Phase 2a Evaluation of Safety, Tolerability, and Pharmacokinetics of PLN-74809 in Patients With Primary Sclerosing Cholangitis (PSC)

Study Overview
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Brief Summary
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A Phase 2a, multicenter, randomized, double-blind, dose-ranging, placebo-controlled, study to evaluate the safety, tolerability, and PK of PLN-74809 in participants with primary sclerosing cholangitis and suspected liver fibrosis

Detailed Description
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Three-part study: Part 1 - 12-week treatment period evaluating 40 mg of PLN-74809 or matching placebo [Complete] Part 2 - 12-week treatment period evaluating two dose groups, 80 mg and 160 mg of PLN-74809 or matching placebo Part 3 - minimum 24-week, up to 48-week treatment period evaluating 320 mg of PLN-74809 or matching placebo

Official Title
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A Randomized, Double-blind, Dose-ranging, Placebo-controlled, Phase 2a Evaluation of the Safety, Tolerability, and Pharmacokinetics of PLN-74809 in Participants With Primary Sclerosing Cholangitis (PSC) and Suspected Liver Fibrosis (INTEGRIS-PSC)

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: PLN-74809
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established clinical diagnosis of large duct PSC based on an abnormal cholangiography as assessed by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and/or percutaneous transhepatic cholangiopancreatography (PTC) in the context of cholestatic liver chemistry Suspected liver fibrosis, as defined by liver stiffness measurement (LSM), assessed by ultrasound-based transient elastography (TE, FibroScan®) OR Enhanced Liver Fibrosis (ELF) Score OR Historical liver biopsy showing fibrosis without cirrhosis (by any scoring system) OR Magnetic resonance elastography (MRE) Serum ALP concentration within normal limits or > 1 times the upper limit of normal (ULN) Participants receiving treatment for IBD are allowed, if on a stable dose from screening and expected to remain stable for the duration of the study Serum AST and ALT concentration ≤ 5 times the upper limit of normal If receiving treatment with UDCA, therapy is at a dose of < 25 mg/kg/day, has been stable for at least 3 months before screening. Exclusion Criteria: Other causes of liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis Small duct PSC with no evidence of large duct involvement (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography) Presence of liver cirrhosis as assessed by liver histology, ultrasound-based liver stiffness measurement, ELF score, MRE, and/or signs and symptoms of hepatic decompensation (including but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy. Serum ALP concentration > 10 times the upper limit of normal.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo<br>|
| Experimental: PLN-74809 Dose Level 1<br>Dose: 40 mg; | Drug: PLN-74809<br>* PLN-74809<br>|
| Experimental: PLN-74809 Dose Level 2<br>Dose: 80 mg; PLN-74809 Dose Level 2 following PLN-74809 Dose Level 1 | Drug: PLN-74809<br>* PLN-74809<br>|
| Experimental: PLN-74809 Dose Level 3<br>Dose: 160 mg; PLN-74809 Dose Level 3 following PLN-74809 Dose Level 2 | Drug: PLN-74809<br>* PLN-74809<br>|
| Experimental: PLN-74809 Dose Level 4<br>Dose: 320 mg; PLN-74809 Dose Level 4 following PLN-74809 Dose Level 3 | Drug: PLN-74809<br>* PLN-74809<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events and laboratory abnormalities, as assessed by CTCAE v5.0 | Nature and proportion of AEs between PLN-74809 and placebo groups | 12-48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PLN-74809 plasma concentrations | Plasma PLN-74809 concentrations (total and unbound concentrations) at each sampling timepoint | 12-48 weeks |