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WO2024023745A1 - Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant - Google Patents

Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant Download PDF

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Publication number
WO2024023745A1
WO2024023745A1 PCT/IB2023/057612 IB2023057612W WO2024023745A1 WO 2024023745 A1 WO2024023745 A1 WO 2024023745A1 IB 2023057612 W IB2023057612 W IB 2023057612W WO 2024023745 A1 WO2024023745 A1 WO 2024023745A1
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Prior art keywords
recombinant
aki
administered
dose
hours
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PCT/IB2023/057612
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English (en)
Inventor
Claudio Calonder
Ghionul IBRAM
Guido JUNGE
Matthew James ROWLAND
Max Philipp TAUBERT
Max WARNCKE
Hermann Markus WEISS
Yinong ZHOU
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Novartis AG
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Novartis AG
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Priority to EP23754430.9A priority Critical patent/EP4561608A1/fr
Priority to IL318380A priority patent/IL318380A/en
Priority to CN202380055750.6A priority patent/CN119604301A/zh
Priority to CA3262869A priority patent/CA3262869A1/fr
Priority to JP2025504179A priority patent/JP2025524942A/ja
Priority to KR1020257005894A priority patent/KR20250044705A/ko
Publication of WO2024023745A1 publication Critical patent/WO2024023745A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y306/00—Hydrolases acting on acid anhydrides (3.6)
    • C12Y306/01—Hydrolases acting on acid anhydrides (3.6) in phosphorus-containing anhydrides (3.6.1)
    • C12Y306/01005—Apyrase (3.6.1.5), i.e. ATP diphosphohydrolase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure generally relates to methods for treating organ injury, in particular acute organ injury, such as acute kidney injury (AKI) using CD39, human recombinant CD39 and variants thereof, such as the recombinant CD39 variant which has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.
  • acute organ injury such as acute kidney injury (AKI)
  • CD39 human recombinant CD39 and variants thereof, such as the recombinant CD39 variant which has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.
  • Acute kidney injury is a silent condition, characterized by a sudden deterioration of kidney function, sometimes with reduced or even complete loss of urine output. Most patients will experience this syndrome during a hospital stay, especially critically ill patients and patients undergoing major surgeries. Recovery from AKI is possible, however, in some patients kidney function will continue to decline further and remain chronically impaired. Some patients will need at least short-term dialysis, or will be left with severe renal impairment and remain dialysisdependent with the need for a kidney transplant.
  • SA-AKI Sepsis associated acute kidney injury
  • AKI is also a frequent and serious complication of cardiopulmonary bypass surgery (CPBS), cardiac surgery associated AKI (CSA-AKI).
  • CPBS cardiopulmonary bypass surgery
  • CSA-AKI cardiac surgery associated AKI
  • AKI is new or worsened renal insufficiency characterized by a relatively abrupt decrease in glomerular filtration rate (GFR), often accompanied by a reduction in urine output.
  • GFR glomerular filtration rate
  • AKI usually occurs within the first 7 days after an initial insult, most commonly following an episode of transient hypotension of any cause, but may also occur in response to nephrotoxins or radio-contrast media.
  • the clinical incidence of AKI is found in 3-18% of all hospitalized adult patients worldwide, and is more common in the context of complex surgery. Depending on the definition, AKI occurs in up to 15-40% of adults after CPBS. Severe AKI requires renal replacement therapy in 1-5% of cases and is associated with a mortality rate of up to 70%.
  • a clinical study conducted with alkaline phosphatase (ALP) in SA-AKI patients showed that AP improved kidney function determined by a composite endpoint of creatinine clearance, requirement for RRT, and duration of RRT.
  • Alkaline phosphatase is an endogenous enzyme that exerts detoxifying effects through dephosphorylation of endotoxins and extracellular ATP.
  • results have suggested a potential mortality benefit with treatment of AP compared to placebo even though the study did not meet its primary endpoint in improving short-term kidney function measured by area-under-the time corrected endogenous creatinine clearance from Day 1 to Day 7.
  • AKI in particular AKI, e.g. sepsis-associated acute kidney Injury (SA-AKI) or cardiac surgery associated AKI (CSA-AKI), using a recombinant CD39 and variants thereof, as defined herein, that are safe, effective and provide sustained responses for patients.
  • SA-AKI sepsis-associated acute kidney Injury
  • CSA-AKI cardiac surgery associated AKI
  • Treatment approaches to enhance extracellular ATP conversion to adenosine using the recombinant CD39 mechanisms of action to hydrolyzing extracellular ATP and ADP to AMP represents a therapeutic strategy to mitigate and dampen acute organ injury in general.
  • the recombinant CD39 is dose dependently inhibiting ATP/LPS- induced IL- 10 secretion as well as ADP and thrombin-induced platelet. Inhibition of thrombin- induced platelet aggregation is attributable to release of ADP from the platelet-dense granules through activation of protease-activated receptor-4 (PAR4) by thrombin inducers. Furthermore, the recombinant CD39, as defined herein inhibits the ATP/LPS -induced IL-ip release in a concentration-dependent manner. Such treatments show anti-inflammation, anti-coagulation and tissue protection that could lead to improvement of renal function and reduction of mortality in subjects suffering from AKI, such as SA- AKI or CSA-AKI.
  • a recombinant CD39 comprising the amino acid sequence of SEQ ID NOs: 1 to 21, and wherein said recombinant CD39 is to be administered to a subject in need thereof, at a dose of from about 0.1 mg/kg to about 10 mg/kg of body weight (mg per kilogram subject body weight (mg/kg)).
  • the recombinant CD39 designated CD39* is provided.
  • CD39* comprises the amino acid sequence of SEQ ID NO: 21, and wherein said recombinant CD39* is to be administered to a subject in need thereof, at a dose of from about 1 mg/kg to about 5 mg/kg.
  • the route of administration is intravenous (IV), IV infusion, of the recombinant CD39 according to the embodiments herein described.
  • an appropriate regimen for a recombinant CD39, as defined herein, is a daily regimen.
  • the recombinant CD39 as defined herein, preferably CD39*, may be administered to the subject at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg or of about 5 mg/kg, delivered IV.
  • the recombinant CD39 as defined herein, preferably CD39*, may be administered to the subject daily, e.g. i.v., at a dosing of about 4-5 mg/kg, by infusion, within a number of hours after AKI or sepsis is first diagnosed for said subject.
  • the recombinant CD39 as defined herein, preferably CD39*, may be administered to the subject, e.g. IV, at a dosing of about 4-5 mg/kg, by infusion within a time interval initiating from suspected or confirmed AKI diagnosis for said subject.
  • the recombinant CD39 as defined herein, preferably CD39*, may be administered to the subject, e.g. IV, at a dosing of about 4-5 mg/kg, by infusion, within about 48 hours, or less, after AKI is first diagnosed for said subject (e.g., within 12 hours, within 24 hours, or within 36 hours, for example).
  • the treatment regimen may stretch over a number of hours to a day to several weeks as determined by a competent caregiver (treating physician).
  • the present invention comprises administering the recombinant CD39, as defined herein, preferably CD39*, to a subject with AKI, e.g. SA-AKI or CSA-AKI, in the range of about 0.1 mg/kg to about 10 mg/kg per treatment, preferably in the range of 1 mg/kg to 5 mg/kg, preferably about 4-5 mg/kg per treatment.
  • a subject receives 4 or 5 mg/kg, per treatment.
  • the subject with AKI, e.g. SA-AKI or CSA-AKI receives the treatment once, within about 48 hours, after AKI e.g. SA-AKI or CSA-AKI, is first diagnosed.
  • the recombinant CD39 as defined herein, preferably CD39*, is to be administered in combination with one or more additional agents.
  • the one or more additional agents is a steroid, a metalloproteinase inhibitor, a serine protease inhibitor, a topical anesthetic emulsion, a spreading factor inhibitor, an anti-nausea agent, or an antibiotic.
  • the disclosure provides new dosing regimens for the recombinant CD39, as defined herein, preferably CD39*, that can be used in methods of treating or preventing AKI, e.g. SA-AKI or CSA-AKI.
  • the disclosure provides new dosing regimens for the recombinant CD39, as defined herein, preferably CD39*, that can be used in methods of treating or preventing sepsis.
  • the disclosure provides new dosing regimens for the recombinant CD39, as defined herein, preferably CD39* for use as a medicament, wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg, in a subject in need thereof.
  • the disclosure provides new methods of treatment using the recombinant CD39, as defined herein, preferably CD39*, wherein the recombinant CD39 is to be administered to a subject in need thereof, at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • SOFA sequential organ failure score
  • the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • the recombinant CD39 according to any one of the above embodiments is to be administered at a dose of about 4 mg/kg of the recombinant CD39.
  • the recombinant CD39 according to any one of the above embodiments, is to be administered at a dose of about 5 mg/kg of the recombinant CD39.
  • the recombinant CD39 according to any one of the above embodiments is to be administered IV, e.g. is to be administered IV during about 2 hours.
