Annexin a1 administration regime

Abstract

The present disclosure relates to an Annexin A1 (AnxA1) N-terminal-peptide and pharmaceutical compositions comprising such Annexin A1 (AnxA1) N-terminal-peptide for use in the treatment of an ischemic condition and / or a reperfusion injury.

Description

[0001] Annexin A1 administration regime

[0002] Technical field

[0003] The present disclosure relates to an Annexin A1 (AnxA1) N-terminal-peptide and pharmaceutical compositions comprising such Annexin A1 (AnxA1) N-terminal-peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0004] Background

[0005] The Annexin super-family consists of 13 calcium phospholipid binding proteins with significant biological and structural homology. Annexins are structurally divided into a highly conserved core domain and a variable N-terminal domain. Annexin A1 (ANXA1, 37 kDa - SEQ ID NO:1) is an anti-inflammatory protein that inhibits extravasation of blood-borne polymorphonuclear leukocyte (PMN) into the surrounding tissue. The protein binds to the N-formyl peptide receptor (FPR) 2 or FPR-L1 receptor, where it initiates a cascade of signaling events. Following an inflammatory stimulus, migration of blood-borne polymorphonuclear leukocyte (PMN) into the surrounding tissue takes place. Transmigration or extravasation of PMN is regulated by mediators such as adhesion molecules, cytokines and proteases, which control the pro-inflammatory and anti-inflammatory processes. The disruptive potential of the PMN is high and potentially self-damaging. Thus, controlling extravasation of PMN and the inflammatory response is important.

[0006] For therapeutic purposes as an anti-inflammatory agent, the full Annexin A1 protein has numerous disadvantages relative to functional fragments or modified versions thereof. The large size of the protein makes it more difficult to deliver by techniques that are possible with a smaller polypeptide (e.g. transdermally or transmucosally). For use to treat inflammation of the eyes, a smaller molecule is expected to be better able to penetrate the corneal epithelium. Also, susceptibility to proteolytic degradation is a particular concern for all peptide pharmaceuticals, especially large ones and especially if oral delivery (preferred by many patients) is contemplated.

[0007] Some Annexin A1 derivatives lacking significant regions on the N-terminal side of the polypeptide have been shown to lack significant activity in some assays of inflammation and mediator release, whereas the full length N-terminus N-acetyl Annexin A1 was deemed biologically active in several systems. A number of peptides primarily derived from the unique N-terminal portion of the Annexin A1 protein have been shown to possess anti-inflammatory properties. One of the most extensively studied Annexin A1 peptides is peptide Ac2-26, which mimics the 2ndto the 26thamino acids of the 54-amino acid N-terminal region. It has been shown that Annexin A1 and its N-terminal peptide (Ac2-26) exert the majority of their anti-inflammatory action through the FPR2 / Lipoxin A4 (FPR2 / Alx) receptor. In vivo the Ac2-26 peptide has been shown to exert an anti-inflammatory effect in models of myocardial ischaemia reperfusion (l / R), mesentery l / R, glycogen peritonitis and IL1 air pouch, where it was reported to significantly reduce the recruitment of neutrophils to the site of injury / inflammation.

[0008] Shorter versions of the Ac2-26 peptide, such as peptides Ac2-12 and Ac2-6, have also been shown to elicit some degree of anti-inflammatory effects in acute models of inflammation. Longer polypeptides with anti-inflammatory effects, such as polypeptides corresponding to amino acid residues 2-48, 2-50 and 11-48, have been disclosed, including protease-resistant V24L variants (WO 2012 / 174397 and WO 2022 / 038281).

[0009] A myocardial infarction, commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. Further tissue damage in the form of reperfusion injury may occur upon reperfusion, i.e. , when blood supply returns to the heart after a period of ischemia or lack of oxygen. Myocardial infarction is a severe condition and there is a need for developing safe and effective treatments with minimal side effects.

[0010] Summary

[0011] There is a need for developing safe and effective treatments of an ischemic condition and / or a reperfusion injury with minimal side effects. The present inventors show that administration of 3 dosages of an AnxA1 N-terminal-peptide for 1 or 3 days significantly improved cardiac output 14 days post ischemia. Surprisingly, administration of 3 dosages of the AnxA1 N-terminal-peptide within 24 hours of reperfusion demonstrated the greatest improvement in cardiac function. Thus, administering 3 dosages of the AnxA1 N-terminal-peptide within 24 hours of establishment of reperfusion (reperfusion start) is sufficient for improving long-term cardiac function. In some embodiments, the present disclosure relates to an Annexin A1 (AnxA1) N- terminal-peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0012] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising an Annexin A1 (AnxA1) N-terminal-peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0013] Description of Drawings

[0014] Figure 1 shows the effect of Peptide 1 treatment for 1 day versus 3 days on cardiac function in a rat model of acute myocardial infarction. Figure 1 shows that three dosages of Peptide 1 administered at establishment of reperfusion (reperfusion start), 3 hours post establishment of reperfusion and 6 hours post establishment of reperfusion during the first 24 hours significantly improve long-term cardiac function. *p<0.05: Oneway Anova vs vehicle.

[0015] Figure 2 shows the effect of immediate and delayed Annexin A1 peptide dosing in a rat model of acute myocardial infarction. Figure 2A shows treatment regime of Group 1, 2 and 3. Figure 2B shows that administration of Peptide 1 significantly reduced infarct size, both when the first dosage was given at establishment of reperfusion (reperfusion start) T=0 (Group 1) when the first dosage was given at one hour post establishment of reperfusion T=1 (Group 2) and when the first dosage was given at two hours post establishment of reperfusion T=2 (Group 3). *p<0.05: One-way Anova vs vehicle.

[0016] #p<0.05, ##p<0.01 : t-test between each treatment group versus vehicle.

[0017] Figure 3 shows the effect of Peptide 1 treatment for 1 day on the prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction. Figure 3A shows the count of endothelial cells 72 hours post-myocardial infarction (Ml) in sham- operated rats, rats treated with the vehicle, and rats administered with 3 doses of 30 pg / kg Peptide 1. Figure 3B shows the presence of anti-inflammatory monocytes / macrophages 24 hours post Ml in sham-operated rats, rats treated with the vehicle, and rats administered with 3 doses of 30 pg / kg Peptide 1.

[0018] Definitions

[0019] The term “a” denotes at least one, i.e. , one or more.

[0020] The terms “approximately” and “about” as referred herein are synonymous. In some embodiments, “approximately” and “about” refer to the recited amount, value, or duration ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 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% or ±0.1%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ±10%, ±5%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ±10%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ±5%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ±1%.

[0021] The term “Dosing interval” as used herein refers to the time period between administration of two dosages.

[0022] The term “Administration time” as used herein refers to the time where an administration or infusion, such as an i.v. infusions, starts.

[0023] A pharmaceutically acceptable excipient is understood as any excipient acceptable to include in a pharmaceutical composition. Pharmaceutically acceptable excipients include, but are not restricted to, bulking agents, tonicity agents, isotonicity modifiers, stabilisers, surfactants, buffers, water, carbohydrates and sugar alcohols.

[0024] An intravenous infusion is the direct injection of a fluid medication into a vein through an intravenous line, needle, cannula or catheter. Administration of drugs via IV infusion is usually necessary when longer or continuous systemic exposures are required to elicit a therapeutic effect. Unlike injection, infusion often uses a pump or the natural force of gravity to deliver fluids into the body.

[0025] The term "therapeutically effective amount" of a compound 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.

[0026] 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 is suffering. The patient to be treated is preferably a mammal, in particular a human being. The patients to be treated can be of various ages.

[0027] Reperfusion refers to restoration of blood flow to a previously ischemic tissue or organ.

[0028] Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue after a period of ischemia or lack of oxygen (anoxia or hypoxia).

[0029] The term “Establishment of reperfusion” as used herein refers to the time point where blood flow to an organ or tissue is restored after having been blocked. This might also be referred to as “Reperfusion start”.

[0030] The term “Post establishment of reperfusion” as used herein refers to a time point occurring after reperfusion has been established. This might also be referred to as “Post reperfusion start”.

[0031] Detailed description

[0032] It is an aspect of the present disclosure to provide an Annexin A1 (AnxA1) N-terminal- peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0033] It is also an aspect of the present disclosure to provide a pharmaceutical composition comprising an Annexin A1 (AnxA1) N-terminal-peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion. It is an aspect of the present disclosure to provide an Annexin A1 (AnxA1) N-terminal- peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are to be administered to a human subject within 24 hours of reperfusion.

[0034] It is also an aspect of the present disclosure to provide a pharmaceutical composition comprising an Annexin A1 (AnxA1) N-terminal-peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of the AnxA1 N-terminal-peptide are to be administered to a human subject within 24 hours of reperfusion.

[0035] It is also an aspect of the present disclosure to provide a method of treating an ischemic condition and / or a reperfusion injury, the method comprising administration of 3 dosages of an Annexin A1 (AnxA1) N-terminal-peptide to a human subject within 24 hours of reperfusion.

[0036] It is also an aspect of the present disclosure to provide a method of treating an ischemic condition and / or a reperfusion injury, the method comprising administration of a pharmaceutical composition comprising an Annexin A1 (AnxA1) N-terminal-peptide and at least one pharmaceutically acceptable excipient to a human subject, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to the human subject within 24 hours of reperfusion.

[0037] It is also an aspect of the present disclosure to provide a method of reducing necrosis caused by an ischemic condition and / or a reperfusion injury, the method comprising administration of 3 dosages of an Annexin A1 (AnxA1) N-terminal-peptide to a human subject within 24 hours of reperfusion.

[0038] It is also an aspect of the present disclosure to provide a method of reducing infarct size of an infarct caused by an ischemic condition and / or a reperfusion injury, the method comprising administration of 3 dosages of an Annexin A1 (AnxA1) N-terminal- peptide to a human subject within 24 hours of reperfusion.

[0039] It is also an aspect of the present disclosure to provide a method of reducing infarct size of a myocardial infarct caused by an ischemic condition and / or a reperfusion injury, the method comprising administration of 3 dosages of an Annexin A1 (AnxA1) N-terminal-peptide to a human subject within 24 hours of reperfusion.

[0040] In some embodiments, the present disclosure relates to the use of an Annexin A1 (AnxA1) N-terminal-peptide for the manufacture of a medicament for use in the treatment of an ischemic condition and / or an inflammatory condition, wherein 3 dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0041] In some embodiments, the ischemic condition is followed by reperfusion.

[0042] In some embodiments, the AnxA1 N-terminal-peptide is administered no more than 3 times to the human subject within 24 hours of reperfusion.

[0043] In some embodiments, the 3 dosages of the AnxA1 N-terminal-peptide are administered once, such as once within 24 hours of reperfusion.

[0044] In some embodiments, the AnxA1 N-terminal-peptide is administered only to the human subject within 24 hours of reperfusion.

[0045] In some embodiments, the 3 dosages of the AnxA1 N-terminal-peptide are 3 daily dosages and are administered to the human subject for 1 day only.

[0046] In some embodiments, no dosages of the AnxA1 N-terminal-peptide are administered to a human subject after 24 hours of reperfusion.

[0047] In some embodiments, all dosages of the AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

[0048] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject within 24 hours of establishment of reperfusion, such as within 24 hours post establishment of reperfusion.

[0049] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 dosages at a dosing interval of 1 to 6 hours; such as at a dosing interval of about 1 to about 2 hours, such as at a dosing interval of about 2 to about 3 hours, such as at a dosing interval of about 3 to about 4 hours, such as at a dosing interval of about 4 to about 5 hours, such as at a dosing interval of about 5 to about 6 hours; such as at a dosing interval of about 1 hour, such as at a dosing interval of about 2 hours, such as at a dosing interval of about 3 hours, such as at a dosing interval of about 4 hours, such as at a dosing interval of about 5 hours, such as at a dosing interval of about 6 hours.

[0050] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 dosages at a dosing interval of about 2 to 4 hours, such as about 2 hours and 30 minutes to about 3 hours and 30 minutes, such as about 2 hours and 45 minutes to about 3 hours and 15 minutes.

[0051] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 dosages at a dosing interval of about 3 hours.

[0052] In some embodiments, a first dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 0 hour of establishment of reperfusion, such as within about 5 minutes of establishment of reperfusion, such as within about 10 minutes of establishment of reperfusion, such as within about 15 minutes of establishment of reperfusion, such as within about 20 minutes of establishment of reperfusion, such as within about 25 minutes of establishment of reperfusion, such as within about 30 minutes of establishment of reperfusion, such as within about 45 minutes of establishment of reperfusion, such as within about 1 hour of establishment of reperfusion, such as within about 1 hour and 15 minutes of establishment of reperfusion, such as within about 1 hour and 30 minutes of establishment of reperfusion, such as within about 1 hour and 45 minutes of establishment of reperfusion, such as within about 2 hours of establishment of reperfusion, such as within about 2 hours and 30 minutes of establishment of reperfusion, such as within about 3 hours of establishment of reperfusion, such as within about 3 hours and 30 minutes of establishment of reperfusion, such as within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion. In some embodiments, a first dosage of the AnxA1 N-terminal-peptide is administered to the human subject within 0 hour to 6 hours of establishment of reperfusion, such as within 0 hour to 5 hours of establishment of reperfusion, such as within 0 hour to 4 hours of establishment of reperfusion, such as within 0 hour to 3 hours of establishment of reperfusion, such as within 0 hour to 2 hours of establishment of reperfusion, such as within 0 hour to 1 hour and 30 minutes hours of establishment of reperfusion, such as within 0 hour to 1 hour of establishment of reperfusion, such as within 0 hour to 30 minutes of establishment of reperfusion.

[0053] In some embodiments, a second dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 2 hours of establishment of reperfusion, such as within about 2 hours and 30 minutes of establishment of reperfusion, such as within about 3 hours of establishment of reperfusion, such as within about 3 hours and 30 minutes of establishment of reperfusion, such as within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 5 hours and 30 minutes of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 6 hours and 30 minutes of establishment of reperfusion, such as within about 7 hours of establishment of reperfusion, such as within about 7 hours and 30 minutes of establishment of reperfusion, such as within about 8 hours of establishment of reperfusion, such as within about 8 hours and 30 minutes of establishment of reperfusion.

[0054] In some embodiments, a second dosage of the AnxA1 N-terminal-peptide is administered to the human subject within 1 hours to 9 hours of establishment of reperfusion, such as within 1 hour and 30 minutes to 8 hours of establishment of reperfusion, such as within 2 hours to 7 hours of establishment of reperfusion, such as within 2 hours to 6 hours of establishment of reperfusion, such as within 2 hours to 5 hours of establishment of reperfusion, such as within 2 hours to 4 hours of establishment of reperfusion, such as within 2 hours and 30 minutes to 3 hours and 30 minutes of establishment of reperfusion. In some embodiments, a third dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 5 hours and 30 minutes of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 6 hours and 30 minutes of establishment of reperfusion, such as within about 7 hours of establishment of reperfusion, such as within about 7 hours and 30 minutes of establishment of reperfusion, such as within about 8 hours of establishment of reperfusion, such as within about 8 hours and 30 minutes of establishment of reperfusion, such as within about 9 hours of establishment of reperfusion, such as within about 9 hours and 30 minutes of establishment of reperfusion, such as within about 10 hours of establishment of reperfusion, such as within about 10 hours and 30 minutes of establishment of reperfusion, such as within about 11 hours of establishment of reperfusion, such as within about 11 hours and 30 minutes of establishment of reperfusion, such as within about 12 hours of establishment of reperfusion.

