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

Phase 1

Completed

• Conditions: NAFLD; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; NASH; Non-alcoholic Fatty Liver Disease; Fatty Liver, Nonalcoholic
• Interventions: Drug: AZD7503 Intervention

• Registration Number: NCT05560607
• Lead Sponsor: AstraZeneca

Brief Summary

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.

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 Timeline

• Study First Submitted: 2022-08-09
• Study Start: 2022-08-12
• Study First Submitted QC: 2022-09-26
• Study First Posted: 2022-09-29
• Primary Completion: 2024-02-27
• Study Completion: 2024-02-27
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-15
• Last Update Posted: 2024-03-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

Not provided

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intervention/ Drug	AZD7503 Intervention	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Research Site; 🇺🇸 San Antonio, Texas, United States