Fatty Liver, Nonalcoholic, NAFLD, NASH, Non-alcoholic Fatty Liver Disease, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Keywords
NASH, NAFLD
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.
Interventions
DRUGAZD7503 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.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with Adverse Events (AEs). | 99 days | To assess adverse events as a variable of safety and tolerability of AZD7503. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Maximum observed plasma (peak) drug concentration (Cmax) of AZD7503 | 99 days | To characterise the PK (Cmax) 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. |
| Change in HSD17B13 mRNA Expression | 31 days | HSD17B13 mRNA expression from baseline to Day 31 will be assessed |
| 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. |
| Time of last observed (quantifiable) concentration (tlast) of AZD7503 | 99 days | To characterise the PK (tlast) 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 |
| 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. |
Countries
United States
Outcome results
None listed