Primary sclerosing cholangitis (PSC) MedDRA version: 20.1 Level: LLT Classification code 10036732 Term: Primary sclerosing cholangitis System Organ Class: 100000004871
Conditions
Interventions
Product Name: PLN-74809
Product Code: PLN-74809
Pharmaceutical Form: Tablet
INN or Proposed INN: Not yet established
CAS Number: 2376257-44-0
Current Sponsor code: PLN-74809-000
Concentration unit: mg
Sponsors
Pliant Therapeutics, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: General and Administrative 1. Aged 18 to 75 years, inclusive. 2. Female participants of childbearing potential (ovulating or premenopausal and not surgically sterile) and male participants with sexual partners of childbearing potential must agree to use highly effective methods of birth control during their participation in the study and for 30 days for female participants and 90 days for male participants and female partners of male participants after the last administration of study drug. Highly effective methods of birth control are defined as those with 99% or greater efficacy. 3. Female participants of nonchildbearing potential must be either surgically sterile (defined as hysterectomy, bilateral tubal ligation, salpingectomy and/or bilateral oophorectomy at least 6 months prior to screening) or postmenopausal (defined as spontaneous amenorrhea for at least 2 years with a follicle-stimulating hormone [FSH] level in the postmenopausal range at screening). 4. Participants must agree to abstain from sperm or egg donation through 90 or 30 days, respectively, after administration of the last dose of study drug. 5. Able to understand the purpose and procedures that are involved in the study and willing to sign a written informed consent form. Primary Sclerosing Cholangitis Diagnosis 6. 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. 7. Serum alkaline phosphatase concentration >1.5 times the upper limit of normal (ULN). 8. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) concentration =5 × ULN. 9. Serum total bilirubin =1.5 × ULN, in the absence of Gilbert's syndrome or hemolysis. 10. Suspected liver fibrosis, as defined by liver stiffness measurement (LSM) =8 kPa but =14.4 kPa, assessed by ultrasound-based transient elastography (TE, FibroScan®). Note: participants with LSM <8 kPa and documented evidence of liver fibrosis by histology (any severity except cirrhosis; any staging system) may be eligible, pending consultation with the Medical Monitor. 11. Platelet count =150,000/mm3. 12. Albumin =3.3 g/dL. 13. International normalized ratio (INR) =1.3 in the absence of anticoagulant therapy. 14. Serum carbohydrate antigen 19-9 (CA19-9) value =130 U/mL. Prior and Concomitant Medications 15. 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, will remain stable from screening through Day 1 (baseline), and is expected to remain stable for the duration of the study. 16. If receiving allowed concomitant medications for the treatment of IBD, therapy must be stable from screening and expected to remain stable for the duration of the study. Medical History and Comorbid Conditions 17. Participants with IBD must have had a colonoscopy showing no evidence of dysplasia within no more than 18 months before screening. 18. Participants with IBD must have no evidence of active disease and a partial Mayo score of <2, with a score of <1 on the Rectal Bleeding domain, between screening through Day 1. 19. Participants with IBD who are receiving treatment with biologics, including tumor necrosis factor-alpha (TNF-a) inhibitors and/or vedolizumab, immunosuppressive agents, or corticoste
Exclusion criteria
Exclusion criteria: Primary Sclerosing Cholangitis Diagnosis 1. Other causes of liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically. 2. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis. 3. Small duct PSC (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography). Liver Disease Status 4. Presence of a clinically significant dominant stricture based on the combination of radiological, biochemical, and clinical features. 5. Presence of a percutaneous drain or bile duct stent. 6. Serum alkaline phosphatase (ALP) concentration >10 times ULN. 7. Worsening of liver disease, defined as 2 consecutive ALP, ALT or AST measurements obtained >2 weeks apart during the screening period that vary by >30%. 8. Ascending cholangitis within 60 days of screening, as assessed clinically. 9. IgG4-associated cholangitis. 10. Positive anti-mitochondrial antibody. 11. Presence of liver cirrhosis as assessed by historical liver histology, ultrasound-based liver stiffness measurement (FibroScan® value >14.4 kPa), and/or signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy). 