Annexin A1-E N-Terminal Peptide, Pharmaceutical Composition

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

31 Annexin A1-E N-Terminal Peptide, Pharmaceutical Composition Technical field

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

[002] The Annexin superfamily 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 the extravasation of blood-borne polymorphonuclear leukocytes (PMNs) into 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 leukocytes (PMNs) into surrounding tissue occurs. PMN transmigration or extravasation is regulated by mediators such as adhesion molecules, cytokines, and proteases, which control pro-inflammatory and anti-inflammatory processes. The disruptive potential of PMN is high and potentially self-destructive.Therefore, it is important to control PMN extravasation and the inflammatory response.

[003] For therapeutic purposes as an anti-inflammatory agent, the complete Annexin A1 protein has numerous disadvantages compared to functional fragments or modified versions thereof. The large size of the protein makes its distribution by possible techniques more difficult. Petition 870250079340, dated 04 / 09 / 2025, pp. 66 / 97 / 31 with a smaller polypeptide (e.g., transdermal or transmucosal). For use in the treatment of eye inflammation, a smaller molecule is expected to be more capable of penetrating the corneal epithelium. Furthermore, susceptibility to proteolytic degradation is a particular concern for all peptide drugs, especially large ones, and particularly if oral administration (preferred by many patients) is contemplated.

[004] Some Annexin A1 derivatives lacking significant regions on the N-terminal side of the polypeptide have demonstrated a lack of significant activity in some inflammation and mediator release assays, while full-length N-terminal N-acetylated Annexin A1 has been found to be biologically active in several systems. Several peptides derived primarily from the unique N-terminal portion of the Annexin A1 protein have demonstrated anti-inflammatory properties. One of the most extensively studied Annexin A1 peptides is the Ac2-26 peptide, which mimics the 2nd to 26th amino acids of the 54-amino acid N-terminal region. Annexin A1 and its N-terminal peptide (Ac2-26) have been shown to exert most of their anti-inflammatory action via 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 ischemia-reperfusion (I / R), mesentery I / R, glycogen peritonitis, and IL1 air pocket, where it was reported to significantly reduce neutrophil recruitment to the site of injury / inflammation.

[005] Shorter versions of the Ac2-26 peptide, such as the 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 to 48, 2 to 50, and 11 to 48, have been described, including protease-resistant V24L variants (WO 2012 / 174397 and WO 2022 / 038281).

[006] A myocardial infarction, commonly known as a Petition 870250079340, dated 04 / 09 / 2025, pp. 67 / 97 3 / 31 A heart attack occurs when blood flow decreases or stops in the coronary artery of the heart, causing damage to the heart muscle. Additional tissue damage in the form of reperfusion injury can occur during reperfusion, that is, when blood supply returns to the heart after a period of ischemia or lack of oxygen. Myocardial infarction is a serious condition, and there is a need to develop safe and effective treatments with minimal side effects. Summary

[007] There is a need to develop safe and effective treatments for ischemic conditions and / or reperfusion injury with minimal side effects. The present inventors show that administering 3 doses of an N-terminal AnxAl peptide over 1 or 3 days significantly improved cardiac output 14 days after ischemia. Surprisingly, administering 3 doses of the N-terminal AnxAl peptide within 24 hours of reperfusion demonstrated the greatest improvement in cardiac function. Therefore, administering 3 doses of the N-terminal AnxAl peptide within 24 hours of establishing reperfusion (reperfusion onset) is sufficient to improve long-term cardiac function.

[008] In some embodiments, the present description refers to an N-terminal Annexin Al (AnxAl) peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal AnxAl peptide are administered to a human subject within 24 hours of reperfusion.

[009] In some embodiments, the present description refers to a pharmaceutical composition comprising an N-terminal Annexin Al (AnxAl) peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal AnxAl peptide are administered to a human subject within 24 hours of reperfusion. Petition 870250079340, dated 04 / 09 / 2025, page 68 / 97 / 31 Description of the Drawings

[0010] Figure 1 shows the effect of treatment with Peptide 1 for 1 day versus 3 days on cardiac function in a rat model of acute myocardial infarction. Figure 1 shows that three doses of Peptide 1 administered at the establishment of reperfusion (reperfusion onset), 3 hours after the establishment of reperfusion, and 6 hours after the establishment of reperfusion during the first 24 hours significantly improve long-term cardiac function. *p<0.05: One-way ANOVA vs. vehicle.

[0011] Figure 2A shows the effect of immediate and delayed dosing of Annexin A1 peptide in a rat model of acute myocardial infarction. Figure 2A illustrates the treatment regimen of Groups 1, 2, and 3 (cf. Figure 2B).

[0012] Figure 2B shows the effect of immediate and late dosing of Annexin A1 peptide in a rat model of acute myocardial infarction. Figure 2B demonstrates that administration of Peptide 1 significantly reduced infarct size, both when the first dose was administered at the establishment of reperfusion (reperfusion start) T=0 (Group 1), when the first dose was administered one hour after the establishment of reperfusion T=1 (Group 2), and when the first dose was administered two hours after the establishment of reperfusion T=2 (Group 3). *p<0.05: One-way ANOVA vs. vehicle. #p<0.05, ##p<0.01: t-test between each treatment group versus vehicle.

[0013] Figure 3A shows the effect of treatment with Peptide 1 for 1 day on the prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction. Figure 3A shows the endothelial cell count 72 hours after myocardial infarction (MI) in rats undergoing sham surgery, rats treated with the vehicle, and rats that were administered 3 doses of 30 pg / kg of Peptide 1.

[0014] Figure 3B shows the effect of treatment with Peptide 1 by Petition 870250079340, dated 04 / 09 / 2025, page 69 / 97 / 31 day in the prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction. Figure 3B shows the presence of anti-inflammatory monocytes / macrophages 24 hours after MI in rats undergoing sham surgery, rats treated with the vehicle, and rats that were administered 3 doses of 30 pg / kg of Peptide 1. Definitions

[0015] The term “a(n)” denotes at least one, that is, one or more.

[0016] The terms “approximately” and “about” mentioned in this document are synonymous. In some modalities, "approximately" and "about" refer to the quantity, value, or duration recited ± 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 categories, "approximately" and "about" refer to the listed quantity, 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 categories, "approximately" and "about" refer to the listed quantity, value, or duration ±10%. In some categories, "approximately" and "about" refer to the listed quantity, value, or duration ±5%. In some categories, "approximately" and "about" refer to the listed quantity, value, or duration ±1%.

[0017] The term “Dosing Interval”, as used in this document, refers to the period of time between the administration of two doses.

[0018] The term “Administration Time” as used in this document refers to the time at which an administration or infusion, such as IV infusions, begins.

[0019] A pharmaceutically acceptable excipient is understood to be any excipient acceptable for inclusion in a pharmaceutical composition. Petition 870250079340, dated 04 / 09 / 2025, pp. 70 / 97 / 31 Pharmaceutically acceptable excipients include, but are not limited to, bulking agents, tonicity agents, isotonicity modifiers, stabilizers, surfactants, buffers, water, carbohydrates, and sugar alcohols.

[0020] An intravenous infusion is the direct injection of a fluid medication into a vein via an intravenous line, needle, cannula, or catheter. Administering drugs via IV infusion is generally necessary when longer or continuous systemic exposures are required to achieve a therapeutic effect. Unlike injection, infusion typically uses a pump or the natural force of gravity to distribute fluids throughout the body.

[0021] The term “therapeutically effective amount” of a compound, as used in this document, refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially interrupt the clinical manifestations of a given disease or disorder and its complications. An amount adequate to achieve this goal is defined as a “therapeutically effective amount.” The effective amounts for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the individual. It is understood that determining an appropriate dose can be achieved using routine experimentation, constructing a matrix of values ​​and testing different points on the matrix, which is within the common skills of a trained physician or veterinarian.

[0022] The terms “treatment” and “treating,” as used in this document, refer to the management and care of a patient for the purpose of combating a condition, disease, or disorder. The term is intended to encompass the full spectrum of treatments for a given condition from which the patient suffers. The patient to be treated is preferably a mammal, in particular a human being. Patients to be treated may be of varying ages. Petition 870250079340, dated 04 / 09 / 2025, page 71 / 97 / 31

[0023] Reperfusion refers to the restoration of blood flow to a previously ischemic tissue or organ.

[0024] Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is tissue damage caused when blood supply returns to tissue after a period of ischemia or lack of oxygen (anoxia or hypoxia).

[0025] The term “Establishment of reperfusion”, as used in this document, refers to the point in time when blood flow to an organ or tissue is restored after it has been blocked. This may also be called “Onset of reperfusion”.

[0026] The term “After reperfusion has been established”, as used in this document, refers to a point in time that occurs after reperfusion has been established. This may also be called “Post-reperfusion onset”. Detailed description

[0027] It is an aspect of the present description to provide an N-terminal Annexin A1 (AnxA1) peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal AnxA1 peptide are administered to a human subject within 24 hours of reperfusion.

[0028] It is also an aspect of the present description to provide a pharmaceutical composition comprising an N-terminal Annexin A1 (AnxA1) peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal AnxA1 peptide are administered to a human subject within 24 hours of reperfusion.

[0029] It is an aspect of the present description to provide an N-terminal Annexin A1 (AnxA1) peptide for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal peptide Petition 870250079340, dated 04 / 09 / 2025, page 72 / 97 / 31 terminal AnxAl doses must be administered to a human individual within 24 hours of reperfusion.

[0030] It is also an aspect of the present description to provide a pharmaceutical composition comprising an N-terminal Annexin A1 (AnxA1) peptide and at least one pharmaceutically acceptable excipient for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of the N-terminal AnxA1 peptide are to be administered to a human subject within 24 hours of reperfusion.

[0031] It is also an aspect of the present description to provide a method of treating an ischemic condition and / or a reperfusion injury, the method comprising administering 3 doses of an N-terminal Annexin A1 peptide (AnxA1) to a human subject within 24 hours of reperfusion.

[0032] It is also an aspect of the present description to provide a method of treating an ischemic condition and / or a reperfusion injury, the method comprising administering a pharmaceutical composition comprising an N-terminal Annexin A1 peptide (AnxA1) and at least one pharmaceutically acceptable excipient to a human subject, wherein 3 doses of the N-terminal AnxA1 peptide are administered to the human subject within 24 hours of reperfusion.

[0033] It is also an aspect of the present description to provide a method of reducing necrosis caused by an ischemic condition and / or a reperfusion injury, the method comprising administering 3 doses of an N-terminal Annexin A1 peptide (AnxA1) to a human subject within 24 hours of reperfusion.

[0034] It is also an aspect of the present description to provide a method for reducing the size of an infarct caused by an ischemic condition and / or a reperfusion injury, the method comprising administering 3 doses of an N-terminal Annexin A1 peptide. Petition 870250079340, dated 04 / 09 / 2025, page 73 / 97 / 31 (AnxAl) to a human individual within 24 hours of reperfusion.

[0035] It is also an aspect of the present description to provide a method for reducing the size of a myocardial infarction caused by an ischemic condition and / or a reperfusion injury, the method comprising administering 3 doses of an N-terminal Annexin A1 peptide (AnxA1) to a human subject within 24 hours of reperfusion.

[0036] In some embodiments, the present description refers to the use of an N-terminal Annexin A1 (AnxA1) peptide for the manufacture of a medicament for use in the treatment of an ischemic and / or inflammatory condition, wherein 3 doses of the N-terminal AnxA1 peptide are administered to a human subject within 24 hours of reperfusion.

[0037] In some modalities, the ischemic condition is followed by reperfusion.

[0038] In some embodiments, the N-terminal peptide of AnxA1 is administered no more than 3 times to the human subject within 24 hours of reperfusion.

[0039] In some modalities, the 3 doses of the N-terminal AnxA1 peptide are administered once, as once within 24 hours of reperfusion.

[0040] In some modalities, the N-terminal peptide of AnxA1 is administered only to the human subject within 24 hours of reperfusion.

[0041] In some embodiments, the 3 doses of the N-terminal peptide of AnxA1 are 3 daily doses and are administered to the human subject for only 1 day.

[0042] In some embodiments, no dose of the N-terminal peptide of AnxA1 is administered to a human subject after 24 hours of reperfusion.

[0043] In some modalities, all doses of the N peptide Petition 870250079340, dated 04 / 09 / 2025, page 74 / 97 / 31 terminal AnxAl doses are administered to a human individual within 24 hours of reperfusion.

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

[0045] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject as 3 doses 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.

[0046] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject as 3 doses at a dosing interval of approximately 2 to 4 hours, such as approximately 2 hours and 30 minutes to approximately 3 hours and 30 minutes, such as approximately 2 hours and 45 minutes to approximately 3 hours and 15 minutes.

[0047] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject as 3 doses at a dosing interval of approximately 3 hours.

[0048] In some embodiments, a first dose of the N-terminal peptide of AnxA1 is administered to the human subject within approximately 0 hours of the establishment of reperfusion, such as within approximately 5 minutes of Petition 870250079340, dated 04 / 09 / 2025, page. 75 / 97 / 31 establishment of the establishment of the establishment of the establishment of the establishment of the establishment of reperfusion, as reperfusion, as reperfusion, as reperfusion, as reperfusion, as reperfusion, as within approximately within approximately within approximately within approximately within approximately within approximately within approximately 10 minutes of the establishment of reperfusion, as within approximately 1 hour of the establishment of reperfusion, as within approximately 1 hour and 15 minutes of the establishment of reperfusion, as within approximately 1 hour and 30 minutes of the establishment of reperfusion, as within approximately 1 hour and 45 minutes of the establishment of reperfusion, as within approximately 2 hours of the establishment of reperfusion, as within approximately 2 hours and 30 minutes of the establishment of reperfusion,such as within approximately 3 hours of establishing reperfusion, such as within approximately 3 hours and 30 minutes of establishing reperfusion, such as within approximately 4 hours of establishing reperfusion, such as within approximately 4 hours and 30 minutes of establishing reperfusion, such as within approximately 5 hours of establishing reperfusion, such as within approximately 6 hours of establishing reperfusion.

[0049] In some embodiments, a first dose of the N-terminal peptide of AnxA1 is administered to the human subject within 0 to 6 hours of the establishment of reperfusion, such as within 0 to 5 hours of the establishment of reperfusion, such as within 0 to 4 hours of the establishment of reperfusion, such as within 0 to 3 hours of the establishment of reperfusion, such as within 0 to 2 hours of the establishment of reperfusion, such as within 0 to 1 hour and 30 minutes of the establishment of reperfusion, such as within 0 to 1 hour of the establishment of reperfusion, such as within 0 to 30 minutes of the establishment of reperfusion. Petition 870250079340, dated 04 / 09 / 2025, pp. 76 / 97 / 31

[0050] In some embodiments, a second dose of the N-terminal peptide of AnxA1 is administered to the human subject within approximately 2 hours of the establishment of reperfusion, such as within approximately 2 hours and 30 minutes of the establishment of reperfusion, such as within approximately 3 hours of the establishment of reperfusion, such as within approximately 3 hours and 30 minutes of the establishment of reperfusion, such as within approximately 4 hours of the establishment of reperfusion, such as within approximately 4 hours and 30 minutes of the establishment of reperfusion, such as within approximately 5 hours of the establishment of reperfusion, such as within approximately 6 hours of the establishment of reperfusion, such as within approximately 5 hours of the establishment of reperfusion, such as within approximately 5 hours and 30 minutes of the establishment of reperfusion, such as within approximately 6 hours of the establishment of reperfusion, such as within approximately 6 hours and 30 minutes of the establishment of reperfusion,such as within approximately 7 hours of establishing reperfusion, such as within approximately 7 hours and 30 minutes of establishing reperfusion, such as within approximately 8 hours of establishing reperfusion, such as within approximately 8 hours and 30 minutes of establishing reperfusion.

[0051] In some embodiments, a second dose of the N-terminal peptide of AnxA1 is administered to the human subject within 1 hour to 9 hours of the establishment of reperfusion, such as within 1 hour and 30 minutes to 8 hours of the establishment of reperfusion, such as within 2 hours to 7 hours of the establishment of reperfusion, such as within 2 hours to 6 hours of the establishment of reperfusion, such as within 2 hours to 5 hours of the establishment of reperfusion, such as within 2 hours to 4 hours of the establishment of reperfusion, such as within 2 hours and 30 minutes to 3 hours and 30 minutes of the establishment of reperfusion.

