The purpose of this study is to find out about the safety and how well the study intervention (elafibranor) works in participants with PBC. The participants in this study will have confirmed PBC with inadequate response or intolerance to UDCA, which is a medication used in the management and treatment of cholestatic liver disease.

PBC is a slowly progressive disease characterised by damage of the bile ducts in the liver, leading to a build-up of bile acids which causes further damage. The liver damage in PBC may lead to scarring (cirrhosis).

PBC may also be associated with multiple symptoms. Many patients with PBC may require a liver transplant or may die if the disease progresses and a liver transplant is not done. In this study all participants will receive a daily dose of elafibranor (the study intervention).

The main aim of this study is to determine if elafibranor reduces alkaline phosphatase (ALP) and total bilirubin levels. High ALP and bilirubin levels in the blood can indicate liver disease.

There will be 4 periods in this study: A screening period (up to 10 weeks) to assess whether the participant can take part. A treatment period (52 weeks) where all eligible participants will receive elafibranor. A variable treatment extension period (2-5 years) from End Of Treatment (EOT) period up to the commercial availability of elafibranor in Japan. A follow-up period (4 weeks) where participants' health will be monitored.

Participants will undergo blood sampling, urine collections, physical examinations, clinical evaluations, electrocardiograms (ECG: recording of the electrical activity of heart), ultrasound examinations (a non-invasive test that passes a probe over skin to look at the bladder, urinary tract, and liver), and Fibroscan® examinations (to measure stiffness of the liver). They will also be asked to fill in questionnaires. Each participant will be in this study for up to approximately 6 years

Inclusion Criteria:

• Must have provided written informed consent and agree to comply with the study protocol.
• Japanese male or female participants aged 18 to 75 years inclusive at Screening Visit 1 (SV1).
• PBC diagnosis as described in the study protocol
• ALP ≥1.67×ULN (mean value based on samples collected at SV1 and SV2).
• TB ≤2×ULN at SV1 and SV2.
• Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS) during each of the 7-day intervals in the 14 days prior to visit (V)1, for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to V1.
• Participants taking UDCA for at least 12 months (stable dose ≥3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for ≥3 months) prior to screening (per country standard-of-care dosing).
• If on colchicine, must be on a stable dose for ≥3 months prior to screening.
• Medications for management of pruritus (for example, cholestyramine, rifampicin, naltrexone, sertraline or nalfurafine hydrochloride) must be on a stable dose for ≥3 months prior to screening.
• Participants taking statins or ezetimibe must be on a stable dose for ≥2 months prior to screening.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

Exclusion Criteria

• History or presence of other concomitant liver disease

• Participants with known cirrhosis who have a Child-Pugh B or C classification.

• Participants with cirrhosis with Child-Pugh A classification are allowed.

• History or presence of clinically significant hepatic decompensation,

• Medical conditions that may cause non-hepatic increases in ALP (for example, Paget's disease) or which may diminish life expectancy to <2 years, including known cancers.

• Known malignancy or history of malignancy within the last 5 years, with the exception of local, successfully treated basal cell carcinoma or in-situ carcinoma of the uterine cervix.

• Participant has a positive test for human immunodeficiency virus (HIV) Type 1 or 2 at screening, or participant is known to have tested positive for HIV.

• Evidence of any other unstable or untreated clinically significant immunological, endocrine, haematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator; other clinically significant medical conditions that are not well controlled.

• History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for men, and more than 20 g pure alcohol per day for women, or other substance abuse within 1 year prior to SV1.

• For female participants: known pregnancy, or has a positive serum pregnancy test, or breastfeeding.

• Administration of the following medications are prohibited as specified below:

  1. 1 month prior to screening: fibrates.
  2. 2 months prior to screening: glitazones.
  3. For participants with previous exposure to obeticholic acid (OCA), OCA should be discontinued 3 months prior to screening.
  4. 3 months prior to screening: azathioprine, cyclosporine (systemic), methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyldopa, sodium valproate/valproic acid isoniazid, or nitrofurantoin).
  5. 12 months prior to screening: antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or chemokines.

• Participants who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or 5 half-lives, whichever is longer, prior to screening; for participants with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening.

• Participants with previous exposure to elafibranor.

• SV1 or SV2 value ALT and/or AST >5×ULN.

• For participants with aminotransferases or TB >ULN at SV1, variability (between SV1 and SV2) of aminotransferases or TB >40%.

• SV1 value albumin <3.0 g/dL.

• Severely advanced participants according to Rotterdam criteria (TB >ULN and albumin <LLN).

• SV1 international normalised ratio (INR) >1.3 due to altered hepatic function.

• SV1 creatine phosphokinase (CPK) >2×ULN.

• SV1 serum creatinine >1.5 mg/dL.

• Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with markers of kidney failure damage or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) calculated by modification of diet in renal disease study (MDRD).

• SV1 platelet count <150×103/μL.

• Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) imaging suggesting presence of liver cancer.

• Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor tablet.

• Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications.

Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and/or EU.

Further details on Ipsen's sharing criteria and process for sharing are available here (https://www.ipsen.com/science/clinical-trials/clinical-data-transparency/).