WO2025133111A1

WO2025133111A1 - Cgrp receptor agonists in ischemic heart disease

Info

Publication number: WO2025133111A1
Application number: PCT/EP2024/087887
Authority: WO
Inventors: Anette Sams Nielsen; Jens Thostrup Bukrinski
Original assignee: Epoqe Pharma Aps
Current assignee: Epoqe Pharma Aps
Priority date: 2023-12-20
Filing date: 2024-12-20
Publication date: 2025-06-26
Anticipated expiration: 2026-06-20

Abstract

Provided is an administration regimen of a CGRP-R agonist for use in the treatment of ischemic heart disease.

Description

CGRP Receptor Agonists in Ischemic Heart Disease

Technical field

The present invention relates a CGRP-R agonist, such as a CGRP analogue, for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist can be administered after a delay, such as is administered more than 1 hour after the ischemic incident and/or wherein said ischemic heart disease has no or delayed coronary reperfusion, such as has an occlusion to the coronary artery lasting for more than 1 hour.

Background

Ischaemic heart disease (IHD), also called coronary heart disease (CHD) or coronary artery disease (CAD) is a major cause of death worldwide. Coronary artery disease is caused by plaque buildup in the wall of the arteries that supply blood to the heart (called coronary arteries). There are two primary coronary arteries, the right coronary artery (RCA) and the left main coronary artery (LMCA). Both of these originate from the root of the aorta.

Acute coronary syndrome (ACS) is a term that describes a range of conditions related to sudden, reduced blood flow to the heart. These conditions include a heart attack and unstable angina. Most myocardial infarctions (‘heart attacks’) are due to underlying coronary artery disease. With coronary artery occlusion - partial or full occlusion, the myocardium is deprived of oxygen. Prolonged deprivation of oxygen supply to the myocardium can lead to myocardial cell death and necrosis. Myocardial infarction is defined as myocardial necrosis in a clinical setting consistent with myocardial ischemia, and may be ameliorated with coronary artery bypass graft surgery and well as via pharmacological therapy (antiplatelet drugs, anticoagulants, nitrates, beta-blockers, statins).

Unstable angina involves sudden, unexpected chest pain or pressure, even while resting. It’s a warning sign of a heart attack and occurs when stable angina worsens. Stable angina (or angina pectoris) is the medical term for chest pain or discomfort due to coronary heart disease. Myocardial infarctions (‘heart attacks’) can be classified as a STEM I (ST-segment elevation myocardial infarction) and an NSTEMI (Non-ST segment-elevation myocardial infarction). ST-segment elevation is also referred to as Q waves.

STEMI results from complete and prolonged occlusion of an epicardial coronary blood vessel and is defined based on ECG (electrocardiogram) criteria. NSTEMI usually results from severe coronary artery narrowing, transient occlusion, or microembolization of thrombus and/or atheromatous material. An NSTEMI is detectable with blood tests but not with an ECG.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is found in about 5 to 6% of patients with acute Ml who undergo coronary angiography.

Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and/or diaphoresis. Acute myocardial infarction (AMI) increases the risk of heart failure (HF).

Current AMI treatment comprises urgent reperfusion by Percutaneous Coronary Intervention (PCI) or pharmacological therapy i.e. thrombolysis which reduces infarct size and improves heart pump function and prognosis. PCI is a non-surgical, invasive procedure used to treat the blockages in a coronary artery during acute coronary syndromes; it opens up narrowed or blocked sections of the artery, restoring blood flow to the heart. This is usually achieved by different methods, the most common being ballooning the narrow segment or deploying a stent to keep the artery open.

In spite of the availability of PCI and thrombolysis, an estimated 10% of patients with AMI die, approx. 35% of patients suffer secondary HF, and, within 30-days, approx. 5- 10% of patients are readmitted (depending on geographical region). Importantly, time is of the essence in treating myocardial infarction and thus dependent on urgent transportation to the hospital for the procedure, which in some areas can be limiting, and it is a fairly expensive procedure even without counting the ambulance transportation, subsequent hospitalization and other indirect costs.

Accordingly, implementation of primary PCI is mainly appropriate for patients presenting to an interventional centre or those who can be transported to one via helicopter or ambulance, preferably within 60 to 90 minutes. Practically, however, PCI is also performed with a further delay given the individual circumstances. For patients presenting to institutions that cannot meet these primary PCI criteria and have no contraindication to thrombolysis, treatment with fibrinolysis followed by PCI (pharmaco- invasive approach) is warranted.

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides. The major CGRP receptor is formed by the co-expression of calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein-1 (RAMP1). These receptors are found throughout the cardiovascular system, specifically in blood vessels. Although CGRP is established as a potent vasodilator, there is little evidence that sufficient endogenous CGRP is released to influence physiological blood pressure regulation, although CGRP-containing nerves surround all cardiovascular tissues. CGRP receptor antagonists and antibodies developed as migraine therapies have minimal effect on blood pressure in healthy individuals. Evidence that CGRP plays a role in cardiovascular protection arises from studies where CGRP has been administered in rodent models of hypertension. CGRP is thus known as a potent vasodilator that can reduce blood pressure and therefore potentially treat hypertension and potentially provide benefit to heart diseases driven by hypertension.

Endogenous CGRP is released in response to local ischemia, e.g. myocardial infarction, which may be a physiological response to re-establish blood flow in the coronary artery upon ischemic cardiac insult via its vasodilatory properties. Exogenous CGRP is known to cause systemic hypotension and increased coronary flow upon administration, nonetheless this is shown not to result in cardioprotective effects in a model of myocardial ischemia: Reducing systemic blood pressure during a myocardial infarction will increase the work load on the ischemic heart, increasing the hearts oxygen needs and further worsening heart ischemia. Further, when arteries near the myocardial obstruction are dilated, this ‘steals’ blood supply from the ischemic area which further reduces the oxygen supply to the heart.

There is a clear distinction between heart diseases driven by hypertension and those driven by occlusion, i.e. obstruction of coronary perfusion. Whereas hypertension may cause cardiac hypertrophy and potentially other complications, obstruction of coronary blood flow causes ischemic heart conditions such as acute myocardial infarction. A preventive effect on hypertension through reduced blood pressure does not have any bearing on an effect on an acute condition caused by coronary occlusion, even though a chronic reduction of hypertension can be said to reduce the risk of developing acute myocardial infarction. Nonetheless, some non-native CGRP analogues have been demonstrated to have a cardioprotective profile with effect in acute Ml (AMI) models when administered immediately (WO 2020/130927).

PCI has generally improved patient survival and prognosis, and if available is superior to current pharmacological reperfusion therapy (fibrinolytic or thrombolytic drugs that dissolves dangerous intravascular clots, or nitroglycerine).

Although the mortality associated with AMI has declined it remains high, and with the risk of readmission and associated risk of heart failure, AMI still represents an area of a high unmet need. In circumstances where PCI is not readily available, e.g. due to lack of resources or available transportation, and where PCI is only available after a delay, patients are currently facing poorer outcomes.

Summary

The present inventors have found that a cardioprotective CGRP analogue is effective in rescuing heart function and reducing myocardial infarct size with a flexible timing of first dose.

As demonstrated herein, treatment of ischemic heart disease can be delayed for more than 1 hour after an ischemic incident while retaining markedly beneficial effects, as demonstrated with delayed administration of a CGRP analogue up until 24 hours after the ischemic incident. Furthermore the delayed administration is surprisingly effective as a stand-alone therapy, demonstrating effectiveness also without reperfusion, i.e. with permanent coronary occlusion not mitigated by e.g. reperfusion intervention such as PCI. Additionally the delayed administration is surprisingly effective also when reperfusion occurs early (within 1 hour of ischemic incident) and when reperfusion occurs late (within 4 hours of ischemic incident). In the case of late reperfusion the CGRP analogue is shown to be effective with both early and late administration to improve the outcome of an otherwise delayed reperfusion intervention.

The art has not previously demonstrated effectiveness of a delayed pharmacological treatment of ischemic heart disease, showing reversal of myocardial damage even at a time point where myocardial cells were thought to be irreversibly damaged or dead. The art has also not previously demonstrated effectiveness of a pharmacological treatment that improves the effect of a delayed reperfusion intervention. No pharmacological therapy has been shown to be more effective than PCI.

CGRP receptor (CGRP-R) agonists, such as peptide-derived CGRP analogues, thus offer great potential to avoid or reduce the urgency of reperfusion in patients with ischemic heart disease and reduce risk of heart failure following myocardial infarction, and to offer effective medicinal treatment even after delayed administration to minimize myocardial injury at a cost which is substantial lower than invasive procedures to make therapy more accessible.

The present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, such as wherein said ischemic heart disease has an occlusion to the coronary artery, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

The present disclosure further provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion lasting for more than 1 hour.

The present disclosure further provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour such as wherein coronary reperfusion intervention is performed more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

In some embodiments the CGRP-R agonist is a CGRP analogue. In some embodiments the CGRP-R agonist is a cardioprotective CGRP analogue.

In some embodiments the CGRP-R agonist is a CGRP analogue selected from alpha- CGRP analogue according to SEQ ID NO:9 and formula I; and the beta-CGRP analogue according to SEQ ID NO:10 and formula II. Description of Drawings

Fig. 1. Effect of a CGRP analogue (‘Analog’, cf. Example 1) on heart function (EF, %, top) and final myocardial infarct ratio (Infarct size, %, bottom) from a minipig Heart Failure/AMI model with permanent occlusion of the middle LAD (no reperfusion). Heart function data (top) are given as mean ± SEM (n = 8) at each timepoint (6 days before the occlusion as well as 7, 14 and 21 days after the occlusion). Animals were dosed with Vehicle at 24, 48, 72 and 96 hours after the occlusion; with the CGRP analogue at 24, 48, 72 and 96 hours after the occlusion; or with the CGRP analogue at 14, 24, 48 and 72 hours after the occlusion. The final myocardial infarct ratio (bottom) was determined at the end of the study (21 days after occlusion) and given as mean ± SEM (n = 8). Statistical differences between vehicle and CGRP analogue groups are given as * when p < 0.05, ** when p < 0.01 , *** when p < 0.001 , and **** when p < 0.001. Statistical differences between early and late CGRP analogue treatment groups are marked with #.

Fig. 2. Effect of a CGRP analogue (‘Analog’, cf. Example 1) on heart function (EF, %, left) and final myocardial infarct ratio (Infarct size, %, right) from the minipig Heart Failure/AMI model where reperfusion was induced 4 hours after occluding of the middle LAD (delayed reperfusion). Heart function data (left) are given as mean ± SEM (n = 8) at each timepoint (6 days before the occlusion as well as 7, 14 and 21 days after the occlusion). Animals were dosed with Vehicle at 24, 48, 72 and 96 hours after the occlusion (where 24 hours after the occlusion is 20 hours after the reperfusion); with the CGRP analogue at 24, 48, 72 and 96 hours after the occlusion; or with the CGRP analogue at 14, 24, 48 and 72 hours after the occlusion. The final myocardial infarct ratio (right) was determined at the end of the study (21 days after occlusion) and given as mean ± SEM (n = 8). Statistical differences between vehicle and CGRP analogue groups are given as * when p < 0.05, ** when p < 0.01 , *** when p < 0.001 , and **** when p < 0.001. Statistical differences between early and late CGRP analogue treatment groups are marked with #.

Fig. 3. A) alpha-CGRP analogue according to formula I; B) beta-CGRP analogue according to formula II (‘Analog’, cf. Example 1).

Fig. 4. Sequence alignment of alpha-CGRP in human (alpha-hCGRP; SEQ ID NO:3), beta-CGRP in human (beta-hCGRP; SEQ ID NO:4), alpha-CGRP in rat (alpha-rCGRP; SEQ ID NO:5), beta-CGRP in rat (beta-rCGRP; SEQ ID NO:6), alpha-CGRP in mouse (alpha-mCGRP; SEQ ID NO:7), and beta-CGRP in mouse (beta-mCGRP; SEQ ID NO:8).

Detailed description

Calcitonin gene-related peptide (CGRP), a member of the calcitonin family, exists in 2 isoforms: aCGRP and pCGRP. aCGRP, a 37 amino-acid peptide, is formed by alternative splicing of the calcitonin gene, in particular in the central and peripheral nervous system, and acts as a potent vasodilator and modulator of cerebrovascular nociception. pCGRP is encoded by a second CGRP gene, predominantly expressed in the enteric sensory system and shares 34 amino acids with aCGRP.

Both CGRP isoforms act on the CGRP receptor (CGRP-R), consisting of the 7- transmembrane calcitonin-like receptor (CLR), a receptor activity-modifying protein type 1 (RAMP1), and a receptor component protein (RCP). All 3 components are required for optimal functioning of the receptor. Its major second messenger is cyclic adenosine monophosphate (cAMP). The amylin-1 receptor is suggested to act as a second CGRP receptor.

Native CGRP has a half-life of less than 30 minutes and a short duration of pharmacological actions after infusion. The vasodilatory action is the dose limiting action of native CGRP. Thus, the pharmacological usefulness of CGRP requires CGRP analogues with prolonged action, (long-acting analogues) Also, for the purposes of the present invention i.e. treatment of ischemic heart diseases such as acute coronary syndrome, the CGRP receptor agonist such as CGRP analogue should also have a cardioprotective profile.

A myocardial infarction or heart attack occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. Recovery of myocardial perfusion in acute myocardial infarction is critical, and may require procedures such as balloon angioplasty and stent placement in the infarct-related coronary artery. A compound that is capable of inducing myocardial perfusion recovery is suitable for treatment of acute myocardial infarction. CGRP analogues with cardioprotective potential are disclosed in WO 2011/051312 and WO 2020/130927. Definitions

The terms “treatment” and “treating” as used herein refer to the management and care of a patient for the purpose of combating a condition, disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient or subject is suffering. The patient to be treated is preferably a mammal, in particular a human being. Treatment of animals, such as mice, rats, dogs, cats, horses, cows, sheep and pigs, is, however, also within the scope of the present context. The patients to be treated can be of various ages. The term ‘subject’ and ‘patient’ may be used interchangeably herein.

The term "therapeutically effective amount" as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the clinical manifestations of a given disease or disorder and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. ‘Amount’ and ‘dosage’ may be used interchangeably herein.

The terms “approximately” and “about” as referred herein are synonymous. In one embodiment, “approximately” and “about” refer to the recited amount, value, or duration ± 5%, ± 4.5%, ± 4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1 %, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1 %, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01%. In one embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5%. In one embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±1 %. In one embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.5%. In one embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.1%. In the context of an amount or dosage the terms “approximately” and “about” refer to the recited amount or dosage ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ±5%, ±4%, ±3%, ±2%, ±1.5%, ±1%, ±0.5%. The terms ‘is administered’ and ‘is to be administered’ may be used interchangeably herein.

An agonist is a compound that activates a receptor to produce a biological response. A CGRP-R agonist as used herein is a compound that acts as an agonist on one or more CGRP receptors. In some embodiments a CGRP-R agonist as used herein is a compound that acts as an agonist on the CGRP receptor (CGRP-R) comprising one or more of CLR, RAMP1 and RCP. In some embodiments a CGRP-R agonist as used herein is a compound that acts as an agonist on the amylin-1 receptor. In some embodiments a CGRP-R agonist as used herein is a compound that acts as an agonist on the CGRP-R and the amylin-1 receptor.

Treatment

Delayed therapy

It is an aspect of the present disclosure to provide a CGRP receptor (CGRP-R) agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

In some embodiments said CGRP-R agonist is administered more than 1 hour after an ischemic incident.

It is an aspect of the present disclosure to provide a CGRP-R agonist for use in the treatment of an acute ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

In some embodiments is provided a CGRP-R agonist for use in the treatment of acute coronary syndrome, such as an acute coronary syndrome selected from the group consisting of unstable angina, myocardial infarction and acute myocardial infarction, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

In some embodiments is provided a CGRP-R agonist for use in the treatment of acute myocardial infarction, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident. It is an aspect of the present disclosure to provide a CGRP-R agonist for use in the treatment of a chronic ischemic heart disease.

In some embodiments is provided a CGRP-R agonist for use in the treatment of a chronic ischemic heart disease, which is not acute myocardial infarction.

In some embodiments is provided a CGRP-R agonist for use in the treatment of a chronic ischemic heart disease, such as wherein said chronic ischemic heart disease has an ischemic incident which is onset of said ischemic heart disease.

One embodiment of the present disclosure provides the use of a CGRP receptor agonist for the manufacture of a medicament for the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

One embodiment of the present disclosure provides for a method for the treatment of ischemic heart disease, said method comprising one or more steps of administering to a subject in need thereof an effective amount of a CGRP receptor agonist, wherein said CGRP receptor agonist is administered more than 1 hour after the ischemic incident.

In some embodiments “the ischemic incident” in the present context is to be understood as the onset of ischemic heart disease, such as onset of one or more symptoms of ischemic heart disease.

In one embodiment ‘the ischemic incident’ as defined herein refers to the diagnosis of ischemic heart disease. In some embodiments said diagnosis is made based on the onset of one or more symptoms of ischemic heart disease.

In one embodiment ‘the ischemic incident’ is diagnosed by electrocardiography (ECG). In one embodiment ‘the ischemic incident’ is diagnosed by the presence or absence of serologic markers (such as troponin I or troponin T and CK).

In some embodiments “the ischemic incident” is defined as onset of one or more symptoms of ischemic heart disease, wherein said one or more symptoms are selected from the group consisting of: Chest discomfort, dyspnoea, deep substernal visceral pain; deep substernal visceral pain radiating to the back, jaw, left arm, right arm, shoulders, or all of these areas; nausea and/or vomiting, syncope, diaphoresis, cyanosis, LV failure, pulmonary oedema, shock, significant arrhythmia, elevated RV filling pressure, and distended jugular veins (often with Kussmaul sign).

In some embodiments “the ischemic incident” is defined as onset of one or more non- prodromal symptoms of ischemic heart disease.

In some embodiments “the ischemic incident” is symptoms of myocardial ischemia. In one embodiment ‘the ischemic incident’ is ECG changes indicative of new myocardial ischemia (such as significant ST/T changes or left bundle branch block). In some embodiments “the ischemic incident” is the development of pathologic Q waves.

In one embodiment ‘the ischemic incident’ is imaging evidence of new loss of myocardium or new regional wall motion abnormality.

In one embodiment ‘the ischemic incident’ is angiography or autopsy evidence of intracoronary thrombus.

In some embodiments “the ischemic incident” is the acute onset of ischemic heart disease. In some embodiments “the ischemic incident” is the acute onset of an acute ischemic heart disease.

In some embodiments “the ischemic incident” is coronary artery occlusion. In some embodiments “the ischemic incident” is obstruction of coronary perfusion.

An occlusion as used herein may be complete or partial, i.e. an occlusion may block the coronary artery completely or block the coronary artery partially. A partial block may be defined as a narrowing of the artery. Occlusion of a coronary artery usually refers to occlusion of a section of the artery.

In some embodiments “the ischemic incident” is complete or partial coronary artery occlusion. In some embodiments “the ischemic incident” is acute or chronic coronary artery occlusion. In some embodiments “the ischemic incident” being coronary artery occlusion is severe coronary artery narrowing, transient occlusion, or microembolization of thrombus and/or atheromatous material. In some embodiments “the ischemic incident” is right coronary artery (RCA) occlusion.

In some embodiments “the ischemic incident” is left main coronary artery (LMCA) occlusion.

In some embodiments “the ischemic incident” is complete and prolonged occlusion of coronary artery.

In some embodiments “the ischemic incident” is acute occlusion of coronary artery.

In some embodiments “the ischemic incident” is severe coronary artery narrowing, transient occlusion, or microembolization of thrombus and/or atheromatous material. In some embodiments “the ischemic incident” is myocardial ischemia.

In some embodiments “the ischemic incident” is myocardial necrosis and/or apoptosis.

In some embodiments “the ischemic incident” is unstable angina.

In some embodiments “the ischemic incident” is myocardial infarction.

In some embodiments “the ischemic incident” is acute myocardial infarction.

In some embodiments “the ischemic incident” is STEMI.

In some embodiments “the ischemic incident” is NSTEMI.

Some embodiment of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

In some embodiments said CGRP-R agonist is administered more than 60 minutes after the ischemic incident, such as about 70 minutes or more, such as about 80 minutes or more, such as about 90 minutes or more, such as about 100 minutes or more, such as about 110 minutes or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered about 2 hours or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered about 2 hours or more after the ischemic incident, such as about 2 hours and 15 minutes or more, such as about 2 hours and 30 minutes or more, such as about 2 hours and 45 minutes or more, such as about 3 hours or more, such as v3 hours and 15 minutes or more, such as about 3 hours and 30 minutes or more, such as about 3 hours and 45 minutes or more, such as 4 hours or more after the ischemic incident In some embodiments said CGRP-R agonist is administered about 24 hours or more after the ischemic incident

In some embodiments said CGRP-R agonist is administered up to 24 hours or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered more than 1 hour after the ischemic incident, such as about 2 hours or more, such as about 3 hours or more, such as about 4 hours or more, such as about 5 hours or more, such as about 6 hours or more, such as about 7 hours or more, such as about 8 hours or more, such as about 9 hours or more, such as about 10 hours or more, such as about 11 hours or more, such as about 12 hours or more, such as about 13 hours or more, such as about 14 hours or more, such as about 15 hours or more, such as about 16 hours or more, such as about 17 hours or more, such as about 18 hours or more, such as about 19 hours or more, such as about 20 hours or more, such as about 21 hours or more, such as about 22 hours or more, such as about 23 hours or more, such as about 24 hours or more, such as about 36 hours or more, such as about 48 hours or more, such as about 60 hours or more, such as about 72 hours or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered up to 48 hours or more, such as up to 72 hours or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered more than 1 hour to 24 hours or more after the ischemic incident, such as 2 hours to 24 hours or more after the ischemic incident, such as 3 hours to 24 hours or more after the ischemic incident, such as 4 hours to 24 hours or more after the ischemic incident.

In some embodiments said CGRP-R agonist is administered 4 to 48 hours or more after the ischemic incident, such as 8 to 48 hours, such as 14 to 36 hours, such as 18 to 30 hours after the ischemic incident.

In some embodiments said CGRP-R agonist is administered more than 60 to 75 minutes after the ischemic incident, such as 75 to 90 minutes after the ischemic incident, such as 90 to 120 minutes after the ischemic incident, such as 2 to 2.5 hours after the ischemic incident, such as 2.5 to 3 hours after the ischemic incident, such as 3 to 3.5 hours after the ischemic incident, such as 3.5 to 4 hours after the ischemic incident, such as 4 to 4.5 hours after the ischemic incident, such as 4.5 to 5 hours after the ischemic incident, such as 5 to 6 hours after the ischemic incident, such as 6 to 7 hours after the ischemic incident, such as 7 to 8 hours after the ischemic incident, such as 8 to 9 hours after the ischemic incident, such as 9 to 10 hours after the ischemic incident, such as 10 to 11 hours after the ischemic incident, such as 11 to 12 hours after the ischemic incident, such as 12 to 18 hours after the ischemic incident, such as 18 to 24 hours after the ischemic incident, such as 24 to 48 hours after the ischemic incident, such as 48 to 72 hours after the ischemic incident.

In some embodiments said CGRP-R agonist is administered 1 day or more after the ischemic incident, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more, such as 1 week or more, such as 8 days or more, such as 9 days or more, such as 10 days or more, such as 11 days or more, such as 12 days or more, such as 13 days or more, such as 14 days or more, such as 2 weeks or more, such as 3 weeks or more, such as 4 weeks or more, such as 1 month or more, such as 5 weeks or more, such as 6 weeks or more, such as 7 weeks or more, such as 8 weeks or more, such as 2 months or more, such as 3 months or more, such as 4 months or more, such as 5 months or more, such as 6 months or more, such as 7 months or more, such as 8 months or more, such as 9 months or more, such as 10 months or more, such as 11 months or more, such as 12 months or more, such as 1 year or more after the ischemic incident.

Therapy and reperfusion

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered as a stand-alone therapy.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered without coronary reperfusion intervention. Coronary reperfusion intervention in the present context encompass pharmacological reperfusion therapy and pharmaco-invasive approaches such as non-pharmacological coronary reperfusion intervention.

Pharmacological reperfusion therapy encompass antiplatelet drugs, anticoagulants, thrombolytic drugs, fibrinolytic drugs, nitroglycerin, nitrates, beta-blockers and statins.

Non-pharmacological coronary reperfusion intervention encompass Percutaneous Coronary Intervention (PCI).

Percutaneous coronary intervention (PCI) is a non-surgical, invasive procedure to relieve the narrowing or occlusion of the coronary artery and improve blood supply to the ischemic tissue. This is usually achieved by different methods, the most common being ballooning the narrow segment or deploying a stent to keep the artery open.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered without simultaneous, separate or subsequent coronary reperfusion intervention.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered without simultaneous, separate or subsequent non-pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI).

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, wherein said ischemic heart disease has i. a permanent occlusion to the coronary artery and/or permanent obstruction of coronary perfusion, or ii. a short-lasting occlusion to the coronary artery and/or short-lasting obstruction of coronary perfusion, or iii. a long-lasting occlusion to the coronary artery and/or long-lasting obstruction of coronary perfusion.

The terms ‘occlusion to the coronary artery’ and ‘obstruction of coronary perfusion’ are used interchangeably herein. A coronary artery occlusion deprives the myocardium of oxygen, and prolonged oxygen deprivation can lead to myocardial ischemia. Coronary artery occlusion may be permanent or non-permanent, and may obstruct the coronary partially or in full. A non-permanent occlusion may be short-lasting or long-lasting.

In some embodiments said ischemic heart disease has a permanent occlusion to the coronary artery. In some embodiments said ischemic heart disease has a permanent obstruction of coronary perfusion. Permanent in this setting means that the occlusion or obstruction is persistent, or lasting, or is not removed or dissolved.

In some embodiments said ischemic heart disease has a permanent occlusion to the coronary artery and said CGRP-R agonist is administered without simultaneous, separate or subsequent coronary reperfusion intervention.

In some embodiments said ischemic heart disease has a permanent occlusion to the coronary artery and said CGRP-R agonist is administered without simultaneous, separate or subsequent non-pharmacological coronary reperfusion intervention, such as PCI.

In some embodiments said CGRP-R agonist is administered with simultaneous, separate or subsequent coronary reperfusion intervention. In some embodiments said CGRP-R agonist is administered with simultaneous, separate or subsequent coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI. Said coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, removes or decreases the occlusion.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery. In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting for about 5 minutes to less than 4 hours, such as 5 to 15 minutes, such as 15 to 30 minutes, such as 30 to 45 minutes, such as 45 to 60 minutes, such as 1 to 1.5 hours, such as 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to 4 less than hours.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting for about 15 minutes or less, such as about 30 minutes or less, such as about 45 minutes or less, such as about 60 minutes or less, such as about 1 .5 hours or less, such as about 2 hours or less, such as about 2.5 hours or less, such as about 3 hours or less, such as about 3.5 hours or less, such as lasting for less than 4 hours.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting for less than about 1 hours, such as less than about 2 hours, such as less than about 3 hours, such as less than about 4 hours.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting for about 1 hour. In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting for about 1 hour to

3 hours.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery lasting less than 4 hours.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery, wherein said short-lasting occlusion is removed or decreased via coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, within 4 hours after the ischemic incident, such as less than

4 hours after the ischemic incident.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, is performed within 15 minutes to less than 4 hours after the ischemic incident.

In some embodiments said ischemic heart disease has a short-lasting occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, is performed within 15 minutes to 4 hours after the ischemic incident; such as within 15 to 30 minutes after the ischemic incident, such as within 30 to 45 minutes, such as within 45 to 60 minutes, such as within 1 to 1.5 hours, such as within 1.5 to 2 hours, such as within 2 to 2.5 hours, such as within 2.5 to 3 hours, such as within 3 to 3.5 hours, such as within 3.5 to 4 hours after the ischemic incident.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery of about 4 hours or more, such as at least 4 hours.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery lasting for at least 4 hours, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 9 hours or more, such as 10 hours or more, such as 11 hours or more, such as 12 hours or more, such as 13 hours or more, such as 14 hours or more, such as 15 hours or more, such as 16 hours or more, such as 17 hours or more, such as 18 hours or more, such as 19 hours or more, such as 20 hours or more, such as 21 hours or more, such as 22 hours or more, such as 23 hours or more, such as 24 hours or more.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery lasting for 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as

14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as

21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours. In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery, wherein said long-lasting occlusion is removed or decreased via coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, 4 hours or more after the ischemic incident, such as at least 4 hours after the ischemic incident.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident, such as at least 4 hours after the ischemic incident.

In some embodiments said ischemic heart disease has a long-lasting occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident, such as 4 to 5 hours after the ischemic incident, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours after the ischemic incident.

Delayed reperfusion

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, such as an obstruction of coronary perfusion lasting for more than 1 hour.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, such as for 1.5 hour or more, such as for 2 hours or more, such as for 2.5 hour or more, such as for 3 hours or more, such as for 3.5 hour or more, such as for 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 9 hours or more, such as 10 hours or more, such as 11 hours or more, such as 12 hours or more, such as 13 hours or more, such as 14 hours or more, such as 15 hours or more, such as 16 hours or more, such as 17 hours or more, such as 18 hours or more, such as 19 hours or more, such as 20 hours or more, such as 21 hours or more, such as 22 hours or more, such as 23 hours or more, such as 24 hours or more.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said CGRP-R agonist is administered 0 to 15 minutes after the ischemic incident, such as 15 to 30 minutes after the ischemic incident, such as 30 to 45 minutes after the ischemic incident, such as 45 to 60 minutes after the ischemic incident, such as 60 to 75 minutes after the ischemic incident, such as 75 to 90 minutes after the ischemic incident, such as 90 to 120 minutes after the ischemic incident, such as 2 to 2.5 hours after the ischemic incident, such as 2.5 to 3 hours after the ischemic incident, such as 3 to 3.5 hours after the ischemic incident, such as 3.5 to 4 hours after the ischemic incident, such as 4 to 4.5 hours after the ischemic incident, such as 4.5 to 5 hours after the ischemic incident, such as 5 to 6 hours after the ischemic incident, such as 6 to 7 hours after the ischemic incident, such as 7 to 8 hours after the ischemic incident, such as 8 to 9 hours after the ischemic incident, such as 9 to 10 hours after the ischemic incident, such as 10 to 11 hours after the ischemic incident, such as 11 to 12 hours after the ischemic incident, such as 12 to 18 hours after the ischemic incident, such as 18 to 24 hours after the ischemic incident, such as 24 to 48 hours after the ischemic incident, such as 48 to 72 hours after the ischemic incident, such as more than 72 hours after the ischemic incident.

In some embodiments said CGRP-R agonist is administered with a separate or subsequent coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI); wherein said coronary reperfusion intervention is performed more than 1 hour after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, such as an obstruction of coronary perfusion lasting for more than 1 hour, wherein said occlusion to the coronary artery is removed or decreased after more than 1 hour by coronary reperfusion intervention.

In some embodiments said occlusion to the coronary artery is removed or decreased after more than 1 hour by pharmacological reperfusion therapy or non-pharmacological coronary reperfusion intervention, such as PCI.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said occlusion to the coronary artery is removed or decreased after more than 1 hour by coronary reperfusion intervention; such as pharmacological reperfusion therapy or non- pharmacological coronary reperfusion intervention, such as PCI.

Delayed reperfusion, early CGRP-R agonist therapy

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, such as an obstruction of coronary perfusion lasting for more than 1 hour, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said CGRP-R agonist is administered within 0 min to 60 minutes after the ischemic incident, such as within 0 min to 45 min after the ischemic incident, such as within 0 min to 30 min after the ischemic incident, such as within 0 to 5 min, 5 to 10 min, 10 to 15 min, 15 to 20 min, 20 to 25 min, 25 to 30 min, 30 to 35 min, 35 to 40 min, 40 to 45 min, 45 to 50 min, 50 to 55 min, or 55 to 60 min after the ischemic incident, such as is administered immediately after the ischemic incident.

Some embodiment of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for at least 1.5 hours, such as at least 2 hours, such as at least 2.5 hours, such as at least 3 hours, such as at least 3.5 hours, such as at least 4 hours, such as at least 2 hours, such as at least 2.5 hours, such as at least 3 hours, such as at least 3.5 hours, such as at least 4 hours, such as at least 4.5 hours, such as at least 5 hours, such as at least 5.5 hours, such as at least 6 hours, such as at least 7 hours, such as at least 8 hours, such as at least 9 hours, such as at least 10 hours, such as at least 11 hours, such as at least 12 hours, such as at least 13 hours, such as at least 14 hours, such as at least 15 hours, such as at least 16 hours, such as at least 17 hours, such as at least 18 hours, such as at least 19 hours, such as at least 20 hours, such as at least 21 hours, such as at least 22 hours, such as at least 23 hours, such as at least 24 hours, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery lasting for 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours.

In some embodiments said CGRP-R agonist is administered with separate or subsequent coronary reperfusion intervention; such as pharmacological reperfusion or non-pharmacological coronary reperfusion intervention, such as PCI.

Some embodiments of the present disclosure provides a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said occlusion is removed or decreased via non-pharmacological coronary reperfusion intervention, such as PCI, more than 1 hour after the ischemic incident, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident. In some embodiments said ischemic heart disease has an occlusion to the coronary artery that is removed or decreased by pharmacological reperfusion more than 1 hour after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery that is removed or decreased via coronary reperfusion intervention, such as non- pharmacological coronary reperfusion intervention, such as PCI, more than 1 hour after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed more than 1 hour after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed more than 2 hours after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery, wherein coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 1.5 hours or more after the ischemic incident, such as 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours after the ischemic incident. Indications

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion lasting for more than 1 hour.

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

In some embodiments the ischemic heart disease is characterized by occlusion to the coronary artery and/or obstruction of coronary perfusion.

In some embodiments the ischemic heart disease is acute coronary syndrome.

In some embodiments the ischemic heart disease is unstable angina.

In some embodiments the ischemic heart disease is selected from the group consisting of stable angina, anginal equivalent, refractory angina, recurrent angina, symptoms of heart failure, new or worsening mitral regurgitation, hemodynamic instability, sustained ventricular tachycardia/fibrillation, and a worsening of troponin levels

In some embodiments the ischemic heart disease is myocardial infarction (Ml). In some embodiments the ischemic heart disease is acute myocardial infarction (AMI).

In some embodiments the acute myocardial infarction (AMI) is STEMI.

In some embodiments the acute myocardial infarction (AMI) is NSTEMI.

In some embodiments the ischemic heart disease is critical coronary artery stenosis, which does not qualify for coronary artery bypass surgery (CABG).

In some embodiments the ischemic heart disease is Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA).

In some embodiments the ischemic heart disease is heart failure (HF).

Some embodiments provide a CGRP-R agonist for use in the treatment of acute coronary syndrome, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident which is coronary artery occlusion, and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour.

Some embodiments provide a CGRP-R agonist for use in the treatment of acute coronary syndrome selected from the group consisting of unstable angina, myocardial infarction (Ml), acute myocardial infarction (AMI), STEMI and NSTEMI, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident which is coronary artery occlusion, and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour.

Some embodiments provide a CGRP-R agonist for use in the treatment of myocardial infarction (Ml), acute myocardial infarction (AMI), STEMI or NSTEMI, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident which is myocardial ischemia, and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour.

Some embodiments provide a CGRP-R agonist for use in the treatment of STEMI, wherein said CGRP-R agonist is administered more than 1 hour from myocardial necrosis and/or diagnosis of STEMI by electrocardiography (ECG), and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour.

In some embodiments said diagnosis of STEMI by electrocardiography (ECG) shows ST-segment elevation.

In some embodiments said diagnosis of STEMI by electrocardiography (ECG) shows ST-segment elevation that is not quickly reversed by nitroglycerin.

Some embodiments provide a CGRP-R agonist for use in the treatment of NSTEMI, wherein said CGRP-R agonist is administered more than 1 hour from myocardial necrosis and/or diagnosis of NSTEMI, and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour.

In some embodiments said diagnosis of NSTEMI is by electrocardiography (ECG).

In some embodiments said diagnosis of NSTEMI by electrocardiography (ECG) does not show ST-segment elevation.

In some embodiments said diagnosis of NSTEMI by electrocardiography (ECG) shows ST-segment depression and/or T-wave inversion.

In some embodiments said diagnosis of NSTEMI is by cardiac markers in blood, such as elevation of one or more of troponin I, troponin T and CK.

In some embodiments said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour and said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

Treatment outcome

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour. In some embodiments said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour and said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

In some embodiments of the present disclosure said administration reduces myocardial infarct size. In some embodiments of the present disclosure said administration reduces myocardial infarct size compared to vehicle/no treatment.

In some embodiments of the present disclosure said administration reduces myocardial infarct size compared to vehicle/no treatment by at least about 30%, such as at least about 40%, such as at least about 50%, such as at least about 60%, such as at least about 70%.

In some embodiments of the present disclosure said administration reduces myocardial infarct size compared to vehicle/no treatment by 30 to 90%, such as 30 to 40%, such as 40 to 50%, such as 50 to 60%, such as 60 to 70%, such as 70 to 80%, such as 80 to 90%.

In some embodiments of the present disclosure said administration reduces myocardial infarct size compared to vehicle/no treatment at day 21 after the ischemic incident.

In some embodiments of the present disclosure said administration improves heart function (EF %). In some embodiments of the present disclosure said administration improves heart function (EF %) compared to vehicle/no treatment.

In some embodiments of the present disclosure said administration improves heart function (EF %) compared to vehicle/no treatment by at least about 5%, such as at least about 10%, such as at least about 15%, such as at least about 20%, such as at least about 25%, such as at least about 30%, such as at least about 35%, such as at least about 40%, such as at least about 45%, such as at least about 50%.

In some embodiments of the present disclosure said administration improves heart function (EF %) compared to vehicle/no treatment by 5 to 50%, such as by 5 to 10%, such as by 10 to 15%, such as by 15 to 20%, such as by 20 to 25%, such as by 25 to 30%, such as by 30 to 35%, such as by 35 to 40%, such as by 40 to 45%, such as by 45 to 50%. In some embodiments of the present disclosure said administration improves heart function (EF %) compared to vehicle/no treatment at day 21 after the ischemic incident.

In some embodiments of the present disclosure said administration maintains at least 70% of baseline heart function (EF %), such as maintains at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% of baseline heart function.

In some embodiments of the present disclosure said administration maintains 70 to 95% of baseline heart function (EF %), such as maintains 70 to 75%, such as 75 to 80%, such as 80 to 85%, such as 85 to 90%, such as 90 to 95% of baseline heart function.

CGRP analogues

The present disclosure provides the use of a CGRP-R agonist as specified. In some embodiments said CGRP-R agonist is a small-molecule drug. In some embodiments said CGRP-R agonist is an antibody. In some embodiments said CGRP-R agonist is a CGRP analogue.

In some embodiments said CGRP-R agonist is cardioprotective. In some embodiments said CGRP-R agonist reduces myocardial infarct size and/or improves heart function (EF%). In some embodiments said CGRP-R agonist induces recovery of myocardial perfusion and/or preserves myocardial perfusion; and/or has a larger potency ratio in coronary artery than in peripheral arteries, such as mesenteric artery and cerebral artery; and/or induces CGRP sensitization after repeated CGRP-receptor stimulation specifically in coronary artery, not in the mesenteric artery.

Some embodiments provide a CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident and/or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, or wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour and said CGRP-R agonist is administered within 60 minutes after the ischemic incident; wherein said CGRP-R agonist is a CGRP analogue. A CGRP analogue according to the present disclosure is a peptide analogue of a CGRP peptide, in particular a non-native or non-naturally occurring peptide analogue of a CGRP peptide, such as a peptide analogue of alpha-CGRP or a peptide analogue of beta-CGRP. In some embodiments said CGRP analogue is not native alpha-CGRP, and is not native beta-CGRP. In some embodiments said CGRP analogue is an analogue of alpha-CGRP or of beta-CGRP with one or more modifications and/or amino acid substitutions.

Preferably said CGRP analogue is metabolically stable. Metabolically stable in the present context means that the half-life is longer than native CGRP, such as native alpha-CGRP and native beta-CGRP. In some embodiments said CGRP analogue is a non-native, metabolically stable peptide analogue of alpha-CGRP or of beta-CGRP.

In some embodiments said CGRP analogue is cardioprotective.

In some embodiments said CGRP analogue reduces myocardial infarct size and/or improves heart function (EF%).

In some embodiments said CGRP analogue induces recovery of myocardial perfusion and/or preserves myocardial perfusion.

In some embodiments said CGRP analogue has a larger potency ratio in coronary artery than in peripheral arteries, such as mesenteric artery and cerebral artery.

In some embodiments said CGRP analogue induces CGRP sensitization after repeated CGRP-receptor stimulation specifically in coronary artery, not in the mesenteric artery.

In some embodiments said CGRP analogue is an analogue of alpha-CGRP.

In some embodiments said CGRP analogue is an analogue of alpha-hCGRP (human).

In some embodiments said CGRP analogue is an analogue of beta-CGRP.

In some embodiments said CGRP analogue is an analogue of beta-hCGRP (human).

CGRP analogues

For several species, CGRP exists both in an alpha and a beta form and both forms are herein considered CGRP compounds. SEQ ID NO:1 covers, for example, CGRP from the following species: pig, sheep, laughing frog, human, mouse, horse, dog, rat, two- coloured leaf frog, Japanese rice fish, Japanese gecko, Japanese buffer fish and salmon; all in alpha and beta form, where applicable:

X1CX2TX3TCX4TX5RLAX6X7LX8RSGGX9X10X11X12X13FVPTX14VX15X16X17X18F (SEQ ID NO:1), wherein Xi is Ala or Ser, X2 is Asp or Asn, X3 is Ala or Ser, X4 is Vai or Ala, X5 is His or Gin, Xe is Gly or Asp, X7 is Leu or Phe, Xs is Ser, Asn or Arg, X9 is Vai, lie, Met or Leu, X10 is Vai, Ala, Leu or Gly, Xn is Lys, Ser, Asn or His, X12 is Ser, Asn, Asp, Pro, X13 is Asp or Asn, X14 is Asp or Asn, X15 is Gly or Ser, X16 is Ala or Ser, X17 is Glu, Gin, Lys or Asn, Xis is Ala or Ser, and the carboxy group in the C terminal amino acid residue is optionally amidated.

The specific amino acid residues are indicated by the usual one- or three-letter codes for the amino acids.

One subgroup of compounds of SEQ ID NO:1 is compounds of the sequence SEQ ID NO:2. SEQ ID NO:2 covers, for example, CGRP from the following species: pig, mouse, human, dog and rat; all in alpha and beta form, where applicable:

XiCX2TATCVTHRLAX6LLX’8RSGGX'9X’ioKX'i2NFVPTXi4VGSX'i₇AF (SEQ ID NO:2), wherein Xi is Ala or Ser, X2 is Asp or Asn, Xe is Asp or Gly, X's is Arg or Ser, X'9 is Vai or Met, X’IO is Vai or Leu, X'12 is Asp, Asn or Ser, X14 is Asp or Asn, X'17 is Glu or Lys, and the carboxy group in the C terminal amino acid residue is optionally amidated.

In some embodiments the term "CGRP analogue" covers SEQ ID NO:1 and SEQ ID NO:2 as well as analogues of SEQ ID NO:1 and of SEQ ID NO:2.

The sequence identity between alpha-CGRP and beta-CGRP is 92% in the human and 97% in the rat.

The differences between the sequence of alpha-CGRP in human (alpha-hCGRP; SEQ ID NO:3), beta-CGRP in human (beta-hCGRP; SEQ ID NO:4), alpha-CGRP in rat (alpha-rCGRP; SEQ ID NO:5), beta-CGRP in rat (beta-rCGRP; SEQ ID NO:6), alpha- CGRP in mouse (alpha-mCGRP; SEQ ID NO:7), and beta-CGRP in mouse (beta- mCGRP; SEQ ID NO:8), is indicated in the alignment shown in Figure 4. In some embodiments the term "CGRP analogue" covers analogues of alpha-CGRP from human, rat and/or mouse.

In some embodiments the term "CGRP analogue" covers analogues of beta-CGRP from human, rat and/or mouse.

In some embodiments the term "CGRP analogue" covers analogues of human alpha- CGRP (SEQ ID NO:3) and of human beta-CGRP (SEQ ID NO:4).

In some embodiments the term "CGRP analogue" covers a sequence selected from SEQ ID NO:9 and SEQ ID NQ:10.

In some embodiments the CGRP analogue of the present disclosure is an analogue of alpha-hCGRP having the sequence as set forth in SEQ ID NO:9:

SCDTATCVTHRLAGLLSRSGGWKNNFVPTNVGSKAF, or a variant of SEQ ID NO:9 having one or more amino acid substitutions and/or having one or more modifications.

SEQ IN NO:9 is the peptide sequence included in the alpha-CGRP analogue according to formula I.

In some embodiments the CGRP analogue of the present disclosure is an analogue of beta-hCGRP having the sequence as set forth in SEQ ID NO: 10:

SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF, or a variant of SEQ ID NQ:10 having one or more amino acid substitutions and/or having one or more modifications.

SEQ IN NO: 10 is the peptide sequence included in the beta-CGRP analogue according to formula II (Analog’, cf. Example 1).

In some embodiments said CGRP analogue have the usual intramolecular disulphide bridge between the two N-terminal Cys residues (usually in positions 2 and 7).

A CGRP analogue of the present disclosure is cardioprotective. It follows that a CGRP analogue of the present disclosure has cardioprotective effects. In some embodiments said CGRP analogue has one or more of the following cardioprotective effects: reduces myocardial infarct size, improves heart function (EF%), induces recovery of myocardial perfusion, preserves myocardial perfusion, has a larger potency ratio in coronary artery than in peripheral arteries, such as mesenteric artery and cerebral artery; induces CGRP sensitization after repeated CGRP-receptor stimulation specifically in coronary artery, not in the mesenteric artery.

In some embodiments a CGRP analogue of the present disclosure is an analogue of any one of SEQ ID NO:s 1 to 10, wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to an amino group present in an amino acid residue of said amino acid sequence, such as wherein an Y-Z moiety is connected to the N- terminal amino acid residue of said amino acid sequence.

In some embodiments a CGRP analogue of the present disclosure is an analogue of any one of SEQ ID NO:s 1 to 10, wherein one, two or three of the amino acid residues is substituted with another amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue of SEQ ID NO:3 or 4, wherein one, two or three of the amino acid residues is substituted with another amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue selected from SEQ ID NO:9 and SEQ ID NQ:10, such as an analogue hacing or comprising a sequence selected from SEQ ID NO:9 and SEQ ID NQ:10.

In some embodiments a CGRP analogue of the present disclosure is an analogue selected from SEQ ID NO:9 or SEQ ID NQ:10, or a variant thereof wherein one, two, three, four or five of the amino acid residues is substituted with another amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue selected from SEQ ID NO:9 or SEQ ID NQ:10, wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to the amino group of the N-terminal amino acid residue of SEQ ID NO:9 or of SEQ ID NO: 10. In some embodiments a CGRP analogue of the present disclosure is an analogue selected from SEQ ID NO:9 or SEQ ID NO:10, or a variant thereof wherein one, two, three, four or five of the amino acid residues is substituted with another amino acid residue and wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to the amino group of the N-terminal amino acid residue of SEQ ID NO:9 or of SEQ ID NQ:10.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein one of the amino acid residues in any one of SEQ ID NO:s 1-10 is substituted with another amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein at least one of the amino acid residues in any one of SEQ ID NO:s 1-10 is substituted with another amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein two of the amino acid residues in any one of SEQ ID NO:s 1-10 is substituted with another individual amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein three of the amino acid residues in any one of SEQ ID NO:s 1-10 is substituted with another individual amino acid residue.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein one or more amino acid residues in any one of SEQ ID NO:s 1-10 are omitted.

In some embodiments a CGRP analogue of the present disclosure is an analogue wherein one or more further amino acid residues in any one of SEQ ID NO:s 1-10 are inserted.

Said one or more amino acid substitutions may be conservative substitutions or nonconservative substitutions.

In some embodiments said one or more amino acid substitutions are conservative substitutions. Herein, "conservative substitution" refers to a change in the amino acid composition of a peptide in which a residue is replaced with a structurally similar substitute that does not substantially alter the activity of the peptide. Thus, a "conservatively substituted variant" of a particular amino acid sequence refers to an amino acid substitution of an amino acid that is not critical for protein activity, or substitution of an amino acid with another amino acid having similar properties (for example, acidic, basic, positively or negatively charged, polar or non-polar, etc.) such that the substitution of even critical amino acid do not substantially alter activity. Conservative substitution tables providing functionally similar amino acids are well known in the art. The following six groups each contain amino acids that are conservative substitutions for one another: 1 ) alanine, serine and threonine, 2) aspartic acid and glutamic acid, 3) asparagine and glutamine, 4) arginine and lysine, 5) isoleucine, leucine, methionine and valine, and 6) phenylalanine, tyrosine and tryptophan. One of skill in the art will appreciate that the above-identified substitutions are not the only possible conservative substitutions. For example, one may regard all charged amino acids as conservative substitutions for each other whether they are positive or negative. In addition, individual substitutions, deletions or additions which alter, add or delete a single amino acid or a small percentage of amino acids in an encoded sequence can also be "conservatively substituted variants."

In some embodiments a CGRP analogue of the present disclosure is an analogue of any one of SEQ ID NO:s 1 to 10, wherein a hydrogen has been removed from one of the amino groups present in an amino acid residue of the CGRP peptide, wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to an amino group present in an amino acid residue in the CGRP peptide. The CGRP peptide in this respect is a CGRP analogue of any one of SEQ ID NO:s 1 to 10 as defined herein, and may in some embodiment be designated “X”.

In some embodiments the acyl group (designated Z) and/or the acyl group connected to the linker (designated Y) shall have a sufficient albumin binding affinity. In some embodiments addition of an -Y-Z-moiety will increase the half-life of the CGRP-peptide X (‘prolonged action’). In some embodiments the linker, Y, is selected from the group consisting of the six groups of the following formulae:

wherein m is 0, 1 , 2, 3, 4, 5 or 6; n is 1 , 2 or 3; s is 0, 1 , 2 or 3; and p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22 or 23, and wherein the carbonyl end of these moieties is connected to the CGRP peptide (designated X) and the amino end of these moieties is connected to the acyl group (designated Z).

The CGRP analogues of the present disclosure can be prepared in a manner commonly known to the skilled person. The CGRP peptide X may for instance be produced by classical peptide synthesis, for example, solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well established techniques. In some embodiments the acyl group present in Z originates from a fatty acid or fatty diacid.

In some embodiments the acyl group present in Z originates from a fatty diacid with an alpha and omega carboxy group.

In some embodiments the acyl group present in Z originates from a fatty acid or fatty diacid with 12-22 carbon atoms.

In some embodiments the acyl group present in Z originates from a fatty acid or fatty diacid with 16 carbon atoms.

In some embodiments the acyl group present in Z originates from a fatty acid or fatty diacid with 18 carbon atoms.

In some embodiments the acyl group present in Z originates from a fatty acid or fatty diacid with 20 carbon atoms.

In some embodiments the moiety of the formula -Y- Z is connected to the CGRP peptide X at the N terminal amino acid residue.

In some embodiments the moiety of the formula -Y-Z is connected to the CGRP peptide X at a lysine residue.

Herein, the expression that an acylated derivative according to the present disclosure has a "prolonged action" means that the half-life or T1 thereof is at least 50 %, preferably at least 100 %, and more preferred at least 500 %, longer than the T1 of the corresponding native CGRP. T1 may be determined by the methods described in WO2011051312A1 .

Specific CGRP analogues

In some embodiments said alpha-CGRP analogue is N-alpha-[2-(2-{2-[(S)-4-Carboxy- 4-(17-carboxyheptadecanoylamino)-butyrylamino]-ethoxy}ethoxy)acetyl](Ser1]alpha- human CGRP peptide; or N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)-butyrylamino]- ethoxy}ethoxy)acetyl]-SEQ ID NO:9; according to formula I (Fig. 3 A).

In some embodiments said alpha-CGRP analogue is N-alpha-[2-(2-{2-[(S)-4-Carboxy- 4-(17-carboxyheptadecanoylamino)-butyrylamino]-ethoxy}ethoxy)acetyl]-SEQ ID NO:9; or a variant thereof wherein one, two, three, four or five of the amino acid residues of SE ID NO:9 is substituted with another amino acid residue.

In some embodiments said beta-CGRP analogue is N-alpha-[2-(2-{2-[(S)-4-Carboxy-4- (17-carboxyheptadecanoylamino)butyryl-amino]ethoxy}ethoxy)acetyl](Ser1]beta-human CGRP peptide; or N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyryl- amino]ethoxy}ethoxy)acetyl]-SEQ ID NO: 10; according to formula II (Fig. 3 B).

In some embodiments said beta-CGRP analogue is

N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyryl- amino]ethoxy}ethoxy)acetyl]-SEQ ID NO:10; or a variant thereof wherein one, two, three, four or five of the amino acid residues of SEQ ID NO: 10 is substituted with another amino acid residue.

The alpha-CGRP analogue according to formula I and the beta-CGRP analogue according to formula II may in some embodiments be synthesized as disclosed in WO2011/051312.

In preferred embodiments the CGRP analogue of the present invention is selected from the group consisting of the alpha-CGRP analogue according to formula I and the beta- CGRP analogue according to formula II. These are disclosed in WO2011/051312.

Some embodiments provide a CGRP analogue selected from the group consisting of the alpha-CGRP analogue according to SEQ ID NO:9 or formula I; and the beta-CGRP analogue according to SEQ ID NQ:10 or formula II, for use in the treatment of ischemic heart disease, wherein said CGRP analogue is administered more than 1 hour after the ischemic incident.

Some embodiments provide a CGRP analogue selected from the group consisting of the alpha-CGRP analogue according to SEQ ID NO:9 or formula I; and the beta-CGRP analogue according to SEQ ID NQ:10 or formula II, for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion, wherein said CGRP analogue is administered more than 1 hour after the ischemic incident.

Some embodiments provide a CGRP analogue selected from the group consisting of the alpha-CGRP analogue according to SEQ ID NO:9 or formula I; and the beta-CGRP analogue according to SEQ ID NO:10 or formula II, for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion lasting for more than 1 hour.

Some embodiments provide a CGRP analogue selected from the group consisting of the alpha-CGRP analogue according to SEQ ID NO:9 or formula I; and the beta-CGRP analogue according to SEQ ID NQ:10 or formula II, for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, wherein said CGRP analogue is administered within 60 minutes after the ischemic incident.

Some particular embodiments provide the beta-CGRP analogue according to SEQ ID NQ:10 as defined herein, or formula II, for the uses according to the present disclosure.

Dosage and administration

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered daily, such as once daily.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered as a single administration or as multiple administrations.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered once, as specified herewith such as administered more than 1 hour after the ischemic incident. It follows that a single administration (or dosage) or a first administration (or dosage) is administered more than 1 hour after the ischemic incident.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered once, as specified herewith such as administered within 60 minutes after the ischemic incident, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour. It follows that a single administration (or dosage) or a first administration (or dosage) is administered within 60 minutes after the ischemic incident.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered daily, such as once daily, for one or more days after the ischemic incident.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered daily, such as once daily, for one day after the ischemic incident.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered daily, such as once daily, for two consecutive days after the ischemic incident, such as for 3 consecutive days, such as for 4 consecutive days, such as for up to 30 consecutive days after the ischemic incident.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered daily, such as once daily, for one or more days after the ischemic incident, wherein each administration (or dosage) is administered about 24 hours apart.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered in an amount or dosage of 0.01 to 100.000 nanomole/kg body weight, such as in an amount or dosage of 0.1 to 10.000 nanomole/kg body weight, for example 0.1 to 1000 nanomole/kg body weight, such as 1 to 100 nanomole/kg body weight.

An aspect of the present disclosure further provides a composition such as a pharmaceutical composition comprising the CGRP-R agonist for use according to the present disclosure. In some embodiments said pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, diluents or carriers.

In one embodiment, the CGRP-R agonist for use according to the present disclosure is administered as an injectable solution or suspension, suitable for intravenous (i.v.), subcutaneous (s.c.) or intraperitoneal (i.p.) administration. In some embodiments the CGRP-R agonist for use according to the present disclosure is administered by intravenous (i.v.), subcutaneous (s.c.) or intraperitoneal (i.p.) administration, or a combination of these.

Examples

EFFECT OF A CGRP ANALOGUE AFTER AMI WITH LATE REPERFUSION (4H) OR WITH NO REPERFUSION (CHRONIC CORONARY ARTERY OCCLUSION)

Objective: The objective of this study was to evaluate the anti-myocardial damage efficacy of a CGRP analogue (the beta-CGRP analogue according to formula II) via intraperitoneal and subcutaneous administration in AMI with 4h reperfusion or no reperfusion in mini pig.

Method: 48 Barna mini pigs were modelled for Heart Failure with middle LAD (left anterior descending artery) occlusion and subsequent 4h-ischemia reperfusion (24 animals) or chronic ischemia without reperfusion (24 animals) and were assigned into 2 times 3 groups based on baseline body weight and baseline EF% (ejection fraction) value. The 3 groups include the vehicle control group (vehicle dosed at 24h, 48h, 72h, 96h post-occlusion), the later administration group (0.1 mg/kg CGRP-analogue at 24h, 48h, 72h, 96h post-occlusion), and the earlier administration group (0.1 mg/kg CGRP- analogue at 0.5h, 24h, 48h, 72h post-occlusion). Each animal was intraperitoneally administrated the 1^st dose and subcutaneously administrated a 2^nd to 4^th dose at 0.1 mg/kg 24 hours after the previous dose (i.e. a single dose daily for 4 days). The following parameters were determined during the experimental period: body weight, ultrasound echocardiography, blood pressure and myocardial infarction ratio. Plasma samples were isolated for potential subsequent biomarker assessment.

Results: A trend towards decreased blood pressure and increased heart rate were observed within 48h post-reperfusion in all groups. No significant difference in blood pressure and heart rate among groups in each of the two studies were observed. The surgery-associated drop in BP is normal.

A significantly decreased EF were observed from pre-occlusion and to day, 14 and 21 in all groups of both studies (p < 0.001). Compared with vehicle control, which has the largest decline in EF post-occlusion, the EF was significantly increased in both CGRP analogue-treatment groups on day 14 and day 21. Both the later administration group (24 hrs) and the early administration group (30 min) demonstrated a marked less reduction in EF compared to vehicle.

At the end of the experiment, myocardial infarction ratio was calculated after TTC staining. Compared with vehicle control, a significant decrease in myocardial infarction ratio was observed in both CGRP analogue-treatment groups in both studies (permanent occlusion or 4hr-delayed reperfusion). Both the later administration group (24 hrs), and the early administration group (30 min) demonstrated a marked reduction of myocardial infarct size, compared to vehicle.

Conclusion: The studies demonstrated that the CGRP analogue significantly improved myocardial infarction size and increased heart function (EF) in Heart Failure, both with a delayed, 4h-ischemia reperfusion, and in Heart Failure with chronic/permanent occlusion (no reperfusion). This applied for both early treatment (30 min) and delayed treatment (24 hrs).

METHODS

Left anterior descending ligation surgery

1. All materials were sterilized before surgery. The surgery room was sustained with ultraviolet irradiation for 0.5 hour.

2. Animals were fasted for at least 12 hours prior to surgery.

3. The fasted animals were anesthetized by Zoletil 50 (IM, 5 mg/kg) and Xylazine (IM, 2mg/kg), Meloxicam (S.C, 0.4 mg/kg) was administrated to provide perioperative and postoperative pain relief.

4. Animals were monitored the following vital signs throughout the surgical period: anal temperature, heart rate, respiration rate and SPO2. The lidocaine (IV bolus, 1 mg/kg) was used to prevent ventricular arrhythmia prior to left anterior descending (LAD) occlusion surgery.

5. A pre-surgery examination was performed meanwhile the endotracheal tube was intubated and ventilated before thoracotomy; 1.5-2.0% isoflurane was used to maintain animals anaesthetized with the help of anaesthetic gas machine till the end of procedure.

6. Hair on the left flank and surgical area were clipped/shaved and surgical area was aseptically prepared by cleansing/scrubbing with povidone iodine and ethyl alcohol.

7. The sterile surgical drapes were put on the animal.

LAD Surgical Procedure

1. The surgical incision was fixed between the 4th and 5th ribs.

2. The 7-8 cm incision was opened by a scalpel and electric knife was advanced slowly through the skin, muscle tissue and heart capsule to expose the left ventricular and atrial appendage. 3. The 4-0 suture line with surgery needle was used for 4h-ischemia reperfusion of the mid-left anterior descending coronary artery. According to ST segment change on ECG, confirm whether the ischemia was successful or not.

4. In the study of AMI with late reperfusion (4h occlusion) the ligature was released to allow blood flow to be reperfused after 4 hours of ischemia. In the study of permanent occlusion, no reperfusion was induced.

5. The incision was double closure and bleeding was stopped by applying pressure over the surgical area.

6. Vital signs were monitored until the animal was fully awake. The animal was returned to the cage after carefully ensuring that the surgical incision was completely closed.

Postoperative Care

1. Post-surgical pain and discomfort was managed with meloxicam (S.C, 0.4 mg/kg) for 3 days.

2. Antibiotics was administered with enrofloxacin (IM, 2.5mg/kg) for 7 days.

Clinical observation

Cage-side clinical observation was conducted twice daily during the entire study. These observations were documented in the raw data and study report.

Body weight measurement

All animals were weighed once a week during the entire study. Body weight was measured to the nearest 0.1 kg and recorded and shared with sponsor. The dosing volume was calculated based on the latest body weight.

Dose administration

The 8 animals in group 1 was dosed with vehicle via IP injection at 24 hours and SC injection at 48, 72 and 96 hours post-occlusion in 4h reperfusion or permanent ligation model,

The 8 animals in group 2 was dosed with the CGRP analogue via IP injection at 24 hours and SC injection at 48, 72 and 96 hours post-occlusion in the 4h reperfusion or permanent occlusion model, the 8 animals in group 3 was dosed with the CGRP analogue via IP at 30 min and SC injection at 24, 48 and 72 hours post-occlusion in the 4h reperfusion and permanent occlusion model.

Ultrasound echocardiography measurement of heart function

The ultrasound echocardiography measurement was performed at the following time points: D -7 (baseline) and D7, D14, D21 post-reperfusion. The animals were fasted and sedated before performing the measurement.

The Left Ventricle End Diastolic Volume (LVEDV) and the Left Ventricle End Systolic Volume (LVESV) was measured and given in mL. These measures were used to calculate the heart pump function as the Ejection Fraction (EF, %). EF was calculated as ((LVEDV-LVESV)/(LVEDV))*100 and given as %.

Blood pressure and HR measurement

Blood pressure and HR were measured at D -7 (baseline) and 1 h, 24h, 48h, and D7, D14, D21 post-reperfusion.

Necropsy and histopathological examination

At the end of the treatment, the animals were sacrificed and the heart collected. The heart weight was measured and then cut to 6 sections, and the weight of each tissue section was measured.

The 6 sections of tissue were stained with TTC and assessed for myocardial infarction ratio. The LV infarct size was analyzed by image J V1.8.0. The LV infarction rate was calculated by the following formulas:

Infarct weight of each tissue section =

Infarct size of each tissue section x Weight of each tissue section Total size of each tissue section

Sum of infarct weiaht of each tissue section

LV Infarct rate = --- - - - - x 100

Sum of weight of each tissue section the infarct size and total size of each tissue section were measurement by image J.

STATISTICAL ANALYSIS

All individual raw data were listed in excel. Descriptive statistics (mean, SE) were generally used to summarize the measurement results, where applicable. Difference between treatment groups at specific time points were analyzed using one-way ANOVA and two tailed T-test. The P value less than 0.05 was considered as significant difference.

Claims

1. A CGRP receptor (CGRP-R) agonist for use in the treatment of ischemic heart disease, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident.

2. The use according to claim 1 , wherein said ischemic heart disease is an acute ischemic heart disease, such as an acute coronary syndrome, such as an acute coronary syndrome selected from the group consisting of unstable angina, myocardial infarction and acute myocardial infarction.

3. A CGRP receptor (CGRP-R) agonist for use in the treatment of a chronic ischemic heart disease, such as wherein said chronic ischemic heart disease has an ischemic incident which is onset of ischemic heart disease.

4. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered more than 60 minutes after the ischemic incident, such as about 70 minutes or more, such as about 80 minutes or more, such as about 90 minutes or more, such as about 100 minutes or more, such as about 110 minutes or more after the ischemic incident.

5. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered about 1.25 hours or more, such as about 1.5 hours or more, such as about 1.75 hours or more after the ischemic incident.

6. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered 2 hours or more after the ischemic incident, such as 2 hours and 15 minutes or more, such as 2 hours and 30 minutes or more, such as 2 hours and 45 minutes or more, such as 3 hours or more, such as 3 hours and 15 minutes or more, such as 3 hours and 30 minutes or more, such as 3 hours and 45 minutes or more, such as 4 hours or more after the ischemic incident.

7. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered 24 hours or more after the ischemic incident.

8. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered up to 24 hours or more after the ischemic incident.

9. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered more than 1 hour after the ischemic incident, such as about 2 hours or more, such as about 3 hours or more, such as about 4 hours or more, such as about 5 hours or more, such as about 6 hours or more, such as about 7 hours or more, such as about 8 hours or more, such as about 9 hours or more, such as about 10 hours or more, such as about 11 hours or more, such as about 12 hours or more, such as about 13 hours or more, such as about 14 hours or more, such as about 15 hours or more, such as about 16 hours or more, such as about 17 hours or more, such as about 18 hours or more, such as about 19 hours or more, such as about 20 hours or more, such as about 21 hours or more, such as about 22 hours or more, such as about 23 hours or more, such as about 24 hours or more, such as about 48 hours or more, such as about 72 hours or more after the ischemic incident.

10. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered up to 48 hours or more after the ischemic incident, such as up to 48 hours or more after the ischemic incident.

11. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered more than 1 hour to 24 hours or more after the ischemic incident, such as 2 hours to 24 hours or more after the ischemic incident, such as 3 hours to 24 hours or more after the ischemic incident, such as 4 hours to 24 hours or more after the ischemic incident.

12. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered 4 to 48 hours or more after the ischemic incident, such as 8 to 48 hours, such as 14 to 36 hours, such as 18 to 30 hours after the ischemic incident.

13. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered more than 60 to 75 minutes after the ischemic incident, such as 75 to 90 minutes after the ischemic incident, such as 90 to 120 minutes after the ischemic incident, such as 2 to 2.5 hours after the ischemic incident, such as 2.5 to 3 hours after the ischemic incident, such as 3 to 3.5 hours after the ischemic incident, such as 3.5 to 4 hours after the ischemic incident, such as 4 to 4.5 hours after the ischemic incident, such as 4.5 to 5 hours after the ischemic incident, such as 5 to 6 hours after the ischemic incident, such as 6 to 7 hours after the ischemic incident, such as 7 to 8 hours after the ischemic incident, such as 8 to 9 hours after the ischemic incident, such as 9 to 10 hours after the ischemic incident, such as 10 to 11 hours after the ischemic incident, such as 11 to 12 hours after the ischemic incident, such as 12 to 18 hours after the ischemic incident, such as 18 to 24 hours after the ischemic incident, such as 24 to 48 hours after the ischemic incident, such as 48 to 72 hours, or more, after the ischemic incident.

14. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered 1 day or more after the ischemic incident, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more, such as 1 week or more, such as 8 days or more, such as 9 days or more, such as 10 days or more, such as 11 days or more, such as 12 days or more, such as 13 days or more, such as 14 days or more, such as 2 weeks or more, such as 3 weeks or more, such as 4 weeks or more, such as 1 month or more, such as 5 weeks or more, such as 6 weeks or more, such as 7 weeks or more, such as 8 weeks or more, such as 2 months or more, such as 3 months or more, such as 4 months or more, such as 5 months or more, such as 6 months or more, such as 7 months or more, such as 8 months or more, such as 9 months or more, such as 10 months or more, such as 11 months or more, such as 12 months or more, such as 1 year or more.

15. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered as a stand-alone therapy.

16. The use according to any of the preceding claims, wherein said ischemic heart disease has a permanent occlusion to the coronary artery and/or permanent obstruction of coronary perfusion.

17. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered without simultaneous, separate or subsequent coronary reperfusion intervention.

18. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered without simultaneous, separate or subsequent non- pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI).

19. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered with a simultaneous, separate or subsequent coronary reperfusion intervention.

20. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered with a simultaneous, separate or subsequent pharmacological coronary reperfusion therapy.

21. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered with a simultaneous, separate or subsequent non- pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI).

22. The use according to any of the preceding claims, wherein said ischemic heart disease has a short-lasting occlusion to the coronary artery and/or short-lasting obstruction of coronary perfusion.

23. The use according to any of the preceding claims, wherein said ischemic heart disease has a short-lasting occlusion to the coronary artery, such as an occlusion lasting for about 5 minutes to less than 4 hours, such as 5 to 15 minutes, such as 15 to 30 minutes, such as 30 to 45 minutes, such as 45 to 60 minutes, such as 1 to 1.5 hours, such as 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to less than 4 hours.

24. The use according to any of the preceding claims, wherein said ischemic heart disease has a short-lasting occlusion to the coronary artery, such as an occlusion lasting for about 15 minutes or less, such as about 30 minutes or less, such as about 45 minutes or less, such as about 60 minutes or less, such as about 1.5 hours or less, such as about 2 hours or less, such as about 2.5 hours or less, such as about 3 hours or less, such as about 3.5 hours or less, such as lasting for less than 4 hours.

25. The use according to any one of claims 19 to 24, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed within 4 hours after the ischemic incident, such as less than 4 hours after the ischemic incident.

26. The use according to any one of claims 19 to 25, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed within 15 minutes to 4 hours after the ischemic incident; such as within 15 to 30 minutes after the ischemic incident, such as within 30 to 45 minutes, such as within 45 to 60 minutes, such as within 1 to 1.5 hours, such as within 1.5 to 2 hours, such as within 2 to 2.5 hours, such as within 2.5 to 3 hours, such as within 3 to 3.5 hours, such as within 3.5 to 4 hours after the ischemic incident.

27. The use according to any of the preceding claims, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery and/or long-lasting obstruction of coronary perfusion.

28. The use according to any of the preceding claims, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery of about 4 hours or more, such as at least 4 hours.

29. The use according to any of the preceding claims, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery, such as an occlusion lasting for at least 4 hours, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 9 hours or more, such as 10 hours or more, such as 11 hours or more, such as 12 hours or more, such as 13 hours or more, such as 14 hours or more, such as 15 hours or more, such as 16 hours or more, such as 17 hours or more, such as 18 hours or more, such as 19 hours or more, such as 20 hours or more, such as 21 hours or more, such as 22 hours or more, such as 23 hours or more, such as 24 hours or more, such as up to 48 hours, such as up to 72 hours.

30. The use according to any of the preceding claims, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery, such as an occlusion lasting for 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours.

31. The use according to any of the preceding claims, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery, such as an occlusion lasting 1 day or more, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more, such as 1 week or more, such as 8 days or more, such as 9 days or more, such as 10 days or more, such as 11 days or more, such as 12 days or more, such as 13 days or more, such as 14 days or more, such as 2 weeks or more, such as 3 weeks or more, such as 4 weeks or more, such as 1 month or more, such as 5 weeks or more, such as 6 weeks or more, such as 7 weeks or more, such as 8 weeks or more, such as 2 months or more, such as 3 months or more, such as 4 months or more, such as 5 months or more, such as 6 months or more, such as 7 months or more, such as 8 months or more, such as 9 months or more, such as 10 months or more, such as 11 months or more, such as 12 months or more, such as 1 year or more.

32. The use according to any one of claims 19 to 21 and 27 to 31 , wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident.

33. The use according to any one of claims 19 to 21 and 27 to 32, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident, such as 4 to 5 hours after the ischemic incident, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours after the ischemic incident.

34. A CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery lasting for more than 1 hour, such as an obstruction of coronary perfusion lasting for more than 1 hour, wherein said CGRP-R agonist is administered within 60 minutes after the ischemic incident.

35. The use according to claim 34, wherein said CGRP-R agonist is administered within 0 min to 60 minutes after the ischemic incident, such as within 0 min to 45 min after the ischemic incident, such as within 0 min to 30 min after the ischemic incident, such as within 0 to 5 min, 5 to 10 min, 10 to 15 min, 15 to 20 min, 20 to 25 min, 25 to 30 min, 30 to 35 min, 35 to 40 min, 40 to 45 min, 45 to 50 min, 50 to 55 min, or 55 to 60 min after the ischemic incident.

36. The use according to any of claims 34 to 35, wherein said ischemic heart disease has an occlusion lasting for at least 1 .5 hours, such as at least 2 hours, such as at least 2.5 hours, such as at least 3 hours, such as at least 3.5 hours, such as at least 4 hours, such as at least 2 hours, such as at least 2.5 hours, such as at least 3 hours, such as at least 3.5 hours, such as at least 4 hours, such as at least 4.5 hours, such as at least 5 hours, such as at least 5.5 hours, such as at least 6 hours, such as at least 7 hours, such as at least 8 hours, such as at least 9 hours, such as at least 10 hours, such as at least 11 hours, such as at least 12 hours, such as at least 13 hours, such as at least 14 hours, such as at least 15 hours, such as at least 16 hours, such as at least 17 hours, such as at least 18 hours, such as at least 19 hours, such as at least 20 hours, such as at least 21 hours, such as at least 22 hours, such as at least 23 hours, such as at least 24 hours.

37. The use according to any of claims 34 to 36, wherein said ischemic heart disease has an occlusion lasting for 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours.

38. The use according to any of claims 34 to 37, wherein said ischemic heart disease has a long-lasting occlusion to the coronary artery, such as an occlusion lasting 1 day or more, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more, such as 1 week or more, such as 8 days or more, such as 9 days or more, such as 10 days or more, such as 11 days or more, such as 12 days or more, such as 13 days or more, such as 14 days or more, such as 2 weeks or more, such as 3 weeks or more, such as 4 weeks or more, such as 1 month or more, such as 5 weeks or more, such as 6 weeks or more, such as 7 weeks or more, such as 8 weeks or more, such as 2 months or more, such as 3 months or more, such as 4 months or more, such as 5 months or more, such as 6 months or more, such as 7 months or more, such as 8 months or more, such as 9 months or more, such as 10 months or more, such as 11 months or more, such as 12 months or more, such as 1 year or more.

39. The use according to any of claims 34 to 38, wherein said CGRP-R agonist is administered with a separate or subsequent coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI).

40. The use according to any one of 34 to 39, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed more than 1 hour after the ischemic incident.

41. The use according to any one of 34 to 40, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 2 hours or more after the ischemic incident.

42. The use according to any one of 34 to 41 , wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 4 hours or more after the ischemic incident.

43. The use according to any one of claims 34 to 42, wherein said coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as PCI, is performed 1.5 hours or more after the ischemic incident, such as 1.5 to 2 hours, such as 2 to 2.5 hours, such as 2.5 to 3 hours, such as 3 to 3.5 hours, such as 3.5 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, such as 8 to 9 hours, such as 9 to 10 hours, such as 10 to 11 hours, such as 11 to 12 hours, such as 12 to 13 hours, such as 13 to 14 hours, such as 14 to 15 hours, such as 15 to 16 hours, such as 16 to 17 hours, such as 17 to 18 hours, such as 18 to 19 hours, such as 19 to 20 hours, such as 20 to 21 hours, such as 21 to 22 hours, such as 22 to 23 hours, such as 23 to 24 hours, such as more than 24 hours after the ischemic incident.

44. A CGRP-R agonist for use in the treatment of ischemic heart disease, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion lasting for more than 1 hour.

45. The use according to claim 44, wherein said ischemic heart disease has an occlusion to the coronary artery and/or obstruction of coronary perfusion lasting for more than 1 hour, such as for 1.5 hour or more, such as for 2 hours or more, such as for 2.5 hour or more, such as for 3 hours or more, such as for 3.5 hour or more, such as for 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 9 hours or more, such as 10 hours or more, such as 11 hours or more, such as 12 hours or more, such as 13 hours or more, such as 14 hours or more, such as 15 hours or more, such as 16 hours or more, such as 17 hours or more, such as 18 hours or more, such as 19 hours or more, such as 20 hours or more, such as 21 hours or more, such as 22 hours or more, such as 23 hours or more, such as 24 hours or more.

46. The use according to any one of claims 44 to 45, wherein said CGRP-R agonist is administered with a separate or subsequent coronary reperfusion intervention, such as non-pharmacological coronary reperfusion intervention, such as Percutaneous Coronary Intervention (PCI); wherein said coronary reperfusion intervention is performed more than 1 hour after the ischemic incident.

47. The use according to any one of claims 44 to 46, wherein said CGRP-R agonist is administered 0 to 15 minutes after the ischemic incident, such as 15 to 30 minutes after the ischemic incident, such as 30 to 45 minutes after the ischemic incident, such as 45 to 60 minutes after the ischemic incident, such as 60 to 75 minutes after the ischemic incident, such as 75 to 90 minutes after the ischemic incident, such as 90 to 120 minutes after the ischemic incident, such as 2 to 2.5 hours after the ischemic incident, such as 2.5 to 3 hours after the ischemic incident, such as 3 to 3.5 hours after the ischemic incident, such as 3.5 to 4 hours after the ischemic incident, such as 4 to 4.5 hours after the ischemic incident, such as 4.5 to 5 hours after the ischemic incident, such as 5 to 6 hours after the ischemic incident, such as 6 to 7 hours after the ischemic incident, such as 7 to 8 hours after the ischemic incident, such as 8 to 9 hours after the ischemic incident, such as 9 to 10 hours after the ischemic incident, such as 10 to 11 hours after the ischemic incident, such as 11 to 12 hours after the ischemic incident, such as 12 to 18 hours after the ischemic incident, such as 18 to 24 hours after the ischemic incident, such as 24 to 48 hours after the ischemic incident, such as 48 to 72 hours after the ischemic incident, such as more than 72 hours after the ischemic incident.

48. The use according to any of the preceding claims, wherein said ischemic heart disease is characterized by occlusion to the coronary artery and/or obstruction of coronary perfusion.

49. The use according to any of the preceding claims, wherein said ischemic heart disease is acute coronary syndrome.

50. The use according to any of the preceding claims, wherein said ischemic heart disease is unstable angina.

51. The use according to any of the preceding claims, wherein said ischemic heart disease is selected from the group consisting of stable angina, anginal equivalent, refractory angina, recurrent angina, symptoms of heart failure, new or worsening mitral regurgitation, hemodynamic instability, sustained ventricular tachycardia/fibrillation, and a worsening of troponin levels.

52. The use according to any of the preceding claims, wherein said ischemic heart disease is myocardial infarction (Ml).

53. The use according to any of the preceding claims, wherein said ischemic heart disease is acute myocardial infarction (AMI).

54. The use according to any of the preceding claims, wherein said ischemic heart disease is STEMI.

55. The use according to any of the preceding claims, wherein said ischemic heart disease is NSTEMI.

56. The use according to any of the preceding claims, wherein said ischemic heart disease is critical coronary artery stenosis, which does not qualify for coronary artery bypass surgery (CABG).

57. The use according to any of the preceding claims, wherein said ischemic heart disease is Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA).

58. The use according to any of the preceding claims, wherein said ischemic heart disease is heart failure (HF).

59. The use according to any of the preceding claims, wherein said administration reduces myocardial infarct size compared to vehicle/no treatment.

60. The use according to any of the preceding claims, wherein said administration reduces myocardial infarct size compared to vehicle/no treatment by at least about 30%, such as at least about 40%, such as at least about 50%, such as at least about 60%, such as at least about 70%.

61 . The use according to any of the preceding claims, wherein said administration reduces myocardial infarct size compared to vehicle/no treatment by 30 to 90%, such as 30 to 40%, such as 40 to 50%, such as 50 to 60%, such as 60 to 70%, such as 70 to 80%, such as 80 to 90%.

62. The use according to any of the preceding claims, wherein said administration reduces myocardial infarct size compared to vehicle/no treatment at day 21 after the ischemic incident.

63. The use according to any of the preceding claims, wherein said administration improves heart function (EF %) compared to vehicle/no treatment.

64. The use according to any of the preceding claims, wherein said administration improves heart function (EF %) compared to vehicle/no treatment by at least about 5%, such as at least about 10%, such as at least about 15%, such as at least about 20%, such as at least about 25%, such as at least about 30%, such as at least about 35%, such as at least about 40%, such as at least about 45%, such as at least about 50%.

65. The use according to any of the preceding claims, wherein said administration improves heart function (EF %) compared to vehicle/no treatment by 5 to 50%, such as by 5 to 10%, such as by 10 to 15%, such as by 15 to 20%, such as by 20 to 25%, such as by 25 to 30%, such as by 30 to 35%, such as by 35 to 40%, such as by 40 to 45%, such as by 45 to 50%.

66. The use according to any of the preceding claims, wherein said administration improves heart function (EF %) compared to vehicle/no treatment at day 21 after the ischemic incident.

67. The use according to any of the preceding claims, wherein said administration maintains at least 70% of baseline heart function (EF %), such as maintains at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% of baseline heart function.

68. The use according to any of the preceding claims, wherein said administration maintains 70 to 95% of baseline heart function (EF %), such as maintains 70 to 75%, such as 75 to 80%, such as 80 to 85%, such as 85 to 90%, such as 90 to 95% of baseline heart function.

69. The use according to any of the preceding claims, wherein the ischemic incident is onset of the ischemic heart disease, such as onset of one or more symptoms of ischemic heart disease.

70. The use according to any of the preceding claims, wherein the ischemic incident is coronary artery occlusion; such as right coronary artery (RCA) occlusion and/or left main coronary artery (LMCA) occlusion.

71. The use according to any of the preceding claims, wherein the ischemic incident is selected from the group consisting of myocardial ischemia, myocardial necrosis and/or apoptosis; unstable angina, myocardial infarction, acute myocardial infarction, STEMI and NSTEMI.

72. The use according to any of the preceding claims, wherein said CGRP-R agonist is a small-molecule drug.

73. The use according to any of the preceding claims, wherein said CGRP-R agonist is a non-native peptide analogue of native alpha-CGRP or a non-native peptide analogue of native beta-CGRP.

74. The use according to any of the preceding claims, wherein said CGRP-R agonist is a metabolically stable analogue of alpha-CGRP or beta-CGRP.

75. The use according to any of the preceding claims, wherein said CGRP-R agonist is a cardioprotective analogue of alpha-CGRP or beta-CGRP.

76. The use according to any of the preceding claims, wherein said analogue of alpha-CGRP or beta-CGRP reduces myocardial infarct size and/or improves heart function (EF %).

77. The use according to any of the preceding claims, wherein said analogue of alpha-CGRP or beta-CGRP induces recovery of myocardial perfusion and/or preserves myocardial perfusion.

78. The use according to any of the preceding claims, wherein said analogue of alpha-CGRP or beta-CGRP has a larger potency ratio in coronary artery than in peripheral arteries, such as mesenteric artery and cerebral artery.

79. The use according to any of the preceding claims, wherein said analogue of alpha-CGRP or beta-CGRP induces CGRP sensitization after repeated CGRP- receptor stimulation specifically in coronary artery, not in the mesenteric artery.

80. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of alpha-CGRP; such as an analogue of any one of alpha-CGRP in human (alpha-hCGRP, SEQ ID NO:3), alpha-CGRP in rat (alpha-rCGRP; SEQ ID NO:5), and alpha-CGRP in mouse (alpha-mCGRP; SEQ ID NO:7).

81. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of beta-CGRP; such as an analogue of any one of beta- CGRP in human (beta-hCGRP; SEQ ID NO:4), beta-CGRP in rat (beta-rCGRP; SEQ ID NO:6), and beta-CGRP in mouse (beta-mCGRP; SEQ ID NO:8).

82. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue selected from SEQ ID NO:9 and SEQ ID NQ:10.

83. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of alpha-CGRP having the sequence of SEQ ID NO:9, or a variant thereof wherein one, two, three, four or five of the amino acid residues of SEQ ID NO:9 is substituted with another amino acid residue.

84. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of alpha-CGRP having the sequence of SEQ ID NO:9, or a variant thereof wherein one, two, three, four or five of the amino acid residues of SEQ ID NO:9 is substituted with another amino acid residue, and wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to the amino group of the N-terminal amino acid residue in SEQ ID NO:9.

85. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of beta-CGRP having the sequence of SEQ ID NO: 10, or a variant thereof wherein one, two, three, four or five of the amino acid residues of SEQ ID NQ:10 is substituted with another amino acid residue.

86. The use according to any of the preceding claims, wherein said CGRP-R agonist is an analogue of beta-CGRP having the sequence of SEQ ID NO: 10, or a variant thereof wherein one, two, three, four or five of the amino acid residues of SEQ ID NO:10 is substituted with another amino acid residue, wherein a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to the amino group of the N-terminal amino acid residue in SEQ ID NQ:10.

87. The use according to any of the preceding claims, wherein in said analogue of alpha-CGRP and/or beta-CGRP: i. at least one amino acid residues is substituted with another amino acid residue, ii. one, two or three of the amino acid residues is substituted with another amino acid residue, iii. one or more amino acid residues are omitted, iv. one or more further amino acid residues are inserted; v. a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to an amino group present in an amino acid residue in the CGRP peptide, vi. a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to a lysine (K) residue in the CGRP peptide; and/or vii. a linker (“Y”) and an acyl group (“Z”) forms an Y-Z moiety which is connected to the N-terminal amino acid residue of the CGRP peptide.

88. The use according to any of the preceding claims, wherein said CGRP-R agonist is N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)- butyrylamino]-ethoxy}ethoxy)acetyl](Ser1]alpha-human CGRP peptide (N- alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)- butyrylamino]-ethoxy}ethoxy)acetyl]-SEQ ID NO:9), according to formula I.

89. The use according to any of the preceding claims, wherein said CGRP-R agonist is N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17- carboxyheptadecanoylamino)butyryl- amino]ethoxy}ethoxy)acetyl](Ser1]beta- human CGRP peptide (N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17- carboxyheptadecanoylamino)butyryl- amino]ethoxy}ethoxy)acetyl]-SEQ ID NO:10), according to formula II.

90. The use according to any of the preceding claims, wherein said CGRP-R agonist is in a composition, such as a pharmaceutical composition.

91. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered daily, such as once daily.

92. The use according to any of the preceding claims, wherein said CGRP-R agonist administered as a single administration or as multiple administrations.

93. The use according to any of the preceding claims, wherein said CGRP-R agonist administered daily, such as once daily, for one or more days after the ischemic incident.

94. The use according to any of the preceding claims, wherein said CGRP-R agonist administered as multiple administrations are each administered about 24 hours apart.

95. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered daily, such as once daily, for two consecutive days after the ischemic incident, such as for 3 consecutive days, such as for 4 consecutive days, such as for up to 30 consecutive days after the ischemic incident.

96. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered by intravenous (i.v.), subcutaneous (s.c.) or intraperitoneal (i.p.) administration, or a combination of these.

97. The use according to any of the preceding claims, wherein said CGRP-R agonist is administered in an amount or dosage of 0.01 to 100.000 nanomole/kg body weight, such as in an amount or dosage of 0.1 to 10.000 nanomole/kg body weight, for example 0.1 to 1000 nanomole/kg body weight, such as 1 to 100 nanomole/kg body weight.