A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy

This is a Phase 1, first in human, unblinded, ascending dose study which will consist of a SAD (single ascending dose) part and an Optional part.

The SAD part of the study will assess the single doses of AZD4063 across 4 cohorts. It will consist of:

• A Screening period
• A Treatment period: The participants will receive a single dose of AZD4063 by subcutaneous (SC) injection
• A Follow-up period

Optional cohorts may be added based on emerging safety, PK and PD data of the preceding cohorts.

Inclusion criteria

• Participants must be 18 to 80 years of age inclusive, at the time of Screening
• Participants with pre-existing positive screening for R14 del PLN mutation
• Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography
• Participants with New York Heart Association (NYHA) function class I-III
• Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure
• Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D)
• Participants with Body mass index (BMI) within the range 18-35 kg/m2
• Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception
• All women of childbearing potential must have a negative pregnancy test at the Screening Visit.

Exclusion criteria

• Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
• Known to have tested positive for Human immunodeficiency virus (HIV)
• Any known genetic mutation associated with hereditary electrical or structural disease
• Congenital long QT syndrome
• QTcF < 350 ms
• Known Short QT syndrome (SQTS) or family history of SQTS
• Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months
• Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator
• History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% > stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting)
• Routinely scheduled outpatient intravenous infusions for heart failure
• Uncontrolled hypertension
• Significant primary valvular disease
• Congenital heart disease
• Left ventricular wall thickness of > 13 mm or with any relative with hypertrophic cardiomyopathy (HCM)
• Recent acute presentation of myocarditis
• Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis)
• Alcohol consumption in excess
• Any laboratory values with the following deviations:

• Alanine Transaminase >2 upper normal limit (ULN)
• Aspartate Transaminase >2 ULN
• Total bilirubin > 2 x ULN
• Estimated GFR < 30 mL/min/1.73 m2
• Hemoglobin <10g/dL
• Any vital sign values with the following deviations at Screening

• Systolic blood pressure > 160 mmHg
• Diastolic blood pressure > 100 mmHg
• Pulse rate > 100 beats per minute
• Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM)
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity
• Any history of cardiotoxic drug exposure with documented cardiomyopathy
• Noncardiac condition that limits expected lifespan to less than 1 year
• Participation in another clinical study with a study intervention administered in the last 3 months
• Participants with a known hypersensitivity to AZD4063
• Participants who have previously received AZD4063 as part of this study
• Participants who are part of a gene therapy trial