  • the recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered to the subject daily, e.g. IV, at a dosing of about 4 or 5 mg/kg, by infusion, within a time interval initiating from suspected or confirmed AKI diagnosis for said subject.
  • the recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered within about 48 hours, or less, after AKI is first diagnosed for said subject (e.g., within 12 hours, within 24 hours, or within 36 hours, for example).
  • the recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered within about 24 hours, or as soon as possible after AKI, or sepsis, is first diagnosed.
  • A23 The recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered within a number of hours after sepsis is first diagnosed for said subject.
  • the recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered to the subject daily, e.g. IV, at a dosing of about 4 or 5 mg/kg, by infusion, within a time interval initiating from suspected or confirmed sepsis diagnosis for said subject.
  • A25 The recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is to be administered within about 48 hours, or less, after sepsis is first diagnosed for said subject (e.g., within 12 hours, within 24 hours, or within 36 hours, for example).
  • A26 The recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.
  • the recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 has the amino acid sequence of SEQ ID NO: 21.
  • A29 The recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is co-administered with an additional therapeutic agent.
  • A30 The recombinant CD39 according to any one of the above embodiments, wherein the recombinant CD39 is co-administered with an additional therapeutic agent selected from a steroid, a metalloproteinase inhibitor, a serine protease inhibitor, a topical anesthetic emulsion, a spreading factor inhibitor, an anti-nausea agent, or an antibiotic.
  • an additional therapeutic agent selected from a steroid, a metalloproteinase inhibitor, a serine protease inhibitor, a topical anesthetic emulsion, a spreading factor inhibitor, an anti-nausea agent, or an antibiotic.
  • A31 The recombinant CD39 according to any one of the above embodiments, wherein the AKI is SA-AKI.
  • A32 The recombinant CD39 according to any of the above embodiments, wherein the AKI is cardiac surgery associated AKI (CSA-AKI).
  • CSA-AKI cardiac surgery associated AKI
  • the recombinant CD39 according to any of the above embodiments, wherein the recombinant CD39 is used in a method for preventing or treating one or more symptoms associated with AKI.
  • a recombinant CD39 for use as a medicament wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • a recombinant CD39 for use in treating or preventing tissue damage wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • a recombinant CD39 for use in treating or preventing tissue damage wherein the tissue damage is acute brain injury (stroke); acute multi-organ failure; delayed graft function after transplantation of kidney or other solid organs; burn damage; radiation damage; acute damage due to trauma and/or hypoxia, such as acute respiratory distress syndrome (ARDS) or lung injury; acute kidney injury, such as acute kidney injury secondary to thoracic surgery (e.g.
  • aortic valve replacement coronary artery bypass surgery
  • sepsis or rhabdomyolysis or toxic effects of antibiotics or other medication acute myocardial injury
  • the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • a method of treating or preventing AKI in a subject, especially a subject in need thereof, said method comprises administering an recombinant CD39, typically in a therapeutically effective amount.
  • B5. The method according to any one of embodiments Bl -B4, wherein the risk of AKI is reduced.
  • B6 The method according to any one of embodiments Bl - B4, wherein the severity of AKI is reduced.
  • B8 The method according to any one of the above embodiments B1-B4, wherein the progression of AKI, e.g. sepsis- AKI, is prevented.
  • B9 The method according to any one of the above embodiments B1-B8, wherein one or more major adverse kidney events are improved, e.g. renal impairment is decreased.
  • BIO A method of treating or preventing sepsis in a subject, especially a subject in need thereof, said method comprises administering an recombinant CD39, typically in a therapeutically effective amount.
  • SOFA sequential organ failure score
  • Bl 3 The method according to any one of the above embodiments Bl -Bl 2, wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • Bl 4 The method according to any one of the above embodiments Bl -Bl 3, wherein the recombinant CD39 is to be administered IV, e.g. is to be administered IV during about 2 hours.
  • Bl 5 The method according to any one of the above embodiments Bl -Bl 4, wherein the recombinant CD39 is to be administered within a number of hours after AKI, or sepsis, is first diagnosed for said subject, e.g. within about 48 hours, or less, after AKI is first diagnosed for said subject (e.g., within 12 hours, within 24 hours, or within 36 hours, for example).
  • Bl 6 The method according to any one of the above embodiments Bl -Bl 5, wherein the recombinant CD39 is to be administered to the subject daily, e.g. IV, at a dosing of about 4 or 5 mg/kg, by infusion, within a time interval initiating from suspected or confirmed AKI diagnosis, or sepsis diagnosis, for said subject.
