WO2020115231A1 - Méthodes et compositions destinées au traitement des voies respiratoires atteintes de mucoviscidose - Google Patents

Méthodes et compositions destinées au traitement des voies respiratoires atteintes de mucoviscidose Download PDF

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WO2020115231A1
WO2020115231A1 PCT/EP2019/083869 EP2019083869W WO2020115231A1 WO 2020115231 A1 WO2020115231 A1 WO 2020115231A1 EP 2019083869 W EP2019083869 W EP 2019083869W WO 2020115231 A1 WO2020115231 A1 WO 2020115231A1
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cftr
rvdl
cystic fibrosis
treatment
compound
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PCT/EP2019/083869
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English (en)
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Valérie URBACH
Brian Harvey
Paul Mcnally
Fiona RINGHOLZ
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université de Paris
Centre National De La Recherche Scientifique (Cnrs)
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Publication of WO2020115231A1 publication Critical patent/WO2020115231A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention is in the field of pneumonology. More particularly, the invention relates to methods and compositions for treating cystic fibrosis airways disease.
  • Cystic fibrosis (CF) airways is characterized by a chronic infection and inflammation. It is the most common lethal monogenic disorder in Caucasians, with an incidence of one bird in 2500-4000 and 70,000 affected people worldwide and kills most of them in their 20s. More particularly, cystic fibrosis (CF) lung disease is characterised by dysregulated ion transport that promotes chronic bacterial infection and inflammation. Efficient mucociliary clearance relies on adequate hydration of the airway surface liquid (ASL). This is achieved through a balance between sodium absorption, mediated by the Epithelial Sodium Channel (ENaC), and chloride secretion via CFTR and calcium-activated chloride channels. In cystic fibrosis (CF), this ion transport equilibrium is impaired, leading to a reduced ASL height that favours chronic bacterial infection and persistent inflammation (1).
  • ASL airway surface liquid
  • CF lungs fail to clear bacteria and are more susceptible to infections.
  • Pseudomonas aeruginosa is a key CF pathogen and its early acquisition is predictive of an accelerated decline in lung function (2).
  • Impaired alveolar macrophage-mediated phagocytosis and bacterial killing have been reported in CF patients (3).
  • Recent studies in young children with CF have identified neutrophil elastase, as a key risk factor for the onset and early progression of CF lung disease (5) that could contribute to Na+ hyper absorption in CF airways by stimulating ENaC activity (6) and that neutrophil expression correlates with lung damage and did not depend on inflammatory status (7).
  • Cystic fibrosis is an autosomal recessive disease linked to mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) whose nature determines the clinical expression and severity of the disease, affecting mainly the respiratory, digestive and genital systems.
  • CFTR cystic fibrosis transmembrane conductance regulator gene
  • CFTR a chloride-ion channel
  • Dehydration of the surface liquid leads to altered muco-ciliary clearance, inflammation and infections at the mucosal epithelia.
  • CF is also characterized by a default of resolution of inflammation.
  • CFTR mutations that reduce CFTR protein function cause accumulation of thick, sticky mucus in the bronchi of the lungs, loss of exocrine pancreatic function, impaired intestinal secretion, and an increase in the concentration of chloride in the sweat (15).
  • lack of CFTR Cl(-) channel function leads to progressive pulmonary damage and ultimately to death.
  • Chronic lung disease is the major cause of mortality and morbidity in CF patients.
  • Patients with CF require numerous therapies to manage these symptoms (16), including mucolytic and antibiotic agents and chest physiotherapy to treat the airway disease and digestive enzymes to replace the loss of exocrine pancreatic function.
  • a CFTR potentiator (Ivacaftor, VX770) has been developed by Vertex Pharmaceuticals (Ramsey BW et al. N Engl J Med, 2011) and has been approved for the treatment of CF patients carrying the G551D mutation (2-5% of all patients). This drug has failed for CF patients with F508del.
  • CFTR correctors have been reported to be active in vitro (18).
  • a combination (Orkambi) of potentiator (Ivacaftor, VX770) and corrector (Lumacaftor, VX809) have been approved for the treatment of CF in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • the invention relates to resolvin D1 (RvDl) compound for use in the treatment of cystic fibrosis airways.
  • RvDl resolvin D1
  • Inventors have performed ex vivo studies on primary cultures of alveolar macrophages and bronchial epithelial cells from children with CF and in human bronchial epithelial cell lines. They have also performed in vivo studies in homozygous F508del-CFTR mice treated with vehicle control or RvDl (0.1-100 nM).
