WO2025238159A1

WO2025238159A1 - Combination therapy comprising azd0780 and ezetimibe

Info

Publication number: WO2025238159A1
Application number: PCT/EP2025/063419
Authority: WO
Inventors: Jaya Birgitte Rosenmeier; Eva HURT DE CAMEJO; Michael Charles Mccarthy
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2024-05-16
Filing date: 2025-05-15
Publication date: 2025-11-20
Anticipated expiration: 2026-11-16

Abstract

A method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of AZD0780 or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

Description

COMBINATION THERAPY COMPRISING AZD0780 AND EZETIMIBE

This application claims priority from U.S. Provisional Patent Application No. 63/648,269, filed May 16, 2024, U.S. Provisional Patent Application No. 63/728,209, filed December s, 2024 and U.S. Provisional Patent Application No. 63/754,004, filed February 5, 2025, the disclosure of which is incorporated by reference herein in their entirety.

The present disclosure relates to methods of lowering LDL-C levels, reducing cardiovascular risk and/or treating cardiovascular disease in a patient in need thereof.

Background

PCSK9, also referred to as “proprotein convertase subtilisin/kexin 9”, is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol (LDL-C) via the enhanced degradation of the LDLRs independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9/LDLR complex is internalized into endosomal/lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes/lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.

For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins have failed to achieve proportional LDL-C lowering effects.

Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDLR, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab showed an about 60-75% decrease in LDL levels. These antibodies lower LDL-C by as much as 60% and lower cardiovascular event rates (Sabatine 2017). The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body.

Cardiovascular diseases often require management over a person’s lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become important factors for patient compliance with maintenance drug treatments.

“AZD0780” refers to a compound with the chemical name 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one structure shown below:

AZD0780 is an effective binder to PCSK9, and is currently in early stage clinical trials. The synthesis of AZD0780 is described in W02020/150473 and W02020/0150474, the contents of which are hereby incorporated by reference in their entirety.

While much progress has been made in the treatment of cardiovascular disease, many patients treated with statins do not reach LDL-C target levels. Accordingly, it is important to develop new cost-effective LDL-C lowering approaches for the effective reduction of cardiovascular risk and treatment of cardiovascular disease.

Summary

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount. In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of AZD0780 or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe, wherein the first amount and the second amount together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) or pharmaceutically acceptable salt thereof and an amount of ezetimibe or a pharmaceutically acceptable salt thereof.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of AZD0780 or pharmaceutically acceptable salt thereof and an amount of ezetimibe.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) or pharmaceutically acceptable salt thereof and an amount of ezetimibe or a pharmaceutically acceptable salt thereof, wherein the amount of AZD0780 or pharmaceutically acceptable salt thereof and the amount of ezetimibe or a pharmaceutically acceptable salt thereof together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of AZD0780 or pharmaceutically acceptable salt thereof and an amount of ezetimibe, wherein the amount of AZD0780 or pharmaceutically acceptable salt thereof and the amount of ezetimibe together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof and a second amount of bempedoic acid or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of AZD0780 or a pharmaceutically acceptable salt thereof and a second amount of bempedoic acid, wherein the first amount and the second amount together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe or a pharmaceutically acceptable salt thereof and a third amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof, wherein the first amount, the second amount and the third amount together comprise a therapeutically effective amount. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of AZD0780 or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe and a third amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid, wherein the first amount, the second amount and the third amount together comprise a therapeutically effective amount.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) or pharmaceutically acceptable salt thereof, an amount of ezetimibe or a pharmaceutically acceptable salt thereof, and an amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of AZD0780 or pharmaceutically acceptable salt thereof, an amount of ezetimibe, and an amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) or pharmaceutically acceptable salt thereof, an amount of ezetimibe or a pharmaceutically acceptable salt thereof and an amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof, wherein the amount of AZD0780 or pharmaceutically acceptable salt thereof, the amount of ezetimibe or a pharmaceutically acceptable salt thereof and the amount of the further agent together comprise a therapeutically effective amount. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject in need thereof comprising administering to the subject an amount of AZD0780 or pharmaceutically acceptable salt thereof, an amount of ezetimibe and an amount of a further agent, where the further agent is selected from one or more statins or bempedoic acid, wherein the amount of AZD0780 or pharmaceutically acceptable salt thereof, the amount of ezetimibe and the amount of the further agent together comprise a therapeutically effective amount.

In some embodiments, disclosed is 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is AZD0780 or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) ezetimibe to said subject.

In some embodiments, disclosed is ezetimibe or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe or a pharmaceutically acceptable salt thereof, and ii) 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is ezetimibe for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe, and ii) AZD0780 or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) bempedoic acid or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is AZD0780 or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) bempedoic acid to said subject. In some embodiments, disclosed is 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, ii) ezetimibe or a pharmaceutically acceptable salt thereof and iii) a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof, to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is AZD0780 or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, ii) ezetimibe and iii) a further agent, where the further agent is selected from one or more statins or bempedoic acid, to said subject.

In some embodiments, disclosed is ezetimibe or a pharmaceutically acceptable salt thereof, for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe or a pharmaceutically acceptable salt thereof, ii) 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)- 2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof, iii) a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof, to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is ezetimibe for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe, ii) AZD0780 or a pharmaceutically acceptable salt thereof, iii) a further agent, where the further agent is selected from one or more statins or bempedoic acid, to said subject. In some embodiments, disclosed is a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) the further agent, ii) 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof, iii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is a further agent, where the further agent is selected from one or more statins or bempedoic acid for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) the further agent, ii) AZD0780 or a pharmaceutically acceptable salt thereof, iii) ezetimibe to said subject.

In some embodiments, disclosed is the use of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is the use of AZD0780 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) ezetimibe to said subject.

In some embodiments, disclosed is the use of ezetimibe or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe or a pharmaceutically acceptable salt thereof and ii) 6'- ([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]- 2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is the use of ezetimibe in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe and ii) AZD0780 or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is the use of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) bempedoic acid or a pharmaceutically acceptable salt thereof to said subject.

In some embodiments, disclosed is the use of AZD0780 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) bempedoic acid to said subject.

In some embodiments, disclosed is the use of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof, ii) ezetimibe or a pharmaceutically acceptable salt thereof and iii) a further agent, where the further agent is selected from one or more statin or bempedoic acid or a pharmaceutically acceptable salt thereof, to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is the use of AZD0780 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof, ii) ezetimibe and iii) a further agent, where the further agent is selected from one or more statin or bempedoic acid, to said subject.

In some embodiments, disclosed is the use of ezetimibe or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe or a pharmaceutically acceptable salt thereof, ii) 6'- ([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]- 2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof, and iii) a further agent, where the further agent is selected from one or more statin or bempedoic acid or a pharmaceutically acceptable salt thereof, to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is the use of ezetimibe in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe, ii) AZD0780 or a pharmaceutically acceptable salt thereof, and iii) a further agent, where the further agent is selected from one or more statin or bempedoic acid, to said subject.

In some embodiments, disclosed is the use of a further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising the further agent, ii) 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof, and iii) ezetimibe or a pharmaceutically acceptable salt thereof, to said subject. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is the use of a further agent, where the further agent is selected from one or more statins or bempedoic acid, in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising the further agent, ii) AZD0780 or a pharmaceutically acceptable salt thereof, and iii) ezetimibe, to said subject.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H- [1 ,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising AZD0780 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H- [1 ,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising bempedoic acid or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising AZD0780 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising bempedoic acid; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H- [1 ,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof; a third pharmaceutical composition comprising a further agent, where the further agent is selected from a statin or bempedoic acid or a pharmaceutically acceptable salt thereof; and instructions for using the first, second and third pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein. In some of these embodiments, the further agent is one or more statin. In other of these embodiments, the further agent is bempedoic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising AZD0780 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe; a third pharmaceutical composition comprising a further agent, where the further agent is selected from a statin or bempedoic acid; and instructions for using the first, second and third pharmaceutical compositions in combination. In some embodiments, the instructions are for use of the combination as described herein.

The combination of AZD0780 or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, and the optional further agent, may result in fewer side effects or be more effective than current monotherapies or combination therapies. In some embodiments, the combination has a synergistic effect in the lowering of LDL-C levels.

Figures

Figure 1 shows the reduction percent change from baseline in LDL-C in patients dosed on dosing with ezetimibe for a 28 day run-in period, followed by dosing additionally with AZD0780 for 21 days.

Figure 2 shows the overall study design for the Phase lib study of AZD0780 in combination with ezetimibe and a statin. Detailed Description

Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower).

The term “LDL-C level” is used herein to mean the amount of LDL-C in the circulating serum of a patient.

AZD0780

In some embodiments, AZD0780 is administered in a dose of 1 to 30 mg per day. The daily dose may be up to 3 mg, 5 mg, 10mg, 15 mg, 20 mg, 25 mg or 30 mg. The daily dose may be at least 1 mg, 2 mg, 3 mg, 5mg, 10 mg, 15 mg, 20 mg, or 25 mg.

In some embodiments, AZD0780 is administered in a daily dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.

In some embodiments, AZD0780 is administered once a day (QD). In some embodiments, AZD0780 is administered in a dose of 1 to 30 mg QD. The once daily dose may be up to 3 mg, 5 mg, 10mg, 15 mg, 20 mg, 25 mg or 30 mg. The once daily dose may be at least 1 mg, 2 mg, 3 mg, 5mg, 10 mg, 15 mg, 20 mg, or 25 mg.

In some embodiments, AZD0780 is administered in a once daily dose (QD) of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. In some embodiments, AZD0780 is administered as a free base, i.e. not in salt form.

In some embodiments, AZD0780 is administered as a pharmaceutically acceptable salt thereof, where the dosage is that of AZD0780 not in a salt form. Unless otherwise stated, any reference in this disclosure to an amount of AZD0780, or pharmaceutically acceptable salt thereof, is based on the AZD0780 free base equivalent weight. For example, “wt%” refers to weight % based on AZD0780 free base equivalent weight.

The language “pharmaceutical composition” includes compositions comprising an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent, wherein the active ingredient is AZD0780 or a pharmaceutically acceptable salt thereof. The language “pharmaceutically acceptable excipient, carrier or diluent” includes compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art. In some embodiments, the pharmaceutical compositions are in solid dosage forms, such as capsules, tablets, granules, powders or sachets. In some embodiments, the pharmaceutical compositions are in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizing agents, co-solvents, or carriers. A sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents. The pharmaceutical compositions could be a solution for iv bolus/infusion injection or a lyophilized system (either alone or with excipients) for reconstitution with a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from non-aqueous solvents or aqueous solvents. The dosage form could also be a concentrate for further dilution for subsequent infusion.

In some embodiments, AZD0780 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, AZD0780 or a pharmaceutically acceptable salt thereof is in tablet dosage form.

Ezetimibe

Ezetimibe refers to a compound with the chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)- 3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one and the structure shown below:

Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells leads them to absorb more cholesterol from circulation and thus lowering the levels of circulating cholesterol. It blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1 L1) protein on the gastrointestinal tract epithelial cells, as well as in hepatocytes; it blocks aminopeptidase N and interrupts a caveolin 1- annexin A2 complex involved in trafficking cholesterol (Phan 2012).

Awad 2018 reported that ezetimibe reduces plasma LDL-C levels by up to 20% when used alone, and that it lowered plasma levels of lipoprotein(a) by about 7%.

In some embodiments, ezetimibe is administered in a dose of 5 to 15 mg per day. The daily dose may be up to 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg. The daily dose may be at least 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

In some embodiments, ezetimibe is administered in a dose of 10 mg per day.

In some embodiments, ezetimibe is administered as a free base, i.e. not in salt form.

In some embodiments, ezetimibe is administered as a pharmaceutically acceptable salt thereof, where the dosage is that of ezetimibe not in a salt form. Unless otherwise stated, any reference in this disclosure to an amount of ezetimibe, or pharmaceutically acceptable salt thereof, is based on the ezetimibe free base equivalent weight. For example, “wt%” refers to weight % based on ezetimibe free base equivalent weight. Bempedoic acid

Bempedoic acid refers to a compound also known as 8-hydroxy-2,2,14,14- tetramethylpentadecanedioic acid and the structure shown below:

Bempedoic acid targets the cholesterol biosynthesis pathway in the liver. Bempedoic acid inhibits ATP-citrate lyase (ACL), two steps upstream of HMG CoA reductase. Bempedoic acid is converted to active coenzyme A form by enzymes found only in the liver and not in muscles (Agarwala and Goldberg 2020)

Bempedoic acid has been approved for use in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated.

In some embodiments, bempedoic acid is administered in a dose of 150 to 200 mg per day. The daily dose may be up to 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. The daily dose may be at least 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg or 180 mg.

In some embodiments, bempedoic acid is administered in a dose of 180 mg per day.

In some embodiments, bempedoic acid is administered as a free acid, i.e. not in salt form.

In some embodiments, bempedoic acid is administered as a pharmaceutically acceptable salt thereof, where the dosage is that of bempedoic acid not in a salt form. Unless otherwise stated, any reference in this disclosure to an amount of bempedoic acid, or pharmaceutically acceptable salt thereof, is based on the bempedoic acid free acid equivalent weight. For example, “wt%” refers to weight % based on bempedoic acid free acid equivalent weight.

Salts of bempedoic acid are described in WO 2020/257573. Statins

Statins include atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin.

US4231938 discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, US4444784 discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Also, US4739073 discloses certain substituted indoles, such as fluvastatin. Also, US4346227 discloses ML- 236B derivatives, such as pravastatin. Also, EP0491226A and US5502199 disclose certain pyridyldihydroxyheptenoic acids, such as cerivastatin. In addition, US5273995 discloses certain 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharmaceutically acceptable form thereof (i.e. LIPITOR®). Atorvastatin calcium (i.e. , atorvastatin hemicalcium), disclosed in US5273995 is currently sold as Lipitor®. US RE37.314 E discloses rosuvastatin and rosuvastatin calcium. EP0304063 and US5011930 disclose pitivastatin. US3983140 discloses mevastatin. US4448784 and US4450171 disclose velostatin. US4804770 discloses compactin. EP0738510A2 discloses dalvastatin. EP0363934A1 discloses fluindostatin. US4450171 discloses dihydrocompactin.

In some embodiments, the statin is selected from atorvastatin, rosuvastatin, lovastatin, pravastatin, simvastatin and fluvastatin.

In some embodiments, the statin is rosuvastatin or a pharmaceutically acceptable salt thereof. In some of these embodiments, the statin is rosuvastatin or rosuvastatin calcium.

Dosing levels

In some embodiments, the statin dosing regimen is a moderate-intensity dosing according to the ACC (American College of Cardiology)/AHA (American Heart Association) (Grundy 2018).

This moderate-intensity dosing may be:

The rosuvastatin may be dosed as rosuvastatin calcium, where the dose given is calculated as rosuvastatin in its free form.

The atorvastatin may be dosed as atorvastatin calcium or atorvastatin calcium trihydrate, where the dose given is calculated as atorvastatin in its free form.

The pravastatin may be dosed as pravastatin calcium, where the dose given is calculated as pravastatin in its free form.

The pitavastatin may be dosed as pitavastatin calcium, where the dose given is calculated as pitavastatin in its free form.

In some embodiments, the statin dosing regimen is a high-intensity dosing according to the ACC (American College of Cardiology)/AHA (American Heart Association) (Grundy 2018).

This high-intensity dosing may be:

As above, the rosuvastatin may be dosed as rosuvastatin calcium, where the dose given is calculated as rosuvastatin in its free form.

As above, the atorvastatin may be dosed as atorvastatin calcium or atorvastatin calcium trihydrate, where the dose given is calculated as atorvastatin in its free form.

In some embodiments, the statin dosing regimen is one appropriate to patients from, for example, Japan:

As above, the pitavastatin may be dosed as pitavastatin calcium, where the dose given is calculated as pitavastatin in its free form.

Combinations

In some embodiments, the treatment is selected from one of the following:

(a) 30 mg QD AZD0780 and 10mg QD ezetimibe;

(b) 30 mg QD AZD0780, 10mg QD ezetimibe and 20 mg QD rosuvastatin;

(c) 30 mg QD AZD0780, 10mg QD ezetimibe and 2.5 mg QD rosuvastatin;

(d) 30 mg QD AZD0780, 10mg QD ezetimibe and 5 mg QD rosuvastatin;

(e) 30 mg QD AZD0780, 10mg QD ezetimibe and 10 mg QD rosuvastatin;

(f) 30 mg QD AZD0780, 10mg QD ezetimibe and 40 mg QD rosuvastatin; and

(g) 30 mg QD AZD0780, 10mg QD ezetimibe and 180 mg QD bempedoic acid.

Previous treatment

In some embodiments, the patient to be treated will have already been previously treated with one or more of the agents to be combined with AZD0780.

Thus, in embodiments where the patient is treated with a combination of AZD0780 and ezetimibe, the patient may have been previously treated with ezetimibe.

Thus, in embodiments where the patient is treated with a combination of AZD0780 and ezetimibe, and bempedoic acid, the patient may have been previously treated with ezetimibe and bempedoic acid. Thus, in embodiments where the patient is treated with a combination of AZD0780, ezetimibe, and one or more statins, the patient may have been previously treated with ezetimibe and one or more statins, and in some embodiments, the same one or more statins to be combined with AZD0780.

In some of these embodiments, the patient to be treated will have already been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks, three weeks, four weeks, two months, three months, four months, five months or six months prior to being treated with a combination of AZD0780 and one or more other agents.

