AZD5004 for Liver Disease

Recruiting at 3 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: AstraZeneca

Disqualifiers: Diabetes, Hypertension, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is a Phase I, multicentre, single-dose, non-randomised, open-label, parallel-group study to examine the PK, safety, and tolerability of AZD5004 in male and female participants with mild, moderate, and severe hepatic impairment compared with participants with normal hepatic function.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, participants with normal liver function must be stable on their current medication for at least 2 weeks before screening.

How does the drug AZD5004 differ from other treatments for liver disease?

AZD5004 is unique because it may target specific genetic mutations in the ABCB4 gene, which are linked to various liver diseases. This approach could offer a more personalized treatment option compared to standard therapies like ursodeoxycholic acid, which is commonly used but not always effective for all patients. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for men and women with varying degrees of liver disease, including those with diabetic liver disease. It aims to include participants with mild, moderate, and severe hepatic impairment as well as those with normal liver function.

Inclusion Criteria

I have had stable liver disease for at least 6 months.

I am between 18 and 80 years old.

My liver impairment is classified as mild, moderate, or severe based on my Child-Pugh score.

Exclusion Criteria

My diabetes is not well-controlled (A1C >10%).

My blood pressure is not well-controlled.

I do not have any significant health issues, including liver disease.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single oral dose of AZD5004 under fasted conditions

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and pharmacokinetics from Day 1 to Day 10

10 days

Multiple visits (in-person)

Treatment Details

Interventions

• AZD5004 (Other)

Trial Overview The study is testing AZD5004 in individuals with different levels of liver health. It's a Phase I trial where everyone gets one dose of the drug openly without being compared to another group or receiving a placebo.

Participant Groups

Group I: Group 4 Experimental Treatment 1 Intervention

A single oral dose of AZD5004 under fasted conditions.

Group II: Group 3 Experimental Treatment 1 Intervention

A single oral dose of AZD5004 under fasted conditions.

Group III: Group 2 Experimental Treatment 1 Intervention

A single oral dose of AZD5004 under fasted conditions.

Group IV: Group 1 Experimental Treatment 1 Intervention

A single oral dose of AZD5004 under fasted conditions.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Fortrea Clinical Research Unit Inc.

Collaborator

Trials

1

Recruited

30+

Findings from Research

In a study of 102 patients with low phospholipid-associated cholelithiasis (LPAC) and intrahepatic cholestasis of pregnancy (ICP), 37% of LPAC patients and 27% of ICP patients had heterozygous mutations in the ABCB4 gene, indicating a significant genetic link to these conditions.

The study also identified ABCB4 deletions in 7% of LPAC patients and 2% of ICP patients, highlighting the need for comprehensive genetic testing to improve diagnosis and potentially guide treatment with ursodeoxycholic acid to prevent biliary complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. Pasmant, E., Goussard, P., Baranes, L., et al.[2021]

In a study of 76 patients with Alagille syndrome treated with maralixibat (MRX) for at least 48 weeks, significant improvements in pruritus, bilirubin, and serum bile acid levels were linked to better event-free survival rates, indicating the treatment's efficacy.

Specifically, a greater than 1-point reduction in pruritus, bilirubin levels below 6.5 mg/dL, and serum bile acids under 200 µmol/L at 48 weeks were strong predictors of both event-free and transplant-free survival over a 6-year follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor. Sokol, RJ., Gonzales, EM., Kamath, BM., et al.[2023]

Variants in the ABCB4 gene can lead to a range of liver diseases, from severe conditions like progressive familial cholestasis type 3 to milder issues such as low phospholipid-associated cholelithiasis, highlighting the gene's critical role in liver health.

While ursodeoxycholic acid is commonly used to treat ABCB4 deficiency-related diseases, its effectiveness has not been confirmed in large clinical trials, and future treatments may involve novel pharmacological strategies or liver transplantation for severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. Stättermayer, AF., Halilbasic, E., Wrba, F., et al.[2021]

A novel missense mutation in the ABCB4 gene was identified as a cause of cholestatic liver disease (CLD) in a family, correlating with the severity of the disease, which ranged from mild symptoms to cirrhosis and death.

The study suggests that genetic testing for ABCB4 mutations should be considered for all patients with unexplained cholestatic liver disease, regardless of their age or when the disease started.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Gotthardt, D., Runz, H., Keitel, V., et al.[2022]

Mutations in the ABCB4 gene, which affect the MDR3 protein responsible for phospholipid transport in bile, are linked to several liver diseases, including the severe pediatric condition PFIC3, which may necessitate liver transplantation.

While most patients with MDR3 deficiency respond well to ursodeoxycholic acid (UDCA) therapy, some PFIC3 patients do not, indicating a need for future targeted pharmacologic treatments or cell therapies for those who require transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Davit-Spraul, A., Gonzales, E., Baussan, C., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. [2023]