Knockdown of HSD17B13 mRNA, Pharmacokinetics, Safety, and Tolerability, of AZD7503 in Non-Alcoholic Fatty Liver Disease

An Open-label, Non-randomized, Multiple-dose Study to Assess the Knockdown of Hepatic HSD17B13 mRNA Expression, Pharmacokinetics, Safety, and Tolerability Following Administration of AZD7503 in Participants With Non-alcoholic Fatty Liver Disease

This is a two-part study. In Part A, eligible participants will undergo a baseline diagnostic liver biopsy to determine non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage, but will not receive study intervention. In Part B, participants with histologically confirmed NAFLD or non-alcoholic steatohepatitis (NASH) will receive study intervention.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease; NAFLD; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; NASH; Fatty Liver, Nonalcoholic
• Intervention / Treatment: Drug: AZD7503 Intervention

Detailed Description

This is a single center, open-label Phase I study to assess knockdown of hepatic HSD17B13 mRNA pharmacokinetics (PK), safety, and tolerability following multiple doses of AZD7503 in male and/or female participants of non-childbearing status with NAFLD or NASH.

In Part A, participants at high risk for NAFLD/NASH meeting inclusion criteria for Part A (Section 5.1) and none of the exclusion criteria noted in Section 5.2 will undergo a diagnostic, baseline liver biopsy per standard clinical care. Participants will be consented for the liver biopsy as a first step to determine eligibility for Part B. In Part B, participants will be consented for study intervention administration and repeat liver biopsy at the end-of-treatment (EOT). Eligible participants will be assigned to 1 study intervention cohort. Two additional cohorts may be added based on data from the FiH study (D9230C00001) and emerging data from this study.

Participants who are selected for Part B based on histopathology evaluation (NAFLD or NASH with NAS of ≥3) will have an assessment of the hepatic HSD17B13 mRNA expression from both the liver biopsy obtained in Part A and the liver biopsy obtained at the end of study intervention administration in Part B. The assessments for hepatic HSD17B13 mRNA expression will be performed after each dose cohort is treated and before moving to the next dose cohort.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78215
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria # Part A

1. Participant must be ≥ 18 to ≤ 70 years of age at the time of signing the informed consent.

2. Participants with suspected or confirmed NAFLD or NASH including laboratory values with any of the following deviations at screening

   1. ALT > ULN,
   2. Imaging demonstrating hepatic steatosis including controlled attenuation parameter (CAP) >290 dB/m, OR Liver stiffness of >7.1 kPa as measured by Fibroscan.
3. Body mass index (BMI) ≥20 kg/m2.

4. Male and /or female of non-child bearing potential.

   Inclusion Criteria # Part B

5. Histologic evidence of NAFLD or NASH with a NAS ≥3 following baseline liver biopsy.

Exclusion Criteria:

1. History or presence of hepatic disease (with the exception of hepatic steatosis, NASH) or evidence of other known forms of known chronic liver
2. History of liver transplant, evidence of cirrhosis, or current placement on a liver transplant
3. Positive results for HIV antigen and hepatitis B surface antigen 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.
4. History of alcohol abuse or excessive intake of alcohol as judged by the investigator.

5. Uncontrolled blood pressure, defined as any of the following during pre-screening and/or Day -1 (mean of 3 measurements):

   1. Systolic blood pressure >160 mmHg.
   2. Diastolic blood pressure >100 mmHg.
6. Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG.
7. Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis results,
8. Known or suspected history of drug abuse as judged by the investigator.
9. Positive screen for drugs of abuse at screening or admission to the study site prior to the administration of the study intervention.
10. Changes to any concomitant medication (initiation, dose change, or cessation) within one month prior to the screening visit.

