A Two-part Study to Investigate the Effects in Adults of Two Doses of Golexanolone in Patients With Primary Biliary Cholangitis (PBC) With Fatigue and Cognitive Dysfunction

Inclusion criteria

• Male and female subjects age ≥ 18 years
• Diagnosis of PBC based on the presence of ≥2 of 3 key disease characteristics
• Clinically significant fatigue defined for the purposes of this study as a PBC-40 fatigue domain score of ≥29 at screening
• Clinically significant cognitive symptoms, defined for the purposes of this study as a PBC-40 cognitive domain ≥16 at screening
• Stable PBC SoC therapy (if any),for at least 3 months prior to randomisation
• For all women of childbearing potential (WOCBP) a negative pregnancy test at screening and a negative urine dip-stick pregnancy test at baseline, prior to first dose of IMP
• WOCBP must be willing to use a contraceptive method with a failure rate of < 1% and agree to continue use of this method for the duration of the study and thereafter for 1 month after the last dosing of the IMP
• Females of non-childbearing potential must have documented tubal ligation or hysterectomy; or be post-menopausal
• Fertile male subjects must be willing to use condom and assure that their female partner will use contraceptive methods with a failure rate of < 1%
• Willing and able to give informed consent
• The subject should be judged by the Investigator to be lucid and oriented to person, place, time, and situation when giving the informed consent

Exclusion criteria

• Child-Pugh class B or C cirrhosis
• Clinical evidence of hepatic decompensation (e.g. current or prior HE, ascites, or variceal bleeding)
• History of hepatocellular carcinoma
• Bilirubin >1.5 x ULN
• Glomerular filtration rate (GFR) <35 mL/min/1.73m2
• Low Haemoglobin (HB), i.e. subjects with moderate/severe anaemia
• Low S-B12 or low P-folate
• Evidence of biliary obstruction
• Any positive result on screening for human immunodeficiency virus (HIV), or hepatitis B (serum hepatitis B surface antigen positive)
• Prolonged QTcF (>500 ms), or any clinically significant abnormality in the resting ECG, as judged by the Investigator (at screening)
• Concomitant disease characterised by chronic fatigue and/or cognitive impairment
• Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption
• Clinically significant sleep apnoea
• An uncontrolled thyroid disorder
• Subjects with a history of or currently active immune disorders (i.e. uncontrolled) other that PBC (including autoimmune disease) and/or diseases requiring immunosuppressive drugs
• Clinical diagnosis of autoimmune hepatitis overlap
• The presence, as judged by the Investigator, of clinically significant concomitant illness which would jeopardise safe participation in the study and /or the interpretation of study findings
• Regular use of prescribed or over the counter (OTC) medications known to cause fatigue or cognitive dysfunction
• Use of prohibited medications within 14 days prior to randomisation
• Anticipated change in PBC medication and/or significant medical or surgical intervention within the duration of the study
• Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week
• Administration of another new chemical entity or has participated in any other clinical study that included drug treatment with the last administration within 3 months prior to administration of IMP in this study
• Females who are pregnant, nursing or actively trying to conceive a child
• Expected inability to swallow the required number of IMP capsules at the applicable dose level
• History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator