[go: up one dir, main page]

WO2024108269A1 - Compositions neuroprotectrices et procédés - Google Patents

Compositions neuroprotectrices et procédés Download PDF

Info

Publication number
WO2024108269A1
WO2024108269A1 PCT/AU2023/051207 AU2023051207W WO2024108269A1 WO 2024108269 A1 WO2024108269 A1 WO 2024108269A1 AU 2023051207 W AU2023051207 W AU 2023051207W WO 2024108269 A1 WO2024108269 A1 WO 2024108269A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
emtinb
pharmaceutically acceptable
variant
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2023/051207
Other languages
English (en)
Inventor
Paul Rennie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NeuroScientific Biopharmaceuticals Ltd
Original Assignee
NeuroScientific Biopharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2022903564A external-priority patent/AU2022903564A0/en
Application filed by NeuroScientific Biopharmaceuticals Ltd filed Critical NeuroScientific Biopharmaceuticals Ltd
Publication of WO2024108269A1 publication Critical patent/WO2024108269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure is in the field of peptide compounds that promote neuronal survival, neurite growth, and myelin formation, pharmaceutical compositions comprising said peptide compounds, and uses thereof for treatment of diseases and conditions where the effects of promoting neural cell proliferation, differentiation and/or survival, and/or promoting neurite growth, and/or promoting myelin formation, are beneficial for treatment, such as neurodegenerative and demyelinating diseases, and other diseases of the central and peripheral nervous system.
  • Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease and Multiple Sclerosis are characterized by the deterioration and loss of neurons as a result of disease, hereditary conditions, or injury, such as traumatic or ischemic spinal cord or brain injury. Therapies that are based on neuronal protection, repair, or regeneration could therefore be effective across neurodegenerative diseases.
  • Myelin sheath of nerve fibers in the central nervous system (CNS) is an insulating material, which protects neuronal cells and enables the saltatory conduction that speeds axonal electric impulse.
  • oligodendrocyte progenitor cells migrate, proliferate, and differentiate into newly formed oligodendrocytes, then those oligodendrocytes (OL) selected by target-dependent survival mechanisms wrap myelin membrane around the axons to form the sheath.
  • OPCs oligodendrocyte progenitor cells
  • OL oligodendrocytes
  • target-dependent survival mechanisms wrap myelin membrane around the axons to form the sheath.
  • Each oligodendrocyte can myelinate many axons, with the number of wraps proportional to the axon diameter and regulated tightly by reciprocal signaling between oligodendrocyte and axons.
  • MS Multiple Sclerosis
  • CNS chronic inflammatory disease of the CNS which typically occurs at young adults, more prevalent in women than in men.
  • MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other and control body functions. The clinical disability is linked to an inflammation of myelin, the protective sheath around the axons of the CNS, which is damaged due to an autoimmune attack and neurodegenerative processes.
  • MS is characterized by significant inflammation, demyelination, neuroglial damage, and neuronal cell death. As a consequence, the white matter of the brain and spinal cord becomes scarred by focal lesions (plaques) leading to neurological dysfunction.
  • RRMS relapsing-remitting
  • PMS focal lesions
  • SPMS secondary progressive MS
  • SPMS progressive course from the onset of symptoms, and such disease pattern is classified as primary progressive MS (PPMS).
  • Patients with relapsing-remitting MS are typically treated with corticosteroids during acute attacks (relapses), and with immunomodulatory- or immunosuppressive drugs to prevent new relapses and progression of disability.
  • immunomodulatory- or immunosuppressive drugs include interferon beta (Avonex®, Rebif®, Betaseron®), glatiramer acetate (Copaxone®), dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®) natalizumab (Tysabri®) and the chemotherapeutic agent mitoxantrone in more severe cases. It is proposed that some of these agents work by suppressing the activity of immune cells that wrongly attack myelin.
  • the present disclosure generally relates to compositions and methods for enhancing neuronal survival, neurite growth, and myelin formation, as well as to methods for the treatment of disease or disorders in subjects where stimulating neuronal survival, neurite growth, myelination or remyelination is beneficial to the subject.
  • the present inventors have surprisingly found that a combination of EmtinB (SAGSCKCKESKSTS) or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof as active therapeutic agents provides an unexpected effect in promoting neuronal survival, neurite growth, and myelin formation.
  • a pharmaceutical composition comprising EmtinB (SAGSCKCKESKSTS) or a variant thereof, wherein the composition is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 10 mg/mL to 700 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 10 mg/mL to 70 mg/mL, from 70 mg/mL to 150 mg/mL, from 150 mg/mL to 230 mg/mL, from 230 mg/mL to 300 mg/mL, from 300 mg/mL to 380 mg/mL, from 380 mg/mL to 450 mg/mL, from 450 mg/mL to 600 mg/mL, or from 600 mg/mL to 700 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 340 mg/mL to 680 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is about 340 mg/mL or about 680 mg/mL.
  • a pharmaceutical composition comprising glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, wherein the composition is formulated to be co-administered with EmtinB (SAGSCKCKESKSTS) or a variant thereof.
  • SAGSCKCKESKSTS EmtinB
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 40 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 20 mg/mL to 40 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 5 mg/mL, from 5 mg/mL to 10 mg/mL, from 10 mg/mL to 15 mg/mL, from 15 mg/mL to 20 mg/mL, from 20 mg/mL to 25 mg/mL, from 25 mg/mL to 30 mg/mL, or from 35 mg/mL to 40 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 10 mg/mL or from 10 mg/mL to 20 mg/mL. [21] In some embodiments, the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 6 mg/mL or about 12 mg/mL. [22] In some embodiments of the first and second aspects, the pharmaceutical composition is formulated for subcutaneous injection. [23] In some embodiments, the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are formulated as separate compositions.
  • the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are formulated to be administered in a sequential manner or in a substantially simultaneous manner.
  • the pharmaceutical composition further comprises or is further formulated to be co-administered with any one or more of the following: L- dopa, a cholinesterase inhibitor, an anticholinergic, a dopamine agonist, a steroid, or an immunomodulator such as an interferon or a monoclonal antibody.
  • the pharmaceutical composition further comprises or is further formulated to be co-administered with a steroid.
  • the steroid is ⁇ -estradiol.
  • a pharmaceutical composition comprising EmtinB (SAGSCKCKESKSTS) or a variant thereof, and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is formulated for subcutaneous injection.
  • the pharmaceutical composition further comprises L- dopa, a cholinesterase inhibitor, an anticholinergic, a dopamine agonist, a steroid, or an immunomodulator such as an interferon or a monoclonal antibody.
  • the pharmaceutical composition further comprises a steroid.
  • the steroid is ⁇ -estradiol.
  • the pharmaceutical composition further comprises mannitol.
  • the pharmaceutical composition has a pH in the range of 5.5 to 8.5, or in the range of 5.5 to 7.0.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 10 mg/mL to 700 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 10 mg/mL to 70 mg/mL, from 70 mg/mL to 150 mg/mL, from 150 mg/mL to 230 mg/mL, from 230 mg/mL to 300 mg/mL, from 300 mg/mL to 380 mg/mL, from 380 mg/mL to 450 mg/mL, from 450 mg/mL to 600 mg/mL, or from 600 mg/mL to 700 mg/mL. [33] In some embodiments, the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is in the range of from 340 mg/mL to 680 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition is about 340 mg/mL or about 680 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 40 mg/mL. In some embodiments, the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 20 mg/mL to 40 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 5 mg/mL, from 5 mg/mL to 10 mg/mL, from 10 mg/mL to 15 mg/mL, from 15 mg/mL to 20 mg/mL, from 20 mg/mL to 25 mg/mL, from 25 mg/mL to 30 mg/mL, or from 35 mg/mL to 40 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of from 1 mg/mL to 10 mg/mL or from 10 mg/mL to 20 mg/mL.
  • the concentration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 6 mg/mL or about 12 mg/mL.
  • the EmtinB or a variant thereof is present in an amount effective to provide a concentration of from 10 ⁇ g/mL to 200 ⁇ g/mL of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in an amount effective to provide a concentration of from 10 ⁇ g/mL to 20 ⁇ g/mL, from 20 ⁇ g/mL to 30 ⁇ g/mL, from 30 ⁇ g/mL to 40 ⁇ g/mL, from 40 ⁇ g/mL to 50 ⁇ g/mL, from 50 ⁇ g/mL to 60 ⁇ g/mL, from 60 ⁇ g/mL to 70 ⁇ g/mL, from 70 ⁇ g/mL to 80 ⁇ g/mL, from 80 ⁇ g/mL to 90 ⁇ g/mL, from 90 ⁇ g/mL to 100 ⁇ g/mL, from 100 ⁇ g/mL to 110 ⁇ g/mL, from 110 ⁇ g/mL to 120 ⁇ g/mL, from 120 ⁇ g/mL to 130 ⁇ g/mL, from 130 ⁇ g/mL to 140 ⁇ g/mL, from 140 ⁇ g/mL, from 140
  • the EmtinB or a variant thereof is present in an amount effective to provide a concentration of from 50 ⁇ g/mL to 150 ⁇ g/mL of EmtinB or a variant thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in an amount effective to provide a concentration of from 1 ⁇ g/mL to 20 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in an amount effective to provide a concentration of from 1 ⁇ g/mL to 15 ⁇ g/mL, from 2 ⁇ g/mL to 14 ⁇ g/mL, from 2 ⁇ g/mL to 13 ⁇ g/mL, from 2 ⁇ g/mL to 12 ⁇ g/mL, from 2 ⁇ g/mL to 11 ⁇ g/mL, from 2 ⁇ g/mL to 10 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in an amount effective to provide a concentration of about 1 ⁇ g/mL, about 2 ⁇ g/mL, about 3 ⁇ g/mL, about 4 ⁇ g/mL, about 5 ⁇ g/mL, about 6 ⁇ g/mL, about 7 ⁇ g/mL, about 8 ⁇ g/mL, about 9 ⁇ g/mL, or about 10 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • a method of treating and/or preventing a neurodegenerative disease or disorder in a subject in need thereof comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of treating and/or preventing a neurodegenerative disease or disorder in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a neurodegenerative disease or disorder, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a neurodegenerative disease or disorder, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof there is also provided a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment and/or prevention of a neurodegenerative disease or disorder.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a neurodegenerative disease or disorder, wherein the treatment and/or prevention comprises co-administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the neurodegenerative disease or disorder is a demyelinating disease.
  • the demyelinating disease is multiple sclerosis.
  • the multiple sclerosis is a relapsing form of multiple sclerosis.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or Huntington's disease. In some embodiments, the neurodegenerative disease is Alzheimer's disease.
  • a method of treating and/or preventing a condition or disease of the central or peripheral nervous system in a subject in need thereof comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of treating and/or preventing a condition or disease of the central or peripheral nervous system in a subject in need thereof the method comprising administering to the subject the pharmaceutical composition of the third aspect.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease of the central or peripheral nervous system, wherein the medicament is formulated to be co- administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease of the central or peripheral nervous system, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof there is also provided a use of a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment and/or prevention of a condition or disease of the central or peripheral nervous system.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a condition or disease of the central or peripheral nervous system, wherein the treatment and/or prevention comprises co-administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the condition or disease is selected from postoperative nerve damage, traumatic nerve damage, impaired myelination of nerve fibers, postischaemic damage, such as after stroke, nerve degeneration associated with diabetes mellitus, disorders affecting the circadian clock or neuro-muscular transmission.
  • a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders in a subject in need thereof comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders in a subject in need thereof comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders, wherein the medicament is formulated to be co- administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders, wherein the treatment and/or prevention comprises co-administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of the third aspect for use in the treatment and/or prevention of a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders.
  • a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in the treatment and/or prevention of a condition or disease selected from conditions or diseases of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders.