  • Bl 7 The method according to any one of the above embodiments Bl -Bl 6, wherein the recombinant CD39 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. B18. The method according to any one of the above embodiments Bl -Bl 7, wherein the recombinant CD39 has the amino acid sequence of SEQ ID NO: 21.
  • Bl 9 The method according to any one of the above embodiments Bl -Bl 8, wherein the recombinant CD39 is administered as monotherapy to said subject.
  • B20 The method according to any one of the above embodiments Bl -Bl 8, wherein the recombinant CD39 is co-administered with an additional therapeutic agent.
  • B21 The method according to embodiment B20, wherein the recombinant CD39 is co- administered with an additional therapeutic agent selected from a steroid, a metalloproteinase inhibitor, a serine protease inhibitor, a topical anesthetic emulsion, a spreading factor inhibitor, an anti-nausea agent, or an antibiotic.
  • a method for treatment using a recombinant CD39 wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • a method for treating or preventing tissue damage using a recombinant CD39 wherein the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • tissue damage is acute brain injury (stroke); acute multi-organ failure; delayed graft function after transplantation of kidney or other solid organs; burn damage; radiation damage; acute damage due to trauma and/or hypoxia, such as acute respiratory distress syndrome (ARDS) or lung injury; acute kidney injury, such as acute kidney injury secondary to thoracic surgery (e.g.
  • stroke acute brain injury
  • ARDS acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • lung injury acute kidney injury, such as acute kidney injury secondary to thoracic surgery
  • aortic valve replacement coronary artery bypass surgery
  • sepsis or rhabdomyolysis or toxic effects of antibiotics or other medication acute myocardial injury
  • the recombinant CD39 is to be administered at a dose of from about 0.1 mg/kg to about 10 mg/kg, for example at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
  • DGF delayed graft function
  • ARDS acute respiratory distress syndrome
  • AMI acute myocardial infarction
  • TBI traumatic brain injury
  • AIS acute ischemic stroke
  • IRI ischemia-reperfusion injury
  • MOF multi-organ failures
  • CD39 refers to the human protein CD39 (Cluster of Differentiation 39), also known as ectonucleoside triphosphate diphosphohydrolase- 1 (NTPDasel or Ecto-ATPDase 1).
  • CD39 is an ectonucleotidase present on the cell surface with a catalytic site on the extracellular face that catalyzes the hydrolysis of y- and P-phosphate residues of triphospho- and diphosphonucleosides to the monophosphonucleoside derivative.
  • Human CD39 in particular has the amino acid sequence of SEQ ID NO: 22 and/or is represented by UniProt entry P49961.
  • a “variant of CD39” refers to a protein derived from human CD39 which has an amino acid sequence being at least 60% identical to human CD39 over the entire length of human CD39.
  • the variant of CD39 only consists of the extracellular domain or a part thereof of human CD39 (amino acids 38 to 478 of SEQ ID NO: 22).
  • the variant of CD39 has an amino acid sequence being at least 80% identical to the extracellular domain of human CD39 over the entire length of amino acid positions 38 to 478 of human CD39.
  • the variant of CD39 is a soluble variant, i.e. a variant which lacks the transmembrane domains of human CD39 and its membrane anchors.
  • the variant has an N terminal deletion of 30 to 50 amino acids, a C terminal deletion of 20 to 40 amino acids and/or a central deletion of 10 to 15 amino acids compared to human CD39.
  • the variant may comprise up to 5 point mutations compared to human CD39.
  • Certain variants of CD39 are disclosed in WO 2020/016804.
  • the human recombinant CD39 variant has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.
  • the “recombinant CD39” refers in particular to the human recombinant CD39 variant having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.
  • the term “about” in relation to a numerical value x means, for example, +/-10%. When used in front of a numerical range or list of numbers, the term “about” applies to each number in the series, e.g., the phrase “about 1-5” should be interpreted as “about 1 - about 5”, or, e.g., the phrase “about 1, 2, 3, 4” should be interpreted as “about 1, about 2, about 3, about 4, etc.”
  • a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • pharmaceutically acceptable means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • treatment or “treat” is herein defined as the application or administration of apyrase according to the invention to a subject, or application or administration a pharmaceutical composition comprising said recombinant CD39 to a subject, or an isolated tissue or cell line from a subject, where the subject has tissue damage, a symptom associated with tissue damage, where the purpose is to alleviate, ameliorate, or improve the tissue damage or any associated symptoms of the tissue damage inter alia by reducing levels of extracellular ATP.
