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WO2024026307A1 - Biomarqueur pour covid longue et fatigue - Google Patents

Biomarqueur pour covid longue et fatigue Download PDF

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Publication number
WO2024026307A1
WO2024026307A1 PCT/US2023/070938 US2023070938W WO2024026307A1 WO 2024026307 A1 WO2024026307 A1 WO 2024026307A1 US 2023070938 W US2023070938 W US 2023070938W WO 2024026307 A1 WO2024026307 A1 WO 2024026307A1
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WIPO (PCT)
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subject
threshold
pcr
post
measure
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Inventor
Betty RAMAN
Ladislav VALKOVIC
Stefan Neubauer
Margaret KOZIEL
Karim Azer
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Axcella Health Inc
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Axcella Health Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging

Definitions

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for coronavirus disease 2019 (COVID-19). Research to determine the full long-term sequelae of COVID- 19 is on-going. Efforts to study and treat long-term sequelae of COVID- 19 are hindered by a paucity of biomarkers and clinical tests to reliably diagnose long COVID. New objective methods for diagnosing long COVTD are needed.
  • the method of diagnosing or confirming a diagnosis further comprises administration of a composition including at least four different amino acid entities.
  • the subject has one or more symptoms or signs selected from the group consisting of anorexia, anxiety, arrythmias, confusion (“brain fog”), dementia, depression, dyspnea, fatigue, hair loss, headache, heart failure, cardiomyopathy, angina, hepatic dysfunction, hyperglycemia, type 2 diabetes, increased heart rate, inflammation, loss of appetite, loss of memory, loss of smell, mood disorder, muscle weakness, myocardial ischemia, post-exertional malaise, diminished neurocognition, diminished sensory function, pulmonary infiltrates or fibrosis, postural orthostatic hypotension, renal dysfunction, and respiratory distress.
  • anorexia anorexia
  • anxiety arrythmias
  • confusion (“brain fog”) dementia
  • depression dyspnea
  • fatigue fatigue
  • hair loss headache
  • heart failure cardiomyopathy
  • angina hepatic dysfunction
  • hyperglycemia type 2 diabetes
  • increased heart rate inflammation
  • loss of appetite loss of memory
  • loss of smell loss of smell
  • the subject has one or more symptoms or signs selected from the group consisting of myalgia, fibromyalgia, idiopathic pulmonary fibrosis, fatigue, muscle fatigue, mitochondrial dysfunction, dyspnea after exertion, postural orthostatic tachycardia syndrome, tachycardia, mood disorders, and depression.
  • the subject with elevated PCr recovery time has been identified as having a score, or has received a score (e.g., a score from a test evaluating fatigue) indicative of fatigue.
  • the subject with elevated PCr recovery time has a score of greater than or equal to 4, 5, 6, 7, 8, 9, or 10 on a CFQ-11 test using bimodal scoring, or a score of greater than or equal to 25, 26, or 27 on a CFQ-11 test using Likert scoring.
  • the subject has one or more of the following characteristics: i. impaired or delayed immune response; ii. increased oxidative stress and/or proinflammatory state; or iii. dysregulated endothelial function (e.g., hypercoagulation or perfusion).
  • the subject after administration, exhibits one or more of the following: i. increased mitochondrial biogenesis; ii. restored (e.g., partially or fully restored) mitochondrial oxidative capacity; iii. restored (e.g., partially or fully restored) cellular respiration and/or cellular energetics; iv. improved cellular response under higher metabolic demand conditions (e.g., exertion), e.g., in muscle; v. improved mitochondrial respiration (e.g., comprising increased substrate mobilization, increased nitric oxide (NO) signaling, enhanced microvascular or tissue perfusion, enhanced vascular conduction, or increased micro- vascular perfusion) vi.
  • NO nitric oxide
  • reduced inflammation e.g., reduce liver inflammation
  • protein breakdown e.g., protein breakdown
  • muscle fatigue post-exercise e.g., normalized (e.g., partially or fully normalized) coagulation function
  • viii improved mitochondrial energetics and/or redox balance, ix. decreased oxidative stress
  • x. improved cellular respiration, antioxidant and/or anti-inflammatory effects xi. increased nucleotide pool availability
  • xii. increased preferential fatty acid oxidation relative to glycolysis xiii. increased level of ketone bodies
  • xiv. decreased FGF-21 xv. decreased vascular permeability
  • xvi. decreased fatigue e.g., from moderate or severe fatigue to mild fatigue; e.g.
  • the fatigue comprises one or both of persistent fatigue and exertional fatigue. In some embodiments, the fatigue comprises one or both of mental fatigue and physical fatigue.
  • the subject had a COVID- 19 infection and is experiencing fatigue.
  • the subject experiences fatigue at at least 4, 8, 12, or 16 weeks after infection with SARS-Cov-2.
  • the subject experiences fatigue at less than 4 weeks (e.g., at less than 3 weeks, 2 weeks, or 1 week) after infection with SARS-Cov-2.
  • the amino acid entities administered further comprises a glycine (G)-amino acid entity.
