A Phase III Study to Assess the Effect of AZD0780 on LDL-C in Patients With HeFH

Eligibility Criteria

• * ≥ 18 years of age at the time of signing the ICF.
• * Diagnosis of HeFH by genetic confirmation or a definite clinical diagnosis, ie, a score \> x using the Dutch Lipid Network \[Nordestgaard et al 2013\] or equivalent as per internationally accepted diagnostic algorithms (AHA \[Gidding et al 2015\], US MEDPED \[Williams et al 1993\], Simon Broome \[Scientific Steering Committee on behalf of the Simon Broome Register Group 1991\], or Japanese Atherosclerosis Society Guidelines \[Okamura et al 2024\])
• * Fasting serum by central laboratory at screening as follows: LDL-C ≥ 55 mg/dL (≥ 1.4 mmol/L) in participants with HeFH and clinical ASCVD or ≥ 70 mg/dL (≥ 1.8 mmol/L) in HeFH without clinical ASCVD. Clinical ASCVD is defined as MI, stable or unstable angina, coronary or other arterial revascularisation, ischaemic stroke, or peripheral artery disease.
• * Participants should be receiving a maximally tolerated lipid lowering regimen including a maximally tolerated statin. Ezetimibe is further strongly recommended.
• 1. Participants must achieve a stable dose (\> 28 days) of lipid lowering therapies before screening.
• 2. Participants who are judged by the treating physician not to tolerate high intensity statins (according to guidelines, typically, atorvastatin ≥ 40 mg once daily or rosuvastatin ≥ 20 mg once daily) may be included if treated with a low- or moderate intensity statin dose.
• 3. Participants not receiving any statins must have documented intolerable side effects to at least 2 different statins, including one at the lowest standard dose or on a chronic medication that would prohibit the use of a statin (according to the prescribing information for the statin in question).
• * Homozygous familial hypercholesterolaemia, 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.