What side effects are associated with this type of intervention?

Common treatments for Primary Sclerosing Cholangitis (PSC) include glucocorticoids, thiopurines, ursodeoxycholic acid (UDCA), and vancomycin. Glucocorticoids can cause side effects such as weight gain, hypertension, and increased risk of infections. Thiopurines may lead to bone marrow suppression, liver toxicity, and increased risk of infections. UDCA is generally well-tolerated but can cause diarrhea and, at higher doses, may be detrimental. Vancomycin, used in some pediatric cases, can cause nephrotoxicity and ototoxicity. These treatments aim to manage symptoms and complications but do not alter the disease's natural progression.

What prior FDA approvals exist?

As of now, there are no FDA-approved treatments specifically for Primary Sclerosing Cholangitis (PSC). Current management strategies often involve off-label use of medications such as ursodeoxycholic acid (UDCA) to improve liver function tests, although its efficacy in altering disease progression is uncertain. Other treatments under investigation include immunosuppressive and anti-inflammatory agents, such as those being studied in trials like PLN-74809. Liver transplantation remains the definitive treatment for advanced PSC.

What other types of research exist?

Promising novel alternatives to PLN-74809 for Primary Sclerosing Cholangitis patients include: 1) RO5459072, a cathepsin S inhibitor, which has shown pharmacodynamic efficacy in clinical studies. 2) BRD5529, a CARD9 inhibitor, which has demonstrated effectiveness in preclinical models of inflammatory signaling. 3) Chol-DsiRNA polyplexes targeting STAT3, which have shown increased potency and therapeutic activity in preclinical breast cancer models and could be explored for liver diseases.

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PLN-74809 for Sclerosing Cholangitis

Phase 2

Waitlist Available

Research Sponsored by Pliant Therapeutics, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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

Be older than 18 years old

Must not have

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)

Other causes of liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 12-48 weeks

Summary

This trial is testing a new medication to help people with a liver condition. The goal is to see if the medication can make the liver healthier by reducing the damage caused by the condition.

Who is the study for?

This trial is for people with a condition called primary sclerosing cholangitis (PSC), which affects the liver's bile ducts. Participants should have abnormal liver tests or suspected liver fibrosis, but not advanced cirrhosis. They can be on stable IBD treatment and must not have other causes of liver disease like autoimmune hepatitis or viral infections.

What is being tested?

The study is testing PLN-74809, a potential new medication for PSC, against a placebo (a substance with no active drug). It's designed to see how safe it is and how the body processes it. People will be randomly assigned to receive either PLN-74809 or placebo without knowing which one they're getting.

What are the potential side effects?

While specific side effects are not listed here, common ones in trials like this may include gastrointestinal symptoms, headaches, fatigue, and possible allergic reactions. The safety profile of PLN-74809 will be closely monitored throughout the study.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with large duct PSC based on specific liver tests.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have liver cirrhosis confirmed by tests or symptoms like jaundice or swelling.

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I do not have liver disease from viruses, alcohol, or other causes.

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My PSC affects only small bile ducts, with no large duct issues confirmed by tests.

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I have been diagnosed with or suspected to have autoimmune hepatitis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 12-48 weeks

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~12-48 weeks

This trial's timeline: 3 weeks for screening, Varies for treatment, and 12-48 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of participants with treatment-related adverse events and laboratory abnormalities, as assessed by CTCAE v5.0

Secondary study objectives

Assessment of PLN-74809 plasma concentrations

Other study objectives

Changes from Baseline to Week 12 in liver fibrosis biomarkers and alkaline phosphatase (ALP) levels

Side effects data

From 2022 Phase 2 trial • 9 Patients • NCT04072315

100%

Gamma-glutamyltransferase increased

100%

Hepatic Enzyme Increased

100%

80%

60%

40%

20%

Study treatment Arm

320 mg

80 mg and 240 mg

80 mg and 120 mg

60 mg

320 mg and 120 mg

120 mg and 240 mg

240 mg and 320 mg

120 mg and 320 mg

Trial Design

5Treatment groups

Experimental Treatment

Placebo Group

Group I: PLN-74809 Dose Level 4Experimental Treatment1 Intervention

Dose: 320 mg; PLN-74809 Dose Level 4 following PLN-74809 Dose Level 3

Group II: PLN-74809 Dose Level 3Experimental Treatment1 Intervention

Dose: 160 mg; PLN-74809 Dose Level 3 following PLN-74809 Dose Level 2

Group III: PLN-74809 Dose Level 2Experimental Treatment1 Intervention

Dose: 80 mg; PLN-74809 Dose Level 2 following PLN-74809 Dose Level 1

Group IV: PLN-74809 Dose Level 1Experimental Treatment1 Intervention

Dose: 40 mg;

Group V: PlaceboPlacebo Group1 Intervention

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

PLN-74809

2020

Completed Phase 2

~260

0 / 5Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Primary Sclerosing Cholangitis (PSC) include ursodeoxycholic acid (UDCA), glucocorticoids, thiopurines, and vancomycin. UDCA works by reducing bile acid toxicity and improving bile flow, which can help alleviate cholestasis and liver inflammation. Glucocorticoids and thiopurines are immunosuppressive agents that reduce inflammation and immune-mediated damage to the bile ducts. Vancomycin, an antibiotic, has shown some promise in small studies, potentially by altering gut microbiota and reducing bacterial translocation that may contribute to PSC. These treatments are crucial for PSC patients as they aim to manage symptoms, slow disease progression, and improve quality of life. While the specific mechanism of PLN-74809 is not detailed, it is likely being investigated for its potential to target similar pathways involved in fibrosis and inflammation, which are central to PSC pathology.

New Therapeutic Targets in Autoimmune Cholangiopathies.β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis.