This is a Phase II, multi-centre, randomized, double-blind, placebo-controlled, crossover study to evaluate the effect of AZD0780 Dose 1 versus placebo on systolic blood pressure (SBP) at Week 4, as measured by 24-hour ambulatory blood pressure monitoring (ABPM) in participants with ASCVD or risk equivalents and LDL-C ≥ 70 mg/dL, on stable medication.

This is a Phase II, multi-centre, randomized, double-blind, placebo-controlled, crossover study to evaluate the effect of AZD0780 Dose 1 versus placebo on systolic blood pressure (SBP) at Week 4, as measured by 24-hour ambulatory blood pressure monitoring (ABPM) in participants with ASCVD or risk equivalents and LDL-C ≥ 70 mg/dL, on stable medication.

Approximately 30 sites in the United Sites will enroll adult participants with Atherosclerotic Cardiovascular Disease or Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol.

Eligible participants will be randomized (1:1) on Period One (1) Day One (1) to One (1) of Two (2) treatment sequences.

Potential participants will be screened to assess their eligibility to enter the study up to 7 days prior to first administration of study intervention. Eligible participants will be randomized to Treatment Sequence AB or BA on Period One (1) Day One (1). A 14-day washout period will be required between the final dose in Period One (1) and start of baseline ABPM in Period Two (2).

In Periods One (1) and Two (2), participants will return to the study site for an outpatient visit (OPV) on Day -1 for the start of the baseline ABPM. The ABPM device will be worn for 25 hours. Participants will return to the study site for an OPV on the following day (Day 1) for removal of the ABPM device and to begin self-administration of AZD0780 or placebo for 29 ± 2 days as per the randomization scheme. First dose of study intervention will be taken after the ABPM device is removed on Day 1 at the study site after the baseline ABPM is qualified (i.e., determined not to require repeat). Additional OPVs will be required on Days 14 (± 2 days), 28 (± 2 days), and 29 (day after Day 28 [± 2 days]). On Days 28 and 29 of each period, the ABPM device will be worn for 25 hours. Study intervention will continue to be taken on each day after the start of Week 4 (Days 28 and 29) 24-hour ABPM for Periods 1 and 2 until a qualified ABPM is obtained. Only 1 repeat may be attempted within 2 days of the end of the first ABPM attempt. Participants will return to the study site for a follow-up visit 14 (± 2) days after the last dose of study intervention in Period Two (2).

Serial pharmacokinetic blood samples will be collected predose and up to 7 hours postdose on Day 14 and predose on Day 28 in each period. Monitoring of adverse events, vital sign measurements, 12-lead electrocardiograms, clinical laboratory tests, and physical examinations will be performed to assess safety and tolerability.

Inclusion Criteria:

1. Participant must be ≥ 18 years of age at the time of signing the informed consent.
2. Participants with a history of ASCVD defined as myocardial infarction, stroke, or symptomatic peripheral arterial disease, or with risk factors hereof.
3. Participants with a fasting serum LDL-C ≥ 70 mg/dL (1.8 mmol/L) at screening.
4. Should be receiving stable SoC therapy for their comorbidities for at least 4 weeks prior to screening. There should be no planned medication or dose changes during study participation.
5. Body mass index ≥ 19.0 kg/m2.
6. Sex: males and females (females of non-childbearing potential).

Exclusion Criteria

1. eGFR < 45 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (2021) at screening.
2. History or presence of gastrointestinal, hepatic, or renal disease, or any other conditions known to interfere with absorption, distribution, metabolism, or excretion of drugs.

4. Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% at screening.

5. Participants with history of coronary artery bypass graft surgery ≤ 6 months prior to screening or percutaneous coronary intervention ≤ 3 months prior to screening.

6. Heart failure with New York Heart Association Class III to IV. 9. Low-density protein or plasma apheresis within 12 months prior to Period 1 Day -1.

10. Uncontrolled hypertension defined as average of triplicate seated SBP > 160 mmHg or DBP > 90 mmHg at screening.

11. Pulse rate after 10 minutes seated rest < 50 or > 100 bpm at screening. 12. Any laboratory values with the following deviations at screening; test may be repeated at the discretion of the investigator if abnormal:

(a) Any positive result on screening for hepatitis B, hepatitis C, or HIV; (b) ALT > 1.5 × ULN; (c) AST > 1.5 × ULN; (d) TBL > ULN; (e) Haemoglobin < 12 g/dL in males or < 11 g/dL in females; (f) Potassium < lower limit of normal. 13. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG as judged by the investigator, including:

1. family history of long QT syndrome;

2. PR interval prolongation > 240 ms;

3. QTcF > 450 ms; (> 470 ms in participants with bundle branch block)

4. any intermittent or persistent high degree atrioventricular-block grade II-III and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias requiring treatment.

   18. Lomitapide within 12 months prior to Period 1 Day -1. 19. Current or previous treatment with drugs for reduction or inhibition of PCSK9 (approved or investigational, eg, evolocumab, alirocumab, or inclisiran) within 12 months prior to Period 1 Day -1.

   20. Fibrate therapy and derivatives are prohibited. 21. Receiving or has received within 14 days of screening, medication that contains a black box warning for significant QT prolongation. A list of prohibited medications can be found in Appendix G.

   22. Nutraceuticals or homeopathic treatments which may have an impact on BP. 26. Participants working 3rd shift or night shifts based on potential changes in circadian rhythm.

   27. Participants with sleep disorders that would affect ABPM measurements, in the investigator's opinion.

   28. Participant arm circumference not appropriate for available ABPM cuff circumference, or participant has a medical device (eg, continuous glucose monitor) that prevents use of the ABPM device, in the opinion of the investigator.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.