[0055] In some embodiments, a third dosage of the AnxA1 N-terminal-peptide is administered to the human subject within 4 hours to 12 hours of establishment of reperfusion, such as within 4 hours and 30 minutes to 11 hours of establishment of reperfusion, such as within 5 hours to 10 hours of establishment of reperfusion, such as within 4 hours to 9 hours of establishment of reperfusion, such as within 4 hours to 8 hours of establishment of reperfusion, such as within 4 hours to 9 hours of establishment of reperfusion, such as within 5 hours and 30 minutes to 6 hours and 30 minutes of establishment of reperfusion

[0056] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at: a. within 0 minute to 15 minutes of establishment of reperfusion, within 3 hours to 3 hours and 15 minutes of establishment of reperfusion and within 6 hours to 6 hours to 3 hours and 15 minutes of establishment of reperfusion, or b. within 15 minutes to 30 minutes of establishment of reperfusion, within 3 hours and 15 minutes to 3 hours and 30 minutes of establishment of reperfusion and within 6 hours and 15 minutes to 6 hours and 30 minutes of establishment of reperfusion, or c. within 30 minutes to 45 minutes of establishment of reperfusion, within 3 hours and 30 minutes to 3 hours and 45 minutes of establishment of reperfusion and within 6 hours and 30 minutes 6 hours and 45 minutes of establishment of reperfusion, or d. within 1 hour and 30 minutes to 1 hour and 45 minutes of establishment of reperfusion, within 4 hours and 30 minutes to 4 hours and 45 minutes of establishment of reperfusion and within 7 hours and 30 minutes 7 hours and 45 minutes of establishment of reperfusion, or e. within 1 hour and 45 minutes to 2 hours of establishment of reperfusion, within 4 hours and 45 minutes to 5 hours of establishment of reperfusion and within 7 hours and 45 minutes to 8 hours of establishment of reperfusion, or f. within 2 hours to 3 hours of establishment of reperfusion, within 5 hours to 6 hours of establishment of reperfusion and within 8 hours to 9 hours of establishment of reperfusion, or g. within 3 hours to 4 hours of establishment of reperfusion, within 6 hours to 7 hours of establishment of reperfusion and within 9 hours to 10 hours of establishment of reperfusion, or h. within 4 hours to 5 hours of establishment of reperfusion, within 7 hours to 8 hours of establishment of reperfusion and within 10 hours to 11 hours of establishment of reperfusion, or i. within 5 hours to 6 hours of establishment of reperfusion, within 8 hours to 9 hours of establishment of reperfusion and within 11 hours to 12 hours of establishment of reperfusion, or j. within 6 hours to 7 hours of establishment of reperfusion, within 9 hours to 10 hours of establishment of reperfusion and within 12 hours to 13 hours of establishment of reperfusion.

[0057] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at: a. within about 0 hour of establishment of reperfusion, within about 3 hours of establishment of reperfusion and within about 6 hours of establishment of reperfusion, or b. within about 15 minutes of establishment of reperfusion, within about 3 hours and 15 minutes of establishment of reperfusion and within about 6 hours and 15 minutes of establishment of reperfusion, or c. within about 30 minutes of establishment of reperfusion, within about 3 hours and 30 minutes of establishment of reperfusion and within about 6 hours and 30 minutes of establishment of reperfusion, or d. within about 1 hour and 30 minutes of establishment of reperfusion, within about 4 hours and 30 minutes of establishment of reperfusion and within about 7 hours and 30 minutes of establishment of reperfusion, or e. within about 1 hour and 45 minutes of establishment of reperfusion, within about 4 hours and 45 minutes of establishment of reperfusion and within about 7 hours and 45 minutes of establishment of reperfusion, or f. within about 2 hours of establishment of reperfusion, within about 5 hours of establishment of reperfusion and within about 8 hours of establishment of reperfusion, or g. within about 3 hours of establishment of reperfusion, within about 6 hours of establishment of reperfusion and within about 9 hours of establishment of reperfusion, or h. within about 4 hours of establishment of reperfusion, within about 7 hours of establishment of reperfusion and within about 10 hours of establishment of reperfusion, or i. within about 5 hours of establishment of reperfusion, within about 8 hours of establishment of reperfusion and within about 11 hours of establishment of reperfusion, or j. within about 6 hours of establishment of reperfusion, within about 9 hours of establishment of reperfusion and within about 12 hours of establishment of reperfusion.

[0058] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at: a. about 15 minutes post establishment of reperfusion, about 3 hours and 15 minutes post establishment of reperfusion and about 6 hours and 15 minutes post establishment of reperfusion, or b. about 30 minutes post establishment of reperfusion, about 3 hours and 30 minutes post establishment of reperfusion and about 6 hours and 30 minutes post establishment of reperfusion, or c. about 1 hour and 30 minutes post establishment of reperfusion, about 4 hours and 30 minutes post establishment of reperfusion and about 7 hours and 30 minutes post establishment of reperfusion, or d. about 1 hour and 45 minutes post establishment of reperfusion, about 4 hours and 45 minutes post establishment of reperfusion and about 7 hours and 45 minutes post establishment of reperfusion, or e. about 2 hours post establishment of reperfusion, about 5 hours post establishment of reperfusion and about 8 hours post establishment of reperfusion, or f. about 3 hours post establishment of reperfusion, about 6 hours post establishment of reperfusion and 9 hours post establishment of reperfusion, or g. about 4 hours post establishment of reperfusion, about 7 hours post establishment of reperfusion and about 10 hours post establishment of reperfusion, or h. about 5 hours post establishment of reperfusion, about 8 hours post establishment of reperfusion and 11 hours post establishment of reperfusion, or i. about 6 hours post establishment of reperfusion, about 9 hours post establishment of reperfusion and about 12 hours post establishment of reperfusion.

[0059] In some embodiments, a first dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 0 hour to 2 hours of establishment of reperfusion, a second dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 2 hours to 5 hours of establishment of reperfusion and a third dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 4 hours to 8 hours of establishment of reperfusion.

[0060] In some embodiments, a first dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 0 hour to 1 hour of establishment of reperfusion, a second dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 2 hours to 4 hours of establishment of reperfusion and a third dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 5 hours and 7 hours of establishment of reperfusion.

[0061] In some embodiments, a first dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 0 hour of establishment of reperfusion, a second dosage of the AnxA1 N-terminal-peptide is administered to the human subject within about 3 hours of establishment of reperfusion and a third dosage of the AnxA1 N- terminal-peptide is administered to the human subject within about 6 hours of establishment of reperfusion.

[0062] In some embodiments, the AnxA1 N-terminal-peptide is administered to the human subject as more than 3 dosages within 24 hours of reperfusion, such as 4, 5 or 6 dosages within 24 hours of reperfusion.

[0063] In some embodiments, the AnxA1 N-terminal-peptide or pharmaceutical composition is administered as intravenous (i.v.) infusions.

[0064] In some embodiments, the AnxA1 N-terminal-peptide or pharmaceutical composition is administered as 1-60 minutes i.v. infusions, such as 10-50 minutes i.v. infusions, such as 20-40 minutes i.v. infusions, such as 30 minutes i.v. infusions.

[0065] In some embodiments, the AnxA1 N-terminal-peptide or pharmaceutical composition is administered as 30 minutes i.v. infusions.

