Methods for treatment of sepsis

Abstract

A method of preventing or treating sepsis in a subject, the method comprising administering to the subject at least 50 µg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day. Also a method of preventing or treating sepsis in a subject, the method comprising administering to the subject annexin 5A at a dosage of at least 17 µg / hour / kg by continuous IV infusion.

Description

[0001] METHODS FOR TREATMENT OF SEPSIS

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates generally to the field of use of annexin A5 in the prevention and / or treatment of sepsis.

[0004] BACKGROUND

[0005] SARS-CoV-2 is a virus of the genus Betacoronavirus and causes coronavirus disease 2019 (COVID-19) (Wiersinga et al., 2020). Severe COVID-19 is complicated by multiorgan dysfunction, including acute respiratory distress syndrome (ARDS), hemodynamic instability, and coagulopathy (Matthay et al., 2020). Morbidity and mortality increase dramatically when COVID-19 is complicated by organ dysfunction (Zhou et al., 2020). To date, there have been approximately 7 million COVID-19-related deaths globally (https: / / covidl9.who.int). Widespread mass vaccination has markedly reduced hospitalization and severity of COVID-19 (Paul et al., 2023). However, severe COVID-19 remains a clinical challenge despite available non-specific treatment options such as dexamethasone, IL-6 receptor and JAK inhibitors (Alhazzani et al., 2020; Petrelli et al., 2021; Wagner et al., 2022).

[0006] Annexin A5 is a ubiquitously expressed protein (~36 kDa) and part of a 12-member annexin protein family (Gerke and Moss, 2002; Mui et al., 2021). Annexin A5 reversibly binds to negatively charged phospholipids, most notably phosphatidylserine, in a Camdependent manner. Annexin A5 has anticoagulant, anti-apoptotic and anti-inflammatory properties (Munoz et al., 2007; Ewing, Mark M et al., 2011; Mui et al., 2021) and is well known as a marker to identify apoptotic cells. Annexin A5 has been shown to bind to bacteria and lipopolysaccharide (LPS) and attenuate LPS-induced tumor necrosis factor alpha (TNF-a) production (Rand et al., 2012). We recently demonstrated that annexin A5 inhibits endothelial inflammation induced by activated platelets and microvesicles in septic conditions via phosphatidylserine binding (Tschirhart et al., 2023). The first study that revealed the anti-inflammatory effects of annexin A5 in sepsis was in mice with endotoxemia in which treatment with recombinant human annexin A5 inhibited the expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNFa) and interleukin-lfy and improved cardiac function and animal survival (Arnold et al., 2014). The findings were supported by a later study using a cecal content injection model of sepsis (Park et al., 2016). The protective effects of annexin A5 in the sepsis models are mediated in part by inhibiting LPS and high-mobility group box-1 (HMGB1) binding to the TLR4 / MD2 complex (Arnold et al., 2014; Park et al., 2016). Additionally, administration of recombinant annexin A5 has been shown to inhibit thrombin formation in abdominal sepsis induced by cecal ligation and puncture in mice (Wang et al., 2018). Since severe COVID- 19 is a manifestation of sepsis and involves these pro-inflammatory and coagulation pathways, annexin A5 is a viable treatment candidate (Singer et al., 2016; Mui et al., 2021).

[0007] Recombinant human annexin A5 (SY-005) has been administered to healthy subjects at intravenous doses of 0.75 to 20 mg per person for up to 7 days and was found to be safe (NCT04217629) (Suzhou Yabao Pharmaceutical R&D Co., Ltd., 2023). We performed a randomized, placebo-controlled pilot trial (NCT04748757) and showed that administration of SY-005 in patients with severe COVID-19 was feasible and safe (Martin et al., 2023). However, the pharmacokinetic (PK) properties of SY-005 in severe COVID-19 are unknown.

[0008] SUMMARY

[0009] In one embodiment, the present disclosure provides for a method of preventing or treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day. In another aspect, the subject is administered 50 pg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day.

[0010] In another embodiment, the present disclosure provides for a method of preventing or treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 100 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day. In one aspect, the subject is administered 100 pg of annexin 5 per kg of the subject once a day or every 4 to 12 hours.

[0011] In another embodiment, the present disclosure provides for a method of preventing or treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 200 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day. In one aspect, the subject is administered 200 pg of annexin 5 per kg of the subject once a day or every 4 to 12 hours.

[0012] In another embodiment, the present disclosure provides for a preventing or treating sepsis in a subject, the method comprising administering to the subject at least 300 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day. In one aspect, the subject is administered 300 pg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day.

[0013] In one embodiment, the present disclosure provides for a method of preventing or treating sepsis in subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 17 pg / hour / kg of annexin A5 by continuous IV infusion. In one aspect, the subject is administered 17 pg / hour / kg of annexin A5 by continuous IV infusion.

[0014] In one embodiment, the present disclosure provides for a method of preventing or treating sepsis in subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 25 pg / hour / kg of annexin A5 by continuous IV infusion. In one aspect, the subject is administered 25 pg / hour / kg of annexin A5 by continuous IV infusion.

[0015] In another embodiment, the present disclosure provides for a method of preventing or treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg / hour / kg of annexin A5 by continuous IV infusion. In one aspect, the subject is administered 50 pg / hour / kg of annexin A5 by continuous IV infusion.

[0016] In one embodiment of the method of treating sepsis of the present disclosure, the administration is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0017] In another embodiment of the method of treating sepsis of the present disclosure, the administration is extended for 2 weeks.

[0018] In another embodiment of the method of treating sepsis of the present disclosure, the administration is extended for more than 2 weeks. In another embodiment of the method of treating sepsis of the present disclosure, the subject is a COVID-19 patient. In aspects, the subject is a COVID-19 patient admitted to the ICU.

[0019] In another embodiment of the method of treating sepsis according to the present disclosure, the subject is treated with a method according to the present disclosure prior to being admitted ot the ICU.

[0020] In another embodiment, the present disclosure relates to annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is in a dosage form of at least 50 pg of annexin A5 per kg of the subject.

[0021] In one embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is of 50 pg of annexin A5 per kg of the subject.

