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WO2024030909A1 - Biomarqueurs de réponse au traitement d'une composition d'acides aminés dans covid long - Google Patents

Biomarqueurs de réponse au traitement d'une composition d'acides aminés dans covid long Download PDF

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Publication number
WO2024030909A1
WO2024030909A1 PCT/US2023/071437 US2023071437W WO2024030909A1 WO 2024030909 A1 WO2024030909 A1 WO 2024030909A1 US 2023071437 W US2023071437 W US 2023071437W WO 2024030909 A1 WO2024030909 A1 WO 2024030909A1
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protein
level
amino acid
subject
administration
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Karen Lavery
Irina LEAF
Joel PRADINES
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

Definitions

  • Efforts to study and treat long-term sequelae of COVID-19 are hindered by a paucity of biomarkers and clinical tests to reliably ascertain the efficacy of therapies for long COVID.
  • New objective methods for assessing response to long COVID therapies are needed.
  • SUMMARY Disclosed herein, at least in part, are methods of assessing a response to post-acute sequelae of COVID-19 (PASC), also known as long COVID.
  • the method of assessing a response 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 1 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) fatigue, mitochondrial dysfunction, dyspnea after exertion, postural orthostatic tachycardia syndrome, tachycardia, mood disorders, and depression.
  • 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 2 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) xvi.
  • the fatigue comprises one or both of persistent fatigue and exertional fatigue.
  • 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).
  • the subject was infected with a gamma strain of SARS-CoV-2 (e.g., a P.1 lineage or a lineage descendent therefrom).
  • a gamma strain of SARS-CoV-2 e.g., a P.1 lineage or a lineage descendent therefrom.
  • the 3 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 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).
  • 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 an eta strain of SARS-CoV-2 (e.g., a B.1.525 lineage or a lineage descendent therefrom). In some embodiments, 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.
  • SARS-CoV-2 e.g., a B.1.525 lineage or a lineage descendent therefrom.
  • the subject was infected with an iota strain of SARS-CoV-2 (e.g., a B.1.526 lineage or a lineage
  • the subject was infected with a Mu strain of SARS-CoV-2 (e.g., a B.1.621 or B.1.621.1 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.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 or BA.5 lineage or a lineage descendent therefrom).
  • the subject is an adult.
  • 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.
  • 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 4 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) dysfunction, and respiratory distress.
  • A2169-7048WO ESS-135.WO
  • 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.
  • the subject has immunologic symptoms or signs, metabolic symptoms or signs, and/or neurologic symptoms or signs.
  • 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-1A, 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
  • increased proinflammatory cytokines e.g., CRP, IL-1A, IL-17a, TNF-alpha
  • decreased cytotoxicity of natural killer cells e.g., expression of cytolytic proteins
  • production of cytokines e.g., increased CD8+ cytotoxic T cells with CD38 activation antigen, T cell exhaustion
  • 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 NF ⁇ B, 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, 5 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) adrenergic, and muscarinic receptors, reduced anaerobic threshold and/or reduced peak
  • the subject has increased levels of inflammatory cytokines relative to a normal subject, e.g., the subject has increased levels of CRP or TNF ⁇ 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 COVID-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. 1 is a schematic of the timeline for the study as described in Example 1.
  • FIG. 2 is a graph depicting the change in level of FGF21 from baseline at Week 4 in LIVRQNac-treated subjects versus placebo.
  • Wilcoxon test p-value 0.083. 6 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO)
  • level of INHBC FIG. 3B
  • FIG. 7A and 7B are graphs depicting the correlation between the change in level of GPX3 and physical fatigue (FIG.
  • 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 7 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 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- 8 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) acceptable excipient(s) and/or carrier(s) utilized, and like factors with the knowledge and expertise of the attending physician.
  • 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.
  • 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).
  • Exemplary government regulatory agencies include: Federal Drug Administration (FDA), European Medicines Agency (EMA), SwissMedic, China Food and Drug Administration (CFDA), or Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
  • FDA Federal Drug Administration
  • EMA European Medicines Agency
  • CFDA China Food and Drug Administration
  • PMDA Japanese Pharmaceuticals and Medical Devices Agency
  • PASC post acute sequelae of COVID-19
  • Other terms used to describe PASC include long COVID, long haul COVID, post-acute COVID, post-acute COVID syndrome (PACS) and/or chronic COVID.
  • 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 9 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 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. Determination of amino acid weight percent and amino acid ratios in a composition 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.
  • 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.
  • Methods of Treatment Based on a diagnosis or confirmation of a diagnosis of PASC, various therapeutic products can be administered to a subject to improve mitochondrial, metabolic, immunologic, musculoskeletal, neurocognitive, and/or pulmonary function. 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 post- acute 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.
  • 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.
  • the T-amino acid entity is L-threonine or a salt thereof.
  • Subjects with Post-Acute Sequelae of COVID-19 PASC
  • 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 11 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 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.
  • A2169-7048WO ESS-135.WO
  • 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.
  • 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.
  • a subject had been vaccinated for COVID-19 after contracting COVID-19.
  • the subject tested positive for SARS-CoV-2 and developed symptoms consistent with infection.
  • the subject tested positive for SARS-COV-2 had symptoms of infection, became antibody negative or asymptomatic, and then was re-infected with another variant of SARS- CoV-2.
  • the subject has tested positive for SARS-CoV-2 more than once.
  • the subject has tested positive for SARS-CoV-21, 2, 3, 4, or more times.
  • 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-19 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.
  • the subject is (e.g., is determined to be) positive for SARS-CoV-2.
  • 12 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 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.
  • FGF21 levels are elevated in skeletal muscle stress, in CFS, and in acute COVID-19 infection.
  • IL-26 is a chronic inflammation cytokine and implicated in autoimmune disease.
  • Activin A/B are inflammatory cytokines implicated in inflammatory bowel disease (IBD), sepsis, and other immune diseases.
  • IBD inflammatory bowel disease
  • Activin A/B levels are elevated following COVID-19 infection.
  • NfL (also called NEFL) is a neuron-specific cytoskeleton protein and a marker of neuro- axonal injury in neuroinflammatory and neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS) and post-concussion.
  • ALS Amyotrophic Lateral Sclerosis
  • MS multiple sclerosis
  • GPX3 is involved in antioxidant response.
  • GPX3 levels are correlated with physical and total fatigue scores in an assay for fatigue (e.g., CFQ-11).
  • methods herein comprise acquiring the level of a protein, e.g., from an assay or from a third party.
  • the level of a protein comprises a numerical value.
  • the level of a protein is a a boolean value, e.g., above or below a given threshold.
  • Vascular Cell Adhesion Molecule 1 Vascular cell adhesion molecule 1 (VCAM-1) is expressed on the surface of endothelial cells and facilitates adhesion of inflammatory cells through interaction with leukocyte integrins (Smadja et al., ("COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects.” Angiogenesis 24(4): 755-788, 2021). Constitutive expression of VCAM-1 is low in healthy individuals but upregulated on the cell surface in response to inflammatory conditions, including COVID-19 (Ambrosino et al., (“Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target.” Biomedicines 10(4), 2022)).
  • VCAM-1 soluble VCAM-1
  • sVCAM-1 soluble VCAM-1
  • ESS-135.WO attorney Reference No.: A2169-7048WO (ESS-135.WO) higher viral load, greater disease severity and increased mortality
  • Bermejo-Martin et al. ("Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.” Crit Care 24(1): 691, 2020); Tong et al., ("Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients.” J Infect Dis 222(6): 894-898, 2020); Birnhuber et al., (“Between inflammation and thrombosis: endothelial cells in COVID- 19.” Eur Respir J 58(3), 2021); Spadaro et al., ("Markers of endothelial
  • VCAM-1 Vascular cell adhesion molecule 1
  • VCAM-1 is expressed on the surface of endothelial cells and facilitates adhesion of inflammatory cells through interaction with leukocyte integrins.
  • increases in circulating VCAM-1 (soluble VCAM-1; sVCAM-1) is a marker of vascular inflammation and endothelial activation.
  • a test for VCAM-1 levels comprises measuring the amount of VCAM-1 in the blood (e.g., serum).
  • VCAM-1 is measured by electrochemiluminescence immunoassay (ECLIA). Measuring VCAM-1 as part of an ECLIA may help diagnose an inflammatory condition.
  • VCAM-1 Constitutive expression of VCAM-1 is low in healthy individuals but upregulated on the cell surface in response to inflammatory conditions, including COVID-19.
  • elevated sVCAM-1 levels are associated with higher viral load, greater disease severity and increased mortality (Bermejo-Martin et al., 2020, supra; Tong et al., 2020, supra; Birnhuber et al., 2021, supra; Spadaro et al., 2021, supra; Vieceli Dalla Sega et al., 2021, supra).
  • VCAM-1 e.g., sVCAM-1
  • ESS-135.WO a composition described 14 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) herein.
  • VCAM-1 e.g., sVCAM-1
  • a control e.g., a subject not treated with a composition described herein.
  • Example 1 Evaluation of LIVRQNac in Subjects with Long COVID Fatigue Long COVID-19 with fatigue is a serious condition with urgent unmet medical need: Long COVID-19 is a chronic, multi-organ disease predominantly characterized by fatigue and muscle weakness (Lopez Leon et al (More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021 Aug 9;11(1):16144. doi: 10.1038/s41598- 021-95565-8.).
  • 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
  • ESS-135.WO Chalder Fatigue scale
  • 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.
  • 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; Valkovi ⁇ 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 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 / chronic fatigue syndrome (ME/CFS).
  • the scale has two scoring systems: bimodal and Likert.
  • the CFQ-11 has been applied to the study of outcomes in COVID-19 (Steven 2021, Tuzon 2021, Townsend 2021). Additionally, the 6-minute walk test (6MWT) 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. Results from this Analysis of this Study An analysis was conducted after 20 subjects (10 subjects taking Test Article and 10 19 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) taking Placebo) in the study completed 4 weeks of treatment.
  • 6MWT 6-minute walk test
  • 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. Magnetic resonance spectroscopy PCr results, measured as described above, indicated an unexpectedly large variation in both Baseline and deviation from the mean (mean 84.56 sec ⁇ 30.816).
  • FGF21 Fibroblast growth factor 21
  • the regulation and biological activity of FGF21 is highly complex and dependent on the physiological context including tissue of origin, systemic concentration, age and synergism with other signaling molecules (Tezze et al., 2019). Metabolic activities encompass effects on insulin sensitivity and glucose homeostasis, ketogenesis and lipid metabolism.
  • Effector pathways downstream of FGF21 include AMPK-Sirt1-PGC1a, ERK/MAPK, PI3K/AKT, IGF-1 and mTOR signaling pathways (Chau et al., 2010; Tezze et al., 2019) and numerous tissues such as central nervous system, skeletal muscle, adipose tissue and others are targets of FGF21 signaling (Sun et al., 2021).
  • FGF21 expression and activity is also regulated in a variety of disease conditions (Tezze et al., 21 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) 2019; Sun et al., 2021) and has been proposed as a biomarker of mitochondrial dysfunction (Lehtonen et al., 2016; Morovat et al., 2017; Scholle et al., 2018; Riley et al., 2022).
  • elevated FGF21 levels were detected in COVID-19 patients aged 54-80 and were correlated with disease severity and mortality (Ajaz et al., 2020).
  • FGF21 was also found to be enriched in circulating extracellular vesicles (EVs) from hospitalized COVID-19 patients (Krishnamachary et al., 2021), convalescent COVID-19 patients (Sun et al., 2021) and in the serum of insulin resistant, hyperglycemic COVID-19 patients (He et al., 2021). Given its prominent role in metabolism and associations with SARS-CoV-2 infection, FGF21 concentrations were measured in plasma samples from the study described in Example 1 above.
  • EVs extracellular vesicles
  • Plasma concentrations of FGF21 were analyzed by ELISA (MRL-US).
  • the data presented below reflect analyses conducted on samples available at the End of Trial (EOT), with samples from 41 subjects from the study described in Example 1 above. Data are expressed as change from Baseline at EOT to correct for potential intrinsic (treatment unrelated) differences between treatment and placebo groups.
  • the statistical test applied is Wilcoxon (Mann-Whitney), a nonparametric test based on ranks. This approach has less statistical power than a parametric test but is more conservative, as it avoids spurious conclusions based on inadequacy of a distribution model.
  • Results: Significant downregulation (p 0.083) of serum FGF21 was observed (FIG. 2) in LIVRQNac treated subjects vs.
  • Activins are multifunctional members of the TGF ⁇ superfamily that regulate a broad array of biological processes including biosynthesis and secretion of reproductive regulatory hormones, embryonic development, wound repair, hematopoiesis, cell proliferation and differentiation, and immune regulation.
  • Activins exist as dimers of two activin beta ( ⁇ ) subunits (also referred to as inhibin ⁇ subunits), of which the best characterized are ⁇ A, ⁇ B and ⁇ C.
  • the ⁇ subunits combine as homodimers or heterodimers to form different activin proteins.
  • the role of activins in immune regulation are well-established. Activins induce both pro- and anti-inflammatory responses in numerous leukocyte types depending on the activation and maturation status of the cells as well as the spatiotemporal context (Morianos et al., 2019).
  • Activin A has been implicated in a variety of pathologies including autoimmune diseases, allergic disorders and viral infection.
  • Viral infection typically leads to elevated blood levels of activin A, which might correlate with IL-6, TNF ⁇ or viral load, depending on the virus (Morianos et al., 2019). Increased levels of activin A have also been reported in bronchial alveolar lavage fluid from patients with acute respiratory disease syndrome (ARDS) (Apostolou et al., 2012).
  • ARDS acute respiratory disease syndrome
  • Activin A is overexpressed in lung microvascular endothelial cells of patients with idiopathic pulmonary arterial hypertension, and acts as an angiocrine factor promoting endothelial dyfunction by inducing degradation of bone morphogenetic protein receptor type 2 (Ryanto et al., 2021).
  • Activin subunit beta A mRNA and Activin A protein are expressed at higher levels in the lung microvascular endothelium of these patients versus other vascular beds (Ryanto et al., 2021). Due to its multifactorial effects and broad tissue distribution, elevation of activins including activin A and activin B in COVID-19 could be attributable to numerous tissue and cell types.
  • LIVRQNac could contribute to the observed improvement in PROs from the study described in Example 1 above by reducing activin-mediated dysfunction of pulmonary tissue and endothelium.
  • Table 2 Levels of activin proteins in LIVRQNac treated subjects vs. placebo.
  • Neurofilament light chain (NfL) can easily diffuse from parenchyma to CSF and blood (Fuchs and Cleveland, 1998; Scherling 2014; Alirezaei 2020) and serve as a key noninvasive biomarker of neuro-axonal injury in diverse neuropathological conditions (Barro 2020).
  • Neuro-axonal injury can affect both the central and peripheral nervous systems and occur in a variety of neurodegenerative and neuroinflammatory diseases.
  • NfL is now being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy.
  • NfL was measured in many clinical trials and translational studies in multiple sclerosis (MS), traumatic brain injury (TBI), stroke, ALS, Alzheimer’s and other diseases. NfL shows the strongest diagnostic value in ALS. NfL levels in ALS are higher than in most diseases due to severe neurodegeneration and the fact that the degeneration affects large myelinated axons that have a high expression of NfL, which could be further amplified by the long length of the axons (Yuan 2017). Two longitudinal studies reported that patients that converted to the symptomatic stage had blood NfL levels higher than healthy controls up to 1 year prior to symptom onset (Benatar 2018, Benatar 2019).
  • Blood NfL has also been investigated as a prognostic biomarker once the disease has been diagnosed.
  • NfL levels at symptom onset were prognostic of the disease progression rate (Lu 2015, Gille 2019, Thouvenot 2020, Weydt 2016, Verde 2019).
  • serum NfL showed an association with brain atrophy over 2 years and number of MRI lesions (Kuhle 2017).
  • Thebault et al demonstrated that serum NfL was predictive of long-term outcomes in MS (Thebault 2020).
  • averaged annual serum NfL levels showed statistically significant associations with fatigue score worsening between years 1 and 10 using Modified Fatigue Impact Scale, MFIS (Chitnis 2018).
  • Interleukin 26 is a proinflammatory cytokine that also possesses antimicrobial properties and can be categorized as a kinocidin. 26 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) IL-26 is expressed on activated T cells, fibroblasts and epithelial cells and stimulates the production of other proinflammatory cytokines in various cell types. Additionally, IL-26 is a driver of chronic inflammation due its ability to act as a carrier of extracellular DNA released from damaged cells. The dysregulated expression of IL-26 may lead to the amplification of inflammatory responses and sustained inflammation.
  • IL-26 Elevated IL-26 levels were found in inflamed tissues and in plasma of patients with rheumatoid arthritis (Corvaisier 2012), IBD (Fuji 2017), hepatitis C virus (HCV) (Miot 2014), and systemic Lupus erythematosus (Brillant 2021). In several diseases, the highest expression of IL-26 was detected in pro-inflammatory IL- 17 producing T cells in chronically inflamed tissues. The roles of IL-26 in normal physiology remain unknown. As an antimicrobial, IL-26 has a direct role in viral infections.
  • GPX3 Glutathione peroxidase 3
  • Glutathione peroxidase 3 belongs to the glutathione peroxidase family and protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides and organic hydroperoxide, by glutathione.
  • GPX3 is the only extracellular GPx.
  • GPX3 has been shown that aging is accompanied by decrease in GPX3 activity (Razygraev 2019). GPX3 is markedly downregulated in breast cancer, possesses significant diagnostic and prognostic values, and attenuated in vitro growth and metastasis of breast cancer (Lu 2020).
  • the 2020 Chang study demonstrated that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein (Chang 2020). GPX3 deficiency has been associated with cardiovascular disease and stroke.
  • Serum GPx3 activity was shown to be inversely associated with mean carotid intima-media thickness and carotid plaque, suggesting that lower GPx3 activity may be an independent predictor for carotid atherosclerosis in T2DM (Ling 2020).
  • GPX3 deficiency promotes vascular dysfunction and platelet-dependent arterial thrombosis and increases cerebral infarct size in mice with permanent MCAO (Forrester 2018).
  • Reactive oxygen species (ROS) have long been known to contribute to the development and severity of IBD.
  • GPx3 was required to mediate the antioxidant effects of GPx1 that was previously shown to protect against dextran sodium sulfate (DSS)- induced colitis and augment intestinal proliferation (Blunt 2022).
  • DSS dextran sodium sulfate
  • Human myoblast in vitro studies showed that oxidative stress induced apoptosis and pre- treatment with retinoic acid rescued cell viability.
  • the anti-cytotoxic effects of retinoic acid were impaired in GPx3 inactivated myoblasts, which indicates that GPx3 regulates the antioxidative effects of retinoic acid and is important for the viability of human muscle stem cells (Haddad 2012).
  • GPX3 was identified as a factor that might be involved in the regulation of myocardial fibrosis under cardiac pressure overload in the single cell transcriptomic analysis used to characterize the dynamic changes associated with fibroblast differentiation. These findings suggested that GPX3 may represent a potential intervention target in myocardial fibrosis (Li 2022). No previous reports are available on the levels of circulating GPX3 in SARS-CoV-2 infections, in COVID or PASC. Methods: Proteomic profiling was performed on plasma samples collected at baseline and at 4 weeks post-treatment from 41 study subjects in the study described in Example 1 above (total 82 samples).
  • the statistical test applied is Wilcoxon (Mann-Whitney), a nonparametric test based on ranks. This approach has less statistical power than a parametric test but is more conservative, as it avoids spurious conclusions based on inadequacy of a distribution model.
  • Glutathione-disulfide reductase encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family that is located in the cytosol and in mitochondria. It is a central enzyme of cellular antioxidant defense that maintains high levels of reduced glutathione in the cytosol. Exercise leads to sustainable cardioprotection through a mechanism involving improved glutathione replenishment.
  • Adaptive cardioprotective signaling is triggered by reactive oxygen species from NADPH oxidase and leads to improved glutathione replenishment through increased GSR activity and redox-dependent modifications in GSR (Frazier 2013).
  • Klotho is an aging-suppressor gene which leads to accelerated aging when disrupted.
  • Klotho haplodeficiency impaired kidney function as evidenced by significant increase in plasma urea and creatinine and a decrease in urinary creatinine in KL +/– mice.
  • the expression and activity of GSR was decreased significantly in renal tubular epithelial cells of KL +/– mice, suggesting that Klotho deficiency downregulated GSR.
  • GSR may be a promising therapeutic approach for aging-related kidney damage (Gao 2020).
  • the 2021 Nadhashpour study assessed comorbidities, clinical symptoms and serum GSR levels in the PCR-negative and PCR-positive COVID-19 outpatients.
  • Proteomic profiling was performed on plasma samples collected at baseline and at 4 weeks post-treatment from 41 study subjects in the study described in Example 1 above (total 82 30 316100602.1 Attorney Reference No.: A2169-7048WO (ESS-135.WO) samples).
  • the statistical test applied is Wilcoxon (Mann-Whitney), a nonparametric test based on ranks.

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Abstract

La présente divulgation concerne des biomarqueurs permettant d'évaluer une réponse à une thérapie pour des séquelles post-aiguës du SARS-CoV-2 (PASC). Dans certains modes de réalisation, le biomarqueur comprend NfL, IL-26, activine, GPX3, GSR, FGF21, ou VCAM1.
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