  • a method of treating and/or preventing a cancer involving neoangiogenesis or a cancer of the neural system in a subject in need thereof comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of treating and/or preventing a cancer involving neoangiogenesis or a cancer of the neural system in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • [75] There is also provided a method of treating and/or preventing a cancer involving neoangiogenesis or a cancer of the neural system in a subject in need thereof, comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a cancer involving neoangiogenesis or a cancer of the neural system, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a cancer involving neoangiogenesis or a cancer of the neural system, wherein the treatment and/or prevention comprises co-administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of the third aspect for use in the treatment and/or prevention of a cancer involving neoangiogenesis or a cancer of the neural system.
  • a method of treating and/or preventing a condition or disease which is an impaired ability to learn and/or impaired memory in a subject in need thereof comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of treating and/or preventing a condition or disease which is an impaired ability to learn and/or impaired memory in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • a method of treating and/or preventing a condition or disease which is an impaired ability to learn and/or impaired memory in a subject in need thereof comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease which is an impaired ability to learn and/or impaired memory, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease which is an impaired ability to learn and/or impaired memory, wherein the medicament is formulated to be co- administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a condition or disease which is an impaired ability to learn and/or impaired memory, wherein the treatment and/or prevention comprises co-administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of the third aspect for use in the treatment and/or prevention of a condition or disease which is an impaired ability to learn and/or impaired memory.
  • the condition or disease is associated with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, or dementia such as multiinfarct dementia.
  • a condition or disease which is a mental disease such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder in a subject in need thereof, the method comprising co-administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • paraphrenia paranoid psychosis
  • a condition or disease which is a mental disease such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of the third aspect.
  • BPD bipolar
  • a condition or disease which is a mental disease such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder in a subject in need thereof, comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • BPD bipolar
  • genetically related unipolar affective disorders such as a disorder of thought
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • BPD bipolar
  • unipolar affective disorders delusional disorders, para
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder.
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • paraphrenia paranoid psychosis
  • schizophrenia schizotypal disorder
  • schizoaffective disorder schizoaffective bipolar
  • genetically related unipolar affective disorders psychogenic psychosis
  • catatonia
  • a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder.
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • paraphrenia paranoid psychosis
  • schizophrenia schizotypal disorder
  • schizoaffective disorder schizoaffective bipolar
  • genetically related unipolar affective disorders psychogenic psychosis
  • catatonia
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder, wherein the treatment and/or prevention comprises co- administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for
  • a pharmaceutical composition of the third aspect for use in the treatment and/or prevention of a condition or disease which is a mental disease, such as a disorder of thought and/or mood, neuropsychiatric disorders including bipolar (BPD), genetically related unipolar affective disorders, delusional disorders, paraphrenia, paranoid psychosis, schizophrenia, schizotypal disorder, schizoaffective disorder, schizoaffective bipolar and genetically related unipolar affective disorders, psychogenic psychosis, catatonia, periodic bipolar and genetically related unipolar affective disorders, cycloid psychosis, schizoid personality disorder, paranoid personality disorder, bipolar and genetically related unipolar affective disorders related affective disorders and subtypes of unipolar affective disorder.
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • paraphrenia paranoid psychosis
  • schizophrenia schizotypal disorder
  • schizoaffective disorder schizoaffective bipolar
  • BPD bipolar
  • unipolar affective disorders delusional disorders
  • paraphrenia paranoid psychosis
  • [104] There is also provided a method of the treatment of body damages due to alcohol consumption in a subject in need thereof, the method comprising co- administering to the subject EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of the treatment of body damages due to alcohol consumption in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • a method of the treatment of body damages due to alcohol consumption in a subject in need thereof comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment of body damages due to alcohol consumption, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of body damages due to alcohol consumption, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment of body damages due to alcohol consumption, wherein the treatment comprises co- administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of the third aspect for use in the treatment of body damages due to alcohol consumption.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a prion disease, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a prion disease, wherein the medicament is formulated to be co-administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof there is also provided a use of a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment and/or prevention of a prion disease.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a prion disease, wherein the treatment and/or prevention comprises co- administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a method of treating and/or preventing a condition or disease characterised by the presence of a sustained inflammatory response in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the third aspect.