[0022] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is of 100 pg of annexin A5 per kg of the subject.

[0023] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is of 200 pg of annexin A5 per kg of the subject.

[0024] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is of 300 pg of annexin A5 per kg of the subject.

[0025] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subj ect, annexin A5 is in a dosage form of at least 17 pg / hour / kg for continuous IV infusion. In one aspect, the dosage form is 17 pg annexin A5 / hour / kg.

[0026] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is 25 pg / hour / kg for continuous IV infusion.

[0027] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is 50 pg / hour / kg for continuous IV infusion.

[0028] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is 75 pg / hour / kg for continuous IV infusion. In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the dosage form is once a day or every 4 to 12 hours per day.

[0029] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the use is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0030] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the use is extended for 2 weeks.

[0031] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the use is extended for more than 2 weeks.

[0032] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the subject is a COVID- 19 patient.

[0033] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the subject has been admitted to an ICU.

[0034] In another embodiment of the annexin A5 for use in the treatment of sepsis in a subject, the subject is treated prior to being admitted to an ICU.

[0035] In another embodiment, the present disclosure relates to a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 50 pg of annexin A5 per kg of the subject. In one aspect, the dosage form in the medicament is 50 pg of annexin A5 per kg of the subject, or the dosage form is 100 pg of annexin A5 per kg of the subject, or the dosage form is 200 pg of annexin A5 per kg of the subject, or the dosage form is 300 pg of annexin A5 per kg of the subject.

[0036] In another embodiment, the present disclosure relates to a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, wherein the medicament includes annexin A5 in a dosage form of at least 17 pg of annexin A5 per hour per kg of the subject for continuous IV infusion. In one aspect, the dosage form is 17 pg of annexin A5 per hour per kg of the subject for continuous IV infusion, or the dosage form is 25 pg annexin A5 / hour / kg for continuous IV infusion, or the dosage form is 50 pg / hour / kg for continuous IV infusion, or the dosage form is 75 pg annexin A5 / hour / kg for continuous IV infusion. In one embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the use is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0037] In another embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the use is extended for 2 weeks.

[0038] In another embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the use is extended for more than 2 weeks.

[0039] In another embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the subject is a COVID- 19 patient.

[0040] In another embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the subject has been admitted to an ICU.

[0041] In another embodiment of the use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, the subject is treated prior to being admitted to an ICU.

[0042] BRIEF DESCRIPTION OF THE FIGURES

[0043] The disclosure will be better understood and objects of the disclosure will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:

[0044] Figs. 1A to IB. Pharmacokinetics of SY-005 and daily pre-dose plasma annexin A5 levels in patients with severe COVID- 19. (1A) Study day 1 plasma annexin A5 concentrations at the end of the 30-minute infusion of placebo (saline), low (50 pg / kg) or high (100 pg / kg) dose SY-005 intravenous infusion (time 0 hours) and at 15 minutes, 30 minutes, 1 hour, and 6 hours. (IB) Evolution of daily pre-dose plasma annexin A5 levels during SY-005 infusion q!2h for 7 days. Figs. 2A to 2C. Effects of SY-005 on blood coagulation. (2A) Activated partial thromboplastin time (aPTT) during the first 6 hours of SY-005 administration on study day 1. (2B and 2C) aPTT and INR measurements, respectively, on study days 1, 4 and 8 before SY-005 or placebo administration. Due to heat inactivation, one sample from each dose group was not suitable for aPTT test resulting in n=4 and n=2 for high and low-dose groups, respectively. Data are mean ± SEM except in A where means of low dose group are shown. There was no statistical significance in 2A, 2B or 2C.

[0045] Fig. 3 A to 3B. ICU length of stay (LOS) in patients with severe COVID- 19 (AX-COVID trial). 3A. ICU LOS was calculated from the time of admission to the ICU until the time of death or discharge from the ICU. Annexin A5 treatment (combined 50 and 100 pg / kg dose groups) increased ICU LOS of non-survivors more than double of the placebo group (22.0±2.9 vs 9.3±1.6 days, P=0.001 by unpaired Student’s T-test), indicating that annexin A5 treated subjects survived longer time than the placebo-treated subjects. 3B. Survivors had no significant difference in ICU LOS between placebo and annexin A5 treatment groups.

[0046] DETAILED DESCRIPTION

[0047] Throughout this application, the text refers to various embodiments of the present compositions and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present disclosure.

[0048] Also throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation or an Arabic number, the complete bibliographic citation for which is found immediately preceding the claims. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this disclosure pertains. Definitions

[0049] As used in the specification and claims, the singular form “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.

[0050] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0051] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.

[0052] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 0.1 or 1.0 as is appropriate. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about” which includes a standard deviation of about 15 %, or alternatively about 10% or alternatively about 5 %. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0053] As used herein, “treating” or “treatment” of a disease in a patient refers to (1) inhibiting the disease or arresting its development; or (2) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable.

[0054] “Preventing” means preventing the symptoms or disease from occurring in a subject, including humans, that is predisposed or does not yet display symptoms of the disease.

[0055] As used herein, the term “pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin (1975) Remington’s Pharm. Sci., 15th Ed. (Mack Publ. Co., Easton).

[0056] A “subject,” “individual” or “patient” is used interchangeably herein, and refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, rats, rabbit, simians, bovines, ovine, porcine, canines, feline, farm animals, sport animals, pets, equine, and primate, particularly human. Besides being useful for human treatment, the present disclosure is also useful for veterinary treatment of companion mammals, exotic animals and domesticated animals, including mammals, rodents, and the like.

[0057] The term “administration” shall include without limitation, administration by ocular, oral, intra-arterial, parenteral (e.g., intramuscular, intraperitoneal, inhalation, transdermal, transnasal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray nasal, vaginal, rectal, sublingual, urethral (e.g., urethral suppository) or topical routes of administration (e.g., gel, ointment, cream, aerosol, ocular etc.) and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration. The disclosure is not limited by the route of administration, the formulation or dosing schedule.

[0058] “COVID-19 subjects” (or patients) are subjects who are septic using Sepsis 3.0 criteria and positive for SARS-CoV-2.

[0059] “pg / kg” means micrograms (pg) of annexin A5 per kilogram of the subject / patient.

[0060] “pg / kg / hour” means micrograms of annexin A5 per kilogram of the subject / patient per hour.

[0061] In this document, reference to annexin A5 includes recombinant human annexin A5 (SY-005).

[0062] Overview

[0063] The present disclosure relates to the use of annexin A5 in the treatment or prevention of sepsis. In embodiments, the present disclosure relates to the use of annexin 5A in the prevention and / or treatment of COVID-19, in particular severe COVID-19.

[0064] As shown in Figs. 3 A and 3B, ICU stay of patients with severe COVID- 19 was significantly longer in patients treated with 50 pg / kg or 100 pg / kg of annexin A5 than patients treated with placebo.

[0065] In this disclosure, the inventors have, surprisingly, shown that annexin A5 is eliminated from the plasma with a terminal half-life of less than 1 hour when annexin A5 administered at 50 pg / kg and 100 pg / kg per person. Further, there were no significant changes in coagulation (Fig. 2B and 2C), and no serious adverse events occurred with both dose treatment q!2h for 7 days (see Martin, C.M., et al. Critical Care Explorations, October 2023, V. 5 (10), 1-7) while ICU length of stay (LOS) was significantly prolonged in the non-survivors (Fig. 3A).

[0066] As such, the present disclosure relates to the use of higher dosages of annexin A5 and / or more frequent dosages of annexin A5 and / or for one day or at least one week of treatment, or for more than one week of treatment, to effectively treat sepsis in the patient. In one aspect, the patient is a COVID-19 patient, including severe COVID-19. The present disclosure, in embodiments, relates to the use of annexin A5 to prevent sepsis in a patient at risk of developing sepsis, such as a COVID-19 patient. Patients at risk of sepsis include any one that is admitted to a health care facility (i.e., hospitals, clinics and so forth). A patient at risk of developing sepsis include patients having infections and other clinical signs or elevated biomarkers of infection (white blood cells, lactic acid, organ biomarkers). A patients at risk of sepsis includes a patient that a clinician suspects that is at risk of developing sepsis. In particular patients at risk of sepsis include patients with infectious illness that warrant hospitalization, e.g. pneumonia (whether viral or bacterial), urinary trac infections, and so forth. Annexin A5 appears to stabilize the progression of organ failure, which in less severe patients may prevent progression to ICU and thus survival. In embodiments of the present disclosure, patients with infectious illness, e.g. pneumonia whether viral or bacterial, urinary tract infection, severe enough to warrant hospitalization (i.e. in ED or on the ward but not necessarily in the ICU) are treated with any of the methods described in the present disclosure.

[0067] In one embodiment, the present disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 8 to 12 hours per day (i.e., 8, 9, 10, 11 or 12 hours per day). In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks). “

[0068] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 6 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks). In one embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 4 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0069] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 100 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 8 or 12 hours per day (i.e., 8, 9, 10, 11 or 12 hours per day). In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0070] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 100 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 6 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0071] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 100 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 4 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week or for about 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days). In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0072] In another embodiment, the present disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 200 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 8 or 12 hours per day (i.e., 8, 9, 10, 11 or 12 hours per day). In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0073] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 200 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 6 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0074] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 200 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 4 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0075] In another embodiment, the present disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 300 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 8 or 12 hours per day (i.e., 8, 9, 10, 11 or 12 hours per day). In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0076] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 300 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 6 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0077] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject 300 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 4 hours per day. In aspects the admistration is for 1 day. In aspects, the administration is extended for up to 1 week (i.e., 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0078] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 17 pg / hour / kg of annexin A5 by continuous intravenous (IV) infusion. In aspects, the administration is extended for up to 1 week (i.e., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0079] In another embodiment, the preent disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 25 pg / hour / kg of annexin A5 by continuous IV infusion. In aspects, the administration is extended for up to 1 week (i.e., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0080] In another embodiment, the present disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 50 pg / hour / kg of annexin A5 by continuous IV infusion. In aspects, the administration is extended for up to 1 week (i.e., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0081] In another embodiment, the present disclosure provides for a method of treating sepsis in a subject, the method comprising, or alternatively consisting essentially of, or alternatively consisting of, administering to the subject at least 75 pg / hour / kg of annexin A5 by continuous IV infusion. In aspects, the administration is extended for up to 1 week (i.e., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and / or 7 days) or about 1 week. In other aspects, the administration is extended for 2 weeks. In another aspect, the administration is extended for more than 2 weeks (i.e., 3, 4, 5, etc. weeks).

[0082] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 50 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day (i.e., 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours per day). In one aspect, annexin A5 is administered in a dosage form of 50 pg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day.

[0083] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 100 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day (i.e., 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours per day). In one aspect, annexin A5 is administered in a dosage form of 100 pg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day. In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 200 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered once a day or every 4 to 12 hours per day (i.e., 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours per day). In one aspect, annexin A5 is administered in a dosage form of 200 pg of annexin A5 per kg of the subject once a day or every 4 to 12 hours per day.

[0084] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 300 pg of annexin A5 per kg of the subject. In one aspect, the annexin A5 is administered every 4 to 12 hours per day (i.e., 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours per day). In one aspect, annexin A5 is administered in a dosage form of 300 pg of annexin A5 per kg of the subject every 4 to 12 hours per day.

[0085] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 17 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is administered in a dosage form of 17 pg / hour / kg for continuous IV infusion.

[0086] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 25 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is administered in a dosage form of 25 pg / hour / kg for continuous IV infusion.

[0087] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 50 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is administered in a dosage form of 50 pg / hour / kg for continuous IV infusion.

[0088] In another embodiment, the present disclosure provides for annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is administered in a dosage form of at least 75 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is administered in a dosage form of 75 pg / hour / kg for continuous IV infusion.

[0089] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 50 pg of annexin A5 per kg of the subject. In one aspect, annexin A5 is formulated in a dosage form of 50 pg of annexin A5 per kg of the subject.

[0090] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein annexin A5 is formulated in a dosage form of at least 100 pg of annexin A5 per kg of the subject. In one aspect, annexin A5 is formulated in a dosage form of 100 pg of annexin A5 per kg of the subject.

