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

• Status: Recruiting
• Trial end date: 2022-05-17
• Target enrollment: 0
• Participant gender: All

Summary

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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: AstraZeneca

Criteria

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 with a BMI of 18-40 kg/m^2 and a weight of 55-120 kg with a diagnosis of stage C HF 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 > 35 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:

• 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)