The purpose of this study is to assess the efficacy and safety of AZD2373 in participants diagnosed with APOL1-Mediated Kidney Disease (AMKD) who are homozygotes or compound heterozygotes for APOL1 high-risk genotypes (G1 and G2). The primary hypothesis to be evaluated is that AZD2373, compared with placebo, will result in a greater reduction in UACR as assessed by the relative change from Baseline in UACR at Week 30.

This is a Phase 2b study to assess efficacy and safety of AZD2373 involving 3 study treatment arms in Part A and 2 study treatment arms in Part B where participants and study personnel including study investigators are blinded to the assigned treatment.

Participants with 300 mg/g or greater UACR and eGFR ≥ 25mL/min/1.73m2 will be recruited into the study. Participants on kidney replacement therapy (dialysis or kidney transplant) or any other organ transplant will be excluded.

The study will have Part A and Part B. Part A (n = 96) will have a 1:1:1 randomization of participants to subgroups receiving weekly subcutaneous injections of 50 mg AZD2373, 150 mg AZD2373, and placebo. Part B (n = 40) will have a 4:1 randomization of participants to subgroups receiving every other week subcutaneous injections of 150 mg or placebo. Part B will begin after Part A is completely enrolled.

Both Part A and Part B will have same participant criteria and schedules. The SoA and visit schedule will not change for Part B.

All participants will remain in the study on treatment until the last participant has completed 30 weeks of treatment. The treatment duration will be up to minimum of 30 weeks of study treatment.

All participants will have the opportunity to enter the OLE study.

Inclusion Criteria:

• Age: Male and female participants of African descent (including, but not limited to, Black, Black African, Black Caribbean, African American, Afro-Caribbean, Afro-Latino, West African, Mixed Black backgrounds, or other self-identified African diaspora heritage) aged 18 to 70 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.

Exclusion Criteria:

• 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, except participants with bundle branch block who should excluded if QTcF> 480 ms.

• Acute coronary syndrome/Acute myocardial infraction with or without any coronary intervention within 6 months.

• Transient ischaemic attack/ stroke within 3 months.

• High grade (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 past use of insulin for more than 3 months and/or any maintenance therapy with insulin within 2 months of screening.
  2. Screening Haemoglobin A1c > 8.0%
  3. Receiving more than one anti-hyperglycaemic agent (excluding SGLT inhibitors and GLP-1 receptor agonists is permitted if prescribed for a purpose other than glycaemic control which can be taken in addition to one other 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.

• A history of trypanosomiasis or leishmaniasis.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org.

Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

AZD2373 (study drug) and placebo will be provided in identical Accessorized pre-filled glass syringes.

The Interactive Response technology / Randomisation and Trial Supply Management (IRT/RTSM) will provide to the investigator(s) or pharmacists the kit identification number to be allocated to the participant at the dispensing visit.

Routines for this will be described in the IRT/RTSM user manual provided to each centre.