[0091] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 200 pg of annexin A5 per kg of the subject. In one aspect, annexin A5 is formulated in a dosage form of 200 pg of annexin A5 per kg of the subject.

[0092] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 300 pg of annexin A5 per kg of the subject. In one aspect, annexin A5 is formulated in a dosage form of 300 pg of annexin A5 per kg of the subject.

[0093] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 17 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is formulated in a dosage form of 17 pg kg for continuous IV infusion.

[0094] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 25 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is formulated in a dosage form of 25 pg kg for continuous IV infusion.

[0095] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 50 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is formulated in a dosage form of 50 pg kg for continuous IV infusion.

[0096] In another embodiment, the present disclosure provides for a use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in as subject, wherein the medicament includes annexin A5 in a dosage form of at least 75 pg / hour / kg for continuous IV infusion. In one aspect, annexin A5 is formulated in a dosage form of 75 pg kg for continuous IV infusion.

[0097] In one embodiment, the method treatment or use is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0098] In another embodiment, the method of treatment or use is extended for 2 weeks.

[0099] In another embodiment, the method of treatment or the use is extended for more than 2 weeks.

[0100] In another embodiment, the method of treatment or the use is extended for as long as the sepsis does not progress (i.e., the subject does not get better) and the drug is satisfactorily tolerated.

[0101] In one embodiment, the subject is a COVID-19 patient. In another embodiment, the subject is a COVID-19 patient admitted to the ICU. As such, the present disclosure relates also to a method of treating COVID-19 (including severe COVID-19) in a patient comprising, or consisting essentially of, or consisting of administering a therapeutically effective amount of annexin A5 to the patient. In one embodiment, the therapeutically effective amount includes 50 pg or more of annexin A5 per kg of the subject, or 100 pg or more of annexin A5 per kg of the subject, or 200 pg or more of annexin A5 per kg of the subject, or 300 pg or more of annexin A5 per kg of the subject. In one embodiment, annexin A5 is administered once a day or every 4 to 12 hours per day. In another embodiment of the method of treating COVID-19 in a patient (including severe COVID-19), annexin 5A is administered at a dosage of 17 pg / hour / kg, or 25 pg / hour / kg or 50 pg / hour / kg or 75 pg / hour / kg by continuous IV infusion.

[0102] In another embodiment, the present disclosure relates to annexin A5 for use in the treatment of COVID- 19 (including severe COVID- 19) and to the use of annexin A5 in the manufacture of a medicament for the treatment of COVID-19 (including severe COVID- 19) in a patient, wherein annexin A5 is provided in a dosage form of 50 pg or more of annexin A5 per kg of the subject, or 100 pg or more of annexin A5 per kg of the subject, or 200 pg or more of annexin A5 per kg of the subject, or 300 pg or more of annexin A5 per kg of the subject. In one embodiment, annexin A5 is administered once a day or every 4 to 12 hours per day. In another embodiment annexin 5 A is in a dosage of 17 pg / hour / kg, or 25 pg / hour / kg or 50 pg / hour / kg or 75 pg / hour / kg by continuous IV infusion..

[0103] In another embodmeint, the subject is treated with any one of the treatments described above prior to being admitted to the ICU.

[0104] In another embodmeint, the subject is treated with any one of the treatments described above to prevent sepsis.

[0105] In order to aid in the understanding and preparation of the within disclosure, the following illustrative, non-limiting, examples are provided.

[0106] EXAMPLE 1

[0107] Materials and Methods

[0108] Study Design

[0109] This was a pilot randomized, double-blind, placebo-controlled trial studying two doses of recombinant human annexin A5 (SY-005) in severe COVID- 19 patients (Martin et al., 2023). SY-005 was produced by Suzhou Yabao Pharmaceutical R&D Co., Ltd, China, and its use as an investigational new trial drug was approved by Health Canada (Control #248696). The inclusion criteria included age >19 years, a positive polymerase chain reaction (PCR) test for SAR-CoV-2 viral infection and being admitted to the ICU for advanced monitoring and interventions. The exclusion criteria included an allergy to any component of the investigational product (annexin A5, sorbitol, or polysorbate 80), pregnancy, not expected to survive beyond 24 hours, a known or suspected risk of serious bleeding complications, full dose therapeutic anticoagulation and / or acute or chronic kidney disease. SY-005 or saline was administered intravenously every 12 hours for 7 days.

[0110] Randomization Procedures

[0111] Participants were randomized (1 : 1 : 1) to a study arm (high dose treatment, low dose treatment or placebo) with randomly permuted blocks of size 3 and 6, resulting in a 2: 1 ratio of participants given SY-005 compared to the placebo. Randomization was stratified by age at enrolment (65 and under or greater than 65) and by ICU site. Randomization was performed by the study pharmacist or delegate using research electronic data capture (REDCap) (Harris et al., 2009, 2019). All other study personnel and participants were blinded to the allocation (Martin et al., 2023).

[0112] Dosage Preparation and Administration

[0113] SY-005 was diluted based on the patient body mass and administered at a dose of 50 or 100 pg / kg body weight in 50 ml of normal saline, which could be stored at 2-8 °C for up to 24 h. Doses were infused over 30 minutes through a dedicated venous line that was flushed with normal saline before and after administration. Placebo-treated patients received 50 ml of normal saline with no additives. SY-005 and placebo were prepared using aseptic technique (Martin et al., 2023).

[0114] Blood Collection

[0115] Blood was obtained from an existing arterial or venous line or by venipuncture. Samples were drawn into a syringe first and then transferred into sodium citrate vacuum tubes. Blood samples were immediately placed on ice and processed within 30 min of blood collection. Blood samples were obtained pre-dose, immediately after the completion of SY- 005 infusion (0 minutes), 15, 30 minutes, 1 and 6 hours post-infusion. Baseline bloodwork included lab blood tests, creatinine, activated partial thromboplastin time (aPTT) and international normalized ratio (INR) of prothrombin time. The estimated glomerular filtration rate (eGFR) was calculated using the 2021 CKD-EPI equation without race (Inker et al., 2021). Blood Processing and Plasma Isolation

[0116] Whole blood was transported in a metal dewar fdled with ice to a biosafety level 2+laboratory. Samples were centrifuged at 1500g for 15 min at 4 °C. Plasma was removed and stored in 250 pl aliquots in a cryogenic freezing vial (Fisherbrand, Cat # 12-567-501) at -80 °C.

