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)

Trial ID: 2022-500790-14-00
Protocol: A3907-002
Sponsor: Albireo AB

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Diseases & Conditions

Cholangitis sclerosing

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of A3907 in patients diagnosed with **Primary Sclerosing Cholangitis (PSC)**, both with and without a Clinically Relevant Stricture (CRS). This is clinically significant as PSC is a chronic liver disease that can lead to liver failure, and understanding the safety profile of A3907 is crucial for its potential therapeutic application.

Secondary objectives include:

Evaluating the **pharmacokinetics** of A3907 to understand its absorption, distribution, metabolism, and excretion.
Assessing the effect of A3907 on **bile acid** levels, which are critical in the pathophysiology of PSC.
Investigating the impact of A3907 on **liver health**, which is essential for determining its therapeutic benefits.
Evaluating the effect of A3907 on **bile acid synthesis**, providing insights into its mechanism of action.

Participants

The clinical trial involves participants diagnosed with **Primary Sclerosing Cholangitis (PSC)**, a chronic liver disease. The study population includes both male and female adults aged between 18 and 75 years. Participants are required to have a clinical diagnosis of large-duct PSC with evidence of more than six months duration, confirmed by imaging techniques such as magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The trial includes individuals with varying health statuses, including those with inflammatory bowel disease (IBD) in clinical remission or mildly active. Participants are expected to maintain stable treatment regimens, particularly concerning the use of ursodeoxycholic acid (UDCA) or bile acid-binding resins. The trial population was selected based on specific inclusion criteria, ensuring that participants are clinically stable for at least three months prior to the screening period. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of the investigational product A3907 in adults diagnosed with **Primary Sclerosing Cholangitis (PSC)**. This is an open-label, Phase II study, which involves the administration of A3907 in the form of a film-coated tablet. The trial is structured to assess the pharmacokinetics and pharmacodynamics of A3907 over a 12-week treatment period. Participants will be required to take the medication orally, with a maximum daily dose of 60 mg and a total dose not exceeding 5280 mg over the course of the study.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18 and 75 years, a clinical diagnosis of large-duct PSC, and certain laboratory parameters. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) through Week 12. Secondary endpoints include changes in serum and urine bile acid levels, liver transaminases, and other biomarkers from baseline to Week 12.

Participants will undergo a series of study visits, starting with the initial screening visit to assess eligibility. This will be followed by regular follow-up visits throughout the 12-week treatment period to monitor safety, tolerability, and pharmacokinetic parameters. The end-of-study visit will conclude the trial, where final assessments will be conducted. The expected duration of participant involvement is approximately 112 days, including the treatment and follow-up periods.

Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial is estimated to conclude by March 2025, with recruitment having started in December 2022. The study aims to provide valuable insights into the effects of A3907 on patients with PSC, potentially contributing to the development of new therapeutic strategies for this condition.

Treatment

The clinical trial involves the administration of the experimental medication **A3907**, which is a **film-coated tablet**. The active substance in this medication is chemically derived and is also named A3907. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The maximum daily dose of A3907 is 60 mg, with a total maximum dose of 5280 mg over the course of the treatment period. The treatment period is set to a maximum of 112 days. The medication is not formulated for pediatric use and is not classified as an orphan drug. The trial aims to evaluate the safety and tolerability of A3907 in adults diagnosed with **Primary Sclerosing Cholangitis** (PSC), with or without a Clinically Relevant Stricture (CRS).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of A3907 to assess its pharmacokinetics and pharmacodynamics in the target population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of Albireo AB, and the medication is identified by the sponsor product code A3907. The study is designed as an open-label, Phase 2 trial, providing insights into the effects of A3907 on the specified patient group.