[0052] In some embodiments, a third dose of the N-terminal peptide of AnxA1 is administered to the human subject within approximately 4 Petition 870250079340, dated 04 / 09 / 2025, page. 77 / 97 / 31 hours from the establishment of reperfusion, such as within approximately 4 hours and 30 minutes from the establishment of reperfusion, such as within approximately 5 hours from the establishment of reperfusion, such as within approximately 6 hours from the establishment of reperfusion, such as within approximately 5 hours from the establishment of reperfusion, such as within approximately 5 hours and 30 minutes from the establishment of reperfusion, such as within approximately 6 hours from the establishment of reperfusion, such as within approximately 6 hours and 30 minutes from the establishment of reperfusion, such as within approximately 7 hours from the establishment of reperfusion, such as within approximately 7 hours and 30 minutes from the establishment of reperfusion, such as within approximately 8 hours from the establishment of reperfusion, such as within approximately 8 hours and 30 minutes from the establishment of reperfusion, such as within approximately 9 hours from the establishment of reperfusion,such as within approximately 9 hours and 30 minutes of establishing reperfusion, such as within approximately 10 hours of establishing reperfusion, such as within approximately 10 hours and 30 minutes of establishing reperfusion, such as within approximately 11 hours of establishing reperfusion, such as within approximately 11 hours and 30 minutes of establishing reperfusion, such as within approximately 12 hours of establishing reperfusion.

[0053] In some embodiments, a third dose of the N-terminal peptide of AnxA1 is administered to the human subject within 4 to 12 hours of the establishment of reperfusion, such as within 4 hours and 30 minutes to 11 hours of the establishment of reperfusion, such as within 5 to 10 hours of the establishment of reperfusion, such as within 4 to 9 hours of the establishment of reperfusion, such as within 4 to 8 hours of the establishment of reperfusion, such as within 4 to 9 hours of the establishment of reperfusion, such as within 5 hours and 30 minutes to 6 hours and 30 minutes of the establishment of reperfusion.

[0054] In some embodiments, the N-terminal peptide of AnxA1 is Petition 870250079340, dated 04 / 09 / 2025, page 78 / 97 / 31 administered to a human individual in 3 daily doses: within 0 to 15 minutes of establishing reperfusion, within 3 to 3 hours and 15 minutes of establishing reperfusion, and within 6 to 3 hours and 15 minutes of establishing reperfusion, or within 15 to 30 minutes of establishing reperfusion, within 3 hours and 15 minutes to 3 hours and 30 minutes of establishing reperfusion, and within 6 hours and 15 minutes to 6 hours and 30 minutes of establishing reperfusion, or within 30 to 45 minutes of establishing reperfusion, within 3 hours and 30 minutes to 3 hours and 45 minutes of establishing reperfusion, and within 6 hours and 30 minutes to 6 hours and 45 minutes of establishing reperfusion, or within 1 hour and 30 minutes to 1 hour and 45 minutes of establishing reperfusion, within 4 hours and 30 minutes to 4 hours and 45 minutes from the establishment of reperfusion and within 7 hours and 30 minutes to 7 hours and 45 minutes from the establishment of reperfusion,or within 1 hour and 45 minutes to 2 hours of the establishment of reperfusion, within 4 hours and 45 minutes to 5 hours of the establishment of reperfusion and within 7 hours and 45 minutes to 8 hours of the establishment of reperfusion, or within 2 hours to 3 hours of the establishment of reperfusion, within 5 hours to 6 hours of the establishment of reperfusion and within 8 hours to 9 hours of the establishment of reperfusion, or within 3 hours to 4 hours of the establishment of reperfusion, within 6 hours to 7 hours of the establishment of reperfusion and within 9 hours to 10 hours of the establishment of reperfusion, or within 4 hours to 5 hours of the establishment of reperfusion, within 7 hours to 8 hours of the establishment of reperfusion and within 10, Petition 870250079340, dated 04 / 09 / 2025, page 79 / 97 / 31 hours to 11 hours from the establishment of reperfusion, or within 5 hours to 6 hours from the establishment of reperfusion, within 8 hours to 9 hours from the establishment of reperfusion and within 11 hours to 12 hours from the establishment of reperfusion, or within 6 hours to 7 hours from the establishment of reperfusion, within 9 hours to 10 hours from the establishment of reperfusion and within 12 hours to 13 hours from the establishment of reperfusion.

[0055] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject in 3 daily doses: within approximately 0 hours of establishing reperfusion, within approximately 3 hours of establishing reperfusion, and within approximately 6 hours of establishing reperfusion, or within approximately 15 minutes of establishing reperfusion, within approximately 3 hours and 15 minutes of establishing reperfusion, and within approximately 6 hours and 15 minutes of establishing reperfusion, or within approximately 30 minutes of establishing reperfusion, within approximately 3 hours and 30 minutes of establishing reperfusion, and within approximately 6 hours and 30 minutes of establishing reperfusion, or within approximately 1 hour and 30 minutes of establishing reperfusion, within approximately 4 hours and 30 minutes of establishing reperfusion, and within approximately 7 hours and 30 minutes of establishing reperfusion, or within approximately 1 hour and 45 minutes of establishing reperfusion,within approximately 4 hours and 45 minutes of establishing reperfusion, and within approximately 7 hours and 45 minutes of establishing reperfusion, or within approximately 2 hours of establishing reperfusion, Petition 870250079340, dated 04 / 09 / 2025, page 80 / 97 / 31 within approximately 5 hours of establishing reperfusion and within approximately 8 hours of establishing reperfusion, or within approximately 3 hours of establishing reperfusion, within approximately 6 hours of establishing reperfusion and within approximately 9 hours of establishing reperfusion, or within approximately 4 hours of establishing reperfusion, within approximately 7 hours of establishing reperfusion and within approximately 10 hours of establishing reperfusion, or within approximately 5 hours of establishing reperfusion, within approximately 8 hours of establishing reperfusion and within approximately 11 hours of establishing reperfusion, or within approximately 6 hours of establishing reperfusion, within approximately 9 hours of establishing reperfusion and within approximately 12 hours of establishing reperfusion.

[0056] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject in 3 daily doses: approximately 15 minutes after reperfusion is established, approximately 3 hours and 15 minutes after reperfusion is established, and approximately 6 hours and 15 minutes after reperfusion is established, or approximately 30 minutes after reperfusion is established, approximately 3 hours and 30 minutes after reperfusion is established, and approximately 6 hours and 30 minutes after reperfusion is established, or approximately 1 hour and 30 minutes after reperfusion is established, approximately 4 hours and 30 minutes after reperfusion is established, and approximately 7 hours and 30 minutes after reperfusion is established, or approximately 1 hour and 45 minutes after reperfusion is established, approximately 4 hours and 45 minutes after reperfusion is established, and approximately 7 hours and 45 minutes after reperfusion is established Petition 870250079340, dated 04 / 09 / 2025, page 81 / 97 / 31 reperfusion, or approximately 2 hours after the establishment of reperfusion, approximately 5 hours after the establishment of reperfusion and approximately 8 hours after the establishment of reperfusion, or approximately 3 hours after the establishment of reperfusion, approximately 6 hours after the establishment of reperfusion and 9 hours after the establishment of reperfusion, or approximately 4 hours after the establishment of reperfusion, approximately 7 hours after the establishment of reperfusion and approximately 10 hours after the establishment of reperfusion, or approximately 5 hours after the establishment of reperfusion, approximately 8 hours after the establishment of reperfusion and 11 hours after the establishment of reperfusion, or approximately 6 hours after the establishment of reperfusion, approximately 9 hours after the establishment of reperfusion and approximately 12 hours after the establishment of reperfusion.

[0057] In some embodiments, a first dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 0 to 2 hours of the establishment of reperfusion, a second dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 2 to 5 hours of the establishment of reperfusion, and a third dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 4 to 8 hours of the establishment of reperfusion.

[0058] In some embodiments, a first dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 0 to 1 hour of the establishment of reperfusion, a second dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 2 to 4 hours of the establishment of reperfusion, and a third dose of the N-terminal AnxA1 peptide is administered to the human subject. Petition 870250079340, dated 04 / 09 / 2025, pp. 82 / 97 / 31 within approximately 5 hours and 7 hours of establishing reperfusion.

[0059] In some embodiments, a first dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 0 hours of the establishment of reperfusion, a second dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 3 hours of the establishment of reperfusion, and a third dose of the N-terminal AnxA1 peptide is administered to the human subject within approximately 6 hours of the establishment of reperfusion.

[0060] In some embodiments, the N-terminal peptide of AnxA1 is administered to the human subject in more than 3 doses within 24 hours of reperfusion, such as 4, 5 or 6 doses within 24 hours of reperfusion.

