EP4243805A1 - Polythérapies pour le traitement d'une infection à coronavirus - Google Patents

Polythérapies pour le traitement d'une infection à coronavirus

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Publication number
EP4243805A1
EP4243805A1 EP21762002.0A EP21762002A EP4243805A1 EP 4243805 A1 EP4243805 A1 EP 4243805A1 EP 21762002 A EP21762002 A EP 21762002A EP 4243805 A1 EP4243805 A1 EP 4243805A1
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EP
European Patent Office
Prior art keywords
therapeutic
composition
category
group
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21762002.0A
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German (de)
English (en)
Inventor
Daniel Joseph Fitzgerald
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Halo Therapeutics Ltd
Original Assignee
Gbiotech Sarl
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Filing date
Publication date
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Publication of EP4243805A1 publication Critical patent/EP4243805A1/fr
Pending legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 therapeutic drug combinations particularly useful for treatment and/or prevention of coronavirus infection.
  • Said therapeutics combinations are focused primarily on small molecule drugs that impact lipidomic systems, metabolomic systems, immunomodulary and inflammatory systems.
  • a further aspect of the invention relates to methods for treating coronavirus infection using said therapeutics combinations.
  • the present invention is, at least in part, based on the following background:
  • SARS-CoV-2 and other human coronaviruses Key to SARS-CoV-2 therapeutic development is a better understanding of the mechanisms which drive its high infectivity, unusually broad tissue tropism and severe pathology (1 ,2,3).
  • coronaviruses there are seven coronaviruses that are known to infect humans.
  • the four endemic human coronaviruses OC43, 229E, HKLI1, and NL63 cause mild, self-limiting upper respiratory tract infections while pandemic virus SARS-CoV-2, and earlier SARS-CoV and MERS-CoV can cause severe pneumonia with acute respiratory distress syndrome, multi-organ failure, and death (3,5).
  • SARS-CoV-2 pathology COVID-19 patients display an odd collection of symptoms not seen with any previous human coronavirus including blood clots, strokes, “COVID toes” and heart attacks (6,7,8). While SARS-CoV did not significantly spread past the lungs, a recent study reported damage or severe inflammation in SARS-CoV-2 patients’ endothelial cells in the heart, kidneys, liver, and intestines, suggestive of a vascular infection rather than a respiratory disease (1). While this significantly expanded tissue tropism might be partially explained by more widespread and effective spike glycoprotein processing systems (9,10,11), the accompanying severe immune dysregulation, inflammation and tissue pathology both inside and outside of the lungs remains poorly understood.
  • SARS-CoV-2 Receptor recognition and cell entry by SARS-CoV-2. Receptor recognition by coronaviruses is an important determinant of viral infectivity and pathogenesis, and represents a major target for antiviral therapeutic development (12).
  • the attachment of SARS-CoV-2 to a host cell is initiated by interactions between the spike (S) glycoprotein and its cognate receptor angiotensin-converting enzyme 2 (ACE2) which are higher affinity than with previous closely related SARS-CoV and also other human coronaviruses (9,13,14).
  • ACE2 angiotensin-converting enzyme 2
  • the S glycoprotein can be processed by a plasma membrane-associated protease, TMPRSS2, which helps to unload virus components into the host cell cytoplasm (9,10).
  • TMPRSS2 plasma membrane-associated protease
  • SARS-CoV-2 has acquired additional novel functions that characterize its harsh disease phenotype. Relative to other human coronaviruses SARS-CoV-2 exhibits more effective protease processing (10,11), and a broader cell tropism to drive rapid unloading of virus into diverse tissues (1 ,17). A novel S1/S2 polybasic furin protease cleavage site stimulates cell-cell fusion and entry into host cells (11).
  • Dysregulated immune response and inflammation triggered by SARS-CoV-2 infection Infection by SARS-CoV-2 also triggers an unusually impaired and dysregulated immune response (18) and a heightened inflammatory response (2).
  • Hyper-immunity and inflammatory responses of the host to SARS-CoV-2 work in synergy with interferon production in the vicinity of infected cells to drive a feed-forward loop to upregulate ACE2 and further escalate infection (19).
  • LA linoleic acid
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 2 or more, preferably 2, 3, 4 or 5, more preferred 2 or 3, especially preferred 2, of the therapeutics selected from the following categories a) to w) a) linoleic acid (“LA”), a derivative, salt or mimetic thereof; b) a broad-spectrum antiviral agent (BSAA); c) a nucleoside analogue; d) a Phospholipase A2 (PLA2) inhibitor; e) a corticosteroid; f) an antibiotic; g) a peroxisome proliferator-activated receptor (PPAR) agonist; h) a protease inhibitor; i) an angiotensin-converting enzyme 2 (ACE2) receptor inhibitor/antagonist; j) a cytokine inhibitor or cytokine release inhibitor; k) a free fatty acid receptor (FFAR) agonist; l) a SGLT l/ll inhibitor/antagonist; m)
  • the terms “therapeutic”, “therapeutic agent”, “therapeutic drug” are used synonymously, and are sometimes also referred to as “drug”, and include, where applicable as understood by the person skilled in the art, prodrugs, pharmaceutically acceptable salts, pharmaceutally active stereoisomers, and/or racematic mixtures of such “therapeutic”, “therapeutic agent”, “therapeutic drug” or “drug”, respectively.