[0066] In some embodiments, the AnxA1 N-terminal-peptide is selected from the group consisting of: a. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 2; Annexin A1 2-50), b. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 3; Annexin A1 2-48), c. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 4; Annexin A1 2-46), d. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 5; Annexin A1 2-50 V24L), e. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6; Annexin A1 2-48 V24L), f. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 7; Annexin A1 2-46 V24L), and g. a functional variant of any one of SEQ ID NOs: 2-7 comprising 1 to 6 individual amino acid substitutions.

[0067] In some embodiments, the functional variant comprises 1-3 individual amino acid substitutions, such as 1 individual amino acid substitution, 2 individual amino acid substitutions or 3 individual amino acid substitutions.

[0068] In some embodiments, the one or more individual amino acid substitutions are conservative amino acid substitutions.

[0069] In some embodiments, the functional variant is a ligand and / or agonist of one or more of Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor 3 (FPR3).

[0070] In some embodiments, the functional variant activates and / or stimulates one or more of Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor 3 (FPR3).

[0071] In some embodiments, the AnxA1 N-terminal-peptide has a C-terminal amidation.

[0072] In some embodiments, the AnxA1 N-terminal-peptide is AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO:

[0073] 6; Annexin A1 2-48 V24L), optionally with a C-terminal amidation.

[0074] In some embodiments, the AnxA1 N-terminal-peptide is administered as dosages of about 15 pg / kg, about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 150 pg / kg, about 200 pg / kg or about 400 pg / kg of the AnxA1 N-terminal-peptide.

[0075] In some embodiments, the ischemic condition and / or a reperfusion injury is a myocardial ischemic condition and / or reperfusion injury of the heart. In some embodiments, the ischemic condition and / or a reperfusion injury is selected from the group consisting of coronary artery diseases, such as angina and myocardial infarction; stroke, heart failure; peripheral artery disease; thromboembolic disease; and venous thrombosis.

[0076] In some embodiments, the ischemic condition and / or a reperfusion injury is coronary artery disease.

[0077] In some embodiments, the ischemic condition and / or a reperfusion injury is myocardial infarction.

[0078] In some embodiments, the ischemic condition and / or a reperfusion injury is acute myocardial infarction.

[0079] In some embodiments, the ischemic condition and / or a reperfusion injury is myocardial infarction followed by reperfusion.

[0080] In some embodiments, the ischemic condition and / or a reperfusion injury is selected from the group consisting of myocardial infarction due to myocardial ischemia / reperfusion, myocardial infarction due to myocardial ischemia, myocarditis, sepsis, sepsis-induced cardiomyopathy, and sepsis-induced myocardial inflammation.

[0081] In some embodiments, the ischemic condition and / or a reperfusion injury is myocardial infarction due to myocardial ischemia or myocardial infarction due to myocardial ischemia / reperfusion.

[0082] In some embodiments, the myocardial infarction is selected from the group consisting of ST-segment elevation myocardial infarction (STEM I) and non-ST-segment elevation myocardial infarction (NSTEMI).

[0083] In some embodiments, the myocardial infarction is ST-elevation myocardial infarction (STEMI).

[0084] In some embodiments, the ischemic condition and / or a reperfusion injury results in an inflammatory immune response and / or tissue destruction. In some embodiments, administration of the AnxA1 N-terminal-peptide reduces or prevents an inflammatory immune response in the ischemic tissue.

[0085] In some embodiments, administration of the AnxA1 N-terminal-peptide reduces necrosis caused by the ischemic condition and / or a reperfusion injury.

[0086] In some embodiments, the necrosis is reduced compared to necrosis caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N-terminal-peptide administrations.

[0087] In some embodiments, administration of the AnxA1 N-terminal-peptide reduces the infarct size of an infarct caused by the ischemic condition and / or a reperfusion injury.

[0088] In some embodiments, the infarct size is reduced compared to infarct size of an infarct caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N-terminal-peptide administrations.

[0089] In some embodiments, administration of the AnxA1 N-terminal-peptide reduces myocardial infarct size of a myocardial infarct caused by the ischemic condition and / or a reperfusion injury.

[0090] In some embodiments, the myocardial infarct size is reduced compared to myocardial infarct size of a myocardial infarct caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N-terminal-peptide administrations.

[0091] In some embodiments, the pharmaceutical composition is a liquid pharmaceutical composition comprising the AnxA1 N-terminal-peptide and at least one pharmaceutically acceptable excipient.

[0092] In some embodiments, the liquid pharmaceutical composition comprises 0.5-10 mg / mL of the AnxA1 N-terminal-peptide, such as 1-10 mg / mL, such as 2-9 mg / mL, such as 3-8 mg / mL, such as 4-6 mg / mL. In some embodiments, the liquid pharmaceutical composition comprises: i) 1-10 mg / mL of the AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol, and iii) 0.5-1.5 % (w / w) of a carbohydrate.

[0093] In some embodiments, the liquid pharmaceutical composition comprises: i) 1-10 mg / mL of the AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycols (PEGs) and polypropylene / ethylene glycol copolymer, and iii) 0.5-1.5 % (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose.

[0094] In some embodiments, the liquid pharmaceutical composition comprises: i) 1-10 mg / mL of the AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol, iii) 0.5-1.5 % (w / w) of a carbohydrate, iv) 0.005-0.015 % (w / w) of a surfactant, and v) 5-15 mM buffer.

[0095] In some embodiments, the liquid pharmaceutical composition has a pH of 8.2-8.4, the liquid pharmaceutical composition comprising i) 1-10 mg / mL of the AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycols (PEGs) and polypropylene / ethylene glycol copolymer, iii) 0.5-1.5 % (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose, iv) 0.005-0.015 % (w / w) of a surfactant selected from the group consisting of Polysorbate-80 and Polysorbate-20, and v) 5-15 mM buffer selected from the group consisting of Acetate buffer, TRIS, Amine-containing buffers, Amino-acid based buffers such as lysine, hydroxy- lysine histidine and glycylglycine, non-phosphate buffers, bicarbonate buffers, HEPES and borate buffers.

[0096] In some embodiments, the liquid pharmaceutical composition is administered as more than three daily i.v. infusions, such as 4, 5 or 6 daily i.v. infusions.

[0097] In some embodiments, the multiple daily i.v. infusions correspond to administration of a dosage of about 15 pg / kg , about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 150 pg / kg, about 200 pg / kg, or about 400 pg / kg of the AnxA1 N-terminal-peptide.

[0098] In some embodiments, the multiple daily i.v. infusions correspond to administration of a dosage of about 15-400 pg / kg, about 25-400 pg / kg, about 50-400 pg / kg, about 100- 400 pg / kg, about 150-400 pg / kg, or about 200-400 pg / kg of the AnxA1 N-terminal- peptide

[0099] In some embodiments, the multiple daily i.v. infusions correspond to administration of a dosage of about 15-400 pg / kg, about 25-400 pg / kg, about 25-200 pg / kg, about 25-150 pg / kg, about 25-100 pg / kg, or about 25-50 pg / kg of the AnxA1 N-terminal-peptide.

[0100] In some embodiments, the multiple daily i.v. infusions correspond to administration of a dosage of about 25-200 pg / kg of the AnxA1 N-terminal-peptide.

[0101] In some embodiments, the liquid pharmaceutical composition is administered as 3 daily i.v. infusions.

[0102] In some embodiments, the liquid pharmaceutical composition is administered 3 times daily each as a 20-40 minutes i.v. infusion, such as each as a 30 minutes i.v. infusion.

[0103] In some embodiments, each i.v. infusion corresponds to administration of a dosage of about 25-200 pg / kg, about 25-150 pg / kg, about 25-100 pg / kg, or about 25-50 pg / kg of the AnxA1 N-terminal-peptide.

