Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses

Definitions

• the present invention relates to new methods for treating a coronavirus infection (e.g. SARS-CoV-02/COVID-19), symptoms and complications thereof, and conditions associated with such an infection, comprising administering a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a coronavirus infection e.g. SARS-CoV-02/COVID-19
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention provides inhibitors of neutrophil elastase (NE), in particular alvelestat, for treating a coronavirus infection and/or preventing progression of a coronavirus disease.
• NE neutrophil elastase
• the coronavirus is SARS-CoV-2 (COVID-19).
• alvelestat is expected to be therapeutically useful due to its ability to inhibit neutrophil elastase.
• neutrophil elastase is essential to neutrophil extracellular traps (NETs) formation ([6]).
• NETs are networks of extracellular DNA fibers, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), released from neutrophils and involved physiologically in capturing bacteria.
• MPO myeloperoxidase
• NE neutrophil elastase
• NETs are cytotoxic to endothelial and epithelial cells; acting as Damage Associated Molecular Pattern Molecules (DAMPs), promoting cytokine release and thromboses ([7]).
• DAMPs Damage Associated Molecular Pattern Molecules
• the physiological inhibitor of NE is Alpha-1 antitrypsin (AAT), but studies in COVID-19 have shown this to be overwhelmed ([8]) and have shown that neutrophils and NETs are a central feature of COVID-19 pathogenesis.
• Treatment with alvelestat according to the present invention may therefore impact the disease progression of coronavirus infections, in particular COVID-19, through inhibition of neutrophil elastase, decreasing levels of NETs, and disruption of NETosis.
• Neutrophil elastase has also been implicated in increasing the infectivity of COVID-19, and therefore, the inhibition of neutrophil elastase could reduce viral replication ([20]).
• the administration of alvelestat or a pharmaceutically acceptable salt thereof may therefore prevent replication of a coronavirus in a subject thereby treating the coronavirus infection and/or preventing progression of coronavirus disease. This may occur via a pathway that involves the inhibition of neutrophil elastase.
• the present invention generally provides a method for treating a coronavirus infection and/or preventing progression of a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for preventing the progression of a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing a symptom or complication of a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for reducing viral replication of a coronavirus, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing tissue injury associated with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing acute lung injury (ALI) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• ALI acute lung injury
• the present invention also generally provides a method for treating or preventing acute respiratory distress syndrome (ARDS) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• ARDS acute respiratory distress syndrome
• the present invention also generally provides a method for treating or preventing inflammation in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing neutrophilia in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• coagulopathy e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding
• the present invention also generally provides a method for treating or preventing one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing antiphospholipid syndrome (APS) (also referred to as antiphospholipid antibody syndrome (APLS)) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• APS antiphospholipid syndrome
• APLS antiphospholipid antibody syndrome
• the present invention also generally provides a method for treating or preventing organ failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• One or more organs e.g. the lungs, kidneys, heart
• the organ failure may be multi-organ failure.
• the present invention also generally provides a method for treating or preventing respiratory failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing renal failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing cardiac failure (e.g. myocarditis) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing a condition associated with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing coronavirus induced coagulopathy complications (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding), comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• coronavirus induced coagulopathy complications e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding
• the present invention also generally provides a method for treating or preventing coronavirus induced respiratory complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing coronavirus induced cardiac complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also generally provides a method for treating or preventing coronavirus induced renal complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the coronavirus is SARS-COV, most preferably COVID-19.
• the neutrophil elastase inhibitor is alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• the term “about” means the recited value ⁇ 10% of the recited value.
• treatment is an approach for obtaining beneficial or desired results.
• beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom associated with a disease or condition.
• Treatment includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
• slowing or arresting the development of one or more symptoms associated with the disease or condition e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition
• relieving the disease or condition e.g., causing the regression of
• prevention refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop.
• prevention may relate to administration of a therapy (e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject.
• the subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.
• preventing progression refers to a regimen that protects against the further development (e.g. worsening) of the disease or disorder in a subject.
• the term “therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
• the effective amount will vary depending on the particular compound, and characteristics of the subject to be treated, such as age, weight, etc.
• the effective amount can include a range of amounts.
• an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
• An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
• Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
• solvate is used herein to describe a molecular complex comprising the compound of the invention and a one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water.
• solvent molecules for example, ethanol or water.
• hydrate is employed when the solvent is water and for the avoidance of any doubt, the term “hydrate” is encompassed by the term “solvate”.
• pharmaceutically acceptable salt means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
• pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
• Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
• suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH, 2011).
• “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms etc. which are suitable for pharmaceutical use.
• subject preferably refers to a human.
• the preferred neutrophil elastase inhibitor used in the invention is alvelestat.
• Alvelestat is a potent, orally bioavailable neutrophil elastase inhibitor described in WO 2005/026123 A1 (Example 94, page 85) and [11], which are incorporated herein by reference in their entirety.
• Alvelestat has the chemical name N- ⁇ [5-(methanesulfonyl)pyridin-2-yl]methyl ⁇ -6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, and the following chemical structure:
• Alvelestat has also been referred to as AZD9668 and MPH996.
• Alvelestat may be used in the invention in any pharmaceutically acceptable form, for example any free base form, salt form, and/or solvate form.
• Alvelestat or a pharmaceutically acceptable salt and/or solvate thereof may be present in any pharmaceutically acceptable physical form, suitably a solid form.
• salts of alvelestat are described in WO 2010/094964 A1, which is incorporated herein by reference in its entirety. Described salts of alvelestat include the tosylate, p-xylene-2-sulfonate, chloride, mesylate, esylate, 1,5-naphthalenedisulfonate and sulfate.
• alvelestat free base or alvelestat tosylate is used in the methods of the invention, more preferably alvelestat tosylate.
• Alvelestat may also be used in any of the methods of the invention in a pharmaceutically acceptable prodrug form.
• Neutrophil elastase is an enzyme that attacks and progressively damages lung tissue.
• Compounds that inhibit NE are reviewed in [9] and are known from various publications including WO2017207430, WO2017102674, WO2016050835, WO2016050835, WO2016016368, WO2016016366, WO2016016365, WO2016016364, WO2016016363, WO2015124563, WO2016020070, WO2015091281, WO2014135414, WO2014122160, WO2015096873, WO2015096872, WO2014029832, WO2014029831, WO2014029830, WO2014009425, WO2013084199, WO2013037809, WO2011103774, WO2011110858, WO2011110859, WO2011110852, WO2011039528, WO2010034996, WO2009061271, WO2009058076, WO2009060206,
• neutrophil elastase inhibitors that may be used in the present invention include sivelestat, ONO-5046-Na, depelestat, Prolastin, KRP-109, DX-890, pre-elafin, MNEI, BAY 85-8501, POL6014, a1-AT, sirtinol, ONO-6818 (2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-1-yl)-N-[(1R, 2R)-1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-hydroxy-3-methylbutan-2-yl]acetamide), elastatinal, SSR 69071 (2-[[6-methoxy-4-(1-methylethyl)-1,1-dioxo-3-oxo-1,2-benzisothiazol
• neutrophil elastase inhibitor includes all pharmaceutically acceptable forms of the compounds, for example all pharmaceutically acceptable salt, solvate, isomer, and prodrug forms.