  • RvDl increased the CF ASL height in human bronchial epithelium and restored the nasal trans-epithelial potential difference in CF mice by decreasing the amiloride-sensitive Na+ absorption and stimulating CFTR-independent Cl- secretion.
  • RvDl 0.1 to lOOnM
  • RvDl was similar or even more potent than the combination of corrector and potentiator (Orkambi, VX809 10pm + VX770 10 pm) used to restore CFTR function on the same cell cultures.
  • RvDl decreased TNFa induced IL- 8 secretion by airway epithelial cells and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages.
  • RvDl resolves CF airway pathogenesis and has therapeutic potential in CF lung disease.
  • the invention relates to resolvin D1 (RvDl) compound for use in the treatment of cystic fibrosis airways.
  • the invention relates to a method for treating cystic fibrosis airways in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of resolving D1 (RvDl) compound.
  • the terms“treating” or“treatment” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • cystic fibrosis airways refers to an autosomal recessive disease linked to mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) whose nature determines the clinical expression and severity of the disease, affecting mainly the respiratory, digestive and genital systems.
  • CTR cystic fibrosis transmembrane conductance regulator gene
  • the lung disease is characterized by 1) abnormal salt and water transport in the airway epithelium, such that too much sodium and too little chloride crosses the epithelial membrane; 2) a defect in glutathione transport out of airway epithelial cells; 3) inspissated secretions and oxidant damage, in part related to salt, water, and glutathione transport abnormalities; 4) impaired ciliary motility associated with thick secretions; 5) chronic colonization with denitrifmg organisms such as Pseudomonas aeruginiosa and Aspergillus fumigatus; and 6) chronic bronchoconstriction associated with recruitment of neutrophils and other inflammatory cells and associated release of bronchoconstricting mediators and, as a result of all of these factors, chronic, progressively worsening, dyspnea.
  • the term“subject” refers to any mammals, such as a rodent, mice, pig, and a primate.
  • the subject is a human afflicted with or susceptible to be afflicted with cystic fibrosis airways.
  • the subject harbors a mutation in CFTR protein.
  • the subject have at least one of the 6 classes of CF mutations including most common mutation F508del-CFTR as well as more rare mutations with no therapeutic tools currently available (premature stop codon).
  • CFTR protein refers to the CFTR protein of 1480 amino acids also called Cystic Fibrosis Transmembrane Regulator.
  • the CFTR protein is a chloride (C1-) channel and is found in the membranes of intestinal and respiratory mucosa.
  • the CFTR protein is represented by the NCBI reference sequence: P13569.3 (SEQ ID NO: 1)
  • CFTR gene refers to the CFTR gene which is located on chromosome 7 and which may be found in NCBI GenBank locus ACOOOl 11 and AC000061, the contents of which are incorporated herein in their entirety by reference.
  • the cDNA for the CFTR gene is found in Audrezet et ak, Hum. Mutat. (2004) 23 (4), 343-357.
  • a nucleic acid sequence for human CFTR is represented by SEQ ID NO: 2.
  • the term "gene” has its general meaning in the art and refers to means a DNA sequence that codes for or corresponds to a particular sequence of amino acids which comprise all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed.
  • the“allele” has its general meaning in the art and refers to an alternative form of a gene (one member of a pair) that is located at a specific position on a specific chromosome which, when translated result in functional or dysfunctional (including non existent) gene products.
  • the term“mutation” has its general meaning in the art and refers to any detectable change in genetic material, e.g. DNA, RNA, cDNA, or any process, mechanism, or result of such a change.
  • This includes gene mutations, in which the structure (e.g. DNA sequence) of a gene is altered, any gene or DNA arising from any mutation process, and any expression product (e.g. protein or enzyme) expressed by a modified gene or DNA sequence. Mutations include deletion, insertion or substitution of one or more nucleotides. The mutation may occur in the coding region of a gene (i.e. in exons), in introns, or in the regulatory regions (e.g.
  • a mutation is identified in a subject by comparing the sequence of a nucleic acid or polypeptide expressed by said subject with the corresponding nucleic acid or polypeptide expressed in a control population. Where the mutation is within the gene coding sequence, the mutation may be a“missense” mutation, where it replaces one amino acid with another in the gene product, or a“non sense” mutation, where it replaces an amino acid codon with a stop codon. A mutation may also occur in a splicing site where it creates or destroys signals for exon-intron splicing and thereby lead to a gene product of altered structure.
  • a mutation in the genetic material may also be“silent”, i.e. the mutation does not result in an alteration of the amino acid sequence of the expression product.
  • mutations identified in CFTR gene or protein are designated pursuant to the nomenclature of Dunnen and Antonarakis (2000). For instance, “>” indicates a substitution at DNA level; (underscore) indicates a range of affected residues, separating the first and last residue affected; “del” indicates a deletion, “dup” indicates a duplication; “ins” indicates a insertion, “inv” indicates an inversion and “con” indicates a conversion. More particularly,“X” denotes that an amino acid is changed to a stop codon (X).
  • the term“homozygous” refers to an individual possessing two copies of the same allele.
  • the term“homozygous mutant” refers to an individual possessing two copies of the same allele, such allele being characterized as the mutant form of a gene.
  • heterozygous refers to an individual possessing two different alleles of the same gene, i.e. an individual possessing two different copies of an allele, such alleles are characterized as mutant forms of a gene.
  • the subject harbors at least one mutation in the CFTR gene.
  • the CFTR gene mutations were classified into six classes according to their resulting damaging effect on the protein. Class I encompasses frameshift, splicing, or nonsense mutations that introduce premature termination codons (PTC), resulting in severely reduced or absent CFTR expression (e.g. W1282X, 1717-1G->A, G542X, R553X, 2183 AA>G). Class II mutations lead to misfolding, premature degradation by the endoplasmic reticulum (ER) quality-control system, and impaired protein biogenesis, severely reducing the number of CFTR molecules that reach the cell surface (e.g. F508del, 2184delA).
  • ER endoplasmic reticulum
  • the gene product having mutations of class III is properly synthesized, transported and incorporated into the cell membrane, but has decreased activity caused by abnormal regulation of the protein. These mutations are frequently situated within one of the nucleotide binding domain (eg. G551D, R560T).
  • Class IV mutations alter the channel conductance by impeding the ion conduction pore, leading to a reduced unitary conductance (e.g. R117H, R334W).
  • Class V CFTR mutations do not change the conformation of the protein but alter its abundance by introducing promoter or splicing abnormalities (e.g. 2789+5G->A, A455E) (19).
  • Class VI mutations destabilize the channel in post-ER compartments and/or at the plasma membrane (PM), by reducing its conformational stability (20) and/or generating additional internalization signals (21). This results in accelerated plasma-membrane turnover and reduced apical CFTR expression (20-21). (e.g. c. 120dell23, rPhe580del).
  • CFTR mutations include, but are not limited to 124del23bp CFTR, CFTRdelel CFTR, Ml V CFTR, Q2X CFT, S4X CFTR, P5L CFTR, S13F CFTR, L15P CFTR, 182delT CFTR, CFTRdele2 CFTR, CFTRdele2-4 CFTR, 185+1G->T CFTR, CFTRdele2,3 CFTR, W19X CFTR, G27R CFTR, G27X CFTR, Q30X CFTR, R31C CFTR, R31L CFTR, Q39X CFTR, A46D CFTR, 296+lG->A CFTR, 296+lG->T CFTR, CFTRdele3-10,14b-16 CFTR, 296+28A->G CFTR, 296+2T->C CFTR, 296+3insT CFTR, 297-3
  • the subject harbors at least one allelic mutation selected from class
  • the subject harbors at least one mutation selected from class I, class
  • the subject harbors at least a mutation of class I in the first allele and at least a mutation of class II in the second allele. In a particular embodiment, the subject harbors at least a mutation of class II in the first allele and at least a mutation of class II in the second allele.
  • the subject harbors at least one allelic mutation in the CFTR gene including, but not limited to F508del-CFTR, R117H CFTR, 2184delA CFTR, W1282X CFTR, 2183AA>G CFTR or G551D CFTR.
  • the subject harbors at least a F508del mutation in the CFTR gene. In one embodiment, the subject harbors at least a 2183AA>G mutation in the CFTR gene. In one embodiment, the subject harbors at least a F508del mutation in the first allele and at least a 2183AA>G mutation in the second allele.
  • resolvin D1 compound refers to one of the potent lipid mediators derived from both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • Resolvin D1 (RvDl) is produced physiologically from the sequential oxygenation of DHA by 15- and 5 -lipoxygenase.
  • resolvins promote the resolution of the inflammatory response back to a non-inflamed state.
  • RvDl is able to have anti-inflammatory effects which are not immunosuppressive.
  • RvDl is able to stimulate the bacteria clearance by increasing airway surface liquid (ASL) and the alveolar macrophage-mediated phagocytosis activity.
  • ASL airway surface liquid
  • RvDl has the following structure (Formula I) and CAS number: 872993-05-0:
  • administering refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., resolving Dl) into the subject, such as by, intravenous, intramuscular, enteral, subcutaneous, parenteral, systemic, local, spinal, nasal, topical or epidermal administration (e.g., by injection or infusion).
  • a disease, or a symptom thereof is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease or symptoms thereof.
  • the RvDl compound is administered by nasal administration.
  • A“therapeutically effective amount” is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject.
  • a “therapeutically effective amount” to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the i) RvDl compound as described above and ii) a classical treatment as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.
  • administering refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., RvDl alone or in a combination with at least one classical treatment of CF airways) into the subject, such as by, intravenous, intramuscular, enteral, subcutaneous, parenteral, systemic, local, spinal, nasal, topical or epidermal administration (e.g., by injection or infusion).
  • administration of the substance typically occurs after the onset of the disease or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease or symptoms thereof.
  • the administration is performed by inhalation.
  • the term“administration simultaneously” refers to administration of 2 active ingredients by the same route and at the same time or at substantially the same time.
  • the term“administration separately” refers to an administration of 2 active ingredients at the same time or at substantially the same time by different routes.
  • administration sequentially refers to an administration of 2 active ingredients at different times, the administration route being identical or different.
  • the term“classical treatment” refers to the treatments used or will be used to treat cystic fibrosis airways.
  • the classical treatment includes, but is not limited to: antibiotics, aerosolized medications (e.g. dornase alfa, hypertonic saline, Denufosol), chest physiotherapy, expiratory pressure physiotherapy, anti-inflammatory compounds (Lenabasum also known as Corbus, Celtaxis), Lung transplantation, lumacaftor, ivacaftor, tezacaftor, elexacaftor or trikafta.
  • tezacaftor also called“l-(2,2-difluoro-2H-l,3-benzodioxol- 5-yl)-N- ⁇ l-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH- indol-5-yl ⁇ cyclopropane-l-carboxamide” has its general meaning in the art and refers to the compound characterized by the formula of:
  • RvDl compound as described above and ii) lumacaftor as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.
  • lumacaftor also called “3- ⁇ 6-[l-(2,2-difluoro-2H-l,3- benzodioxol-5-yl)cyclopropaneamido]-3-methylpyridin-2-yl ⁇ benzoic acid” or“VX809” has its general meaning in the art and refers to the compound characterized by the formula of:
  • ivacaftor also called“N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 4-oxo- l,4-dihydroquinoline-3 -carboxamide” or“VX770” has its general meaning in the art and refers to the compound characterized by the formula of: Formula IV
  • the combination of Lumacaftor/ivacaftor is already commercially available under the brand name Orkambi® in the form of 200 mg of /125 mg tablets (Lumacaftor/ivacaftor) for the treatment of cystic fibrosis.
  • RvDl compound as described above and ii) Orkambi® as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.
  • the i) RvDl compound as described above and ii) an anti- inflammatory compound as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.
  • the i) RvDl compound as described above and ii) Lenabasum as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.
  • Dibenzo(b,d)pyran-9-carboxylic acid, 3 -( 1 , 1 -dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro- 1 - hydroxy-6, 6-dimethyl-, (6aR,10aR)” is a candidate drug ongoing in phase 2 study.
  • Lenabasum has general meaning in the art and refers to the compound characterized by the formula of:
  • acebilustat developed by celaxis, also called“Benzoic acid, 4- (((1 S,4S)-5-((4-(4-(2-oxazolyl)phenoxy)phenyl)methyl)-2,5-diazabicyclo(2.2. l)hept-2- yl)methyl)-“ is a candidate drug ongoing in phase 2 study.
  • Acebilustat has its general meaning in the art and refers to the compound characterized by the formula of:
  • the term“elexacaftor” also called“N-[(l,3-dimethyl-lH-pyrazol-4- yl)sulfonyl]-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-lH-pyrazol-l-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3 -carboxamide” or“VX-445” has its general meaning in the art and refers to the compound characterized by the formula of:
  • the combination of elexacaftor/tezacaftor/ivacaftor is already commercially available under the brand name TrikaftaTM in the form of 100mg/50mg/75mg and
  • the invention in a second aspect, relates to a pharmaceutical composition for use in the treatment of cystic fibrosis.
  • resolvin D1 alone and/or with a classical treatment as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • pharmaceutically acceptable excipients such as biodegradable polymers
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual , buccal, and inhalation administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the resolving D1 compound can be formulated into a composition in a neutral or salt form.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the compound RvDl according to the invention wherein said compound is used by inhalation administration.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Resolvin D1 effects on airway surface liquid (ASL) height in polarised, differentiated CF Bronchial Epithelial Cells.
  • ASL height in pm was measured by live cell confocal fluorescence microscopy using Texas red®-dextran to stain the ASL.
  • (D) CF cells were treated with either vehicle control (Cont) or with BAPTA-AM (10 pM) (intracellular calcium chelator) for 20 min followed by RvDl (1 nM) for 30 min (**P ⁇ 0.01, ***P ⁇ 0.001, n 5, ANOVA).
  • FIG. 1 Effect of RvDl on nasal potential in WT and F508del-CFTR mice.
  • A Representative nasal potential (VTE) recordings obtained in F508del-CFTR mice. Amiloride (10 mM) and low Cl- solution were perfused at the time indicated on the graph.
  • C Effect of RvDl on the amiloride- sensitive nasal potential difference (AVTE amiloride) in F508del-CFTR and WT mice.
  • FIG. 4 Resolvin D1 effect on the phagocytic capacity and bacterial killing of primary alveolar macrophages from children with CF (CFAM).
  • B CFAM were treated with either vehicle control (Cont) or RvDl (100 nM) for 3h and then exposed to PAOl bacteria. After 30 min, the non-engulfed bacteria were removed and CFAM were treated with gentamicin to kill residual extracellular and membrane-bound bacteria.
  • Bronchoalveolar lavage fluid (B AL) and bronchial brushings were collected through the Study of Host Immunity and Early Lung Disease in CF (11). Studies were carried out in accordance with European community guidelines and approved by the Research Ethics Committee of Our Lady’s Children’s Hospital Crumlin (Dublin). Human airway epithelial cell culture
  • bronchial epithelial cells Primary cultures of bronchial epithelial cells were grown from bronchial brushings or biopsies obtained from 5 healthy donors and 6 children with CF (4 F508del-CFTR homozygous and 2 F508del-CFTR heterozygous (F508del/2789+5G>A and F508del/H199Y). The CF epithelia showed similar electrophysiological profiles in untreated conditions. Humna bronchial epithelial cell lines were also used; Non-CF NuLi-1 and CF (F508del homozygous) CuFi-1 (22). Epithelial cells were cultured on permeable supports under an air-liquid interface until reaching a high trans-eithelial electrical resistance, (TEER >700 W/ah2) (23).
  • TEER trans-eithelial electrical resistance
  • Texas red (2mg/ml, Invitrogen) was applied to the ASL of bronchial epithelial cells 24h prior imaging and Perfluorocarbon-72 (3M, St. Paul, USA) was added before acquisition to prevent evaporation.
  • the ASL images were captured with a Zeiss LSM 510 Meta microscope (40X) and analysed using Zeiss LSM Image Browser. Each biological repeat represents the mean of 27 ASL height measurements per culture insert.
  • Differentiated HBE cells were mounted in Ussing chambers and short-circuit-current SCC was measured under voltage clamp conditions and a Cl- gradient across the epithelium (see online Supplement).
  • the SCC decreased after amiloride (IOOmM) and increased after forskolin (IOmM) /IBMX (IOOmM) treatment.
  • IOOmM amiloride
  • IBMX IOOmM
  • the use of these drugs served as an indicator of SCC changes reflecting ENaC and CFTR activity, respectively.
  • Alveolar macrophages were isolated from the BAL of 3 CF female children ( ⁇ 6y, F508del homozygous), re-suspended in primary AM medium (online data), plated in 96 well plates and incubated (humidified, 37.2 °C, 21% oxygen, 5% C02) overnight. The following morning, non-adherent cells were aspirated and discarded. The adherent cells were washed twice with pre-warmed Ca2+ and Mg2+ free PBS. Alveolar Macrophage Phagocytosis Assay
  • the phagocytic capacity of Alveolar Macrophages was measured by their ability to engulf IgG & FITC labelled beads (Cayman Chemical, Ann Arbour, MI). Phagocytosis was quantified by the fluorescence intensity of engulfed FITC labelled complexes using a plate reader (Synergy MX Biotek Instruments, Winooski, VT).
  • Results are presented as mean and standard error of the mean (SEM).
  • SEM standard error of the mean
  • the non- parametric Wilcoxon-Mann-Whitney rank sum test was used when comparing two groups.
  • the one-way analysis of variance (ANOVA) was used in the cases of multiple comparisons.
  • Resolvin D1 restores ASL height in CF bronchial epithelial cells
  • ENaC activity contributes to the increased ASL height induced by Resolvin D1
  • the possible role of ENaC in causing an ASL height increase in response to RvDl was tested in CuFi-1 cells by either inhibiting or stimulating ENaC activity using amiloride or human neutrophil elastase, respectively (figure IB).
  • Resolvin D1 decreases TNFa-induced IL8 secretion via preservation of IKB
  • RvDl can modulate inflammatory responsiveness in CF airway epithelia.
  • Resolvin D1 restores nasal potential difference in CF and non-CF mice
  • VTE nasal transepithelial electrical potential difference
  • RvDl 10 nM
  • the phagocytic activity of CF (F508del) alveolar macrophages was measured after treatment with either vehicle control or RvDl (100 nM) and incubation with fluorescently latex beads. A greater proportion of alveolar macrophages treated with RvDl was observed to have engulfed labelled beads.
  • CF alveolar macrophages were pre treated with either vehicle control or RvDl (100 nM) and exposed to P. aeruginosa lab strain PAOl (2x1014 CFU/ml) for 3 h.
  • RvDl has multiple roles in reversing CF airway epithelial dysfunction by synergistically correcting abnormalities in airway epithelial ion transport and airway surface liquid dynamics; airway epithelial cell IL8 production; and bacterial killing capacities of CF alveolar macrophages. RvDl thus displays high therapeutic potential in CF lung disease.

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Abstract

La présente invention concerne le composé de résolvine D1 (RvD1) destiné à être utilisé dans le traitement de la mucoviscidose (CF). Les inventeurs ont effectué des études ex vivo sur des cultures primaires de macrophages alvéolaires et de cellules épithéliales bronchiques d'enfants atteints de CF et dans des lignées cellulaires épithéliales bronchiques humaines. Ils ont également effectué des études in vivo chez des souris homozygotes F508del-CFTR traitées avec un témoin véhicule ou RvD1 (1 à 100 nM). Ils ont démontré que RvD1 augmente la hauteur de l'ASL CF dans l'épithélium bronchique humain et restaure la différence de potentiel trans-épithélial nasal chez des souris CF par diminution de l'absorption de Na+ sensible à l'amiloride et à la stimulation de la sécrétion de Cl- indépendante de CFTR. Ils ont observé que RvD1 réduit la sécrétion d'IL-8 induite par le TNFα et améliore la capacité phagocytaire et la capacité de destruction bactérienne des macrophages alvéolaires CF humains. Ainsi, RvD1 résout la pathogenèse des voies respiratoires CF et présente un potentiel thérapeutique dans la maladie pulmonaire CF.
PCT/EP2019/083869 2018-12-06 2019-12-05 Méthodes et compositions destinées au traitement des voies respiratoires atteintes de mucoviscidose WO2020115231A1 (fr)

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CN114010627A (zh) * 2021-10-15 2022-02-08 武汉大学 专门促消退介质的药物新用途
WO2022228577A1 (fr) * 2021-04-30 2022-11-03 中国海洋大学 Nouveau dérivé de benzotropone, son procédé de préparation et son utilisation
WO2023237626A1 (fr) * 2022-06-07 2023-12-14 Institut National de la Santé et de la Recherche Médicale Composés médiateurs lipidiques pro-résolution spécialisés (spm) destinés à être utilisés dans le traitement de la fibrose kystique et d'une infection par aspergillus fumigatus chez un patient souffrant de fibrose kystique

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022228577A1 (fr) * 2021-04-30 2022-11-03 中国海洋大学 Nouveau dérivé de benzotropone, son procédé de préparation et son utilisation
CN114010627A (zh) * 2021-10-15 2022-02-08 武汉大学 专门促消退介质的药物新用途
WO2023237626A1 (fr) * 2022-06-07 2023-12-14 Institut National de la Santé et de la Recherche Médicale Composés médiateurs lipidiques pro-résolution spécialisés (spm) destinés à être utilisés dans le traitement de la fibrose kystique et d'une infection par aspergillus fumigatus chez un patient souffrant de fibrose kystique

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