[0061] In some embodiments, the N-terminal peptide of AnxA1 or the pharmaceutical composition is administered as intravenous (iv) infusions.

[0062] In some embodiments, the N-terminal peptide of AnxA1 or the pharmaceutical composition is administered as IV infusions of 1 to 60 minutes, as IV infusions of 10 to 50 minutes, as IV infusions of 20 to 40 minutes, as IV infusions of 30 minutes.

[0063] In some embodiments, the N-terminal AnxA1 peptide or pharmaceutical composition is administered as 30-minute IV infusions.

[0064] In some embodiments, the N-terminal AnxA1 peptide is selected from the group consisting of: AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPY PTFNPSSDVAA (SEQ ID NO: 2; Annexin A1 2 to 50), AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPY PTFNPSSDV (SEQ ID NO: 3; Annexin A1 2 to 48), AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPY PTFNPSS (SEQ ID NO: 4; Annexin A1 2 to 46), AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSSDVAA (SEQ ID NO: 5; Annexin A1 2 to 50 V24L), Petition 870250079340, dated 04 / 09 / 2025, p. 83 / 97 / 31 AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSSDV (SEQ ID NO: 6; Annexin A1 2 to 48 V24L), AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSS (SEQ ID NO: 7; Annexin A1 2 to 46 V24L) and a functional variant of any of the SEQ ID NOs: 2 to 7 comprising 1 to 6 individual amino acid substitutions.

[0065] In some embodiments, the functional variant comprises 1 to 3 individual amino acid substitutions, such as 1 individual amino acid substitution, 2 individual amino acid substitutions, or 3 individual amino acid substitutions.

[0066] In some embodiments, one or more individual amino acid substitutions are conservative amino acid substitutions.

[0067] In some embodiments, the functional variant is a ligand and / or agonist of one or more Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2), and Formyl Peptide Receptor 3 (FPR3).

[0068] In some embodiments, the functional variant activates and / or stimulates one or more of the Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2), and Formyl Peptide Receptor 3 (FPR3).

[0069] In some embodiments, the N-terminal AnxA1 peptide has a C-terminal amidation.

[0070] In some embodiments, the N-terminal peptide of AnxA1 is AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6; Annexin A1 2 to 48 V24L), optionally with a C-terminal amidation.

[0071] In some embodiments, the N-terminal AnxA1 peptide is administered in doses of approximately 15 mg / kg, approximately 25 mg / kg, approximately 50 mg / kg, approximately 100 mg / kg, approximately 150 mg / kg, approximately 200 mg / kg, or approximately 400 mg / kg of the N-terminal AnxA1 peptide. Petition 870250079340, dated 04 / 09 / 2025, p. 84 / 97 / 31

[0072] In some modalities, the ischemic condition and / or a reperfusion injury is an ischemic condition of the myocardium and / or a reperfusion injury of the heart.

[0073] In some modalities, the ischemic condition and / or a reperfusion injury is selected from the group consisting of coronary artery disease, such as angina and myocardial infarction; stroke, heart failure; peripheral arterial disease; thromboembolic disease; and venous thrombosis.

[0074] In some modalities, the ischemic condition and / or a reperfusion injury is coronary artery disease.

[0075] In some modalities, the ischemic condition and / or a reperfusion injury is myocardial infarction.

[0076] In some modalities, the ischemic condition and / or a reperfusion injury is acute myocardial infarction.

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

[0078] In some modalities, 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.

[0079] In some modalities, the ischemic condition and / or a reperfusion injury is myocardial infarction due to myocardial ischemia or myocardial infarction due to myocardial ischemia / reperfusion.

[0080] In some modalities, myocardial infarction is selected from the group consisting of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

[0081] In some modalities, myocardial infarction is myocardial infarction Petition 870250079340, dated 04 / 09 / 2025, p. 85 / 97 / 31 myocardium with ST segment elevation (STEMI).

[0082] In some modalities, the ischemic condition and / or a reperfusion injury results in an inflammatory immune response and / or tissue destruction.

[0083] In some modalities, administration of the N-terminal peptide of AnxA1 reduces or prevents an inflammatory immune response in ischemic tissue.

[0084] In some modalities, administration of the N-terminal peptide of AnxA1 reduces necrosis caused by ischemic conditions and / or reperfusion injury.

[0085] In some modalities, necrosis is reduced compared to necrosis caused by an ischemic condition and / or a reperfusion injury in a human individual who is not receiving any administration of N-terminal AnxA1 peptide.

[0086] In some modalities, administration of the N-terminal peptide of AnxA1 reduces the size of an infarct caused by an ischemic condition and / or a reperfusion injury.

[0087] In some modalities, the size of the infarct is reduced compared to the size of an infarct caused by an ischemic condition and / or a reperfusion injury in a human individual who is not receiving any administration of N-terminal AnxA1 peptide.

[0088] In some modalities, administration of the N-terminal peptide of AnxA1 reduces the size of a myocardial infarction caused by ischemic conditions and / or reperfusion injury.

[0089] In some modalities, the size of the myocardial infarction is reduced compared to the size of the myocardial infarction of a myocardial infarction caused by an ischemic condition and / or a reperfusion injury in a human individual who is not receiving any administration of N-terminal AnxA1 peptide. Petition 870250079340, dated 04 / 09 / 2025, pp. 86 / 97 / 31

[0090] In some embodiments, the pharmaceutical composition is a liquid pharmaceutical composition comprising the N-terminal peptide of AnxA1 and at least one pharmaceutically acceptable excipient.

[0091] In some embodiments, the liquid pharmaceutical composition comprises 0.5 to 10 mg / mL of the N-terminal peptide of AnxA1, as 1 to 10 mg / mL, as 2 to 9 mg / mL, as 3 to 8 mg / mL, as 4 to 6 mg / mL.

[0092] In some embodiments, the liquid pharmaceutical composition comprises: 10 mg / mL of the N-terminal peptide of AnxA1, 5% (w / w) of a sugar alcohol, and 0.5 to 1.5% (w / w) of a carbohydrate.

[0093] In some embodiments, the liquid pharmaceutical composition comprises: 10 mg / mL of the N-terminal peptide of AnxA1, 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 0.5 to 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: at 10 mg / mL of the N-terminal peptide of AnxA1, at 5% (w / w) of a sugar alcohol, 0.5 to 1.5% (w / w) of a carbohydrate, 0.005 to 0.015% (w / w) of a surfactant, and 15 mM of buffer.

[0095] In some embodiments, the liquid pharmaceutical composition Petition 870250079340, dated 04 / 09 / 2025, page 87 / 97 / 31 has a pH of 8.2 to 8.4, the liquid pharmaceutical composition comprising 10 mg / mL of the N-terminal peptide of AnxA1, 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, 0.5 to 1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose, 0.005 to 0.015% (w / w) of a surfactant selected from the group consisting of Polysorbate-80 and Polysorbate-20, and 15 mM of buffer selected from the group consisting of acetate buffer, TRIS, amine-containing buffers, amino acid-based buffers such as lysine, hydroxylysine, 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 IV infusions, such as 4, 5 or 6 daily IV infusions.

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

[0098] In some modalities, multiple daily IV infusions correspond to the administration of a dose of approximately 15 to 400 pg / kg, approximately 25 to 400 pg / kg, approximately 50 to 400 pg / kg, approximately 100 to 400 pg / kg, approximately 150 to 400 pg / kg, or approximately 200 to 400 pg / kg of the N-terminal AnxA1 peptide.

[0099] In some modalities, multiple daily IV infusions correspond to the administration of a dose of approximately 15 to 400 pg / kg, approximately Petition 870250079340, dated 04 / 09 / 2025, p. 88 / 97 / 31 of 25 to 400 gg / kg, approximately 25 to 200 gg / kg, approximately 25 to 150 gg / kg, approximately 25 to 100 gg / kg or approximately 25 to 50 gg / kg of the N-terminal AnxAl peptide.

[00100] In some modalities, multiple daily IV infusions correspond to the administration of a dose of approximately 25 to 200 mg / kg of the N-terminal peptide of AnxA1.

[00101] In some embodiments, the liquid pharmaceutical composition is administered as 3 daily IV infusions.

[00102] In some embodiments, the liquid pharmaceutical composition is administered 3 times a day, each as an IV infusion of 20 to 40 minutes, or each as an IV infusion of 30 minutes.