  • the amino acid entities administered further comprise one, two, three or more (e.g., all) of a histidine (H)-amino acid entity, a lysine (K)- amino acid entity, a phenylalanine (F)-amino acid entity, and a threonine (T)-amino acid entity.
  • the subject was infected with an alpha strain of SARS-CoV-2 (e.g., a B.1.1.7 or Q lineage or a lineage descendent therefrom).
  • the subject was infected with a beta strain of SARS-CoV-2 (e.g., a B.1.351 lineage or a lineage descendent therefrom).
  • a gamma strain of SARS-CoV-2 e.g., a P.l lineage or a lineage descendent therefrom.
  • the subject was infected with a delta strain of SARS-CoV-2 (e.g., a B.1.617.2 or AY lineage or a lineage descendent therefrom). In some embodiments, the subject was infected with an epsilon strain of SARS-CoV-2 (e.g., a B.1.427 or B.1.429 lineage or a lineage descendent therefrom). In some embodiments, the subject was infected with an eta strain of SARS-CoV-2 (e.g., a B.1.525 lineage or a lineage descendent therefrom).
  • a delta strain of SARS-CoV-2 e.g., a B.1.617.2 or AY lineage or a lineage descendent therefrom.
  • the subject was infected with an epsilon strain of SARS-CoV-2 (e.g., a B.1.427 or B.1.429 lineage or a lineage descendent therefrom).
  • the subject was infected with
  • the subject was infected with an iota strain of SARS-CoV-2 (e.g., a B.1.526 lineage or a lineage descendent therefrom). In some embodiments, the subject was infected with a kappa strain of SARS-CoV-2 (e.g., a B.1.617.1 lineage or a lineage descendent therefrom). In some embodiments, the subject was infected with a 1.617.3 strain of SARS-CoV-2 or a lineage descendent therefrom.
  • an iota strain of SARS-CoV-2 e.g., a B.1.526 lineage or a lineage descendent therefrom.
  • the subject was infected with a kappa strain of SARS-CoV-2 (e.g., a B.1.617.1 lineage or a lineage descendent therefrom).
  • the subject was infected with a 1.617.3 strain of SARS-CoV-2 or a lineage descendent therefrom.
  • the subject was infected with a Mu strain of SARS-CoV-2 (e.g., a B.l .621 or B.l .621 .1 lineage or a lineage descendent therefrom).
  • a Mu strain of SARS-CoV-2 e.g., a B.l .621 or B.l .621 .1 lineage or a lineage descendent therefrom.
  • the subject was infected with a zeta strain of SARS-CoV-2 (e.g., a P.2 lineage or a lineage descendent therefrom).
  • the subject was infected with an Omicron strain of SARS-CoV-2 (e.g., a B.l.1.529, BA.l, BA.1.1, BA.2, BA.3, BA.4 or BA.5 lineage or a lineage descendent therefrom).
  • the subject is an adult. In some embodiments, the subject is between 18 and 65 years of age (e.g., between 18 and 30, 30 and 40, 40 and 50, 50 and 60, or 60 and 65 years of age). In some embodiments, the subject is an adolescent or a child. In some embodiments, the subject is 17 years of age or younger. In some embodiments, the subject is between 1 and 17 years of age (e.g., between 1 and 5, 5 and 10, 10 and 15, or 15 and 17). In some embodiments, the subject has fatigue-predominant PASC. In some embodiments, the subject has PCr recovery constant of >40 seconds or >50 seconds.
  • Another aspect of the invention further provides a method for treating a subject diagnosed with post-viral fatigue, particularly post-acute sequelae of COVID- 19 comprising administering to a subject in need thereof an effective amount of the composition of any one of aspects or embodiments disclosed herein.
  • a subject has one or more symptoms or signs selected from the group consisting of anorexia, anxiety, arrhythmias, confusion (“brain fog”), dementia, depression, dyspnea, fatigue, hair loss, headache, heart failure, cardiomyopathy, angina, hepatic dysfunction, hyperglycemia, type 2 diabetes, increased heart rate, inflammation, loss of appetite, loss of memory, loss of smell, mood disorder, muscle weakness, myocardial ischemia, post-exertional malaise, diminished neurocognition, diminished sensory function, pulmonary infiltrates or fibrosis, postural orthostatic hypotension, renal dysfunction, and respiratory distress.
  • a subject has one or more symptoms or signs selected from the group consisting of myalgia, fibromyalgia, idiopathic pulmonary fibrosis, fatigue, muscle fatigue, mitochondrial dysfunction (e.g., increase lactic acid production), dyspnea after exertion, postural orthostatic tachycardia syndrome, tachycardia, mood disorders, and depression.
  • an immunologic symptom or sign is selected from the group consisting of increased markers of inflammation (e.g., erythrocyte sedimentation rate, c reactive protein), increased proinflammatory cytokines (e.g., CRP, IL-1 A, IL- 17a, TNF-alpha), decreased cytotoxicity of natural killer cells, expression of cytolytic proteins, and production of cytokines, increased CD8+ cytotoxic T cells with CD38 activation antigen, T cell exhaustion, and increased autoantibodies, especially against targets in CNS and autonomic nervous system.
  • increased markers of inflammation e.g., erythrocyte sedimentation rate, c reactive protein
  • proinflammatory cytokines e.g., CRP, IL-1 A, IL- 17a, TNF-alpha
  • decreased cytotoxicity of natural killer cells e.g., CRP, IL-1 A, IL- 17a, TNF-alpha
  • decreased cytotoxicity of natural killer cells e.g., CD8+ cytotoxic
  • a metabolic symptom or sign is selected from the group consisting of increased lactic acid, reduced ATP generation from glucose by the tricarboxylic acid (TCA) cycle, reduced levels of fatty acids and of acyl-carnitine, reduced levels of amino acids via the urea cycle, impaired oxidative phosphorylation, redox imbalance (e.g., increased levels of oxidants, e.g., peroxides and superoxides, isoprostanes, at rest and/or after exercise or exertion; decreased levels of antioxidants, e.g., decreased levels of alpha-tocopherol, e.g., thiobarbituric acid reactive substances), increased inducible nitric oxide synthase (iNOS), increased NFKB, increased nitric oxide (NO), peroxynitrite, and/or nitrate (e.g., after exercise or exertion), elevated levels of brain ventricular lactic acid, and increased blood glucose (e.g., new
  • a neurologic symptom or sign is selected from the group consisting of cognitive deficits (e.g., in attention and reaction time), impaired response to cognitive, motor, visual, and auditory challenges, abnormal nerve conduction studies, abnormal imaging of the brain, hypoperfusion and/or metabolic dysfunction of glial cells, neuroinflammation characterized by widespread activation of both astrocytes and microglia, downregulation of the hypothalamic-pituitary-adrenal (HPA) axis, impaired response of one region of the brain to signals from another region (impaired connectivity), disordered sympathetic and parasympathetic activity, increased levels of tissue repair-indicative proteins (e.g., alpha-2-macroglobulin, keratin 16, orosomucoid), autoantibodies targeting cholinergic, adrenergic, and muscarinic receptors, reduced anaerobic threshold and/or reduced peak work (e.g., after exercise or exertion), and increased lactic acid in muscle and the need
  • the subject has increased levels of inflammatory cytokines relative to a normal subject, e.g., the subject has increased levels of CRP or TNFa relative to a normal subject e.g., without the one or more symptoms or without post-acute sequelae of COVID-19.
  • the subject exhibits muscle atrophy or has a decreased ratio of muscle tissue to adipose tissue relative to a normal subject, e.g., without the one or more symptoms or without post-acute sequelae of COVID- 19.
  • the subject exhibits brain fog or has a decreased neurocognitive function relative to a normal subject, e.g., without the one or more symptoms or without post-acute sequelae of CO VID-19.
  • the subject exhibits dyspnea or has a decreased pulmonary function relative to a normal subject, e.g., without the one or more symptoms or without post-acute sequelae of COVID- 19.
  • the subject exhibits decreased metabolic function relative to a normal subject, e.g., without the one or more symptoms or without post-acute sequelae of COVID- 19.
  • the subject exhibits abnormal (e.g., increased) immunologic function relative to a normal subject, e.g., without the one or more symptoms or without post-acute sequelae of COVID-19.
  • FIG. l is a schematic of the timeline for the study as described in Example 1. DETAILED DESCRIPTION
  • amino acid entity refers to a (L)-amino acid in free form or salt form (or both), the L-amino acid residue in a peptide smaller than 20 amino acid residues (e.g., oligopeptide, e.g., a dipeptide or a tripeptide), a derivative of the amino acid, a precursor of the amino acid, or a metabolite of the amino acid.
  • An amino acid entity includes a derivative of the amino acid, a precursor of the amino acid, a metabolite of the amino acid, or a salt form of the amino acid that is capable of effecting biological functionality of the free L-amino acid.
  • An amino acid entity does not include a naturally occurring polypeptide or protein of greater than 20 amino acid residues, either in whole or modified form, e.g., hydrolyzed form.
  • XXX amino acid entity refers to an amino acid entity that if a free amino acid, comprises free XXX or XXX in salt form; if a peptide, refers to a peptide (e.g., a dipeptide or a tripeptide) comprising an XXX residue; if a derivative, refers to a derivative of XXX; if a precursor, refers to a precursor of XXX; and if a metabolite, refers to a XXX metabolite.
  • L-amino acid entity refers to free L or L in salt form, a peptide (e.g., a dipeptide or a tripeptide) comprising a L residue, a L derivative, a L precursor, or a metabolite of L;
  • XXX is arginine (R)
  • R-amino acid entity refers to free R or R in salt form, a peptide (e.g., a dipeptide or a tripeptide) comprising a R residue, a R derivative, a R precursor, or a metabolite of R;
  • XXX is glutamine (Q)
  • Q-amino acid entity refers to free Q or Q in salt form, a peptide (e.g., a dipeptide or a tripeptide) comprising a Q residue, a Q derivative, a Q precursor, or a metabolite of Q; and where XXX is N-
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 15%, more typically, within 10%, and more typically, within 5% of a given value or range of values.
  • an effective amount means an amount of an amino acid, or pharmaceutical composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., to positively modify one, two, or more of a subject’s symptoms, e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically- acccptablc cxcipicnt(s) and/or carricr(s) utilized, and like factors with the knowledge and expertise of the attending physician.
  • the term “PCr recovery time” refers to (1) the amount of time required for a phosphocreatine (PCr) level to reach or exceed a predetermined value (e.g., after exercise), or (2) the rate at which a PCr level increases.
  • the PCr recovery time comprises a time constant of PCr resynthesis (rpcr).
  • the predetermined value is less than (e.g., 50% less than) the baseline PCr level before exercise.
  • a “pharmaceutical composition” described herein comprises at least one amino acid and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is used as a therapeutic, a nutraceutical, a medical food, or as a supplement.
  • pharmaceutically acceptable refers to amino acids, materials, excipients, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This may be a standaid used by the pharmaceutical industry or by agencies or entities (e.g., government or trade agencies or entities) regulating the pharmaceutical industry to ensure one or more product quality parameters are within acceptable ranges for a medicine, pharmaceutical composition, treatment, or other therapeutic.
  • a product quality parameter can be any parameter regulated by the pharmaceutical industry or by agencies or entities, e.g., government or trade agencies or entities, including but not limited to composition; composition uniformity; dosage; dosage uniformity; presence, absence, and/or level of contaminants or impurities; and level of sterility (e.g., the presence, absence and/or level of microbes).
  • agencies or entities e.g., government or trade agencies or entities, including but not limited to composition; composition uniformity; dosage; dosage uniformity; presence, absence, and/or level of contaminants or impurities; and level of sterility (e.g., the presence, absence and/or level of microbes).
  • exemplary government regulatory agencies include: Federal Drag Administration (FDA), European Medicines Agency (EMA), SwissMedic, China Food and Drag Administration (CFDA), or Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
  • PASC post acute sequelae of COVID-19
  • PES post-acute COVID syndrome
  • a composition, formulation or product is “therapeutic” if it provides a beneficial clinical effect.
  • a beneficial clinical effect can be shown by lessening the progression of a disease and/or alleviating one or more symptoms of the disease.
  • the terms “treat,” “treating,” or “treatment” of PASC refer in one embodiment, to ameliorating PASC, (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating a symptom of PASC, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of PASC.
  • the weight ratio of a particular amino acid or particular amino acids in a composition or mixture of amino acids is the ratio of the weight of the particular amino acid or amino acids in the composition or mixture compared to the total weight of amino acids present in the composition or mixture. This value is calculated by dividing the weight of the particular amino acid or of the particular amino acids in the composition or mixture by the weight of all amino acids present in the composition or mixture. It is understood that NAC is considered to be an amino acid for the purpose of this calculation.
  • various therapeutic products can be administered to improve mitochondrial, metabolic, immunologic, musculoskeletal, neurocognitive, and/or pulmonary function, e.g., in a patient with post-acute sequelae of COVID- 19. They can be administered to treat (e.g., reverse, reduce, ameliorate, or prevent) a disorder, e.g., post-acute sequelae of COVID- 19 in a subject.
  • composition as described herein can also be administered to treat (e.g., reverse, reduce, ameliorate, or prevent) a disorder, e.g., myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-infectious fatigue syndrome, post-critical illness syndrome, or post-intensive care unit syndrome, following illness or infection, e.g., related to post-acute sequelae of COVID- 19 in a subject.
  • a disorder e.g., myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-infectious fatigue syndrome, post-critical illness syndrome, or post-intensive care unit syndrome
  • a disorder e.g., myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-infectious fatigue syndrome, post-critical illness syndrome, or post-intensive care unit syndrome
  • a disorder e.g., myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post
  • the present disclosure provides methods of treating post- acute sequelae of COVID- 19 selected from myalgia, fibromyalgia, idiopathic pulmonary fibrosis, fatigue, muscle fatigue, mitochondrial dysfunction, dyspnea after exertion, postural orthostatic tachycardia syndrome, and tachycardia in subject diagnosed or in whom diagnosis is confirmed in accordance with the invention.
  • an effective amount of the composition can be administered (e.g., according to a dosage regimen described herein) to treat a subject with postacute sequelae of COVID-19.
  • a method described herein comprises administering a composition as described in International Applications WO/2018/118941 or WO/2018/ 118957, each of which is herein incorporated by reference in its entirety.
  • a method described herein comprises a treatment as described in International Application PCT/US22/38200, which is herein incorporated by reference in its entirety.
  • a method described herein comprises administering one or more of, e.g., all of, a histidine (H)-amino acid entity, a lysine (K)-amino acid entity, a phenylalanine (F)-amino acid entity, and a threonine (T)-amino acid entity.
  • H-amino acid entity is selected from the group consisting of L-histidine, histidinol, histidinal, ribose-5- phosphate, carnosine, histamine, urocanate, and N-acetyl histidine, or a salt of any of the forgoing.
  • the H-amino acid entity is L-histidine or a salt thereof.
  • the K-amino acid entity is selected from the group consisting of L-lysine, diaminopimelate, trimethyllysine, carnitine, saccharopine, and N-acetyl lysine, or a salt of any of the forgoing.
  • the K-amino acid entity is L-lysine or a salt thereof.
  • the F-amino acid entity is selected from the group consisting of from L-phenylalanine, phenylpyruvate, tyrosine, and N-acetyl-phenylalanine, or a salt of any of the forgoing. In some embodiment, the F-amino acid entity is L-phenylalanine or a salt thereof.
  • the T-amino acid entity is selected from the group consisting of L-threonine, homoserine, O-phosphohomoserine, oxobutyrate, and N-acetyl-threonine, or a salt of any of the forgoing. In some embodiments the T-amino acid entity is L-threonine or a salt thereof.
  • a subject has post-acute sequelae of COVID- 19.
  • a subject has one or more symptoms selected from the group consisting of anorexia, anxiety, arrhythmias, confusion (“brain fog”), dementia, depression, dyspnea, fatigue, hair loss, headache, heart failure, cardiomyopathy, angina, hepatic dysfunction, hyperglycemia, type 2 diabetes, increased heart rate, inflammation, loss of appetite, loss of memory, loss of smell, mood disorder, muscle weakness, myocardial ischemia, post-exertional malaise, diminished neurocognition, diminished sensory function, pulmonary fibrosis, postural orthostatic hypotension, renal dysfunction, and respiratory distress.
  • a subject has one or more symptoms selected from the group consisting of myalgia, muscle fatigue, fatigue, dyspnea after exertion, postural orthostatic tachycardia syndrome, tachycardia, mood disorders, and depression.
  • the subject has been infected with a virus selected from the group consisting of SARS-CoV-1, SARS-CoV-2, MERS, influenza A or B, herpesviruses (Epstein-Bair virus, human cytomegalovirus, and human herpesviruses 6A and 6B), Ebola virus, West Nile virus, dengue virus, Ross river virus, enteroviruses, and human parvovirus B19.
  • a subject has been infected with a coronavirus (e.g., a human alpha coronavirus (e.g., HCoV-229E or HCoV-NL63), a human betacoronavirus (HCoV-OC43 or HKU1), SARS-CoV-1 , SARS-CoV-2, and/or MERS).
  • a coronavirus e.g., a human alpha coronavirus (e.g., HCoV-229E or HCoV-NL63), a human betacoronavirus (HCoV-OC43 or HKU1), SARS-CoV-1 , SARS-CoV-2, and/or MERS.
  • a subject has been hospitalized for acute COVID- 19.
  • a subject has been hospitalized for one or more symptoms of post-acute sequelae of COVID-19.
  • a subject had not been vaccinated for COVID- 19 prior to contracting COVID-19.
  • a subject had not been vaccinated (e.g., partially vaccinated or fully vaccinated) for COVID- 19 prior to contracting COVID- 19. In some embodiments, a subject had been vaccinated for COVID- 19 after contracting COVID- 19.
  • the subject has tested positive for SARS-CoV-2 more than once. In certain embodiments, the subject has tested positive for SARS-CoV-2 1, 2, 3, 4, or more times. In some embodiments, the subject has been diagnosed with more than one infection of SARS-CoV-2 (e.g., 1, 2, 3, 4, or more separate SARS-CoV-2 infections).
  • a subject tested positive for COVID-19 e.g., about 1, 2, 3, or 4 weeks before administration.
  • a subject tested positive for COVID-19 at least twice over a period of time, e.g., at least 3 or 4 weeks, before administering a composition described herein.
  • a subject had acute COVID- 19 for about 3, 4, 5, 6, 8, 10, or 12 weeks, before administering a composition described herein.
  • a subject had one or more symptoms of acute COVID- 10 for at least 3 or 4 weeks, before administration of a composition described herein.
  • a subject is (e.g., is determined to be) negative for SARS-CoV-2 at the time of administration of a composition described herein. In some embodiments, at the time of administration of a composition described herein, the subject is (e.g., is determined to be) positive for SARS-CoV-2. In some embodiments, at the time of administration, the subject no longer has detectable SARS-CoV-2 in a nasal sample at the time they are administered the composition.
  • PCr recovery time is measured using magnetic resonance spectroscopy (MRS). In some embodiments, PCr recovery time is measured using magnetic resonance imaging (MRI). In some embodiments, PCr recovery time is measured using 31 P chemical shift imaging ( 31 P-CSI). In some embodiments, PCr recovery time is measured using 31 P-Rapid Acquisition with Relaxation Enhancement (RARE) MRI. In some embodiments, PCr recovery time is measured using a biopsy. In some embodiments, a method of measuring (e.g., a method of measuring PCr recovery time) is performed as described in Greenman, et al., Acad Radiol. 2011 July; 18(7): 917-923, herein incorporated by reference in its entirety.
  • a method described herein comprises a step of comparing a value to a threshold, e.g., of comparing the measure of PCr recovery time to a PCr threshold.
  • the method further comprises comparing the value to a second threshold.
  • the method may comprise determining if the value is above the PCr threshold and below a second threshold, e.g., determining whether the value is within a range bounded by the two thresholds.
  • a randomized, double-blind, placebo-controlled Phase 2a trial was conducted to evaluate the efficacy and safety of a LIVRQNac Test Article in patients with moderate to severe fatigue related to long COVID (>12 weeks after initial infection). Enrollment in the study has been completed, with 41 patients randomized evenly to receive either 67.8 grams per day of LIVRQNac or a matched placebo in two divided doses for 28 days, with a one-week safety follow-up period.
  • the total study duration for each subject is approximately 9 weeks and comprising of a Screening Period of up to 4 weeks, a Treatment Period of up to 4 weeks, and a Follow-up Period of 1 week (FIG. 1).
  • the primary efficacy endpoint is the mean change from baseline at Week 4 in the phosphocreatine (PCr) recovery rate following moderate exercise, as assessed by phosphorus magnetic resonance spectroscopy ( 31 P-MRS), which is evaluated at Screening and End of Trial (EOT) (visit 4).
  • PCr phosphocreatine
  • 31 P-MRS phosphorus magnetic resonance spectroscopy
  • EOT Screening and End of Trial
  • 6MWT 6-minute walk test
  • Chalder Fatigue scale which have been successfully validated and used in previous studies on chronic fatigue syndrome (Mantha 2020) were utilized.
  • the LIVRQNac Test Article is an orally active mixture of 5 specific AAs (leucine, isoleucine, valine, arginine, glutamine), and N-acetylcysteine (Nac) as presented in Table 1. Table 1. Amino Acid and Excipient Composition Within LIVRQNac Test Article
  • Total may be >100% due to rounding off a Arginine is sourced as arginine monohydrochloride
  • Test Article is supplied in a dry powder form that is dissolved in approximately 6 oz (approximately 180 mL) of water to form a uniform suspension and is administered orally, twice daily, as an orange-flavored drink.
  • the primary objective of this study was to assess the impact of LIVRQNac on muscle function (metabolism) following exercise.
  • a change in the time constant of phosphocreatine (PCr) recovery from baseline after 4 weeks treatment as measured by 31 P-MRS was chosen as the primary endpoint as it is objective and sensitive to changes in mitochondrial function.
  • 31 P-MRS is used to estimate the concentration of high-energy phosphate compounds; thus, the bioenergetic state of a tissue can be characterized in vivo as it may reflect changes in mitochondrial function (Prompers 2006; Kemp 2015; Valkovic 2016).
  • 31 P-MRS has been used to assess mitochondrial function in a variety of conditions, including heart failure patients (Menon 2021 ), diabetes (Ripley 2018), and mitochondrial abnormalities following drug administration (Fleischman 2007). If, as expected, a composition comprising LIVRQNac improves mitochondrial oxidative capacity, then a decrease, relative to subject baseline, in the phosphocreatine recovery time is predicted. The assumption at the beginning of the trial was that individuals with prolonged fatigue after COVID- 19 would have a baseline PCr of 50 seconds, which would be comparable to aged individuals or those with heart failure.
  • the Chalder Fatigue Scale (CFQ-11) and the 6MWT have been utilized in multiple therapeutic areas and several indications and have been paramount in characterizing the patient's condition and overall quality of life. Both these tests are suitable in evaluating scientifically supported and logical combination of symptoms that are common in patients with long COVID- 19 with fatigue and inform the design of a subsequent study with appropriate power to detect differences in these key endpoints.
  • the fatigue scale developed by Chalder et al. is an 11-item scale intended to measure the severity of fatigue-related symptoms, both mental and physical, experienced by individuals with myalgic encephalomyelitis I chronic fatigue syndrome (ME/CFS).
  • the scale has two scoring systems: bimodal and Likert.
  • bimodal respondents answer each question with a 1 or a 0 to indicate the questions apply to them or not.
  • Likert system respondents can give a score of 0 to 3 to indicate how each statement applies to them, from “less than usual” to “much more than usual”. The scores are then summed, and a higher score indicates more severe fatigue- related symptomatology.
  • the “Physical Fatigue” items include questions such as “Do you have problems with tiredness?” or “Do you lack energy?” The remaining items constitute a “Mental Fatigue” factor with questions such as “Do you have difficulty concentrating?” or “Do you make slips of the tongue when speaking?”
  • the total scale demonstrated sufficient internal consistency with alpha coefficients of 0.89 (Chalder 1993).
  • CFQ-11 Scale At the 90% sensitivity level for the CFQ-11 Scale (with a score > 14.50) a specificity of 0.61 was detected, and these scales were able to identify 90% of those individuals with CFS (Jason 2011).
  • Chalder et al.’s Fatigue Scale is a verbal rating measure that has strong internal consistency.
  • 6-minute walk test is a validated clinical test to assess the cardiopulmonary reserve and fundamentally designed for use in adults with chronic respiratory disease (Holland 2014) and therefore may be an appropriate test to evaluate functional status of COVID- 19 patients.
  • PCr phosphocrcatinc
  • the results for the 6MWT showed that there was no significant change from Baseline in the LIVRQNac Test Article Group versus the Placebo Group in the distance walked at Week 4 whether calculated as absolute change in distance or percent predicted.
  • the mean 6MWT was 533 M ⁇ 106 M, or approximately 85% predicted with approximately one quarter of subjects below the 75% of the predicted distance based on age or gender; these results are consistent with the literature. These results may be due to the relatively short duration of the study (4 weeks) and the unexpected severity and magnitude of fatigue encountered by this patient population.
  • 31 P magnetic resonance spectroscopy This Example describes measurement of phosphocreatine recovery in subjects following moderate exercise as assessed by 31 P magnetic resonance spectroscopy (MRS).
  • 31 P-MRS is used to estimate the concentration of high-energy phosphate compounds; thus, the bioenergetic state of a tissue can be characterized in vivo as it may reflect changes in mitochondrial function.
  • 31 P-MRS has been used to assess mitochondrial function in a variety of conditions, including heart failure patients, diabetes, and mitochondrial abnormalities following drug administration.
  • Protocol description Participants underwent MRS and dynamic 31 P MRS of skeletal muscle in the whole body 3T MRI system. Subjects were positioned supine, feet first in the MRI system with the dual tuned 1H/31P surface coil (Rapid Biomedical) strapped to the calf muscle (gastrocnemius medialis) of their dominant leg. The dominant leg also had an exercise band strapped to the ball of the foot and the other end was held by the participants. After positioning, localizer images were acquired and Bo shimming was performed to improve field homogeneity in the region of interest.
  • 1H/31P surface coil Rostrocnemius medialis
  • Stimulated Echo Acquisition Mode sequence was used for 1 H MRS localization and the voxel of interest was positioned in the gastrocnemius medialis muscle.
  • excitation frequency was centered on the acetyl-carnitine ACC to cover the spectral region from extra- and intra-myocellular lipids (EMCL and IMCL) CH2 and CH3 resonances and creatine (Cr).
  • the excitation frequency was centered between the C2H and C4H resonance of carnosine (Car). Five transients centered on the water resonance frequency were then acquired for reference.
  • DRESS Depth resolved surface coil spectroscopy
  • FID free induction decay
  • [ACC] LH2O] x (SACC/SH2O) x (nu2o/nAcc) x Wn2
  • S represents signals corrected for relaxation
  • n is the number of protons in the respective molecule
  • [H2O] 55,556 mmol/L
  • WH20 is the approximate water content of skeletal muscle tissue, i.e. 0.77 L/kg wet weight of tissue. The same equation was used for Car concentration quantification, using details for Car.
  • the y -ATP signal was used as an internal concentration reference, assuming a stable ATP concentration of 8.2 mmol/L in the skeletal muscle.
  • rpcr time constant of PCr resynthesis
  • the maximal rate of oxidative phosphorylation (Qmax) was calculated according to the ADP-bascd model of Michaelis and Menten.
  • ADP concentration is typically too low to be detected, but was calculated using a CK equilibrium, using the equilibrium constant KCK ⁇ 1.66 x 109 M 1 and assuming that at rest 15% of total Cr represents free Cr [Cr]:
  • ADPJ (LCrJ x LATPJ) / (
  • Step 2 1 H-MRS voxel position
  • the calibration sequence was used to plan the voxel position.
  • the voxel was placed inside the gastrocnemius medialis muscle, avoiding subcutaneous adipose tissue.
  • the size of the voxel was adjusted to fit the muscle if necessary.
  • the volume was adjusted to be placed over the whole calf muscle close to the RF coil.
  • Step 3 Shimming and power adjustment
  • the calibration sequence increased reference voltage by 10V for each repetition. After the scan was finished, the Spectroscopy card was opened, and the repetition with highest water signal was found, which was used to set the reference voltage in the 1 H-MRS scans.
  • the measurement parameters were copied and volume was adjusted from the calibration sequence, and the reference voltage was set.
  • the acetyl-camitine (ACC) and IMCL acquisition sequence was run.
  • the carnosine acquisition sequence was run, followed by running of the water acquisition sequence.
  • Step 5 31 P-MRS volume of interest (VO I) position
  • the calibration sequence was used to plan the VOI position.
  • the VOI was placed inside the gastrocnemius medialis muscle, avoiding soleus muscle.
  • the volume was adjusted, copied over from the 1H-MRS acquisitions.
  • Step 6 31 P-MRS Frequency and power adjustment
  • the X-frequency was set to PCr using the following:
  • the calibration sequence increased reference voltage by 10V for each repetition. After the scan was finished, the Spectroscopy card was opened, and the repetition with highest PCr signal was found, which was used to set the reference voltage in the 31 P-MRS scans.
  • the VOI position was copied and volume adjusted from the calibration sequence, and the reference voltage was set. Following instructions to the patient, the dynamic experiment was started. During the first minute, the subject continued to lay still and listen for the exercise signal. After the first minute, the exercise, i.e. plantar flexion, was started, which was performed once every TR (following the audio signal). The exercise frequency was observed, and the subject was instructed to adjust or stop for a moment and start again after next signal. The exercise was performed for 5 minutes if possible. If the subject had to stop before the 5 minutes were up, the time at which the patient stopped was recorded. After the exercise period, the patient was instructed to relax but to keep the leg in the same position as before, i.e., no motion during the recovery. Once the scan was finished, the subject was taken out of the MR system.
  • Step 8 31 P-MRS check
  • PCr signals were compared between the three acquisitions.
  • PCr signal at the end of exercise acquisition is -30% less than at the end of recovery.
