Assessment of Safety, Tolerability, Immunogenicity, and Pharmacokinetics of AZD3427

This is a multi-center single and multiple ascending dose study (SAD and MAD).

Part A (SAD) will include 7 cohorts (8 healthy volunteers in each cohort) and will randomize to AZD3427 or placebo, in a 6:2 ratio. One cohort will entirely include participants of Japanese descent.

Part B (MAD) will include 6 cohorts (8 heart failure patients in each cohort) and will randomize to AZD3427 or placebo in a 6:2 ratio. Of these, 3 cohorts will contain participants with heart failure with reduced ejection fraction [HFrEF] and the other 3 cohorts will comprise of participants with heart failure with HF with ejection fraction (EF) ≥ 41%. There will be a maximum screening period of 27 days. Participants in part A and B will undergo study drug administration on Day 1. In addition, participants in part B will return for 4 additional doses on Days 8, 15, 22, and 29. Participants will be followed for at least 50 days after the last dose of study drug.

Inclusion criteria

• Part A will include healthy men and non-pregnant, non-lactating females of non-childbearing potential with a body mass index (BMI) of 18-30 kg/m^2 and a weight of 55-100 kg. One cohort will require participants be of Japanese descent
• Part B will include men and non-pregnant, non-lactating females of non-childbearing potential
• Participants have a BMI of 18-40 kg/m^2 and a weight of 55-136 kg
• Participants with a diagnosis of stage C HF New York Heart Association (NYHA) Class I-III on stable medical therapy for at least 12 weeks
• Participants with diagnosis of HFrEF will be defined as those with EF ≤ 40% and HF with EF ≥ 41%
• Participants either with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) > 125 pg/mL or BNP > 35 pg/mL (46)

Exclusion criteria

Both Part A and Part B will exclude participants with any of the following:

• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study drug or planned surgical procedure before study completion
• History of vascular and left ventricular aneurysms or prior dissections
• Any history of joint hypermobility, Marfan's syndrome, or any connective tissue disorder
• Clinical signs and symptoms consistent with Coronavirus disease-19 or confirmed infection within the last 4 weeks
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity injection devices or to drugs with a similar chemical structure or class to AZD3427 or any component of AZD3427

In addition, Part A will exclude participants with any of the following:

• Alanine Aminotransferase (ALT) > Upper limit of normal (ULN)
• Aspartate Aminotransferase (AST) > ULN
• Total bilirubin > ULN (unless due to Gilbert's syndrome)
• Creatinine > ULN
• White blood cell (WBC) count < Lower limit of normal (LLN)
• Hemoglobin < LLN
• Prolonged QTcF > 450 m
• Shortened QTcF < 340 ms
• Family history of long QT syndrome
• PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
• PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third-degree atrioventricular (AV) block, or AV dissociation
• Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS > 110 ms. Participants with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of eg, ventricular hypertrophy or pre-excitation

In addition, Part B will exclude participants with any of the following:

• Atrial fibrillation or flutter occurring in the past year
• Clinically significant ventricular arrhythmias under treatment
• High-degree AV block II-III or sinus node dysfunction
• Implanted permanent pacemaker or implantable cardioverter defibrillator for which the participant is pacing-dependent
• Severe right-sided valvular heart disease; severe mitral regurgitation; moderate or severe mitral stenosis, severe aortic regurgitation and mild, moderate or severe aortic stenosis
• Other conditions where vasodilatory therapy may be contraindicated (hypertrophic obstructive cardiomyopathy, and restrictive cardiomyopathy)
• Congenital heart disease
• NYHA HF Class IV
• Occurrence in the last 6 months of acute coronary syndrome, percutaneous coronary intervention, cerebrovascular accident or transient ischemic attack, HF hospitalization; history or suspicion of cardiac amyloidosis
• ALT > 1.5 × ULN
• AST > 1.5 × ULN
• Total bilirubin > ULN (unless due to Gilbert's syndrome)
• Impaired renal function, defined as eGFR < 30 mL/min/1.73m^2 assessed by the Chronic Kidney Disease Epidemiology Collaboration equation
• WBC < LLN
• Hemoglobin < 10g/L
• PR (PQ) interval prolongation (> 220 ms)
• Participants with persistent BBB and QRS (ECG interval measured from the onset of the QRS complex to the J point) duration > 130 ms. Participants with intraventricular conduction delay and QRS duration < 130 ms