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WO2024129057A1 - Méthodes de traitement d'une lésion cardiaque - Google Patents

Méthodes de traitement d'une lésion cardiaque Download PDF

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Publication number
WO2024129057A1
WO2024129057A1 PCT/US2022/052553 US2022052553W WO2024129057A1 WO 2024129057 A1 WO2024129057 A1 WO 2024129057A1 US 2022052553 W US2022052553 W US 2022052553W WO 2024129057 A1 WO2024129057 A1 WO 2024129057A1
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WO
WIPO (PCT)
Prior art keywords
angiotensin
subject
catecholamine
vasopressin
troponin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/052553
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English (en)
Inventor
Emily SEE
James Wilkie
Lakhmir Chawla
Rinaldo Bellomo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Proletariat Therapeutics Inc
Original Assignee
Proletariat Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Proletariat Therapeutics Inc filed Critical Proletariat Therapeutics Inc
Priority to JP2025556765A priority Critical patent/JP2025538841A/ja
Priority to EP22968694.4A priority patent/EP4633658A1/fr
Priority to PCT/US2022/052553 priority patent/WO2024129057A1/fr
Publication of WO2024129057A1 publication Critical patent/WO2024129057A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins

Definitions

  • Vasodilatory shock is a life-threatening condition of circulatory failure that results in hypotension, reduced tissue perfusion, progressive organ failure, and an increased risk of death.
  • Patients with vasodilatory shock are commonly treated with a vasopressor such as a catecholamine and/or vasopressin to act as vasoconstrictors to increase blood pressure.
  • Catecholamines are monoamine neurotransmitters having a catechol and a sidechain amine.
  • Catecholamines include epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine.
  • Catecholamines cause general physiological changes that prepare the body for physical activity (the fight-or-flight response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system.
  • Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and anti diuresis.
  • vasopressin is Cyclo (1 -6) L-Cy steinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L- Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinam.
  • Administration of both catecholamines and vasopressin have been shown to be effective in many patients to maintain mean arterial pressure at a desired level. However, administration of both catecholamines and vasopressin can have toxic effects.
  • Angiotensin II has only been studied in patients with catecholamine-refractory vasodilatory shock.
  • double-blind ATHOS-3 trial Angiotensin II for the Treatment of High-Output Shock trial
  • adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were administered angiotensin II and 70% of patients achieved a MAP > 75 mmHg or a > 10 mmHg increase in MAP without change in baseline vasopressor therapy at 3 hours, compared to only 23% of subjects who received placebo (p ⁇ 0.0001).
  • Chawla describes methods of administering angiotensin II to a subject having high output shock and undergoing treatment with a catecholamine, wherein the angiotensin II is effective to raise or maintain mean arterial pressure (MAP) of the subject, and reducing the dose of the catecholamine.
  • MAP mean arterial pressure
  • U.S. Patent 9,220,745. Chawla does not provide any evidence that the administration of angiotensin II will enable sufficient reduction of catecholamine administration to an extent sufficient to treat (e.g., mitigate, prevent) any catecholamine- associated toxicity, or in particular cardiac injury associated with catecholamine administration.
  • SAH subarachnoid hemorrhage
  • DCI delayed cerebral ischemia
  • treating refers to partially or completely alleviating, ameliorating, relieving, mitigating, preventing, delaying onset of, inhibiting, or slowing progression of, reducing severity of, and/or reducing incidence of cardiac injury. Treatment can be administered to a subject who does not exhibit signs of cardiac injury and/or to a subject who exhibits signs of cardiac injury.
  • an “effective amount” of a composition is that amount of composition which is sufficient to provide a beneficial effect to the subject to which the composition is administered.
  • the phrase “therapeutically effective amount”, as used herein, refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition, including alleviating symptoms of such diseases.