  • PCr signal at the end of recovery is similar to at the rest.
  • PCr recovery rate time constants were determined at baseline, i.e. prior to administration of placebo or LIVRQNac using the methods described in Example 2. Measured rpcr in subjects with fatigue related to long COVID- 19 are summarized in Table 2.

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Abstract

La présente divulgation concerne des biomarqueurs pour diagnostiquer des séquelles post-aiguës de la COVID-19 (PASC, « post-acute sequelae of COVID-19 »). Dans certains modes de réalisation, le biomarqueur comprend un temps de récupération de phosphocréatine (PCr). Dans certains modes de réalisation, le patient souffrant de PASC a un temps de récupération de PCr plus long qu'un patient sain.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018118957A1 (fr) 2016-12-19 2018-06-28 Axcella Health Inc. Compositions d'acides aminés et méthodés de traitement de maladies et troubles musculaires
WO2018118941A1 (fr) 2016-12-19 2018-06-28 Axcella Health Inc. Compositions d'acides aminés et méthodes de traitement de maladies hépatiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018118957A1 (fr) 2016-12-19 2018-06-28 Axcella Health Inc. Compositions d'acides aminés et méthodés de traitement de maladies et troubles musculaires
WO2018118941A1 (fr) 2016-12-19 2018-06-28 Axcella Health Inc. Compositions d'acides aminés et méthodes de traitement de maladies hépatiques

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Efficacy, Safety, Tolerability of AXA1125 in Fatigue After COVID-19 Infection", 7 June 2022 (2022-06-07), XP055968884, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/study/NCT05152849> [retrieved on 20221007] *
ANONYMOUS: "History of Changes for Study: NCT05152849 Efficacy, Safety, Tolerability of AXA1125 in Fatigue After COVID-19 Infection", 5 June 2022 (2022-06-05), XP055968879, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT05152849?V_3=View#StudyPageTop> [retrieved on 20221007] *
AUGUSTIN ET AL.: "Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study", LANCET REG HEALTH EUR., vol. 6, 18 May 2021 (2021-05-18), pages 100122
BARNES P R ET AL: "Skeletal muscle bioenergetics in the chronic fatigue syndrome.", JOURNAL OF NEUROLOGY NEUROSURGERY & PSYCHIATRY., vol. 56, no. 6, 1 June 1993 (1993-06-01), GB, pages 679 - 683, XP093089036, ISSN: 0022-3050, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489619/pdf/jnnpsyc00479-0097.pdf> DOI: 10.1136/jnnp.56.6.679 *
CROOK: "Long covid-mechanisms, risk factors, and management", 13MJ, vol. 374, 26 July 2021 (2021-07-26), pages nl648
ERRATUM, BMJ, vol. 374, 3 August 2021 (2021-08-03), pages nl944
ERRATUM, LANCET RESPIR MED, vol. 10, no. 1, January 2022 (2022-01-01), pages e9
EVANS ET AL.: "Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID); a UK multicentre, prospective cohort study.", LANCET RESPIR MED., vol. 9, no. l 1, 7 October 2021 (2021-10-07), pages 1275 - 1287
GREENMAN ET AL., ACAD RADIOL., vol. 18, no. 7, July 2011 (2011-07-01), pages 917 - 923
HALPIN ET AL.: "Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation", J MED VIROL., 2020
HUANG ET AL.: "1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study", LANCET, vol. 398, no. 10302, 2021, pages 747 - 758
KIEREN G HOLLINGSWORTH ET AL: "Impaired cardiovascular response to standing in Chronic Fatigue Syndrome", EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, WILEY-BLACKWELL PUBLISHING LTD, GB, vol. 40, no. 7, 23 May 2010 (2010-05-23), pages 608 - 615, XP071217446, ISSN: 0014-2972, DOI: 10.1111/J.1365-2362.2010.02310.X *
LOPEZ LEON ET AL.: "More than 50 long-term effects of COVID-19: a systematic review and meta-analysis", SCI REP., vol. 11, no. 1, 9 August 2021 (2021-08-09), pages 16144
LOPEZ-LEON SANDRA ET AL: "More than 50 long-term effects of COVID-19: a systematic review and meta-analysis", SCIENTIFIC REPORTS, vol. 11, no. 1, 9 August 2021 (2021-08-09), XP055839326, Retrieved from the Internet <URL:https://www.nature.com/articles/s41598-021-95565-8.pdf> DOI: 10.1038/s41598-021-95565-8 *
OSTOJIC SERGEJ M.: "Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome", NUTRIENTS, vol. 13, no. 2, 4 January 2021 (2021-01-04), CH, pages 503, XP093012559, ISSN: 2072-6643, DOI: 10.3390/nu13020503 *
SIGFRID ET AL.: "Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the 1SAR1C WHO Clinical Characterisation Protocol", LANCET REG HEALTH EUR., vol. 8, 6 August 2021 (2021-08-06), pages 100186
TOWNSEND ET AL.: "Persistent poor health after COVID-19 is not associated with respiratory complications or initial disease severity", ANN AM THORAC SOC., vol. 18, no. 6, 2021, pages 997 - 1003

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