  • treatment is also intended the application or administration of a pharmaceutical composition comprising an recombinant CD39 to a subject, or application or administration of a pharmaceutical composition comprising apyrase of the invention to an isolated tissue or cell line from a subject, where the subject has an tissue damage or a symptom associated with tissue damage, where the purpose is to alleviate, ameliorate, or improve the tissue damage or any associated symptoms of the tissue damage.
  • prevent refers to prophylactic or preventative treatment; it is concerned about delaying the onset of, or preventing the onset of the disease, disorders and/or symptoms associated thereto.
  • administering means providing a compound of the invention and prodrugs thereof to a subject in need of treatment.
  • Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and in any route of administration.
  • a “therapeutically effective dose” refers to a dose (an amount) of a recombinant CD39 that is effective, upon single or multiple dose administration to a patient (such as a human) for treating, preventing, preventing the onset of, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder, or prolonging the survival of the patient beyond that expected in the absence of such treatment.
  • a patient such as a human
  • an individual active ingredient e.g., recombinant CD39
  • the term refers to that ingredient alone.
  • the term refers to combined doses or amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • doctor regimen means the regimen used to treat an illness, e.g., the dosing protocol used during the treatment of AKI, SA-AKI or CSA-AKI.
  • phrases “means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an intravenous (i.v.) drip and bag, a pump, a patch pump, etc.
  • a patient may self-administer the drug (i.e., administer the drug on their own behalf) or a physician may administer the drug.
  • AKI e.g. severe AKI
  • This classification system stages AKI into three levels based on the extent of sCr elevation in parallel with the degree and duration of oliguria; patients are classified based on the worst finding (either sCr or oliguria). Three stages of AKI are classified in the table below:
  • the diagnosis of sepsis can be done for example according to the criteria defined by The Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3), with an additional diagnosis of AKI (stage 1 or greater using the KDIGO serum creatinine-based criteria).
  • cardiac surgery is used to refer to non-emergent open chest cavity major cardiopulmonary bypass (CPB) surgery with expected CPB time >1 hour, defined be any of the following options: a. combined coronary artery bypass grafting (CABG) surgery and surgery of one or more cardiac valve (valve(s) surgery) b. surgery of more than one cardiac valve (valve surgery) c. surgery of the aortic root or ascending part of the aorta, or in combination with the aortic valve d. aortic root or ascending part of the aorta, combined with CABG and/or valve(s) surgery.
  • CABG coronary artery bypass grafting
  • valve(s) surgery surgery of more than one cardiac valve
  • valve surgery c. surgery of the aortic root or ascending part of the aorta, or in combination with the aortic valve
  • aortic root or ascending part of the aorta combined with CABG and/or valve(s) surgery.
  • “Sequential Organ Failure Assessment Score” The SOFA (sequential organ failure assessment) score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments. Following the development of new definitions, it is now used as a key criterion in the diagnosis of sepsis syndrome on an individual patient level. The score is routinely calculated on admission to ICU and at each 24-hour period that follows. It is composed of six criteria which reflect the function of a specific organ system (respiratory, cardiovascular, renal, neurological, hepatic and hematological) and allocates a score of 0-4.
  • Scores ranges from 0-24, with higher scores indicating greater dysfunction.
  • the SOFA score has been applied in a range of clinical and research applications.
  • Acute Physiology and Chronic Health Evaluation The APACHE-II (Acute Physiology and Chronic Health Evaluation II) score is a severity-of-disease classification system for the assessment of critically unwell patients. It is applied within 24 hours of admission of a patient to an ICU or intermediate/HDU. An integer score from 0-71 is computed based on several measurements: higher scores correspond to more severe disease and a higher risk of death in ICU patients.
  • RRT Random replacement therapy
  • MAKE Major Adverse Kidney Events
  • the disclosure relates to the use recombinant CD39 according to the invention for the treatment of sepsis associated acute kidney injury, SA-AKI.
  • the disclosure relates to the use recombinant CD39 according to the invention for the treatment of cardiac surgery associated acute kidney injury, CSA-AKI.
  • Therapeutic proteins are typically formulated either in aqueous form ready for administration or as lyophilizate for reconstitution with a suitable diluent prior to administration.
  • a protein may be formulated either as a lyophilizate, or as an aqueous composition, for example in pre- filled syringes.
  • Suitable formulation can provide an aqueous pharmaceutical composition or a lyophilizate which can be reconstituted to give a solution with a high concentration of the therapeutic protein active ingredient and a low level of protein aggregation for delivery to a patient.