[0117] Annexin A5 ELISA

[0118] To comply with the biosafety standards of Western University, frozen plasma samples were thawed and heat-inactivated at 56 °C for 30 minutes before they were transported on ice from London Health Sciences Centre to Western University for analysis. Plasma samples were analyzed using a human annexin A5 ELISA kit (AB223863, Lot No. 2101027017, Abeam, Waltham, MA, USA). The standard curve was constructed using normal human plasma with annexin A5 levels below 0. 1 ng / mL. All plasma samples were heated at 60 °C for 30 minutes to denature annexin A5 for optimal antibody binding before they were added to the microplate wells. Colorimetric densities were obtained using a SpectraMax M5 plate reader (Molecular Devices, San Jose, CA, USA). The interday accuracy and coefficient of variation (CV) assessed at 500 ng / mL were 11.7% and 5.6%, respectively. The detection limit was 0.1 ng / mL. Since the anti -annexin A5 antibody recognizes both endogenous and recombinant annexin A5, the average endogenous annexin A5 values were subtracted from the total annexin A5 measurements to obtain SY-005 plasma concentrations.

[0119] Activated partial thromboplastin time (aPTT) andINR of prothrombin time

[0120] The aPTT test was measured in plasma samples that were not heat inactivated. Fifty microliters of aPTT reagent (Pacific Hemostasis aPTT-XL, Thermo Scientific, USA) were incubated with 50 pL of plasma for 5 min at 37°C in sterile 96-well plates. Clotting was initiated by adding 50 pL of CaCU (20 mM). Absorbances were determined before and after CaCh addition at 3 second intervals for 10 min at 405 nm using a SpectraMax M5 plate reader (Molecular Devices, San Jose, CA, USA) (Pratt and Monroe, 1992). To assess the INR of prothrombin time, plasma samples were incubated with the Dade® Inovin® reagent that contains recombinant human tissue factor, synthetic phospholipids, Ca2+, buffers and stabilizers to trigger coagulation. The time to the formation of a fibrin clot was measured by the transmitted light intensity using a coagulation analyzer (Sysmex CS-2500 System, Siemens, Germany).

[0121] Pharmacokinetic and Statistical Analysis

[0122] The following PK parameters were calculated with non-compartmental analysis using a software program (PCModFit V7.7, GD Allen): area under the concentration-time curve (AUC) from 0 to the last observation time (AUCt) and from 0 to infinity (AUC, ). maximum drug concentration (Cmax), terminal half-life (ti / 2), volume distribution (Vd) and clearance (Cl) (Allen, 1990). Mann-Whitney U test was used to compare parameters between low and high-dose groups. One-way ANOVA followed by the Kruskal-Wallis test was used to compare baseline parameters among three treatment groups. A P value of less than 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism software (version 9.5).

[0123] RESULTS

[0124] Participant characteristics

[0125] A total of 17 patients were enrolled in the study, 13 of whom had biological samples available for this study in the placebo (n=5), low (50 pg / kg, n=3) and high (100 pg / kg, n=5) dose SY-005 treatment groups. The low-dose group had only 3 patients because the consent was revoked in one patient and another patient was diagnosed with pulmonary embolism requiring therapeutic anticoagulation after randomization and before study drug administration, excluding them from the study. The PK blood samples of 4 patients were not obtained due to the unavailability of research staff on weekends and holidays. Table 1 summarizes the demographic characteristics of participants. Age, body weight, body mass index, serum creatinine, eGFR, serum albumin, platelet counts and INR were similar among the treatment groups ( >0.05).

[0126] Pharmacokinetics of SY-005

[0127] Endogenous annexin A5 levels before SY-005 administration were similar among the three treatment groups (Table 1). Placebo treatment did not change plasma annexin A5 levels (Fig. 1A). SY-005 treatment dose-dependently increased plasma SY-005 levels with Cmax of 402.4 and 848.9 ng / mL, which decreased to 3.7 and 7.4 ng / mL at 6 hours following 30 minutes of 50 and 100 pg / kg infusion, respectively (Fig. 1A and Table 2). C max WHS significantly higher in the high dose than in the low dose SY-005 treatment group (P<0.05) and was increased by 201- and 424-fold over endogenous annexin A5 levels in low and high dose groups, respectively. The elimination half-life (ti / 2) of SY-005 was similar between low and high dose groups (0.92 vs 0.96 hours). All other pharmacokinetic parameters including Xz, AUCt, AUG,, clearance, mean residence time (MRT), volume distribution (Vd) and volume distribution at steady state (Vss) were not significantly different between low and high-dose SY-005 treatment groups (P>0.05, Table 2).

[0128] Annexin A5 plasma levels were determined daily immediately prior to the morning SY-005 treatment. Neither the low nor high-dose SY-005 treatment increased daily predose circulating annexin A5 levels (Fig. IB), suggesting minimal plasma SY-005 accumulation in either of the treatment groups. Baseline eGFR was normal in patients who received SY-005 (range 104.2-125.0 mL / min / 1.73m2) and there was no relationship between eGFR and SY-005 clearance in this study population.

[0129] Effects of SY-005 on coagulation

[0130] Severe COVID-19 can be complicated by coagulopathy (Godoy et al., 2020), and annexin A5 has been shown to have a moderate anticoagulant effect (Gerke and Moss, 2002; Mui et al., 2021). To assess the effects of SY-005 on blood coagulation, aPTT was quantified on study day 1 during the first 6 hours after SY-005 administration. Additionally, aPTT and INR were determined at baseline (day 1), day 4 and day 8 after SY -005 treatment. Both low and high doses of SY-005 did not significantly affect aPTT in the first 6 hours (Fig. 2A), and there was no significant effect on aPTT (Fig. 2B) or INR (Fig. 2C) at day 4 and day 8 during SY-005 treatment.

