A Phase IIb Study of AZD5462 in Patients With Chronic Heart Failure

This is a Phase IIb randomized, double-blind, placebo-controlled, multi-center, dose-ranging study to evaluate the efficacy, safety, and pharmacokinetic (PK) of AZD5462 on top of standard of care in 2 cohorts of participants with HF: Cohort A, and Cohort B.

The study will include 3 periods and approximately 12 study visits:

• Screening period of up to 4 weeks (at least 1 study visit)
• Treatment period of 24 weeks (8 study visits)
• Follow-up period of 4 weeks (3 study visits)

Eligible participants in each cohort will be randomized equally 1:1:1:1 to receive a once daily dose (OD) of 3 dose levels (low, medium, or high) oral dose of AZD5462 tablets or placebo.

Inclusion criteria

• Participants must have a pre-existing diagnosis of HF NYHA FC II to IV.
• Participants must be on stable HF standard of care medication for at least 4 weeks prior to consent and during the Screening period.
• Minimum body mass index (BMI) of 18 kilograms per meter square (kg/m^2) at Screening.
• For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential.
• All male participants should refrain from fathering a child or donating sperm until 3 months after the final study Follow-up Visit. Non-sterilised male participants should avoid fathering a child either by true abstinence or use of a condom for all sexual intercourse with a female partner of childbearing potential from the first dose until 3 months after the final Follow-up Visit.

Exclusion criteria

• Historical or current evidence of a clinically significant disease or disorder including, but not limited to:

• Myocardial infarction, stroke, transient ischaemic attack, coronary artery bypass grafting, or percutaneous coronary intervention within 12 weeks prior to consent or transcatheter structural heart interventions or cardiac valve surgery within 6 months prior to consent.
• Sarcoidosis, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, or hypertrophic (obstructive) cardiomyopathy.
• History of untreated clinically significant valve disease or a Screening confirmation of severe aortic stenosis, severe mitral stenosis, moderate or severe aortic insufficiency or severe mitral insufficiency.
• Amyloidosis, Fabry disease, or haemochromatosis.
• Pericardial disease (i.e., visually significant white pericardium on echocardiogram).
• Known coagulation disorders.
• Current diagnosis of active hepatitis.
• Severe pulmonary disease that is not expected to improve over time, as assessed by the investigator.
• Decompensated HF or any cardiopulmonary hospitalisation, except planned hospitalisation without worsening of cardiac or pulmonary functions, within 4 weeks prior to consent or during the Screening period.
• History of active malignancy within 2 years, except for fully excised or treated basal cell carcinoma, or ≤ 2 squamous cell carcinomas of the skin and participants who are under investigation for breast or cervical cancer, including participants with a pap smear of grade ≥ 3.
• History of hypersensitivity to AZD5462 or any component of AZD5462 drug product.
• Known history of drug or alcohol abuse within 24 months of Screening.
• Congenital long QT syndrome or history of QT prolongation associated with other medications that required discontinuation of that medication.
• Cardiac ventricular arrhythmia that requires treatment.
• History of or anticipated heart transplant.
• Current or planned cardiac resynchronization therapy/bi-ventricular pacemaker or mechanical assist device implantation.
• Any planned highly invasive cardiovascular procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter etc).
• Positive hepatitis C antibody, or hepatitis B virus surface antigen at Screening. Participants with positive hepatitis B virus core antibody can be included in the study as long as hepatitis B virus surface antigen is negative, and there are no other signs of an active hepatitis B.
• Known to have historically tested positive for Human Immunodeficiency Virus.