  • High concentrations of protein are useful as they reduce the amount of material which must be delivered to a patient (the dose). Reduced dosing volumes minimize the time taken to deliver a fixed dose to the patient.
  • the aqueous compositions of the invention with high concentration of proteins are particularly suitable for subcutaneous administration.
  • the invention provides an aqueous pharmaceutical composition, suitable for administration in a subject, e.g., for subcutaneous administration, comprising a therapeutic protein.
  • the therapeutic protein may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may contain, in addition to a therapeutic protein, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • the characteristics of the carrier will depend on the route of administration.
  • the pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder.
  • indications for use according to the present invention require immediate treatment, rather than oral administration and may be given as an IV or liquid formulation.
  • a recombinant CD39 (in the following "CD39*") having the amino acid sequence of SEQ ID NO: 21, is an engineered, highly effective, soluble, and stabilized human recombinant CD39 enzyme.
  • the enzyme hydrolyzes extracellular ATP and ADP to adenosine monophosphate (AMP), which is a rate limiting step in conversion of extracellular ATP to adenosine.
  • AMP is further catalyzed by the ecto-5’ -nucleotidase CD73 to adenosine.
  • CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells, driving a shift from an ATP-driven pro-inflammatory environment to an anti-inflammatory milieu induced by adenosine. It is becoming increasingly appreciated that rebalancing this equilibrium could change the course and outcome of several pathophysiological events, such as SA-AKI.
  • CD39* has been investigated extensively in preclinical models. In human whole blood CD39* dose dependently inhibited ATP/Lipopolysaccharide (LPS)-induced IL- 10 secretion as well as ADP induced platelet aggregation. CD39* has been proven beneficial in preclinical models of acute organ injuries, including mouse models of ischemia-reperfusion induced AKI where CD39* was dose dependently preserving kidney function. The protection could be shown in terms of kidney structure, kidney inflammation, and acute tubular necrosis, which are also hallmarks of human AKI pathophysiology (results not shown).
  • LPS Lipopolysaccharide
  • Biomarkers of target engagement and proximal pharmacodynamic extracellular ATP and ADP in the urine of animals after AKI are dose-dependently reduced and extracellular AMP and adenosine are dose-dependently increased.
  • This study is a Phase I, randomized, placebo-controlled, participant-blinded study in healthy volunteers.
  • a single IV. dose of CD39* (0.1, 0.3, 1.0 and 2.0 mg/kg, and 4.0 mg/kg) have been administered as a 2-hour infusion to healthy participants.
  • CD39* was safe and well tolerated without any immunogenicity findings.
  • the pathway engagement markers demonstrate dose-dependent and reversible inhibition of (i) ex vivo ADP-induced platelet aggregation and (ii) ex vivo LPS/ATP-induced IL-10 release in CD39* treated subjects resulting in ex vivo IC90s of 0.25 and 7.8 pg/mL for inhibition of platelet aggregation and IL- 10 release, respectively.
  • CD39* at doses higher than 0.1 mg/kg induced a dose dependent and reversible reduction of free inorganic pyrophosphate (PPi) levels with maximum effect reached within hours post dose.
  • PPi free inorganic pyrophosphate
  • Exposure determined by Cmax and AUCinf demonstrated dose proportional behavior for this dose range.
  • Dose proportionality was also demonstrated by assessing correlation between dose and Cmax and between dose and AUC via a power model.
  • CD39* exposure was investigated throughout SAD Cohorts 1 to 4 (0.1, 0.3, 1.0 and 2.0 mg/kg IV) in human skin by quantifying CD39* in interstitial fluid collected via suction blisters at 24 h and 168 h post-dose.
  • CD39* exposure in interstitial fluid increased in a fairly dose proportional manner.
  • mean interstitial fluid concentrations increased 3-, 10 and 33-fold at 24 hours post-dose and 3-, 9- and 18-fold at 168 hours post-dose, respectively.
  • Example 4 A method of treating sepsis associated acute kidney injury comprising administering a therapeutically effective dose of recombinant CD39* to a subject in need of such treatment
  • ICU intensive care unit
  • HDU intermediate/high dependency unit
  • SOFA sequential organ failure assessment
  • KDIGO kidney disease improving global outcomes
  • Participants will be randomly assigned to receive either CD39* at 2 mg/kg or placebo using a 3: 1 allocation ratio (CD39*:placebo).
  • a single dose of the study treatment will be administered via 2-hour IV at the randomization visit in a participant and investigator-blinded fashion.
