A Study to Understand the Safety, Tolerability, and Activity of Drug in Body Over a Period of Time of AZD2693, in Subjects of Non-Childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects

NCT04142424 | Completed Phase 1 FDA Drug

• 1 other identifier: D7830C00001
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase 1, first-in-human (FiH), single-ascending-dose (SAD) study, will assess the safety and tolerability and characterize the pharmacokinetics (PK) of AZD2693, following subcutaneous (SC) SAD administration of AZD2693 in male and female subjects of non-childbearing potential in overweight but otherwise healthy subjects, and healthy Chinese and Japanese subjects.

Conditions

Metabolic Disorders; Non-alcoholic Steatohepatitis

Keywords

Single-ascending-dose; First-in-human; Chinese; Japanese; Dyslipidemia; Type II diabetes mellitus; Non-alcoholic fatty liver disease

Outcome Measures

Primary Outcomes (1)

• Number of subjects experiencing adverse events and serious adverse events

  To investigate the safety and tolerability of SC administration of SAD of AZD2693

  From baseline (Day 1) until Day 112 (Week 16, Final follow-up)

Secondary Outcomes (20)

• Area under the concentration-time curve from time zero extrapolated to infinity (AUC)

  At Day 1 pre-dose, 0.25 hours [h], 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose

• Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC(0-48h)]

  At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose

• Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)

  At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose

• Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)

  At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose

• Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)

  At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose

Study Arms (9)

Cohort 1 healthy subjects: AZD2693 Dose 1

EXPERIMENTAL

Subjects will receive a subcutaneous (SC) injection of single dose 1 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 2 healthy subjects: AZD2693 Dose 2

EXPERIMENTAL

Subjects will receive a SC injection of single dose 2 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 3 healthy subjects: AZD2693 Dose 3

EXPERIMENTAL

Subjects will receive a SC injection of single dose 3 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 4 healthy subjects: AZD2693 Dose 4

EXPERIMENTAL

Subjects will receive a SC injection of single dose 4 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 5 healthy subjects: AZD2693 Dose 5

EXPERIMENTAL

Subjects will receive a SC injection of single dose 5 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 6 healthy subjects: AZD2693 Dose 6

EXPERIMENTAL

Subjects will receive a SC injection of single dose 6 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 7 healthy Japanese subjects: AZD2693 Dose 7

EXPERIMENTAL

Subjects will receive a SC injection of single dose 7 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 8 healthy Japanese subjects: AZD2693 Dose 8

EXPERIMENTAL

Subjects will receive a SC injection of single dose 8 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Cohort 9 healthy Chinese subjects: AZD2693 Dose 9

EXPERIMENTAL

Subjects will receive a SC injection of single dose 9 of AZD2693 or placebo matched to AZD2693 on Day 1.

Drug: AZD2693; Drug: Placebo

Interventions

AZD2693 DRUG

Subjects will receive SC injection of AZD2693 as per the arms they are randomized.

Cohort 1 healthy subjects: AZD2693 Dose 1; Cohort 2 healthy subjects: AZD2693 Dose 2; Cohort 3 healthy subjects: AZD2693 Dose 3; Cohort 4 healthy subjects: AZD2693 Dose 4; Cohort 5 healthy subjects: AZD2693 Dose 5; Cohort 6 healthy subjects: AZD2693 Dose 6; Cohort 7 healthy Japanese subjects: AZD2693 Dose 7; Cohort 8 healthy Japanese subjects: AZD2693 Dose 8; Cohort 9 healthy Chinese subjects: AZD2693 Dose 9

Placebo DRUG

Subjects will receive SC injection of placebo matched to AZD2693, as per the arms they are randomized.

Cohort 1 healthy subjects: AZD2693 Dose 1; Cohort 2 healthy subjects: AZD2693 Dose 2; Cohort 3 healthy subjects: AZD2693 Dose 3; Cohort 4 healthy subjects: AZD2693 Dose 4; Cohort 5 healthy subjects: AZD2693 Dose 5; Cohort 6 healthy subjects: AZD2693 Dose 6; Cohort 7 healthy Japanese subjects: AZD2693 Dose 7; Cohort 8 healthy Japanese subjects: AZD2693 Dose 8; Cohort 9 healthy Chinese subjects: AZD2693 Dose 9

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-child-bearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria: A. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone levels in the postmenopausal range B. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• Have a body mass index between 25 and 32 kg/m\^2 for healthy subjects, or between 18 and 32 kg/m\^2 for healthy Japanese and Chinese subjects, and weigh at least 60 kg (or 50 kg for healthy Japanese and Chinese subjects)
• Willing to participate in mandatory retrospective genotyping analysis for PNPLA3 1148M and the provision of blood and buccal swab samples for this analysis
• Willing and able to comply with all required study procedures
• Applicable to Japanese and Chinese subjects only:
• A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan
• A Chinese subject is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China

You may not qualify if:

• History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study
• History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP
• Any clinically significant cardiovascular event within the last 6 months prior to the Screening Visit
• Any laboratory values with the following deviations at Screening or Day -1:
• Alanine aminotransferase \> upper limit of normal (ULN)
• Aspartate aminotransferase \> ULN
• Creatinine \> ULN
• White blood cell count \< lower limit of normal (LLN)
• Hemoglobin \< LLN
• Platelet count \< LLN
• Activated partial thrombin time \> ULN and prothrombin time \> ULN
• Estimated glomerular filtration rate (eGFR) \< 90 mL/min/1.73m\^2 calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and applying the standard correction factor for African Americans to the CKD-EPI by multiplying the GFR estimate by 1.159; (eGFR \< 60 mL/min/1.73m\^2 for healthy Japanese and Chinese subjects) and confirmed
• Urinary albumin-to-creatinine ratio \> 3 mg/μmol (30 mg/g)
• Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Glendale, California, 91206, United States

Location

Related Publications (1)

• Armisen J, Rauschecker M, Sarv J, Liljeblad M, Wernevik L, Niazi M, Knochel J, Eklund O, Sandell T, Sherwood J, Bergenholm L, Hallen S, Wang S, Kamble P, Bhat M, Maxvall I, Wang Y, Lee RG, Bhanot S, Guo S, Romeo S, Lawitz E, Fjellstrom O, Linden D, Blau JE, Loomba R. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. J Hepatol. 2025 Jul;83(1):31-42. doi: 10.1016/j.jhep.2024.12.046. Epub 2025 Jan 9.

  PMID: 39798707 DERIVED

MeSH Terms

Conditions

Metabolic Diseases; Non-alcoholic Fatty Liver Disease; Dyslipidemias; Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases; Lipid Metabolism Disorders; Diabetes Mellitus; Glucose Metabolism Disorders; Endocrine System Diseases

Study Officials

• David Han, MD

  Parexel Early Clinical Unit - Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects in this study will be categorized as follows: 1. Overweight/mildly obese, but otherwise healthy subjects: There will be 6 cohorts, with 8 subjects in each cohort. 2. Japanese and Chinese subjects: There will be 2 cohorts for Japanese subjects, and one cohort for Chinese subjects, with 8 subjects in each cohort.

Study Record Dates

• First Submitted: October 22, 2019
• First Posted: October 29, 2019
• Study Start: October 28, 2019
• Primary Completion: November 12, 2021
• Study Completion: November 12, 2021
• Last Updated: November 26, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• 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.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified 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.

Locations

US (1)