A Study to Assess the Safety and Efficacy of LB-P8 in Patients With PSC

This is phase 2, randomized, double-blind, placebo-controlled, multicenter study to assess the safety and efficacy of LB-P8 in adult patients with primary sclerosing cholangitis(PSC).

* Part 1 will evaluate safety and tolerability of 2 pre-selected dose level of LB-P8 (low-dose\[1×10\^10 CFU/capsule\] and high dose \[1×10\^11 CFU/capsule\]) in adult patients with PSC. Part 1 plans to enroll a maximum number of 12 patients based on a "3+3" study design.
* Part 2 will evaluate safety and efficacy in adult patients with PSC. Eligible patients with PSC will be randomized in a 1:1:1 ratio to receive treatment with low-dose LB-P8(1×10\^10 CFU/capsule), high-dose LB-P8(1×10\^11 CFU/capsule) or matched placebo capsule. Part 2 plans to enroll and randomize 75 patients to obtain 60 evaluable patients.

• LB-P8 low-dose (Drug): One capsule QD (1×10\^10 CFU/day) oral administration
• LB-P8 high-dose (Drug): One capsule QD (1×10\^11 CFU/day) oral administration
• Placebo (Drug): One capsule QD oral administration

Primary outcomes

• Safety and tolerability of 2 different doses of LB-P8 [(Part 1) Up to 4 weeks of treatment from the Baseline]: Occurrence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) by CTCAE V5.0
• Safety and tolerability of LB-P8 [(Part 2) Up to 24 weeks of treatment from the Baseline]: Occurrence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) by CTCAE V5.0
• Mean percent change from baseline in Serum Concentrations of Alkaline Phosphatase (ALP) [(Part 2) Up to 24 weeks of treatment from the Baseline]

Secondary outcomes

• Change from baseline in ALP [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Percentage of patients who achieve ALP of <1.5 × upper limit of normal (ULN) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in enhanced liver fibrosis (ELF™) [(Part 2) Up to 24 weeks of treatment from the Baseline]: Hyaluronic acid, procollagen-3 N-terminal peptide, and a tissue inhibitor of metalloproteinase 1 will be assessed in blood for ELF test.
• Changes from baseline in biliary metrics (biliary strictures and dilatations) [(Part 2) Up to 24 weeks of treatment from the Baseline]: Biliary metrics (biliary strictures and dilatations) will be assessed by magnetic resonance cholangiopancreatography (MRCP)
• Changes from baseline in liver stiffness [(Part 2) Up to 24 weeks of treatment from the Baseline]: Liver stiffness will be measured by transient elastography (FibroScan®)
• Change from baseline in alanine aminotransferase (ALT) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in aspartate aminotransferase (AST) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in gamma glutamyl transferase (GGT) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in prothrombin time (PT) and partial prothrombin time (PTT) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in international normalized ratio (INR) [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in total and direct bilirubin [(Part 2) Up to 24 weeks of treatment from the Baseline]
• Change from baseline in fasting serum bile acid level [(Part 2) Up to 24 weeks of treatment from the Baseline]
• The percentage of patients who experience liver disease progression [(Part 2) Up to 24 weeks of treatment from the Baseline]: The percentage of patients who experience progression to cirrhosis, clinical decompensation rates, liver transplant, newly diagnosed cholangiocarcinoma, MELD score increase from <12 to >15 and Death from any cause

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Age: 18 to 75 years
* A diagnosis of PSC based on cholangiographic evidence of PSC in accordance with American Association for the Study of Liver Diseases (AASLD) guidelines
* ALP >1.5 times the ULN at screening
* PSC with or without IBD, such as ulcerative colitis or Crohn's disease
* If patients are being administered biologic or advanced therapeutic treatments, immunosuppressants, systemic corticosteroids, obeticholic acid, fibrates, or statins, they must be on a stable dose for ≥3 months prior to, and including, Day 0 and plan to remain on a stable dose throughout the study
* If patients are receiving ursodeoxycholic acid, they must be on a stable dose (not exceeding 23 mg/kg/day) for >3 months prior to screening
* Patient agrees to stop all probiotics for at least 2weeks prior to treatment
* Patient is unable to conceive and/or patient who's partner is unable to become pregnant and/or agree to use effective methods of contraception when engaging in heterosexual intercourse

Exclusion Criteria:

* Treatment with any investigational agents within 3 months or 5 half-lives, whichever is longer prior to treatment or during the study. Gene therapy or other long-lasting investigational agents with unknown half-life is not allowed
* History of a liver transplant or anticipated need for a liver transplant within 1 year
* Patients who show evidence of significant worsening of hepatic function will be excluded.
* Evidence of compensated or decompensated cirrhosis based on histology, relevant medical complications, or laboratory parameters
* Model for end-stage liver disease (MELD) score as below, unless the MELD is driven by anticoagulant therapy, vitamin deficiency, or kidney disease:
* MELD Score of >12 (decompensated cirrhosis) for Part 1 of the study
* MELD Score of >12 for Part 2 of the study
* Small-duct PSC (in the absence of large duct PSC)
* Secondary causes of sclerosing cholangitis including IgG4 associated sclerosing cholangitis
* Any history of cholangiocarcinoma, gallbladder cancer, or hepatocellular carcinoma
* History of any malignancy with lymph node or regional metastases within 5 years or current malignancy undergoing active treatment
* Patients who require chronic use of antibiotics, received antibiotics in the last 1 month, or received Rebyota or Vowst (applicable for patients with Clostridioides difficile infection)
* In patients with ulcerative colitis, partial Mayo score of >6 or, patients with Crohn's disease if CDAI of >220
* Chronic kidney injury
* Recent acute cholangitis (within 90 days)
* Patients with indwelling biliary drain (or stent), total proctocolectomy with ileal anal pouch, partial large bowel resections or history of small bowel resection
* Other causes of liver disease, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), AIH/PSC overlap syndrome, alpha-1-antitrypsin deficiency, viral hepatitis, iron overload syndrome, Wilson disease, nonalcoholic steatohepatitis, and/or alcohol related liver disease. Additionally, positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti HCV) (detectable HCV RNA in the serum), or human immunodeficiency virus antibodies (anti HIV)
* Active drug (known or suspected use of illicit drugs or drugs of abuse) or alcohol abuse disorder
* Female patients who are pregnant, nursing, or planning to become pregnant during the study
* Clinically significant and/or active infection
* Subjects with a greater degree of immunosuppression, as evidenced by Alsolute neutrophil count <500 cells/mL or in the investigator's judgement immunosuppressed and at higher risk of infection