Safety and Tolerability of A3907 in Primary Sclerosing Cholangitis

Study Overview
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Brief Summary
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This study will test a drug called A3907 to see how safe and tolerated it is for treating people with Primary Sclerosing Cholangitis (PSC).

Detailed Description
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The primary goal of this study in participants with PSC who are treated with A3907 is to assess the safety and tolerability of A3907 following repeat doses. Secondary goals include evaluation of the pharmacokinetic properties of A3907 (the study of how the body interacts with A3907 for the entire duration of exposure) and changes in safety parameters via laboratory testing such as liver enzymes, bile acid levels and markers of bile acid synthesis.

Official Title
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An Open Label, Phase 2 Study to Evaluate the Effect of A3907 on Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Adults With Primary Sclerosing Cholangitis (PSC)

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: A3907


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Clinical and radiological diagnosis of large-duct PSC via magnetic resonance cholangiopancreatography movement-related cortical potential (MRCP) or equivalent imaging modality that excludes biliary obstruction and malignancy within 6 months before screening Alkaline phosphatase (ALP) > 1.5 × upper limit of normal (ULN) but ≤ 10 × ULN Total bilirubin < 3 × ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN Baseline serum bile acid level at Screening must be > ULN Clinically stable for at least 3 months prior to screening Key exclusion criteria: Presence of documented secondary sclerosing cholangitis, small duct PSC, known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis or other causes of chronic liver disease Biliary intervention within 3 months prior to study enrollment or planned Inflammatory bowel disease (IBD) with uncontrolled moderate to severe activity and/or on treatment with any immunosuppressive, immunomodulator, or biologic agent for treatment of IBD. Treatment with corticosteroids in the previous 4 weeks History of human immunodeficiency virus infection or any other known relevant infection (e.g., tuberculosis) History of colostomy or colectomy History of malignancy, including hepatocellular carcinoma within the past 10 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated History of transplants, including liver transplantation, or currently on active transplantation list Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis Liver cirrhosis as assessed by any of the following: historical liver histology suspected liver fibrosis liver stiffness measurement, assessed by FibroScan (FibroScan value > 14.4 kPa) current or history of signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal haemorrhage, and/or hepatic encephalopathy) Treatment with rifampicin, CYP3A4 substrates, vitamin D or fibrates (unless patient is on a stable dose ≥ 6 months prior to baseline) and with medications that slow gastrointestinal motility Exposure to an investigational drug, biologic agent, or medical device within 30 days prior to Screening, or 5 half-lives of the study agent, whichever is longer Platelet count < 150 000/mm3 Albumin level < 3.0 g/dL International normalised ratio (INR) > 1.4 (the patient may be treated with vitamin K intravenously, and if INR is ≤ 1.4 at resampling, the patient may be enrolled) Advanced renal disease glomerular filtration rate (GFR) <70 mL/min/1.73 m2)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg (Arm 1)<br>10mg tablet A3907 administered orally once daily for 12 weeks. | Drug: A3907<br>* A3907 is an oral, systemically available, potent inhibitor of the apical sodium bile acid transporter (ASBT).<br>|
| Experimental: 30 mg (Arm 2)<br>30mg (3x10 mg tablets) A3907 administered orally once daily for 12 weeks. | Drug: A3907<br>* A3907 is an oral, systemically available, potent inhibitor of the apical sodium bile acid transporter (ASBT).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related adverse events | Number of participants with treatment related adverse events as assessed by CTCAE v 5.0 | From baseline through week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters for A3907 including, but not limited to, maximum observed plasma concentration (Cmax), and area under the plasma concentration time curve (AUC) |  | From baseline through week 12 | 
| Change in serum and urine individual and total bile acid levels |  | From baseline through week 12 | 
| Change in ALT, AST, gamma-glutamyltransferase (GGT), ALP and bilirubin levels |  | From baseline through week 12 | 
| Change in serum C4 level |  | From baseline through week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSC, Primary Sclerosing Cholangitis