WO2021217084A1 - Utilisation d'acides gras nitro et d'analogues de ceux-ci pour la prévention et/ou le traitement d'une atteinte pulmonaire aiguë et/ou d'une infection à sras-cov-2 - Google Patents

Utilisation d'acides gras nitro et d'analogues de ceux-ci pour la prévention et/ou le traitement d'une atteinte pulmonaire aiguë et/ou d'une infection à sras-cov-2 Download PDF

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WO2021217084A1
WO2021217084A1 PCT/US2021/028969 US2021028969W WO2021217084A1 WO 2021217084 A1 WO2021217084 A1 WO 2021217084A1 US 2021028969 W US2021028969 W US 2021028969W WO 2021217084 A1 WO2021217084 A1 WO 2021217084A1
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subject
treatment
compound
formula
dose
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PCT/US2021/028969
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Francisco SALVA
William W. Leong
Robert N. Willette
Theodore Danoff
Gerald O'brien
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Imara Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • ALI acute lung injury
  • ALI caused by viral respiratory infections, such as ALI caused by infection with coronaviruses, notably infection with SARS-CoV-2.
  • Patients with acute lung injury are at risk of progressing to intubation, with a particularly difficult and unpredictable treatment course made especially bleak by the potential for rationing of mechanical ventilators.
  • ALI is associated with cellular infiltration of the airways and inflammation.
  • Interleukin-6 (IL-6) and GM-CSF are among the cytokines implicated in ALI.
  • agents that specifically inhibit IL-6 such as tocilizumab
  • agents that inhibit GM-CSF such as gemsilumab
  • agents that are more generally anti-inflammatory such as hydroxychloroquine
  • ALI acute lung inflammation
  • ARDS acute respiratory distress syndrome
  • ALI acute respiratory distress syndrome
  • ALI acute respiratory distress syndrome
  • ARDS ALI with concomitant pneumonia
  • ARDS with concomitant pneumonia comprise: administering an effective amount of a compound of Formula I,
  • Formula I or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof to a subject who has or is at risk for developing or worsening of acute lung inflammation (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia, wherein:
  • X is selected from H, alkyl, substituted alkyl, alkenyl, nitroalkenyl, substituted alkenyl, substituted nitroalkenyl, a is from 0-30; b is from 0-30;
  • R 1 is selected from H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, - C(0)-R 2 , gluconate, glycoside, glucuronide, tocopherols, and PEG groups;
  • R 2 is selected from alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and at least one pharmaceutically acceptable carrier or excipient.
  • R 1 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, or pentyl.
  • R 1 is H.
  • the compound of Formula I is nitro-oleic acid.
  • the compound of Formula I is 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof.
  • the compound of Formula I is 9-nitro-9(E)-octadec-9-enoic acid (CXA-9), or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof.
  • the subject has or is at risk for developing or worsening of ALI. In some embodiments, the subject has or is at risk for developing or worsening of ARDS. In some embodiments, the subject has or is at risk for developing or worsening of ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • the subject has confirmed or suspected viral infection.
  • the infection is by a virus selected from the group consisting of coronavirus, influenza virus, rhinovirus, respiratory syncytial virus, metapneumovirus, adenovirus, and boca virus.
  • the virus is an influenza virus selected from the group consisting of parainfluenza virus 1, parainfluenza virus 2, influenza A virus, and influenza B virus.
  • the virus is a coronavirus selected from the group consisting of coronavirus OC43, coronavirus 229E, coronavirus NL63, coronavirus HKU1, middle east respiratory syndrome beta coronavirus (MERS-CoV), severe acute respiratory syndrome beta coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).
  • coronavirus OC43 coronavirus 229E
  • coronavirus NL63 coronavirus HKU1
  • coronavirus HKU1 middle east respiratory syndrome beta coronavirus
  • SARS-CoV severe acute respiratory syndrome beta coronavirus
  • COVID-19 SARS-CoV-2
  • the coronavirus is SARS-CoV-2 (COVID-19).
  • the subject is not hospitalized.
  • the subject is hospitalized.
  • the subject is not on a ventilator.
  • the administration of the compound of Formula I reduces or eliminates the subject’s need for assisted ventilation.
  • the compound of Formula I is administered intravenously.
  • the compound of Formula I is administered enterically.
  • the compound of Formula I is administer by mouth (p.o.).
  • the compound of Formula I is administered via an enteral feeding tube.
  • the enteral feeding tube is a nasogastric tube.
  • the compound of Formula I is mixed with an enteral feeding formula.
  • the effective amount of the compound of Formula I is between 25 milligrams to 1,000 milligrams per day.
  • the daily dose of the compound of Formula I is 75 milligrams. In some embodiments, the daily dose of the compound of Formula I is 150 milligrams. In some embodiments, the daily dose of the compound of Formula I is 225 milligrams. In some embodiments, the daily dose of the compound of Formula I is 300 milligrams. In some embodiments, the daily dose of the compound of Formula I is 375 milligrams. In some embodiments, the daily dose of the compound of Formula I is 450 milligrams. In some embodiments, the daily dose of the compound of Formula I is 525 milligrams. In some embodiments, the daily dose of the compound of Formula I is 600 milligrams.
  • the dose is administered enterically.
  • the dose is administered as a single daily dose.
  • the dose is administered as a plurality of equally divided subdoses.
  • the dose is 150 mg BID for a total dose of 300 mg per day.
  • the does is 150 mg TID for a total dose of 450 mg per day.
  • the dose is 300 mg BID for a total dose of 600 mg per day.
  • the dose is administered as unequally divided sub-doses.
  • the dose is 300 mg in the morning, followed by 150 mg in the afternoon or evening, for a total of 450 mg per day.
  • the subject has a body temperature of greater than 37.5 °C. In some embodiments, the body temperature of the subject is measured at one or more sites selected from the group consisting of an oral cavity, a rectal cavity, axilla area and tympanic membrane.
  • the method reduces the body temperature of the subject.
  • the subject has a pre-treatment C-creative protein (CRP) level greater than 2 mg/L. In some embodiments, the subject has a pre-treatment CRP level greater than 5 mg/L. In some embodiments, the subject has a pre-treatment CRP level greater than 10 mg/L. In some embodiments, the subject has a pre-treatment CRP level greater than 20 mg/L. In some embodiments, the subject has a pre-treatment CRP level greater than 30 mg/L. In some embodiments, the subject has a pre-treatment CRP level greater than 40 mg/L. [0036] In some embodiments, the method reduces the subject’s serum CRP levels below pretreatment levels.
  • CRP C-creative protein
  • the post-treatment CRP level of the subject is not more than 45 mg/L. In some embodiments, the post-treatment CRP level of the subject is not more than 40 mg/L. In some embodiments, the post-treatment CRP level of the subject is not more than 35 mg/L. In some embodiments, the post-treatment CRP level of the subject is not more than 30 mg/L. In some embodiments, the post-treatment CRP level of the subject is not more than 20 mg/L. In some embodiments the post-treatment CRP level of the subject is not more than 5 mg/L. In some embodiments, the post-treatment CRP level of the subject is not more than 1 mg/L.
  • the method reduces the CRP level by at least 10% as compared to pre-treatment levels.
  • the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% as compared to pre-treatment levels.
  • the subject has a pre-treatment serum IL-6 level of at least 2 pg/ml. In some embodiments, the subject has a pre-treatment serum IL-6 level of at least 2.5 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 10 pg/ml, 20 pg/ml, 30 pg/ml, 40 pg/ml, 50 pg/ml, 60 pg/ml, 70 pg/ml, 80 pg/ml, 90 pg/ml, 100 pg/ml, 150 pg/ml or 200 pg/ml.
  • the method reduces the subject’s serum IL-6 levels below pretreatment levels.
  • the serum IL-6 level is decreased by at least 10% as compared to pre-treatment levels. In some embodiments, the serum IL-6 level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.
  • the subject has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0. In some embodiments, the subject has pre-treatment NLR greater than 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.
  • NLR neutrophil-to-lymphocyte ratio
  • the subject has a post-treatment NLR less than 3.18.
  • the administration of the compound of Formula I improves the NLR by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pretreatment levels.
  • the subject has a pre-treatment respiration rate of fewer than 12 breaths or more than 25 breaths per minute.
  • the method improves the respiration rate of the subject.
  • the subject has a post-treatment respiration rate between 12 to 20 breaths per minute.
  • the subject has a pre-treatment oxygen saturation level of no more than 90%. In some embodiments, the subject has a pre-treatment oxygen saturation level of no more than 85%, 80%, 75%, 70%, or 65%.
  • the method improves the oxygen saturation level of the subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, or 30%, as compared to pre-treatment levels.
  • the method improves the oxygen saturation level of the subject to 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98%, or 99%.
  • the method reduces the subject’s need for supplemental oxygen.
  • the subject is older than 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years of age.
  • the subject is older than 60 years of age.
  • the subject is younger than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 years of age.
  • the method further comprises administering an effective amount of at least one second therapeutic agent wherein each of the at least one second therapeutic agent is selected from the group consisting of an antiviral agent, an angiotensin receptor blocker (ARB), an IL-6 antagonist, a GM-CSF inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • each of the at least one second therapeutic agent is selected from the group consisting of an antiviral agent, an angiotensin receptor blocker (ARB), an IL-6 antagonist, a GM-CSF inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • the IL-6 antagonist is selected from the group consisting of an anti-IL-6 antibody or an antigen binding fragment thereof, an anti-IL-6 receptor antibody or an antigen binding fragment thereof, and a JAK/STAT inhibitor.
  • the IL-6 antagonist is an anti-IL-6 antibody or antigen binding fragment thereof. [0059] In some embodiments, the IL-6 antagonist is an anti-IL-6 receptor antibody or an antigen binding fragment thereof.
  • the IL-6 antagonist is a JAK/STAT inhibitor.
  • the present disclosure provides for a method comprising enterically administering 150 mg to 600 mg per day of 10-nitro-9(E)-octadec-9- enoic acid (CXA-10), or a salt, stereoisomer, deuterated analog, fluorinated analog, or prodrug thereof, to a subject with confirmed or suspected infection with SARS-CoV-2 (COVID-19).
  • CXA-10 10-nitro-9(E)-octadec-9- enoic acid
  • COVID-19 SARS-CoV-2
  • the subject does not have ALI or ARDS.
  • the subject has ALI or ARDS but is not on a ventilator.
  • the CXA-10 is administered by mouth (p.o.).
  • the CXA-10 is administered via an enteral feeding tube.
  • the enteral feeding tube is a nasogastric tube.
  • CXA-10 is mixed with an enteral feeding formula.
  • the daily dose of CXA-10 is 150 mg. In another embodiment, the daily dose of CXA-10 is 225 mg. In some embodiments, the daily dose of CXA-10 is 300 mg. In some embodiments, the daily dose of CXA-10 is 375 mg. In some embodiments, the daily dose of CXA-10 is 450 mg. In some embodiments, the daily dose of CXA-10 is 525 mg. In some embodiments, the daily dose of CXA-10 is 600 mg.
  • the dose of CXA-10 is administered as a single daily dose.
  • the dose of CXA-10 is administered as a plurality of equally divided sub-doses.
  • the dose of CXA-10 is 150 mg BID for a total dose of 300 mg per day.
  • the dose of CXA-10 is 150 mg TID for a total dose of 450 mg per day.
  • the dose of CXA-10 is 300 mg BID for a total dose of 600 mg per day.
  • the dose of CXA-10 is administered as unequally divided subdoses.
  • the dose of CXA-10 is 300 mg followed by 150 mg for a total of 450 mg per day.
  • CXA-10 is formulated in a pharmaceutical composition comprising CXA-10 and at least one pharmaceutically acceptable carrier or excipient.
  • at last one of the at least one pharmaceutically acceptable carrier or excipient is triglyceride.
  • the triglyceride is a medium chain triglyceride (MCT).
  • MCT is selected from hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.
  • the pharmaceutical composition comprises Miglyol.
  • the pharmaceutical composition is an oral unit dosage form.
  • the oral unit dosage form is a capsule.
  • the capsule comprises hydroxypropyl methylcellulose (HMPC).
  • FIG. 1 shows a schematic representation of the key therapeutic mechanisms of CXA- 10.
  • GSH glutathione
  • hemeoxygenase-1, KEAPl Kelch-like ECH-associated protein-, NRF2
  • Nuclear factor (erythroid-like)-like 2, NF-kB Nuclear factor KB, NQOl
  • NADPFfquinone oxidoreductase, SOD superoxide dismutase.
  • Viral infection of the lungs can lead to acute lung injury (ALI).
  • the patient s inflammatory response to clear the invading viral pathogens, which can progress to cytokine release syndrome (CRS, colloquially known as “cytokine storm”), at times significantly contributes to the morbidity and mortality of patients suffering from ALI.
  • ALI can also occur independently of viral infection.
  • CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) is a specific isomer of nitro-oleic acid (OA-NO2) with electrophilic properties that facilitate rapid and reversible protein adduction reactions with cysteine, and to a lesser extent histidine, residues (Baker et al ., ./. Biol. Chem. 282(42):31085-93), but not DNA bases.
  • OA-NO2 nitro-oleic acid
  • CXA-10 attaches covalently, but reversibly, to key signaling proteins that are involved in metabolic and inflammatory processes, thereby modulating their activity, leading to cellular and tissue-protective anti-oxidant, anti-inflammatory and anti-fibrotic effects.
  • the present disclosure provides methods for preventing and/or treating ALI, ARDS, and/or respiratory viral infections by administering an effective amount of CXA-10 and other nitro-containing fatty acids, esters, amides or analogues thereof.
  • the present disclosure provides methods for enterically administering 150 mg-600 mg per day of 10-nitro-9(E)-octadec-9-enoic acid (CXA 10), or a salt, stereoisomer, deuterated analog, fluorinated analog, or prodrug thereof, to a subject with confirmed or suspected infection with SARS-CoV-2 (COVID-19).
  • CXA 10 10-nitro-9(E)-octadec-9-enoic acid
  • COVID-19 SARS-CoV-2
  • the patient does not have ALI or ARDS.
  • the patient is not on a ventilator.
  • substituted refers that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal bonding valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl alkenyl, alkynyl, alkoxy, acyl, amino, ami do, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo, nitro, alky sulfmyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • substituents there may be one, two, three, four, five, or six substituents.
  • the above definition is not intended to include impermissible substitution patterns (i.e., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • substituted aryl includes, but is not limited to, "alkylaryl.”
  • the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non- hydrogen substituent is not present. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl as used herein has 1 to 50 carbon atoms ((C 1 -C 50 )alkyl), 1 to 20 carbon atoms ((C 1 -C 20 )alkyl), 1 to 12 carbon atoms ((C 1 -C 12 )alkyl), 1 to 8 carbon atoms ((C 1 -C 8 )alkyl), 1 to 6 carbon atoms ((C 1 -C 6 )alkyl), or 1 to 4 carbon atoms ((C 1 -C4)alkyl).
  • alkyl groups may, for example, include methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n -hexyl, 2-hexyl, 3- hexy,, and 3 -methyl pentyl.
  • alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • butyl can include n-butyl, sec-butyl, isobutyl and t-butyl
  • propyl can include n-propyl and isopropyl.
  • substituted alkyl refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as 0-, N-, S-, -S(0)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocycl
  • haloalkyl refers to an alkyl group substituted with one or more halo, which may be selected independently.
  • haloalkyl may include alkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
  • Haloalkyl may include, for example, -CH 2 F, -CHF2, CF3, -CH2CI, - CHC1 2 , -CC1 3 , -CH 2 CHFC1, -CHFCH 3 , -CH 2 Br, and -CH 2 CHFCH2CH 2 Br.
  • cycloalkyl refers to a monocyclic or polycyclic saturated hydrocarbon, in some embodiments, cycloalkyl has 3 to 50 carbon atoms ((C 3 - C 50 )cycloalkyl), 3 to 20 carbon atoms ((C 3 -C 20 )cycloalkyl), 3 to 12 carbon atoms ((C 3 - C 12 )cycloalkyl), 3 to 8 carbon atoms ((C 3 -C 8 )cycloalkyl), 3 to 6 carbon atoms ((C 3 - C 6 )cycioalkyl), or 3 to 5 carbon atoms ((C3-C5)cycloalkyl).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- 1H-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and bicyclo[l.l.l]pentane.
  • substituted cycloalkyl and “substituted bicycloalkyl” refer to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, bicycloalkyl, substituted bicycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted
  • heteroalkyl refers to an alkyl substituent in which one or more of the carbon atoms and any attached hydrogen atoms are independently replaced with the same or different heteroatomic group.
  • 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic substituent.
  • alkylene refers to a di-radical alkyl group. Unless otherwise indicated, such groups include saturated hydrocarbon chains containing from 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may be heteroatom-containing. “Lower alkylene” refers to alkylene linkages containing from 1 to 6 carbon atoms. Examples include, methylene (-CH 2 -), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH 2 -CH(CH 3 ) - CH2-), hexylene (-(CH2)6-) and the like.
  • alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (CoC-) unsaturation.
  • alkynyl groups include, but are not limited to, acetylenyl (CoCH), and propargyl (CH2CoCH).
  • aryl refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring, wherein all of the ring atoms of the at least one hydrocarbon aromatic ring are carbon. Wherein aryl includes a polycyclic system, no aromatic ring heteroatoms are present.
  • Aryl may include groups with a single aromatic ring (e.g, phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthryl).
  • Aryl may further include groups with one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl, 2,3-dihydro- 1H-indene; 1,2,3,4-tetrahydronapbthalene).
  • aryl includes groups with an aromatic hydrocarbon ring fused to a non- aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, Q, and S.
  • aryl includes groups with a phenyl ring fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., chromane; thiochromane; 2,3-dihydrobenzofuran; indoline).
  • aryl as used herein has from 6 to 14 carbon atoms ((CV Ci4)aryl), or 6 to 10 carbon atoms ((C 6 -Cio)aryl). Where the aryl includes fused rings, the aryl may connect to one or more substituents or moieties of the formulae described herein through any atom of the fused ring for which valency permits.
  • substituted aryl refers to an aryl moiety substituted with one or more substituent groups in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra.
  • Aryl is intended to include stable cyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated C 3 -C 14 moieties, exemplified but not limited to phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazoyl, pyrimidinyl, and oxazoyl; which may further be substituted with one to five members selected from the group consisting of hydroxy, C 1 -C 8 alkoxy, C 1 -C 8 branched or straight-chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, halogen, trifluoromethyl, cyano, and carboxyl (see i.e., Katritzky, Handbook of Heterocyclic Chemistry). If not otherwise indicated, the term "aryl" includes unsubstituted, substituted, and/or heteroatom- containing aromatic substituents.
  • heteroaryl refers to an aromatic group of from 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring ⁇ i.e., pyridinyl or furyl) or multiple condensed rings ⁇ i.e., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N oxide (N ⁇ 0), sulfmyl, or sulfonyl moieties.
  • Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • arylalkyl refers to an alkyl group with an aryl substituent
  • alkylaryl refers to an aryl group with an alkyl substituent, wherein “alkyl” and “aryl” are as defined above.
  • arylalkyl and alkylaryl groups herein contain 6 to 30 carbon atoms.
  • Arylalkyl and alkylaryl groups may, for example, but are not limited to, contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.
  • heterocycle refers to a saturated or partially saturated, but not aromatic, group having from 2 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Cycloalkyl or heterocycloalkyl refers to a group having x number of ring carbon atoms excluding the ring heteroatoms.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused, bridged and spiro ring systems.
  • one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, sulfonyl moieties.
  • heterocycles can be saturated or partially unsaturated, monocyclic or bicyclic, bridged, or fused.
  • substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, dexahydroindole, dihydropyridine, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, imidazolinone, piperidine, piperazine, indoline, phthalimi
  • amino refers to the group -NRR’ wherein R and R’ are independently hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, arylalkyl, and substituted and/or heteroatom- containing variants thereof.
  • the term “carbamoyl” refers to the group NH 2 CO-.
  • the groups are used interchangeably and refer to a “cyclohexyl” group.
  • cyano and “carbonitrile” refer to the group -CN.
  • halo and halogen are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
  • nitro refers to the group -NO2.
  • oxetanyl refers to the group of a four-membered saturated cycloalkane ring with three carbon atoms and one oxygen atom.
  • sulfinyl refers to the divalent group -SO-.
  • sulfonyl refers to the group -SO2R, where R may be alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, arylalkyl, or alkylaryl. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and pyridyl sulfonyl.
  • tetrahydrofuranyl refers to the group of a five- membered saturated cycloalkane ring with four carbon atoms and one oxygen atom.
  • thiocyanate refers to the group -SCN.
  • isothiocyante refers to the group -NCS.
  • thiol or “mercapto” refers to the group -SH.
  • the present invention contemplates various stereoisomers and mixtures thereof, and includes enantiomers.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations. See, for example, Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009
  • Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present disclosure.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration, where the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • references to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium, 14 C, 32 P and 35 S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
  • compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.
  • the term “promoiety” refers to a form of protecting group that, when used to mask a functional group within an active agent, converts the active agent into a prodrug.
  • the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
  • the promoiety is attached to an amine, a hydroxyl, or a carboxylic acid group of the subject compounds.
  • the promoiety is an acyl or substituted acyl group. In certain cases, the promoiety is an alkyl or substituted alkyl group.
  • prodrug refers to compounds that are transformed in vivo to provide a compound or pharmaceutically acceptable salt, hydrate or solvate of the compound described herein.
  • the transformation can occur by various mechanisms (i.e., esterase, amidase, phosphatase, oxidative and/or reductive metabolism) in various locations I (i.e., in the intestinal lumen or upon transit into the intestine, blood, or liver).
  • subject refers to an animal to be treated, including but not limited to human and non-human primates, rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like.
  • patient refers to a human subject.
  • the term “treat”, along with linguistic variants thereof such as “treatment”, is used in its broadest sense understood in the medical arts, and explicitly includes medical interventions that arrest or retard development of signs or symptoms of a disease without requiring relief of existing symptoms, or cure.
  • the term “treat” as used herein includes a medical intervention that arrests or retards development of signs or symptoms of acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) without requiring relief of existing symptoms of ALI or ARDS.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • the phrase “therapeutically effective amount” refers to the amount of a compound that is effective to treat a subject.
  • “preventing” a disease refers to preventing development of the full clinical manifestation of a disease. “Preventing” does not require prevention of all signs and symptoms of a disease.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a compound (i.e., a compound of Formula I described herein) calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • a compound i.e., a compound of Formula I described herein
  • the specifications for unit dosage forms depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • IL-6 interleukin 6
  • IL-6 polypeptide refers to a human polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP 000591 and having IL-6 biological activity.
  • IL-6 is a pleotropic cytokine with multiple biologic functions.
  • Exemplary IL-6 biological activities include immunostimulatory and pro-inflammatory activities.
  • IL-6 antagonist is used synonymously with “IL-6 antagonist” and refers to an agent that is capable of decreasing the biological activity of IL-6.
  • IL-6 antagonists include agents that decrease the level of IL-6 polypeptide in serum, including agents that decrease the expression of an IL-6 polypeptide or nucleic acid; agents that decrease the ability of IL-6 to bind to the IL-6R; agents that decrease the expression of the IL-6R; and agents that decrease signal transduction by the IL-6R receptor when bound by IL-6.
  • the IL-6 antagonist decreases IL-6 biological activity by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.
  • IL-6 antagonists include IL-6 binding polypeptides, such as anti-IL-6 antibodies and antigen binding fragments or derivatives thereof; IL-6R binding polypeptides, such as anti-IL-6R antibodies and antigen binding fragments or derivatives thereof; and synthetic chemical molecules, such as JAK1 and JAK3 inhibitors.
  • IL-6 antibody refers to an antibody that specifically binds IL-6 ligand.
  • Anti-IL-6 antibodies include monoclonal and polyclonal antibodies that are specific for IL-6 ligand, and antigen-binding fragments or derivatives thereof. IL-6 antibodies are described in greater detail below.
  • C-reactive protein or “CRP” refers to a polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided atNCBI Accession No. NP_000558 and having complement activating activity. CRP levels increase in response to inflammation, and can be measured with an hsCRP (high- sensitivity C-reactive protein) test.
  • biological sample refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject).
  • the biological sample is serum or blood.
  • pre-treatment means prior to the first administration of a compound of Formula I according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than a compound of Formula I.
  • post-treatment means after the administration of a compound of Formula I according the methods described herein. Post-treatment includes after any administration of a compound of Formula I at any dosage described herein. Posttreatment also includes after the bolus treatment phase of a compound of Formula I, and also after continuous administration of a compound of Formula I at any dosage described herein.
  • the present disclosure provides a method of treating a subject who has, or who is at risk for developing or for worsening of, acute lung inflammation (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • the method comprises administering an effective amount of a compound of Formula I,
  • Formula I or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof to a subject who has or who is at risk for developing or worsening of acute lung inflammation (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia, wherein:
  • X is selected from H, alkyl, substituted alkyl, alkenyl, nitroalkenyl, substituted alkenyl, substituted nitroalkenyl, -C(0)-R 2 , -OR 1 , -NR 1 R 2 , a is from 0-30; b is from 0-30;
  • R 1 is selected from H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, - C(0)-R 2 , gluconate, glycoside, glucuronide, tocopherols, and PEG groups; and
  • R 2 is selected from alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, or pentyl.
  • R 1 is H.
  • the compound of Formula I is nitro-oleic acid.
  • the compound of Formula I is represented by the structure of one of the compounds in Table 1 or Table 2.
  • the compound of Formula I is 10-nitro-9(E)-octadec-9- enoic acid according to Formula II (“CXA-10”) or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof.
  • the compound of Formula I is 9-nitro-9(E)-octadec-9- enoic acid according to Formula III (“CXA-9”) or a salt, stereoisomer, deuterated analog, or fluorinated analog thereof.
  • the compound of Formula I is in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the method comprises administering an isotopically- labeled compound which is identical to a compound of Formula I except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (“isotopologues”).
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H (“D"), 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound described herein can have one or more H atoms replaced with deuterium.
  • the compound of Formula I is formulated in a pharmaceutical composition that further comprises at least one pharmaceutically acceptable carrier or excipient.
  • the method comprises administering an effective amount of the pharmaceutical composition to a subject who has or is at risk for developing or for worsening of acute lung inflammation (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • ALI acute lung inflammation
  • ARDS acute respiratory distress syndrome
  • ALI with concomitant pneumonia or ARDS with concomitant pneumonia.
  • the pharmaceutical composition comprises a plurality of compounds of Formula I, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition comprises CXA- 10
  • At last one of the at least one pharmaceutically acceptable carrier or excipient is a triglyceride.
  • the triglyceride is a medium chain triglyceride (MCT).
  • MCT is selected from hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.
  • the pharmaceutical composition comprises Miglyol.
  • the pharmaceutical composition is formulated as an oral unit dosage form.
  • the oral unit dosage form is a capsule comprising a pharmaceutical composition comprising a compound of Formula I.
  • the capsule comprises hydroxypropyl methylcellulose (HMPC).
  • the subject to be treated has confirmed or suspected viral infection.
  • the infection is by a virus selected from the group consisting of coronavirus, influenza virus, rhinovirus, respiratory syncytial virus, metapneumovirus, adenovirus, and boca virus.
  • the virus is a coronavirus selected from the group consisting of coronavirus OC43, coronavirus 229E, coronavirus NL63, coronavirus HKU1, middle east respiratory syndrome beta coronavirus (MERS-CoV), severe acute respiratory syndrome beta coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).
  • the coronavirus is SARS-CoV-2.
  • the patient is infected with severe acute respiratory syndrome beta coronavirus (SARS-CoV) and the patient has severe acute respiratory syndrome (SARS).
  • SARS-CoV severe acute respiratory syndrome beta coronavirus
  • MERS-CoV middle eastern respiratory syndrome virus
  • MERS middle east respiratory syndrome
  • the patient is infected with SARS-CoV-2 virus and the patient has coronavirus disease 2019 (COVID-19).
  • the virus is an influenza virus selected from the group consisting of parainfluenza virus 1, parainfluenza virus 2, influenza A virus, and influenza B virus.
  • the subject has a pre-treatment fever.
  • the subject has a body temperature of greater than 37.5 °C.
  • the subject’s pre-treatment body temperature is 37.6°C or greater, 37.7°C or greater, 37.8°C or greater, 37.9°C or greater, 38°C or greater , 38.1°C or greater , 38.2°C or greater , 38.3°C or greater , 38.4°C or greater , 38.5°C or greater , 38.6°C or greater , 38.7°C or greater , 38.8°C or greater , 38.9°C or greater , 39°C or greater , 39.1°C or greater , 39.2°C or greater , 39.3°C or greater , 39.4°C or greater , 39.5°C or greater , 39.6°C or greater , 39.7°C or greater , 39.8°C or greater , 39.9°
  • the patient has a pre-treatment body temperature greater than 37.5°C for 24 hours or more, 48 hours or more, 72 hours or more, 96 hours or more, 5 days or more, 6 days or more, 1 week or more, 1.5 weeks or more, or 2 weeks or more.
  • the body temperature is measured from clinically accessible measurement sites on the patient.
  • the measurement site is the patient’s forehead, temple, and/or other external body surfaces.
  • the measurement site is the oral cavity, rectal cavity, axilla area, or tympanic membrane.
  • the subject to be treated has a pre-treatment blood oxygen saturation level (SpO 2 ) of less than 95%. In some embodiments, the patient has a blood oxygen saturation level (SpO 2 ) of less than 94%. In some embodiments, the patient has a blood oxygen saturation level (SpO 2 ) of 93% or less.
  • the patient has an SpO 2 level of 92% or less, 91% or less, 90% or less, 89% or less, 88% or less, 87% or less, 86% or less, 85% or less, 84% or less, 83% or less, 82% or less, 81% or less, 80% or less, 79% or less, 78% or less, 77% or less, 76% or less, or 75% or less.
  • the subject to be treated has ALI with concomitant pneumonia or ARDS with concomitant pneumonia.
  • the subject with ALI with concomitant pneumonia or ARDS with concomitant pneumonia has severe acute respiratory syndrome (SARS).
  • the subject with ALI with concomitant pneumonia or ARDS with concomitant pneumonia has middle eastern respiratory syndrome (MERS).
  • the subject with ALI with concomitant pneumonia or ARDS with concomitant pneumonia has coronavirus disease 2019 (COVID-19).
  • the subject to be treated is not hospitalized.
  • the subject is hospitalized.
  • the subject is not on a ventilator.
  • the subject is older than 60 years of age. In another some embodiments, the subject is older than 50 years of age. In some embodiments, the subject is older than 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 years of age.
  • the subject to be treated is younger than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 years of age.
  • the subject to be treated has elevated pre-treatment levels of serum C-reactive protein (CRP).
  • CRP serum C-reactive protein
  • the subject has a pre-treatment CRP level of at least 2 mg/L. In certain embodiments, the subject has a pre-treatment CRP level of at least 5 mg/L. In certain embodiments, the subject’s pre-treatment CRP level is at least 2 mg/L, 2.5 mg/L, 3 mg/L, 3.5 mg/L, 4 mg/L, 4.5 mg/L, or 5 mg/L. In certain embodiments, the subject has pretreatment CRP levels of at least 7.5 mg/L, 10 mg/L, 12.5 mg/L, or 15 mg/L. In certain embodiments, the subject’s pre-treatment CRP level is at least 7.5 mg/L.
  • the subject has a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the subject has a pre-treatment CRP level of at least 12.5 mg/L. In certain embodiments, the subject has a pre-treatment CRP level of at least 15 mg/L. In certain preferred embodiments, the subject has a pre-treatment CRP level of at least 10 mg/L. In some embodiments, the subject has pre-treatment CRP levels of at least 20 mg/L, 25 mg/L,
  • the subject’s pre-treatment CRP level is at least 20 mg/L. In certain embodiments, the subject has a pretreatment CRP level of at least 25 mg/L. In certain embodiments, the subject has a pretreatment CRP level of at least 30 mg/L. In certain embodiments, the subject has a pretreatment CRP level of at least 35 mg/L. In certain embodiments, the subject’s pre-treatment
  • CRP level is at least 40 mg/L. In certain embodiments, the subject has a pre-treatment CRP level of at least 45 mg/L. In certain embodiments, the subject has a pre-treatment CRP level of at least 50 mg/L. In certain preferred embodiments, the subject has a pre-treatment CRP level of at least 40 mg/L.
  • the subject has elevated pre-treatment serum levels of IL-6.
  • the subject has a pre-treatment serum IL-6 level of at least 2 pg/ml. In certain embodiments, the subject has a pre-treatment serum IL-6 level of at least 2.5 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 10 pg/ml, 20 pg/ml, 30 pg/ml, 40 pg/ml, 50 pg/ml, 60 pg/ml, 70 pg/ml, 80 pg/ml, 90 pg/ml, 100 pg/ml, 150 pg/ml or 200 pg/ml.
  • the subject has a pretreatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0. In certain embodiments, the subject has a pre-treatment NLR greater than 3.0. In certain embodiments, the subject has pre-treatment NLR greater than 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or 3.9. In certain embodiments, the subject has pre-treatment NLR greater than 4.0.
  • NLR neutrophil-to-lymphocyte ratio
  • the subject has a post-treatment NLR less than 3.18.
  • the compound of Formula I is administered intravenously.
  • the compound of Formula I is administered enterically. In certain embodiments, the compound of Formula I is administer by mouth (p.o.). In certain embodiments, the compound of Formula I is administered via an enteral feeding tube. In particular embodiments, the enteral feeding tube is a nasogastric tube. In some embodiments, the compound of Formula I is mixed with an enteral feeding formula.
  • the effective amount of the compound of Formula I is between 25 milligrams to 1,000 milligrams per day.
  • the daily dose of the compound of Formula I is 75 milligrams. In some embodiments, the daily dose of the compound of Formula I is 150 milligrams. In some embodiments, the daily dose of the compound of Formula I is 225 milligrams. In some embodiments, the daily dose of the compound of Formula I is 330 milligrams. In some embodiments, the daily dose of the compound of Formula I is 375 milligrams. In some embodiments, the daily dose of the compound of Formula I is 450 milligrams. In some embodiments, the daily dose of the compound of Formula I is 525 milligrams. In some embodiments, the daily dose of the compound of Formula I is 600 milligrams.
  • the dose is administered enterically.
  • the dose is administered as a single daily dose.
  • the dose is administered as a plurality of equally divided sub-doses.
  • the dose is 150 mg twice a day (BID) for a total dose of 300 mg per day. In certain embodiments, the dose is 150 mg three times a day (TD) for a total dose of 450 mg per day. In certain embodiments, the dose is 300 mg BID for a total dose of 600 mg per day.
  • the dose is administered as unequally divided subdoses. In some embodiments, the dose is 300 mg followed by 150 mg for a total dose of 450 mg per day.
  • the methods described herein further comprise administering an effective amount of at least one second therapeutic agent selected from the group consisting of an antiviral agent, an angiotensin receptor blocker (ARB), an IL-6 antagonist, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • an antiviral agent an angiotensin receptor blocker (ARB)
  • ARB angiotensin receptor blocker
  • IL-6 antagonist hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • the second therapeutic agent is an anti-viral agent
  • the method of the present disclosure further comprises administering an effective amount of an anti-viral agent.
  • the anti-viral agent is selected from the group consisting of favipiravir, remdesivir, and a combination of lopinavir and ritonavir.
  • the anti-viral agent is favipiravir.
  • the anti-viral agent is remdesivir.
  • the anti -viral agent is a combination of lopinavir and ritonavir.
  • the method of the present disclosure further comprises administering an antibacterial agent.
  • the antibacterial agent is selected from the group consisting of azithromycin, tobramycin, aztreonam, ciprofloxacin, meropenem, cefepime, cetadizine, imipenem, piperacillin-tazobactam, amikacin, gentamicin and levofloxacin.
  • the antibacterial agent is azithromycin.
  • Angiotensin Receptor Blocker [ARBI) Angiotensin Receptor Blocker
  • the second therapeutic agent is an ARB
  • the method of the present disclosure further comprises administering an effective amount of an ARB.
  • the ARB is selected from losartan, valsartan, azilsartan, candesartan, eprosartan, irgesartan, olmesartan, and telmisartan.
  • the subject is further administered an IL-6 antagonist.
  • the IL-6 antagonist is selected from the group consisting of: an anti-IL-6 receptor antibody or an antigen binding fragment thereof; an anti-IL-6 antibody or an antigen binding fragment thereof; and a JAK/STAT inhibitor.
  • the IL-6 antagonist is an anti-IL-6 receptor (anti-IL- 6R) antibody or antigen-binding fragment or derivative thereof.
  • anti-IL-6R antibody or antigen-binding fragment thereof reduces biological signaling by IL-6 receptor.
  • the anti-IL-6R antibody or antigen-binding fragment thereof prevents or reduces binding of IL-6 to the IL-6R.
  • the IL-6 antagonist is a monoclonal composition comprising a single species of anti-IL-6R antibody, or antigen-binding fragment thereof. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6R antibodies, or antigen-binding fragments thereof, each of the plurality having unique CDRs.
  • the anti-IL-6R antibody or antigen binding fragment is a Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain antibody, linear antibody, or V domain antibody.
  • the anti-IL-6R antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the anti-IL-6R antibody comprises a heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4. [00203] In some embodiments, the IL-6 antagonist is immunoconjugate or fusion protein comprising an IL-6R antigen-binding fragment.
  • the antibody is bispecific or multispecific, with at least one of the antigen-binding portions having specificity for IL-6 receptor.
  • the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In some embodiments, the antibody is murine.
  • the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 100 nM. In some embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In particular embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 1 nM, 750 pM, or 500 pM.
  • the anti-IL-6R antibody has a K D for binding human IL-6 receptor of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.
  • the anti-IL-6R antibody has an elimination half-life following intravenous administration of at least 7 days. In certain embodiments, the anti-IL- 6R antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.
  • the anti-IL-6R antibody has a human IgG constant region with at least one amino acid substitution that extends serum half-life as compared to the unsubstituted human IgG constant domain.
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab.
  • the antibody or antigen-binding portion thereof comprises the tocilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length tocilizumab antibody.
  • the anti-IL-6R antibody is a derivative of tocilizumab.
  • the tocilizumab derivative includes one or more amino acid substitutions in the tocilizumab heavy and/or light chain V regions.
  • the tocilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the tocilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the tocilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the tocilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab.
  • the antibody or antigen-binding portion thereof comprises the sarilumab heavy chain V region and light chain V region.
  • the antibody is the full-length sarilumab antibody.
  • the anti-IL-6R antibody is a derivative of sarilumab.
  • the sarilumab derivative includes one or more amino acid substitutions in the sarilumab heavy and/or light chain V regions. [00219] In certain embodiments, the sarilumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the sarilumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the sarilumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the sarilumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of vobarilizumab.
  • the antibody or antigen-binding portion thereof comprises the vobarilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length vobarilizumab antibody.
  • the anti-IL-6R antibody is a derivative of vobarilizumab.
  • the vobarilizumab derivative includes one or more amino acid substitutions in the vobarilizumab heavy and/or light chain V regions.
  • the vobarilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the vobarilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the vobarilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the vobarilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the antibody or antigen-binding portion thereof comprises the heavy chain V region and light chain V region of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the antibody is a full-length selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the anti-IL-6R antibody is a derivative of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), or an antibody described in US 2012/0225060.
  • the IL-6 antagonist is an antibody specific for the complex of IL-6 and IL-6R.
  • the antibody has the six CDRs of an antibody selected from those described in US 2011/0002936, which is incorporated herein by reference in its entirety.
  • the IL-6 antagonist is an anti-IL-6 antibody or antigen-binding fragment thereof.
  • the anti-IL-6 antibody or antigen-binding fragment thereof neutralizes the biological activity of human IL-6.
  • the neutralizing antibody prevents binding of IL-6 to the IL-6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to the soluble IL-6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to the membrane-bound IL- 6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to both the soluble IL-6 receptor and the membrane-bound IL-6 receptor.
  • the IL-6 antagonist is an anti-IL-6 monoclonal antibody. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6 antibodies, each of the plurality having unique CDRs.
  • the anti-IL-6 antibody is selected from the group consisting of: ziltivekimab, siltuximab, gerilimzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101 (Femta Pharmaceuticals, Lonza).
  • the antigen-binding fragment is a fragment of an antibody selected from the group consisting of: ziltivekimab, siltuximab, gerilimzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB- 007 (EBI-029; Eleven Bio), and FM101 (Femta Pharmaceuticals, Lonza).
  • the IL-6 antagonist is an antagonist peptide.
  • the IL-6 antagonist is C326 (an IL-6 antagonist by Avidia, also known as AMG220), or FE301, a recombinant protein inhibitor of IL-6 (F erring International Center S.A., Conaris Research Institute AG).
  • the anti- IL-6 antagonist comprises soluble gpl30, FE301 (Conaris/F erring).
  • the IL-6 antagonist is an inhibitor of the JAK signaling pathway.
  • the JAK inhibitor is a JAKl-specific inhibitor.
  • the JAK inhibitor is a JAK3-specific inhibitor.
  • the JAK inhibitor is a pan-JAK inhibitor.
  • the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decemotinib, ruxolitinib, upadacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, peficitinib, momelotinib, INCB- 039110, ABT-494, INCB-047986 and AC-410.
  • the IL-6 antagonist is a STAT3 inhibitor.
  • the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense molecule.
  • small molecule JAK inhibitors and STAT inhibitors are administered orally.
  • the inhibitor is administered once or twice a day at an oral dose of 0.1 - 1 mg, 1 - 10 mg, 10 - 20 mg, 20 - 30 mg, 30 - 40 mg, or 40 - 50 mg. In some embodiments, the inhibitor is administered once or twice a day at a dose of 50 - 60 mg, 60 - 70 mg, 70 - 80 mg, 80 - 90 mg, or 90 - 100 mg. In some embodiments, the inhibitor is administered at a dose of 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg PO once or twice a day. In some embodiments, the inhibitor is administered at a dose of 75 mg or 100 mg PO once or twice a day.
  • the method further comprises administering an anti- malarial agent.
  • the anti-malarial agent is hydroxychloroquine. In certain embodiments, the anti-malarial agent is chloroquine.
  • the method further comprises administering a COVID- 19 immune serum or plasma, or a composition comprising isolated or recombinantly expressed anti-SARS-CoV-2 antibodies having sequences derived from COVID-19 immune serum or plasma.
  • the method further comprises administering a GM-CSF antagonist (synonymously, inhibitor).
  • a GM-CSF antagonist is gimsilumab.
  • the subject following treatment (post-treatment) with a compound of Formula I, the subject has a reduction in one or more signs and/or symptoms of ALI or ARDS.
  • the administration of an effective amount of a compound of Formula I results in a reduction in the subject’s body temperature.
  • the subject, post-treatment with an effective amount of a compound of Formula I has a body temperature of 37.5°C or below.
  • the patient, post-treatment with an effective amount of a compound of Formula I has a body temperature ranging from of 36°C to 37.5°C.
  • the dose is adjusted to effect a reduction in the subject’s body temperature.
  • the administration of an effective amount of a compound of Formula I improves the blood oxygen saturation level (SpO?) of the subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, or 30% as compared to pre-treatment levels.
  • SpO blood oxygen saturation level
  • the administration of an effective amount of a compound of Formula I raises the blood oxygen saturation level (SpO 2 ) of the subject to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%.
  • the administration of an effective amount of a compound of Formula I raises the subject’s SpO 2 to at least 94% or 95%.
  • the dose is adjusted to effect an increase in the Sp0 2 of the subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, or 30%as compared to pre-treatment levels.