In some embodiments, the patient to be treated will have already been previously treated with one or more of:

(i) ezetimibe;

(ii) bempedoic acid; and

(iii) one or more statins.

The dosage of the one or more other agents (e.g. ezetimibe, bempedoic acid, one or more statins) used in the previous treatment may be the same dosage as described herein.

Treatment

The term “treatment” is used synonymously with “therapy”. Similarly, the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a paediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans.

The reduction of cardiovascular events through the lowering of LDL-C by inhibition of PCSK9 has been described, e.g., in Robinson 2015.

Lowering LDL-C levels leads to significant reduction in major vascular events including myocardial infarction, coronary deaths, stroke, and coronary revascularizations (Collins 2016). Current clinical guidelines for LDL-C reduction and the consequent reduction of CVD (cardiovascular disease) risk are summarised in Atar 2021. Additional evidence demonstrates that aggressively lowering LDL-C levels to < 40 mg/dL lowers CVD risk in a wider range of patients (Marston 2021).

In some embodiments, reduction of LDL-C to less than 100 mg/dL, less than 70 mg/dL, less than 55 mg/dL or less than 40 mg/dL may be achieved by the treatment disclosed herein.

In some embodiments, in patients with elevated LDL-C (such as greater than 100 mg/dL), reduction of the untreated level of LDL-C by greater than or equal to 30%, 40%, 50%, 60%, 65%, 70% or 75% may be achieved by the treatment disclosed herein. The term untreated as used herein refers to the level as measured before any LDL-C lowering treatment has been administered, i.e. the LDL-C baseline level.

In some embodiments, the treatment disclosed herein reduces cardiovascular risk (i.e., the incidence of myocardial infarction, ischemic stroke and urgent coronary revascularization, cardiovascular death) in adults with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event (such as myocardial infarction, resuscitated cardiac arrest, fatal coronary heart disease (CHD), fatal and non-fatal stroke, and other atherosclerotic or cardiovascular death). The risk for a first ASCVD event for a patient within 10 years can be categorized into those at low (<5%), borderline (5 to <7.5%), intermediate (7.5 to <20%), and high (>20%) risk (Wong 2022).

In some embodiments, the treatment disclosed herein reduces LDL-C, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).

Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure. In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

In some embodiments, the treatment of a cardiovascular disease includes reducing the LDL- C level to less than 100 mg/dL, less than 70 mg/dL, less than 55 mg/dL or less than 40 mg/dL. In some embodiments, the treatment of a cardiovascular disease in patients with elevated LDL-C (such as greater than 100 mg/dL), includes reduction of the untreated level of LDL-C by greater than or equal to 30%, 40%, 50%, 60%, 65%, 70% or 75%.

In certain embodiments, the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-C and VLDL-Cholesterol (very low-density lipoprotein-cholesterol). In addition, the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C and atherogenic lipoproteins. In certain embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects having a gain-of-function mutation in the PCSK9 gene also benefit with treatment with the disclosed compounds and compositions counteracting the mutation through their inhibition of PCSK9.

In some embodiments the:

(i) AZD0780 or a pharmaceutically acceptable salt thereof;

(ii) ezetimibe or a pharmaceutically acceptable salt thereof; and

(iii) optional further agent, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof; are administered separately, sequentially or simultaneously.

In some embodiments, AZD0780 or a pharmaceutically acceptable salt thereof is given simultaneously with ezetimibe or a pharmaceutically acceptable salt thereof; and the optional further agent. In some of these embodiments, these are taken without food (e.g. no food at least 2 hours before dosing and at least 1 hour after dosing). In other of these embodiments, these are taken with food.

In the clinical trial NCT05384262 (Part A2), it was found that the pharmacokinetics of AZD0780 were not affected by dosing after intake of a high-calorie, high-fat breakfast. Patients

In some embodiments, the patient to be treated has a LDL-C < 190 mg/dL before starting treatment.

In some embodiments, the patient to be treated has a LDL-C > 100 mg/dL before starting treatment.

In some embodiments, the patient to be treated has triglycerides of < 400 mg/dL before starting treatment.

In some embodiments, the patent to be treated has a BMI between 18 and 35 kg/m² inclusive and weighs at least 50 kg and no more than 120 kg inclusive prior to the start of treatment.

In some embodiments, the patient to be treated has a LDL-C < 4.9 mmol/L before starting treatment.

In some embodiments, the patient to be treated has a LDL-C > 2.6 mmol/L before starting treatment.

In some embodiments, the patient to be treated has triglycerides of < 10.3 mmol/L before starting treatment.

In some embodiments, the patient to be treated meets at least one of the inclusion criteria set out in example 1.

In some embodiments, the patient to be treated does not meet at least one of the exclusion criteria set out in example 1.

Examples

The combinations of the application will now be further explained by reference to the following non-limiting examples. Abbreviations

The following abbreviations are used herein: Example 1

This study (D7960C00017/NCT06742853) is a randomized, single-blind, placebo- controlled study in healthy participants with elevated LDL-C. The study aims to assess the PK, safety, tolerability, and efficacy of AZD0780 in combination with ezetimibe, ezetimibe/rosuvastatin, and ezetimibe/bempedoic acid.

There will be a 4-week run-in period where participants will self-administer one of the following treatments at home or in the Clinical Unit during residential visits (Days -28 to Day -1):

• Cohort 1 : Ezetimibe 10 mg QD

• Cohort 2: Ezetimibe 10 mg + rosuvastatin 20 mg QD

• Cohort 3 (optional cohort): Bempedoic acid 180 mg + ezetimibe 10 mg QD Participants will then be randomized in each cohort to receive either AZD0780 30 mg or placebo (to be administered with ezetimibe, ezetimibe/rosuvastatin, or ezetimibe/bempedoic acid) at a 1 :1 ratio for 4 weeks (Days 1 to 28). Up to approximately 120 participants will be randomized in this study.

Approximately 40 participants will be included in each cohort with approximately 20 participants randomized to placebo and approximately 20 participants randomized to AZD0780.

This study will comprise of:

• A Screening Period of maximum 28 days (Days -56 to -29).

• A Run-in Period of 28 days (Days -28 to -1) during which participants will selfadminister ezetimibe, ezetimibe/rosuvastatin, or ezetimibe/bempedoic acid QD at home or at the Clinical Unit during residential visits. Participants will report to the Clinical Unit on Days -28 and -14 for the required non-residential visits.

• A Treatment Period of 28 days (Days 1 to 28) during which participants will selfadminister ezetimibe, ezetimibe/rosuvastatin, or ezetimibe/bempedoic acid together with AZD0780 30 mg or placebo QD at home or at the Clinical Unit during residential visits. During the Treatment Period participants will be resident at the Clinical Unit from the day before study intervention administration (Day -1) until at least 7 hours after study intervention administration on Day 1 (discharged on Day 1) or, if required for logistical reason, participants may be kept overnight and discharged on Day 2. Participants will also report to the Clinical Unit for non-residential visits on Days 8, 15, 22, and 29. • A Follow-up Period consisting of 2 follow-up visits, one and 2 weeks after the last study intervention administration.

On visits with extended PK sampling (Days 1 and 15), no food will be permitted for 1 hour post-dosing.

Inclusion Criteria

For inclusion in the study participants must fulfil the following criteria:

1. Provision of signed and dated, written informed consent prior to any study-specific procedures.

2. Healthy male and female of non-childbearing potential participants aged 18 to 75 years (inclusive) at time of informed consent with suitable veins for cannulation or repeated venipuncture.

3. All females must have a negative serum pregnancy test at the Screening Visit and on Admission to the Clinical Unit (or a negative urine pregnancy test on Admission for London study centre).

4. Females of non-childbearing potential must be confirmed at the Screening Visit by fulfilling one of the following criteria:

(a) Postmenopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range.

(b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation or tubal occlusion.

5. Sexually active fertile male participants with partners of childbearing potential must adhere to prescribed contraception methods from the time of first administration of study intervention administration until 3 months after the study Follow-up Visit.

6. Have a BMI > 18 kg/m² and weigh at least 50 kg at the Screening Visit.

7. Fasting LDL-C > 100 mg/dL but < 190 mg/dL (> 2.6 mmol/L but < 4.9 mmol/L for London study centre) at the Screening Visit.

8. Fasting triglycerides < 400 mg/dL (or < 10.3 mmol/L for London study centre) at the Screening Visit.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

1. History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant’s ability to participate in the study.

2. History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. 3. Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.

4. Any laboratory values with the following deviations at the Screening Visit or on Admission to the Clinical Unit. Abnormal values may be repeated once per visit at the discretion of the investigator:

(a) ALT > ULN.

(b) AST > ULN.

(c) TBL > ULN.

(d) Estimated glomerular filtration rate < 70 mL/min/1.73 m² calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at the screening visit.

(e) Haemoglobin < LLN at the screening visit or admission.