• the neutrophil elastase inhibitor is a small molecule compound, i.e. has a molecular weight of less than about 900 daltons.
• the neutrophil elastase inhibitors are inhibitors of human neutrophil elastase.
• alvelestat Although many embodiments of this invention relate to alvelestat, it should be understood that for each and every embodiment described herein referring to “alvelestat”, the invention also provides a corresponding embodiment involving the use of “a neutrophil elastase inhibitor”.
• the invention generally provides methods for treating a coronavirus infection and/or preventing progression of a coronavirus disease in a subject in need thereof comprising administering to the subject an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof. Accordingly, the present invention provides a method for treating a coronavirus infection and/or preventing progression of coronavirus disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention also provides a method for treating or preventing a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating or preventing a symptom of a coronavirus infection. In an embodiment, the present invention provides a method for treating or preventing a complication of a coronavirus infection. In an embodiment, the method for treating or preventing a symptom or a complication of a coronavirus infection is a method for ameliorating a symptom or a complication of a coronavirus infection. In an embodiment, the method for treating or preventing a symptom or a complication of a coronavirus infection is a method for preventing worsening of a symptom or a complication of a coronavirus infection. Preferably, the symptom or complication is a respiratory symptom or complication.
• the coronavirus infection is a viral respiratory disease.
• coronavirus is a group of related RNA viruses that can cause diseases in mammals and birds. In human subjects, these viruses can cause respiratory tract infections, other symptoms, and/or complications. Lethal varieties of coronaviruses can cause severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus MERS, and COVID-19.
• SARS severe acute respiratory syndrome coronavirus
• MERS Middle East respiratory syndrome coronavirus
• COVID-19 severe acute respiratory syndrome coronavirus
• coronavirus is used interchangeably with “virus” in this disclosure.
• coronavirus and “coronavirus infection” can be used interchangeably in this disclosure.
• Severe acute respiratory syndrome coronavirus is a species of coronavirus that infects at least humans and bats.
• SARS-CoV is an enveloped positive-sense single-stranded RNA virus that enters its host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.
• ACE2 angiotensin-converting enzyme 2
• SARS-CoV-2 and “COVID-19” can be used interchangeably.
• the coronavirus infection is severe acute respiratory syndrome coronavirus (SARS-CoV).
• SARS-COV may be of any strain.
• the SARS-CoV is SARS-CoV-1.
• the SARS-CoV is SARS-CoV-2 (COVID-19).
• the coronavirus infection is Middle East respiratory syndrome coronavirus (MERS-CoV).
• MERS-CoV Middle East respiratory syndrome coronavirus
• the present invention provides a method for treating SARS-CoV and/or preventing progression of SARS-CoV disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating or preventing COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating a SARS-CoV infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the method for treatment of the present invention comprises treating or preventing a symptom or complication attributable to a SARS-COV infection, such as COVID-19.
• the present invention provides a method for treating or preventing a disease or condition associated with a SARS-COV infection, such as COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating or preventing a symptom or complication associated with a SARS-COV infection, such as COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for treating a symptom of a coronavirus infection. In an embodiment, the present invention provides a method for preventing a symptom of a coronavirus infection.
• the disease, condition, symptom, and complication may be caused by or be attributable to a coronavirus infection.
• Acute respiratory distress syndrome is a type of respiratory failure which can be characterized by inflammation in the lungs. Symptoms can include at least one of shortness of breath, rapid breathing, and bluish skin coloration. Causes of ARDS may include at least one of a coronavirus infection, sepsis, pancreatitis, trauma, pneumonia, and aspiration. The underlying mechanism may involve diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. ARDS may impair the lungs' ability to exchange oxygen and carbon dioxide.
• An adult diagnosis may be based on a PaO 2 /FiO 2 ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg, optionally despite a positive end-expiratory pressure (PEEP) of more than 5 cm H 2 O.
• PaO 2 /FiO 2 ratio ratio of partial pressure arterial oxygen and fraction of inspired oxygen
• a coronavirus infection may cause ARDS via a pathway that involves neutrophils and neutrophil extracellular traps (NETs). It has been established that NETs increase in patients with ARDS ([10]).
• the present invention provides a method for the treatment or prevention of ARDS.
• the present invention provides a method for the treatment or prevention of ARDS in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of ARDS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of ARDS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Acute lung injury can be defined as a lung inflammation that develops in response to a pulmonary and/or generalized acute diseases.
• the clinical features of acute lung injury may vary from at least one of mild, self-limiting dyspnoea to rapidly progressive and fatal respiratory failure.
• a coronavirus infection may cause ALI via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of ALI.
• the present invention provides a method for the treatment or prevention of ALI in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of ALI associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of ALI arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Systemic inflammatory response syndrome can be an exaggerated defense response of the body to a noxious stressor (e.g. at least one of infection, trauma, surgery, acute inflammation, ischemia, reperfusion, and malignancy) to localize and then eliminate the endogenous or exogenous source of the stressor.
• a coronavirus infection may cause SIRS via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of SIRS.
• the present invention provides a method for the treatment or prevention of SIRS in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of SIRS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of SIRS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Pulmonary fibrosis (also referred to as fibrosing lung disease) is a condition in which the lungs become scarred over time. Symptoms can include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing.
• a coronavirus infection may cause pulmonary fibrosis, possibly via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).
• NETs neutrophil extracellular traps
• the present invention provides a method comprising the treatment or prevention of pulmonary fibrosis. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is pulmonary fibrosis. In an embodiment, the present invention provides a method for treatment wherein the subject has pulmonary fibrosis and a coronavirus infection.
• Pneumonia can be an inflammatory condition of the lung(s) which can affect the small air sacs known as alveoli. Symptoms can include at least one of productive or dry cough, chest pain, fever and difficulty breathing.
• the present invention provides a method for the treatment or prevention of pneumonia.
• the present invention provides a method for the treatment or prevention of pneumonia in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of pneumonia associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of pneumonia arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the pneumonia is viral pneumonia.
• Inflammation of the lung(s) can also be termed pneumonitis.
• inflammation of the lung(s) can be a general symptom or complication from any disease or condition (e.g. ARDS, ALI, and/or pneumonia).
• Inflammation of the lung(s) can be aggravated by or caused by a coronavirus infection.
• a coronavirus infection may cause inflammation of the lung(s) via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of inflammation of the lungs.
• the present invention provides a method for the treatment or prevention of inflammation of the lungs in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of inflammation of the lungs associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of inflammation of the lungs arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Respiratory failure can result from inadequate gas exchange by the respiratory system, meaning that oxygen levels and/or carbon dioxide levels cannot be kept at normal levels.
• a drop in the oxygen carried in blood can be known as hypoxemia; a rise in carbon dioxide levels is called hypercapnia.
• Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be either acute or chronic.
• the definition of respiratory failure can include increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing.
• a coronavirus infection may cause respiratory failure NETs.
• the present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2).
• the present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need
• Coagulopathy (which can also be termed as a bleeding disorder) can be a condition in which the blood's ability to coagulate (form clots) is impaired. Coagulopathy can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spontaneously or following an injury or medical and dental procedures. Without wishing to be bound by theory, a coronavirus infection may cause coagulopathy via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of coagulopathy.
• the present invention provides a method for the treatment or prevention of coagulopathy in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of coagulopathy associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of coagulopathy arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Coagulopathy includes thrombosis (such as arterial thrombosis, venous thrombosis, and microthrombosis), excessive bleeding, and disseminated intravascular coagulation.
• coagulopathy is thrombosis, such as arterial thrombosis, venous thrombosis, and microthrombosis.
• coagulopathy is arterial thrombosis.
• coagulopathy is venous thrombosis.
• coagulopathy is disseminated intravascular coagulation.
• coagulopathy is excessive bleeding.
• coagulopathy is thromboses and complications thereof.
• coagulopathy is thromboses and excessive bleeding.
• Antiphospholipid syndrome is an autoimmune disorder. APS can cause blood clots (thrombosis) in both arteries and veins. APS can occur when a subject's immune system produces antibodies that attack phospholipids. Without wishing to be bound by theory, a coronavirus infection may cause APS via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of APS.
• the present invention provides a method for the treatment or prevention of APS in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of APS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of APS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Multi-organ failure can also be referred to as multiple organ dysfunction syndrome or multiple organ failure.
• a coronavirus infection may cause multi-organ failure via a pathway that involves neutrophils and NETs.
• the present invention provides a method for the treatment or prevention of multi-organ failure.
• the present invention provides a method for the treatment or prevention of multi-organ failure in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of multi-organ failure associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of multi-organ failure arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the organs may be any organs, for example, the heart, lung or kidney.
• the organ failure comprises renal failure.
• the organ failure comprises heart failure.
• Cytokine release syndrome is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and/or certain drugs.
• SIRS systemic inflammatory response syndrome
• a coronavirus infection may cause CRS via a pathway that involves neutrophils and NETs.
• the present invention provides a method comprising the treatment or prevention of CRS.
• the present invention provides a method for treatment wherein the symptom or complication is CRS.
• the present invention provides a method for treatment wherein the subject has CRS and a coronavirus infection.
• a cytokine storm also called cytokine storm syndrome (CSS) or hypercytokinemia
• CCS cytokine storm syndrome
• a coronavirus infection may cause a cytokine storm via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).
• NETs neutrophil extracellular traps
• the present invention provides a method comprising the treatment or prevention of a cytokine storm.
• the present invention provides a method for treatment wherein the symptom or complication is a cytokine storm.
• the present invention provides a method for treatment wherein the subject has a cytokine storm and a coronavirus infection.
• Dyspnea can also be termed “shortness of breath” or “air hunger”. Without wishing to be bound by theory, a coronavirus infection may cause dyspnea, possibly via a pathway that involves neutrophils and NETs.
• the present invention provides a method comprising the treatment or prevention of a dyspnea.
• the present invention provides a method for treatment wherein the symptom or complication is dyspnea.
• the present invention provides a method for treatment wherein the subject has dyspnea and a coronavirus infection.
• Shock can be a life-threatening condition that occurs when the body is not receiving enough blood flow. Lack of blood flow can mean that cells and organs do not get enough oxygen and nutrients to function properly. Organs can be damaged as a result. Without wishing to be bound by theory, a coronavirus infection may cause shock via a pathway that involves neutrophils and NETs.
• the present invention provides a method comprising the treatment or prevention of a shock.
• the present invention provides a method for treatment wherein the symptom or complication is shock.
• the present invention provides a method for treatment wherein the subject has shock and a coronavirus infection.
• Hypoxemia can refers to the low level of oxygen in blood, and the more general term hypoxia can refer to an abnormally low oxygen content in any tissue or organ, or the body as a whole. Hypoxemia can cause hypoxia (hypoxemic hypoxia), but hypoxia can also occur via other mechanisms. Without wishing to be bound by theory, a coronavirus infection may cause hypoxemia via a pathway that involves neutrophils and NETs.
• the present invention provides a method comprising the treatment or prevention of hypoxemia.
• the present invention provides a method for treatment wherein the symptom or complication is hypoxemia.
• the present invention provides a method for treatment wherein the subject has hypoxemia and a coronavirus infection.
• Neutrophilia (sometimes also called neutrophil leukocytosis or neutrocytosis) is leukocytosis of neutrophils, i.e. a high number of neutrophils in the blood.
• Leukocytosis is a condition in which the white cell (leukocyte count) is above the normal range in the blood, and can be a sign of an inflammatory response.
• Neutrophilia can be a sign of an inflammatory response, possibly due to a coronavirus infection. Without wishing to be bound by theory, a coronavirus infection may cause neutrophilia via a pathway that involves neutrophils and NETs.
• the present invention provides a method comprising the treatment or prevention of neutrophilia.
• the present invention provides a method for treatment wherein the symptom or complication is neutrophilia.
• the present invention provides a method for treatment wherein the subject has neutrophilia and a coronavirus infection.
• a neurological disorder or complication is any disorder or complication of the nervous system.
• the nervous system includes the peripheral nervous system (PNS) and the central nervous system (CNS).
• the PNS generally includes the nerves and ganglia outside the brain and spinal cord.
• the CNS generally includes the brain and spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms.
• coronavirus e.g. COVID-19, who also have neurological disorders or complications.
• the neurological complications may cause COVID-19 symptoms such as loss of taste and/or loss of smell.
• a coronavirus infection may cause a neurological complication via a pathway that involves neutrophils and NETs.
• the administration of alevelstat or a pharmaceutically acceptable salt thereof may prevent replication of a coronavirus in a subject thereby reducing neurological complications.
• the present invention provides a method for the treatment or prevention of a neurological complication.
• the present invention provides a method for the treatment or prevention of a neurological complication in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of a neurological complication associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of a neurological complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the neurological complication is a complication of the PNS. In some embodiments, the neurological complication is a complication of the CNS.
• the neurological complication is encephalopathy.
• Encephalopathy can be any disorder or disease of the brain.
• Encephalopathy can include chronic degenerative conditions.
• Encephalopathy is not a single disease, but rather encephalopathy is a syndrome of overall brain dysfunction.
• Signs and/or symptoms of encephalopathy can include an altered mental state or delirium. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep-wake cycle and consciousness of a subject. An altered state of consciousness may range from failure of selective attention to drowsiness.
• the neurological complication is a loss of smell. In some embodiments, the neurological complication is anosmia. In some embodiments, the neurological complication is ageusia. In some embodiments, the neurological complication is a loss of taste.
• GBS Guillain-Barré syndrome
• a coronavirus infection e.g. a COVID-19 infection
• GBS may be a potential neurological complication from a coronavirus infection.
• NETs neutrophil extracellular traps
• the present invention provides a method comprising the treatment or prevention of GBS. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is GBS. In an embodiment, the present invention provides a method for treatment wherein the subject has GBS and a coronavirus infection.
• Thrombosis can occur in veins (venous thrombosis) or in arteries (arterial thrombosis). Venous thrombosis can lead to congestion of the affected part of the body, while arterial thrombosis (and rarely severe venous thrombosis) can affect the blood supply and/or can lead to damage of the tissue supplied by that artery (e.g. ischemia and necrosis).
• a piece of either an arterial or a venous thrombus can break off as an embolus which can travel through the circulation and lodge somewhere else as an embolism. This type of embolism is known as a thromboembolism.
• VTE venous thromboembolism
• An arterial embolus may travel further down the affected blood vessel where it can lodge as an embolism.
• a coronavirus infection may cause thrombosis via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).
• DIC Disseminated intravascular coagulation
• a microthrombus can be a microscopic clump of fibrin, platelets, and red blood cells.
• Symptoms of DIC may include one or more of chest pain, shortness of breath, leg pain, problems speaking, and/or problems moving parts of the body. DIC may be accompanied by ARDS.
• the present invention provides a method for the treatment or prevention of thrombosis.
• the present invention provides a method for the treatment or prevention of thrombosis in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of thrombosis associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of thrombosis arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the thrombosis is venous thrombosis.
• the thrombosis is arterial thrombosis.
• the thrombosis is VTE which cause a pulmonary embolism.
• the thrombosis is microthrombosis.
• Thrombosis in a subject can cause non-vessel thrombotic complications.
• vascular catheter thrombosis, vasculopathy, and/or vascular catheter thrombosis can be the treatment or prevention of a complication of thrombosis.
• the complication is vascular catheter thrombosis.
• the complication is vasculopathy.
• the complication is vascular catheter thrombosis.
• the present invention provides a method comprising the treatment or prevention of one or more conditions selected from the group consisting of: a disease with signs and/or symptoms similar to Kawasaki disease, acute respiratory distress syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome, alveolar-capillary damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot, bronchiectasis, cardiac complications, cardiovascular complications, chest tightness, coagulopathy, coagulopathy and/or excessive bleeding, coagulopathy complications, coughing, coughing up sputum, cystic fibrosis, cytokine release syndrome, cytokine storm hyperinflammation, cytokine storm syndrome, DIC and/or excessive bleeding, Dyspnea, Encephalitis, Encephalopathy, excessive bleeding, fatigue, fever, Guilla
• the present invention provides a method comprising the treatment of a symptom or complication of a coronavirus infection selected from the group consisting of: a disease with signs and/or symptoms similar to Kawasaki disease, acute respiratory distress syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome, alveolar-capillary damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot, bronchiectasis, cardiac complications, cardiovascular complications, chest tightness, coagulopathy, coagulopathy and/or excessive bleeding, coagulopathy complications, coughing, coughing up sputum, cystic fibrosis, cytokine release syndrome, cytokine storm hyperinflammation, cytokine storm syndrome, DIC and/or excessive bleeding, Dyspnea, Encephalitis, Encephalopathy,
• the present invention provides a method for treating or preventing a condition in a subject with a coronavirus infection, in particular COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the condition is selected from condition disclosed herein.
• the present invention also provides a method for treating or preventing coronavirus induced respiratory complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present disclosure encompasses all subjects having or at risk of coronavirus infection.
• the subject may be suffering from a symptom or complication of a coronavirus infection, or may be asymptomatic.
• the subject may have been diagnosed with a coronavirus infection or may be suspected of having a coronavirus infection.
• a subject with a symptom of a coronavirus injection, or a symptom attributable to a coronavirus infection can treated by a method of the present invention.
• Diagnosis or confirmation of a coronavirus infection can be carried out by the skilled clinician.
• One test can detect the presence of the virus currently in the subject (e.g. a PCR (polymerase chain reaction) test) and a second test that can detect a previous response to the virus by a subject's immune system (e.g. an antibody test).
• the PCR test may confirm that the virus is currently in a subject, by detecting the presence of the viral RNA in e.g. a sample from the subject's nose and/or throat.
• the antibody test can analyse a blood sample from the subject to determine whether a subject's immune system has previously responded to the virus already.
• the PCR test and/or the antibody test can be used to diagnose a subject with a coronavirus infection.
• a chest CT or a radiograph scan can also be used to confirm coronavirus infection.
• a subject in need of treatment by the present invention has a confirmed SARS-Cov-2 infection (e.g. confirmed by PCR from a nasopharyngeal or lower respiratory tract sample).
• a subject in need of treatment by the present invention has lung imaging showing pulmonary infiltrates consistent with COVID-19 lung disease (e.g. imaging can be undertaken by a chest X-ray or CT scan).
• a pulmonary infiltrate can be a substance denser than air, such as pus, blood, or protein, which lingers within the parenchyma of the lungs.
• the subject has risk factors for aggravated severity of the infection.
• Risk factors include co-morbidities such as obesity, hypertension, or diabetes (e.g. type 2 diabetes).
• Subjects at greater risk include those over 65 years of age, and those in black, Asian and minority ethnic groups.
• the subject has one more risk factors selected from being over 65, being in a black, Asian and/or a minority ethnic group, having obesity, hypertension, and/or diabetes (such as type 2 diabetes).
• the subject is in a black, Asian and/or a minority ethnic group.
• the subject is a paediatric subject. In an embodiment, the subject is less than 18 years of age.
• a complication in the paediatric population may be an inflammatory disease, disorder or syndrome.
• the inflammatory disease, disorder or syndrome may be a complication from a coronavirus infection.
• a coronavirus infection may cause an inflammatory disease, disorder or syndrome in the paediatric population a pathway that involves neutrophils and neutrophil extracellular traps (NETs).
• NETs neutrophil extracellular traps
• the present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome in a paediatric subject.
• the present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome in a paediatric subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome associated with a coronavirus infection in a paediatric subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome arising as a symptom or complication of a coronavirus infection in a paediatric subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• Kawasaki disease is a syndrome of unknown cause that can result in a fever and mainly affects paediatric subjects.
• Kawasaki disease may be a form of vasculitis. This is where blood vessels become inflamed throughout the body.
• the inflammatory disease, disorder or syndrome is Kawasaki disease. In some embodiments, the inflammatory disease, disorder or syndrome is similar to Kawasaki disease.
• the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome. In some embodiments, the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome Temporally associated with coronavirus. In some embodiments, the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS).
• PIMS-TS Paediatric Inflammatory Multisystem Syndrome
• PIMS-TS signs and/or symptoms can include abdominal pains, diarrhoea and/or fever.
• Subjects with PIMS-TS show more biomarkers of inflammation and/or cardiac enzymes. This is suggestive that the heart is under strain.
• the subject has PIMS-TS and a cardiac disorder.
• the subject requires hospitalisation. Hospitalisation refers to the admission to hospital for treatment.
• the subject requires ventilation. In an embodiment, the ventilation is mechanical ventilation. In other embodiments, the subject does not require ventilation.
• the WHO 9 point ordinal scale for the clinical improvement of patients diagnosed with SARS-CoV-2 (COVID-19) is:
• Noninvasive ventilation can refer to the administration of ventilatory support without using an invasive artificial airway (endotracheal tube or tracheostomy tube).
• non-invasive ventilation can involve the use of breathing support administered through a face mask, nasal mask, or a helmet. Air, optionally with added oxygen, can be given through the mask device, optimally under positive pressure.
• Intubation can be the process of inserting a tube, called an endotracheal tube, through the mouth and then into the airway. Intubation may be done so that a subject can be placed on a ventilator to assist with breathing.
• a subject in need of treatment by the method of present invention has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale.
• Methods according to the invention also comprise improving or preventing worsening of the condition of the subject on the WHO 9-Point Ordinal Scale.
• the method for treatment of a coronavirus infection comprises improving or preventing worsening of the condition of the subject according to the WHO 9-point ordinal scale.
• the method comprises improving the condition of the subject by at least 1 point according to the WHO 9-point ordinal scale.
• the method comprising improving the condition of the subject by at least 2 points according to the WHO 9-point ordinal scale.
• the subject has a score of Grade 3 on the WHO 9-point Ordinal Scale prior to starting treatment.
• the subject has a score of Grade 4 on the WHO 9-point Ordinal Scale prior to starting treatment.
• the subject has a score of Grade 5 on the WHO 9-point Ordinal Scale prior to starting treatment.
• the subject has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale prior to starting treatment.
• the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 29 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 20 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 10 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 5 days of treatment.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof improves the grading by at least 1 grade according to the WHO 9-point ordinal scale.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents the grading from worsening.
• a biomarker can be a measurable indicator of the severity or presence of a disease state. Relevant blood biomarkers can be used to detect signals of effect. Term “biomarker” may be used interchangeably with “blood biomarker” in the present disclosure.
• one or more blood biomarkers can be used to characterize the effect of alvelestat on blood pharmacodynamic markers of Neutrophil Extracellular Trap (NET) activation, elastase, inflammatory and/or coagulopathy activity.
• the effect is characterized relative to the baseline level of the biomarker in a blood sample from a subject prior to treatment according to the present invention.
• the change from baseline level of the biomarker is determined over a relevant treatment period, for example 10 days of treatment.
• Acute-phase proteins can be a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response can be called the acute-phase response.
• the acute-phase reaction can involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors.
• a coronavirus infection e.g. COVID-19
• the subject in need of treatment has an acute phase response.
• the subject in need of treatment may have an acute phase response.
• the subject in need of treatment may exhibit neutrophil activation (e.g. increased C-reactive protein and/or absolute neutrophilia).
• the subject in need of treatment may have an activated NETosis pathway.
• the subject may have an acute innate inflammatory response, optionally in response to a coronavirus (e.g. COVID-19) infection.
• the acute innate inflammatory response comprises one or more of elevated pro-inflammatory cytokines, elevation of acute phase reactants and/or cytokine storm.
• a subject with a coronavirus infection may display one or more of increased levels of inflammation, increased levels of coagulation activation products, increased levels neutrophils, increased levels of neutrophil elastase activity, increased levels of NETs, and increased levels of NETosis.
• At least an increased level of NETs (and by analogy neutrophils, NETosis, neutrophil elastase activity, and inflammation) may cause increased levels of cytokines, and optionally a cytokine storm, by various pathways. All the neutrophil, neutrophil elastase and NET related pathways may manifest in or contribute to diseases or conditions, such as ARDS.
• a subject displaying increased levels of inflammation, increased levels of neutrophils, increased levels of neutrophil elastase activity, increased levels of NETs, and/or increased levels of NETosis may be in need of the methods of treatment of the present invention.
• Levels/activities can be determined by analyzing one or more blood biomarkers in the subject.
• the subject may have increased neutrophil elastase activity. In an embodiment, the subject may have increased levels of NETosis. In an embodiment, the subject may have increased levels of NETs. In an embodiment, the subject may have inflammation, optionally lung inflammation. In an embodiment, the increased levels, activity and/or inflammation may be present in the subject prior to treatment by the method for treatment of the present invention. In an embodiment, the increased levels, activity and/or inflammation may be determined prior to treatment.
• the increased levels, activity and/or inflammation may be determined by one or more blood biomarkers.
• the neutrophil elastase inhibition or change in activity may be determined by one or more blood biomarkers.
• the one or more blood biomarker are plasma desmosine isodesmosine, and/or A-alpha-Val (A-alpha-Val360).
• the one or more blood biomarkers are selected from the group consisting of cell-free DNA, citrullinated histone H3, Myeloperoxidase (MPO), Myeloperoxidase (MPO)-DNA complexes, and Proteinase-3.
• the one or more blood biomarkers are selected from the group consisting of absolute and/or percentage neutrophil count, absolute and/or percentage lymphocyte count, neutrophil-lymphocyte ratio [NLR], Erythrocyte Sedimentation Rate (ESR), C-Reactive protein, fibrinogen, complement components (e.g. C2, C4, C3, C5), Total Hemolytic complement, complement breakdown products (e.g. C3a, C3b, C4a, C4b), procalcitonin, pro-inflammatory cytokines (e.g. selected from IL-1beta, IL-6, IL-8, and TNF-alpha), and D-Dimer.
• the one or more blood biomarkers are measured by markers of inflammation.
• the markers of inflammation are selected from proinflammatory cytokines (e.g. selected from IL-1beta, IL-6, IL-8 and TNF-alpha) and coagulopathy (d-dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and platelet count).
• proinflammatory cytokines e.g. selected from IL-1beta, IL-6, IL-8 and TNF-alpha
• coagulopathy d-dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and platelet count.
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of the formation of NETs or NET activation.
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of NETosis (e.g. at least one of cell-free DNA; citrullinated histone H3; Myeloperoxidase (MPO); Myeloperoxidase (MPO)-DNA complexes; and Proteinase-3).
• NETosis e.g. at least one of cell-free DNA; citrullinated histone H3; Myeloperoxidase (MPO); Myeloperoxidase (MPO)-DNA complexes; and Proteinase-3.
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of neutrophils or neutrophil elastase activity.
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of inflammation (e.g. at least one of absolute neutrophil count; absolute lymphocyte count; neutrophil-lymphocyte ratio [NLR]; Erythrocyte Sedimentation Rate (ESR); C-Reactive protein; fibrinogen, complement components (e.g. C2, C4, C3, C5), Total Hemolytic complement, complement breakdown products (e.g. C3a, C3b, C4a, C4b); and/or procalcitonin).
• inflammation e.g. at least one of absolute neutrophil count; absolute lymphocyte count; neutrophil-lymphocyte ratio [NLR]; Erythrocyte Sedimentation Rate (ESR); C-Reactive protein; fibrinogen, complement components (e.g. C2, C4, C3, C5), Total Hemolytic complement, complement breakdown products
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of pro-inflammatory cytokines (e.g. at least one of IL-1beta, IL-6, IL-8, and/or TNF-alpha).
• pro-inflammatory cytokines e.g. at least one of IL-1beta, IL-6, IL-8, and/or TNF-alpha.
• one or more blood biomarkers can be used to characterize the inhibition and/or reduction of coagulopathy (e.g. as measured by one or more of D-Dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and/or platelet count).
• coagulopathy e.g. as measured by one or more of D-Dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and/or platelet count.
• blood biomarkers can be used to characterize the inhibition and/or reduction of plasma desmosine, isodesmosine, and/or A-alpha-Val.
• PaO 2 /FiO 2 is the ratio of partial pressure arterial oxygen (PaO 2 ) and fraction of inspired oxygen (FiO 2 ).
• PaO 2 /FiO 2 is a comparison between the oxygen level in the blood and the oxygen concentration that is breathed. This may help determine the degree of any problems with how the lungs transfer oxygen to the blood.
• the PaO 2 /FiO 2 (and the SaO 2 /FiO 2 ) ratio is a parameter to assess respiratory dysfunction.
• a PaO 2 /FiO 2 ratio less than about 300 can be used to confirm a diagnosis of a disease or condition, e.g. ARDS.
• a PaO 2 /FiO 2 ratio of about 200-about 300 may confirm a diagnosis of disease or condition, e.g. ARDS.
• a subject requiring treatment according to the present invention may have a PaO 2 /FiO 2 ratio less than about 300.
• SaO 2 refers to arterial oxygen saturation, and can be determined by an arterial blood gas test. Pulse oximetry can be used to estimate the percentage of oxygen bound to hemoglobin in the blood, e.g. arterial oxygen saturation.
• the ratio of O 2 saturation to fraction inspired O 2 (SaO 2 /FiO 2 ) is a reliable, non-invasive surrogate for PaO 2 /FiO 2 .
• SaO 2 /FiO 2 can be predictive for 3-day worsening in patients with coronavirus infection (e.g. a COVID-19 infection).
• a SaO 2 /FiO 2 ratio of about 200-about 300 may confirm a diagnosis of a disease or condition, e.g. ARDS.
• a subject requiring treatment according to the present invention may have a SaO 2 /FiO 2 ratio less than about 300.
• the methods of the invention lead to an improvement or the prevention of worsening in SaO 2 /FiO 2 (or PaO 2 /FiO 2 ), e.g. an increase in the SaO 2 /FiO 2 (or PaO 2 /FiO 2 ).
• SaO 2 /FiO 2 (or PaO 2 /FiO 2 ) is less than about 300.
• SaO 2 /FiO 2 (or PaO 2 /FiO 2 ) is about 300 to about 200.
• SaO 2 /FiO 2 (or PaO 2 /FiO 2 ) is about 200 to about 100.
• SaO 2 /FiO 2 (or PaO 2 /FiO 2 ) is about 100 to about 200.
• Pulse oximetry can be used to approximate SaO 2 .
• Pulse oximetry be can be used to determine SpO 2 (peripheral oxygen saturation). Therefore, a pulse oximeter can be also used to approximate SaO 2 .
• An SaO 2 or SpO 2 of about 95-100% is a normal arterial blood oxygen saturation level in a subject.
• An SaO 2 or SpO 2 of less than or equal to about 95% may indicate that a subject is in need of a method of treatment provided by the present invention.
• Methods according to the invention may also comprise improving one or more pulmonary function parameters in a subject.
• methods according to the invention may improve or prevent worsening of SaO 2 /FiO 2 of a subject.
• a method for increasing SaO 2 /FiO 2 in a subject with a coronavirus infection by administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• a NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• the coronavirus is SARS-COV, e.g. COVID-19.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof increases SaO 2 /FiO 2 by at least about 1%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 15%, 20%, 30%, 40% or 50% compared to a baseline SaO 2 /FiO 2 measurement.
• the baseline measurement may be measured on day 1 of the treatment.
• the change in SaO 2 /FiO 2 measurement is the change in the baseline measurement over a relevant treatment period, e.g. over 10 days of treatment.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents SaO 2 /FiO 2 from worsening.
• one parameter is the forced expiratory volume in 1 second (FEV1), which is the volume of air (in liters) exhaled in the first second during forced exhalation after maximal inspiration.
• FEV1 forced expiratory volume in 1 second
• the method for treatment comprises improving or preventing worsening of forced expiratory volume in 1 second (FEV1) in the subject.
• FEV1 forced expiratory volume in 1 second
• an improvement is where the volume increases relative to baseline level in the subject measured prior to treatment.
• the invention also provides methods of inhibiting neutrophil elastase, NETs and/or NETosis in a subject suffering from, or at risk of, any of the conditions described herein, including a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• the present invention also provides alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for use in a method of treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19.
• a coronavirus infection e.g. COVID-19
• Any embodiment of the present invention which relates to a method of treatment.
• the invention provides a further embodiment relating to alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for use in that method.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for manufacture of a medicament for treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19.
• the invention provides a further embodiment relating to the use of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for that method.
• the dose of the neutrophil inhibitor to be administered will depend on the disease being treated, the severity of the disease, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).
• the daily dose is from 0.5 to 1000 mg per day, for example from 50 to 800 mg per day, in particular 50 to 600 mg per day, more particularly 120 mg to 550 mg, even more particularly 200 to 500 mg.
• the daily dose is about 240, 270, 300, 330, 360, 390, 420, 450 or 480 mg per day.
• the dose may be administered as a single dose or as a divided dose, for example wherein the total daily dose is divided in to two or more fractions, administered during the day.
• a dose may be administered daily, or multiple times a day (for example twice daily), or multiple times a week, or monthly, or multiple times a month.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day (BID dosing).
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day, wherein each dose is equivalent to up to 240 mg of alvelestat free base, for example 60 mg twice a day, 90 mg twice a day, 120 mg twice a day, 150 mg twice a day, 180 mg twice a day, 210 mg twice a day, or 240 mg twice a day.
• 240 mg is administered twice a day.
• Compounds may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration. For example, for between about one day and four weeks, for between about one week and two weeks.
• alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered for about 10 days.
• alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 10 days, wherein each dose on day 1 of treatment is equivalent to 120 mg, wherein each dose on day 2 of treatment is equivalent to 180 mg, and wherein each dose on days 3-10 of treatment is equivalent to 240 mg.
• the subject on day 1 the subject has 120 mg bid (4 ⁇ 30 mg tablets bid). In an embodiment, on day 2 the subject has 180 mg bid (6 ⁇ 30 mg tablets bid). In an embodiment, on days 3-10 the subject has 240 mg bid (8 ⁇ 30 mg tablets bid).
• alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for a duration longer than 10 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for a duration longer than 10 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 14 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 30 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 60 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 90 days.
• the neutrophil inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, can be administered to a subject in the form of a pharmaceutical composition.
• the invention provides a method of treating or preventing any of the conditions described herein comprising administering a pharmaceutical composition comprising an effective amount of a neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.
• a pharmaceutical composition comprising an effective amount of a neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.
• compositions may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.
• “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans. All compositions may optionally contain excipients such as those set forth in the Shesky et al, Handbook of Pharmaceutical Excipients, 8 th edition, 2017. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
• compositions include those suitable for various administration routes, including oral administration.
• the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
• the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 22 nd Edition, 2012.
• a preferred pharmaceutical composition is a solid dosage form, including a solid oral dosage form, such as a tablet.
• Tablets may contain excipients including glidants, fillers, binders and the like.
• the pharmaceutical compositions can be administered in any form and route which makes the compound bioavailable.
• the pharmaceutical compositions can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
• the pharmaceutical compositions are administered orally.
• compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
• the pharmaceutical composition is a tablet.
• Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic.
• the amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration.
• the methods may further include the step of administering to the subject one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents.
• the administration of the one or more additional therapeutic agents may occur prior to, concurrently with, or after the administration of the neutrophil inhibitor.
• the neutrophil inhibitor e.g. alvelestat or a pharmaceutically acceptable salt or solvate thereof, can also be administered in combination with any standard of care appropriate for a coronavirus infection, e.g. COVID-19.
• Therapies to assist in the methods according to the present invention can be selected from organ support, anti-coagulation treatment (e.g. to reduce risk of venous and arterial thrombosis), treatment of infection, and/or treatment of sepsis.
• organ support, anti-coagulation, treatment of infection, and/or sepsis can be combined with the methods for treatment of the present invention.
• the one or more additional therapeutic agents may be any therapeutic agent.
• the one or more additional therapeutic agent may be selected from the group consisting of an antiviral agent, an anti-TNF agent, an anti-inflammatory agent, an analgesic agent, a steroid, an antibody, an immunosuppressive agent, a vaccine, an antimalarial agent, and an enzymatic agent.
• One or more additional therapeutic agents can be selected from those approved in treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19.
• one or more additional therapeutic agents can be selected from remdesivir, nitric oxide, lopinavir and ritonavir, favipiravir, atlizumab, angiotensin II, interferon (e.g. inhaled interferon) dexamethasone, and hydroxychloroquine.
• the one or more additional therapeutic agents is remdesivir or a pharmaceutically acceptable salt thereof.
• the one or more additional therapeutic agents is dexamethasone or a pharmaceutically acceptable salt thereof.
• the one or more additional therapeutic agents is interferon (e.g. inhaled interferon) or a pharmaceutically acceptable salt thereof.
• the one or more additional therapeutic agents is Sivelestat or a pharmaceutically acceptable salt thereof.
• One or more additional therapeutic agents can be selected from those undergoing clinical trials for treating of a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19.
• the one or more additional therapeutic agents can be selected from: immunotherapy with anti-COVID-19 antibodies, BPI-002, Ifenprodil, Brilacidin, Duvelisib, Tramadol, C21, Deferoxamine, Azithromycin, Methylprednisolone, Chlorpromazine, Enoxaparin, DAS181, Isotretinoin, Sirolimus, Lactoferrin, Clopidogrel, Rivaroxaba, Clevudine, MCN (Methylene blue, vitamin C, N-acetyl cysteine), Pegylated interferon lambda, CPI-006, epoprostenol, Recombinant Bacterial ACE2 receptors, Recombinant Human ACE2, heparin, Fondapar
• the one or more additional therapeutic agents can include immunosuppressive agents, anti-infective agents, anti-inflammatory agents, pain relievers, antiviral agents, steroids, antibodies, vaccines, and enzymatic agents.
• the one or more additional therapeutic agents are immunosuppressive agents.
• immunosuppressive agents For example, one, two, or preferably three immunosuppressive agents may be administered.
• the immunosuppressive agents may, for example, be selected from the group consisting of corticosteroids (e.g. methylprednisolone, prednisone, prednisolone, budesonide, and/or dexamethasone), janus kinase inhibitors (e.g. tofacitinib), calcineurin inhibitors (e.g. cyclosporine, and/or tacrolimus), mTOR inhibitors (e.g. sirolimus, everolimus, and/or temsirolimus), biologics (e.g.
• corticosteroids e.g. methylprednisolone, prednisone, prednisolone, budesonide, and/or dexamethasone
• janus kinase inhibitors e.g. tofacitinib
• calcineurin inhibitors e.g. cyclosporine, and/or tacrolimus
• abatacept adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and/or vedolizumab
• monoclonal antibodies e.g. basiliximab, and/or daclizumab
• tyrosine kinase inhibitors e.g. imatinib, thalidomide, pentostatin, azathioprine, mycophenolate, and/or methotrexate.
• the neutrophil elastase inhibitor of the invention may be administered with a corticosteroid.
• the immunosuppressive agent is a corticosteroid, for example selected from the following types: Hydrocortisone, Acetonides (and related substances), Betamethasone, Halogenated, and/or Prodrug esters.
• the Hydrocortisone type includes Hydrocortisone, Hydrocortisone acetate, Cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone.
• the Acetonides include Amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide.
• the Betamethasone type includes Beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.
• the Halogenated type includes Alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.
• the Prodrug ester type includes Ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate.
• the one of more therapeutic agents is an anti-TNF agent.
• the anti-TNF agent is selected from: infliximab, etanercept, certolizumab, golimumab, adalimumab, adalimumab, Thalidomide, lenalidomide, pomalidomide, pentoxifylline, and/or bupropion.
• the methods further include the step of administering to the subject a triple combination of immunosuppressive agents, for example tacrolimus, mycophenolate and a corticosteroid.
• immunosuppressive agents for example tacrolimus, mycophenolate and a corticosteroid.
• the one or more additional therapeutic agents may be anti-infective agents.
• Anti-infective agents include antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoals, antituberculosis agents, and antivirals.
• the one or more additional therapeutic agents are antiviral agents.
• one, two, or preferably three antivirals agent may be administered.
• the antiviral agents may, for example, be selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol Umifenovir, Atazanavir, Atripla, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir, Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Favilavir, Fomivirsen, Fosamprenavir, Foscar
• the one or more additional therapeutic agents is a vaccine.
• the vaccine may, for example, be selected from the group consisting of VPM1002, MMR vaccine. ChAdOx1 nCoV-19, BCG vaccine, PrEP-001, mRNA-1273, CoronaVac, Ad5-nCoV, a coronavirus-based vaccine, V-SARS, NVX-CoV2372, Inactivated SARS-CoV-2 Vaccine, GX-19, BNT162 mRNA vaccine, AV-COVID-19, ZyCoVD, S-protein vaccine, RUTI vaccine, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA vaccine, CVnCoV vaccine, bacTRL-Spike, TNX-1800, and anti-SARS-CoV-2 convalescent plasma.
• the one or more additional therapeutic agents may be selected from the group of prednisone, methylprednisone, budesonide, beclomethasone dipropionate, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tilomisole, imuthiol, antithymocyte globulin, azathioprine, azodiacarbonide, bisindolyl maleimide VIII, brequinar, chlorambucil, CTLA4-Ig, cyclophosphamide, deoxyspergualin, dexamethasone, leflunomide, mercaptopurine, 6-mercaptopurine, methotrexate, methylprednisolone, mizoribine, mizoribine monophosphate, muromonab CD3, mycophenolate mofetil, OKT3, rho (D) immune globin, vitamin D analogs, MC1288), daclizumab, inflix
• the one or more additional therapeutic agents is an analgesic agent.
• the analgesic agent may, for example, be selected from the group consisting of acetaminophen, a Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. one or more of ibuprofen, naproxen, and/or celecoxib), paracetamol, acetylsalicylic acid, and/or codeine.
• NSAIDs Non-steroidal anti-inflammatory drugs
• the methods may further include the step of administering to the subject one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents when the subject requires ventilation.
• one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents includes a corticosteroid when the subject requires ventilation.
• the corticosteroid is dexamethasone.
• the ventilation is mechanical ventilation.
• each of the agents administered individually or combined in a combination therapy or regimen may be administered at an initial dose that may then over time be reduced by a medical professional to reach a lower effective dose.
• Alvelestat used in the following examples may be synthesised according to WO 2005/026123 A1 (Example 94, page 85).
• Example 1 Alvelestat is a Potent and Specific Inhibitor of Neutrophil Elastase (NE)
• the calculated p IC 50 (IC 50 ) and K values for alvelestat for human NE are 7.9 (12 nM) and 9.4 nM, respectively.
• Alvelestat is at least 600-fold more selective for human NE compared with another serine protease cathepsin G, and at least 1900-fold more selective for human NE comprised with other serine proteases (proteinase-3, chymotrypsin, pancreatic elastase and trypsin).
• serine proteases proteinase-3, chymotrypsin, pancreatic elastase and trypsin.
• Alvelestat shows good crossover potency for NE from other species, including mice.
• p IC 50 (IC 50 ) values in whole-blood, cell-associated, and explosive-release assays were 7.36 (44 nM), 7.32 (48 nM), and 7.30 (50 nM), respectively.
• alvelestat is a specific, potent, and rapidly reversible inhibitor of human NE.
• the potent inhibitory activity of alvelestat on NE in biochemical assays was confirmed in whole-blood and cell-based systems.
• alvelestat has the potential to be useful in patients with coronavirus infection, in particular SARS-COV such as COVID-19, by impacting progression to ARDS through disruption of NETosis.
• NETs neutrophil extracellular traps
• NETs are networks of extracellular DNA fibers, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), released from neutrophils and involved physiologically in capturing bacteria.
• MPO myeloperoxidase
• NE neutrophil elastase
• DAMPs Damage Associated Molecular Pattern Molecules
• Neutrophil elastase is essential to NET formation ([6]) and remains active when decorating the NET fibers.
• the physiological inhibitor of NE is Alpha-1 antitrypsin (AAT), but studies in COVID-19 have shown this to be overwhelmed ([8]).
• Alvelestat is an oral, specific, NE inhibitor, with experience in over 1000 healthy volunteers and patients with lung disease. Its safety profile is now well-established. Furthermore, there has been evidence of mechanistic effect of alvelestat in 4-week duration clinical studies of neutrophil-driven diseases (significant decrease in biomarkers of elastase activity and inflammation in cystic fibrosis ([16]), and clinically significant improvement in lung function and inflammation in bronchiectasis ([17]). In experimental models of ARDS, alvelestat protected the lung from inflammation and injury through NET inhibition ([18]). The use of alvelestat is therefore expected to ameliorate and/or prevent lung damage in patients with coronavirus infection, in particular SARS-COV, such as COVID-19.
• coronavirus infection in particular SARS-COV, such as COVID-19.
• Alvelestat is administered as part of a Phase Ib/II single-center, 2:1 randomized, blinded, placebo-controlled, parallel group, first in disease study to evaluate the safety, tolerability, PK and explore mechanism of action and clinical effect of alvelestat in patients hospitalized with proven COVID-19 lung disease.
• Alvelestat, dosed at 240 mg orally twice per day for 10 days added to standard of care (SoC) is assessed versus placebo added to SoC, in adult patients ( ⁇ 18 years) with COVID-19 respiratory disease.
• CT Computerised Tomography
• This population is known to have an acute phase response and evidence for neutrophil activation (raised CRP and absolute neutrophilia, with activation of the NETosis pathway ([12]), therefore giving potential to detect a mechanistic signal in the study.
• neutrophil elastase may be a key pathogenic driver and its inhibition stand the greatest chance of success.
• the duration of dosing will be for 10 days. Deterioration in COVID-lung disease in hospitalized patients to intubation is rapid and bimodal with modes as 3-4 days and 9 days from the date first symptoms recorded ([19]) and even shorter period from date of hospital admission with the most patients worsening within the first 3 days ([20]). Therefore, 10 days treatment will provide NE inhibition to cover the critical risk period.
• a within-patient dose-escalation approach commencing at 120 mg bid Day 1, increasing to 180 mg bid Day 2 and 240 mg bid Days 3 to 10, will be used to address tolerability (headache) issues that have been identified for alvelestat. In association with the short-term dosing, it is anticipated that this approach will be successful in supporting patients to complete the course. Dose de-escalation, including to 120 mg bid, will be allowed if required for toleration as 120 mg bid is still predicted to provide adequate NE inhibition. Dose de-escalation below 120 mg bid will not be permitted.
• alvelestat/placebo alvelestat administered twice daily (bid) for Numbers and % of subjects who experience 10 days at least 1 treatment-emergent adverse event to Day 10 (acute treatment period) or End of Treatment (EoT)
• Adverse events of special interest liver function abnormalities, corrected QT interval, infections, and neutropenia
• clinically significant safety monitoring labs tests to Day 10 (acute treatment period) or EoT Numbers and % of subjects who experience at least 1 treatment-emergent adverse event from EoT to Day 29 (Final Outcome Assessment) Numbers and % of subjects that discontinue alvelestat to Day 10 Secondary
• Alvelestat will show effectiveness in one or more of the above endpoints.
• the study is divided into 3 periods: a screening period, treatment period, and follow up period:
• a treatment period consisting of within-subject dose-escalation of alvelestat/matched placebo 120 mg bid Day 1, 180 mg/matched placebo bid Day 2 and 240 mg/matched placebo bid Days 3 to 10 given on top of standard of care (SoC—per local clinical guidelines).
• Safety assessments including vital signs, liver and renal function, EKG, and hematology, will be assessed at baseline, then as per the Schedule of Assessments (SoA) for the remainder of the 10-day treatment period.
• Adverse events and concomitant medications will be collected daily. Blood will be collected at baseline during study drug treatment for exploratory efficacy biomarkers and oxygen deficit assessments (SaO2/FiO2).
• PK sampling will be collected on 4 occasions, at initiation of dosing, at the 2 dose escalation steps and at end of treatment (EoT) for steady state analysis.
• the clinical outcome (WHO ordinal scale) will be completed during the treatment period at Baseline (Day 1), and EoT (Day 10).
• Baseline Day 1
• EoT Day 10
• Those subjects who are unable to complete the treatment period for any reason, including those discharged from hospital prior to completion of Day 10 will discontinue study drug and undergo an EoT assessment.
• FOA Final Outcome Assessment
• the placebo and alvelestat tablets are indistinguishable. Investigator, site study team, and participants will remain blinded to the study treatment allocation until the end of the study.
• SARS-CoV-2 PCR testing Chest CT or radiograph scans are performed to confirm SARS-CoV-2 infection and lung involvement and conducted as part of the participant's routine clinical management will be utilized for screening purposes, including those performed for initial assessment at hospitalization prior to screening period.
• Laboratory testing performed for clinical management may be used for screening assessment if obtained within 3 days of planned randomization.
• EKG performed for clinical management may be used for screening assessment if obtained within 7 days of planned randomization.
• samples will be stored and analysis may be performed on additional biomarker variants thought to play a role in neutrophil elastase-induced damage to evaluate their association with observed neutrophil activation responses to alvelestat.
• the ratio of O 2 saturation to fraction inspired O 2 (SaO 2 /FiO 2 ) is a reliable, non-invasive surrogate for PaO2/FiO2 and predictive for 3-day worsening in patients with COVID-19 infection ([20]). This will be collected at baseline and during the study, measured as per local standard operating procedures.
• each assessment will be recorded as a number based on the status categories below. Where possible the timing of each assessment should be similar (i.e. morning or evening throughout)
• Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, and pulse oximetry.

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