Efficacy

The efficacy of the investigational product A3907 in the clinical trial will be assessed through several secondary endpoints. These include pharmacokinetic (PK) parameters such as Cmax and area under the plasma concentration-time curve (AUC). Additionally, changes from baseline to Week 12 in serum and urine individual and total bile acid levels will be evaluated. Liver transaminases, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and total and direct bilirubin levels will also be measured to assess changes from baseline to Week 12. Furthermore, the change from baseline to Week 12 in **7α-hydroxy-4-cholesten-3-one (C4)**, a biomarker of bile acid synthesis, will be analyzed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adults between 18 and 75 years of age (inclusive). 2. Have a clinical diagnosis of large-duct PSC with evidence of more than 6 months duration with either a consistent magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis and historical evidence of elevated alkaline phosphatase (ALP). 3. Willing to sign informed consent. 4. Women of childbearing potential (WOCBP) and males with female partners of childbearing potential must agree to use contraception as detailed in Section 9.3.18. Women of nonchildbearing potential (WONCBP) must meet the definition in Section 9.3.18 and have a confirmatory follicle stimulating hormone [FSH] level ≥ 40 mIU/mL . 5. Alkaline Phosphatase (ALP) value > 1.5 × upper limit of normal (ULN) but ≤ 10 ×ULN at Visit 1 (Screening Period). Before starting 12 weeks treatment variability of < 30% between ALP values at Visit 1 and Visit 2 must be confirmed. If variability is > 30 % a third ALP value may be obtained. If the third ALP value meets >1.5 × ULN but ≤ 10 × ULN the patient can start the 12-week treatment period. 6. Arms 1-3 Only: Total bilirubin < 1.5 × ULN (unless due to Gilberts Syndrome or hemolysis) and normal direct bilirubin. 7. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN 8. Serum bile acid level > ULN 9. Arms 1 - 3 Only: An MRCP or equivalent imaging modality performed within 6 months before the Screening Period that is consistent with PSC without a clinically relevant stricture. 10. Arm 4 Only: An MRCP or equivalent imaging modality performed within 6 months before the Screening Period that is consistent with PSC with a clinically relevant stricture, or clinically relevant bile duct obstruction (see Inclusion # 12 for additional information). 11. Use of ursodeoxycholic acid (UDCA) with a total daily dose ≤ 23 mg/kg/day, or bile acid-binding resins are permitted, with a minimum of 3 months of stable treatment prior to the Screening Period, and expected to remain on a stable dose through the 12-week treatment period; or a minimum of 3 months off UDCA prior to the Screening Period if UDCA was recently discontinued. 12. If a patient has inflammatory bowel disease (IBD) with a minimum disease duration of 4 weeks, this diagnosis should be documented. Inflammatory bowel disease should be in clinical remission or mildly active according to Crohn’s Disease Activity Index (CDAI), partial Mayo score for Crohn’s Disease (CD) and ulcerative colitis (UC), respectively (i.e., patients with CDAI score < 220 and Mayo score < 5, respectively). Patients with IBD should have had a colonoscopy performed within one year prior to the Screening Period with results showing no evidence of dysplasia or cancer.
Clinically stable for at least 3 months prior to the Screening Period. 14. Arm 4 Only: One stable clinically relevant biliary stricture of at least 4 weeks duration on contrast enhanced MRI/MRCP with > 75% reduction of duct diameter in the common bile duct or hepatic duct without suspicion of cholangiocarcinoma (further established by imaging and stable CA 19-9 below ULN repeated twice over 1 month), or cholelithiasis. Subjects may have signs or symptoms of worsening obstructive cholestasis (increasing jaundice, nausea, anorexia, steatorrhea and worsening or new onset pruritus), deterioration of liver function (i.e., decreasing platelet count, increasing international normalized ratio [INR]) and/could be listed for liver transplantation due to their clinically relevant biliary stricture. 15. Arm 4 Only: MELD Score < 35

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Exclusion Criteria

Medical History - 1. Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis). 2. Biliary intervention within 3 months prior to study enrollment or planned. 3. Presence of alternative causes of chronic liver disease, including alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis, or active hepatitis B or C. 4. IBD with uncontrolled moderate to severe activity and/or on treatment with any immunosuppressive, immunomodulator, or biologic agent for treatment of IBD (i.e. azathioprine, 6 mercaptopurine, tacrolimus, methotrexate, infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod). Treatment with corticosteroids (including budesonide, budesonide MMX and beclomethasone) in the previous 4 weeks. 5. History of human immunodeficiency virus infection or any other known relevant infection (e.g., tuberculosis). 6. History of colostomy or colectomy. 7. 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. 8. History of transplants, including liver transplantation, or currently on active transplantation list. 9. Current or a history of ascites, encephalopathy, or history of esophageal variceal bleeding. 10. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis. 11. Small duct PSC (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography). 12. Liver cirrhosis as assessed by any of the following: a. historical liver histology • suspected liver fibrosis, defined by liver stiffness measurement, assessed by FibroScan (FibroScan value > 14.4 kPa). b. signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal haemorrhage, and/or hepatic encephalopathy). 13. Are female of childbearing potential, including those who are pregnant or lactating 14. History of alcohol or substance abuse in the previous 2 years. Patients must agree to refrain from illicit drug (including marijuana) and alcohol use during the study 15. Hypersensitivity to investigational medicinal product (A3907) and excipients. 16. Presence of any contraindication for undergoing MRCP (e.g., pacemaker). Treatment - 17. Administration of medications that slow gastrointestinal motility (Section 8.6.2). 18. Treatment with rifampicin 19. Treatment with CYP3A4 substrates acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. 20. Treatment with vitamin D or fibrates, unless patient is on a stable dose ≥ 6 months prior to baseline. 21. 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. Laboratory Exclusions - 22. Platelet count < 150 000/mm3. 23. Albumin level < 3.0 g/dL. 24. 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). 25. Advanced renal disease (glomerular filtration rate [GFR] < 70 mL/min/1.73 m2 ) Miscellaneous - 26. Any other conditions or abnormalities which, in the opinion of the investigator (or designee), may compromise the safety of the patient or interfere with the patient participating in or completing the study.