5. Any clinically important abnormalities in clinical chemistry, haematology, or urinalysis results other than those described under exclusion criterion number 4, at Screening and/or Admission to the Clinical Unit, as judged by the investigator. Abnormal values may be repeated once per visit at the discretion of the investigator.

6. Any positive result on Screening for serum HBsAg, hepatitis B core antibody or human immunodeficiency virus.

7. Abnormal vital signs, after at least 10 minutes supine rest, at the Screening Visit and on Admission to the Clinical Unit, defined as any of the following (average of triplicate BP and heart rate measurements). Abnormal values may be repeated once per visit at the discretion of the investigator:

(a) Systolic BP < 90 mmHg or > 140 mmHg.

(b) Diastolic BP < 50 mmHg or > 90 mmHg.

(c) Heart rate < 50 or > 90 bpm.

8. Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, at the Screening Visit and/or on Admission to the Clinical Unit. ECG recording may be repeated once for each visit at the discretion of the investigator. ECG recordings will be performed in triplicate.

(a) Prolonged QTcF > 450 ms.

(b) Shortened QTcF < 340 ms.

(c) Family history of long QT syndrome.

(d) PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation). (e) PR (PQ) interval prolongation (> 220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third-degree AV block, or AV dissociation.

(f) Persistent or intermittent complete bundle branch block. Subjects with intraventricular conduction delay and QRS < 120 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.

9. Current smokers or those who have smoked or used nicotine products (including e- cigarettes) within the previous 3 months prior to Screening.

10. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the investigator.

11. Positive screen for drugs of abuse, or alcohol or cotinine at Screening and/or on Admission to the Clinical Unit.

12. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD0780, ezetimibe, rosuvastatin, and bempedoic acid.

13. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) defined as the regular consumption of more than 500 mg of caffeine per day (e.g., > 5 cups of coffee [one cup -100 mg caffeine]; one cup of tea -30 mg caffeine) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the investigational site.

14. Use of drugs with enzyme inducing properties such as St John’s Wort within 3 weeks prior to the first administration of study intervention.

15. Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of > 3 x daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.

16. Treatment with any lipid-lowering therapy or AZD0780 within the 3 months prior to Screening.

17. Treatment with drugs for reduction or inhibition of PCSK9 within the last 12 months prior to Screening (approved or investigational and apart from AZD0780).

18. Current or previous administration of inclisiran.

19. Taking moderate/strong inhibitors or inducers of CYP3A4 and CYP2A6.

20. Taking, within 14 days of Screening and throughout the study, medication that contain a black box warning or significant QT prolongation

21 Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to the Screening Visit. 22. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days or 5 half-lives (whichever is longest) of the first administration of AZD0780 in this study.

23. Involvement in the planning and/or conduct of the study.

24. Judgment by the investigator that the participant should not participate in the study if they have any ongoing or recent (i.e. , during the Screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.

25. Participants who have medical dietary restrictions or are unable/unwilling to comply with the meals provided in the unit during the stay at the Clinical Unit.

26. Participants who cannot communicate reliably with the investigator.

27. Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Lifestyle Considerations

Meals and Dietary Restrictions

1 . For all study visits including Screening, participants must be fasted for 8 hours prior to safety and lipid profile blood sampling.

2. Participants should refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice, pomelos, exotic citrus fruits, or grapefruit hybrids from 48 hours before the start of study intervention until completion of the final Follow-up Visit.

3. Participants must abstain from consuming products containing taurine or glucuronolactone from 72 hours before each study visit and for the duration of the stay in the Clinical Unit. Sports drinks containing only glucose and electrolytes are allowed.

4. Participants must abstain from consuming products containing poppy seeds for 72 hours before each study visit.

5. On Days 1 and 15 (extended PK sampling), participant will be fasted for 10 hours prior to dosing until 1 hour after dosing. No fluids will be allowed apart from water which can be given until 1 hour prior to dosing and then from 1 hours after dosing (excluding 240 mL water used in conjunction with study intervention administration).

Caffeine and Alcohol

1 . Prior to each study visit participants should abstain from caffeine-containing foods and beverages for 24 hours prior to check-in until discharge from the Clinical Unit. Participants should also limit their caffeine intake to equivalent of 3 servings of coffee per day (1 serving = 12 oz soda, 6 oz coffee, or 8 oz tea). 2. Prior to each study visit, participants should abstain from alcohol for 72 hours prior to check-in. Participants should also abstain from alcohol for 72 hours before their final Follow-up Visit. During the participants’ outpatient periods, participants should not consume more than 3 units (males) or 2 units (females) per day during the off-site days during the study (1 unit is equal to approximately half pint [284 mL] of beer, one small glass [125 mL] of wine, or one measure [25 mL] of spirits).

Activity

Participants will abstain from strenuous exercise for 72 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities during studies, e.g., watching television, and reading.

Other Restrictions

1. Participants will be required to abstain from blood or plasma donation until 3 months after the final medical examination at the study follow-up.

2. Male Participants should not donate sperm for the duration of the study and for at least 3 months after the study final Follow-up Visit.

Administration of Study Intervention

Each participant will participate in a 28-day run-in period. During the run-in participants will receive QD doses of ezetimibe 10 mg (Cohort 1), ezetimibe 10 mg + rosuvastatin 20 mg (Cohort 2) or bempedoic acid 180 mg + ezetimibe 10 mg (Cohort 3 - optional cohort).

The 28-day treatment period will begin with daily dosing commencing on Day 1. Each participant will receive QD oral doses of ezetimibe 10 mg (Cohort 1), ezetimibe 10 mg + rosuvastatin 20 mg (Cohort 2) or bempedoic acid 180 mg + ezetimibe 10 mg (Cohort 3 - optional cohort) along with either AZD0780 or placebo. No food or fluid restrictions apply for at home dosing.

On days where PK samples are to be collected the participant should refrain from taking the study intervention prior to coming to the Clinical Unit.

On Days 1 and 15, the dose will be administered on an empty stomach (after an overnight fast, with no food at least 10 hours prior to dosing) with approximately 240 mL of water. Participants will be allowed to drink water to prevent dehydration until 1 hour before dosing. Water will be allowed ad libitum from 1 hour after dosing and a light breakfast or meal will be given 1 hour at the earliest after dosing. All the drugs will be administered orally as tablets.

Discontinuation of Study Intervention

Subjects may have been discontinued from study intervention in the following situations:

• Any significant and clinically relevant changes in the safety parameters, e.g., ECG, BP, pulse, and laboratory assessments, making the continuation of study intervention unjustified.

• A case of Potential Hy’s Law (HL) defined as ‘an increase in AST or ALT > 3 x ULN and TBL > 2 x ULN’ where no other reason, other than IMP, can be found to explain the combination of increases.

• If a participant becomes pregnant during the study, study intervention should be discontinued immediately.

• If a participant reports symptoms which are considered unacceptable by the participant or the investigator, he/she will be discontinued from study intervention.

• Any severe non-serious AE or SAE that is judged as possibly related to the study intervention by the investigator and which in the opinion of the investigator warrants discontinuation of the participant from the active protocol for his well-being.

• Participant decision. Participants are free at any time to discontinue treatment, without prejudice to further treatment.

• Severe noncompliance to study protocol.

Adverse Events

Definition of Adverse Events

An Adverse Event is the development of any untoward medical occurrence in a patient or clinical study participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (e.g., an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated with the use of a medicinal product, whether or not it is considered related to the medicinal product.

The term AE is used to include both serious and non-serious AEs and can include a deterioration of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout periods, even if no study intervention has been administered. Definition of Serious Adverse Event

An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, followup), that fulfils one or more of the following criteria:

• Results in death. • Is immediately life-threatening.

• Requires inpatient hospitalization or prolongation of existing hospitalization.

• Results in persistent or significant disability or incapacity.

• Is a congenital anomaly or birth defect.

• Is an important medical event that may jeopardize the participant or may require medical treatment to prevent one of the outcomes listed above.

Objectives and Endpoints

Pharmacokinetics

Blood Sample Collection

Blood samples for the determination of plasma concentrations of AZD0780, ezetimibe, and ezetimibe-glucuronide, and if applicable bempedoic acid and ESP15228 (active metabolite of bempedoic acid), will be collected for each treatment period as specified below: Pharmacodynamics

Blood samples will be collected for measurement of LDL-C, lipid profile, (direct LDL-C, LDL- C ultra, total cholesterol, non-HDL-C, HDL-C, LDL-C [Friedewald], triglycerides), total PCSK9 (standard and drug tolerant assay), ApoB, and Lp(a) as specified below: Safety Assessments

Planned time points for all the safety assessments are specified below:

Height and Weight

Height and weight will be measured and recorded and BMI will be calculated.

Physical Examinations

A complete physical examination will be performed and include assessments of the following: general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal, and neurological systems.

A brief physical examination will include, at a minimum, an assessment of the general appearance, skin, abdomen, cardiovascular, and respiratory system.

