A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients

• Status: Recruiting
• Trial end date: 2022-12-12
• Target enrollment: 0
• Participant gender: All

Summary

This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple ascending doses in participants with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 0 to 3 and homozygous for the patatin-like phospholipase domain-containing 3 (PNPLA3) 148M risk allele.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AstraZeneca
• Collaborator: Parexel

Criteria

Inclusion Criteria:

• An MRI-PDFF ≥7% and one of the following:

• Previous liver biopsy: Acceptable if taken in the previous 3 years for fibrosis stages F0 to F2, or within the previous 1 year for stage F3; or

• Previous imaging results taken in the previous 2 years: An MRE between 2.55 kPa and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1 kPa and 9.9 kPa; or

• Participant's consent for a liver biopsy or MRE/VCTE at screening, if previous biopsies or MRE/VCTE imaging data are not available.

• Participants who are homozygous for rs738409 (PNPLA3 148M).

• Body weight ≥50 kg and BMI within the range 25 to 45 kg/m˄2 (inclusive).

• Male, or female of non-childbearing potential.

• Participants should agree to follow protocol defined contraceptive procedures.

• Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical study (this may be checked at the optional Pre-Screening Visit).

• Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Samples (this may be checked at the optional Pre-Screening Visit):

• The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Samples is not given.

• The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression.

• Provision of 3 blood samples (3 x 4 ml in ethylene-diamine-tetra-acetic acid [EDTA] tubes).

• Provision of 3 buccal swabs.

• Provision of signed and dated written optional genetic research information informed consent prior to collection of samples for optional genetic research for the Genomic Initiative and the clustered regularly interspaced short palindromic repeats (CRISPR) technology (this may be checked at the optional Pre-Screening Visit).

Exclusion Criteria:

• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.

• History of liver transplant, or current placement on a liver transplant list (this may be checked at the optional Pre-Screening Visit).

• History or presence of hepatic disease (with the exception of hepatic steatosis, NASH) or evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, primary biliary cirrhosis, primary sclerotic cirrhosis, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (this may be checked at the optional Pre-Screening Visit).

• If a participant has a positive result at the screening visit for hepatitis C antibody, the investigator will document that the participant has hepatitis C RNA below the limit of detection and has not received curative treatment in the last 3 years.

• Histological or imaging (MRE or VCTE) evidence of cirrhosis.

• Any positive result at the Screening Visit for serum hepatitis B surface antigen and human immunodeficiency virus.

• Participants with history or pre-existing renal disease, as defined below:

• estimated glomerular filtration rate < 60 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula) or

• urinary albumin-to-creatinine ratio > 3 mg/μmol (30 mg/g).

• Clinically significant cardiovascular event within the last 6 months prior to the Screening Visit.

• Participants with a positive SARS-CoV-2 infection test at Screening Visit.

• Participants with a significant Coronavirus disease 2019 (COVID-19) illness within 6 months of enrolment:

• Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment.

• Participants with diagnosis of COVID-19 with significant findings from pulmonary imaging tests.

• Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy.

• Suspicion of or known Gilbert's syndrome.

• Weight loss of more than 5% within the last 6 months prior to randomization. Plans to initiate a weight loss diet or to undergo bariatric surgery.

• Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).

• History of major bleed or high-risk of bleeding diathesis.

• Changes to any concomitant medication (initiation, dose change, or cessation) that may impact the study readouts (as judged by the investigator) within 1 month prior to the Screening Visit. This criterion does not apply to medication prescribed for occasional use.

• Use of anabolic steroids and systemic treatment with glucocorticosteroids within 3 months prior to the Screening Visit.