  • a therapeutically effective amount of angiotensin II is an amount that is sufficient to increase blood pressure and/or to treat cardiac injury. Such therapeutic effect on cardiac injury may be determined by evaluating the effect on cardiac troponin levels.
  • the dose administration can last from about 0.25 hours to about 120 hours, e.g., from about 1 hour to about 7 hours, 2 hours to about 6 hours, or about 3 hours to about 5 hours.
  • the therapeutic regimen can be started within, e.g., 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, or 72 hours, after the onset of acute symptoms.
  • compositions of the invention can be administered in a variety of conventional ways.
  • the compositions of the invention are suitable for parenteral administration. These compositions may be administered, for example, intraperitoneally, intravenously, intra-arterially, intrarenally, or intrathecally.
  • the compositions of the invention are injected intravenously.
  • a method of administering a therapeutically effective substance formulation or composition of the invention would depend on factors such as the age, weight, and physical condition of the patient being treated, and the disease or condition being treated. The skilled worker would, thus, be able to select a method of administration optimal for a patient on a case-by-case basis.
  • the method of the invention involves administering angiotensin II to a subject.
  • the subject may have hypotension, normotension, or hypertension depending on the clinical context and disease state.
  • One aspect of the invention is a method comprising administering to a subject, wherein the subject has cardiac injury.
  • a subject having cardiac injury may be identified based on the presence of a detectable amount of troponin in blood.
  • a subject having cardiac injury may also be identified based on the presence of an elevated amount of troponin present in the blood.
  • Diagnosis of cardiac injury is often based on detecting the presence of Troponin I (cardiac troponin I, denoted cTnl) and/or troponin T (cardiac troponin T, denoted cTnT).
  • Myocardial injury is defined as being present when blood levels of cTn are increased above the 99th percentile upper reference limit (URL).
  • the injury may be acute, as evidenced by a newly detected dynamic rising and/or falling pattern of cTn values above the 99th percentile URL, or chronic, in the setting of persistently elevated cTn levels.
  • Cardiac troponin T and I are measured by immunoassay methods. Roche Diagnostics distributes its proprietary cTnT and a variety of diagnostic companies make cTnl immunoassay methods available on many different immunoassay platforms.
  • the 99th percentile cutoff for cardiac troponin T (cTnT) is 0.01 ng/mL.
  • the reference range for the high sensitivity troponin T is a normal ⁇ 14 ng/L, borderline of 14-52 ng/L, and elevated of >52 ng/L.
  • a subject having cardiac injury may also be identified based on echocardiography, e.g., by the presence of regional wall motion abnormalities (RWMA) visible in an echocardiogram.
  • RWMA regional wall motion abnormalities
  • a subject having cardiac injury may be identified based on a combination of the presence of e.g., elevated cardiac troponin and by the presence of regional wall motion abnormalities (RWMA).
  • the subject having cardiac injury may be a subject whose cardiac injury is associated with, e.g., is a result of, being administered or having been administered a catecholamine (e.g., catecholamine-induced cardiac injury) and/or vasopressin.
  • a catecholamine e.g., catecholamine-induced cardiac injury
  • vasopressin e.g., vasopressin-induced cardiac injury
  • Such a subject may be administered or may have been administered a catecholamine and/or vasopressin at a dose level that creates cardiac injury or may be administered or may have been administered a catecholamine and/or vasopressin for a duration long enough to create a cardiac injury.
  • a subject not having cardiac injury may also be identified based on echocardiography, e.g., by the absence of regional wall motion abnormalities (RWMA) visible in an echocardiogram.
  • a subject having cardiac injury may be identified based on a combination of the absence of e.g., elevated cardiac troponin and by the absence of regional wall motion abnormalities (RWMA).
  • the subject not having cardiac injury may be at risk of cardiac injury.
  • Subjects having a risk of cardiac injury may be subjects having cardiac risk factors including hypertension, diabetes mellitus, heart failure, coronary artery disease, atrial fibrillation/flutter, and cerebrovascular disease, advanced age, history of smoking, history of pulmonary or kidney disease and/or diagnosis with COVID-19.
  • the subject having a risk of cardiac injury may be a subject who is being administered or has been administered a catecholamine.
  • a subject may be administered or may have been administered a vasopressor, such as a catecholamine and/or vasopressin, at a dose level that creates cardiac injury or may be administered or may have been administered a vasopressor, such as a catecholamine and/or vasopressin, for a duration long enough to create a cardiac injury.
  • a vasopressor such as a catecholamine and/or vasopressin
  • the subject is undergoing standard-of-care treatment with a vasopressor, e.g., a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) and/or vasopressin at or prior to the time the angiotensin II is administered.
  • a vasopressor e.g., a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) and/or vasopressin at or prior to the time the angiotensin II is administered.
  • a vasopressor e.g., a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) and/or vasopressin at or prior to
  • the methods can also comprise administering angiotensin II in combination with a conventional vasopressor (e.g., a catecholamine and/or vasopressin) and then adjusting (e.g., reducing or titrating downward or discontinuing) the dose of the conventional vasopressor (e.g., a catecholamine and/or vasopressin) as compared to the starting dose of the conventional vasopressor.
  • a conventional vasopressor e.g., a catecholamine and/or vasopressin
  • the methods comprising administration of angiotensin II are effective to raise the blood pressure of the subject to a mean arterial pressure (MAP) of about 65 mm Hg or above, or about 70 mm Hg or above, or about 75 mm Hg or above, or about 80 mm Hg, or about 85 mm Hg or above, or about 90 mm Hg or above, or about 95 mm Hg or above, or about 100 mm Hg or above.
  • MAP mean arterial pressure
  • the subject has elevated blood troponin levels (e.g., increased high sensitivity cardiac troponin, Troponin I, or the like) at the time of the administration of angiotensin II.
  • the administration of the therapeutically effective amount of angiotensin II to the subject prevents further increases in the amount of blood troponin in the subject.
  • the administration of the therapeutically effective amount of angiotensin II to the subject reduces further increases in the amount of blood troponin in the subject (e.g., compared to the increase that would be observed in the absence of angiotensin administration).
  • the administration of the therapeutically effective amount of angiotensin II to the subject has the effect of reducing the amount of blood troponin in the subject.
  • the method further comprises a step of determining the blood troponin level of the subject prior to administration of angiotensin II. In some aspects of the invention, the method further comprises a step of determining the blood troponin level of the subject after administration of angiotensin II. In other aspects of the invention, the method further comprises comparing the blood troponin level of the subject prior to administration of angiotensin II to the blood troponin level of the subject after administration of angiotensin II. Further, in some aspects, the method comprises a step of adjusting the dose of the angiotensin II based on the subjects blood pressure, usage of a catecholamine, and the level of blood troponin determined following administration of angiotensin II.
  • the subject having catecholamine-associated cardiac injury has elevated blood troponin levels (e.g., increased high sensitivity cardiac troponin, Troponin I, or the like) at the time of the administration of angiotensin II.
  • the administration of the therapeutically effective amount of angiotensin II to the subject prevents further increases in the amount of blood troponin in the subject.
  • the administration of the therapeutically effective amount of angiotensin II to the subject reduces further increases in the amount of blood troponin in the subject (e.g., compared to the increase that would be observed in the absence of angiotensin administration).
  • the method comprises a step of adjusting the dose of the angiotensin II based on the subject’s blood pressure, the dose of catecholamine and level of blood troponin determined following administration of angiotensin II.
  • the dose of angiotensin II is increased or titrated upward when the level of blood troponin determined following administration of angiotensin II is greater than or equal to the amount of troponin present before administering angiotensin II.
  • the methods of the invention include each of the following methods.
  • a method of treating cardiac injury in a subject comprising administering a therapeutically effective amount of angiotensin II to a subject in need thereof.
  • the blood troponin is a high sensitivity cardiac troponin (hs-cTn).
  • a method of treating catecholamine-associated or vasopressin-associated cardiac injury in a subject comprising administering angiotensin II to a subject in need thereof.
  • the method of claim 12 wherein the subject has cardiac injury.
  • the method of claim 13 wherein the subject has increased blood troponin.
  • the method of claim 14, wherein the blood troponin is a high sensitivity cardiac troponin (hs-cTn).
  • the method of any one of claims 14-15, wherein the blood troponin is Troponin I.
  • the method of any one of claims 14-16, wherein increased blood troponin is blood troponin levels above the 99 th percentile upper reference limit.
  • the method of claim 19, wherein the administration of angiotensin II allows for discontinuation of the administration of catecholamine and/or vasopressin.
  • a method of treating catecholamine-associated or vasopressin-associated cardiac injury in a subject wherein the subject does not have cardiac injury comprising administering angiotensin II to a subject in need thereof.
  • a method of treating catecholamine-associated and/or vasopressin-associated cardiac injury in a subject who has been previously administered a catecholamine and/or vasopressin comprising the steps of (1) administering angiotensin II to the subject and (2) discontinuing administration of the catecholamine and/or vasopressin.
  • a method of treating catecholamine associated cardiac injury comprising administering angiotensin II to a subject receiving catecholamine and/or vasopressin at an initial dose, comprising the steps of (1) administering angiotensin II to the subject and (2) administering catecholamine and/or vasopressin to the subject at a dose that is lower than the initial dose.
  • angiotensin II can be increased in a subject if the amount of troponin present in a sample obtained from the subject after administering angiotensin II is greater than or equal to the amount of troponin present in a sample obtained from the subject before administering angiotensin II. 41.
  • a method of increasing blood pressure in a subject in need of being held in a hypertensive state comprising these steps of administering angiotensin II.
  • the pH of the compositions of the invention may be any pH that provides desirable properties for the formulation or composition. Desirable properties may include, for example, therapeutically effective substance (e.g., angiotensin II) stability, increased therapeutically effective substance retention as compared to compositions at other pHs, and improved filtration efficiency.
  • the pH of the compositions of the invention may be from about 3.0 to about 9.0, e.g., from about 5.0 to about 7.0.
  • the pH of the compositions of the invention may be 5.5 ⁇ 0.1, 5.6 ⁇ 0.1, 5.7 ⁇ 0.1, 5.8 ⁇ 0.1, 5.9 ⁇ 0.1, 6.0 ⁇ 0.1, 6. l ⁇ 0.1, 6.2 ⁇ 0.1, 6.3 ⁇ 0.1, 6.4 ⁇ 0.1, or 6.5 ⁇ 0.1.
  • Stabilizing agents help increase the stability of a therapeutically effective substance in compositions of the invention. This may occur by, for example, reducing degradation or preventing aggregation of a therapeutically effective substance. Without wishing to be bound by theory, mechanisms for enhancing stability may include sequestration of the therapeutically effective substance from a solvent or inhibiting free radical oxidation of the anthracy cline compound. Stabilizing agents are well known in the art. Accordingly, the stabilizing agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary stabilizing agents that may be used in the compositions of the invention. Stabilizing agents may include, but are not limited to, emulsifiers and surfactants.
  • ARB angiotensin receptor blocker
  • CRRT continuous renal replacement therapy
  • ICU intensive care unit
  • ACE inhibitor 12 121 (78 to 200) 183 (129 to 232)

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Abstract

L'invention concerne des méthodes de traitement d'une lésion cardiaque chez un sujet comprenant l'administration d'une quantité thérapeutiquement efficace d'angiotensine II au sujet. L'invention concerne également des méthodes de traitement d'une lésion cardiaque associée à la catécholamine chez un sujet, comprenant l'administration d'une quantité thérapeutiquement efficace d'angiotensine II au sujet. Le sujet peut avoir une lésion cardiaque, ou le sujet peut être à risque d'avoir une lésion cardiaque.
PCT/US2022/052553 2022-12-12 2022-12-12 Méthodes de traitement d'une lésion cardiaque Ceased WO2024129057A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2025556765A JP2025538841A (ja) 2022-12-12 2022-12-12 心損傷を処置する方法
EP22968694.4A EP4633658A1 (fr) 2022-12-12 2022-12-12 Méthodes de traitement d'une lésion cardiaque
PCT/US2022/052553 WO2024129057A1 (fr) 2022-12-12 2022-12-12 Méthodes de traitement d'une lésion cardiaque

Applications Claiming Priority (1)

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PCT/US2022/052553 WO2024129057A1 (fr) 2022-12-12 2022-12-12 Méthodes de traitement d'une lésion cardiaque

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WO2024129057A1 true WO2024129057A1 (fr) 2024-06-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150164980A1 (en) * 2013-12-18 2015-06-18 The George Washington University a Congressionally Chartered Not-for-Profit Corporation Angiotensin ii alone or in combination for the treatment of hypotension
WO2021038078A1 (fr) * 2019-08-30 2021-03-04 4TEEN4 Pharmaceuticals GmbH Orientation de thérapie et/ou surveillance de thérapie permettant le traitement d'un choc
US20210292715A1 (en) * 2018-07-17 2021-09-23 The Regents Of The University Of California Cells differentiated from immunoengineered pluripotent cells

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150164980A1 (en) * 2013-12-18 2015-06-18 The George Washington University a Congressionally Chartered Not-for-Profit Corporation Angiotensin ii alone or in combination for the treatment of hypotension
US20210292715A1 (en) * 2018-07-17 2021-09-23 The Regents Of The University Of California Cells differentiated from immunoengineered pluripotent cells
WO2021038078A1 (fr) * 2019-08-30 2021-03-04 4TEEN4 Pharmaceuticals GmbH Orientation de thérapie et/ou surveillance de thérapie permettant le traitement d'un choc

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GARCIA BRUNO, SU FUHONG, DEWACHTER LAURENCE, FAVORY RAPHAËL, KHALDI AMINA, MOIROUX-SAHRAOUI ALEXANDER, ANNONI FILIPPO, VASQUES-NÓV: "Myocardial effects of angiotensin II compared to norepinephrine in an animal model of septic shock", CRITICAL CARE, BIOMED CENTRAL LTD LONDON, GB, vol. 26, no. 1, GB , XP093184436, ISSN: 1364-8535, DOI: 10.1186/s13054-022-04161-3 *
KIM JUNE-SUNG, KIM MUYEOL, KIM YOUN-JUNG, RYOO SEUNG MOK, SOHN CHANG HWAN, AHN SHIN, KIM WON YOUNG: "Troponin Testing for Assessing Sepsis-Induced Myocardial Dysfunction in Patients with Septic Shock", JOURNAL OF CLINICAL MEDICINE, MULTIDISCIPLINARY DIGITAL PUBLISHING INSTITUTE (MDPI), CH, vol. 8, no. 2, CH , pages 239, XP093184432, ISSN: 2077-0383, DOI: 10.3390/jcm8020239 *
MARíN-CABALLOS ANTONIO J; MURILLO-CABEZAS FRANCISCO; CAYUELA-DOMíNGUEZ AURELIO; DOMíNGUEZ-ROLDáN JOSE M; RINC&: "Cerebral perfusion pressure and risk of brain hypoxia in severe head injury: a prospective observational study", CRITICAL CARE, BIOMED CENTRAL LTD LONDON, GB, vol. 9, no. 6, 14 October 2005 (2005-10-14), GB , pages R670 - R676, XP021012408, ISSN: 1364-8535, DOI: 10.1186/cc3822 *

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JP2025538841A (ja) 2025-11-28
EP4633658A1 (fr) 2025-10-22

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