Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40%

Inclusion Criteria:

Part A

1. ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.

2. Documented stable symptomatic HF (New York Heart Association Class II-IV) for atleast 1 month at Screening (Visit 1) (transient HF in the setting of an MI does notqualify), with a medical history of typical symptoms of HF and receiving optimaltherapy for HF as determined by the health-care physician.

3. LVEF > 40% at Screening (Visit 1). All participants will undergo a localechocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF > 40% eligibility criteria before randomisation.

4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be < 50 meters.

5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3)

6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) atScreening (Visit 1) for patients with BMI ≤30 kg/m2.

NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.

The ECG performed at Screening should be used for heart rhythm evaluation.

7.At least one of the following:

1. Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy atthe echocardiogram performed at Screening (Visit 1). Left atrial enlargement isdefined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 mL/m2. Leftventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in men.

2. Spectral tissue Doppler echocardiography - E/e' ratio (average of septal andlateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).

3. Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280 cm/s) (PASP > 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directlymeasured pulmonary capillary wedge pressure > 15 mmHg at rest within the past 12months or > 25 mmHg at exercise documented by right heart catheterisation within 12months prior to Screening (Visit 1).

4. HF decompensation within 6 months before Randomisation (Visit 3), defined ashospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduledvisit without hospitalisation.

8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2

9.Male or female of non-childbearing potential. Part B

1. Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing theinformed consent.

2. Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure ≥ 6 weeksbefore Screening (Visit 1), and receiving optimal therapy for HF as determinedby the health-care physician, with at least intermittent need for diuretictreatment.

3. LVEF >40% and evidence of structural heart disease (ie, left ventricularhypertrophy orleft atrial enlargement [defined by at least one of the following:LAenlargement and/or left ventricular hypertrophy at the echocardiogramperformed at Screening (Visit 1). Left atrial enlargement is defined by atleast 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34mL/m2. Left ventricular hypertrophy is defined by septal thickness or posteriorwall thickness ≥ 1.1 cm orLVMI > 95 g/m2 in women and > 115 g/m2 in men.]) documented by the most recentechocardiogram, or cardiacmagnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If noechocardiogram is available, it can be performed at Screening (Visit 1).

4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be < 50meters

5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 2).

6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrialfibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤ 30 kg/m2.NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrialfibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.The ECG performed at Screening should be used for heart rhythm evaluation

7. Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2

8. Male or female of non-childbearing potential.

Exclusion Criteria: Part A

1 eGFR < 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaborationformula) at Screening (Visit 1).

2. Systolic blood pressure < 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3blood pressure lowering medications or ≥ 180 mmHg irrespective of treatments atRandomisation

3. Heart rate > 110 bpm or < 50 bpm at Randomisation

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

5. History or ongoing allergy/hypersensitivity reactions to drugs (including but notlimited to rash, angioedema, acute urticaria).

6. Presence of any disease or condition rather than HF constituting the main reasonfor limiting the ability to exercise/reduced exercise capacity.

7. Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1)

8. Documented history of ejection fraction ≤ 40%.i.e. HF with recovered ejectionfraction. Transient ejection fraction decrease e.g. in the setting of an MI does notapply

9. Any planned cardiovascular procedure (eg, coronary revascularisation, ablation ofatrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery,etc).

10. Any cardiac event (eg, myocardial infarction, unstable angina), coronaryrevascularisation (percutaneous coronary intervention or coronary artery bypassgrafting), ablation of atrial fibrillation/flutter, valve repair/replacement,implantation of a cardiac resynchronisation therapy device within 12 weeks prior toScreening (Visit 1) or between Screening and Randomisation. Patients who underwent asuccessful atrial fibrillation/flutter cardioversion, can be enrolled in the studyafter 4 weeks.

11. Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/withoutanaemia requiring ongoing or planned IV iron treatment.

12. Participants with hyperthyroidism, uncontrolled hypothyroidism (including butnot limited to TSH ≥10 mIU/mL), or any clinically significant thyroid disease asjudged by the investigator.

13. ALT or AST ≥ 2 × ULN at Screening (Visit 1).

14. Pulmonary arterial hypertension, chronic pulmonary embolism, severe pulmonarydisease including COPD (ie, requiring home oxygen, chronic nebulizer therapy orchronic oral steroid therapy, or hospitalization for exacerbation of COPD requiringventilatory support within 12 months prior to Screening (Visit 1).

15. Any active infection requiring oral, intravenous or intramuscular treatment atScreening (Visit 1) and/or at Randomisation.

23 Any signs or confirmation of COVID-19 infection:

• Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks priorto Screening (Visit 1) or at Randomisation.

• Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 1).

24. Any concomitant medications known to be a potent CYP3A4 inducers orinhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil

25. Previous enrolment and randomisation in the present study. (Participantswho where screened and screen failed and not randomised in Part A can bescreened for possible entry to Part B). All exclusion criteria in Part A are applicable to Part B with the followingexceptions: Exclusion criteria 4; 19 Exclusion Criteria specific for Part B only [criteria numeration for Part B]

26. Life expectancy < 2 years due to other reasons than cardiovascular disease.

27. HF due to any of the following: known infiltrative cardiomyopathy (eg, amyloid,sarcoid, lymphoma, endomyocardial fibrosis), active myocarditis, constrictivepericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy orobstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricularcardiomyopathy/dysplasia (ARVC/D), or uncorrected primary valvular disease.

28. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonarydisease including COPD (ie, requiring home oxygen, chronic nebulizer therapy orchronic oral steroid therapy, or hospitalization for exacerbation of COPD requiringventilatory support within 12 months prior to Screening [Visit 1]).