  • the dose is adjusted to raise the Sp02 of the subject to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%.
  • the administration of an effective amount of a compound of Formula I reduces the subject’s need for supplemental oxygen.
  • the dose is adjusted to effect a reduction in the subject’s need for supplemental oxygen.
  • the administration of an effective amount of a compound of Formula I improves the respiration rate of the subject.
  • the subject has a post-treatment respiration rate of between 12 to 20 breaths per minute.
  • the dose is adjusted to result in a post-treatment respiration rate of between 12 to 20 breaths per minute.
  • the administration of a compound of Formula I improves the NLR by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.
  • the administration of a compound of Formula I results in eliminating the subject’s need for assisted ventilation.
  • the dose is adjusted to eliminate the subject’s need for assisted ventilation.
  • the administration of a compound of Formula I to the subject results in the reduction in the risk of respiratory morbidity and mortality.
  • the dose is adjusted to reduce the risk of respiratory morbidity and mortality.
  • the administration of an effective amount of a compound of Formula I reduces the subject’s serum IL-6 levels below pre-treatment levels.
  • the dosage regimen is adjusted to achieve a reduction in the patient’s serum IL-6 levels below pre-treatment levels.
  • the serum IL-6 level is decreased by at least 10% as compared to pre-treatment levels. In some embodiments, the serum IL-6 level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 50% as compared to pre-treatment levels.
  • the serum IL-6 level is decreased by at least 60% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the serum IL-6 level is decreased by at least 90% as compared to pre-treatment levels.
  • the administration of an effective amount of a compound of Formula I reduces the patient’s serum CRP levels below pre-treatment levels.
  • the dosage regimen is adjusted to achieve a reduction in the subject’s serum CRP levels below pre-treatment levels.
  • the CRP level is decreased by at least 10% as compared to pre-treatment levels. In various embodiments, the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 20% as compared to pretreatment levels. In certain embodiments, the CRP level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 50% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 60% as compared to pre-treatment levels.
  • the CRP level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 90% as compared to pre-treatment levels.
  • the post-treatment CRP level of the subject is no more than 45 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 40 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 35 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 30 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 20 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 5 mg/L. In certain embodiments, the post-treatment CRP level of the subject is no more than 1 mg/L.
  • the goal of this study is to evaluate efficacy and safety of CXA-10 vs. placebo as measured by changes in hospital course (e.g., need for mechanical ventilation), biomarkers (hsCRP, IL-6), and AEs in hospitalized, non-critically ill patients with COVID-19 pneumonitis.
  • This study is a double-blind, placebo controlled and parallel group study, performed across 10 to 20 test centers in the United States.
  • the primary objective of this study is to evaluate the percentage of the enrolled patients that are free of mechanical ventilation at 30 days.
  • the safety object of this study is to evaluate the safety and tolerability of CXA-10 administration in tested subjects as assessed by physical exam, adverse effects, clinical laboratories, and ECGs.
  • the primary endpoint of this study is to evaluate the fraction of randomized patients who require mechanical ventilation.
  • Presence of at least one chronic medical comorbidity such as diabetes, COPD, hypertension, CV disease, and etc.
  • CAP Community Acquired Pneumonia due to COVID-19, such as increasing cough, fever (>38 °C as measured by any conventional clinical method, such as forehead, tympanic, oral, axillary, rectal, etc., and dyspnea).
  • the investigational product of this study is CXA-10 formulated as 150 mg hard-shell capsules that are orally administered. Matching placebo capsules are also available.
  • Pharmacokinetics modeling and simulation for the ongoing PAH and FSGS Phase 2 studies have suggested that 150 mg or 300 mg per day as a single dose with food would be the optimal dose. SAD has evaluated single doses up to 600 mg per day (fasted) and MAD has evaluated repeat dose of up to 450 mg per day (fed). Food improves GI tolerability (reduces nausea and diarrhea side effects) and in preliminary evaluation increases exposure by about 30%.
  • the dosage of CXA-10 for this study is 3 times per day (TID) with doses about 8 hours apart.
  • the screening phase will be 48 hours.
  • the maintenance phase of this study will be 12 days. For patients who have not had an adequate clinical response, this phase of treatment can be extended to 18 days.
  • the total duration of this study is 12 to 13 weeks, which does not include study time for startup, database lock, or data analysis.
  • a telephonic follow up is included as part of this study at 6 months postdischarge to assess the long-term post-infection sequala.
  • Initial plan is to use the patient reported outcome tool SF-36 for assessment.

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Abstract

La présente invention concerne des procédés associés à l'utilisation d'acides gras nitro et d'analogues de ceux-ci pour le traitement et/ou la prévention d'infections pulmonaires aiguës et d'états ou de maladies associés. Dans certains modes de réalisation, les procédés concernent le traitement et/ou la prévention d'atteintes pulmonaires à médiation par coronavirus.
PCT/US2021/028969 2020-04-24 2021-04-23 Utilisation d'acides gras nitro et d'analogues de ceux-ci pour la prévention et/ou le traitement d'une atteinte pulmonaire aiguë et/ou d'une infection à sras-cov-2 WO2021217084A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120136034A1 (en) * 2009-07-31 2012-05-31 University Of Pittsburgh -Of The Commonwealth Syst Fatty acids as anti-inflammatory agents
US20150051283A1 (en) * 2013-06-14 2015-02-19 Complexa, Inc. Composition and method for inhibition of pkng from mycobacterium tuberculosis
US20180256509A1 (en) * 2014-12-10 2018-09-13 Albert Einstein College Of Medicine, Inc. Nanoparticle Compositions and Methods Thereof to Restore Vascular Integrity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120136034A1 (en) * 2009-07-31 2012-05-31 University Of Pittsburgh -Of The Commonwealth Syst Fatty acids as anti-inflammatory agents
US20150051283A1 (en) * 2013-06-14 2015-02-19 Complexa, Inc. Composition and method for inhibition of pkng from mycobacterium tuberculosis
US20180256509A1 (en) * 2014-12-10 2018-09-13 Albert Einstein College Of Medicine, Inc. Nanoparticle Compositions and Methods Thereof to Restore Vascular Integrity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REDDY ARAVIND T., LAKSHMI SOWMYA P., REDDY RAJU C.: "The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice", PPAR RESEARCH, vol. 2012, 26 July 2012 (2012-07-26), pages 1 - 12, XP055867491 *

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