[0131] This study examined the PK profile of two doses of SY-005 (50 and 100 pg / kg) in a randomized, double-blind, placebo-controlled pilot trial in severe COVID-19 patients with normal renal function. Our data show that the infusion of SY-005 dose-dependently increased Cmax, Xz, AUCt and AUG, . SY-005 was eliminated rapidly from the plasma with a clearance of 7.52 and 15.19 L / h and an elimination half-life of 0.92 and 0.96 hours for low and high doses, respectively, indicating a rapid elimination in patients with severe COVID- 19. These results are important for planning further studies of this novel therapeutic agent for the treatment of COVID-19 and sepsis. Endogenous annexin A5 in all treatment groups was similar to the normal basal circulating plasma levels of healthy volunteers (Matsuda et al., 2003; Van Heerde et al., 2003; Burgmaier et al., 2017). Plasma SY-005 concentrations were obtained by subtracting endogenous levels from total annexin A5 concentrations. Our data show that SY-005 clearance and elimination half-life are similar to that of healthy volunteers in a phase I trial of SY-005, in which this drug was cleared within 6 hours post-infusion at 5 and 10 mg per person, which are equivalent to 41 and 82 pg / kg doses, respectively (NCT04217629; Suzhou Yabao Pharmaceutical R&D Co., Ltd., 2023). This PK profde supports more frequent intravenous dosing, possibly every 6-8 hours to achieve adequate therapeutic effect in future trials.

[0132] Annexin A5 has been used to label apoptotic cell death for diagnostic imaging in patients with cancer (Corsten et al., 2006) and acute myocardial infarction (Hofstra et al., 2000) because of its ability to bind to the externalized phosphatidylserine, a characteristic feature of apoptosis. The "mTc-labelled annexin A5 administrated intravenously in patients with acute myocardial infarction displayed a half-life of 17 to 62 hours with a clearance of 1.2 to 2.8 L / h (Boersma et al., 2003). The longer half-life and lower clearance of radiolabeled annexin A5 are attributed to the radiochemical properties of the conjugated annexin A5 with radio ligand ester or thiolate bonds (Boersma et al., 2003, 2005).

[0133] Acute kidney injury occurs in 20 to 40% of COVID-19 patients admitted to the ICUs, and approximately 20% of these patients require renal replacement therapy (Ronco et al., 2020; Chan et al., 2021). Renal dysfunction reduces the elimination of drugs and their metabolites that are primarily cleared by the kidneys. Several reports identified that the accumulation of radiolabelled annexin A5 in humans and rodents was most pronounced and rapid in the kidney and that 57% of the injected dose was excreted in the urine around their half-life (ti / 2), suggesting that kidneys are the main route of elimination of the radiolabelled annexins A5 (Boersma et al., 2003, 2005; Cheng et al., 2013). In our study, all COVID-19 patients had normal baseline eGFR (104 to 125 mL / min / 1.73m2) and serum creatinine levels. Both low and high doses of SY-005 were cleared within 6 hours from plasma following intravenous infusion. Further, intravenous infusions of either low or high doses of SY-005 every 12 hours for 7 days did not cause significant accumulation in plasma. Future studies should investigate the impact of acute and chronic kidney disease on SY- 005 clearance, pharmacokinetics, and potential complications. Coagulopathy occurs in severe COVID-19 patients and its clinical manifestations include a hypercoaguable state, venous and arterial thrombosis, and disseminated intravascular coagulation (DIC) (Godoy et al., 2020). In the present study, patients with suspected risk of bleeding or on therapeutic anticoagulation were excluded. Baseline platelet account, aPTT and INR were normal in all patients. SY-005 treatment acutely within 6 hours and with daily q!2h administration for 7 days did not affect aPTT or INR, suggesting that SY-005 does not significantly alter blood coagulation in patients with severe COVID- 19. The results are consistent with previous studies that annexin A5 does not prolong bleeding times in rodents even at very high doses (1.0 mg / kg body weight, i.v.) (Romisch et al., 1991).

[0134] In severe COVID-19, the pharmacokinetics of SY-005 dosed at 50 and 100 pg / kg in patients with normal renal function showed a dose-dependent increase in SY-005 plasma levels, with subsequent rapid clearance. SY-005 did not accumulate in plasma, and there was no significant effect on blood coagulation during the 7-day study period. These data suggest that SY-005 dosed at either 50 or 100 pg / kg achieved blood concentrations in COVID- 19 patients with normal renal function that are compatible with therapeutic dose without causing harm, supporting its further investigation in a larger randomized clinical trial.

[0135] Table 1. Demographics of study patients with severe CO VID-19 who were randomized to placebo, low (50 pg / kg) and high (100 pg / kg) dose SY-005 treatment groups.

[0136] Data are given as median with range in brackets. Chi-square analysis for sex and one-way ANOVA followed by the Kruskal-Wallis test for all other parameters showed no statistical significance among 3 groups. Endogenous annexin A5 plasma levels were determined before SY- 005 or placebo treatment. eGFR, estimated glomerular filtration rate.

[0137] Table 2, Pharmacokinetics of SY-005 following a 30-min intravenous infusion in severe COVID-

[0138] 19 patients

[0139] Data are mean ± standard deviation (SD) and analyzed by Mann Whitney U test. Tmax, maximum drug time ; Cmax, maximum drug concentration; AUCt, area under the curve until the last observation time; AUC,. area under the curve extrapolated to infinity; Zz, terminal phase elimination rate constant; MRT, mean residence time; Vd, volume distribution; Vss, steady state volume distribution.

