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 informed consent.
• Willing and able to give written informed consent and to comply with the requirements of the study.
• Definite or probable PBC diagnosis as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:

• Documented history of elevated ALP levels ≥1.67×ULN of the local reference range.
• Documented history of positive antimitochondrial antibodies (AMA) titer or positive PBC-specific antibodies (anti-GP210 or anti-SP100 or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]).
• 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 a stable dose for >3 months prior to Screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to Screening). Intolerance to UDCA is defined as participants unable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported gastrointestinal symptoms such as diarrhea and abdominal pain.
• For participants receiving obeticholic acid (OCA), fenofibrate, or bezafibrate treatment 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 prior to Screening.
• For participants previously treated with bezafibrate or fenofibrate, and these agents were discontinued prior to screening, they must have been discontinued >3 months prior to Screening.
• Female participants of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥4 weeks before Randomization and must agree to continue strict contraception up to 90 days after the last dose of investigational medicinal product (IMP).

• For the purposes of this trial, women of childbearing potential are defined as "Fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy."
• Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female participants who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state. Confirmation with more than one FSH measurement is required.
• Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods are:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associate with the study treatments). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
• Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomization before dosing.
• Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method. This requirement begins at the time of informed consent and ends 90 days after receiving the last dose of IMP.
• Male participants must be willing not to donate sperm, and female study participants must be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP.

Exclusion criteria

• A positive pregnancy test or breastfeeding for female participants.
• Any historical or current hepatic decompensation event defined as variceal/portal hypertension 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 or current model for end stage liver disease (MELD) score of ≥12 unless the participant is on anticoagulant therapy, or a Child-Pugh Score of ≥6.
• Cirrhosis with complications, including history or presence of hepatocellular carcinoma.
• Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screening serum 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 anticoagulant therapy. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the participant may be eligible for the study.
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2, as calculated by the central laboratory using the chronic kidney disease-epidemiology collaboration (CKD- EPI) equation.
• Thyroid-stimulating hormone >ULN at Screening. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at 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 of hepatitis C, with a sustained virologic response for at least 6 months prior to Screening], active hepatitis B [HBsAg positive], nonalcoholic steatohepatitis [NASH], alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis-PBC overlap syndrome, primary sclerosing cholangitis, Gilbert's Syndrome).
• Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's disease).
• Known history of human immunodeficiency virus (HIV) infection.
• Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator).
• Positive urine drug screen (if not due to prescriptional use of a concomitant medication, as confirmed by the Investigator) at Screening. Participants on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not exclusionary and may be allowed if the prescription and diagnosis are 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 5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an interventional clinical trial.
• Evidence of any of the following cardiac conduction abnormalities: A QTc Fridericia interval >450 milliseconds for males or >470 milliseconds for females, as calculated by the central reader. Participants with a second- or third-degree atrioventricular block 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 nonmelanoma skin cancer.
• The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Screening Visit 1.
• A history of bone marrow disorder including aplastic anemia, or any current marked anemia defined as hemoglobin <10.0 g/dL.
• Prior treatment with setanaxib or participation in a previous setanaxib clinical trial.
• Unstable cardiovascular disease.
• Presence of any laboratory abnormality or condition that, in the opinion of the Investigator, 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 or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation.
• Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebo compounds.