WO2022226495A1 - Méthodes de traitement d'un traumatisme médullaire - Google Patents

Méthodes de traitement d'un traumatisme médullaire Download PDF

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Publication number
WO2022226495A1
WO2022226495A1 PCT/US2022/071800 US2022071800W WO2022226495A1 WO 2022226495 A1 WO2022226495 A1 WO 2022226495A1 US 2022071800 W US2022071800 W US 2022071800W WO 2022226495 A1 WO2022226495 A1 WO 2022226495A1
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Prior art keywords
dapansutrile
sci
spinal cord
recovery
improvement
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PCT/US2022/071800
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English (en)
Inventor
Charles A. Dinarello
Jesus AMO-APARICIO
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Olatec Therapeutics Llc
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Publication of WO2022226495A1 publication Critical patent/WO2022226495A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K31/275—Nitriles; Isonitriles

Definitions

  • the present invention relates to dapansutrile, or its pharmaceutically acceptable solvates, for treating spinal cord injury.
  • the nervous system is divided into two parts: the central nervous system (CNS), which includes the brain and the spinal cord, and the peripheral nervous system, which includes nerves and ganglions outside of the brain and the spinal cord. While the peripheral nervous system is capable of repair and regeneration, the central nervous system is unable to self-repair and regenerate.
  • CNS central nervous system
  • peripheral nervous system While the peripheral nervous system is capable of repair and regeneration, the central nervous system is unable to self-repair and regenerate.
  • traumatic injuries to the CNS such as traumatic brain injury and spinal cord injury (SCI) affect over 90,000 people each year. These traumatic insults to the CNS cause axonal loss, disrupt neuronal connections, and ultimately result in permanent blindness, paralysis, and other losses in cognitive, motor, and sensory functions.
  • SCI spinal cord injury
  • SCI leads to the loss of motor, sensory, and autonomic functions below the lesion site.
  • SCI being one of the main causes of death and disability, there is currently no effective treatment.
  • Neurological deficits after SCI are due to the immediate neural damage produced by the injury itself but also to a secondary phase of tissue degeneration that occurs over several weeks after initial trauma.
  • Various events are involved in triggering secondary damage following SCI, such as ischemia, excitotoxicity, necrosis, apoptosis, and inflammation, among others.
  • the inflammatory response elicited after neurotrauma is thought to be one of the main contributors to secondary tissue damage [1] Therefore, suppressing inflammation could be a clinically beneficial approach to minimize functional impairments after acute SCI.
  • IL-1- based therapies from other agents is the lack of opportunistic infections.
  • IL1 blocking biologies increase the risk of routine bacterial infection, these easily treated with antibiotics; opportunistic infections are rare with IL1 blockers [6]
  • FIGs. 2A-2D Effects of dapansutrile in the functional recovery and tissue preservation after SCI.
  • (2C) Myelin sparing in the lesion area of mice treated with 60 mg/kg twice a day (middle curve) or 200 mg/kg once a day (top curve) of dapansutrile for 7 days after SCI. Control mice were treated with saline (bottom curve).
  • Two-way RM- ANOVA with Bonferroni’s post hoc correction was used to analyze differences between groups in (2A).
  • Chi-square test to compare proportions in (2B).
  • Multiple t-test comparisons with Holm- Sidak’s post hoc were used to analyze significant differences between groups in (2C).
  • FIGs. 3A-3B Assessment of neurons and astrocytes after treatment with dapansutrile.
  • FIGs. 4A-4C Effects of dapansutrile (OLT1177 ® ) on NLRP3 activation in the spinal cord at 24 h post-injury.
  • 4A Representative immunoblotting showing NLRP3, pro-IL-Ib, ASC, andcaspase-1. Molecular weight (KDa) of each protein is marked on the left side b-acting was used as loading control.
  • 4B Graphs showing the quantification of NLRP3, pro-IL-Ib, ASC, and caspase-1 in mice treated with saline or dapansutrile (200 mg/kg) after SCI.
  • FIGs. 5A-5E Effects of dapansutrile (OLT1177 ® ) in myeloid cell accumulation in the spinal cord after contusion injury.
  • 5A-5C Number of macrophages, microglia, and neutrophils in the spinal cord of mice treated with daily administration of dapansutrile (200mg/kg) or saline at 1 (A), 3 (B), and 5 (C) days after lesion.
  • 5D, 5E Representative density plots of flow cytometry analysis showing microglia, macrophages, and neutrophils in the spinal cord at 3 days (D) and 5 days (E) days post-injury. Cell numbers are included in parenthesis.
  • SCI Spinal cord injury
  • the present invention is directed to a method of treating SCI.
  • the method comprises administering to a subject suffering from SCI an effective amount of a compound of 3- methanesulfonylpropionitrile (dapansutrile), or a pharmaceutically acceptable solvate thereof, to treat SCI.
  • Dapansutrile is a b-sulfonyl nitrile synthetic compound of 140 KDa that selectively inhibits NLRP3 inflammasome [7] Dapansutrile is safe for use in humans.
  • Solvates are addition complexes in which the compound is combined with an acceptable co-solvent in some fixed proportion.