[00103] In some embodiments, each IV infusion corresponds to the administration of a dose of approximately 25 to 200 mg / kg, approximately 25 to 150 mg / kg, approximately 25 to 100 mg / kg, or approximately 25 to 50 mg / kg of the N-terminal AnxA1 peptide.

[00104] In some embodiments, the liquid pharmaceutical composition is administered by IV infusion at a flow rate of approximately 0.5 to 10 mL / min, such as 0.5 to 10 mL / min, such as 0.5 to 5 mL / min, such as 0.5 to 4 mL / min, such as 0.5 to 3 mL / min, such as 1 to 2 mL / min, such as approximately 1.5 mL / min.

[00105] In some embodiments, the liquid pharmaceutical composition is administered by IV infusion at a rate of 1.5 mL / min. Examples

[00106] In the following Examples, the reference to 'Peptide 1' is identified in this document as AMVSEFLKQAWFIENEEQEYVQTLK SSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6 (Annexin A1 2 a 48 V24L)), with a C-terminal amidation.

[00107] Example 1: Effect of treatment with Peptide 1 for 1 day versus 3 days on cardiac function in a rat model of acute myocardial infarction Petition 870250079340, dated 04 / 09 / 2025, p. 89 / 97 / 31 Method:

[00108] Myocardial infarction was induced in male Sprague Dawley rats. On day 0, rats were anesthetized with a mixture of 2 to 2.2% isoflurane USP (Abbot Laboratories, Montreal, Canada) in oxygen and placed on a heating pad (set to 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 via a positive pressure rodent respirator (model CWE SAR-830 / P) set to ~10 mL / kg body weight at a rate of 70 to 80 beats / 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 coronary artery (LAD), approximately 2 to 3 mm below the left atrium.The suture was briefly clamped to check the size and location of myocardial ischemia based on color change and then tied to produce a large anterolateral myocardial infarction (affecting approximately 45% of the LV). The suture was kept in place for 30 minutes (30 minutes of ischemia), followed by reperfusion. A sham-procedure group of rats was also included. Peptide 1 (or vehicle) was administered into the tail vein three times, with the first dose administered at the establishment of reperfusion (reperfusion onset), the second dose 3 hours after the establishment of reperfusion, and the third dose 6 hours after the establishment of reperfusion. Group 1 received 3 x 10 ug / kg for 3 days, Group 2 received 3 x 30 ug / kg for 3 days, Group 4 received 3 x 100 ug / kg for 3 days, and Group 5 received 3 x 30 ug / kg for only 1 day.Fourteen days after the ischemia, cardiac function was assessed by transthoracic echocardiography (Q9 model echocardiograph, Chison Medical Imaging Co. connected to a 12.0 MHz Chison probe). Results: Petition 870250079340, dated 04 / 09 / 2025, pp. 90 / 97 / 31

[00109] As demonstrated in Figure 1, vehicle treatment was associated with the development of impaired cardiac function, with a 25% reduction in cardiac output compared to sham animals. Administration of Peptide 1 for 1 or 3 days significantly improved cardiac output 14 days after ischemia by 20 to 30% compared to vehicle treatment. Rats that received 3 x 30 µg / kg of Peptide 1 for only 1 day showed the greatest improvement in cardiac function, and cardiac output levels were comparable to those of sham animals (79.5 mL vs 81.1 mL, respectively). Thus, three doses of Peptide 1 administered at the establishment of reperfusion (reperfusion initiation), 3 hours after the establishment of reperfusion, and 6 hours after the establishment of reperfusion during the first 24 hours significantly improve long-term cardiac function.

[00110] Example 2: Effect of immediate and delayed dosage of Annexin A1 peptide in a rat model of acute myocardial infarction Method:

[00111] Myocardial infarction was induced by 30 minutes of ischemia through obstruction of coronary perfusion by occlusion of the left coronary artery, followed by 24 hours of reperfusion. Sprague Dawley rats were treated by administration of Peptide 1 (30 ug / kg) three times, with treatment starting at the time of reperfusion establishment (reperfusion onset) (T0h, T3h, T6h) (Group 1), or with a late treatment start, beginning 1 hour after reperfusion establishment (T1h, T4h, T7h) (Group 2), or 2 hours after reperfusion establishment (T2h, T5h, T8h) (Group 3).

[00112] At the end of the 24-hour reperfusion period, the left coronary artery was reoccluded and Evans blue dye solution was injected. The hearts were removed from the rats and stored at -20°C before being cut into 1 mm thick cross-sections. The sections Petition 870250079340, dated 04 / 09 / 2025, pp. 91 / 97 / 31 cardiac specimens were incubated with triphenyltetrazolium chloride (TTC, 1%) at 37°C for 30 minutes to demarcate viable and non-viable myocardium within the risk zone. The risk area and the infarcted area were determined using imaging software. Results:

[00113] Peptide 1 significantly reduced infarct size when administered 3 times, with the first dose given at the establishment of reperfusion (reperfusion initiation) (Group 1). Delaying the start of Peptide 1 treatment by one and two hours reduced infarct size to a similar degree as when Peptide 1 was administered immediately at the establishment of reperfusion (Figure 2B). Thus, Peptide 1 has cardioprotective effects both when administered at the establishment of reperfusion and at least two hours after the establishment of reperfusion.

[00114] Example 3: Effect of treatment with Peptide 1 for 1 day on the prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction Method:

[00115] Myocardial infarction was induced in male Sprague Dawley rats. On day 0, rats were anesthetized with a 2–2.2% isoflurane USP mixture (Abbot Laboratories, Montreal, Canada) in oxygen and placed on a heating pad (set to 37°C) to maintain body temperature. The animals were intubated and immediately ventilated with a 2–2.2% isoflurane USP mixture (Abbot Laboratories, Montreal, Canada) in oxygen via a rodent positive pressure respirator (model CWE SAR-830 / P) set to ~10 mL / kg body weight at a rate of 70–80 beats / min. The pericardium was opened to expose the heart, and a 5–0 wax-coated braided silk suture (Sofsilk™) was placed around the descending coronary artery. Petition 870250079340, dated 04 / 09 / 2025, p. 92 / 97 / 31 left anterior (LAD), approximately 2 to 3 mm below the left atrium. The suture was briefly clamped to check the size and location of myocardial ischemia based on color change and then tied to produce a large anterolateral myocardial infarction (affecting approximately 45% of the LV). The suture was maintained in place for 30 minutes (30 minutes of ischemia), followed by reperfusion. A group of rats undergoing a sham procedure was also included. PEPTIDE 1 (30 ug / kg) or vehicle was administered into the tail vein three times, with the first dose administered at the beginning of reperfusion, the second dose 3h after reperfusion, and the third dose 6h after reperfusion. On day 1 or 3, the animals were anesthetized again and the thoracic cavity was reopened to expose the heart. The heart was collected and perfused through the aorta, without crossing the aortic valve, with 10 mL of cold PBS to wash the coronary arteries.The left ventricle and septum were placed in the well of a 6-well plate containing 1 mL of cold PBS and cut into pieces of approximately 1 to 2 mm3. Cardiomyocytes were dispersed using the neonatal cardiac dissociation kit (Miltenyi Biotec, #130-098-373).

[00116] After cell dissociation, erythrocytes were lysed with 2 mL of FACS lysis solution (BD Biosciences, #555899).

[00117] Superbright Complete Staining Buffer (ThermoFisher Scientific, #SB-4401-42, 150 pL) was added to 1.5 x 10⁶ cardiac cells to avoid non-specific polymer interactions. The cells were stained with an antibody mixture, and all samples were protected from light and kept at room temperature for 20 min (see Table 1). In each batch, an unstained sample was added.

[00118] Finally, the cells were fixed with 2% PFA for 10 min at room temperature and protected from light. Table 1: Antibody mixture for cardiac samples Marker Supplier Ref Fluorochrome Antibody Clone Volume for 1.5x106 cells CD45 BD Biosciences 746429 BV480 OX-1 1.6 jil. Petition 870250079340, dated 04 / 09 / 2025, pages 93 / 97 / 31 CD11b / c BD Biosciences 743981 BV711 OX-42 0.4 ill. RP-1 BD Biosciences 550002 PE RP-1 4 ill. MHC-II Thermo Fisher Scientific 17-0920-82 APC HIS19 0.8 ill. CD31 BD Biosciences 744357 BV421 TLD-3A12 0.2 ill. Zombie NIR™ Biolegend Attachable Viability Kit 423105 1 ill. CD3 BD Biosciences 563949 BV605 1F4 2 ill. CD45R Thermo Fisher Scientific 25-0460-82 PE-Cy7 B220 0.5 ill.

