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)

Inclusion Criteria:
General and Administrative
1. Aged 18 to 75 years, inclusive.
2. Female participants of childbearing potential must use a contraceptive
method with a failure rate of <1% per year or remain abstinent (refrain from
heterosexual intercourse) during the treatment period and for 1 month after the
last dose of study drug.
Male participants with female partners of childbearing potential must agree to
use contraceptive measures or remain abstinent (refrain from heterosexual
intercourse) during screening and the treatment period and for at least 3
months after the last dose of study drug.
3. Female participants of nonchildbearing potential must be surgically sterile
or postmenopausal.
4. Participants must agree to abstain from sperm or egg donation for the
duration of the study, through 3 months or 1 month, 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
elevated cholestatic liver chemistries.
7. Serum alkaline phosphatase concentration within normal ranges or > 1 × 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 hemolysis.
Participants with serum total bilirubin > 1.5 × ULN may be enrolled if they
have Gilbert*s Syndrome and a direct bilirubin < 0.6 mg/dL.
10. Suspected liver fibrosis, as defined by any of the following:
- Enhanced Liver Fibrosis (ELF) Score >= 7.7 at Screening OR
- Liver stiffness measurement (LSM) >= 8 kPa but <= 14.4 kPa, assessed by
FibroScan® OR
- Historical liver biopsy showing fibrosis without cirrhosis (by any scoring
system) OR
- Magnetic resonance elastography (MRE) >= 2.4 kPa but <= 4.9 kPa
11. Platelet count >= 140,000/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 α) inhibitors and/or vedolizumab,
immunosuppressive agents, or corticosteroids must have been receiving a stable
dose for at least 3 months before screening. The dose must remain stable from
screening through Day 1 (baseline), and expected to remain stable for the
duration of the study.
20. Estimated glomerular filtration rate >= 60 mL/min, according to the
Cockcroft-Gault equation.

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 with no evidence of large duct involvement (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 increase
by > 30% and represent either a Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 that is associated with new or worsening symptoms or a CTCAE
Grade 2 with or without new or worsening symptoms, as defined by CTCAE Version
5.0.
8. Ascending cholangitis within 60 days of screening, as assessed clinically or
use of antibiotics for acute cholangitis within 60 days of screening.
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), MRE
> 4.9 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. Clinical evidence of active bacterial, viral, or fungal 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 Screening Visit 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 (i.e., strong) inhibitors or inducers of cytochrome P450 (CYP)
3A4, 2C9 or 2C19; potent inhibitors or inducers of and P-glycoprotein (P-gp)
(e.g., itraconazole), breast cancer resistance protein (BCRP) or OATP1B1organic
anion transporting polypeptide (OATP) 1B1/1B3 transporters P-gp substrates with
a narrow therapeutic window should also be excluded.
22. Current treatment or anticipated need for treatment with immunomodulating
agents (such as interleukins and interferons), radiation therapy, or cytotoxic
or chemotherapeutic agents.
23. Hypersensitivity to PLN-74809 or to any of the excipients, or placebo.
Screening Assessments
24. Pregnancy or breastfeeding or male participant whose female partner is
pregnant.
25. History of weekly alcohol consumption > 21 units for male participants or >
14 units for female participants (1 unit = 1 oz/30 mL of alcohol contained in
12 oz/360 mL of beer, 4 oz/120 mL of wine, or 1 oz/30 mL of 40% proof alcohol).
26. Positive urine drug screen at screening unless the positive result is due
to a medical treatment for a comorbid condition.
27. Any other clinically significant disorders or prior therapy that, in the
opinion of the Investigator, would make the participant unsuitable for the
study or unable to comply with the dosing and protocol requirements.
28. Prior use of an investigational drug within 5 half-lives or 30 days before
screening, whichever time is longer, or the use of an investigational device
within 30 days before screening.
29. Participation in an earlier part of the current study (ie, Part 1 or 2)
within 6 months of dosing for a subsequent part (ie, Part 2 or 3).