  • Co-solvents include, but are not limited to, water, acetic acid, ethanol, and other appropriate organic solvents.
  • An effective amount is an amount effective to treat SCI by ameliorating the symptoms of SCI.
  • Spinal cord injury may result in death or impairment of cells, e.g., neurons and associated loss of function. Death or impairment of cells can negatively impact recovery. For example, neurodegeneration may reduce the potential for recovery of neuronal functions following spinal cord injury. Cells impacted by spinal cord injury may undergo immediate death or impairment or, alternatively, delayed death or impairment.
  • Outcomes of spinal cord injury include the impairment or death of cells, e.g. neurons (neurodegeneration). Aspects of neurodegeneration may include decreased neuronal survival, decreased axon sparing, and/or decreased axon growth. Neurodegeneration may limit functional recovery following spinal cord injury or inhibit other post-injury neuronal activities, such as neuronal (e.g., axonal) growth, neuronal (e.g. axonal) regeneration (e.g. axonal sprouting), or neuronal repair.
  • neuronal e.g., axonal
  • axonal regeneration e.g. axonal sprouting
  • neuronal repair e.g. axonal sprouting
  • the present invention targets the NLRP3 inflammasome with dapansutrile to arrest neuroinflammation and reduce functional impairments after acute SCI in humans.
  • the present method treats SCI by improving or ameliorating one or more post SCI symptoms as described above.
  • the present method decreases cellular impairment or cell death (e.g., neurodegeneration), improves functional recovery, and/or improves post-injury neuronal activities. In one embodiment, the present method promotes nerve function following injury to a CNS neuron.
  • cellular impairment or cell death e.g., neurodegeneration
  • the present method promotes nerve function following injury to a CNS neuron.
  • the present method provides a method for preserving neuron viability and/or promoting axon regeneration and nerve function in a subject affected with SCI.
  • the present method protects against neurological deficits, myelin degeneration, and myelin loss.
  • the present method ameliorates inflammation after SCI and leads to beneficial effects on functional and histopathological outcomes after SCI.
  • the present method results in one or more responses selected from the group consisting of improved neuronal survival, improved neuronal regeneration, improvement/recovery of motor function, improvement/recovery of fine motor coordination, improvement/recovery from muscle spasticity, improvement/recovery from paresis or paralysis of one or both sides, reduction in severity and/or number of seizure disorders, improvement/recovery of balance, improvement/recovery of gait, improvement/recovery of sensory function, ameliorate impairment of sensation, and ameliorate impairment of motor function.
  • the present invention provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and an active compound of dapansutrile, or a pharmaceutically acceptable solvate thereof.
  • the active compound or its pharmaceutically acceptable solvate in the pharmaceutical compositions in general is in an amount of about 0.01- 20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, or 0.5-10%, or 1-5% (w/w), for a topical formulation; about 0.1-5% for an injectable formulation, 0.1-5% for a patch formulation, about 1-90% for a tablet formulation, and 1-100% for a capsule formulation.
  • the active compound used in the pharmaceutical composition in general is at least 90%, preferably 95%, or 98%, or 99% (w/w) pure.
  • the pharmaceutical composition is in a dosage form such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injectable solutions, patches, or the like.
  • the pharmaceutical composition is in the form of an aerosol suspension of respirable particles comprising the active compound, which the subject inhales.
  • the respirable particles can be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation. In general, particles having a size of about 1 to 10 microns, preferably 1-5 microns, are considered respirable.
  • the respirable particles including dapansutrile can be prepared into dry powder using well-known art of super critical fluid technology. In such a case, the compound is admixed with appropriate excipients and milled into a homogenous mass using suitable solvents or adjuvants. Following this, this mass is subjected to mixing using super critical fluid technology and suitable particle size distribution achieved.
  • the particles in the formulation need to be within a desired particle size range such that the particles can be directly inhaled into the lungs using a suitable inhalation technique or introduced into the lungs via a mechanical ventilator.
  • the active compound is incorporated into an acceptable carrier, including creams, gels, lotions or other types of suspensions that can stabilize the active compound and deliver it to the affected area by topical applications.
  • an acceptable carrier including creams, gels, lotions or other types of suspensions that can stabilize the active compound and deliver it to the affected area by topical applications.
  • the above pharmaceutical composition can be prepared by conventional methods.
  • Pharmaceutically acceptable carriers which are inactive ingredients, can be selected by those skilled in the art using conventional criteria.
  • Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous based solutions, suspensions, emulsions, microemulsions, micellar solutions, gels, and ointments.
  • the pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxy toluene, tocopherols, and ascorbyl palmitate; surfactants such as lecithin, phospholipids, including but not limited to phosphatidylcholine, phosphatidylethanolamine and phosphatidyl inositiol; poloxa
  • Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, these include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.
  • preservatives include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.
  • a tablet formulation or a capsule formulation of the active compound may contain other excipients that have no bioactivity and no reaction with the active compound.
  • Excipients of a tablet may include fillers, binders, lubricants and glidants, disintegrators, wetting agents, and release rate modifiers.
  • Binders promote the adhesion of particles of the formulation and are important for a tablet formulation. Examples of binders include, but not limited to, carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, karaya gum, starch, starch, and tragacanth gum, poly(acrylic acid), and polyvinylpyrrolidone.
  • a patch formulation of the active compound may comprise some inactive ingredients such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D- sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, povidone (polyvinylpyrrolidone), propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water.
  • a patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate) or di ethylene glycol monoethyl ether.
  • Topical formulations including the active compound can be in a form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension.
  • the inactive ingredients in the topical formulations for example include, but not limited to, lauryl lactate (emollient/permeation enhancer), diethylene glycol monoethyl ether (emollient/permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology/texture modifier), caprylic/capric triglyceride, (emollient), octisalate, (emollient/ETV filter), silicone fluid (emollient/diluent), squalene (emollient), sunflower oil (emollient), and silicone dioxide (thickening agent).
  • lauryl lactate emollient/permeation enhancer
  • diethylene glycol monoethyl ether emollient/permeation enhancer
  • DMSO so
  • the present invention is directed to a method of treating SCI.
  • the method comprises the steps of first identifying a subject suffering from SCI, and administering to the subject the active compound dapansutrile, in an amount effective to treat SCI.
  • Dapansutrile is small and penetrates the CNS rapidly for reducing the local inflammation.
  • the inventors have shown that NLRP3 is activated after spinal cord injury and that dapansutrile can inhibit NLRP3 activation in the contused spinal cord in an animal model. Dapansutrile ameliorates inflammation after SCI and leads to beneficial effects on functional and histopathological outcomes after SCI.
  • dapansutrile is able to promote significant protections against myelin loss at more distant regions from the injury epicenter. Dapansutrile leads to significant enhancement in myelin preservation at the injury epicenter and at some rostral and caudal regions.
  • the inventors have shown that dapansutrile protects against neurological deficits, myelin degeneration, and neuronal loss in a lower extent after SCI in mice.
  • dapansutrile reduces the infiltration of neutrophils and monocytes.
  • This mechanism of dapansutrile’ s efficacy is highly relevant to SCI because early infiltration of neutrophils and monocytes into the lesioned area of the spinal cord significantly contributes to secondary damage and locomotor impairments.
  • Dapansutrile is small and penetrates the CNS rapidly for reducing the local inflammation. There is no blood brain barrier that limits its penetration into the CNS.
  • the pharmaceutical composition of the present invention can be applied by systemic administration and local administration.
  • Systemic administration includes oral, parenteral (such as intravenous, intramuscular, subcutaneous or rectal), and other systemic routes of administration.
  • systemic administration the active compound first reaches plasma and then distributes into target tissues.
  • Local administration includes topical administration.
  • Dosing of the composition can vary based on the extent of the disease and each patient’s individual response.
  • plasma concentrations of the active compound delivered can vary; but are generally 0.1-1000 pg/mL or 1-100 pg/mL.
  • the pharmaceutical composition is administrated orally to the subject.
  • the dosage for oral administration is generally at least 1 mg/kg/day and less than 100 mg/kg/day.
  • the dosage for oral administration is 1-100, or 5-50, or 10-50 mg/kg/day, for a human subject.
  • the dosage for oral administration is 100- 10,000 mg/day, and preferably 200-1000, 200-2000, 500-2000, 500-4000, 500-4000, 1000- 5000, 2000-5000, 2000-6000, or 2000-8000 mg/day for a human subject.
  • the drug can be orally taken once, twice, three times, or four times a day.
  • the patient is treated daily for 7- 14 days, up to 1 month, 2 months, or 3 months, or for lifespan.
  • the pharmaceutical composition is administrated intravenously to the subject.
  • the dosage for intravenous bolus injection or intravenous infusion is generally 0.03 to 20 or 0.03 to 10 mg/kg/day.
