(Expected) side effects

This study will evaluate the safety, tolerability and influence on itching, bile acids and liver enzyme changes in patients with PBC (Primary Biliary Cirrhosis) treated with A4250

A4250PBCpruritus (EudraCT 2014-004070-42) is an open-label exploratory study.

The primary objective of this study is to assess the safety and tolerability of A4250, 1.5 - 3 mg orally during a four-week treatment period, in patients with PBC and cholestatic pruritus, as determined by the occurrence of treatment-emergent serious adverse events (SAEs).

Other safety objectives of this study include assessment of the safety and tolerability of A4250 during a four-week treatment period, as determined by the occurrence of treatment-emergent adverse events (AEs) and changes in other safety parameters including liver and kidney function tests and vital signs.

Exploratory efficacy objectives of this study are to demonstrate the efficacy of A4250 orally on pruritus variables and on QoL and lysophosphatidic acid formation as well as evaluation of changes in pharmacodynamic parameters of bile acid metabolism such as serum and fecal bile acids, C4 and fibroblast growth factor 19 (FGF19) assessments and assessment of surrogate markers of cholestatic liver disease such as alkaline phosphatase, transaminases and bilirubin.

Major Inclusion Criteria:

• Diagnosis of PBC or PBC-Autoimmune hepatitis overlap as established according to American Association for the Study of Liver Diseases/European Association for the Study of Liver (AASLD/EASL) definitions. Definite or probable PBC diagnosis, as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:
• History of elevated alkaline phosphatase (ALP) levels (>1.67 ULN) for at least 6 months prior to Day 1
• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)
• Liver biopsy consistent with PBC;
• Ursodeoxycholic acid (UDCA) non-responders defined as >6 months of UDCA and at the time of enrolment a serum ALP >1.67 ULN;
• Laboratory markers of cholestasis identified within 3 months of Visit 1;
• Treatment with cholestyramine at a dose >4g BID or colestipol > 5mg for at least 3 months;
• The patient has a VAS-Itch of at least 30 mm during the day before baseline (Visit 2);
• The patient is a male or non-pregnant female ≥18 years of age and ≤80 years of age with body mass index (BMI) ≥18.5 but <35 kg/m2;

Major Exclusion Criteria:

• Any condition that, in the opinion of the Investigator constitutes a risk for the patient or a contraindication for participation and completion of the study, or could interfere with study objectives, conduct, or evaluations;
• Jaundice of extrahepatic origin;
• The patient has a structural abnormality of the GI tract;
• The patient has a known, active, clinically significant acute or chronic infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti infectives within 4 weeks of treatment start (study day 1) or completion of oral anti-infective treatment within 2 weeks prior to start of screening period;
• The patient has unexplained and clinically significant GI alarm signals (e.g., lower GI bleeding or heme-positive stool, iron-deficiency anaemia, unexplained weight loss) or systemic signs of infection or colitis;