[0140] EXAMPLE 2 Investigation of clinical benefit of annexin A5 (SY-005)

[0141] 20 patients with severe COVID-19 are randomized (1:1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 50pg / kg every 8 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0142] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0143] A daily dosage range is about 50pg / kg every 8 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0144] EXAMPLE 3

[0145] Investigation of clinical benefit of annexin A5 (SY-005)

[0146] 20 patients with severe COVID-19 are randomized (1:1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 50pg / kg every 6 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0147] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0148] A daily dosage range is about 50pg / kg every 6 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0149] EXAMPLE 4 Investigation of clinical benefit of annexin A5 (SY-005)

[0150] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 50pg / kg every 4 hours. Placebo-treated patients receive of normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0151] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0152] A daily dosage range is about 50pg / kg every 4 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0153] EXAMPLE 5

[0154] Investigation of clinical benefit of annexin A5 (SY-005)

[0155] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 50pg / kg every 12 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0156] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0157] A daily dosage range is about 50pg / kg every 12 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0158] EXAMPLE 6 Investigation of clinical benefit of annexin A5 (SY-005)

[0159] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 100pg / kg every 8 hours. Placebo-treated patients receive of normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0160] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0161] A daily dosage range is about 100pg / kg every 8 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0162] EXAMPLE 7

[0163] Investigation of clinical benefit of annexin A5 (SY-005)

[0164] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 100pg / kg every 6 hours. Placebo-treated patients receive of normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0165] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0166] A daily dosage range is about 100pg / kg every 6 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0167] EXAMPLE 8 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 100pg / kg every 4 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0168] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0169] A daily dosage range is about 100pg / kg every 4 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0170] EXAMPLE 9

[0171] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 100pg / kg every 12 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0172] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0173] A daily dosage range is about 100pg / kg every 12 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0174] EXAMPLE 10

[0175] Investigation of clinical benefit of annexin A5 (SY-005) 20 patients with severe COVID-19 are randomized (1:1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 200pg / kg every 8 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0176] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0177] A daily dosage range is about 200pg / kg every 8 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0178] EXAMPLE 11

[0179] Investigation of clinical benefit of annexin A5 (SY-005)

[0180] 20 patients with severe COVID-19 are randomized (1:1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 200pg / kg every 6 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0181] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0182] A daily dosage range is about 200pg / kg every 6 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0183] EXAMPLE 12 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 200pg / kg every 4 hours. Placebo-treated patients receive normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0184] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0185] A daily dosage range is about 200pg / kg every 4 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0186] EXAMPLE 13

[0187] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 200pg / kg every 12 hours. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0188] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0189] A daily dosage range is about 200pg / kg every 12 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0190] EXAMPLE 14

[0191] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 300pg / kg every 4 hours. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 2 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0192] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0193] A daily dosage range is about 300pg / kg every 4 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0194] EXAMPLE 15

[0195] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 300pg / kg every 6 hours. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0196] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0197] A daily dosage range is about 300pg / kg every 6 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0198] EXAMPLE 16

[0199] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Placebo-treated patients received normal saline with no additives. Drug-treated patients receive SY-005 at a dosage of 300pg / kg every 8 hours. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0200] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0201] A daily dosage range is about 300pg / kg every 8 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0202] EXAMPLE 17

[0203] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 300pg / kg every 12 hours. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated.

[0204] Main variables for evaluation: Safety (adverse events), standard serum biochemistry.

[0205] A daily dosage range is about 300pg / kg every 12 hours as a single dose or in divided doses. SY-005 may be administered by any conventional route, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.

[0206] EXAMPLE 18

[0207] Single / multiple dose-escalation, randomized, double blind, placebo-controlled study for safety, tolerability and pharmacokinetic study in healthy human subjects. Each subject will receive only one dose level of SY-005.

[0208] Subjects: healthy subjects (50 / 50 men and women; from 18 to 65 years-old; weights no less han 50kg for males and no less than 45 kg for women; having BMI from 18 kg / m2to 26 kg / m2). The specification for the SY-005 injection was lmL:5mg. Intravenous constant rate drip of 50 mL over 30 minutes at a drip rate of 100 mL / h.

[0209] The study includes three dose levels. Dose groups: Group 1 : 40 mg SY-005 once a day (QD) at 3-day intervals + 20 mg SY-005 twice-daily dosage (BID) for 7 days, 21 days observation period; Group 2: 60 mg SY-005 QD at 3-day intervals + 30 mg SY-005 BID for 7 days, 21 days observation period; Group 3: 80 mg QD at 3-days intervals + 40 mg BID for 7 days, 21 days observation period. Two sentinel dosing groups (1 placebo and 1 test drug group) were set up for each dose group. Enrollment of the other cases in that dose grou (1 placebo and 5 test grops) was carried out after completion of the sentinel group’s singe + multiple 7-day administration for a two-day observation discharge.

[0210] During the dose-escalation process, the same subject can only participate in one dose group trial.

[0211] Dudring the dose-escalation process, administration of the next dose grop may begin only afterall subjects in the previous group have been evaluated for safety and tolerability.

[0212] The study consisted of the following components (i) a 14-day screening period, (ii) a 1-day baseline period (iii) a 1-day dosing period for a signle dose, (iv) a 3-day observation period for a single dose; (v) a 7-day dosing period for multiple doses; and (vi) a 21-day post-dose follow-up period. Each subject is expected to have 45 days (14-day screening, 10-day trial period, and a 21-day post-dose follow-up period).

[0213] EXAMPLE 19

[0214] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 17 pg / hour / kg by continuous IV infusion. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated. Main variables for evaluation: Safety (adverse events), standard serum biochemistry. A daily dosage range of SY-005 is about 17 pg / hour / kg as a continous IV infusion.

[0215] EXAMPLE 20

[0216] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 25 pg / hour / kg by continuous IV infusion. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated. Main variables for evaluation: Safety (adverse events), standard serum biochemistry. A daily dosage range is about 25 pg / hour / kg as a continous IV infusion.

[0217] EXAMPLE 21

[0218] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 50 pg / hour / kg by continous IV infusion. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated. Main variables for evaluation: Safety (adverse events), standard serum biochemistry. A daily dosage range is about 50 pg / hour / kg as a continous IV infusion.

[0219] EXAMPLE 22

[0220] 20 patients with severe COVID-19 are randomized (1 : 1) to a study arm (SY-005 dose treatment or placebo). Drug-treated patients receive SY-005 at a dosage of 75 pg / hour / kg by continous IV infusion. Placebo-treated patients received normal saline with no additives. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months. Initially patients receive treatment for 1 to 4 weeks. Thereafter, they remain on treatment for as long as their disease does not progress and the drug is satisfactorily tolerated. Main variables for evaluation: Safety (adverse events), standard serum biochemistry. A daily dosage range is about 75 pg / hour / kg as a continous IV infusion.

