Assessment of Safety, Tolerability, Immunogenicity, and Pharmacokinetics of AZD3427
Assessment of Safety, Tolerability, Immunogenicity, and Pharmacokinetics of AZD3427
This first-time-in-human (FTIH) study will be conducted to evaluate the safety, tolerability,
 pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single doses of AZD3427
 in healthy volunteers and multiple doses of AZD3427 in patients with heart failure (HF).
This is a multi-center single and multiple ascending dose study (SAD and MAD) planned in 96
 participants. Part A (SAD) will include 6 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 preserved
 ejection fraction [HFpEF]. 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 60-100 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 with a BMI of 18-40 kg/m^2 and a weight of 60-120 kg with a diagnosis of New
 York Heart Association (NYHA) Class I-III on stable medical therapy for at least 12
 weeks. The HFrEF will be defined as those with EF ≤ 40% and HFpEF defined as EF ≥ 50%,
 both with either N-terminal prohormone of brain natriuretic peptide (NT-proBNP) > 125
 pg/mL or BNP > 100 pg/mL

 Exclusion Criteria:

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

 -  Any history of atrial fibrillation or flutter requiring anti-arrhythmic or ablation
 therapy or 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 < LLN

 -  PR (PQ) interval prolongation (> 220 ms)