  • a method of treating and/or preventing a condition or disease characterised by the presence of a sustained inflammatory response in a subject in need thereof comprising administering to the subject a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease characterised by the presence of a sustained inflammatory response, wherein the medicament is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a condition or disease characterised by the presence of a sustained inflammatory response, wherein the medicament is formulated to be co- administered with EmtinB or a variant thereof.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a condition or disease characterised by the presence of a sustained inflammatory response, wherein the treatment and/or prevention comprises co- administering the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of the third aspect for use in the treatment and/or prevention of a condition or disease characterised by the presence of a sustained inflammatory response.
  • the condition or disease is brain inflammation or autoimmune disease.
  • the condition or disease is Guillain-Barré syndrome, its variant form, such as Miller Fisher syndrome, or another complement dependent neuromuscular disorder.
  • the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are formulated as separate compositions.
  • the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are administered, or are formulated to be administered, in a sequential manner or in a substantially simultaneous manner. In some embodiments, the EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are administered, or are formulated to be administered, via subcutaneous injections. [137] In some embodiments, the pharmaceutical composition or the medicament is administered, or is formulated to be administered, via subcutaneous injection. [138] In some embodiments, the EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, is to be administered via subcutaneous injections.
  • the EmtinB or a variant thereof is to be administered in an amount in the range of from 10 mg to 700 mg. In some embodiments, the EmtinB or a variant thereof is to be administered in an amount in the range of from 10 mg to 70 mg, from 70 mg to 150 mg, from 150 mg to 230 mg, from 230 mg to 300 mg, from 300 mg to 380 mg, from 380 mg to 450 mg, from 450 mg to 600 mg, or from 600 mg to 700 mg. In some embodiments, the EmtinB or a variant thereof is to be administered in an amount in the range of from 340 mg to 680 mg.
  • the EmtinB or a variant thereof is to be administered in an amount of about 340 mg or about 680 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount in the range of from 1 mg to 40 mg. In some embodiments, the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount in the range of from 20 mg to 40 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount in the range of from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 15 mg, from 15 mg to 20 mg, from 20 mg to 25 mg, from 25 mg to 30 mg, or from 35 mg to 40 mg. In some embodiments, the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount in the range of from 1 mg to 10 mg or from 10 mg to 20 mg. In some embodiments, the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount of about 6 mg or about 12 mg.
  • the EmtinB or a variant thereof is to be administered in an amount effective to provide from 10 ⁇ g to 200 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain. In some embodiments, the EmtinB or a variant thereof is to be administered in an amount effective to provide from 10 ⁇ g to 20 ⁇ g, from 20 ⁇ g to 30 ⁇ g, from 30 ⁇ g to 40 ⁇ g, from 40 ⁇ g to 50 ⁇ g, from 50 ⁇ g to 60 ⁇ g, from 60 ⁇ g to 70 ⁇ g, from 70 ⁇ g to 80 ⁇ g, from 80 ⁇ g to 90 ⁇ g, from 90 ⁇ g to 100 ⁇ g, from 100 ⁇ g to 110 ⁇ g, from 110 ⁇ g to 120 ⁇ g, from 120 ⁇ g to 130 ⁇ g, from 130 ⁇ g to 140 ⁇ g, from 140 ⁇ g to 150 ⁇ g, from 150 ⁇ g to 160 ⁇ g, from 160 ⁇ g to 170
  • the EmtinB or a variant thereof is to be administered in an amount effective to provide from 50 ⁇ g to 150 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount effective to provide from 1 ⁇ g to 20 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount effective to provide from 1 ⁇ g to 15 ⁇ g, from 2 ⁇ g to 14 ⁇ g, from 2 ⁇ g to 13 ⁇ g, from 2 ⁇ g to 12 ⁇ g, from 2 ⁇ g to 11 ⁇ g, from 2 ⁇ g to 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is to be administered in an amount effective to provide about 1 ⁇ g, about 2 ⁇ g, about 3 ⁇ g, about 4 ⁇ g, about 5 ⁇ g, about 6 ⁇ g, about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, or about 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.
