Dose-Ranging Safety, Tolerability, and Efficacy Study of AZD2373 in Participants With APOL1-Mediated Kidney Disease

Open to people ages 18-65

• Age: Male and female participants aged 18 to 65 years, inclusive at the time of informed consent.
• Participants who have high-risk APOL1 genotype (G1/G1; G1/G2; G2/G2). The screening period can be extended if there are delays related to the shipment, handling, or processing of genotype results.
• A geometric mean UACR ≥ 300 mg/g calculated based on the mean of readings taken from 3 FMV urine samples collected on 3 consecutive days. Since the mean will be assessed for eligibility, any of the 3 readings may fall below 300 mg/g.
• eGFR ≥ 25 mL/min/1.73m2.
• Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• Participants with diagnosis of Type 1 diabetes mellitus.
• Body Mass Index > 45 kg/m2.
• SBP > 180 mmHg/DBP > 110 mmHg (measured when the participant is considered to be at steady state, and preferably when they have taken their BP medications that same day).
• QTcF > 470 ms.
• Acute coronary syndrome/Acute myocardial infraction +/- coronary intervention with Percutaneous coronary intervention or Coronary artery bypass grafting within 6 months.
• Transient ischaemic attack/ stroke within 3 months.
• High second to third degree AV block or clinically significant sinus node dysfunction untreated with pacemaker.
• A history of ventricular arrhythmias requiring treatment.
• Participants with Type 2 diabetes mellitus must be excluded if ANY of the following conditions are present:
  1. Current or any past use of insulin
  2. Screening Haemoglobin A1c > 8.0%
  3. Receiving more than one oral anti-hyperglycaemic agent (excluding SGLT inhibitors which can be taken in addition to one other oral anti-hyperglycaemic agent).
• Participant on kidney replacement therapy (dialysis or kidney transplant) or any other organ transplant.
• History or serologic evidence of autoimmune-mediated glomerular disease including but not limited to: lupus nephritis (positive lupus serology), ANCA associated vasculitis (antineutrophil cytoplasmic antibody), membranous nephropathy (anti-phospholipase A2 receptor antibody or other autoantibody associated with membranous nephropathy), anti-GBM disease (anti-GBM antibody), or IgA nephropathy.
• Another underlying cause of kidney disease that is not associated with APOL1, including but not limited to polycystic kidney disease or, congenital anomalies of the kidney and urinary tract.
• History of a diagnosed coagulopathy, a major unexplained bleeding event, or other high-risk bleeding diathesis.