  • the pharmaceutical composition is administrated subcutaneously to the subject.
  • the dosage for subcutaneous administration is generally 0.3-20 or 0.3-3 mg/kg/day.
  • the present invention may be used in combination with one or more other treatments that treat SCI.
  • the present invention is useful in treating a mammal subject or a mammal patient.
  • the present invention is particularly useful in treating humans.
  • a “subject” and a “patient” are used interchangeably in the application.
  • Dapansutrile (OLT1177 ® ; Olatec Therapeutics LLC) diluted in sterile saline solution was injected intraperitoneally once a day, starting 1 hour after lesion, for seven days. Two different administration protocols were used: (i) 60 mg/kg twice a day, and (ii) 200 mg/kg once a day. Control mice were treated with sterile saline solution using the same administration protocol.
  • BMS Basso Mouse Scale
  • mice were perfused with 4% paraformaldehyde (Sigma- Aldrich) in 0.1 M phosphate buffer.
  • Flow cytometry from spinal cord was performed according to described protocol [28] At 1, 3, and 5 days after injury, animals received an intraperitoneal injection of sodium pentobarbital (Dolethal). Blood was removed by perfusion with 60 mL of 0.9% NaCl and a piece of 6 mm of the spinal cord, centered into the injury site, was taken from each mouse. Cell suspensions of the spinal cord were obtained by enzymatic disaggregation using a mixture of collagenase (Sigma- Aldrich) and DNase (Roche) and mechanic disaggregation followed by passage through 70-pm cell strainers (Fisher).
  • Cells were labeled with the following antibodies: CD45- PerCP (eBioscience), CDllb-PE-Cy7 (eBioscience), and F4/80- PE (eBioscience). 1:200 dilutions were used for each antibody. Proper isotypes for each antibody were used.
  • mice were fixed with 1% paraformaldehyde (Sigma- Aldrich) in 0.1 M of phosphate buffer and analyzed using the FACSCanto flow cytometer (BD Bioscience). Cell gating and quantification were performed using FlowJo ® software. Microglia cells were defined as CD451ow and CD1 lb+, whereas macrophages were defined as CD45high, CDllb+, and F4/80+. Granulocytes, mainly neutrophils, were defined as CD45high, CDllb+, and F4/80- [28,30] 4 mice per group were used.
  • BMS scores show the locomotor progression of mice receiving 60 mg/kg twice a day (middle curve) or 200mg/kg once a day (top curve) of dapansutrile (OLT1177 ® ) for 7 days after SCI.
  • Control mice were treated with saline (bottom curve).
  • the results show that mice treated with 60 mg/kg of dapansutrile twice a day for 7 days had an improved functional recovery, although statistical differences against saline group were not observed (FIG. 2A).
  • Mice treated with 200 mg/kg of dapansutrile once a day for 7 days showed a significant enhancement in the functional performance in comparison with mice treated with saline.
  • FIG. 2B shows functional distribution of different groups at 28dpi.
  • the 73% of the mice treated with saline showed hindlimb plantar placement, meaning that they were able to place the full feet on the ground, but in which only the 6% showed occasional stepping (FIG. 2B).
  • the animals treated with the 60 mg/kg dose of dapansutrile all of them showed hindlimb plantar placement and 50% of them also showed hindlimb plantar stepping, being occasional (42%) or frequent (8%).
  • mice treated with 200 mg/kg of dapansutrile showed hindlimb plantar placement and 75% of them were able to perform occasional (37.5%) or frequent (37.5%) hindlimb plantar stepping (FIG. 2B).
  • the results are summarized in Table 1. Chi-square test verified that functional proportions were significantly determined by the group.
  • mice Per cent of mice after saline treatment or dapansutrile treatment
  • FIG. 2C shows myelin sparing in the lesion area of mice treated with 60mg/kg twice a day (green) or 200mg/kg once a day (top curve) of dapansutrile for 7 days after SCI. Control mice were treated with saline (bottom curve).
  • FIG. 2D shows the representative micrograph of each group; the myelinated are at the injury epicenter. The results show that spinal cord cross sections stained for LFB revealed that These findings indicate that NLRP3 is activated after spinal cord injury. Differences were evident from 300 pm rostral to 150 pm caudal sections from the lesion core (FIGs. 2C and 2D). However, the 200 mg/kg dose, but not 60 mg/kg dose of dapansutrile, was also able to promote significant protections against myelin loss at more distant regions from the injury epicenter (FIGs. 2C and 2D).
  • FIGs. 3A-3B show the assessment of neurons and astrocytes after treatment with dapansutrile.
  • dapansutrile increased number of NeuN+ cells at ventral horns at rostral and caudal regions from the injury epicenter.
  • Significant differences against saline-treated mice were only found at sections located at 750 pm rostral (R) and 600 pm caudal (C) to the lesion core (FIG. 3A).
  • No significant differences in the GFAP signal were found after dapansutrile treatment, however, this drug tended to increase astrocyte immunoreactivity at the lesion epicenter and adjacent sections (FIG. 3B).
  • Dapansutrile also appeared to reduce the number microglia and neutrophils at 5 days after injury, but these differences were not significant. Together these results demonstrate that dapansutrile ameliorates inflammation after SCI and leads to beneficial effects on functional and histopathological outcomes after SCI.

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Abstract

La présente invention a pour objet une méthode de traitement d'un traumatisme médullaire. La méthode comprend l'administration à un sujet dont l'état le nécessite, de 3-méthanesulfonylpropionitrile (dapansutrile), ou d'un solvate de ce dernier pharmaceutiquement acceptable, en quantité efficace. De préférence, l'administration se fait par voie orale.
PCT/US2022/071800 2021-04-22 2022-04-19 Méthodes de traitement d'un traumatisme médullaire WO2022226495A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200237706A1 (en) * 2010-12-15 2020-07-30 Olatec Therapeutics Llc 3-methanesulfonylpropionitrile for treating inflammation and/or pain

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200237706A1 (en) * 2010-12-15 2020-07-30 Olatec Therapeutics Llc 3-methanesulfonylpropionitrile for treating inflammation and/or pain

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMO-APARICIO JESUS, GARCIA-GARCIA JOANA, PUIGDOMENECH MARIA, FRANCOS-QUIJORNA ISAAC, SKOURAS DAMARIS B., DINARELLO CHARLES A., LOP: "Inhibition of the NLRP3 inflammasome by OLT1177 induces functional protection and myelin preservation after spinal cord injury", EXPERIMENTAL NEUROLOGY, vol. 347, January 2022 (2022-01-01), pages 1 - 10, XP086884524, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/articie/abs/pii/S0014488621002971> [retrieved on 20220526] *
APARICIO JESÚS AMO: "Modulation of the inflammatory response after spinal cord injury", PH.D., ACADEMIC DISSERTATION, 2019, pages 1 - 11, 88-101, XP055983151, Retrieved from the Internet <URL:https://www.tdx.cat/bitstream/handie/10803/668008/jaa1de1.pdf?sequence=5.xmt> [retrieved on 20220525] *
SÁNCHEZ-FERNÁNDEZ ALBA, SKOURAS DAMARIS B., DINARELLO CHARLES A., LÓPEZ-VALES RUBÈN: "OLT1177 (Dapansutrile), a selective NLRP3 inflammasome inhibitor, ameliorates experimental autoimmune encephalomyelitis pathogenesis", FRONTIERS IN IMMUNOLOGY, vol. 10, 1 November 2019 (2019-11-01), pages 1 - 10, XP055983152, Retrieved from the Internet <URL:https://www.frontiersin.org/articles/10.3389/fimmu.2019.02578/full> [retrieved on 20220523] *

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