Vital Signs

At the specific time points, the following variables will be collected after the participant has rested in the supine position for at least 10 minutes:

• Systolic BP (mmHg)

• Diastolic BP (mmHg)

• Pulse (bpm)

• Tympanic or oral temperature (°C).

All BP and pulse will be measured in triplicate at all time points, and the mean value will be used.

Electrocardiograms

Safety 12-lead Electrocardiograms will be performed at the specified time points.

Clinical Safety Laboratory Tests

Blood and urine samples for determination of clinical chemistry, hematology, coagulation, urinalysis, drugs of abuse, alcohol and cotinine, viral serology, and pregnancy will be taken at the specified time points. Additional safety samples may be collected if clinically indicated at the discretion of the investigator. The following laboratory variables will be measured:

Results

The following results have a data cut-off of 17 March 2025, whilst the study continues. The reduction in LDL-C at days 8, 15 and 22 of AZD0780 or placebo treatment on top of the ezetimibe treatment are shown below. The mean is the geometric least squares mean of the log-transformed change in LDL-C from baseline measured at day 0. n is the number of patients for which the data is presented.

These data are illustrated in Figure 1 which shows the reduction in LDL-C during the ezetimibe 28 day run-in period, and the additional reduction on the additional dosing of AZD0780. The baseline for this graph is the LDL-C level at the start of the run-in period.

Example 2

The combination therapy of AZD0780, ezetimibe and a statin was investigated as part of a larger overall study (D7960C00006/NCT06173570) into the combination of AZD0780 and a statin.

This was a randomized, multicentre, parallel-group, double-blind, placebo-controlled, doseranging, Phase lib study in participants with dyslipidemia. Overall 426 patients started treatment, of which 404 completed treatment. Of these 81 participants were treated with a statin and ezetimibe, of which 75 completed treatment.

The study population consisted of male and female participants of non-childbearing potential, 18 to 75 years of age with a fasting LDL-C of > 70 (1.8 mmol/L) and < 190 mg/dL (4.9 mmol/L) at screening. The Participants also received moderate or high-intensity statin therapy for at least 2 months prior to screening, along with ezetimibe. The Participants continued with their statin and ezetimibe therapy throughout the study.

Participants were randomized to once daily dosing of placebo or one of the AZD0780 doses. Dosing was supervised and documented by study staff when study intervention was administered in the clinic. Eligible participants in the whole study were randomized across 5 different treatment arms in a 1:1 :1:1:1 ratio for a 12-week treatment period. The treatment arms were AZD0780 1 mg, AZD0780 3 mg, AZD0780 10 mg, AZD0780 30 mg, and placebo, all in addition to the continuing statin (and ezetimibe) therapy.

The study comprised 3 periods totalling up to 17 weeks:

• A screening period of up to 3 weeks

• A treatment period of 12 weeks o Dispensing visits will be at Week 1 , Week 4, and Week 8 o The visit frequency will be at Week 1 , Week 2, and Week 4; then once monthly up to Week 12

• A final follow-up visit at Week 14 (safety follow-up period) The treatment arms were placebo, AZD0780 1 mg once daily, AZD0780 3 mg once daily, AZD0780 10 mg once daily, and AZD0780 30 mg once daily, during the 12 week treatment period.

The overall study design is illustrated in Figure 2. The clinical trial was performed as outline below.

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Male and females of non-childbearing potential 18 to 75 years of age, inclusive, at the time of signing the informed consent.

2. Participants with a fasting LDL-C > 70 mg/dL (1.8 mmol/L) and < 190 mg/dL (4.9 mmol/L) at screening.

3. Participants with fasting triglycerides < 400 mg/dL (< 4.52 mmol/L) at screening.

4. Should be receiving moderate or high-intensity statin therapy for > 2 months prior to screening, according to ACC/AHA guidelines on blood cholesterol management, or to local guidelines, eg, Japanese Atherosclerosis Society guidelines.

5. There should be no planned medication or dose change during study participation. Fibrate therapy and derivatives are prohibited.

6. Body mass index of at least 19.0 kg/m² .

7. Male participants:

(a) Males must be surgically sterile or using, in conjunction with their female partner, a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the final follow up visit to prevent pregnancy in a partner. Acceptable methods of contraception include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy. A barrier method is not necessary if the female partner is sterilized. Male study participants must not donate or bank sperm during this same time period.

8. Female participants:

(a) Female participants must not be pregnant and must have a negative pregnancy test at screening and randomization, must not be lactating, and must not be of childbearing potential. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomization without an alternative medical cause. The following age- specific requirements apply: (i) Women < 50 years of age would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range.

(ii) Women > 50 years of age would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.

9. Restrictions for male participants

(a) All male participants should avoid fathering a child by either true abstinence or by using (together with their female partner/spouse) a highly effective contraception form of birth control in combination with a barrier method, starting from the time of study intervention administration until 3 months after the Final Follow-Up visit. Acceptable methods of preventing pregnancy include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy.

(b) Male participants who have been sterilized are required to use 1 barrier method of contraception (condom) from the time of study intervention administration until after the Final Follow-Up Visit. A barrier method is not necessary if the female partner is sterilized.

(c) Male participants should not donate sperm for the duration of the study and for at least 3 months post last follow-up visit.

10. Capable of giving signed informed consent

11. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.

Exclusion Criteria

1. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m² using the Chronic Kidney Disease-Epidemiology Collaboration equation at Visit 1.

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.

3. Any uncontrolled or serious disease, or any medical (e.g., known major active infection or major haematological, renal, metabolic, gastrointestinal, respiratory, or endocrine dysfunction) or surgical condition that, in the opinion of the investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk.

4. Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% at Visit 1.

5. Acute ischemic cardiovascular event in the last 12 months prior to randomization however patients can be included if it is > 6 months from coronary artery bypass graft (CABG) surgery and > 3 months after percutaneous coronary intervention (PCI).

6. Heart failure with New York Heart Association (NYHA) Class lll-IV. 7. Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.

8. Recipient of any major organ transplant, e.g., lung, liver, heart, bone marrow, renal.

9. LDL or plasma apheresis within 12 months prior to randomization.

10. Uncontrolled hypertension defined as average sitting SBP > 160 mmHg or DBP > 90 mmHg at Visit 1. It is recommended that antihypertensive treatment should be considered/initiated at the Pl’s discretion and in accordance with applicable clinical guidelines in order to optimize blood pressure for participants with hypertension during the clinical study.

11. Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm at Visit 1.

12. Any laboratory values with the following deviations at Screening Visit 1; 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 x ULN

(c) AST > 1.5 x ULN

(d) TBL > ULN

(e) Haemoglobin < 12 g/dL in men or < 11 g/dL in women

(f) Potassium < LLN

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 shortened QTcF< 340ms; family history of long QT syndrome; PR interval shortening < 120 ms; PR interval prolongation >220 ms, intermittent second or third degree AV block or AV dissociation; persistent or intermittent complete bundle branch block, incomplete bundle branch, or interventricular conduction delay with QRS > 110 ms

14. QTcF > 450 ms; high degree atrioventricular-block grade Il-Ill and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias.

15. Known or suspected history of drug abuse as judged by the investigator.

16. History of alcohol abuse or excessive intake of alcohol as judged by the investigator.

17. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure.

18. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study intervention. History or evidence of any other clinically significant disorder (e.g., cognitive impairment), condition, or disease other than those outlined above that, in the opinion of the investigator or Sponsor physician, if consulted, may compromise the ability of the participant to give written informed consent, would pose a risk to participant safety, or interfere with the study evaluation, procedures, or completion.

19. Current/previous administration of inclisiran.

20. Lomitapide within 12 months prior to randomization.

21. Previous administration of PCSK9 inhibition treatment within 12 months prior to randomization (approved or investigational).

22. Fibrate therapy and derivatives are prohibited.

23. Receiving or has received within 14 days of screening, medication that contains a black box warning for significant QT prolongation.

24. Participation in another clinical study with a study intervention administered in the last 3 months prior to randomization or 5 half-lives from last dose to first administration of study intervention, whichever is the longest.

25. Received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days of last follow-up to first administration of the study intervention of this study or 5 half-lives from last dose to first administration of study intervention, whichever is the longest.

26. Use of other investigational products or investigational devices during the course of the study.

27. Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site or their close relatives).

28. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.

29. As judged by the investigator, any evidence of disease conditions that, in the investigator’s opinion, makes it undesirable for the participant to participate in the trial.

30. Previous screening in the present study. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened. At the investigator’s discretion, participants may be rescreened once during the recruitment period.

31. Participants who cannot communicate reliably with the investigator.

32. Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

33. Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss > 500 mL (> 400 mL in Japan only) during the 3 months prior to screening visit.

