Overview

The present phase 1b/2 randomised, double-blind, placebo-controlled, two-part study is designed to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of two dose levels of golexanolone compared with placebo among subjects with a history of non-cirrhotic or Child-Pugh class A cirrhotic Primary Biliary Cholangitis (PBC) with clinically significant fatigue and cognitive symptoms on stable background standard of care (SoC) PBC medication. The objectives of this research study are to assess the safety and tolerability as well the pharmacokinetic (PK) characteristics of golexanolone administered 40 mg BID for 5 days in the target population (part A) and to assess the safety and tolerability, the effects of golexanolone on health-related quality of life (HRQoL), including fatigue, day-time sleepiness and cognitive function as well as Investigator's overall impression of treatment effect of 28 days twice per day (BID) treatment with two dose levels of golexanolone versus placebo (part B).

Eligibility

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