A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4248 in Healthy Participants and Participants With Chronic Kidney Disease and Type 2 Diabetes and to Assess Home Measurements of Creatinine in a Non Interventional Cohort

This is a Phase I, first in human (FIH), randomized, single-blind, placebo-controlled study of AZD4248 involving healthy participants (Parts A and B) and participants with DKD (Part C) and to assess home measurements of creatinine in a prospective, non-interventional cohort in participants with DKD (Part D).

The study consists of 4 parts:

• Part A: SAD. Part A will consist of Parts A1 (single ascending doses in healthy participants), A2 (single dose in healthy Chinese participants), and A3 (IV infusion in healthy participants).
• Part B: MAD. Part B will consist of Parts B1 (multiple ascending doses in healthy participants) and B2 (multiple ascending doses in healthy participants of Japanese descent).
• Part C: Multiple dosing in participants with DKD.
• Part D: Multi-site, non-interventional, prospective cohort evaluation of home-based creatinine self-measurement in participants with DKD.

Key Inclusion Criteria:

• Healthy participants with suitable veins for cannulation or repeated venipuncture.

Parts A and B:

• Have a body mass index (BMI) between 18 and 30 kilograms per millimeter (kg/m2), inclusive.
• For Chinese participants (Part A2): participants are to be Chinese, defined as having both parents and 4 grandparents who are Chinese. This includes second and third generation participants of Chinese descent whose parents or grandparents are living in a country other than China.
• For Japanese participants (Part B2): participants are to be Japanese, defined as having both parents and 4 grandparents who are Japanese. This includes second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.

Part C:

• Have a BMI between 20 and 40 kg/m2, inclusive.
• Have a diagnosis of diabetic kidney disease (DKD).
• Hemoglobin A1C (HbA1c) of ≤ 10.5%.
• Participants are required to be on a stable dose of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 6 weeks prior to Visit 1 and throughout the Screening Period. In addition, participants should be on stable doses of all other medication for ≥ 6 weeks before Screening.

Part D:

• Have a BMI between 20 and 35 kg/m2, inclusive.
• Have a diagnosis of DKD as defined by a) diagnosis of type 2 diabetes (T2D) b) eGFR values and c) urine albumin to creatinine ratio (UACR) values.
• HbA1c of ≤ 10.5%.
• Participants are required to be on a stable dose of ACEi or ARB for at least 6 weeks prior to Visit 1 and throughout the Screening Period. In addition, participants should be on stable doses of all other medication for ≥ 6 weeks before Screening.
• Participants must be able and motivated to use the home creatinine device and smartphone independently by successfully performing the test without assistance from site staff.
• Participants must be able to read and understand English sufficient to participate in site visits and home testing.

Key Exclusion Criteria:

• History of any clinically important disease or disorder which may put the participant at risk because of participation in the study or influence the results.
• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or human immunodeficiency virus (HIV).

Parts A and B:

• History or presence of gastrointestinal, hepatic, or renal disease.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4248.
• Participants who have previously received AZD4248.

Part C:

• History or presence of gastrointestinal, hepatic, or renal disease.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4248.
• Use of drugs that are strong or moderate CYP3A4 inhibitors/inducers or P-gp inhibitors from within 3 weeks before Screening until the end of the last sample collection.
• Participants who have previously received AZD4248.
• Participants on serum creatinine-altering drugs should be on long-term treatment at a stable dose prior to study entry.
• Expected change of dosing regimen during the study.
• History of clinically significant heart or vascular disease.
• New York Heart Association Class 2, 3, or 4 or history of hospitalization for heart failure within 6 months of screening.
• Ventricular arrhythmias requiring treatment.
• Amputation due to peripheral artery disease.
• Severe chronic obstructive pulmonary disease as judged by the Investigator or hospitalization for exacerbation in the last 6 months.

Part D:

• Participants on serum creatinine-altering drugs should be on long-term treatment at a stable dose prior to study entry.
• Expected change of dosing regimen during the study.