Lifestyle Considerations

Pregnancy

Participants will be instructed that if they or their partner becomes pregnant during the study this should be reported to the investigator. The investigator should also be notified of pregnancy occurring during the study but confirmed after completion of the study. In the event that a participant’s partner is subsequently found to be pregnant after the participant is included in the study, then consent will be sought from the partner (via the participant’s request that their partner contact the study site) and, if granted, any pregnancy will be followed, and the status of mother and/or child will be reported to the Sponsor after delivery.

Meals and Dietary Restrictions

For all study visits (including screening), participants must be fasted for 8 hours prior to blood sampling for LDL-C and other lipid profile. No fluids will be allowed apart from water, which can be given until 1 hour before blood sampling for LDL-C and other lipid profile.

Caffeine, Alcohol, and Tobacco

Participants who use alcohol may participate in the study unless their consumption is deemed excessive by the investigator.

Activity

Participants should not start any new physical training activities or increase the intensity of their usual physical training from 5 days prior to randomization until the end of the study.

Discontinuation of Study Intervention

An individual participant will not receive further IMP if any of the following occur in the participant in question:

• Hy’s Law (HL) defined as ‘an increase in AST of ALT > 3 x ULN and TBL > 2 x ULN’ where no other reason, other than IMP, can be found to explain the combination of increases.

• A severe hypersensitivity reaction.

• Participant decision. The participant is at any time free to discontinue treatment, without prejudice to further treatment.

• An SAE that is assessed as possibly related to the study intervention by the Investigator.

• An AE or other safety reasons as judged by the investigator and/or sponsor where continued treatment may put the participant at undue risk.

• Severe noncompliance with the protocol

• Pregnancy; if a participant becomes pregnant during the study the study intervention should be discontinued immediately and a Sponsor representative notified. • Signs or symptoms of severe hepatic impairment (see Liver Chemistry Stopping Criteria below)

• Cardiovascular findings (see Cardiac Stopping Criteria below)

• Respiratory symptoms (see Respiratory stopping criteria below)

Liver Chemistry Stopping Criteria

Discontinuation of study intervention for abnormal liver tests is required by the investigator when a participant meets one of the conditions outlined below or in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules, if the investigator believes that it is in best interest of the participant.

• ALT and/or AST are > 3 x ULN and TBL > 2 x ULN

• ALT and/or AST are > = 5 x ULN for > 14 consecutive days, at any time after initial confirmatory results

• ALT and/or AST are > 8 x ULN

• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper

• quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

• ALT or AST > 3 x ULN and INR (international normalized ratio) > 1.5 (applicable for participants with a baseline INR < 1.1)

Cardiac Stopping Criteria

Discontinuation of study intervention for abnormal cardiac tests is required by the investigator when a participant meets one of the conditions outlined below:

• Average absolute (regardless of baseline value) cardiac QTc interval corrected for heart rate by QTcF > 500 msec, or an increase of QTcF > 60 msec above the baseline value, confirmed (persistent for > 5 minutes) on a repeat 12-lead ECG.

Any one of the following:

• Tachycardia, defined as resting supine pulse rate > 125 beats per minute persisting for at least 10 minutes.

• Symptomatic bradycardia, defined as resting supine pulse rate < 40 beats per minute while awake, persisting for at least 10 minutes.

• Asymptomatic bradycardia, defined as resting supine pulse rate < 30 beats per minute while awake persisting for at least 10 minutes.

• Hypertension, defined as an increase from baseline in resting supine systolic > 40 mmHg or above 180 mmHg and persisting for at least 10 minutes and/or increase from baseline in resting supine diastolic BP > 20 mmHg or above 100 mmHg and persisting for at least 10 minutes. Respiratory stopping criteria

Discontinuation of study intervention is required by the investigator when a participant with respiratory disease meets the condition below:

• Exacerbation of known respiratory disease that requires hospital admission.

Adverse Events

Definition of Adverse Events

An AE is the development of any untoward medical occurrence in a subject or clinical study subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (e.g., an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

The term AE is used to include both serious and non-serious AEs and can include a deterioration of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout periods, even if no study intervention has been administered.

Definitions of Serious Adverse Event

A SAE is an AE occurring during any study phase (i.e. , run-in, treatment, washout, followup), that fulfils one or more of the following criteria:

• Results in death.

• Is immediately life-threatening.

• Requires in-patient hospitalization or prolongation of existing hospitalization.

• Results in persistent or significant disability or incapacity or substantial disruption of

• the ability to conduct normal life functions.

• Is a congenital anomaly or birth defect.

• Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above.

Endpoints

The primary endpoint of the study is percent change from baseline of LDL-C at Week 12. Secondary endpoints of the study are percent change from baseline to Week 12 in:

Non-HDL-C

Very-low-density lipoprotein cholesterol (VLDL-C) • ApoA1

• ApoB

• Total cholesterol

• HDL-C • Triglycerides

• Lp(a)

• Remnant cholesterol (calculated from standard lipid profile)

• High-sensitivity C-reactive protein (hsCRP) Results

The reduction in LDL-C (placebo adjusted) is shown below for each dose level of AZD0780.

There were statistically significant reductions in LDL-C from baseline to week 12 for all

AZD0780 doses compared with placebo. Reductions in LDL-C were evident by Week 1 and reached steady state by approximately Week 2.

There were no AE leading to withdrawal of the subjects from the study.

AZD0780 was safe and tolerable with no new safety concerns identified in the study.

References

A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein. Statements

A1. A method of lowering LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of AZD0780 or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe, wherein the first amount and the second amount together comprise a therapeutically effective amount.

A2. The method according to statement A1 , which is a method of lowering LDL-C levels.

A3. The method according to statement A2, wherein the subject is an adult with primary hyperlipidemia.

A4. The method according to any one of statements A1 to A3, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

A5. The method according to any one of statements A1 to A4, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) great than or equal to 75%.

A6. The method according to statement A1 , which is a method of reducing cardiovascular risk.

A7. The method according to statement A6, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event. A8. The method according to statement A1 , which is a treatment of a cardiovascular disease.

A9. The method according to statement A8, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

A10 The method according to either statement A8 or statement A9, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

A11. The method according to any one of statements A8 to A10, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

A12. The method according to any one of statements A1 to A11 , wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

A13. The method according to statement A12, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

A14. The method according to statement A13, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

A15. The method according to any one of statements A1 to A14, wherein the ezetimibe is administered in a dose of 5 to 15 mg per day.

A16. The method according to statement A15, wherein the ezetimibe is administered in a dose of 10 mg per day. A17. The method according to any one of statements A1 to A16, wherein a further agent is administered to said subject, where the further agent is selected from one or more statins or bempedoic acid.

A18. The method according to statement A17, wherein a statin is administered in a moderate-intensity dosing or high-intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

A19. The method according to statement A17, wherein a statin is administered according to one of the following:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(l) Rosuvastatin, 2.5 to 20 mg once daily, optionally as rosuvastatin calcium; or

(m) Simvastatin, 10 to 20 mg once daily.

A20. The method according to statement A19, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

A21. The method according to statement A17, wherein bempedoic acid is administered in a dose of 150 to 200 mg per day.

A22. The method according to statement A21, wherein bempedoic acid is administered in a dose of 180 mg per day. A23. The method according to any one of statements A1 to A22, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

A24. The method according to statement A23, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

A25. The method according to statement A24, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two months prior to starting the method of treatment.

A26. The method according to any one of statements A1 to A25, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

A27. The method according to any one of statements A1 to A26, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

A28. AZD0780 or a pharmaceutically acceptable salt thereof for use in lowering LDL-C levels, reducing cardiovascular risk and/or the treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) ezetimibe to said subject.

A29. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A28, wherein the treatment is a method of lowering LDL-C levels.

A30. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A29, wherein the subject is an adult with primary hyperlipidemia.

A31. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A30, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL. A32. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A31, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) great than or equal to 75%.

A33. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A28, wherein the treatment is a method of reducing cardiovascular risk.

A34. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A33, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

A35. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A28, wherein the treatment is a treatment of a cardiovascular disease.

A36. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A35, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

A37. AZD0780 or a pharmaceutically acceptable salt thereof for use according to either statement A35 or statement A36, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

A38. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A35 to A37, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia; (b) hyperlipidemia; or

(c) coronary artery disease.

A39. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A38, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

A40. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A39, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

A41. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A40, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

A42. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A41, wherein the ezetimibe is administered in a dose of 5 to 15 mg per day.

A43. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A42, wherein the ezetimibe is administered in a dose of 10 mg per day.

A44. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A43, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid.

A45. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A44, wherein a statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

A46. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A44, wherein the statin is administered according to one of the following: (a) Atorvastatin, 10 to 20 mg once daily; (b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

A47. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A46, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

A48. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A44, wherein bempedoic acid is administered in a dose of 150 to 200 mg per day.

A49. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A48, wherein bempedoic acid is administered in a dose of 180 mg per day.

A50. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A49, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

A51. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A50, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

A52. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement A51 , wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least six months prior to starting the method of treatment.

