WO2021204814A1 - Nachr, tel que de la nicotine, destiné à être utilisé dans la prévention et le traitement de la covid-19 - Google Patents

Nachr, tel que de la nicotine, destiné à être utilisé dans la prévention et le traitement de la covid-19 Download PDF

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Publication number
WO2021204814A1
WO2021204814A1 PCT/EP2021/058960 EP2021058960W WO2021204814A1 WO 2021204814 A1 WO2021204814 A1 WO 2021204814A1 EP 2021058960 W EP2021058960 W EP 2021058960W WO 2021204814 A1 WO2021204814 A1 WO 2021204814A1
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Prior art keywords
nachr
ligand
pharmaceutically acceptable
acceptable salt
cov
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PCT/EP2021/058960
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English (en)
Inventor
Makoto MIYARA
Zahir AMOURA
Florence TUBACH
Felix Augusto REY
Jean-Pierre Changeux
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Assistance Publique - Hopitaux De Paris
Institut Pasteur
Sorbonne Universite
Centre National De La Recherche Scientifique (Cnrs)
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Priority claimed from EP20315125.3A external-priority patent/EP3892274A1/fr
Priority claimed from EP20315196.4A external-priority patent/EP3900723A1/fr
Application filed by Assistance Publique - Hopitaux De Paris, Institut Pasteur, Sorbonne Universite, Centre National De La Recherche Scientifique (Cnrs) filed Critical Assistance Publique - Hopitaux De Paris
Publication of WO2021204814A1 publication Critical patent/WO2021204814A1/fr

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    • 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
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • 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

  • NACHR SUCH NICOTINE, FOR USE IN THE PREVENTION AND THE TREATMENT OF COVID-19
  • the present invention relates to a new therapeutic or veterinary use of a known compound, for preventing and/or treating viral infections caused by at least one Betacoronavirus, in particular by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), this viral infection in humans being designated as COVID-19 disease.
  • Betacoronavirus in particular by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), this viral infection in humans being designated as COVID-19 disease.
  • SARS-CoV-2 belongs to the species Coronavirus, in the genus Betacoronavirus and family Coronaviridae.
  • Coronaviruses are enveloped viruses with a helically symmetrical capsid. They have a single-stranded, positive-sense RNA genome and are capable of infecting cells in birds and mammals.
  • the morphology of the virions is typical, with a halo of protein protuberances ( Spike ) which gave them their name of crown virus'.
  • Betacoronavirus genus (B-CoVs or Beta- CoVs), comprising virus infecting animals and/or humans, is subdivided into four lineages designated as A, B, C and D:
  • Lineage A also designated as subgenus Embecovirus includes HCoV-OC43 and HCoV-HKU1 , virus able to infect various species;
  • Lineage B also designated as subgenus Sarbecovirus includes SARS-CoV-1 , SARS-CoV-2, and Bat SL-CoV-WIV1 ;
  • Lineage C also designated as subgenus Merbecovirus includes Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4), Pipistrellus bat coronavirus HKU5 (BtCoV- HKU5), and MERS-CoV, able to infect notably camels and humans;
  • Lineage D also designated as subgenus Nobecovirus includes Rousettus bat coronavirus HKU9 (BtCoV-HKU9).
  • Betacoronavi ruses of the greatest clinical importance concerning humans are:
  • coronavirus infections can cause respiratory pathologies associated with symptoms similar to the common cold, bronchiolitis and more serious diseases such as the Severe Acute Respiratory Syndrome caused by SARS-CoV-1 , which generated an epidemic in 2003, and the Middle Eastern Respiratory Syndrome caused by MERS-CoV, which generated an epidemic in 2012.
  • SARS-CoV-2 is the betacoronavirus causing the coronavirus epidemic of 2019-2020, generating the form of pneumonia known as coronavirus disease 2019 or COVID-19.
  • SARS-CoV-2 genome was sequenced for the first time on 5 January 2020 by a team from Fudan University in Shanghai (China). Its genome consists of a single-stranded RNA of 29,903 nucleotides. It is 79.5% similar to that of SARS-CoV-1 , and 96% similar to that of bat coronavirus, suggesting that the origin of the SARS-CoV-2 virus is zoonotic and is found in bats (Zhou P et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020).
  • SARS-CoV-2 Symptoms of infection with SARS-CoV-2 are roughly similar to those of seasonal influenza infections: they include fever, fatigue, dry cough, shortness of breath, difficult breathing, pneumonia, renal failure, and may lead to death in severe cases. Recently, neurologic and psychiatric manifestations have been described.
  • Antiviral compounds known for their therapeutic activity on other types of viruses, are currently tested in clinical trials.
  • the French High Council for Public Health issued an opinion on March 23, 2020 on the therapeutic recommendations for the management of COVID-19 disease.
  • This official notice proposes in particular to use the following therapeutic compounds: Remdesivir, Lopinavir/Rotinavir and Hydroxychloroquine.
  • Remdesivir has been initially developed for the treatment of Ebola virus infections.
  • Remdesivir is a broad -spectrum antiviral compound, acting as a nucleoside analogue, specifically an adenosine analogue. Its presence misleads the viral polymerase and causes a reduction in viral RNA synthesis.
  • Lopinavir is a viral protease inhibitor, previously used against the human immunodeficiency virus (HIV). Lopinavir inhibits the production of functional proteins by the new virions, thereby blocking the spread of the virus. Lopinavir is rapidly degraded in the body. For this reason, it is administered in fixed combination with Ritonavir, which inhibit cytochrome P450 monooxygenases, thereby slowing the degradation of Lopinavir by these enzymes.
  • Hydroxychloroquine initially known for its anti-malaria activity, has been shown to have an apparent efficacy in the treatment of Covid-19 (Yao et al., 2020). However, clinical data are still limited.
  • o systemic hyperinflammatory syndrome with increased levels of circulating pro-inflammatory cytokines
  • o atypical acute respiratory distress syndrome with loss of neurological control of lung perfusion regulation, and hypoxic vasoconstriction.
  • SARS-CoV-2 virus enters the nervous system, invades the brain stem and affects the medullary neurons of the respiratory centers. Further studies have been performed to understand the physiological mechanisms of such central nervous system invasion.
  • the angiotensin converting enzyme ACE2 represents the principal receptor molecule for cell entry of SARS-CoV-2 (Lan, J. et al. Structure of the SARS-CoV-2 spike receptor binding domain bound to the ACE2 receptor. Nature, 2020).
  • the ACE2 is expressed in the brain, in both neurons and glia. Nevertheless, additional receptors or co-receptors for the entry of SARS-CoV-2 are not excluded.
  • a first object of the present invention is a ligand having a modulatory effect on neuronal nicotinic acetylcholine receptor (nAChR) or a pharmaceutical salt thereof for use for preventing and/or treating viral infections due to at least one betacoronavirus, preferably a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS-CoV-2.
  • nAChR neuronal nicotinic acetylcholine receptor
  • a pharmaceutical salt thereof for use for preventing and/or treating viral infections due to at least one betacoronavirus, preferably a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS-CoV-2.
  • SARS-CoV Severe Acute Respiratory Syndrome-related coronavirus
  • a second object of the present invention is a transdermal delivery device comprising a ligand having a modulatory effect on neuronal nicotinic acetylcholine receptor (nAChR) or a pharmaceutically acceptable salt thereof for use for preventing and/or treating viral infections due to at least one betacoronavirus, advantageously a Severe Acute Respiratory Syndrome-related coronavirus, in particular SARS-CoV-2.
  • nAChR neuronal nicotinic acetylcholine receptor
  • This effector ligand of neuronal nicotinic acetylcholine receptor is in particular nicotine.
  • Figure 1 discloses the amino acid sequence alignment of the motifs found in toxins from snakes of the Ophiophagus (cobra) and Bungarus genera, in G from three RABV strains and in S from SARS-CoV-2.
  • Betacoronavirus designates any virus belonging to the Betacoronavirus genus (6-CoVs or Beta-CoVs), in particular any betacoronavirus belonging to one of the four lineages designated as A, B, C and D. It designates a betacoronavirus infecting animals and/or humans. In particular, this designation includes the betacoronavi ruses infecting human organisms chosen among OC43, HKU1 , SARS-CoV- 1 , SARS-CoV-2 and MERS-CoV.
  • “Viral infections due to at least one betacoronavirus” designates the fact that host cells of an organism have been infected by at least one betacoronavirus, the whole organism being said to have a viral infection.
  • a betacoronavirus infection in humans is usually diagnosed by a healthcare professional, based on observation of the infected patient's symptoms. Additional biological tests may be required to confirm the diagnosis: blood and/or sputum and/or bronchoalveolar fluid tests.
  • Infection by a betacoronavirus can be established, for example, by molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • Conventional diagnostic methods comprise techniques of molecular biology such as PCR, which is well known to the person in the field.