[0221] References

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[0264] Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054-1062. doi: 10.1016 / S0140-6736(20)30566-3.

[0265] Through the embodiments that are illustrated and described, the currently contemplated best mode of making and using the disclosure is described. Without further elaboration, it is believed that one of ordinary skill in the art can, based on the description presented herein, utilize the present disclosure to the full extent. All publications cited herein are incorporated by reference.

[0266] Although the description above contains many specificities, these should not be construed as limiting the scope of the disclosure, but as merely providing illustrations of some of the presently embodiments of this disclosure.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of preventing or treating sepsis in a subject, the method comprising administering to the subject at least 50 pg of annexin A5 per kg of the subject.

2. The method of claim 1, wherein the subject is administered 50 pg of annexin A5 per kg of the subject.

3. A method of preventing or treating sepsis in a subject, the method comprising administering to the subject at least 100 pg of annexin A5 per kg of the subject.

4. The method of claim 3, wherein the subject is administered 100 pg of annexin A5 per kg of the subject.

5. A method of preventing or treating sepsis in a subject, the method comprising administering to the subject at least 200 pg of annexin A5 per kg of the subject.

6. The method of claim 5, wherein the subject is administered 200 pg of annexin A5 per kg of the subject.

7. A method of preventing or treating sepsis in a subject, the method comprising administering to the subject at least 300 pg of annexin A5 per kg of the subject.

8. The method of claim 5, wherein the subject is administered 300 pg of annexin A5 per kg of the subject.

9. The method according to any one of claims 1 to 8, wherein annexin A5 is administered once a day or every 4 to 12 hours per day.

10. A method of preventing or treating sepsis in a subject, the method comprising administering to the subject annexin 5A at a dosage of at least 17 pg / hour / kg by continuous IV infusion.

11. The method of claim 10, wherein the dosage is 17 pg / hour / kg.

12. The method of claim 10, wherein the dosage is 25 pg / hour / kg.

13. The method of claim 10, wherein the dosage is 50 pg / hour / kg of annexin A5.

14. The method of claim 10, wherein the dosage is 75 pg / hour / kg of annexin A5.

15. The method according to any one of claims 1 to 14, wherein the administration is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

16. The method according to any one of claims 1 to 14, wherein the administration is extended for 2 weeks.

17. The method according to any one of claims 1 to 14, wherein the administration is extended for more than 2 weeks.

18. The method according to any one of claims 1 to 17, wherein the subject is a COVID- 19 patient.

19. The method according to any one of claims 1 to 18, wherein the subject has been admitted to an ICU.

20. The method according to any one of claims 1 to 18, wherein the subject is treated prior to being admitted to an ICU.

21. Annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is in a dosage form of at least 50 pg of annexin A5 per kg of the subject.

22. The use of claim 21, wherein the dosage form is of 50 pg of annexin A5 per kg of the subject.

23. The use of claim 21, wherein the dosage form is of 100 pg of annexin A5 per kg of the subject.

24. The use of claim 21, wherein the dosage form is of 200 pg of annexin A5 per kg of the subject.

25. The use of claim 21, wherein the dosage form is of 300 pg of annexin A5 per kg of the subject.

26. The use according to any one of claims 21 to 25, wherein the dosage form is once a day or every 4 to 12 hours per day27. Annexin A5 for use in the treatment of sepsis in a subject, wherein annexin A5 is in a dosage form of at least 17 pg / hour / kg for continuous IV infusion.

28. The annexin A5 for use of claim 27, wherein the dosage form is 17 pg / hour / kg.

29. The annexin A5 for use of claim 27, wherein the dosage form is 25 pg / hour / kg.

30. The annexin A5 for use of claim 27, wherein the dosage form is 50 pg / hour / kg.

31. The annexin A5 for use of claim 27, wherein the dosage form is 75 pg / hour / kg.

32. The annexin A5 for use according to any one of claims 21 to 31, wherein the use is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

33. The annexin A5 for use according to any one of claims 21 to 31, wherein the use is extended for 2 weeks.

34. The annexin A5 for use according to any one of claims 21 to 31, wherein the use is extended for more than 2 weeks.

35. The annexin A5 for use according to any one of claims 21 to 31, wherein the subject is a COVID-19 patient.

36. The annexin A5 for use according to any one of claims 21 to 31, wherein the subject has been admitted to an ICU.

37. The annexin A5 for use according to any one of claims 21 to 31, wherein the subject is treated prior to being admitted to an ICU.

38. A use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis in a subject, wherein the medicament includes annexin A5 in a dosage form of at least 50 pg of annexin A5 per kg of the subject.

39. The use of annexin A5 of claim 38, wherein the dosage form is 50 pg of annexin A5 per kg of the subject, or the dosage form is 100 pg of annexin A5 per kg of the subject, or the dosage form is 200 pg of annexin A5 per kg of the subject, or the dosage form is 300 pg of annexin A5 per kg of the subject.

40. A use of annexin A5 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of sepsis, wherein the medicament includes annexin A5 in a dosage form of at least 17 pg / hour / kg for continuous IV infusion.

41. The use of annexin A5 of claim 40, wherein the dosage form is 17 pg / hour / kg for continuous IV infusion, or the dosage form is 25 pg / hour / kg for continuous IV infusion, or the dosage form is 50 pg / hour / kg for continuous IV infusion, or the dosage form is 75 pg / hour / kg for continuous IV infusion.

42. The use of annexin A5 according to any one of claims 38 to 41, wherein the use is extended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

43. The use of annexin A5 according to any one of claims 38 to 41, wherein the use is extended for 2 weeks.

44. The use of annexin A5 according to any one of claims 38 to 41, wherein the use is extended for more than 2 weeks.

45. The use of annexin A5 according to any one of claims 38 to 41, wherein the subject is a COVID- 19 patient.

46. The use of annexin A5 according to any one of claims 38 to 41, wherein the subject has been admitted to an ICU.

47. The use of annexin A5 according to any one of claims 38 to 41, wherein the subject is treated prior to being admitted to an ICU.

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