A53. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A52, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

A54. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements A28 to A53, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

A55. Ezetimibe for use in lowering LDL-C levels, reducing cardiovascular risk and/or the treatment of a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe, and ii) AZD0780 or a pharmaceutically acceptable salt thereof to said subject.

A56. Ezetimibe for use according to statement A55, wherein the treatment is a method of lowering LDL-C levels.

A57. Ezetimibe for use according to statement A56, wherein the subject is an adult with primary hyperlipidemia.

A58. Ezetimibe for use according to any one of statements A55 to A57, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

A59. Ezetimibe for use according to any one of statements A55 to A58, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%; (f) greater than or equal to 70%; or

(g) great than or equal to 75%.

A60. Ezetimibe for use according to statement A55, wherein the treatment is a method of reducing cardiovascular risk.

A61. Ezetimibe for use according to statement A60, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

A62. Ezetimibe for use according to statement A55, wherein the treatment is a treatment of a cardiovascular disease.

A63. Ezetimibe for use according to statement A62, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

A64. Ezetimibe for use according to either statement A62 or statement A63, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

A65. Ezetimibe for use according to any one of statements A62 to A64, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

A66. Ezetimibe for use according to any one of statements A62 to A65, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

A67. Ezetimibe for use according to statement A66, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780. A68. Ezetimibe for use according to statement A67, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

A69. Ezetimibe for use according to any one of statements A55 to A68, wherein the ezetimibe is administered in a dose of 5 to 15 mg per day.

A70. Ezetimibe for use according to statement A69, wherein the ezetimibe is administered in a dose of 10 mg per day.

A71. Ezetimibe for use according to any one of statements A55 to A70, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid.

A72. Ezetimibe for use according to statement A71, wherein a statin is administered in a moderate-intensity dosing or high-intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

A73. Ezetimibe for use according to statement A71, wherein the statin is administered according to one of the following:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily. A74. Ezetimibe for use according to statement A73, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

A75. Ezetimibe for use according to statement A71, wherein bempedoic acid is administered in a dose of 150 to 200 mg per day.

A76. Ezetimibe for use according to statement A75, wherein bempedoic acid is administered in a dose of 180 mg per day.

A77. Ezetimibe for use according to any one of statements A55 to A76, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

A78. Ezetimibe for use according to statement A77, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

A79. Ezetimibe for use according to statement A78, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least six months prior to starting the method of treatment.

A80. Ezetimibe for use according to any one of statements A55 to A79, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

A81. Ezetimibe for use according to any one of statements A55 to A80, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

A82. The use of AZD0780 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in lowering LDL-C levels, reducing cardiovascular risk and/or the treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) ezetimibe to said subject. A83. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A82, wherein the treatment is a method of lowering LDL-C levels.

A84. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A83, wherein the subject is an adult with primary hyperlipidemia.

A85. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A84, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

A86. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A85, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) great than or equal to 75%.

A87. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A82, which is a method of reducing cardiovascular risk.

A88. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A87, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

A89. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A82, which is a treatment of a cardiovascular disease.

A90. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A89, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

A91. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to either statement A89 or statement A90, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

A92. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A89 to A91 , wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

A93. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A92, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

A94. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A93, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

A95. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A94, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

A96. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A95, wherein the ezetimibe is administered in a dose of 5 to 15 mg per day.

A97. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A96, wherein the ezetimibe is administered in a dose of 10 mg per day. A98. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A97, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid.

A99. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A98, wherein the statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

A100. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to either statement A98 or statement A99, wherein the statin is administered according to one of the following:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

A101. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A100, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

A102. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A98, wherein bempedoic acid is administered in a dose of 150 to 200 mg per day. A103. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A 102, wherein bempedoic acid is administered in a dose of 180 mg per day.

A104. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A82 to A103, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

A105. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A104, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

A106. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement A105, wherein the subject has been treated with one or more statins for a period of at least six months prior to starting the method of treatment.

A107. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A92 to A106, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

A108. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements A92 to A107, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

A109. The use of ezetimibe in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe and ii) AZD0780 or a pharmaceutically acceptable salt thereof to said subject.

A110. The use of ezetimibe according to statement A109, wherein the treatment is a method of lowering LDL-C levels.

A111. The use of ezetimibe according to statement A110, wherein the subject is an adult with primary hyperlipidemia. A112. The use of ezetimibe according to any one of statements A109 to A111, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

A113. The use of ezetimibe according to any one of statements A109 to A112, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) great than or equal to 75%.

A114. The use of ezetimibe according to statement A109, which is a method of reducing cardiovascular risk.

A115. The use of ezetimibe according to statement A114, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

A116. The use of ezetimibe according to statement A109, which is a treatment of a cardiovascular disease.

A117. The use of ezetimibe according to statement A116, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

A118. The use of ezetimibe according to either statement A116 or statement A117, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

A119. The use of ezetimibe according to any one of statements A116 to A118, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

A120. The use of ezetimibe according to any one of statements A109 to A119, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

A121 . The use of ezetimibe according to statement A120, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

A122. The use of ezetimibe according to statement A121 , wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

A123. The use of ezetimibe according to any one of statements A109 to A122, wherein the ezetimibe is administered in a dose of 5 to 15 mg per day.

A124. The use of ezetimibe according to statement A123, wherein the ezetimibe is administered in a dose of 10 mg per day.

A125. The use of ezetimibe according to any one of statements A109 to A124, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid

A126. The use of ezetimibe according to statement A125, wherein a statin is administered in a moderate-intensity dosing or high-intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

A127. The use of ezetimibe according to statement A125, wherein the statin is administered according to one of the following: (a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

A128. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement A127, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

A129. The use of ezetimibe according to statement A125, wherein bempedoic acid is administered in a dose of 150 to 200 mg per day.

A130. The use of ezetimibe according to statement A129, wherein bempedoic acid is administered in a dose of 180 mg per day.

A131. The use of ezetimibe according to any one of statements A109 to A130, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

A132. The use of ezetimibe according to statement A131, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment. A133. The use of ezetimibe according to statement A132, wherein the subject has been treated with one or more statins for a period of at least six months prior to starting the method of treatment. A134. The use of ezetimibe according to any one of statements A109 to A133, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

A135. The use of ezetimibe according to any one of statements A109 to A134, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

A136. A kit comprising: a first pharmaceutical composition comprising AZD0780 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe; and instructions for using the first and second pharmaceutical compositions in combination.

Further Statements

B1. A method of lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease, comprising administering to a subject in need thereof, a first amount of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'- bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof and a second amount of ezetimibe or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

B2. The method according to statement B1 , which is a method of lowering LDL-C levels.

B3. The method according to statement B2, wherein the subject is an adult with primary hyperlipidemia.

B4. The method according to any one of statements B1 to B3, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

B5. The method according to any one of statements B1 to B4, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

B6. The method according to statement B1 , which is a method of reducing cardiovascular risk.

B7. The method according to statement B6, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event. B8. The method according to statement B1 , which is treating a cardiovascular disease.

B9. The method according to statement B8, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

B10. The method according to either statement B8 or statement B9, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

B11. The method according to any one of statements B8 to B10, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

B12. The method according to any one of statements B1 to B11 , wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

B13. The method according to statement B12, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

B14. The method according to statement B13, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

B15. The method according to any one of statements B1 to B14, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

B16. The method according to statement B15, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day. B17. The method according to any one of statements B1 to B16, wherein a further agent is administered to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

B18. The method according to statement B17, wherein a statin is administered in a moderate-intensity dosing or high-intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

B19. The method according to statement B17, wherein a statin is administered according to one of the following regimens:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

B20. The method according to statement B19, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

B21. The method according to statement B17, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 150 to 200 mg per day.

B22. The method according to statement B21 , wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 180 mg per day. B23. The method according to any one of statements B1 to B22, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

B24. The method according to statement B23, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

B25. The method according to statement B24, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two months prior to starting the method of treatment.

B26. The method according to any one of statements B1 to B25, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

B27. The method according to any one of statements B1 to B26, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

B28. 6'- ([( 1 S,3S)-3-([5-(Difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'- bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof for use in a treatment which is lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject.

B29. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B28, wherein the treatment is a method of lowering LDL-C levels.

B30. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B29, wherein the subject is an adult with primary hyperlipidemia.

B31. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B30, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or (d) less than 40 mg/dL.

B32. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B31, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

B33. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B28, wherein the treatment is a method of reducing cardiovascular risk.

B34. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B33, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

B35. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B28, wherein the treatment is treating a cardiovascular disease.

B36. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B35, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

B37. AZD0780 or a pharmaceutically acceptable salt thereof for use according to either statement B35 or statement B36, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. B38. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B35 to B37, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

B39. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B38, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

B40. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B39, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

B41. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B40, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

B42. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B41, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

B43. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B42, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

B44. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B43, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

B45. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B44, wherein a statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association). B46. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B44, wherein the statin is administered according to one of the following regimens:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

B47. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B46, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

B48. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B44, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 150 to 200 mg per day.