12. Presence of hepatic impairment, end-stage liver disease, and/or a model for end-stage liver disease (MELD) score =15. 13. Prior or planned liver transplantation during the study. Medical History and Comorbid Conditions 14. Presence of end-stage renal disease that requires dialysis. 15. History, current clinical or radiological suspicion, or diagnosis of cholangiocarcinoma, other hepatobiliary malignancy, colorectal cancer, or other abdominal malignancy at any time. 16. Human immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, and/or hepatitis C virus infection, with the exception of those who have been successfully treated for hepatitis C infection and have achieved sustained virologic response for =1 year 17. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or treated cervical carcinoma in situ. 18. Active infection that required antibiotic or antifungal therapy within 30 days before screening. 19. History of unstable or deteriorating cardiac disease within the previous 6 months, including, but not limited to: a. Unstable angina pectoris or myocardial infarction b. Congestive heart failure requiring hospitalization c. Uncontrolled clinically significant arrhythmias d. Clinically significant electrocardiogram (ECG) abnormalities, including but not limited to, QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 msec for males or >460 msec for females at the Screening visit (including Day -1) or prior to administration of the initial dose of study drug. 20. Surgery within the 4 weeks before administration of study drug. Prior and Concomitant Medications 21. Currently receiving and expected to remain on treatment during the study with: potent and concomitant inhibitors or inducers of CYP3A4, 2C9 and 2C19 (i.e., simultaneous inhibition or induction of all 3 CYP isoforms); potent inhibitors or inducers of P-gp, BCRP or OATP1B1/1B3 transporters; digoxin (a P-gp substrate with a narrow therapeutic window). 22. Current treatment or anticipated need for treatment with immunomodulating agents (such as interleukins and interferons),
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of PLN-74809 following daily administration for up to 12 weeks in participants with PSC;Secondary Objective: To assess the pharmacokinetics (PK) of PLN-74809 in participants with PSC. ;Timepoint(s) of evaluation of this end point: Week 16;Primary end point(s): The primary endpoint is the nature and proportion of AEs between PLN-74809 and placebo groups (descriptive). Safety data from all participants who received at least one dose of study drug will be incorporated into the final safety analysis. AEs will be collected from the time the participant signs the ICF until the last study visit. Treatment-emergent adverse events (TEAEs) are defined as AEs that emerged or worsened in severity after the first administration of study drug. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). All AEs will be graded for severity per the CTCAE grading scale and listed by participant and summarized by last treatment taken at onset of AE. All AEs will be listed by participant and summarized by last treatment taken at onset of AE. The incidence of AEs, the incidence of TEAEs, the incidence of treatment-related AEs, and the severity of AEs will be summarized by system organ class, preferred term, and maximum severity. In cases where a participant reports multiple occurrences of the same event (preferred term), the greatest severity will be included in the summary. The number and percentage of participants with SAEs and treatment-related SAEs and participants who withdraw prematurely due to an AE will be tabulated by study treatment and dose. Clinical laboratory test parameters will be graded using the CTCAE grading scale for individual participants and values outside the reference ranges will be flagged. The incidence of treatment-emergent laboratory abnormalities will be summarized by severity and treatment group. For each parameter, summary statistics will be calculated for each measure and su | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Plasma PLN-74809 concentrations (total and unbound concentrations) at each sampling timepoint will be presented in listings and descriptive summary statistics by dose and visit. The data will also be presented graphically. ;Timepoint(s) of evaluation of this end point: Week 16 | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Netherlands, Norway, United Kingdom, United States
Contacts
Public ContactMonica Sandberg
Pliant Therapeutics Inc.
Outcome results
None listed