  • prevention means preventing, or reducing the likelihood of the occurrence of, an infection in a human or animal organism by at least one coronavirus.
  • treatment refers to fighting the betacoronavirus infection in a human or animal organism.
  • the rate of viral infection (infectious titer) in the organism decrease, and preferably the betacoronavirus completely disappear from the organism within a shorter period of time than expected without treatment.
  • treatment also refers to reducing the symptoms associated with the betacoronavirus infection (respiratory syndrome, kidney failure, fever, etc.).
  • a ligand having a modulatory effect on neuronal nicotinic acetylcholine receptor (nAChR), in particular nicotine, for its use according to the invention may be intended to be administered to a human being or to non-human animals.
  • nAChR neuronal nicotinic acetylcholine receptor
  • COVID-19 disease mean the disease linked to the infection with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2).
  • the “symptomatic COVID-19 disease” is characterized by a patient who shows at least one symptom of the COVID-19 disease.
  • the most common symptoms of the COVID-19 disease are fever, muscle aches, headaches, fatigue, loss of taste and smell and respiratory symptoms such as a dry cough, difficulty breathing and a lack of oxygen.
  • a symptomatic disease is in contrast to an asymptomatic disease which is characterized by a patient who is a carrier for a disease or infection but experiences no symptoms.
  • the “severe symptomatic COVID-19 disease” is characterized by severe symptoms of the COVID-19 disease, in particular respiratory symptoms. Severe symptoms are acute respiratory distress syndrome and/or hyper- inflammatory state that require hospitalization of the patient, especially in the intensive care unit (ICU).
  • ICU intensive care unit
  • COVID-19 patients are patients infected with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2).
  • a “transdermal delivery device” is an adhesive device which can administer, for medical purposes, an active principle through the skin. Such a device provides direct administration of active principle to the blood system without passing by the digestive system, as is the case with tablets, capsules or syrups.
  • the abbreviation “LATA” designates the phase of “Limitation and discontinuation of active therapies” where palliative care begins, to accompany patients at the end of life.
  • ICU refers to an intensive care unit, a special department of a hospital or health care facility that provides intensive treatment medicine.
  • pharmaceutically acceptable is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • pharmaceutically acceptable salt is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • the pharmaceutically acceptable salts comprise:
  • acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N- methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the present inventors postulated that such ligand of nAChR can sterically (or allosterically) compete with the SARS-CoV-2 binding to at least one of the nAChRs, thereby preventing or reducing the hyperinflammatory syndrome that may be lethal for the patient.
  • the present inventors have analyzed for the first time the smoking habits of patients that have been diagnosed from being infected by SARS-CoV-2. Severe cases (“inpatients”) and non-severe cases (“outpatients”) have been included and followed. Their results show for the first time that, compared to the French general population, the COVID-19 population exhibited a significantly decreased current daily smoker rate by 80.3% for outpatients and by 73.9% for inpatients.
  • Cerebral nicotinic acetylcholine receptor “neuronal nicotinic acetylcholine receptor” and “nAChR” are synonymous and designate any type of oligomeric receptors able to bind acetylcholine and nicotine, specifically expressed in the peripheral and central nervous system of mammalians. These receptors are pentameric structures, composed of combinations of five subunits. Twelve neuronal nAChR subunits have been described, designated as alpha2 to alphalO and beta2 to beta4; they are differentially expressed throughout the nervous system and combine to form various nAChRs. The a4b2 and al nAChR oligomers are the two most frequent, accounting for about 95% of the whole nAChR population in the human brain.
  • nAChRs are neurotransmitters whose conformation changes when allosteric interactions take place between topographically distinct sites, which leads to a reversible conformational change of the protein and modulates the opening of the central ion channel.
  • the endogenous ligand of these receptors is acetylcholine, but they are also reactive to different external ligands such as nicotine, alcohol and toxins.
  • ligand having a modulatory effect on neuronal nicotinic acetylcholine receptor designate any orthosteric and/or allosteric ligand of any nAChR, that bind to this nAChR and have a modulatory effect on this receptor.
  • This term includes activators and inhibitors of nAChRs. It includes all nAChR agonists, partial agonists, positive allosteric modulators (PAMs), antagonists, partial agonists, or negative allosteric modulators (NAMs). It includes direct and indirect modulators.
  • a direct stimulation requires the binding of the agent to said receptor (agonists, antagonists), while an indirect stimulation does not involve the binding of said agent to said receptor (i.e. it acts on the receptor via another mechanism of action, like PAMs and NAMs).
  • said nAChR effector ligand is a beta-2 nAChR antagonist and/or beta-2 nAChR NAM that reduces acetylcholine signaling through beta-2- containing nAChR(s).
  • the beta-2 nAChR referred to in the present application contains one, two or three beta-2 subunits, preferably two or three beta-2 subunits, and more preferably two beta-2 subunits.
  • the nAChR effector ligand modulate the activity of a nAChR selected from the group consisting of : alpha-2 alpha-5 beta-2, alpha-2 beta-2, alpha-3 beta-2, alpha-4 beta-2, alpha-6 beta-2, alpha-7 beta-2, alpha-3 alpha-5 beta-2, alpha-3 alpha-6 beta-2, alpha- 4 alpha-5 beta-2, alpha-4 beta-2 beta-3 and alpha-5 alpha-6 beta-2.
  • Said beta-2 nAChR antagonist can be chosen in the group consisting of: Dihydro-beta- erythroidine, Erysodine, (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5 - pyridinyl]-7-azabicyclo[2.2.1] heptane, 2-fluoro-3-(4-nitro- phenyl)deschloroepibatidine,Coclaurine, Mecamylamine, Tubocurarine and the like.
  • Said beta-2 nAChR NAM can be chosen in the group consisting of : Amantadine, UCI- 3002, COB-3, KAB-18, Lynx-1 , Lynx-2, COB-1 , COB-2, DDR-15, DDR-13, DDR-18, APB-8, DDR-1 , DDR-2, KAB-21 , DDR-19, KAB-24, KAB-22, KAB-23, KAB-19, KAB-20, KAB-30, IB- 2, PPB-12, PPB-13, IB-4, COB-4, LYPD6, LYPD6B, PSCA, PATE-M, SLURP1 , SLURP2, ly6A/E, ly6B-G, Ly6G6E, ly6H, SLEEPLESS, Odr-2, Boudin, Nl-lynx1 , Nl-lynx2, Pr-lynx1 , Erabutoxin b, Bucandin, Candoxin, Fasciculins, al
  • said nAChR effector ligand can be an alpha-7 nAChR antagonist and/or alpha-7 nAChR NAM.
  • Said alpha-7 nAChR antagonist can be chosen in the group consisting of : ethanol, hydroxynorketamine, ketamine, kynurenic acid, lobeline, methyllycaconitine (MLA), Norketamine, Quinolizidine (-)-1-epi-207l, S76892, dizocilpine (+)-MK-801.
  • Said alpha-7 nAChR NAM can be chosen in the group consisting of: 1 ,2, 3, 3a, 4, 8b- hexahydro-2-benzyl-6-N,N-dimethylamino-1 -methylindeno[1 ,2,-b]pyrrole (HDMP), 2,3,6 MP-TQS, cistrans-4-(2,3,6-trimethylphenyl)-3a,4,5,9b-tetrahydro-3H- cyclopenta[c]quinoline-8-sulfonamide, 2,6MP-TQS, cis-trans-4-(2,6-dimethylphenyl)- 3a,4,5,9b-tetrahydro-3H cyclopenta[c]quinoline-8-sulfonamide, BNC210, EVP-6124, Methanandamide.
  • the subject is provided with a combination of a beta- 2 nAChRs effector ligand with an alpha-7 nAChR effector ligand.
  • a beta- 2 nAChRs effector ligand with an alpha-7 nAChR effector ligand.
  • nicotinic ligands have been evaluated for their ability to help smokers to quit tobacco addiction, as nicotine replacement therapy.
  • these nicotinic ligands one can cite the following compounds: varenicline, cytisine, dianicline, ABT-418, ABT-089, CP-601927, and CP-601932. Any of the compounds can be used in the present invention.
  • Nicotinic acetylcholine receptor ligands have also been evaluated as potential therapeutic agents for cognitive disorders (Terry AV, Callahan PM. Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery. Nicotine Tob Res. 2019;21 (3):383-394).
  • the effector ligand of the invention preferably mimics the action of nicotine on nAChRs. Nicotine binding sites in the brain are mostly composed of a4 and 62 subunits.
  • the nAChR effector ligand used in the invention is therefore preferably a ligand stimulating a462 nACh receptors.
  • Said a462 stimulating ligand can be an agonist of the a462 nAChR or a positive allosteric modulator (PAM) of a462 nAChR.
  • PAM positive allosteric modulator
  • Said a462 nAChR agonist can be chosen in the group consisting of: varenicline, cytisine, ispronicline, A-366833, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine, TC-2559, and the like (as reviewed in Wilkerson JL et al, Advances in the In vitro and In vivo pharmacology of Alpha4beta2 nicotinic receptor positive allosteric modulators Neuropharmacology 168, 2020).
  • Said positive allosteric modulator (PAM) of a462 nAChR can be chosen in the group consisting of: physostigmine, galantamine, desformylflustrabromine (dFBr; N-(2-[6- bromo-2(1 ,1 -dimethyl-2-propyl)-1Hindol-3-yl]ethyl-N-methylamine), NS9283 (3-[3-
  • high-affinity nicotine binding sites there are other high-affinity nicotine binding sites that are less well characterized. These include nicotinic receptors composed of a4, 62, and a5 subunits and receptors that contain a3, 62 and 64. High-affinity nicotine binding sites in the brain can also contain a6 and 62 in addition to the other subunits. Heterologous expression of different combinations of the subunits showed that high-affinity nicotine binding sites result from various subunit combinations, such as a462, a362, a462a5, a362a5, a364a5, a662, a664, a66263, a66463 and a66463a5.
  • the nAChR effector ligand used in the invention is therefore preferably a ligand stimulating the a462, a362, a462a5, a362a5, a364a5, a662, a664, a66263, a66463 and a66463a5 nAChR.
  • the nAChR effector ligand used in the invention does not stimulate an alpha-7 nAChR i.e., it does not enhance the activity of an nAChR having an alpha-7 subunit.
  • the considered nAChR effector ligand is nicotine.
  • the nAChR effector ligand is a nicotine derivative.
  • the nAChR effector ligand is a monoclonal antibody specifically targeting at least one nAChR.
  • the nAChR effector ligand is not ivermectin, nor any agonist or PAM of an alpha-7 nAChR.
  • the present invention relates to the use of at least one nAChR effector ligand or a pharmaceutical salt thereof to prepare a medicament intended to prevent and/or treat patients that have been diagnosed to be infected with at least one betacoronavirus.
  • the invention addresses at least one nAChR effector ligand or a pharmaceutical salt thereof, for use for preventing and/or treating viral infections due to at least one betacoronavirus in a subject suffering thereof.
  • the present invention also discloses a method for preventing or treating any subject that has been diagnosed to be infected with at least one betacoronavirus, said method comprising administering to said subject an effective amount of at least one nAChR effector ligand or of a pharmaceutical salt thereof.
  • the method of the invention can comprise a diagnosis step as preliminary step.
  • the said infection can be diagnosed or detected by any conventional means, such as molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • treatment of the invention designates nAChR effector ligand or a pharmaceutical salt thereof, in all the embodiments disclosed below.
  • said betacoronavirus is chosen in the group consisting of: OC43, HKU1, SARS-CoV-1 , SARS-CoV-2 and MERS-CoV.
  • said betacoronavirus is a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), and even more particularly, a SARS-CoV-2 virus.
  • SARS-CoV-2 virus designates on the one hand the coronavirus identified for the first time in Wuhan in China, and sequenced in early 2020 by a team from Fudan University in Shanghai (Zhou et al., 2020); and on the other hand, includes all variants related to this first identified viral strain, which appeared subsequently, and in particular the following SARS-CoV-2 variant strains: i. the “Wuhan-like” strain disclosed in Zhou et al., 2020; ii.
  • said subject is a human patient.
  • Said patient can be older than 75 years old, between 65 and 74 years old, between 15 and 44 years old, or below 15 years old.
  • said human patient is older than 65 years old, even more preferably older than 75 years old.
  • Said subject can be a smoker or a non-smoker. Preferably, it is a non-smoker.
  • said subject is an animal chosen in the group consisting of: bats, hedgehog, camels, mice, humans, pigs, cats, among others. Any other animal that can be infected with a betacoronavirus could also benefit from the treatment of the invention.
  • the treatment of the invention is administered to subjects (animals or humans) that have been diagnosed to be infected with at least one betacoronavirus but do not present any symptom yet.
  • the treatment of the invention is administered to subjects (animals or humans) that display at least one symptom of the COVID-19 disease, e.g., fever, muscle aches, headaches, fatigue, loss of taste, loss of smell or respiratory symptoms such as a dry cough.
  • the treatment of the invention is administered to subjects (animals or humans) that suffer from severe symptomatic COVID-19 disease and experience for example difficulty in breathing and/or a lack of oxygen.
  • the treatment of the invention is also useful to prevent and/or treat acute respiratory distress syndrome associated with betacoronavirus infection.
  • the purpose of the treatment of the invention is to increase the survival rate of the infected subjects.
  • At least one nAChR effector ligand is used, meaning that a combination of two, three, four or more nAChR effector ligands could be used for preventing and/or treating viral infections due to at least one betacoronavirus.
  • At least one of the nAChR effector ligands is nicotine.
  • the used nAChR effector ligand is nicotine.
  • the nicotine ((S)-3-(1-methyl-2-pyrrolidinyl)pyridine) may be in any forms such as a free base or a pharmaceutically acceptable salt such as a hydrochloride salt.
  • the nicotine is in a free base form (hereinafter occasionally referred to as "nicotine free base").
  • the nAChR effector ligand in particular nicotine, or the pharmaceutically acceptable salt thereof, may be administered via oral, parenteral, topical, transcutaneous, nasal or buccal route.
  • the nAChR effector ligand in particular nicotine, or the pharmaceutically acceptable salt thereof, is administered via transcutaneous route.
  • the nAChR effector ligand in particular nicotine, or the pharmaceutically acceptable salt thereof, is administered using a transdermal delivery device, more advantageously using a transdermal patch.
  • transdermal delivery device or the patch uses the cutaneous pathway to provide direct administration of active principle to the blood system without passing by the digestive system.
  • Transdermal delivery devices in particular transdermal patches, comprising at least one nAChR effector ligand, in particular nicotine, or a pharmaceutically acceptable salt thereof, are commonly known and marketed.
  • the transdermal delivery device is advantageously type IVa patches.
  • the transdermal patch comprises a support layer, a self-adhesive matrix layer comprising the nAChR effector ligand, in particular nicotine, or the pharmaceutically acceptable salt thereof, and a detachable protective film.
  • support layer is meant any support layer typically used in the field of patches.
  • detachable protective film is meant all detachable protective films capable of protecting the device’s matrix before the device is used. These films typically used in the field of transdermal devices are well-known to the person skilled in the art.
  • the matrix layer according to the invention is self-adhesive.
  • self-adhesive is meant that the matrix layer is able to keep the device according to the invention bound to a support, for example the skin, in a stable manner, with no need for the use of other means of bonding.
  • self-adhesive is meant that the matrix layer allows the device to adhere to the skin for at least 12 hours, preferentially for about 12 to 48 hours, more preferentially for about 24 hours.
  • the transdermal delivery device allow the release of a nAChR effector ligand, in particular nicotine, or a pharmaceutically acceptable salt thereof, from the matrix layer by an average delivery rate comprised between 5 and 100 pg/cm 2 /h, advantageously between 10 pg/cm 2 /h and 50 pg/cm 2 /h, for a time interval comprised between 1 and 24 hours.
  • the release rate may be measured by any permeation technique known to the person skilled in the art, in particular via permeation kinetics, for example on the abdominal skin of nude mouse arranged on the surface of a glass (Franz) cell.
  • the transdermal patch used in the context of the invention is the patch marketed as Nicopatch® or Nicopatchlib®.
  • the transdermal delivery device of the invention comprises between 5 mg and 30 mg of nicotine or a pharmaceutically acceptable salt thereof, advantageously between 10 mg and 25 mg, more advantageously between 14 mg and 25 mg, in particular 21 mg.
  • the nAChR effector ligand, in particular nicotine, or the pharmaceutically acceptable salt thereof is administered via oral or buccal route, in particular buccal route.
  • the nAChR effector ligand, in particular nicotine, or the pharmaceutically acceptable salt thereof is advantageously administered via buccal route using pharmaceutical sucking lozenges or sublingual tablets.
  • the sublingual tablets or sucking lozenges comprise advantageously between 1mg and 30 mg of nicotine or a pharmaceutically acceptable salt thereof, advantageously between 1 mg and 20 mg, more advantageously between 1 mg and 10 mg, in particular 2 mg.
  • the pharmaceutical tablets or sucking lozenges can thus be administered several times per day.
  • a nAChR effector ligand in particular nicotine, or pharmaceutically acceptable salt thereof, is administered in a dosage of between 5 and 30 mg per 24 hours, advantageously between 10 mg and 25 mg per 24 hours, more advantageously between 14 mg and 25 mg per 24 hours, in particular 21 mg per 24 hours.
  • Eligible patients were those with a confirmed diagnosis of COVID-19 at the APHP Pitie- Salpetriere Hospital, Paris, France, either hospitalized in medical wards of medicine, but not in ICUs (inpatients) or having consulted for this infection in the infectious disease department and who did not require hospital care until the end of the acute infectious episode (outpatients).
  • COVID-19 was defined as a positive result on real-time reverse- transcriptase- polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens (NPRS).
  • RT-PCR real-time reverse- transcriptase- polymerase-chain-reaction
  • Smoking status was collected, patients were specifically asked if they were current smokers (and if so, if they smoked every day or occasionally), former smokers, or not smokers ever.
  • Daily smokers are individuals reporting daily smoking or reporting a daily frequency of the number of cigarettes (manufactured or rolled) or other tobacco products (cigar, cigarillos, pipe, shisha).
  • Occasional smokers are individuals reporting smoking but not every day and only reporting no consumption of tobacco product per day.
  • the group of ex-smokers includes anyone having smoked in the past, occasionally or daily, and who reported not smoking at the time of the investigation. Under the term "never smoker" people never smoked and those who just tried once or twice.
  • Age class by 10-year class
  • sex by 10-year class
  • comorbidities known to have potentially an impact on the prognosis of covid-19 infection diabetes, hypertension, obesity, immunodepression, respiratory disease (COPD), clinical manifestations of COVID infection, out- or inpatient status.
  • COVID respiratory disease
  • Smoking rate in the population of reference The population of reference to compute Standardized incidence ratios is the French population.
  • Recent rates of current daily smokers have been reported for year 2018 by sex and age class (of 10 years) from the General survey Barometre de Santeopathic France (Public Health Barometer), a cross sectional phone survey made yearly on representative sample of 18-75-year-old people living in mainland France, with a on 2- level random sampling (Andler, R. et al. Reduction of daily smoking rate among adults: results from the 2018 sante Cyprus france health barometer. Bull Epidemiol Hebd 15, 271 -277 (2019)). The 2018 survey involved a sample of 9,074 adults of 18-75-year- old. The completion of the survey took place from January 10 to July 25, 2018.
  • the standardized incidence ratios were used to compare current daily smoker rates in the COVID19 inpatients and outpatients, respectively, to current daily smoker rates in a reference population, here the French general population in 2018.
  • the SIR is the ratio of observed number of current daily smokers in the COVID19 patients to the number of current daily smokers that would be expected, on the basis of age- and gender-specific current daily smokers’ rates, in the general population.
  • the SIR was estimated and the 95% confidence interval calculated.
  • the inpatient group was composed of 343 patients, median age 65 years: 206 men (60.1%, median age 66 years) and 137 women (39.9%, median age 65 years).
  • the rate of daily smokers was 4.4 (5.4% of men and 2.9% of women).
  • the outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6 %, median age 43 years, and 77 women (55.4 %, median age 44 years).
  • the daily smokers’ rate was 5.3% (5.1% of men and 5.5 % of women).
  • nAChR cerebral nicotinic acetylcholine receptor
  • angiotensin converting enzyme ACE2 represents the principal receptor molecule for SARS-CoV-2 (Yan, R. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367, 1444-1448, doi:10.1126/science. abb2762 (2020)).
  • the ACE2 is expressed in the brain, in both neurons and glia, being in particular present in the brain stem and in the regions responsible for regulation of cardiovascular function including subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla. Yet additional receptors or co-receptors are not excluded.
  • medRxiv doi:https://doi.org/10.1101 /2020.02.22.20026500 (2020)).
  • the median time from the first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to the intensive care was 8.0 days. Therefore, the latency period may be enough for the virus to enter the nervous system, invade the brain stem and affect the medullary neurons of the respiratory centers.
  • the nAChR is known to play a critical role in the host-pathogen interaction in the case of other well-documented viruses, such as the rabies virus (RABV).
  • nAChRs are present in the lung epithelium.
  • the non-neuronal cholinergic system contributes to the regulation of cell functions such as cell-cell interaction, apoptosis, and proliferation and it is well established that human bronchial epithelial cells contain nAChRs.
  • the airway epithelium expresses a3, a.4, a5, al, a9, b2, and bA subunits for nAChRs and their contribution has been discussed in the framework of airway epithelial basal cell proliferation-differentiation and their alteration in lung cancers.
  • These nAChRs are mentioned here as possible targets of Covid-19 infection of the lung, which would take place concomitantly with, and/or as a consequence of, the neuro-infection.
  • nAChR pathway is likely to be engaged in the Covid-19 inflammatory syndrome.
  • the nervous system through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, IL-1 , IL-6, IL-18 and attenuate systemic inflammatory responses).
  • This physiological mechanism termed the ‘cholinergic anti-inflammatory pathway’ has major implications in immunology and in therapeutics.
  • Macrophages mediate physiologic control of cytokine production by auto/paracrine acetylcholine through the nAChR expressed in these cells.
  • the profile of cytokines massively secreted following a loss of control by acetylcholine through dysregulation of macrophage nAChR are IL1 , IL6, TNF and IL18.
  • This cytokine profile has striking analogies with the cytokine storm syndrome, leading to the hyperinflammatory syndrome, that has been described in a subgroup of COVID-19 patients (Chen, G. et al. Clinical and immunologic features in severe and moderate Coronavirus Disease 2019. J Clin Invest, doi:10.1172/ JCI137244 (2020)).
  • nAChR modulation by COVID-19 might thus account for the hyperinflammatory features observed in a subgroup of COVID-19 patients, mimicking bona fide the macrophage activation syndrome.
  • cryo-EM structure of the trimeric SARS-CoV-2 spike (S) protein revealed an insertion with respect to that of SARS-CoV-1 , in a loop that is disordered in the reported structure, and which has a polybasic sequence that corresponds to a furin site (Walls, A. C. et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, doi : 10.1016/j . cell.2020.02.058 (2020)).
  • this exposed loop of the SARS-CoV-2 S protein also contains a motif (SEQ ID NO:1 : YQTQTNSPRRAR) that is homologous to that of snake neurotoxins (SEQ ID NO:2: CDGFCSSRGKR and that of the bungarotoxin SEQ ID NO:6: CDAFCSSRGKV) and to the RABV neurotoxin-like region (SEQ ID NO:3-5) (figure 1 ).
  • Covid- 19 infection is a nAChR disease that could be prevented and may be controlled by a nAChR effector ligand, in particular by nicotine.
  • This nAChR effector ligand would then sterically or allosterically compete with the SARS-CoV-2 binding to the nAChR. This legitimates the use of a nAChR effector ligand, in particular nicotine, as a protective agent against SARS-CoV-2 infection and the subsequent deficits it causes in the CNS.
  • a therapeutic assay has been set up to assess the role of nicotine (and other nicotinic agents) patches in hospitalized patients and in the general population against COVID-19 infection.
  • the primary objective of this assay is to assess the efficacy of nicotine patches in terms of prevention of unfavorable evolution in hospitalized COVID-19 patients. Its end point is when unfavorable evolution is observed. “Unfavorable evolution” is herein defined by either death or transfer to ICU or indication for ICU transfer but LATA.
  • the second objective is to assess the efficacy of nicotine patches in terms of survival at day 14 and day 28 post-COVID-19 detection, in particular their effect on the number of transfers to ICU, indication for ICU transfer but LATA, non-invasive ventilation or on the time to discharge.
  • the percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [Time Frame: Days 3, 5, 8, 11 , 15, 29] was assessed.
  • the SARS-CoV-2 was quantified in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11 , 15, 29 ] and in blood [ Time Frame: Days 3, 5, 8 and 11 ].
  • the nicotine patch was NICOPATCHLIB® (21 mg, 14 mg or 7 mg) (Pierre Fabre): Transluscent, Ultra-thin, Square shape with round corners, 5,3 x 5,6 cm
  • the dosage was 21 mg per day during two weeks, 14 mg/day during the third week and 7 mg/day during the fourth week.
  • the placebo patch was TEGADERM®: Transluscent, Ultra-thin, Square shape with round corners, 4,4 cm x 4,4 cm.
  • a placebo patch of the exact same size of NICOPATCHLIB® was also used.

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Abstract

L'invention concerne un ligand ayant un effet modulateur sur le récepteur nicotinique neuronal de l'acétylcholine (nAChR) ou un sel pharmaceutique de celui-ci destiné à être utilisé pour prévenir et/ou traiter des infections virales dues à au moins un bêtacoronavirus, de préférence un coronavirus associé au syndrome respiratoire aigu sévère.
PCT/EP2021/058960 2020-04-06 2021-04-06 Nachr, tel que de la nicotine, destiné à être utilisé dans la prévention et le traitement de la covid-19 WO2021204814A1 (fr)

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Citations (1)

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WO2017149534A1 (fr) * 2016-02-29 2017-09-08 Nicogen Ltd. Formulation de nicotine et aérosols

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017149534A1 (fr) * 2016-02-29 2017-09-08 Nicogen Ltd. Formulation de nicotine et aérosols

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