A Study of CS0159 in Patients With PBC With Inadequate Response or Intolerance to UDCA

Exclusion Criteria39

• Previous exposure to CS0159;
• History of allergy to the CS0159 or its excipients or drugs of similar chemical classes;
• Advanced PBC as defined by the Rotterdam criteria (albumin\<1.0×LLN AND TB \>1.0× ULN);
• Patients who have had clinically significant complications of hepatic cirrhosis with clinically significant portal hypertension (CSPH), including the following:
• History of liver transplantation, current placement on a liver transplant list, current MELD -Na score ≥ 12;
• History of confirmed esophagogastric variceal bleeding;
• Clinically significant ascites requiring intervention, such as sodium restriction, diuretic therapy, or therapeutic paracentesis;
• Any secondary complications resulting from clinically significant ascites, such as spontaneous bacterial peritonitis, hepatorenal syndrome, or hepatic hydrothorax;
• Hepatic encephalopathy requiring drug therapy;
• Portopulmonary hypertension and/or hepatopulmonary syndrome;
• Hepatocellular carcinoma;
• Other concomitant liver disease including:
• Autoimmune hepatitis (AIH) (simplified AIH diagnostic score \>6), PBC-AIH overlap syndrome, or overlap with other autoimmune liver diseases
• Positive HBsAg or positive HCV RNA (tested for in case of known cured HCV infection or positive HCV Ab at screening)
• Primary sclerosing cholangitis (PSC)
• History or clinical evidence of Alcoholic liver disease (ALD)
• Biopsy confirmed Non-alcoholic steatohepatitis (NASH)
• Gilbert's Syndrome
• History or evidence of alpha-1 antitrypsin deficiency
• Liver stiffness measured by transient elastography (TE) \> 16.9 Kpa;
• Patient has a positive test for HIV at screening, or active syphilis \[defined as positive Treponema pallidum antibody (TP Ab) and a rapid plasma reagin (RPR) card test titer ≥1:8; for low titers (e.g., 1:1 or 1:2), clinical judgment is required to determine if it is active syphilis\];
• Administration of the following medications are prohibited as specified below:
• Use of medications, food, and drinks (e.g., grapefruit juice) that are strong or moderate CYP3A4 inhibitors or inducers within 14 days before randomization;
• Use of P-glycoprotein (P-gp) substrate drugs within 14 days before randomization;
• months prior to randomization: fibrates, glitazones, seladelpar and elafibranor.
• months prior to randomization: obeticholic acid (OCA), azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, systemic corticosteroids and budesonide (˃2 weeks); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin).
• Patients with systemic treatment for pruritus (e.g., with bile acid sequestrants \[BAS\]) within 3 months prior to randomization.
• months prior to randomization: antibodies or immunotherapy directed against ILs or other cytokines or chemokines;
• Medical conditions that may cause non-hepatic increases in ALP (e.g., paget's disease);
• Patients with severe arrhythmia, or a QTcF interval corrected by Fridericia's formula ≥450 ms (males) or ≥470 ms (females) at screening \[Fridericia's formula: QTcF=QT/(RR\^0.33)\];
• History or presence of any disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the large intestine, eg, inflammatory bowel disease, prior or planned (during the study period) bariatric surgery (such as gastroplasty, roux-en-Y gastric bypass);
• History of malignancy (except for those with a disease-free survival of ≥5 years) or currently under evaluation for malignancy; except for cured squamous or non-invasive skin basal cell carcinoma and cervical carcinoma in situ;
• Drug abuse or heavy alcohol use from 12 months prior to randomization throughout the entire clinical study period. Heavy alcohol use is defined as an average weekly alcohol consumption of more than approximately 7 standard drinks for females and more than approximately 14 standard drinks for males. One standard drink is defined as any beverage containing 14g of pure alcohol, such as 12 oz/360 mL of beer (5% alcohol), 8 oz/240 mL of malt liquor (7% alcohol), 5 oz/150 mL of wine (12% alcohol), or 1.5 oz/45 mL of distilled spirits (40% alcohol);
• Poor blood pressure control is indicated after treatment by a systolic pressure greater than 160 mmHg or diastolic pressure greater than 100 mmHg during screening;
• Pregnancy, planned pregnancy, lactation;
• Treatment with any other investigational therapy or device within 30 days or within 5 half-lives, whichever is longer, prior to screening;
• Mental instability or incompetence that may compromise the validity of informed consent or ability to adhere to study requirements;
• Any other condition(s) that would compromise the safety of the patient or compromise the quality of the clinical study, as judged by the investigator.
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