Safety and Tolerability Study of AZD4831 in Patients With Heart Failure.

This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in
patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection
Fraction (HRmrEF). The study will be conducted at approximately 10 sites in 5 countries (USA,
Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for
eligibility, signing the informed consent and enrolled to the study at visit 1. The study
will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized
at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for 90 days.
After approximately 30 days of treatment, an interim analysis will be done to analyse the
safety, tolerability and target engagement. After the evaluation, the recruitment to Part B
may proceed. In Part B the remaining 59 patients will be randomized and treated for
approximately 90 days.

Inclusion Criteria:

Informed consent

1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
CSP

2. Provision of signed and dated, written informed consent form prior to any mandatory
study specific procedures, sampling, and analyses

Age

3. Patient must be 45 to 85 years of age inclusive, at the time of signing the informed
consent form

Type of patient and disease characteristics

4. Signs and symptoms of HF in judgement of Investigator AND

1. Stable NYHA II-IV and

2. Ejection fraction (EF) ≥ 40 % and

3. Elevated NT-proBNP or BNP in the last 1 year defined as:

o Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus rhythm,
NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF),

or

o Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 ng/L with
sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF

4. And at least one of the following:

- Hospitalization with HF as primary cause in last 12 months

- Structural heart disease on echo according to ESC guidelines i.e. either
enlarged Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM
index > 95 g/m2 in women and > 115 g/m2 in men)

- Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg at
exercise

- Spectral tissue Doppler echocardiography - E/e' ratio ≥13 at rest

Weight

5. Body Mass Index (BMI) range 18-35kg/m2

Sex

6. Male or female of nonchildbearing potential

Reproduction

7. Female patients must be 1 year post-menopausal or surgically sterile

8. Male patients must be surgically sterile or using an acceptable method of
contraception (defined as barrier methods in conjunction with spermicides) for the
duration of the study (from the time they sign consent) and for 3 months after the
last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients
must not donate or bank sperm during this same time period

Genetic sampling

9. For inclusion in this genetic research, patients must fulfil all of the inclusion
criteria described above and provide informed consent for the genetic sampling and
analysis

Exclusion Criteria:

Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR
<45 ml/min/1.73m2 or dialysis

Life expectancy < 3 years due to other reasons than cardiovascular disease

Any skin disorder, history of, or ongoing clinically significant allergy/hypersensitivity

Current decompensated HF

Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic,
congenital or any primary cardiomyopathy) in judgment of investigator

Current hemodynamically significant valve disease in opinion of investigator

EF ever documented < 40%

Any current life-threatening dysrhythmia

Probable alternative primary reason for patient's symptoms in judgment of investigator,
including but not limited to:

1. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the
absence of left-sided HF

2. Anaemia: Hb <100 mg/L (10g/dL)

3. Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic O2,
nebulizer or oral steroid therapy)

Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous coronary
intervention (PCI) < 3 months

Known or clinically judged significant macrovascular coronary artery disease (CAD) that has
not been revascularized

Heart transplantation or left ventricular assist device ever

Patients with known thyroid disease with or without treatment or thyroid stimulating
hormone (TSH), triiodothyronine (T3) and thyroxine (T4) outside normal range levels

Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit of normal
(ULN). Resampling will not be allowed during the same screening period if detected abnormal
values do not have reasonable explanation and are not expected to return to normal level
within few days.

Positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus
core antibody, at screening