A Phase III Study of AZD0780 on Major Adverse CV Events in Patients With a History of ASCVD Events or at High Risk for a First Event

Inclusion Criteria:

• Meets one of the following:

1. Participants with history of an ASCVD event: Participants ≥ 18 years of age atthe time of signing the ICF with a history of MI or ischaemic stroke suspectedto be due to atherosclerotic vascular disease ≥ 1 month prior to randomisation (presumed lacunar or cardioembolic strokes are not qualifying events), orrevascularisation for symptomatic lower limb PAD any time prior to screeningAdditional risk factors based on the level of the LDL-C and timing of MI orstroke:o Participants with an LDL-C ≥ 75 mg/dL (≥ 1.9 mmol/L) need to have at leastone of the other additional risk factors (i to viii) below.ii) T2DM requiring ongoing medical therapy iii) Age ≥ 65 years v) Previousabove ankle amputation due to PAD vi) Previous diagnosis of non-end stage CKD

2. Participants at increased risk of a first ASCVD event: Male participant ≥ 50years of age or female participant ≥ 55 years of age at the time of signing theICF with LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L), with no prior history of MI,ischaemic stroke due to atherosclerotic disease, or leg revascularisation forsymptomatic lower limb PAD, and with diagnostic evidence of at least one of thefollowing disease categories (i, ii, or iii):

(i) Significant atherosclerotic artery disease (ii) High-risk Type 1 or Type 2diabetes mellitus with manifestation of at least one of the following end-organdiseases:

1. Nephropathy - Persistent (≥ 2 readings) microalbuminuria (urinealbumin/creatinine ratio ≥ 30 mg/g) and/or persistent eGFR < 60 mL/min/1.73 m2.At least one reading must come from the medical record within the last 12months in addition to the reading from screening

2. Retinopathy - Treated diabetic retinopathy (surgical intervention or injectabletherapy) or prior diagnosis made by a relevant healthcare specialist

3. Neuropathy - Treated neuropathy (medical therapy for pain relief or symptomalleviation) or prior diagnosis made by a relevant healthcare specialist

4. ABI < 0.9 or > 1.4 - confirmed either in study during screening orrandomisation, or from the medical record within the last 5 years (iii)Documented atherosclerosis of less significanceFor (ii) and (iii), participants need to have at least one of the additionalrisk factors below:

5. CKD with eGFR x mL/min/1.73 m2

6. Current tobacco use

7. Age ≥ 65

8. T2DM (if included on the less significant atherosclerosis criterion iii)

• Participants should receive a background lipid lowering regimen anticipated toachieve at least a ~50% reduction in LDL-C. Except in cases of intolerance, theregimen should include a high intensity statin therapy or lower intensity statintherapy in combination with an oral agent with proven outcome benefit (eg, ezetimibeand/or bempedoic acid).

Participants must achieve a stable background lipid lowering therapy > 28 days before screening.

Exclusion criteria:

• Any underlying known disease, or condition including homozygous familialhypercholesterolaemia, or LDL or plasma apheresis within 12 months prior torandomisation, that, in the opinion of the investigator, might interfere with theinterpretation of the clinical study results.

• Any revascularisation procedure planned within the next 3 months.

• Available imaging assessment within the last 3 years showing either coronary calciumscore of zero, or a coronary computed tomography angiography with noatherosclerosis.

• Calculated eGFR < 15 mL /min/1.73 m2 at screening.

• Any laboratory values with the following deviations at screening:

• AST or ALT > 3 × ULN

• TBL > 2 × ULN (except for participants with Gilbert's syndrome where TBL 3 ×ULN is acceptable provided direct bilirubin < 1.5 × ULN)

• Fasting triglycerides ≥ 400 mg/dL (≥ 4.52 mmol/L).

• Creatine kinase > 5 × ULN

• Urine albumin/creatinine ratio ≥ 500 mg/g

• Uncontrolled T2DM defined as HbA1c ≥ 9.5% at screening.

• Inadequately treated hypothyroidism defined as TSH > 1.5 × ULN at screening orparticipants whose thyroid replacement therapy was initiated or modified within thelast 3 months prior to screening.

• Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 monthsof screening or planned use during the study.

• Use of gemfibrozil within one week prior to the Screening Visit or planned useduring the study.

• Use of PCSK9 inhibitors: evolocumab/alirocumab within 12 weeks of the ScreeningVisit or planned use during the study, or inclisiran within 18 months of theScreening Visit or planned use during the study, or any other approved PCSK9inhibitor use within 5 half lives prior to the Screening Visit or planned use duringthe study.