11. Any laboratory values with following deviations at screening (one re-test allowed):

    1. (a) ALT >3X ULN
    2. (b) AST >3X ULN
    3. (c) TBL >ULN or INR ≥1.3
    4. (d) ALP >1.5X ULN
    5. (e) eGFR <60 mL/min/1.73 m2 (calculated using CKD Epidemiology Collaboration
    6. [CKD-EPI] formula) and applying the standard correction factor for African
    7. American to the (CKD-EPI) by multiplying the GFR estimate by 1.159 and
    8. confirmed.
    9. (f) Platelets <150 × 109/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention/ Drug; Investigation of the knockdown of hepatic HSD17B13 mRNA expression, PK, safety, and tolerability following multiple dose administration of AZD7503 in male participants and female participants of non-childbearing potential with NAFLD or NASH	Drug: AZD7503 Intervention; Part A: Participants will be screened for histologic evidence of NAFLD or NASH and all eligibility criteria in part A prior to enrollment in part B. Part B: Participants consented to part B will be administered the study drug over the course of 31 days. At the end of the study a liver biopsy will be collected to measure for endpoints.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Adverse Events (AEs).	To assess adverse events as a variable of safety and tolerability of AZD7503.	99 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HSD17B13 mRNA Expression	HSD17B13 mRNA expression from baseline to Day 31 will be assessed	31 days
Number of participants with positive anti-drug antibodies to AZD7503	To explore the formation of ADAs.	99 days
Area under plasma concentration time-curve from zero to infinity (AUCinf) of AZD7503	To characterise the PK (AUCinf) of AZD7503 following SC administration of AZD7503	99 days
Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD7503	To characterize the PK (AUClast) of AZD7503 following SC administration of AZD7503.	99 days
Maximum observed plasma (peak) drug concentration (Cmax) of AZD7503	To characterise the PK (Cmax) of AZD7503 following SC administration of AZD7503.	99 days
Time to reach peak or maximum observed concentration or responsefollowing drug administration (tmax) of AZD7503	To characterise the PK (tmax) of AZD7503 following SC administration of AZD7503.	99 days
Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t½λz) of AZD7503	To characterise the PK (t½λz) of AZD7503 following SC administration of AZD7503.	99 days
Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD7503	To characterise the PK (MRTinf) of AZD7503 following SC administration of AZD7503.	99 days
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD7503	To characterise the PK (CL/F) of AZD7503 following SC administration of AZD7503.	99 days
Apparent volume of distribution at steady state following extravascular administration based on terminal phase(Vz/F) of AZD7503	To characterise the PK (Vz/F) of AZD7503 following SC administration of AZD7503.	99 days
Time of last observed (quantifiable) concentration (tlast) of AZD7503	To characterise the PK (tlast) of AZD7503 following SC administration of AZD7503.	99 days
Lowest observed drug concentration (Ctrough) before next dose of AZD7503	To characterise the PK (Ctrough) of AZD7503 following SC administration of AZD7503.	99 days
Apparent volume of distribution at steady state following extravascular administration (Vss/F) of AZD7503	To characterise the PK (Vss/F) of AZD7503 following SC administration of AZD7503.	99 days
Accumulation ratio for AUC of AZD7503.	To characterize the PK (Rac AUC) of AZD7503 following SC administration of AZD7503	99 days
Accumulation ratio for Cmax (Rac Cmax) of AZD7503	To characterize the PK (Rac Cmax) of AZD7503 following SC administration of AZD7503.	99 days
Partial area under plasma concentration-time-curve from time 0 to time t (AUC(0-t)) of AZD7503	To characterise the PK (AUC(0-t)) of AZD7503 following SC administration of AZD7503	99 days

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• d9230c00003-Redacted_CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2022
• Primary Completion (Actual): November 20, 2023
• Study Completion (Actual): February 27, 2024

Study Registration Dates

• First Submitted: August 9, 2022
• First Submitted That Met QC Criteria: September 26, 2022
• First Posted (Actual): September 29, 2022

Study Record Updates

• Last Update Posted (Actual): July 20, 2025
• Last Update Submitted That Met QC Criteria: July 17, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: NAFLD; NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: D9230C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No