A Phase III Study to Assess the Effect of AZD0780 on LDL-C in Patients With Clinical ASCVD or at Risk for a First ASCVD Event

Inclusion Criteria:

• ≥ 18 years of age at the time of signing the ICF

• History of clinical ASCVD or at risk for a first ASCVD event:

1. Clinical ASCVD is defined as MI, stable or unstable angina, coronary or otherarterial revascularisation, ischaemic stroke, or peripheral artery disease.

2. A participant is considered at risk for a first ASCVD event if the participanthas one or more of the following conditions: atherosclerotic vascular disease (≥ 50% stenosis in ≥ 2 coronary artery territories or in ≥ 2 vascular beds [coronary, carotid, lower extremity], diagnosed by any imaging modality),diabetes mellitus, hypertension, cigarette smoking, chronic kidney disease (moderate to severe stage), or obesity. Investigators can also use the ACC/AHAor ESC or other relevant national clinical guidelines for risk assessment toidentify participants with at least moderate risk for ASCVD.

• Fasting serum LDL-C by central laboratory at screening as follows: LDL-C ≥ 55 mg/dL (≥ 1.4 mmol/L) in participants with clinical ASCVD or ≥ 70 mg/dL (≥ 1.8 mmol/L) inparticipants without clinical ASCVD but at risk for a first ASCVD event

• 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).

Thus, the background lipid-lowering therapy must consist of one of the following:

• A high intensity LDL lowering regimen

(i) A high intensity statin regimen, as defined by country specific guidelines OR: (ii) A lower intensity statin regimen in combination with ezetimibe and/or bempedoic acid :

OR:

• A maximum tolerated statin regimen - Oral combination therapy with ezetimibe and/or bempedoic acid is strongly recommended.

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

Exclusion criteria:

• Homozygous familial hypercholesterolaemia, known diagnosis of HeFH, LDL apheresis orplasma apheresis within 12 months prior to screening, or any other underlying knowndisease or condition that may interfere with interpretation of the clinical studyresults as judged by the Investigator.

• Any of the following laboratory values at screening:

• Calculated eGFR < 15 mL/min/1.73 m2

• AST or ALT > 3 × ULN

• TBL > 2 × ULN (except for patients with Gilberts syndrome, where TBL 3 × ULN isacceptable provided direct bilirubin < 1.5 × ULN)

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

• Creatine kinase > 5 × ULN

• Urine albumin-to-creatinine ratio ≥ 500 mg/g

• Uncontrolled type 2 diabetes mellitus 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 monthsprior to screening or planned use during the study.

• Use of gemfibrozil within 1 week prior to screening or planned use during the study.

• Use of PCSK-9 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. Any other approved PCSK-9 inhibitoruse within 5 half-lives prior to the screening visit or planned use during thestudy.