[00119] One or two days after cell staining, all samples were read with a flow cytometer (Sony ID7000) with Accucount Fluorescent Particles (Spherotech, ACFO-50-5, lot AP02) for an absolute cell count. Results:

[00120] Figure 3A illustrates the endothelial cell count 72 hours after myocardial infarction (MI) in rats undergoing sham surgery, rats treated with the vehicle, and rats administered 3 doses of 30 pg / kg of Peptide 1. Notably, in rats that received Peptide 1, there was a remarkable 2.4-fold increase in the number of endothelial cells compared to the vehicle. This elevation in endothelial cell count during the initial phase of myocardial infarction suggests a potential for neovascularization in the injured tissue. Neovascularization plays a crucial role in supplying essential nutrients and oxygen to the healing infarct, thus contributing to a more robust cardiac recovery.

[00121] In addition, the presence of anti-inflammatory monocytes / macrophages in the heart was evaluated 24 hours after MI following treatment with Peptide 1. These cell types play a key role in resolving inflammation, promoting scar formation, and facilitating neovascularization. As illustrated in Figure 3B, there is an observable increase in anti-inflammatory monocytes / macrophages in animals treated with the vehicle. Interestingly, 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. This increase Petition 870250079340, dated 04 / 09 / 2025, pp. 94 / 97 / 31 unexpectedly suggests that Peptide 1 may contribute to a better resolution of inflammation in the myocardium. Sequence overview

[00122] The 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 MAMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVS PYPTFNPSSDVAALHKAIMVKGVDEATIIDILTKRNNAQRQQIKAAYL QETGKPLDETLKKALTGHLEEVVLALLKTPAQFDADELRAAMKGLG TDEDTLIEILASRTNKEIRDINRVYREELKRDLAKDITSDTSGDFRNAL LSLAKGDRSEDFGVNEDLADSDARALYEAGERRKGTDVNVFNTILTT RSYPQLRRVFQKYTKYSKHDMNKVLDLELKGDIEKCLTAIVKCATSK PAFFAEKLHQAMKGVGTRHKALIRIMVSRSEIDMNDIKAFYQKMYGI SLCQAILDETKGDYEKILVALCGGN (SEQ ID NO: 1).

[00123] AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPY PTFNPSSDVAA (SED ID NO: 2; Anexina A1 2 a 50)

[00124] AMVSEFLKQAWFIENEEQEYVQTVKS SKGGPGSAVSPY PTFNPSSDV (SED ID NO: 3; Anexina A1 2 a 48)

[00125] AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPY PTFNPSS (SED ID NO: 4; Anexina A1 2 a 46)

[00126] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSSDVAA (SED ID NO: 5; Anexina A1 2 a 50 V24L)

[00127] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSSDV (SED ID NO: 6; Annexin A1 2 to 48 V24L)

[00128] AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPY PTFNPSS (SED ID NO: 7; Annexin A1 2 to 46 V24L)

[00129] AMVSEFLKQAWFIENEEQEYVQTVK (SED ID NO: 8; Annex A1 2 to 26), Petition 870250079340, dated 04 / 09 / 2025, pages 95 / 97 / 31 AMVSEFLKQAWFIENEEQEYVQTLK (SED ID NO: 9; Annexin A1 2 to 26 V24L)

[00130] All peptides can be C-terminally amidated (NH2). Petition 870250079340, dated 04 / 09 / 2025, pp. 96 / 97

Claims

1 / 21 CLAIMS 1. Annexin A1 N-terminal peptide (AnxAl), characterized in that it is for use in the treatment of an ischemic condition and / or a reperfusion injury, wherein 3 doses of said AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

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

3. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered no more than 3 times to a human subject within 24 hours of reperfusion.

4. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said 3 doses of said AnxA1 N-terminal peptide are administered once, as once within 24 hours of reperfusion.

5. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered only to the human subject within 24 hours of reperfusion.

6. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said 3 doses of said AnxA1 N-terminal peptide are 3 daily doses and are administered to the human individual for only 1 day.

7. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that no dose of said AnxA1 N-terminal peptide is administered to a human subject after 24 hours of reperfusion.

8. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that all doses of said AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

9. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject within 24 hours of the establishment of reperfusion, as within 24 hours after the establishment of reperfusion.

10. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 doses at a dosing interval of 1 to 6 hours; as at a dosing interval of about 1 to about 2 hours, as at a dosing interval of about 2 to about 3 hours, as at a dosing interval of about 3 to about 4 hours, as at a dosing interval of about 4 to about 5 hours, as at a dosing interval of about 5 to about 6 hours; as at a dosing interval of about 1 hour, as Petition 870250079340, dated 04 / 09 / 2025, p. 39 / 97 3 / 21 at a dosing interval of about 2 hours, as at a dosing interval of about 3 hours, as at a dosing interval of about 4 hours, as at a dosing interval of about 5 hours, as at a dosing interval of about 6 hours.

11. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 doses at a dosing interval of approximately 2 to 4 hours, such as approximately 2 hours and 30 minutes to approximately 3 hours and 30 minutes, such as approximately 2 hours and 45 minutes to approximately 3 hours and 15 minutes.

12. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 doses at a dosing interval of approximately 3 hours.

13. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a first dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 0 hours of the establishment of reperfusion, such as within approximately 5 minutes of the establishment of reperfusion, such as within approximately 10 minutes of the establishment of reperfusion, such as within approximately 15 minutes of the establishment of reperfusion, such as within approximately minutes of the establishment of reperfusion, such as within approximately minutes of the establishment of reperfusion, such as within approximately minutes of the establishment of reperfusion, such as within approximately minutes of the establishment of reperfusion, such as within approximately 1 hour of the establishment of reperfusion, such as within approximately 1 hour and 15 minutes. Petition 870250079340, dated 04 / 09 / 2025, p.40 / 97 4 / 21 of the establishment of reperfusion, such as within approximately 1 hour and 30 minutes of the establishment of reperfusion, such as within approximately 1 hour and 45 minutes of the establishment of reperfusion, such as within approximately 2 hours of the establishment of reperfusion, such as within approximately 2 hours and 30 minutes of the establishment of reperfusion, such as within approximately 3 hours of the establishment of reperfusion, such as within approximately 3 hours and 30 minutes of the establishment of reperfusion, such as within approximately 4 hours of the establishment of reperfusion, such as within approximately 4 hours and 30 minutes of the establishment of reperfusion, such as within approximately 5 hours of the establishment of reperfusion, such as within approximately 6 hours of the establishment of reperfusion.

14. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a first dose of said AnxA1 N-terminal peptide is administered to the human subject within 0 to 6 hours of the establishment of reperfusion, such as within 0 to 5 hours of the establishment of reperfusion, such as within 0 to 4 hours of the establishment of reperfusion, such as within 0 to 3 hours of the establishment of reperfusion, such as within 0 to 2 hours of the establishment of reperfusion, such as within 0 to 1 hour and 30 minutes of the establishment of reperfusion, such as within 0 to 1 hour of the establishment of reperfusion, such as within 0 to 30 minutes of the establishment of reperfusion.

15. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a second dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 2 hours of the establishment of reperfusion, as within approximately 2 hours and 30 minutes of the establishment of reperfusion, as within Petition 870250079340, dated 04 / 09 / 2025, p. 41 / 97 5 / 21 approximately 3 hours after the establishment of reperfusion, such as within approximately 3 hours and 30 minutes after the establishment of reperfusion, such as within approximately 4 hours after the establishment of reperfusion, such as within approximately 4 hours and 30 minutes after the establishment of reperfusion, such as within approximately 5 hours after the establishment of reperfusion, such as within approximately 6 hours after the establishment of reperfusion, such as within approximately 5 hours after the establishment of reperfusion,such as within approximately 5 hours and 30 minutes of establishing reperfusion, such as within approximately 6 hours of establishing reperfusion, such as within approximately 6 hours and 30 minutes of establishing reperfusion, such as within approximately 7 hours of establishing reperfusion, such as within approximately 7 hours and 30 minutes of establishing reperfusion, such as within approximately 8 hours of establishing reperfusion, such as within approximately 8 hours and 30 minutes of establishing reperfusion.

16. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a second dose of said AnxA1 N-terminal peptide is administered to the human subject within 1 hour to 9 hours of the establishment of reperfusion, such as within 1 hour and 30 minutes to 8 hours of the establishment of reperfusion, such as within 2 hours to 7 hours of the establishment of reperfusion, such as within 2 hours to 6 hours of the establishment of reperfusion, such as within 2 hours to 5 hours of the establishment of reperfusion, such as within 2 hours to 4 hours of the establishment of reperfusion, such as within 2 hours and 30 minutes to 3 hours and 30 minutes of the establishment of reperfusion.

17. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that a third dose of said AnxA1 N-terminal peptide is administered to the human subject. Petition 870250079340, dated 04 / 09 / 2025, p. 42 / 97 6 / 21 within approximately 4 hours of establishing reperfusion, as within approximately 4 hours and 30 minutes of establishing reperfusion, as within approximately 5 hours of establishing reperfusion, as within approximately 6 hours of establishing reperfusion, as within approximately 5 hours of establishing reperfusion, as within approximately 5 hours and 30 minutes of establishing reperfusion, as within approximately 6 hours of establishing reperfusion, as within approximately 6 hours and 30 minutes of establishing reperfusion, as within approximately 7 hours of establishing reperfusion,such as within approximately 7 hours and 30 minutes of establishing reperfusion, such as within approximately 8 hours of establishing reperfusion, such as within approximately 8 hours and 30 minutes of establishing reperfusion, such as within approximately 9 hours of establishing reperfusion, such as within approximately 9 hours and 30 minutes of establishing reperfusion, such as within approximately 10 hours of establishing reperfusion, such as within approximately 10 hours and 30 minutes of establishing reperfusion, such as within approximately 11 hours of establishing reperfusion, such as within approximately 11 hours and 30 minutes of establishing reperfusion, such as within approximately 12 hours of establishing reperfusion.

18. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a third dose of said AnxA1 N-terminal peptide is administered to the human subject within 4 to 12 hours of the establishment of reperfusion, such as within 4 hours and 30 minutes to 11 hours of the establishment of reperfusion, such as within 5 to 10 hours of the establishment of reperfusion, such as within 4 to 9 hours of the establishment of reperfusion, such as within 4 to 8 hours of the establishment of reperfusion, such as within 4 to 9 hours of the establishment of reperfusion, such as within 5 hours and 30 minutes to 6 hours and 30 minutes of the establishment of reperfusion. Petition 870250079340, dated 04 / 09 / 2025, page 43 / 97 7 / 21 19. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 daily doses: a. within 0 minutes to 15 minutes of the establishment of reperfusion, within 3 hours to 3 hours and 15 minutes of the establishment of reperfusion and within 6 hours to 6 hours to 3 hours and 15 minutes of the establishment of reperfusion, or b. within 15 minutes to 30 minutes of the establishment of reperfusion, within 3 hours and 15 minutes to 3 hours and 30 minutes of the establishment of reperfusion and within 6 hours and 15 minutes to 6 hours and 30 minutes of the establishment of reperfusion, or c. within 30 to 45 minutes of establishing reperfusion, within 3 hours and 30 minutes to 3 hours and 45 minutes of establishing reperfusion, and within 6 hours and 30 minutes to 6 hours and 45 minutes of establishing reperfusion, or d.within 1 hour and 30 minutes to 1 hour and 45 minutes of the establishment of reperfusion, within 4 hours and 30 minutes to 4 hours and 45 minutes of the establishment of reperfusion and within 7 hours and 30 minutes to 7 hours and 45 minutes of the establishment of reperfusion, or e. within 1 hour and 45 minutes to 2 hours of the establishment of reperfusion, within 4 hours and 45 minutes to 5 hours of the establishment of reperfusion and within 7 hours and 45 minutes to 8 hours of the establishment of reperfusion, or f. within 2 hours to 3 hours of the establishment of reperfusion, within 5 hours to 6 hours of the establishment of reperfusion and within 8 hours to 9 hours of the establishment of reperfusion, or Petition 870250079340, dated 04 / 09 / 2025, page 44 / 97 8 / 21 g. within 3 to 4 hours of reperfusion establishment, within 6 to 7 hours of reperfusion establishment, and within 9 to 10 hours of reperfusion establishment, or h.within 4 to 5 hours of establishing reperfusion, within 7 to 8 hours of establishing reperfusion, and within 10 to 11 hours of establishing reperfusion, or i. within 5 to 6 hours of establishing reperfusion, within 8 to 9 hours of establishing reperfusion, and within 11 to 12 hours of establishing reperfusion, or j. within 6 to 7 hours of establishing reperfusion, within 9 to 10 hours of establishing reperfusion, and within 12 to 13 hours of establishing reperfusion.

20. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 daily doses: a. within about 0 hours of the establishment of reperfusion, within about 3 hours of the establishment of reperfusion and within about 6 hours of the establishment of reperfusion, or b. within about 15 minutes of the establishment of reperfusion, within about 3 hours and 15 minutes of the establishment of reperfusion and within about 6 hours and 15 minutes of the establishment of reperfusion, or c. within about 30 minutes of the establishment of reperfusion, within about 3 hours and 30 minutes of the establishment of reperfusion and within about 6 hours and 30 minutes of the establishment of reperfusion, or d. within approximately 1 hour and 30 minutes of the establishment Petition 870250079340, dated 04 / 09 / 2025, page.45 / 97 9 / 21 of reperfusion, within approximately 4 hours and 30 minutes of establishing reperfusion and within approximately 7 hours and 30 minutes of establishing reperfusion, or e. within approximately 1 hour and 45 minutes of establishing reperfusion, within approximately 4 hours and 45 minutes of establishing reperfusion and within approximately 7 hours and 45 minutes of establishing reperfusion, or f. within approximately 2 hours of establishing reperfusion, within approximately 5 hours of establishing reperfusion and within approximately 8 hours of establishing reperfusion, or g. within approximately 3 hours of establishing reperfusion, within approximately 6 hours of establishing reperfusion and within approximately 9 hours of establishing reperfusion, or h. within approximately 4 hours of establishing reperfusion, within approximately 7 hours of establishing reperfusion, and within approximately 10 hours of establishing reperfusion, or i.within approximately 5 hours of establishing reperfusion, within approximately 8 hours of establishing reperfusion, and within approximately 11 hours of establishing reperfusion, or j. within approximately 6 hours of establishing reperfusion, within approximately 9 hours of establishing reperfusion, and within approximately 12 hours of establishing reperfusion.

21. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human subject as 3 daily doses: a. approximately 15 minutes after the establishment of reperfusion, approximately 3 hours and 15 minutes after the establishment of reperfusion and approximately 6 hours and 15 minutes after the establishment of reperfusion, or b. approximately 30 minutes after the establishment of reperfusion, approximately 3 hours and 30 minutes after the establishment of reperfusion and approximately 6 hours and 30 minutes after the establishment of reperfusion, or c. approximately 1 hour and 30 minutes after reperfusion is established, approximately 4 hours and 30 minutes after reperfusion is established, and approximately 7 hours and 30 minutes after reperfusion is established, or d.approximately 1 hour and 45 minutes after reperfusion is established, approximately 4 hours and 45 minutes after reperfusion is established, and approximately 7 hours and 45 minutes after reperfusion is established, or e. approximately 2 hours after reperfusion is established, approximately 5 hours after reperfusion is established, and approximately 8 hours after reperfusion is established, or f. approximately 3 hours after reperfusion is established, approximately 6 hours after reperfusion is established, and approximately 9 hours after reperfusion is established, or g. approximately 4 hours after reperfusion is established, approximately 7 hours after reperfusion is established, and approximately 10 hours after reperfusion is established, or h. approximately 5 hours after reperfusion is established, approximately 8 hours after reperfusion is established, and approximately 11 hours after reperfusion is established, or i.approximately 6 hours after reperfusion is established, approximately 9 hours after reperfusion is established, and approximately 12 hours after reperfusion is established.

22. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that a first dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 0 to 2 hours of the establishment of reperfusion, a second dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 2 to 5 hours of the establishment of reperfusion, and a third dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 4 to 8 hours of the establishment of reperfusion.

23. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a first dose of said AnxA1 N-terminal peptide is administered to the human subject within about 0 to 1 hour of the establishment of reperfusion, a second dose of said AnxA1 N-terminal peptide is administered to the human subject within about 2 to 4 hours of the establishment of reperfusion, and a third dose of said AnxA1 N-terminal peptide is administered to the human subject within about 5 to 7 hours of the establishment of reperfusion.

24. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that a first dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 0 hours of the establishment of reperfusion, a second dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 3 hours of the establishment of reperfusion, and a third dose of said AnxA1 N-terminal peptide is administered to the human subject within approximately 6 hours of the establishment of reperfusion.

25. Annexin A1 N-terminal peptide (AnxA1) or Petition 870250079340, dated 04 / 09 / 2025, page 48 / 97 12 / 21 pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered to the human individual in more than 3 doses within 24 hours of reperfusion, such as 4, 5 or 6 doses within 24 hours of reperfusion.

26. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide or pharmaceutical composition is administered as intravenous (iv) infusions.

27. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide or pharmaceutical composition is administered as IV infusions of 1 to 60 minutes, as IV infusions of 10 to 50 minutes, as IV infusions of 20 to 40 minutes, or as IV infusions of 30 minutes.

28. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said N-terminal AnxA1 peptide or pharmaceutical composition is administered as 30-minute IV infusions.

29. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said N-terminal AnxA1 peptide is selected from the group consisting of: a. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVS PYPTFNPSSDVAA (SEQ ID NO: 2; Annexin A1 2 to 50), b. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVS PYPTFNPSSDV (SEQ ID NO: 3; Annexin A1 2 to 48), Petition 870250079340, dated 04 / 09 / 2025, page 49 / 97 13 / 21 c. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVS PYPTFNPSS (SEQ ID NO: 4; Annexin A1 2 to 46), d. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVS PYPTFNPSSDVAA (SEQ ID NO: 5; Annexin A1 2 to 50 V24L), e.g. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSP YPTFNPSSDV (SEQ ID NO: 6; Annexin A1 2 to 48 V24L), f. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSP YPTFNPSS (SEQ ID NO: 7; Annexin A1 2 to 46 V24L) and g. a functional variant of any of the SEQ ID NOs: 2 to 7 comprising 1 to 6 individual amino acid substitutions.

30. N-terminal Annexin A1 (AnxA1) peptide or pharmaceutical composition for use according to claim 29, characterized in that said functional variant comprises 1 to 3 individual amino acid substitutions, such as 1 individual amino acid substitution, 2 individual amino acid substitutions or 3 individual amino acid substitutions.

31. N-terminal Annexin A1 (AnxA1) peptide or pharmaceutical composition for use according to claim 29 or 30, characterized in that said one or more individual amino acid substitutions are conservative amino acid substitutions.

32. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of claims 29 to 31, characterized in that said 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).

33. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of claims 29 to 32, characterized in that said variant Petition 870250079340, dated 04 / 09 / 2025, page 50 / 97 14 / 21 functionally activates and / or stimulates one or more of Formyl Peptide Receptor 1 (FPR1), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor 3 (FPR3).

34. N-terminal annexin A1 (AnxA1) peptide or pharmaceutical composition for use according to any of the preceding claims, characterized in that said N-terminal anxA1 peptide has a C-terminal amidation.

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

36. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said AnxA1 N-terminal peptide is administered in doses 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. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is an ischemic condition of the myocardium and / or reperfusion injury of the heart.

38. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is selected from the group consisting of coronary artery diseases such as angina and myocardial infarction; stroke, heart failure; peripheral arterial disease; thromboembolic disease; and venous thrombosis.

39. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or a reperfusion injury is coronary artery disease.

40. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is myocardial infarction.

41. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is acute myocardial infarction.

42. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is myocardial infarction followed by reperfusion.

43. N-terminal annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said ischemic condition and / or 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. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury is myocardial infarction due to myocardial ischemia or myocardial infarction due to myocardial ischemia / reperfusion.

45. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to claim 40, characterized in that 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. ​​N-terminal annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to claim 40, characterized in that said myocardial infarction is ST-segment elevation myocardial infarction (STEMI).

47. N-terminal Annexin A1 peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that said ischemic condition and / or reperfusion injury results in an inflammatory immune response and / or tissue destruction.

48. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to any of the preceding claims, characterized in that administration of said AnxA1 N-terminal peptide reduces or prevents an inflammatory immune response in ischemic tissue.

49. N-terminal annexin A1 peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that administration of said N-terminal anxA1 peptide reduces necrosis caused by said ischemic condition and / or reperfusion injury. Petition 870250079340, dated 04 / 09 / 2025, p. 53 / 97 17 / 21 50. Annexin A1 N-terminal peptide (AnxAl) or pharmaceutical composition for use according to claim 49, characterized in that necrosis is reduced compared to necrosis caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any administration of AnxA1 N-terminal peptide.

51. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that administration of said AnxA1 N-terminal peptide reduces the size of an infarct caused by said ischemic condition and / or a reperfusion injury.

52. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to claim 51, characterized in that the infarct size is reduced compared to the infarct size of an infarct caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any administration of AnxA1 N-terminal peptide.

53. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use in accordance with any of the preceding claims, characterized in that administration of said AnxA1 N-terminal peptide reduces the size of a myocardial infarction caused by said ischemic condition and / or a reperfusion injury.

54. Annexin A1 N-terminal peptide (AnxA1) or pharmaceutical composition for use according to claim 53, characterized in that the size of the myocardial infarction is reduced compared to the size of the myocardial infarction of a myocardial infarction caused by an ischemic condition and / or a reperfusion injury in a human subject not receiving any administration of Annexin A1 N-terminal peptide.

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

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

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

58. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition comprises: i) 1 to 10 mg / mL of said N-terminal AnxA1 peptide, ii) 3 to 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 to 1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose and arabinose.

59. Liquid pharmaceutical composition for use in accordance with Petition 870250079340, dated 04 / 09 / 2025, page 55 / 97 19 / 21 any of the preceding claims, characterized in that said liquid pharmaceutical composition comprises: i) 1 to 10 mg / mL of said N-terminal AnxA1 peptide, ii) 3 to 5% (w / w) of a sugar alcohol, iii) 0.5 to 1.5% (w / w) of a carbohydrate, iv) 0.005 to 0.015% (w / w) of a surfactant, and ev) 5 to 15 mM of buffer.

60. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition has a pH of 8.2 to 8.4, said liquid pharmaceutical composition comprising i) 1 to 10 mg / mL of said N-terminal AnxA1 peptide, ii) 3 to 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 to 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 to 0.015% (w / w) of a surfactant selected from the group that consists of Polysorbate-80 and Polysorbate-20, ev) 5 to 15 mM of 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. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition is administered as more than three daily IV infusions, such as 4, 5 or 6 daily IV infusions. Petition 870250079340, dated 04 / 09 / 2025, p. 56 / 97 20 / 21 62. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that multiple daily IV infusions correspond to the administration of a dose 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 N-terminal AnxA1 peptide.

63. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that multiple daily IV infusions correspond to the administration of a dose of about 15 to 400 pg / kg, about 25 to 400 pg / kg, about 50 to 400 pg / kg, about 100 to 400 pg / kg, about 150 to 400 pg / kg or about 200 to 400 pg / kg of said N-terminal AnxA1 peptide.

64. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that multiple daily IV infusions correspond to the administration of a dose of about 15 to 400 pg / kg, about 25 to 400 pg / kg, about 25 to 200 pg / kg, about 25 to 150 pg / kg, about 25 to 100 pg / kg or about 25 to 50 pg / kg of said N-terminal AnxA1 peptide.

65. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that multiple daily IV infusions correspond to the administration of a dose of approximately 25 to 200 pg / kg of said N-terminal AnxA1 peptide.

66. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition is administered as 3 daily IV infusions.

67. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition is administered 3 times a day, each as an IV infusion of 20 to 40 minutes, or each as an IV infusion of 30 minutes.

68. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that each IV infusion corresponds to the administration of a dose of about 25 to 200 pg / kg, about 25 to 150 pg / kg, about 25 to 100 pg / kg or about 25 to 50 pg / kg of said N-terminal AnxA1 peptide.

69. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition is administered by IV infusion at a flow rate of about 0.5 to 10 mL / min, such as 0.5 to 10 mL / min, such as 0.5 to 5 mL / min, such as 0.5 to 4 mL / min, such as 0.5 to 3 mL / min, such as 1 to 2 mL / min, such as about 1.5 mL / min.

70. Liquid pharmaceutical composition for use according to any of the preceding claims, characterized in that said liquid pharmaceutical composition is administered by IV infusion at a flow rate of 1.5 mL / min. Petition 870250079340, dated 04 / 09 / 2025, p. 58 / 97

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