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

Non-alcoholic Fatty Liver Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05560607
• Other study ID #: D9230C00003
• Status: Completed
• Phase: Phase 1
• Start date: August 12, 2022
• Est. completion date: February 27, 2024

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: February 27, 2024
• Est. primary completion date: February 27, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Fatty Liver, Nonalcoholic
• Liver Diseases
• NAFLD
• NASH
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis

Intervention

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.

Locations

Country	Name	City	State
United States	Research Site	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with Adverse Events (AEs).	To assess adverse events as a variable of safety and tolerability of AZD7503.	99 days
Secondary	Change in HSD17B13 mRNA Expression	HSD17B13 mRNA expression from baseline to Day 31 will be assessed	31 days
Secondary	Number of participants with positive anti-drug antibodies to AZD7503	To explore the formation of ADAs.	99 days
Secondary	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
Secondary	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
Secondary	Maximum observed plasma (peak) drug concentration (Cmax) of AZD7503	To characterise the PK (Cmax) of AZD7503 following SC administration of AZD7503.	99 days
Secondary	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
Secondary	Half-life associated with terminal slope (?z) of a semi logarithmic concentration time curve (t½?z) of AZD7503	To characterise the PK (t½?z) of AZD7503 following SC administration of AZD7503.	99 days
Secondary	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
Secondary	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
Secondary	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
Secondary	Time of last observed (quantifiable) concentration (tlast) of AZD7503	To characterise the PK (tlast) of AZD7503 following SC administration of AZD7503.	99 days
Secondary	Lowest observed drug concentration (Ctrough) before next dose of AZD7503	To characterise the PK (Ctrough) of AZD7503 following SC administration of AZD7503.	99 days
Secondary	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
Secondary	Accumulation ratio for AUC of AZD7503.	To characterize the PK (Rac AUC) of AZD7503 following SC administration of AZD7503	99 days
Secondary	Accumulation ratio for Cmax (Rac Cmax) of AZD7503	To characterize the PK (Rac Cmax) of AZD7503 following SC administration of AZD7503.	99 days
Secondary	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