[0104] In some embodiments, the liquid pharmaceutical composition is administered by i.v. infusion with a flow rate of about 0.5 to 10 mL / min., such as of 0.5 to 10 mL / min., such as of 0.5 to 5 mL / min., such as of 0.5 to 4 mL / min., such as of 0.5 to 3 mL / min., such as of 1 to 2 mL / min., such as of about 1.5 mL / min.

[0105] In some embodiments, the liquid pharmaceutical composition is administered by i.v. infusion with a flow rate of 1.5 mL / min.

[0106] Examples

[0107] In the following Examples, reference to ‘Peptide T is identified herein as AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6 (Annexin A1 2-48 V24L)), with a C-terminal amidation.

[0108] Example 1 : Effect of Peptide 1 treatment for 1 day versus 3 days on cardiac function in a rat model of acute myocardial infarction

[0109] Method:

[0110] Myocardial infarction was induced in male Sprague Dawley rats. On day 0 rats were anaesthetized with a mixture of 2 to 2.2% isoflurane USP (Abbot Laboratories, Montreal Canada) in oxygen, and placed on a heating pad (set at 37°C) to maintain body temperature. The animals were intubated and immediately ventilated with a mixture of 2 to 2.2% isoflurane USP (Abbot Laboratories, Montreal Canada) in oxygen by means of a positive-pressure rodent respirator (CWE model SAR-830 / P) set at =10mL / kg bodyweight at a frequency of 70-80 strokes / min. The pericardium was opened to expose the heart and a 5-0 wax coated braided silk suture (Sofsilk™) was placed around the left anterior descending (LAD) coronary artery, approximately 2-3 mm below the left atrium. The suture was briefly snared to verify the size and location of myocardial ischemia based on colour change and was then tied to produce a large anterolateral myocardial infarction (affecting around 45%of the LV). The suture was kept in place for 30 minutes (30 minutes of ischemia) followed by reperfusion. A group of rats receiving sham procedure was also included. Peptide 1 (or vehicle) was administrated in the tail vein three times, with the first dosage administered at establishment of reperfusion (reperfusion start), the second dosage 3 hours post establishment of reperfusion, and the third dosage 6 hours post establishment of reperfusion. Group 1 received 3x10 ug / kg for 3 days, Group 2 received 3x30 ug / kg for 3 days, Group 4 received 3x100 ug / kg for 3 days and Group 4 received 3x30 ug / kg for 1 day only. Fourteen days after ischemia, cardiac function was assessed by transthoracic echocardiography (echocardiograph model Q9, ChisonMedical Imaging Co. connected to a Chison 12.0 MHz probe).

[0111] Results:

[0112] As demonstrated in Figure 1 , vehicle treatment was associated with development of impaired cardiac function with 25% reduction in cardiac output compared to sham animals. Peptide 1 administration for 1 day or 3 days significantly improved cardiac output 14 days post ischemia by 20-30 % compared to vehicle treatment. Rats receiving 3x30 ug / kg Peptide 1 for 1 day only demonstrated the greatest improvement in cardiac function, and the cardiac output levels were comparable to that of sham animals (79,5 mL vs 81 ,1 ml, respectively). Thus, three dosages of Peptide 1 administered at establishment of reperfusion (reperfusion start), 3 hours post establishment of reperfusion and 6 hours post establishment of reperfusion during the first 24 hours significantly improve long-term cardiac function.

[0113] Example 2: Effect of immediate and delayed Annexin A1 peptide dosing in a rat model of acute myocardial infarction

[0114] Method:

[0115] Myocardial infarction was induced by 30 minutes ischemia via obstruction of coronary perfusion by occlusion of the left coronary artery followed by 24 hours reperfusion. Sprague Dawley rats were treated by administration with Peptide 1 (30 ug / kg) three times with treatment initiation either at the time of establishment of reperfusion (reperfusion start) (TOh, T3h, T6h) (Group 1), or with a delayed treatment initiation starting either at 1 hour post establishment of reperfusion (T1h, T4h, T7h) (Group 2), or at 2 hours post establishment of reperfusion (T2h, T5h, T8h) (Group 3).

[0116] At the end of 24 hours reperfusion period, the left coronary artery was reoccluded and Evans blue dye solution injected. Hearts were excised from the rat and stored at -20°C before being sliced into 1 mm thick transverse sections. Heart sections were incubated with triphenyltetrazolium chloride (TTC, 1%) at 37°C for 30 minutes to demarcate the viable and nonviable myocardium within the risk zone. Area at risk and infarcted area were determined using image software. Results:

[0117] Peptide 1 significantly reduced infarct size when administered 3 times, with the first dosage given at establishment of reperfusion (reperfusion start) (Group 1). Delaying the initiation of treatment with Peptide 1 for both one and two hours reduced infarct size to a similar degree as when Peptide 1 was administered immediately at establishment of reperfusion (Figure 2B). Thus, Peptide 1 has cardioprotective effects both when administered at establishment of reperfusion and at least two hours post establishment of reperfusion.

[0118] Example 3: Effect of Peptide 1 treatment for 1 day on the prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction

[0119] Method:

[0120] Myocardial infarction was induced in male Sprague Dawley rats. On day 0 rats were anaesthetized with a mixture of 2 to 2.2% isoflurane USP (Abbot Laboratories, Montreal Canada) in oxygen, and placed on a heating pad (set at 37°C) to maintain body temperature. The animals were intubated and immediately ventilated with a mixture of 2 to 2.2% isoflurane USP (Abbot Laboratories, Montreal Canada) in oxygen by means of a positive-pressure rodent respirator (CWE model SAR-830 / P) set at =10mL / kg bodyweight at a frequency of 70-80 strokes / min. The pericardium was opened to expose the heart and a 5-0 wax coated braided silk suture (Sofsilk™) was placed around the left anterior descending (LAD) coronary artery, approximately 2-3 mm below the left atrium. The suture was briefly snared to verify the size and location of myocardial ischemia based on colour change and was then tied to produce a large anterolateral myocardial infarction (affecting around 45%of the LV). The suture was kept in place for 30 minutes (30minutesof ischemia) followed by reperfusion. A group of rats receiving sham procedure was also included. PEPTIDE 1 (30 ug / kg) or vehicle was administrated in the tail vein three times, with the first dose administered at reperfusion start, the second dose 3h post reperfusion, and the third dose 6h post reperfusion. On day 1 or 3 the animals were re-anesthetized and the chest cavity was re-opened to expose the heart. The heart was harvested and perfused through the aorta, without crossing the aortic valve with 10 mL of cold PBS to wash the coronaries. The left ventricle + septum were placed in the well of a 6-well plate containing 1 mL of cold PBS and cut in pieces of approximately 1-2 mm3. The cardiomyocytes were dispersed using the Neonatal heart dissociation kit (Miltenyi Biotec, #130-098-373). After cell dissociation, erythrocytes were lysed with 2 mL of the FACS lysing solution (BD Biosciences, #555899).

[0121] Super Bright Complete Staining Buffer (ThermoFisher Scientific, #SB-4401-42, 150 pL) was added to 1.5 x 106 cardiac cells to prevent non-specific polymer interactions. Cells were stained with an antibody mix and all samples were protected from light and kept at room temperature for 20 min (see Table 1). At each batch, one unstained sample was added.

[0122] Finally, cells were fixed with PFA 2% for 10 min at room temperature and protected from light.

[0123] Table 1 : Antibody mix for cardiac samples One or two days after cell staining, all samples were read them with the flow cytometer (Sony ID7000) with Accucount Fluorescent particles (Spherotech, ACFO-50-5, lot AP02) for an absolute cell counting.

[0124] Results:

[0125] Figure 3A illustrates the count of endothelial cells 72 hours post-myocardial infarction (Ml) in sham-operated rats, rats treated with the vehicle, and rats administered with 3 doses of 30 pg / kg Peptide 1. Remarkably, in rats receiving Peptide 1 , there was a notable 2.4 fold increase in the number of endothelial cells compared to vehicle. This elevation in endothelial cell count during the early phase of myocardial infarction suggests a potential for neovascularization in the injured tissue. Neovascularization plays a crucial role in supplying the healing infarct with essential nutrients and oxygen, thereby contributing to a more robust cardiac recovery.

[0126] Furthermore, the presence of anti-inflammatory monocytes / macrophages in the heart 24 hours post-MI following Peptide 1 treatment was assessed. These cell types play a pivotal role in resolving inflammation, promoting scar formation, and facilitating neovascularization. As depicted in Figure 3B, there is an observable rise in antiinflammatory monocytes / macrophages in animals treated with the vehicle. I ntriguingly , the administration of Peptide 1 leads to an additional 1.9 fold increase in the number of anti-inflammatory monocytes / macrophages compared to the vehicle-treated group.

[0127] This unexpected augmentation suggests that Peptide 1 may contribute to an enhanced resolution of inflammation in the myocardium.

[0128] Sequence overview

[0129] Full length Annexin A1 (homo sapiens) has the following sequence: >sp|P04083|ANXA1_HUMAN Annexin A1 OS=Homo sapiens GN=ANXA1 PE=1 SV=2

[0130] MAMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAALHKAIMV KGVDEATIIDILTKRNNAQRQQIKAAYLQETGKPLDETLKKALTGHLEEVVLALLKTPAQ FDADELRAAMKGLGTDEDTLIEILASRTNKEIRDINRVYREELKRDLAKDITSDTSGDFR NALLSLAKGDRSEDFGVNEDLADSDARALYEAGERRKGTDVNVFNTILTTRSYPQLR RVFQKYTKYSKHDMNKVLDLELKGDIEKCLTAIVKCATSKPAFFAEKLHQAMKGVGTR HKALIRIMVSRSEIDMNDIKAFYQKMYGISLCQAILDETKGDYEKILVALCGGN (SEQ ID NO: 1). AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SED ID NO: 2; Annexin A1 2-50)

[0131] AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SED ID NO: 3; Annexin A1 2-48) AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SED ID NO: 4; Annexin A1 2-46)

[0132] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SED ID NO: 5; Annexin A1 2-50 V24L)

[0133] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SED ID NO: 6; Annexin A1 2-48 V24L)

[0134] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SED ID NO: 7; Annexin A1 2-46 V24L)

[0135] AMVSEFLKQAWFIENEEQEYVQTVK (SED ID NO: 8; Annexin A1 2-26),

[0136] AMVSEFLKQAWFIENEEQEYVQTLK (SED ID NO: 9; Annexin A1 2-26 V24L) All peptides may be C-terminally amidated (-NH2).

Claims

Claims1. An Annexin A1 (AnxA1) N-terminal-peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of said AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

2. A pharmaceutical composition comprising an Annexin A1 (AnxA1) N-terminal- peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 dosages of said AnxA1 N-terminal-peptide are administered to a human subject within 24 hours of reperfusion.

3. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered no more than 3 times to the human subject within 24 hours of reperfusion.

4. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said 3 dosages of said AnxA1 N- terminal-peptide are administered once, such as once within 24 hours of reperfusion.

5. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered only to the human subject within 24 hours of reperfusion.

6. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said 3 dosages of said AnxA1 N- terminal-peptide are 3 daily dosages and are administered to the human subject for 1 day only.

7. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein no dosages of said AnxA1 N-terminal-peptide are administered to a human subject after 24 hours of reperfusion.

8. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein all dosages of said AnxA1 N- terminal-peptide are administered to a human subject within 24 hours of reperfusion.

9. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject within 24 hours of establishment of reperfusion, such as within 24 hours post establishment of reperfusion.

10. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as 3 dosages at a dosing interval of 1 to 6 hours; such as at a dosing interval of about 1 to about 2 hours, such as at a dosing interval of about 2 to about 3 hours, such as at a dosing interval of about 3 to about 4 hours, such as at a dosing interval of about 4 to about 5 hours, such as at a dosing interval of about 5 to about 6 hours; such as at a dosing interval of about 1 hour, such as at a dosing interval of about 2 hours, such as at a dosing interval of about 3 hours, such as at a dosing interval of about 4 hours, such as at a dosing interval of about 5 hours, such as at a dosing interval of about 6 hours.11 . The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as 3 dosages at a dosing interval of about 2 to 4 hours, such as about 2 hours and 30 minutes to about 3 hours and 30 minutes, such as about 2 hours and 45 minutes to about 3 hours and 15 minutes.

12. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide isadministered to the human subject as 3 dosages at a dosing interval of about 3 hours.

13. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a first dosage of said AnxA1 N- terminal-peptide is administered to the human subject within about 0 hour of establishment of reperfusion, such as within about 5 minutes of establishment of reperfusion, such as within about 10 minutes of establishment of reperfusion, such as within about 15 minutes of establishment of reperfusion, such as within about 20 minutes of establishment of reperfusion, such as within about 25 minutes of establishment of reperfusion, such as within about 30 minutes of establishment of reperfusion, such as within about 45 minutes of establishment of reperfusion, such as within about 1 hour of establishment of reperfusion, such as within about 1 hour and 15 minutes of establishment of reperfusion, such as within about 1 hour and 30 minutes of establishment of reperfusion, such as within about 1 hour and 45 minutes of establishment of reperfusion, such as within about 2 hours of establishment of reperfusion, such as within about 2 hours and 30 minutes of establishment of reperfusion, such as within about 3 hours of establishment of reperfusion, such as within about 3 hours and 30 minutes of establishment of reperfusion, such as within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion.

14. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a first dosage of said AnxA1 N- terminal-peptide is administered to the human subject within 0 hour to 6 hours of establishment of reperfusion, such as within 0 hour to 5 hours of establishment of reperfusion, such as within 0 hour to 4 hours of establishment of reperfusion, such as within 0 hour to 3 hours of establishment of reperfusion, such as within 0 hour to 2 hours of establishment of reperfusion, such as within 0 hour to 1 hour and 30 minutes hours of establishment of reperfusion, such as within 0 hour to 1 hour of establishment of reperfusion, such as within 0 hour to 30 minutes of establishment of reperfusion.

15. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a second dosage of said AnxA1 N- terminal-peptide is administered to the human subject within about 2 hours of establishment of reperfusion, such as within about 2 hours and 30 minutes of establishment of reperfusion, such as within about 3 hours of establishment of reperfusion, such as within about 3 hours and 30 minutes of establishment of reperfusion, such as within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 5 hours and 30 minutes of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 6 hours and 30 minutes of establishment of reperfusion, such as within about 7 hours of establishment of reperfusion, such as within about 7 hours and 30 minutes of establishment of reperfusion, such as within about 8 hours of establishment of reperfusion, such as within about 8 hours and 30 minutes of establishment of reperfusion.

16. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a second dosage of said AnxA1 N- terminal-peptide is administered to the human subject within 1 hours to 9 hours of establishment of reperfusion, such as within 1 hour and 30 minutes to 8 hours of establishment of reperfusion, such as within 2 hours to 7 hours of establishment of reperfusion, such as within 2 hours to 6 hours of establishment of reperfusion, such as within 2 hours to 5 hours of establishment of reperfusion, such as within 2 hours to 4 hours of establishment of reperfusion, such as within 2 hours and 30 minutes to 3 hours and 30 minutes of establishment of reperfusion.

17. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a third dosage of said AnxA1 N- terminal-peptide is administered to the human subject within about 4 hours of establishment of reperfusion, such as within about 4 hours and 30 minutes of establishment of reperfusion, such as within about 5 hours of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, suchas within about 5 hours of establishment of reperfusion, such as within about 5 hours and 30 minutes of establishment of reperfusion, such as within about 6 hours of establishment of reperfusion, such as within about 6 hours and 30 minutes of establishment of reperfusion, such as within about 7 hours of establishment of reperfusion, such as within about 7 hours and 30 minutes of establishment of reperfusion, such as within about 8 hours of establishment of reperfusion, such as within about 8 hours and 30 minutes of establishment of reperfusion, such as within about 9 hours of establishment of reperfusion, such as within about 9 hours and 30 minutes of establishment of reperfusion, such as within about 10 hours of establishment of reperfusion, such as within about 10 hours and 30 minutes of establishment of reperfusion, such as within about 11 hours of establishment of reperfusion, such as within about 11 hours and 30 minutes of establishment of reperfusion, such as within about 12 hours of establishment of reperfusion.

18. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a third dosage of said AnxA1 N- terminal-peptide is administered to the human subject within 4 hours to 12 hours of establishment of reperfusion, such as within 4 hours and 30 minutes to 11 hours of establishment of reperfusion, such as within 5 hours to 10 hours of establishment of reperfusion, such as within 4 hours to 9 hours of establishment of reperfusion, such as within 4 hours to 8 hours of establishment of reperfusion, such as within 4 hours to 9 hours of establishment of reperfusion, such as within 5 hours and 30 minutes to 6 hours and 30 minutes of establishment of reperfusion19. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at: a. within 0 minute to 15 minutes of establishment of reperfusion, within 3 hours to 3 hours and 15 minutes of establishment of reperfusion and within 6 hours to 6 hours to 3 hours and 15 minutes of establishment of reperfusion, or b. within 15 minutes to 30 minutes of establishment of reperfusion, within 3 hours and 15 minutes to 3 hours and 30 minutes of establishment ofreperfusion and within 6 hours and 15 minutes to 6 hours and 30 minutes of establishment of reperfusion, or c. within 30 minutes to 45 minutes of establishment of reperfusion, within 3 hours and 30 minutes to 3 hours and 45 minutes of establishment of reperfusion and within 6 hours and 30 minutes 6 hours and 45 minutes of establishment of reperfusion, or d. within 1 hour and 30 minutes to 1 hour and 45 minutes of establishment of reperfusion, within 4 hours and 30 minutes to 4 hours and 45 minutes of establishment of reperfusion and within 7 hours and 30 minutes 7 hours and 45 minutes of establishment of reperfusion, or e. within 1 hour and 45 minutes to 2 hours of establishment of reperfusion, within 4 hours and 45 minutes to 5 hours of establishment of reperfusion and within 7 hours and 45 minutes to 8 hours of establishment of reperfusion, or f. within 2 hours to 3 hours of establishment of reperfusion, within 5 hours to 6 hours of establishment of reperfusion and within 8 hours to 9 hours of establishment of reperfusion, or g. within 3 hours to 4 hours of establishment of reperfusion, within 6 hours to 7 hours of establishment of reperfusion and within 9 hours to 10 hours of establishment of reperfusion, or h. within 4 hours to 5 hours of establishment of reperfusion, within 7 hours to 8 hours of establishment of reperfusion and within 10 hours to 11 hours of establishment of reperfusion, or i. within 5 hours to 6 hours of establishment of reperfusion, within 8 hours to 9 hours of establishment of reperfusion and within 11 hours to 12 hours of establishment of reperfusion, or j. within 6 hours to 7 hours of establishment of reperfusion, within 9 hours to 10 hours of establishment of reperfusion and within 12 hours to 13 hours of establishment of reperfusion.

20. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at:a. within about 0 hour of establishment of reperfusion, within about 3 hours of establishment of reperfusion and within about 6 hours of establishment of reperfusion, or b. within about 15 minutes of establishment of reperfusion, within about 3 hours and 15 minutes of establishment of reperfusion and within about 6 hours and 15 minutes of establishment of reperfusion, or c. within about 30 minutes of establishment of reperfusion, within about 3 hours and 30 minutes of establishment of reperfusion and within about 6 hours and 30 minutes of establishment of reperfusion, or d. within about 1 hour and 30 minutes of establishment of reperfusion, within about 4 hours and 30 minutes of establishment of reperfusion and within about 7 hours and 30 minutes of establishment of reperfusion, or e. within about 1 hour and 45 minutes of establishment of reperfusion, within about 4 hours and 45 minutes of establishment of reperfusion and within about 7 hours and 45 minutes of establishment of reperfusion, or f. within about 2 hours of establishment of reperfusion, within about 5 hours of establishment of reperfusion and within about 8 hours of establishment of reperfusion, or g. within about 3 hours of establishment of reperfusion, within about 6 hours of establishment of reperfusion and within about 9 hours of establishment of reperfusion, or h. within about 4 hours of establishment of reperfusion, within about 7 hours of establishment of reperfusion and within about 10 hours of establishment of reperfusion, or i. within about 5 hours of establishment of reperfusion, within about 8 hours of establishment of reperfusion and within about 11 hours of establishment of reperfusion, or j. within about 6 hours of establishment of reperfusion, within about 9 hours of establishment of reperfusion and within about 12 hours of establishment of reperfusion.

21. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as 3 daily dosages at:a. about 15 minutes post establishment of reperfusion, about 3 hours and 15 minutes post establishment of reperfusion and about 6 hours and 15 minutes post establishment of reperfusion, or b. about 30 minutes post establishment of reperfusion, about 3 hours and 30 minutes post establishment of reperfusion and about 6 hours and 30 minutes post establishment of reperfusion, or c. about 1 hour and 30 minutes post establishment of reperfusion, about 4 hours and 30 minutes post establishment of reperfusion and about 7 hours and 30 minutes post establishment of reperfusion, or d. about 1 hour and 45 minutes post establishment of reperfusion, about 4 hours and 45 minutes post establishment of reperfusion and about 7 hours and 45 minutes post establishment of reperfusion, or e. about 2 hours post establishment of reperfusion, about 5 hours post establishment of reperfusion and about 8 hours post establishment of reperfusion, or f. about 3 hours post establishment of reperfusion, about 6 hours post establishment of reperfusion and 9 hours post establishment of reperfusion, or g. about 4 hours post establishment of reperfusion, about 7 hours post establishment of reperfusion and about 10 hours post establishment of reperfusion, or h. about 5 hours post establishment of reperfusion, about 8 hours post establishment of reperfusion and 11 hours post establishment of reperfusion, or i. about 6 hours post establishment of reperfusion, about 9 hours post establishment of reperfusion and about 12 hours post establishment of reperfusion.

22. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of the preceding claims, wherein a first dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 0 hour to 2 hours of establishment of reperfusion, a second dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 2 hours to 5 hours of establishment of reperfusion and a third dosage of said AnxA1 N-terminal-peptide is administered to the human subject within about 4 hours to 8 hours of establishment of reperfusion.

23. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of the preceding claims, wherein a first dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 0 hour to 1 hour of establishment of reperfusion, a second dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 2 hours to 4 hours of establishment of reperfusion and a third dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 5 hours and 7 hours of establishment of reperfusion.

24. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of the preceding claims, wherein a first dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 0 hour of establishment of reperfusion, a second dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 3 hours of establishment of reperfusion and a third dosage of said AnxA1 N-terminal- peptide is administered to the human subject within about 6 hours of establishment of reperfusion.

25. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered to the human subject as more than 3 dosages within 24 hours of reperfusion, such as 4, 5 or 6 dosages within 24 hours of reperfusion.

26. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide or pharmaceutical composition is administered as intravenous (i.v.) infusions.

27. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide or pharmaceutical composition is administered as 1-60 minutes i.v. infusions, such as 10-50 minutes i.v. infusions, such as 20-40 minutes i.v. infusions, such as 30 minutes i.v. infusions.

28. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide or pharmaceutical composition is administered as 30 minutes i.v. infusions.

29. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is selected from the group consisting of: a. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 2; Annexin A1 2-50), b. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 3; Annexin A1 2-48), c. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 4; Annexin A1 2-46), d. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 5; Annexin A1 2-50 V24L), e. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6; Annexin A1 2-48 V24L), f. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 7; Annexin A1 2-46 V24L), and g. a functional variant of any one of SEQ ID NOs: 2-7 comprising 1 to 6 individual amino acid substitutions.

30. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 29, wherein said functional variant comprises 1-3 individual amino acid substitutions, such as 1 individual amino acid substitution, 2 individual amino acid substitutions or 3 individual amino acid substitutions.

31. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of claims 29 to 30, wherein said one or more individual amino acid substitutions are conservative amino acid substitutions.

32. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of claims 29 to 31 , wherein said functional variant is a ligand and / oragonist of one or more of Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor s (FPR3).

33. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any of claims 29 to 32, wherein said functional variant activates and / or stimulates one or more of Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor s (FPR3).

34. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide has a C-terminal amidation.

35. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6; Annexin A1 2-48 V24L), optionally with a C-terminal amidation.

36. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal-peptide is administered as dosages of about 15 pg / kg, about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 150 pg / kg, about 200 pg / kg or about 400 pg / kg of said AnxA1 N-terminal-peptide.

37. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is a myocardial ischemic condition and / or reperfusion injury of the heart.

38. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is selected from the group consisting of coronary artery diseases, such as angina and myocardial infarction; stroke, heart failure; peripheral artery disease; thromboembolic disease; and venous thrombosis.

39. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is coronary artery disease.

40. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is myocardial infarction.

41. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is acute myocardial infarction.

42. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is myocardial infarction followed by reperfusion.

43. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is selected from the group consisting of myocardial infarction due to myocardial ischemia / reperfusion, myocardial infarction due to myocardial ischemia, myocarditis, sepsis, sepsis-induced cardiomyopathy, and sepsis- induced myocardial inflammation.

44. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury is myocardial infarction due to myocardial ischemia or myocardial infarction due to myocardial ischemia / reperfusion.

45. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 40, wherein said myocardial infarction is selected from the group consisting of ST-segment elevation myocardial infarction (STEMI) and non-ST- segment elevation myocardial infarction (NSTEMI).

46. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 40, wherein said myocardial infarction is ST-elevation myocardial infarction (STEMI).

47. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or a reperfusion injury results in an inflammatory immune response and / or tissue destruction.

48. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N- terminal-peptide reduces or prevents an inflammatory immune response in the ischemic tissue.

49. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N- terminal-peptide reduces necrosis caused by said ischemic condition and / or a reperfusion injury.

50. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 49, wherein the necrosis is reduced compared to necrosis caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N-terminal-peptide administrations.

51. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N- terminal-peptide reduces the infarct size of an infarct caused by said ischemic condition and / or a reperfusion injury.

52. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 51, wherein the infarct size is reduced compared to infarct size of an infarct caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N-terminal-peptide administrations.

53. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N- terminal-peptide reduces myocardial infarct size of a myocardial infarct caused by said ischemic condition and / or a reperfusion injury.

54. The AnxA1 N-terminal-peptide or pharmaceutical composition for use according to claim 53, wherein the myocardial infarct size is reduced compared to myocardial infarct size of a myocardial infarct caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any AnxA1 N- terminal-peptide administrations.

55. The pharmaceutical composition for use according to any one of the preceding claims, wherein said pharmaceutical composition is a liquid pharmaceutical composition comprising said AnxA1 N-terminal-peptide and at least one pharmaceutically acceptable excipient.

56. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition comprises 0.5-10 mg / mL of said AnxA1 N-terminal-peptide, such as 1-10 mg / mL, such as 2-9 mg / mL, such as 3-8 mg / mL, such as 4-6 mg / mL.

57. The liquid pharmaceutical composition for use according to any one of the preceding claims, said liquid pharmaceutical composition comprising: i) 1-10 mg / mL of said AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol, and iii) 0.5-1.5 % (w / w) of a carbohydrate.

58. The liquid pharmaceutical composition for use according to any one of the preceding claims, said liquid pharmaceutical composition comprising: i) 1-10 mg / mL of said AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycols (PEGs) and polypropylene / ethylene glycol copolymer, andiii) 0.5-1.5 % (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose.

59. The liquid pharmaceutical composition for use according to any one of the preceding claims, said liquid pharmaceutical composition comprising: i) 1-10 mg / mL of said AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol, iii) 0.5-1.5 % (w / w) of a carbohydrate, iv) 0.005-0.015 % (w / w) of a surfactant, and v) 5-15 mM buffer.

60. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition has a pH of 8.2-8.4, said liquid pharmaceutical composition comprising i) 1-10 mg / mL of said AnxA1 N-terminal-peptide, ii) 3-5 % (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycols (PEGs) and polypropylene / ethylene glycol copolymer, iii) 0.5-1.5 % (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose, iv) 0.005-0.015 % (w / w) of a surfactant selected from the group consisting of Polysorbate-80 and Polysorbate-20, and v) 5-15 mM buffer selected from the group consisting of Acetate buffer, TRIS, Amine-containing buffers, Amino-acid based buffers such as lysine, hydroxy-lysine histidine and glycylglycine, non-phosphate buffers, bicarbonate buffers, HEPES and borate buffers.

61. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition is administered as more than three daily i.v. infusions, such as 4, 5 or 6 daily i.v. infusions.

62. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the multiple daily i.v. infusions correspond to administration of a dosage of about 15 pg / kg , about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 150 pg / kg, about 200 pg / kg, or about 400 pg / kg of said AnxA1 N-terminal-peptide.

63. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the multiple daily i.v. infusions correspond to administration of a dosage of about 15-400 pg / kg, about 25-400 pg / kg, about 50-400 pg / kg, about 100-400 pg / kg, about 150-400 pg / kg, or about 200-400 pg / kg of said AnxA1 N-terminal-peptide64. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the multiple daily i.v. infusions correspond to administration of a dosage of about 15-400 pg / kg, about 25-400 pg / kg, about 25-200 pg / kg, about 25-150 pg / kg, about 25-100 pg / kg, or about 25-50 pg / kg of said AnxA1 N-terminal-peptide.

65. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the multiple daily i.v. infusions correspond to administration of a dosage of about 25-200 pg / kg of said AnxA1 N-terminal- peptide.

66. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition is administered as 3 daily i.v. infusions.

67. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition is administered 3 times daily each as a 20-40 minutes i.v. infusion, such as each as a 30 minutes i.v. infusion.

68. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein each i.v. infusion corresponds to administration of adosage of about 25-200 pg / kg, about 25-150 pg / kg, about 25-100 pg / kg, or about 25-50 pg / kg of said AnxA1 N-terminal-peptide.

69. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition is administered by i.v. infusion with a flow rate of about 0.5 to 10 mL / min., such as of 0.5 to 10 mL / min., such as of 0.5 to 5 mL / min., such as of 0.5 to 4 mL / min., such as of 0.5 to 3 mL / min., such as of 1 to 2 mL / min., such as of about 1.5 mL / min.

70. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said liquid pharmaceutical composition is administered by i.v. infusion with a flow rate of 1.5 mL / min.

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