowed if the prescription and diagnosisare reviewed and approved by the Investigator.

• Participants receiving prohibited medications within 3 months of Screening Visit 1.

• Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 5half-lives of the IMP (if known) (whichever is longer) or current enrollment in aninterventional clinical trial.

• Evidence of any of the following cardiac conduction abnormalities: A QTc Fridericiainterval >450 milliseconds for males or >470 milliseconds for females, as calculatedby the central reader. Participants with a second- or third-degree atrioventricularblock are to be excluded.

• History of a malignancy within 5 years of Screening with the following exceptions:

• Adequately treated carcinoma in situ of the cervix.

• Adequately treated basal or squamous cell cancer or other localized nonmelanomaskin cancer.

• The occurrence of any acute infection requiring systemic antibiotic therapy withinthe 2 weeks prior to Screening Visit 1.

• A history of bone marrow disorder including aplastic anemia, or any current markedanemia defined as hemoglobin <10.0 g/dL.

• Prior treatment with setanaxib or participation in a previous setanaxib clinicaltrial.

• Unstable cardiovascular disease.

• Presence of any laboratory abnormality or condition that, in the opinion of theInvestigator, could interfere with or compromise a participant's treatment,assessment, or compliance with the protocol and/or study procedures.

• Any other condition which, in the opinion of the Investigator, constitutes a risk orcontraindication for the participation of the participant in the study, or thatcould interfere with the study objectives, conduct, or evaluation.

• Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebocompounds.