Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection

Abstract

The invention relates to treatments for coronavirus infections by administering a neutrophil elastase inhibitor, such as alvelestat.

1 . A method for treating a coronavirus infection and/or preventing progression of a coronavirus disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. 
     
     
         2 . 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. 
     
     
         3 . A method for reducing viral replication of coronavirus, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof. 
     
     
         4 . A method for treating or preventing a lung or respiratory condition in a subject having a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject. 
     
     
         5 . The method of any preceding claim, wherein the coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome coronavirus (MERS-CoV). 
     
     
         6 . The method of any of  claims 1 - 5 , wherein the coronavirus is SARS-CoV, optionally, wherein the SARS-CoV is SARS-CoV-1 or SARS-CoV-2. 
     
     
         7 . The method of any preceding claim, wherein the coronavirus is SARS-CoV-2 (COVID-19). 
     
     
         8 . A method for treating and/or preventing progression of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. 
     
     
         9 . A method for reducing viral replication of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. 
     
     
         10 . A method for treating or preventing a symptom or complication of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. 
     
     
         11 . The method of any preceding claim, comprising the treatment or prevention of one or more symptom, complication or condition 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, Guillain-Barré syndrome, heart failure, heart inflammation, heart palpitations, hyperinflammation, hypoxemia, inflammation disorders, inflammation disorders in paediatric subjects, inflammation of the lungs, Kawasaki disease, loss of appetite, loss of smell, loss of taste, lung consolidation, microthrombosis, multi-organ failure, muscle ache, neurological complications, neurological disorders, neutrophilia, Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS), Pericarditis, Pleurisy, Pneumonia, pulmonary disease, pulmonary embolism, pulmonary fibrosis, pulmonary oedema, renal complications, renal failure, respiratory failure, seizure, septic shock, shock, shortness of breath, stroke, Systemic inflammatory response syndrome (SIRS), Thromboses, thromboses and/or excessive bleeding, thrombosis or thromboses including venous and arterial thrombosis, thrombotic complications, vascular catheter thrombosis, vasculitis, vasculopathy, venous thrombosis, and viral pneumonia. 
     
     
         12 . The method of any preceding claim, comprising the treatment or prevention of ALI, ARDS, APS, respiratory failure, organ failure, a coagulopathy complication, inflammation, and/or neutrophilia. 
     
     
         13 . The method of any preceding claim, comprising treating or preventing coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding). 
     
     
         14 . A method for treating or preventing ALI, ARDS, neutrophilia, coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding), respiratory failure, inflammation, lung injury, thrombosis, and/or thrombosis in a subject with organ failure, in particular SARS-COV (e.g. COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. 
     
     
         15 . The method of any preceding claim, wherein the subject also suffers from a disease selected from obesity, hypertension, and diabetes (e.g. type 2 diabetes); and/or
 wherein the subject requires hospitalisation; and/or   wherein the subject has pulmonary disease; and/or   wherein the subject has evidence of pulmonary disease on an imaging method, optionally wherein the imaging method is a chest radiograph and/or Computerised Tomography (CT); and/or   wherein: (i) the subject does not require ventilation, or (ii) the subject requires ventilation, optionally wherein the ventilation is mechanical ventilation; and/or   wherein: (i) the subject does not require intubation, or (ii) the subject requires intubation; and/or   wherein the subject does not have multi-organ failure; and/or   wherein the subject has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale.   
     
     
         16 . The method of any preceding claim comprising inhibiting neutrophil elastase and/or reducing neutrophil elastase activity. 
     
     
         17 . The method of any preceding claim, wherein the subject has elevated neutrophil elastase activity;
 and/or wherein the subject has elevated levels of NETosis; and/or   wherein the subject has elevated levels of NETs; and/or   wherein the subject has inflammation, optionally lung inflammation; and/or   wherein the subject has an acute innate inflammatory response; and/or   wherein the acute innate inflammatory response comprises one or more of elevated pro-inflammatory cytokines, elevation of acute phase reactants and/or cytokine storm; and/or   wherein the subject has elevated inflammation.   
     
     
         18 . The method of any preceding claim, comprising improving or preventing worsening of SaO 2 /FiO 2  (the ratio of O 2  saturation to fraction inspired O 2 ) in the subject. 
     
     
         19 . The method of any preceding claim, comprising improving or preventing worsening of SaO 2 /FiO 2 , PaO 2 /FiO 2  or SpO 2 . 
     
     
         20 . The method of the preceding claim, wherein the SaO 2 /FiO 2  is increased in the subject. 
     
     
         21 . The method of any preceding claim, wherein SaO 2 /FiO 2  in the subject is less than about 300; for example
 wherein SaO 2 /FiO 2  in the subject is about 300 to about 200; or   wherein SaO 2 /FiO 2  in the subject is about 200 to about 100.   
     
     
         22 . The method of any preceding claim, wherein SaO 2 /FiO 2  in the subject is greater than about 300. 
     
     
         23 . The method of any preceding claim comprising improving or preventing worsening of SpO 2  (peripheral oxygen saturation) in the subject; and/or
 wherein SpO 2  is measured by a pulse oximeter, optionally wherein SpO 2  is less than or equal to 95% before treatment.   
     
     
         24 . The method of any preceding claim, comprising improving or preventing worsening of forced expiratory volume in 1 second (FEV1) in the subject. 
     
     
         25 . The method of any preceding claim, comprising improving or preventing worsening of the condition of the subject according to the WHO 9-point ordinal scale. 
     
     
         26 . The method of any preceding claim, comprising improving the condition of the subject according to the WHO 9-point ordinal scale; for example
 comprising improving the condition of the subject by at least 1 point according to the WHO 9-point ordinal scale, for example   comprising improving the condition of the subject by at least 2 points according to the WHO 9-point ordinal scale.   
     
     
         27 . The method of any preceding claim wherein alvelestat is in the form of the free base. 
     
     
         28 . The method of any preceding claim wherein alvelestat is in the form of alvelestat tosylate. 
     
     
         29 . The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof in a tablet. 
     
     
         30 . The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof twice daily. 
     
     
         31 . The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof at a dose of alvelestat of up to 240 mg twice daily; for example at a dose of alvelestat of 60 mg, 120 mg, 180 mg or 240 mg twice daily, preferably 240 mg twice daily. 
     
     
         32 . The method of any preceding claim, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for 10 days. 
     
     
         33 . The method of any preceding claim, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof at a dose of alvelestat of 120 mg bid on day 1, 180 mg bid on day 2, and 240 mg bid on days 3-10. 
     
     
         34 . The method of any preceding claim, wherein the twice daily doses are given about 12 hours apart. 
     
     
         35 . The method of any preceding claim, wherein the daily dose(s) results in a plasma concentration of alvelestat of greater than or equal to 300 nM. 
     
     
         36 . The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof by oral administration. 
     
     
         37 . The method of any preceding claim, further comprising administering to the subject one or more additional therapeutic agents. 
     
     
         38 . The method of  claim 37 , wherein the one or more additional therapeutic agents is selected from remdesivir, nitric oxide, lopinavir and ritonavir, favipiravir, atlizumab, angiotensin II, interferon (e.g. inhaled interferon), dexamethasone and hydroxychloroquine. 
     
     
         39 . The method of  claim 37 , wherein the one or more additional therapeutic agents is selected from an antiviral agent, an anti-inflammatory agent, an analgesic agent, a steroid, an antibody, a vaccine, an antimalarial agent, and an enzymatic agent; optionally:
 (i) wherein the vaccine is 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, and combinations thereof; or   (ii) wherein the one or more additional therapeutic agents is an antiviral agent, for example
 wherein the antiviral agent is 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, Foscarnet, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir formerly (Kutapressin), Nitazoxanide, Norvir, Oseltamivir, OYA1, Penciclovir, Peramivir, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, Raltegravir, Remdesivir, Ribavirin, Rilpivirine (Edurant), Rilpivirine, Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, Taribavirin (Viramidine), Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Umifenovir, Valaciclovir, Valganciclovir (Valtrex), Vicriviroc, Vidarabine, Zalcitabine, Zanamivir (Relenza), Zidovudine, umifenovir, danoprevir and ritonavir, carrimycin, camostat, baloxavir marboxil, azithromycin, triazayirin, oseltamivir, nitazoxanide, famotidine, emtricitabine and tenofovir disoproxil fumarate, Convalescent Plasma, ASC09 and ritonavir, VERU-111, selinexor, PP-001, piclidenoson, merimepodib, ionafarnib, IMU-838, hyperimmune plasma, galidesivir, FW-1022, Niclosamide, FP-025, fluidase, elsulfavirine, EIDD-2801, clevudine, bemcentinib, azvudine, ATR-002, AQCH, aplidin, LY-CoV555, NKG2D-ACE2 CAR-NK Cells, meplazumab, CYNK-001, brequinar, TY027, NK cells, mefuparib, leflunomide, JS016, FT516, COVID-HIG, and BC007, and combinations thereof; or 
   (iii) wherein the analgesic agent is selected from the group consisting of acetaminophen, a Non-steroidal anti-inflammatory drug (NSAIDs) (e.g. one or more of ibuprofen, naproxen, and/or celecoxib), paracetamol, acetylsalicylic acid, and codeine, and combinations thereof; or   (iv) wherein the one or more additional therapeutic agents is a steroid agent, optionally
 wherein the steroid agent is a corticosteroid, for example 
 wherein the corticosteroid is selected from methylprednisolone, prednisone, prednisolone, budesonide, and/or dexamethasone. 
   
     
     
         40 . The method of  claim 37 , wherein the one or more additional therapeutic agents is an anti-TNF agent wherein the anti-TNF agent is selected from infliximab, etanercept, certolizumab, golimumab, adalimumab, adalimumab, Thalidomide, lenalidomide, pomalidomide, pentoxifylline, and/or bupropion. 
     
     
         41 . The method of  claim 37  wherein the one or more therapeutic agents is selected from the group consisting of 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, Fondapariniux, Argatroban, TXA127, AG0301-COVID19, Baricitinib, 13 cis retinoic acid, All trans retinoic acid, ABX464, Clazakizumab, IFX-1, camostat mesilate, mavrilimumab, Pamrevlumab, Povidone-iodine, Zanubrutinib, Famotidine, Nitazoxanide and atazanavir/ritonavir, Losartan, Ivermectin, Dapagliflozin, REGN10933+REGN1 0987, Recombinant human angiotensin-converting enzyme 2 (rhACE2), Bemiparin, Ozanimod, Naproxen, Intravenous Immune Globulin, Plitidepsin, Colchicine, Interferon beta-1b, Clofazimine, Ruxolitinib, NK cells, IL15-NK cells, NKG2D CAR-NK cells, ACE2 CAR-NK cells, NKG2D-ACE2 CAR-NK cells, Acalabrutinib, Sarilumab, BDB-001, Nafamostat, Telmisartan, Thymalfasin, Interferon Beta-1A, Bicalutamide, Ciclesonide, Doxycycline, Anakinra, Estradiol, Prazosin, Pentoxifylline, Rivaroxaban, Umifenovir, MRx-4DP0004, Crizanlizumab, Siltuximab, Tetrandrine, avdoralimab, Olokizumab, lanadelumab, Pacritinib, Montelukast, Sargramostim, Apilimod, Sildenafil, Zilucoplan, OP-101, Gimsilumab, TJM2 (a neutralising antibody), TZLS-501 (a monoclonal antibody), leronlimab, Infliximab, Tocilizumab, chloroquine, hydroxychloroquine, APN01, Dornase alfa, dexamethasone, ibuprofen, paracetamol, aspirin, Bivalirudin, AT-001, Probiorinse, SCB-2019, Amiodarone, Verapamil, Atorvastatin, Angiotensin peptide (1-7) derived plasma, CAP-1002, Etoposide, Tofacitinib, AVM0703, hydrocortisone, Tranexamic acid, Bromhexine, Imatinib, Lenalidomide, N-Acetyl cysteine, Dipyridamole, lactoferrin, Ravulizumab, Atovaquone, Simvastatin, PHR160, Ulinastatin, Melatonin, RhACE2 APN01, XPro1595, AT-527, EDP1815, Ambrisentan, Methotrexate, Degarelix, LY3819253, BAT2020, Quercetin, N-803, STI-1499, RBT-9, Levilimab, Peginterferon Lambda-la, Levamisole, Formoterol, Budesonide, Abivertinib, AV-COVID-19, PUL-042, Defibrotide, Virazole, RTB101, co-trimoxazole, nangibotide, RESP301, Vazegepant, IC14, Enzalutamide, Bevacizumab, Human immunoglobulin, immunoglobulin, Fluvoxamine, DFV890, MSTT1041A, Sofusbuvir, Camostat, LAU-7b, thalidomide, metenkefalin, tridecactide, MAS825, SAB-185, Nivolumab, Sirukumab, MV130, Indomethacin, Iloprost, Lenzilumab, TD-0903, ATYR1923, Silymarin, Imitrine, Isoprinosine, Eculizumab, TJ003234, Fluoxetine, Octagam, CD24Fc, Garadacimab, Dociparastat, NK-1R antagonist, CK0802, Recombinant human plasma gelsolin (Rhu-pGSN), Diphenhydramine, Oxytocin, ANG-3777, AMY-101, ACE inhibitors (ACEls), angiotensin receptor blockers, LEAF-4L6715, LEAF-4L7520, Lucinactant, Opaganib, poractant alfa, Ethyl eicosapentaenoic acid, Interleukin-7, SBI-101, Pyridostigmine Bromide, Artemisinin, Artesunate, CYT107, BLD-2660, Sevoflurane, IMM-101, GLS-1200, Prasugrel, HB-adMSCs, P2Et ( Caesalpinia spinosa  extract), LB1148, Dexmedetomidine, TY027, BMS-986253, PTC299, Hidroxicloroquina, CERC-002, captopril, DUR-928, DeltaRex-G, Valsartan, ArtemiC, aviptadil, MK-5475, ASC09F, Thiazidem, NA-831, Naltrexone, Ketamine, Nintedanib, Calcifediol, Secukinumab, PB1046, T89, MenACWY, Leronlimab, azoximer bromide, SNDX-6352, TL-895, Linagliptin, Alteplase, Ibudilast, Ibrutinib, XAV-19, BNT162a1, BNT162b1, BNT162b2, BNT162c2, CM4620, CSTC-Exo, Spironolactone, Conestat alfa, Tirofiban, Acetylsalicylic acid, cholecalciferol, Plaquenil, SAR443122, Pertuzumab, Trastuzumab, Tradipitant, and TAK-981, and combinations thereof.