  • Non-LA therapeutics or “non-LA therapeutic drugs” or “non-LA drugs”.
  • Preferred combinations of therapeutic agents according to the invention are as follows: At least one therapeutic of category a) and at least one therapeutic of category b).
  • preferred combinations of therapeutics are as follows: At least one therapeutic of category j) and at least one therapeutic of category k).
  • Still further preferred combinations of therapeutics according to the invention are as follows:
  • At least one therapeutic of category I) and at least one therapeutic of category r are provided.
  • the invention is also preferably directed to the following combinations of therapeutics: At least one therapeutic of category m) and at least one therapeutic of category n).
  • the invention is preferably directed to the following combinations of therapeutics:
  • Other preferred embodiments of the invention include the following combinations of therapeutics:
  • Also preferred according to the invention are the following combinations of therapeutics: At least one therapeutic of category r) and at least one therapeutic of category s).
  • Still other preferred embodiments are the following combinations of therapeutics: At least one therapeutic of category t) and at least one therapeutic of category u). At least one therapeutic of category t) and at least one therapeutic of category v). At least one therapeutic of category t) and at least one therapeutic of category w).
  • Another preferred embodiment of the invention is the following combination of therapeutics: At least one therapeutic of category v) and at least one therapeutic of category w).
  • “derivative or “mimetic” of LA is generally a structure having the necessary requirements for binding to the coronavirus S protein or a fragment or mutant thereof as disclosed herein, in particular to a binding pocket of the coronavirus S protein or a fragment or mutant thereof as disclosed herein, combining at least the following structural features: at least two, preferably exactly two, basic amino acid residues, typically being directly following one another in the amino acid sequence of said coronavirus S protein or a fragment or mutant thereof as defined herein, and a tube-like cavity in the structure of said coronavirus S protein or a fragment or mutant thereof as disclosed herein formed by lipophilic acid residues.
  • the binding site is also composed by an alpha-helix gating said hydrophobic tube.
  • Typical derivatives or mimetics of LA have a polar head group and an apolar extended tail group, wherein the polar head group is coordinated by said at least two, or exactly two, basic amino acid residues, and said apolar tail group fits into said hydrophobic tube.
  • a derivative or mimetic of LA is characterised by the following general formula (I): wherein
  • Q is selected from O, S and NH, and ismost preferred O;
  • R1 is selected from OR, NHR3, and SH, wherein R3 is H or a short chain alkyl or substitutet alkyl group having 1 to 3 carbon atoms, and is preferably NH2 or OH, most preferred OH; and R2 is a straight unsubstituted or substituted hydrocarbyl group having from 13 to 21 C atoms, preferably 17 C atoms, optionally linked or bound to a detectable label.
  • R1 is selected from OR, NHR3, and SH, wherein R3 is H or a short chain alkyl or substitutet alkyl group having 1 to 3 carbon atoms, and is preferably NH2 or OH, most preferred OH; and R2 is a straight unsubstituted or substituted hydrocarbyl group having from 13 to 21 C atoms, preferably 17 C atoms, optionally linked or bound to a detectable label.
  • the group R2 has at least one unsaturated C-C bond, more preferably two unsaturated C-C bonds.
  • the group R2 has 1 , 2, 3, 4 or 5 unsaturated C-C bonds. More preferably, at least one unsaturated C-C bond is between C-8 and C-9. In other preferred embodiments, at least one unsaturated C-C bond is between C-11 and C-12 of the hydrocarbyl group.
  • the one or more unsaturated C-C- bond(s) in the hydrocarbyl groups is/are C-C double bonds.
  • Preferred embodiments of compounds of formula (I) are outlined as follows (indicated by trivial name(s) and according to the lipid number and omega-x nomenclature):
  • An especially preferred compound is oleic acid (18:1 cis-9).
  • fatty acid of formula (I) is arachidonic acid (20:4 (n-6); also denoted as “AA”or “ARA”).
  • a compound (fatty acid of formula (I)) includecde elaidic acid (18:1 trans-9), eicosapentaenoic acid (20:5 (n-3), stearic acid (18:0), gamma-linoleic acid (also denoted as “GLA”; 18:3 (n-6)), calendic acid (18:3 (n-6)), arachidic acid (synonym: eicosanoic acid; 20:0), and dihomo-gamma-linoleic acid (20:3 (n-6)).
  • Still other preferred embodiments of a compound include docosadienoic acid (22:2 (n-6)), adrenic acid (22:4 (n-6)), palmitic acid (16:0) and behenic acid (synonym: docosanoic acid; 22:0).
  • a compound of formula (I) such as preferred compounds as outlined above include salts, anions and conjugates of such compounds (or fatty acids, respectively) as defined herein.
  • a “salt” of LA or generally a “salt” of a compound of formula (I), respectively, is typically an LA salt or generally a salt of a compound of formula (I), respectively, selected from the alkali metal and earth alkaline metals of the periodic system.
  • Preferred alkaline salts of LA or generally preferred salts of a compound of formula (I), respectively, are those of sodium, kalium and lithium.
  • Preferred earth alkaline salts of LA or generally preferred earth alkaline salts of a compound of formula (I), respectively, are those of calcium and barium. It is to be understood that the “salts” of a compond of formula (I) are preferably salts of preferred fatty acid compounds as outlined above.
  • a “salt” of LA according to the invention may be also or alternatively used according to the invention to refer to the anionic form of LA or its mimetics or derivatives, in particular compounds (in particular fatty acids) of formula (I), preferably those preferred embodiments as outlined above.
  • Broad-spectrum antiviral agents are agents that at least target, i.e. inhibit, more than one virus within a family of viruses, especially preferred BSAAs for use in the invention inhibit viruses belonging to two or more viral families.
  • Broad-spectrum antiviral agents for use in the invention include, but are not limited to, Nitazoxanide, Favipiravir, Mycophenolic acid, Remdesivir, Cidofovir, Chloroquine, Niclosamide, Amodiaquine, Brincidofovir, El PA (also known as amiloride), Emetine, BCX4430 (also known as Galidesivir), Gemcitabine, Rapamycin (also known as Sirolimus), ABT-263, Berberine, Cyclosporine (preferably Cyclosporina A), Brequinar, Obatoclax, Luteolin, Ribavirin, Tilorone (also known as Amixin), Glycyrrhizin, Eflornithine, Sorafenib, Suramin, Monensin, Arbidol (also known as Umifenovir), Sunitinib, Labyrinthopeptin A2, Silvestrol, Emodin, Amiodarone, Ra
  • Preferred nucleoside analogues for use in the invention include, but are not limited to, deoxyadenosine analogues, adenosine analogues, deoxycytidine analogues, guanosine analogues, deoxyguanosine analogues, thymidine analogues, deoxythymidine analogues, deoxyuridine analogues, and mixtures of two or more thereof.
  • nucleoside analogues for use in the invention are typically antiviral agents, and may be BSAAs.
  • the person skilled in the art is readily able to differentiate nucleoside analogues which inhibit only one virus (or one family of viruses) and nucleoside analogues for use in the invention which inhibit viruses of two or more virus families.
  • nucleoside analogues for use in the invention include, but are not limited to abacavir, aciclovir, cytarabine, didanosine, emtricitabine, entecavir, favipiravir, galidesivir, gemcitabine, idoxuridine, lamivudine, remdesivir, ribavirin, stavudine, taribavirin, telbivudine, trifluridine, vidarabine, zalcitabine, zidovudine, and mixtures of two or more thereof
  • Preferred small-molecule synthetic PLA2 inhibitors for use in the invention are selected from cytosolic PLA2 (cPLA2) inhibitors, calcium-independent PLA2 (iPLA2) inhibitors, secreted PLA2 (sPLA2) inhibitors and lipoprotein-associated PLA2 (LpPLA2) inhibitors, and mixtures of two or more thereof.
  • cPLA2 cytosolic PLA2
  • iPLA2 calcium-independent PLA2
  • sPLA2 secreted PLA2
  • LpPLA2 inhibitors lipoprotein-associated PLA2
  • Preferred cPLA2 inhibitors for use in the invention include, but are not limited to, Giripladib, PF-5212372/ZPL-5212372, AVX001 , GK470, ASB14780, Pyrrophenone, RSC-3388, AACOCF3, and GK452, Quercetin, Honokiol, and mixtures of two or more thereof.
  • Preferred iPLA2 inhibitors for use in the invention include, but are not limited to GK187, FKGK11 , FKGK18, BEL, and mixtures of two or more thereof.
  • Preferred sPLA2 inhibitors for use in the invention include, but are not limited to, Varespladib, Varespladib methyl, AZD2716, GK241 , Celastrol, and mixtures of two or more thereof.
  • Preferred LpPLA2 inhibitors for use in the invention include, but are not limited to, Darabladib, Rilapladib, GSK2647544, SB-435495, and mixtures of two or more thereof.
  • Preferred corticosteroids for use in the invention include glucocorticoids and mineralocorticoids as well as mixtures thereof.
  • Preferred glucocorticoids for use in the invention include, but are not limited to, beclometasone, betamethasone, cortison, deoxycorticosterone acetate, dexamethasone, fludrocortisone acetate, methylprednisolone, prednisone, prednisolone, triamcinolone as well as mixtures of two or more thereof, and most preferably is dexamethasone.
  • a preferred mineralocorticoid for use in the invention is aldosterone.
  • Preferred antibiotics for use in the invention include, but are not limited to, aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, glycopeptides, lipoglycopeptides, ketolides, macrolides, monobactams, oxazolidinones, penicillins, polypeptide antibiotics, rifamycins, sulfonamides, streptogramins, tetracyclines, and mixtures of two or more thereof.
  • Preferred polypeptide antibobiotics include gramicidins.
  • Preferred gramicidins include gramicidin D wich is a mix of ionophoric antibiotics, gramicidin A, B and C, which typically make up about 80%, about 5%, and about 15% of gramicidin D, respectively.
  • gramicidin D comprises or consists of six different types of gramicidin molecules, namely gramicidin A1 , A2, B1 , B2, C1 and 02.
  • Gramicidin D including gramicidine A1 , A2, B1, B2, C1 and C2, can be extracted from Brevibacillus brevis soil bacteria.
  • Gramicidines contained in gramicidin D are linear peptides with having amino acids. Further gramicidins for use in the inventuin include the cyclic peptides gramicidin S, gramicidine J1 and gramicidin J2.
  • antibiotics for use in the invention include, but are not limited to, vancomycin, telithromycin, erythromycin, aztreonamm, linezolid, tedizolid, quinupristin, dalfopristin, azithromycin, gramicidin D, gramicidin S and mixtures of two or more thereof, with azithromycin being particularly preferred.
  • Preferred PPAR agonists for use in the invention are typically selected from PPAR-alpha agonists, PPAR-gamma agonists, and PPAR-delta agonists, whereby specific PPAR agonists may have dual specificity such as being PPAR-alpha agonists and PPAR-gamma agonists, or being PPAR-gamma agonists, and PPAR-delta agonists, or being PPAR-alpha agonists, PPAR-delta agonists, and mixtures of two or more thereof.
  • Preferred dual action PPAR agonists for use in the invention include, but are not limited to, aleglitazar, elafibranor, lobeglitazone muraglitazar, naveglitazar, saroglitazar, tesaglitazar, and mixtures of two or more thereof.
  • PPAR agonists have single or a predominantly specificity for a particular PPAR, for example the following preferred compounds:
  • Preferred PPAR-alpha agonists for use in the invention are fibrates, and preferred fibrates for use in the invention include, but are not limited to clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, and mixtures of two or more thereof, with fenofibrate being a particularly preferred fibrate for use in the present invention.
  • Preferred PPAR-gamma agonists are typically selected from thiazolidinediones and AMG- 131 and mixtures thereof.
  • Preferred thiazolidinediones for use in the invention include, but are not limited to, Rosiglitazone and Pioglitazone and mixtures thereof.
  • Preferred PPAR-delta agonists include, but are not limited to, 15(S)-HETE, 15(R)-HETE, and 15-HpETE, GW0742, Telmisarta, and mixtures of two or more thereof.
  • Preferred protease inhibitors are typically selected from TMPRSS2 protease inhibitors and furin (PCSK3) protease inhibitors, and mixtures thereof.
  • TMPRSS2 protease inhibitors for use in the invention include, but are not limited to, bromhexine, nafamostat mesylate camostat mesylate, and mixtures of two or more thereof.
  • protease inhibitors for use in the present invention include, but are not limited to, Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Asunaprevir, Boceprevir, Grazoprevir, Glecaprevir, Paritaprevir, Simeprevir, Telaprevir, and mixtures of two or more thereof.
  • Preferred ACE2 receptor inhibitors/antagonists are typically selected from peptide ACE2 receptor inhibitors/antagonists, antibody ACE2 receptor inhibitors/antagonists, and small molecule ACE2 receptor inhibitors/antagonists as well as mixtures of two or more thereof.
  • Preferred cytokine inhibitor or cytokine release inhibitors for use in the invention include, but are not limited to, interleukin receptor antagonists, bruton tyrosine kinase (BTK) inhibitors, a7Ach receptor agonists, prostaglandins inhibitors, cyclooxygenase inhibitors, plateletactivating factor inhibitors, tumour necrosis factor (TNF) inhibitors, and mixtures of two or more thereof.
  • Preferred interleukin receptor antagonists for use in the invention are antagonists of an interleukin receptor selected from the group consisting of IL-1 receptor, IL-6 receptor and IL- 33 receptor.
  • cytokine inhibitors or cytokine release inhibitors include, but are not limited to, acalabrutinib, adalimumab, anakinra, infliximab, siltuximab, tocilizumab (an IL-6 receptor antagonist), lenzilumab, and mixtures of two or more thereof.
  • Preferred free fatty acid receptor (FFAR) agonists for use in the invention are agonists of FFARs, preferably selected from FFAR1, FFAR2, FFAR3, FFAR4, and GPR84, with agonists of FFAR1 being particularly preferred.
  • Preferred SGLT l/ll inhibitor/antagonists for use in the present invention include, but are not limited to, canagliflozin, cloperastine, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, tofogliflozin, trihexyphenidyl, and mixtures of two or more thereof.
  • Preferred kinase inhibitor/antagonists for use in the invention include, but are not limited to, ARRY-797, apilimod, bencentinib, berzosertib, bosutinib, dasatinib, dinaciclib, gilteritinib, imatinib, nilotinib, ponatinib, ralimetinib, silmitasertib, tomivosertib, vistusertib, and mixtures of two or more thereof.
  • kinase inhibitors/antagonists for use in the invention are preferably selected from Bruton’s tyrosine kinase (BTK) inhibitors, such as preferably acalabrutinib, ibrutinib, and zanubrutinib, and Janus kinase (JAK) inhibitors, such as preferably baricitinib, ruxolitinib, tofacitinib, and mixtures of two or more thereof.
  • BTK tyrosine kinase
  • JK Janus kinase
  • interferons for use in the invention include, but are not limited to, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21 , IFNAB1 , IFNW, IFNAE1 , IFNK, interferon-alfa, interferon alfa 2a, interferon alfa 2b, Pegylated interferon alfa 2a, Pegylated interferon alfa 2b, Human leukocyte interferon-alpha, Interferon beta 1a, Interferon beta 1b, Interferon gamma 1b, and mixtures of two or more thereof.
  • Preferred interleukins (ILs) for use in the invention include IL 1 , IL 2, IL 3, IL IL 4, IL 5, IL 6, IL 7, IL 8, IL 9, IL 10, IL 11, IL 12, IL 13, IL 14, IL 15, IL 16, IL 17, IL 18, IL 19, IL 20, IL 21 , IL 22, IL 23, IL 24, IL 25, IL 26, IL 27, IL 28, IL 29, IL 30, IL 31 , IL 32, IL 33, IL 34, IL 35, IL 36, and mixtures of two or more thereof.
  • Preferred lipid lowering/dislipidemia drugs for use in the invention include, but are not limited to, acipimox, ApoA-1 Milano, avasimibe, bempedoic acid, bile acid sequestrants, CETP inhibitors, colesevelam, ezetimibe, implitapide, lecithin, lomitapide, mipomersen, niacin, Omega-3 supplements, PCSK9 inhibitors, phytosterols, squalene synthase inhibitor, statins, succinobucol, torcetrapib, and mixtures of two or more thereof.
  • PCSK9 inhibitors for use in the invention are typically selected from PCSK9 inhibiting antibodies, such as preferably alirocumab, evolocumab, 1D05-lgG2, RG-7652, LY3015014 and mixtures of two or more thereof, and PCSK9 targeted iRNA agents, such as preferably inclisiran.
  • PCSK9 inhibiting antibodies such as preferably alirocumab, evolocumab, 1D05-lgG2, RG-7652, LY3015014 and mixtures of two or more thereof
  • PCSK9 targeted iRNA agents such as preferably inclisiran.
  • Preferred bile acid sequestrants for use in the invention include, but are not limited to, Cholestyramine, Colestipol and Colesevelam, and mixtures of two or more thereof.
  • Preferred statins for use in the invention include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and mixtures of two or more thereof.
  • Preferred antihypertensives for use in the invention include, but are not limited to, aliskiren, amlodipine, benazepril, losartan, olmesartan, perindopril, Diltiazem valsartan, and mixtures of two or more thereof.
  • Preferred Bromodomain inhibitors for use in the invention include, but are not limited to, ABBV-744, CPI-0610, RVX-208, dBET6, JQ1, MZ1 , and mixtures of two or more thereof.
  • Preferred anti-inflammatory drugs for use in the invention include, but are not limited to nonsteroidal anti-inflammatory drugs, antileukotrienes, immune selective anti-inflammatory derivatives, and mixtures of two or more thereof.
  • the pharmaceutical composition of the invention is particularly useful for treatment and/or prevention of a coronavirus infection.
  • Further subject matter of the invention is a method for treatment and/or prevention of a coronavirus infection comprising the step of administering an effective amount of the pharmaceutical composition according to the invention to a subject in need thereof, preferably a human subject.
  • the therapeutic and preventive, respectively uses of the invention of the invention also include such uses and methods, respectively, for treatment of coronavirus infection wherein the use or method, respectively, is generally a combined therapy (including preventive therapy) employing 2 or more, such as 2, 3, 4, or 5, preferably 2 or 3, most preferred 2, of the therapeutics according to the categories a) to w), including preferred embodiments thereof as outlined above. That means, according to the invention, that the 2 or more therapeutics selected from the categories a) to w) may not only be applied in the form of a single pharmaceutical composition as defined herein, but may also be applied in separate form, preferably in separate pharmaceutical compositions, either simultaneously or sequentially.
  • the invention also provides uses of a combination of 2 or more therapeutics selected from the categories a) to w), including preferred embodiments thereof as outlined above, treatment and/or prevention of a coronavirus infection.
  • the present invention provides a method for treatment and/or prevention of a coronavirus infection comprising the step of administering effective amounts of 2 or more, preferably 2, 3, 4, or 5, of the therapeutics of above-defined categories a) to w), including preferred embodiments thereof as outlined above, to a subject in need thereof, preferably a human subject.
  • the coronavirus infection is caused by a coronavirus causing respiratory disease, more preferred pneumonia.
  • the coronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, SARS-CoV-2 and mutants thereof. Treatment and/or prevention of infections by SARS-CoV-2, or a mutant virus related to SARS-CoV-2, are especially preferred embodiments of the invention.
  • Mutants of a virus as defined herein have at least 80 %, preferably at least 90 %, more preferably at least 95 %, even more preferred at least 96 %, still further preferred at least 97 %, still further preferred at least 98 %, most preferred at least 99 % amino acid sequence homology with the wild-type coronavirus, especially preferred with the wild type SARS-CoV- 2.
  • composition of the invention or the combination of therapeutics as defined herein are preferably administered systemically or topically to a subject.
  • topical administration it is to be understood that, according to the invention, this term is considered to be the route of administration, and shall include administrations occurring locally, but having a systemic pharmacological effect.
  • a preferred topical administration of the inventive composition or combination of therapeutics involves administration to the respiratory tract of subject, including administration to the upper respiratory tract such as nasal and/or pharyngeal and/or laryngeal administration and/or administration to the mouth, and/or lower respiratory tract such as administration to the trachea and/or primary bronchi and/or lungs of a subject, preferably as an aerosol formulation, more preferably as a spray formulation, or a dry powder formudation.
  • the inventive composition or combination of therapeutics is/are administrated to the upper respiratory tract, more preferably by nasal administration.
  • Nasal administration also synonymously referred to according to the invention as “intra-nasal” administration, generally includes administration to the nasal cavity, and preferably comprises administration into one or both, preferably both, nostrils.
  • Systemic administration of the pharmaceutical composition or combination of therapeutics, respectively, is preferably by oral administration or by intravenous injection or infusion to a subject.
  • the pharmaceutical composition according to the invention as well as any pharmaceutical composition comprising a therapeutic according to a category of a) to w) as defined herein (in particular, for providing a combination therapy with separated therapeutics as outlined above) contain the active pharmaceutical compound(s) (APC) or agents (APA), respectively, (i.e. the therapeutic(s) according to above categories a) to w), in combination with at least one pharmaceutically acceptable carrier.
  • APC active pharmaceutical compound(s)
  • APA agents
  • the linoleic acid or derivative or salt or mimetic thereof is present in a composition containing said LA or derivative or salt or mimetic thereof.
  • a composition comprises liver cod oil.
  • hydrophobic substances such as fatty acids and related molecules, in particular LA, salts, derivatives and mimetics thereof as disclosed herein show a low degree of water solubility (about 100 mg/l in the case of LA)
  • inventive composition comprises at least one, optionally pharmaceutically acceptable, carrier for lipophilic substances.
  • carriers for lipophilic substances can be components having one or more binding sites for lipophilic substances, in particular LA or derivative or salt or mimetic thereof as defined herein.
  • a carrier for LA or derivative or salt or mimetic thereof as defined herein can also be a solubilizer for lipophilic substances such as LA or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor.
  • Preferred suitable carriers for lipophilic substances include, but are not limited to, proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc., preferably proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc. having one or more binding sites for LA or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor.
  • Suitable carriers for use in the invention are disclosed, e.g. in Kalepou et al. (2013) Acta Pharmaceutica Sinica B 3 (6), 361-372.
  • Preferred solubilizers for lipophilic substances in the context of the invention are cyclodextrin, ethanol, propylene glycol and a polypropylene glycol, including mixtures of two or more us such solubilizers.
  • solubilizer(s) is/are and their amounts, in particular their molecular ratio to the LA or derivative or salt or mimetic thereof as defined and described herein, more preferably a compound of formula (I), most preferred LA and/or oleic acid, are preferably selected such that they substantially prevent formation of lipid vesicles, which will regularly form in particular in aqueous compositions.
  • Preferred solubilizers prevent hydrophobic interaction between individual active substances (i.e. LA or derivative or salt or mimetic thereof as defined and described herein, more preferably a compound of formula (I), most preferred LA and/or oleic acid) by complexing the lipid molecules in a form such that they are shielded from a polar environment, in particular in aqueous solutions.
  • cyclodextrin is an a-cyclodextrin, a p-cyclodextrin, a y-cyclodextrin, a 5-cyclodextrin or a mixture of two or more thereof.
  • the cyclodextrin preferably an a-cyclodextrin, a - cyclodextrin, a y-cyclodextrin, a 5-cyclodextrin or a mixture of two or more thereof, is a cyclodextrin derivative selected from O-methylated, acetylated, hydroxypropylated, hydroxyethylated, hydroxyisobutylated, glucosylated, maltosylated and sulfoalkylether cyclodextrin and mixtures of two or more thereof.
  • Derivatives of cyclodextrins are disclosed, e.g. in US Patent No.
  • the cyclodextrin is a P-cyclodextrin and/or a derivative thereof, preferably hydroxypropyl-p-cyclodextrin, such as 2 hydroxypropyl-p-cyclodextrin and/or 3- hydroxypropyl-p-cyclodextrin and/or 2,3- dihydroxypropyl-p-cyclodextrin, dimethyl-p-cyclodextrin, trimethyl-p-cyclodextrin, randomly methylated p-cyclodextrin, hydroxyethyl-p-cyclodextrin, 2-hydroxyisobutyl-p-cyclodextrin, glucosyl-p-cyclodextrin and maltosyl--p-cyclodextrin.
  • hydroxypropyl-p-cyclodextrin such as 2 hydroxypropyl-p-cyclodextrin and/or 3- hydroxypropyl-p-cyclodextrin and/
  • cyclodextrins for use in the present invention are sulfoalkylether-modified cyclodextrins, preferably mixtures of such sulfoalkylether cyclodextrins, more preferred sulfoalkylether p-cyclodextrins, most preferred sulfobutylether-ss-cyclodextrin.
  • Preferred alkylated and sulfoalkylated cyclodextrins and mixtures of such alkylated and sulfoalkylether dextrins are described in WO 98/50077 A1, WO 00/41704 A1, WO 2007/050075 A1, WO 2009/013434 A2, WP 2009/018069 A2, WO 2013/13666 A1 , WO 2016/029179 A1 and WO 2021/101842 A1.
  • Preferred sulfoalkylether cyclodextrins, in particular mixtures of such sulfalkylether cyclodextrins, for use in the invention are available under the trademark Captisol®.
  • compositions that can bind fatty acids, in particular LA (or a derivative or a salt or a mimetic thereof). More preferred proteins of this type are fatty acid binding proteins (FABPs) so that said composition preferably comprises at least one FABP together with LA or a derivative or salt of mutant thereof.
  • FABPs for use in the present invention include FABP1 , FABP2, FABP3, FABP4, FABP5, FABP6, FABP7, FABP8, FABP9, FABP10, FABP11 and FABP12.
  • Other preferred solubility improvers are albumin proteins, such as bovine serum albumin (BSA) or human serum albumin (HSA).
  • BSA bovine serum albumin
  • HSA human serum albumin
  • the composition can therefore comprise one or more of such serum albumin proteins, optionally in addition to at least one FABP.
  • LA Linoleic acid
  • LA Linoleic acid
  • LA the derivative, salt of mimetic thereof is used in combination with one or more non-LA therapeutics as defined herein for treatment and/or prevention of coronavirus infections.
  • Non-LA therapeutics of present invention refers to therapeutics of categories (b) to w) as outlined above.
  • non-LA therapeutics are small molecule drugs that preferentially impact lipidomic systems (e.g. dislipidemia drugs) and/or metabolomic systems (e.g. catabolic and anabolic drugs).
  • the present invention includes methods for prevention and/or treatment of a coronavirus infection comprising the step of administering an effective amount of LA or a salt or a derivative or mimetic thereof in combination with one or more non-LA therapeutics to a human or animal subject, preferably a human subject.
  • an “effective amount” of an active substance for use in the inventive therapeutic or preventive, respectively, uses and methods as disclosed herein, preferably LA or a salt or a derivate of mimetic thereof as defined herein, together in combination with one or more non- LA therapeutics as defined herein.
  • An “effective amount” is an amount of the active substance(s) exerting an effect suitable for at least improving the condition, in particular of a coronavirus infection as disclosed herein, especially COVID-19, preferably substantially improving said condition, optimally curing said condition.
  • an effective amount is preferably in the range in a daily dose, which may be administered in one or more unit doses, of about 1 mg/kg body weight to about 1400 mg/kg body weight, more preferably about 5 mg/kg body weight to about 50 mg/kg body weight, wherein body weight means weight of the subject treated.
  • a preferred effective amount is, e.g., a daily dose, which may be administered in one or more unit doses, of about 0.1 mg/kg bodyweight to about 50 mg/kg bodyweight, more preferred of about 1 mg/kg bodyweight to about 10 mg/kg bodyweight, wherein body weight means weight of the subject treated.
  • Therapeutics as defined herein are useful for the treatment and/or prevention of a coronavirus infection.
  • the present invention is also directed to methods for prevention and/or treatment of a coronavirus infection comprising the step of administering an effective amount one or more non-LA therapeutics as defined herein to a subject, preferably a human subject, in need thereof.
  • the present invention is also directed to the use of combinations of two or more non-LA therapeutics for the preparation of a medicament for the treatment and/or prevention of a coronavirus infection.
  • the coronavirus infection is an infection by a coronavirus causing a respiratory disease, in particular pneumonia, preferably in humans. More preferred, the coronavirus infection is an infection by SARS-CoV, MERS-CoV and/or SARS-CoV-2, with infections by SARS-CoV-2 are most preferred.
  • the LA or derivative or salt or mimetic thereof and/or the at least one non-LA therapeutics may be administered systemically or topically to a subject.
  • the administration of two or more non-LA therapeutics in the absence of LA or derivative or salt or mimetic thereof may be administered systemically or topically to a subject.
  • a preferred topical administration of the active substance(s) involves administration to the lungs of a subject, preferably as an aerosol formulation of the active compound(s).
  • Systemic administration of the active substance(s) is preferably carried out by administering the active substance(s) orally and/or by intra-venous infection to a subject.
  • Oral administration can by embodied by mixing the active substance(s) with a food.
  • the LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein is/are administered in the form of a composition comprising the LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein with at least one, optionally pharmaceutically acceptable, carrier for lipophilic substances.
  • Preferred suitable carriers for lipophilic substances include, but are not limited to, proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc., preferably proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc. having one or more binding sites for linoleic acid or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor.
  • Suitable carriers for use in the invention are disclosed, e.g. in Kalepou et al. (2013) Acta Pharmaceutica Sinica B 3 (6), 361-372.
  • Preferred proteins of this type are, e.g., albumin proteins, preferably human serum albumin, and fatty acid binding proteins, preferably one or more selected from FABP1 , FABP2, FABP3, FABP4, FABP5, FABP6, FABP7, FABP8, FABP9, FABP10, FABP11 and FABP12.
  • albumin proteins preferably human serum albumin
  • fatty acid binding proteins preferably one or more selected from FABP1 , FABP2, FABP3, FABP4, FABP5, FABP6, FABP7, FABP8, FABP9, FABP10, FABP11 and FABP12.
  • LA or derivative or salt or mimetic thereof as defined herein and/or one, two or more non-LA therapeutics as defined herein as defined herein is mixed with the carrier ex vivo before administration to the subject.
  • compositions for use in the invention containing the above active components may contain further ingredients typically present in dosage for oral or intravenous (IV) injection application for providing and/or improving various parameters.
  • additional ingredients for use in the present invention include excipients, other carriers, fillers, glidants, dispersants, plasticizers, wetting agents, anti-tacking agents, neutralization agents, colorants, pigments, opacifiers, flavours, taste improvement agents such as sweeteners, buffers, injection-aids, and the like.
  • compositions for preventive and/or therapeutic uses and methods as disclosed herein is readily able to identify specific compounds and substances of the above and other types as well as their combinations and amounts to be used. Further guidance can be found in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, in particular pages 1289-1329.
  • Quantitative determination of potential effectiveness of a given combination therapy for treating human coronavirus infection Quantification of potential effectiveness of a given combination therapy for treating coronavirus infection can be carried out by an in vitro experiment which investigates the effect of one component of the therapy with and without the second or more additional components of the combination therapy in a cell culture experiment which determines inhibition of coronavirus replication. It is anticipated that if a combination therapy is potentially effective as a therapeutic intervention for coronavirus infection, the presence of only one component of the therapy in inhibiting coronavirus replication will be less effective than a combination of the first component with a second (or more) additional therapeutics of the potential combination therapy.
  • Table 1 Theoretical reduction in virus titer.
  • SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell 181, 1016-1035 e1019, doi:10.1016/j.cell.2020.04.035 (2020).
  • RT-PCR for SARS-CoV-2 quantitative versus qualitative [published online ahead of print, 2020 May 20], Lancet Infect Dis. 2020;S1473-3099(20)30424-2. doi:10.1016/S1473-3099(20)30424-2

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Abstract

La présente invention concerne des combinaisons de médicaments thérapeutiques particulièrement utiles pour le traitement et/ou la prévention d'une infection à coronavirus. Lesdites combinaisons thérapeutiques sont principalement focalisées sur des médicaments à petites molécules qui sont des systèmes lipidomiques, des systèmes métabolomiques, des systèmes immunomodulateurs et inflammatoires. Un autre aspect de l'invention concerne des méthodes de traitement d'une infection à coronavirus au moyen desdites combinaisons thérapeutiques.
EP21762002.0A 2020-08-07 2021-08-06 Polythérapies pour le traitement d'une infection à coronavirus Pending EP4243805A1 (fr)

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CN114469913B (zh) * 2022-02-17 2024-03-22 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） Tilorone用于预防/治疗非洲猪瘟病毒感染的应用
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