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 patients with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 1 to 3 and homozygous for the PNPLA3 148M risk allele.
Name: AZD2693
Name: Placebo
Description: Safety and tolerability will be evaluated in terms of number of subjects with adverse events and/or abnormal values of vital signs and/or clinical laboratory and/or electrocardiogram and/or renal assessments and/or blood assessments.
Measure: Number of participants with adverse events Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.
Measure: Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC) Time: Baseline (Day 1), Week 8, Week 12Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.
Measure: Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC) Time: Baseline (Day 1), Week 8, Week 12Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Absolute change from baseline in Alanine Aminotransferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Percent change from baseline in Alanine Aminotransferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Absolute change from baseline in Aspartate Aminotransferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Percent change from baseline in Aspartate Aminotransferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Absolute change from baseline in Gamma Glutamyl Transferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
Measure: Percent change from baseline in Gamma Glutamyl Transferase Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.
Measure: Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.
Measure: Percent change from baseline in ELF score Time: Up to 36 weeks (From Screening to Final Visit)Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
Measure: Absolute change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. Time: Days 1, 29, 50, and 78Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
Measure: Percent change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. Time: Days 1, 29, 50, and 78Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
Measure: Absolute change from baseline in disease-specific biomarkers Time: Days 1, 29, 50, and 78Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
Measure: Percentage change from baseline in disease-specific biomarkers Time: Days 1, 29, 50, and 78Description: To characterise effects of AZD2693 on lipid handling compared to placebo.
Measure: Absolute change from baseline β-Hydroxybutyrate and lipid profile Time: Days 1, 29, 50, and 78Description: To characterise effects of AZD2693 on lipid handling compared to placebo
Measure: Percent change from baseline β-Hydroxybutyrate and lipid profile Time: Days 1, 29, 50, and 78Description: Single dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
Measure: Maximum observed plasma drug concentration (Cmax) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Time to reach maximum observed plasma concentration (tmax) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h)) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
Measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
Measure: Mean residence time (MRT) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Time delay between drug administration and the first observed concentration in plasma (tlag) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Time of the last quantifiable concentration (tlast) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Maximum observed plasma drug concentration at steady state (Cssmax) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Minimum observed drug concentration at steady state (Cssmin) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Time to reach maximum observed plasma concentration at steady state (tssmax) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the concentration-time curve in the dose interval (AUCss) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Observed maximum plasma concentration divided by the dose administered (Cssmax/D) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Accumulation ratio based on Cmax (RacCmax) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Accumulation ratio based on AUC (RacAUC) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
Measure: Temporal change parameter in systemic exposure (TCP) Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
Measure: Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
Measure: Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last)) Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
Measure: Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2)) Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
Measure: Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last)) Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
Measure: Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR) Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.Allocation: Randomized
Sequential Assignment
There is one SNP
- Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical trial. --- I148M ---
- Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Sample: - The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Samples is not given. --- I148M ---
- The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression. --- I148M ---