B49. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B48, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 180 mg per day.

B50. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B49, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment. B51. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B50, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

B52. AZD0780 or a pharmaceutically acceptable salt thereof for use according to statement B51 , wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least six months prior to starting the method of treatment.

B53. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B52, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

B54. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of statements B28 to B53, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

B55. Ezetimibe or a pharmaceutically acceptable salt thereof for use in a treatment which is lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe or a pharmaceutically acceptable salt thereof, and ii) 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'- bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof to said subject.

B56. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B55, wherein the treatment is a method of lowering LDL-C levels.

B57. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B56, wherein the subject is an adult with primary hyperlipidemia.

B58. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B57, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or (d) less than 40 mg/dL.

B59. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B58, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

B60. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B55, wherein the treatment is a method of reducing cardiovascular risk.

B61. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B60, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

B62. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B55, wherein the treatment is treating a cardiovascular disease.

B63. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B62, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

B64. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to either statement B62 or statement B63, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. B65. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B62 to B64, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

B66. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B62 to B65, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

B67. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B66, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

B68. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B67, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

B69. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B68, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

B70. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B69, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

B71. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B70, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

B72. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B71 , wherein a statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association). B73. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B71 , wherein the statin is administered according to one of the following regimens:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

B74. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B73, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

B75. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B71 , wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 150 to 200 mg per day.

B76. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B75, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 180 mg per day.

B77. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B76, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment. B78. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B77, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

B79. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to statement B78, wherein the subject has been treated with one or more of the agents to be combined with AZD0780 for a period of at least six months prior to starting the method of treatment.

B80. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B79, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

B81. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of statements B55 to B80, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

B82. The use of 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a treatment which is lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising AZD0780 or a pharmaceutically acceptable salt thereof and ii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject.

B83. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B82, wherein the treatment is a method of lowering LDL-C levels.

B84. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B83, wherein the subject is an adult with primary hyperlipidemia.

B85. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B84, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL; (b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

B86. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B85, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

B87. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B82, which is a method of reducing cardiovascular risk.

B88. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B87, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

B89. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B82, which is treating a cardiovascular disease.

B90. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B89, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

B91. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to either statement B89 or statement B90, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. B92. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B89 to B91 , wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

B93. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B92, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

B94. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B93, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

B95. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B94, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

B96. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B95, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

B97. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B96, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

B98. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B97, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

B99. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B98, wherein the statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

B100. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to either statement B98 or statement B99, wherein the statin is administered according to one of the following regimens:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

B101. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B100, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

B102. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B98, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 150 to 200 mg per day.

B103. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B102, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 180 mg per day. B104. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B82 to B103, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

B105. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B104, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

B106. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to statement B105, wherein the subject has been treated with one or more statins for a period of at least six months prior to starting the method of treatment.

B107. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B92 to B106, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

B108. The use of AZD0780 or a pharmaceutically acceptable salt thereof according to any one of statements B92 to B107, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

B109. The use of ezetimibe or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a treatment which is the lowering of LDL-C levels, reducing cardiovascular risk and/or treatment of a cardiovascular disease wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising ezetimibe or a pharmaceutically acceptable salt thereof and ii) 6'- ([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]- 2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof to said subject.

B110. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B109, wherein the treatment is a method of lowering LDL-C levels.

B111. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B110, wherein the subject is an adult with primary hyperlipidemia. B112. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B111 , wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

B113. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B112, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

B114. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B109, which is a method of reducing cardiovascular risk.

B115. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B114, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

B116. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B109, which is a treatment of a cardiovascular disease.

B117. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B116, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

B118. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to either statement B116 or statement B117, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

B119. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B116 to B118, wherein the cardiovascular disease to be treated is:

(a) hypercholesterolemia, such as familial hypercholesterolemia;

(b) hyperlipidemia; or

(c) coronary artery disease.

B120. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B119, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

B121. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B120, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

B122. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B121, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

B123. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B122, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

B124. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B123, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

B125. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B124, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof. B126. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B125, wherein a statin is administered in a moderate-intensity dosing or high- intensity dosing, as defined by the ACC (American College of Cardiology) and the AHA (American Heart Association).

B127. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B125, wherein the statin is administered according to one of the following regimens:

(a) Atorvastatin, 10 to 20 mg once daily;

(b) Fluvastatin, 40 mg twice daily, or 80 mg once daily;

(c) Lovastatin, 40 to 80 mg once daily;

(d) Pitavastatin, 1 to 4 mg once daily;

(e) Pravastatin, 40 to 80 mg once daily;

(f) Rosuvastatin, 5 to 10 mg once daily, optionally as rosuvastatin calcium;

(g) Simvastatin, 20 to 40 mg once daily;

(h) Atorvastatin, 40 to 80 mg once daily;

(i) Rosuvastatin, 20 to 40 mg once daily, optionally as rosuvastatin calcium;

(j) Atorvastatin, 10 to 40 mg once daily;

(k) Fluvastatin, 60 mg once daily;

(m) Simvastatin, 10 to 20 mg once daily.

B128. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B127, wherein the statin is rosuvastatin which is administered according to one of the following:

(a) 2.5 to 20 mg once daily, optionally as rosuvastatin calcium;

(a) 5 to 10 mg once daily, optionally as rosuvastatin calcium; or

(a) 20 to 40 mg once daily, optionally as rosuvastatin calcium.

B129. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B125, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 150 to 200 mg per day.

B130. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B129, wherein bempedoic acid or a pharmaceutically acceptable salt thereof is administered in a dose of 180 mg per day. B131. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B130, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

B132. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B131, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 for a period of at least two weeks prior to starting the method of treatment.

B133. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to statement B132, wherein the subject has been treated with one or more statins for a period of at least six months prior to starting the method of treatment.

B134. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B133, wherein the subject to be treated has a LDL-C < 190 mg/dL before starting treatment.

B135. The use of ezetimibe or a pharmaceutically acceptable salt thereof according to any one of statements B109 to B134, wherein the subject to be treated has a LDL-C > 100 mg/dL before starting treatment.

B136. A kit comprising: a first pharmaceutical composition comprising AZD0780 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

Claims

1. 6'- ([( 1 S,3S)-3-([5-(Difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'- bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof for use in a treatment which is lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said AZD0780 or a pharmaceutically acceptable salt thereof, and ii) ezetimibe or a pharmaceutically acceptable salt thereof to said subject.

2. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the treatment is a method of lowering LDL-C levels.

3. AZD0780 or a pharmaceutically acceptable salt thereof for use according to either claim 1 or claim 2, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

4. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

5. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the treatment is a method of reducing cardiovascular risk.

6. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the treatment is a method of treating a cardiovascular disease.

7. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 6, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

8. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 7, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

9. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 8, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

10. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

11. AZD0780 or a pharmaceutically acceptable salt thereof for use according to claim 10, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

12. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 11, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

13. AZD0780 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment.

14. Ezetimibe or a pharmaceutically acceptable salt thereof for use in a treatment which is lowering LDL-C levels, reducing cardiovascular risk and/or treating a cardiovascular disease in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) ezetimibe or a pharmaceutically acceptable salt thereof, and, and ii) 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H- [1 ,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof to said subject.

15. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to claim 14, wherein the treatment is a method of lowering LDL-C levels.

16. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to either claim 14 or claim 15, wherein the LDL-C level is reduced to:

(a) less than 100 mg/dL;

(b) less than 70 mg/dL;

(c) less than 55 mg/dL; or

(d) less than 40 mg/dL.

17. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 16, wherein the reduction of the untreated level of LDL-C is by:

(a) greater than or equal to 30%;

(b) greater than or equal to 40%;

(c) greater than or equal to 50%;

(d) greater than or equal to 60%;

(e) greater than or equal to 65%;

(f) greater than or equal to 70%; or

(g) greater than or equal to 75%.

18. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to claim 14, wherein the treatment is a method of reducing cardiovascular risk.

19. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to claim 14, wherein the treatment is a method of treating a cardiovascular disease.

20. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 19, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered once daily.

21. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to claim 20, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 to 30 mg per day of AZD0780.

22. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to claim 21, wherein the AZD0780 or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day of AZD0780.

23. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 22, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 5 to 15 mg per day.

24. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 23, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg per day.

25. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 19, wherein said treatment further comprises, the separate, sequential or simultaneous administration of iii) a further agent to said subject, where the further agent is selected from one or more statins or bempedoic acid or a pharmaceutically acceptable salt thereof.

26. Ezetimibe or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 25, wherein the subject has been previously treated with one or more of the agents to be combined with AZD0780 prior to starting the method of treatment

27. A kit comprising: a first pharmaceutical composition comprising 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1,3'-bipyridin]-2-one (“AZD0780”) or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.