Safety and Tolerability of A3907 in Primary Sclerosing Cholangitis

Exclusion Criteria

• •1. Presence of documented secondary sclerosing cholangitis, small duct PSC, known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis or other causes of chronic liver disease
• •2. Arm 1-3 Only: Biliary intervention within 3 months prior to study enrollment or planned.
• •3. Arm 4 Only: Planned Biliary intervention between the Screening Period and baseline.
• •4. Presence of alternative causes of chronic liver disease, including alcohol-associated liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis, autoimmune hepatitis, or active hepatitis B or C.
• •5. IBD with uncontrolled moderate to severe activity and/or on treatment with any immunosuppressive, immunomodulator, or biologic agent for treatment of IBD (i.e. azathioprine, 6 mercaptopurine, tacrolimus, methotrexate, infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod). Treatment with corticosteroids (including budesonide, budesonide MMX and beclomethasone) in the previous 4 weeks.
• •6. History of human immunodeficiency virus infection or any other known relevant infection (e.g. tuberculosis).
• •7. History of ileectomy, colostomy or colectomy.
• •8. History of malignancy, including hepatocellular carcinoma and cholangiocarcinoma within the past 10 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
• •9. Alpha-fetoprotein (AFP) \> 20 ng/mL (at the Screening Visit) with 4-phase liver CT or MRI suggesting presence of liver cancer.
• •10. History of transplants, including liver transplantation, or currently on active transplantation list (Arms 1 3). Arm 4 may be on an active liver transplantation list.
• •11. Current or a history of hepatic decompensation events including, but not limited to ascites, encephalopathy, or history of esophageal variceal bleeding.
• •12. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis.
• •13. Small duct PSC (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography) without large duct PSC.
• •14. Liver cirrhosis as assessed by any of the following:
• •1. historical liver histology.
• •2. liver stiffness measurement, assessed by FibroScan (FibroScan value \> 14.4 kPa), in addition to clinical assessment and biochemical markers at the discretion of the investigator.
• •3. signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal haemorrhage, and/or hepatic encephalopathy).
• •15. History of bacterial cholangitis within 60 days prior to the Screening Period, or if the patient is on antibiotics for prophylaxis of recurrent cholangitis.
• •16. Females who are pregnant, lactating, or breast feeding.
• •17. History of alcohol or substance abuse in the previous 2 years. Patients must agree to refrain from illicit drug (including marijuana) and alcohol use during the study.
• •18. Hypersensitivity to investigational medicinal product (A3907) and its excipients.
• •19. Presence of any contraindication for undergoing MRCP (e.g. pacemaker).
• •20. Any other condition or abnormality which, in the opinion of the investigator (or designee), may compromise the safety of the patient or interfere with the patient participating in, or completing the study.
• •21. Administration of medications that slow gastrointestinal motility.
• •22. Treatment with rifampicin.
• •23. Exposure to oral drugs that are strong inhibitors or inducers of CYP3A4 enzymes (e.g. grapefruit juice, ritonavir, itraconazole, ketoconazole, troleandomycin, rifampin, St John's wort, etc.) within 14 days prior to the Screening Period, or 5 half-lives of the drug, whichever is longer.
• •24. Exposure to oral drugs that are substrates of CYP3A4 enzymes (e.g. codeine, ciclosporin \[cyclosporin\], diazepam, etc.) during the study.
• •25. Treatment with vitamin D or fibrates, unless patient is on a stable dose ≥ 6 months prior to baseline.
• •26. Exposure to an investigational drug, biologic agent, or medical device within 30 days prior to the Screening Period, or 5 half-lives of the study agent, whichever is longer.
• •27. Platelet count \< 150 000/mm3
• •28. Albumin level \< 3.0 g/dL
• •29. INR \> 1.3 (the patient may be treated with vitamin K intravenously, and if INR is ≤ 1.3 at resampling, the patient may be enrolled).
• •30. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget's disease). A GGT or ALP isoenzymes should be obtained for confirmation of biliary origin;
• •31. Glomerular filtration rate \[GFR\] \< 60 mL/min/1.73 m2