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

This is a randomised, double-blind, placebo-controlled, parallel-group Phase III study to evaluate the effect on the reduction of LDL-C and the safety and tolerability of AZD0780 versus placebo, administered as xx mg once daily orally, on top of a high intensity lipid-lowering regimen. The target population is adults ≥ 18 years of age with LDL-C ≥ 55 mg/dL and history of clinical ASCVD or ≥ 70 mg/dL and at risk for a first ASCVD event.

The study will be conducted at approximately 470 centres in approximately 21 countries.

The screening period is up to 14 days (and may be conditionally extended), starts at the date of signed informed consent, and ends on the day before the randomisation visit. Participants will be randomised in a 1:1 ratio to either AZD0780 or placebo for a treatment period of 52 weeks and a 10-day safety follow-up. Those randomised to the AZD0780 group will receive AZD0780 xx mg orally once daily during the treatment period, while those in the placebo group will receive matching placebo. The study will include approximately 2800 randomised participants. An independent data monitoring committee will, on a regular basis, review accumulating data from the study, evaluate adverse effects of the IMP, and make recommendations regarding whether to halt or modify the study.

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:

• Clinical ASCVD is defined as MI, stable or unstable angina, coronary or other arterial revascularisation, ischaemic stroke, or peripheral artery disease.
• A participant is considered at risk for a first ASCVD event if the participant has 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/AHA or ESC or other relevant national clinical guidelines for risk assessment to identify 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) in participants without clinical ASCVD but at risk for a first ASCVD event
• Participants should receive a background lipid lowering regimen anticipated to achieve at least a ~50% reduction in LDL-C. Except in cases of intolerance, the regimen should include a high intensity statin therapy or lower intensity statin therapy in combination with an oral agent with proven outcome benefit (eg, ezetimibe and/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 or plasma apheresis within 12 months prior to screening, or any other underlying known disease or condition that may interfere with interpretation of the clinical study results 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 is acceptable 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 or participants whose thyroid replacement therapy was initiated or modified within the last 3 months prior to screening
• Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 months prior 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 screening visit or planned use during the study or inclisiran within 18 months of the screening visit or planned use during the study. Any other approved PCSK-9 inhibitor use within 5 half-lives prior to the screening visit or planned use during the study.