  • the study treatment must be administered within 48 hours, after SA-AKI is first diagnosed, but ideally as soon as possible.
  • Two PK samples will be taken at Day 1, one prior to study treatment and one immediately after the completion of IV infusion (within 15 minutes), and additional samples will be taken at Day 2, 3, 5, 8, 14, 30, 60 and 90, optimally always at the same time of the day as when dosing of CD39* started on Day 1. All participants will be followed-up for a total duration of 90 days.
  • Total exposure (AUCinf) of a single dose of 2 mg/kg in human is approximately 10.4-fold lower compared to the NOAEL overall exposure from 4 IV doses of 10 mg/kg CD39* administered q4d in the 2 weeks minipig study (compared to AUCtau,ss from the 4th dose in minipig at steady state the exposure margin is 2.6-fold) and Cmax shows a 7-fold margin to the NOAEL exposure. Participants will be followed-up for a total duration of 90 days.
  • Weight is less than 40 kg or more than 125 kg .
  • AKI diagnosis according to the AKI inclusion criteria for a period longer than 48 hours prior to study drug administration.
  • Presence of AKI for a period longer than 48 hours prior to study drug administration as suggested by clinical manifestations, e.g., prolonged oliguria or severe renal dysfunction (e.g., serum creatinine > 4 mg/dL) on admission without a history of CKD.
  • prolonged oliguria or severe renal dysfunction e.g., serum creatinine > 4 mg/dL
  • AKI is most likely attributable to causes other than sepsis such as nephrotoxic drugs (Nonsteroidal anti-inflammatory drugs (NSAIDs), contrast, aminoglycosides), other medical conditions (e.g. heart failure, liver failure, acute abdominal aortic aneurysm, dissection, renal artery stenosis) or urinary obstruction.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • contrast e.g. contrast, contrast, aminoglycosides
  • other medical conditions e.g. heart failure, liver failure, acute abdominal aortic aneurysm, dissection, renal artery stenosis
  • urinary obstruction e.g. heart failure, liver failure, acute abdominal aortic aneurysm, dissection, renal artery stenosis
  • Patients with septic shock treated with hydrocortisone e.g., 3 x 100 mg can be included.
  • Active hepatitis defined as (a) abnormal liver enzymes (Alanine aminotransferase (ALT), Gamma-glutamyl transferase (GGT), ALP > 3x Upper Limit of Normal (ULN) or (b)) for active hepatitis B or C infection, a positive Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) serology or patients with advanced chronic liver disease, confirmed by a Child-Pugh score of 10-15 (Class C).
  • ALT Alanine aminotransferase
  • GTT Gamma-glutamyl transferase
  • ULP Upper Limit of Normal
  • HBV Hepatitis B Virus
  • HCV Hepatitis C Virus
  • Study treatment drug will be administered as an 2 hour IV infusion (approximately) via a perfusor syringe at the clinical site by the study personnel in accordance with the specified study procedures.
  • Example 5 A randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to evaluate the safety, tolerability and efficacy of single i.v. infusion of CD39* in adult patients at risk for acute kidney injury following cardiac surgery
  • Participants enrolling into this study will be managed according to current medical and surgical standard of care and as per standard institutional procedures.
  • the study will consist of a pre-operative period (screening visit), a treatment period (Day 1) and a follow-up period (Day 2 to Day 90). Participants will be followed up on Day 2, 3, 4, 5 , 6 and Day 8 in hospital (or at home/in rehab until if discharged earlier than Day 8), and then as an out-patient until the end of study (Day 30 and 90 visits).
  • BMI Body weight (kg) / [Height (m)] 2
  • vital signs systolic and diastolic blood pressure and pulse rate
  • Sitting vital signs should be within the following ranges: a. oral body temperature between 35.0-37.5 °C b. blood pressure (systolic 100-160 mmHg, diastolic ⁇ 100 mmHg) c. pulse rate (50-100/min) stable with or without medication as per Investigator assessment.
  • the Investigator may obtain two additional readings, so that up to three consecutive assessments are made. At least the last reading must be within the ranges provided above in order for the participant to qualify.
  • CABG coronary artery bypass grafting
  • MICS Minimally invasive cardiac surgeries
  • TAVI Transcatheter aortic valve implantation
  • TAVR transcatheter aortic valve replacement
  • - Pre-existing coagulation factor deficiency including, but not limited to fibrinogen ⁇ 2.5-2.8 g/L
  • MIDCAB minimally invasive direct coronary artery bypass
  • LVAD left ventricular assist device
  • IABP intra-aortic balloon counterpulsation
  • liver disease or liver injury as indicated by abnormal liver function tests ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase and serum bilirubin will be tested.
  • HBV Hepatitis B
  • HCV Hepatitis C
  • HBsAg Hepatitis Ag test, or if standard local practice, a positive HBV core antibody test, excludes a participant. .
  • Active hepatitis defined by active AST/ALT???( from sepsis trial?) History of drug abuse or unhealthy alcohol use # within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening. # Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined as “Five or more drinks on the same occasion on each of 5 or more days in the past 30 days.” Pregnant or nursing (lactating) women. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and until the end of study. Highly effective contraception methods include:
  • Example 6 A multicenter, randomized, double-blind, placebo-controlled, four-arm, parallel-group, dose-finding phase 2b study to investigate the safety and efficacy of CD39* in the treatment of patients with sepsis-associated acute kidney injury (SA-AKI)
  • the reference pre-sepsis serum creatinine should be estimated using the following order of preference:
  • the secondary estimands are defined by the evaluation of study treatment effect on the following endpoints and summary measures: • MAKE (death, RRT, >25% reduction in eGFR) at Day 90: The summary measure is the odds ratio of participants with MAKE.
  • RRT dependency at Day 90 The summary measure is the odds ratio of participants using RRT.
  • Proportion of participants with >25% reduction in eGFR at Day 90 The summary measure is the odds ratio of participants with >25% reduction in eGFR.
  • KDIGO AKI stage The summary measure is the status change from baseline in KDIGO AKI stage at Day 14.

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Abstract

La présente invention concerne l'utilisation pour traiter une lésion organique, en particulier une lésion organique aiguë, telle qu'une lésion rénale aiguë (AKI), à l'aide de CD39, de CD39 recombinant humain et de variants de celui-ci.
PCT/IB2023/057612 2022-07-29 2023-07-27 Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant Ceased WO2024023745A1 (fr)

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EP23754430.9A EP4561608A1 (fr) 2022-07-29 2023-07-27 Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant
IL318380A IL318380A (en) 2022-07-29 2023-07-27 Treatment of acute organ injury using CD39, recombinant CD39
CN202380055750.6A CN119604301A (zh) 2022-07-29 2023-07-27 使用cd39、重组cd39用于急性器官损伤的治疗
CA3262869A CA3262869A1 (fr) 2022-07-29 2023-07-27 Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant
JP2025504179A JP2025524942A (ja) 2022-07-29 2023-07-27 Ｃｄ３９、組換えｃｄ３９を使用した急性臓器障害の治療
KR1020257005894A KR20250044705A (ko) 2022-07-29 2023-07-27 Cd39, 재조합 cd39를 사용하는 급성 기관 손상의 치료

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WO2020016804A1 (fr) 2018-07-18 2020-01-23 Novartis Ag Apyrases solubilisées, méthodes et utilisation

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Publication number Priority date Publication date Assignee Title
WO2020016804A1 (fr) 2018-07-18 2020-01-23 Novartis Ag Apyrases solubilisées, méthodes et utilisation

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Title
"UniProt", Database accession no. P49961
DWYER KAREN M ET AL: "Conversion of extracellular ATP into adenosine: a master switch in renal health and disease", NATURE REVIEWS. NEPHROLOGY, vol. 16, no. 9, 1 September 2020 (2020-09-01), pages 509 - 524, XP037370495, ISSN: 1759-5061, DOI: 10.1038/S41581-020-0304-7 *
GRENZ ALMUT ET AL: "Contribution of E-NTPDasel (CD39) to renal protection from ischemia-reperfusion injury", THE FASEB JOURNAL, vol. 21, no. 11, 18 April 2007 (2007-04-18), US, pages 2863 - 2873, XP093093243, ISSN: 0892-6638, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.06-7947com> DOI: 10.1096/fj.06-7947com *
PETER PICKKERS ET AL: "Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial", CRITICAL CARE, BIOMED CENTRAL LTD LONDON, GB, vol. 16, no. 1, 23 January 2012 (2012-01-23), pages R14, XP021117576, ISSN: 1364-8535, DOI: 10.1186/CC11159 *
WANG YING ET AL: "Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment", NATURE REVIEWS. NEPHROLOGY, vol. 13, no. 11, 1 November 2017 (2017-11-01), GB, pages 697 - 711, XP055840761, ISSN: 1759-5061, Retrieved from the Internet <URL:https://www.nature.com/articles/nrneph.2017.119.pdf> DOI: 10.1038/nrneph.2017.119 *

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