  • the present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.
  • Figure 2 shows the effect of EmtinB and Copaxone on neurites length of rat primary cortical neurons expressed in percentage of control after 19 days of culture, as described herein. mean ⁇ s.e.m; ** p ⁇ 0.01, *** p ⁇ 0.001, **** p ⁇ 0.0001, stats vs Control, one-way Anova followed by Dunnett’s test.
  • Figure 3 shows the effect of EmtinB and Copaxone on myelin sheath area of rat primary cortical neurons expressed in percentage of control after 19 days of culture, as described herein. mean ⁇ s.e.m; * p ⁇ 0.05, **** p ⁇ 0.0001 stats vs Control, one-way Anova followed by Dunnett’s test.
  • Description of Embodiments [149] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, cell culture, molecular biology and pharmacy). Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
  • administering as used herein is to be construed broadly and includes administering the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described herein to a subject as well as providing the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described herein to a cell such as a neuronal cell.
  • an effective amount refers to an amount of the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described herein which is sufficient to elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • Undesirable effects e.g. side effects, are sometimes manifested along with the desired effect; hence, a practitioner balances the potential benefits against the potential risks in determining what an appropriate "effective amount” is.
  • the exact amount required varies from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount”.
  • an appropriate "effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the effective amount in this context includes an amount required to treat, prevent, improve or ameliorate a condition associated with impaired neuronal survival, neurite growth, or myelin sheath.
  • ameliorate is included relieving of adverse symptoms, inducing a state of comfort or wellbeing or removing or reducing biochemical, physiological or clinical markers of the disease or the condition.
  • the effective amount may vary depending on such factors as, for example, the disease or condition being treated, the mode and method of administration of the active compounds, the size of the subject, or the severity of the disease or condition.
  • treating include administering an effective amount of the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described herein sufficient to reduce or delay the onset or progression of a specified disease, disorder or condition, or to reduce or eliminate at least one symptom of the disease, disorder or condition.
  • treatment includes that the disease or disorder is cured, however, it does not necessarily mean that the disease, disorder or condition is completely cured.
  • preventing include administering an effective amount of the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described herein sufficient to avoid the onset of a specified disease, disorder or condition, or to avoid at least one symptom of the disease, disorder or condition.
  • the active therapeutic agents or the pharmaceutical composition comprising the active therapeutic agents as described are administered prior to clinical manifestation of the unwanted disease, disorder or condition (e.g., disease or other unwanted state of the host animal such as, but not limited to, myelination disturbances, myelin deficiencies, myelin loss and ineffective myelin repair) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted disease, disorder or condition e.g., disease or other unwanted state of the host animal such as, but not limited to, myelination disturbances, myelin deficiencies, myelin loss and ineffective myelin repair
  • therapeutic agent includes molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition.
  • the terms include without limitation pharmaceutically acceptable salts thereof and prodrugs.
  • agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.
  • a “patient,” “subject,” or “host” to be treated by the methods described herein may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease, disorder or condition.
  • a subject regardless of whether a human or non-human animal may be referred to as an individual, subject, animal, host or recipient as well as patient.
  • "survival”, in particular “neuronal cell survival”, relates to the processes associated with maintenance and/or recovery of cell function after the damage of a cell, in particular a neuronal cell.
  • the therapeutic agents of the present disclosure may be capable of stopping or attenuating the processes committing the cell to death, such as inhibiting apoptosis of neural cells initiated by cell damage due trauma or disease.
  • neuronal cells such as progenitor cells, immature neural cells or embryonic stem cells or mature neural cells having normal functional characteristics defined in the art.
  • neuronal cells such as progenitor cells, immature neural cells or embryonic stem cells or mature neural cells having normal functional characteristics defined in the art.
  • Estimation of capability of a candidate compound to stimulate neuronal cell survival may be done by using any known method or assay for estimation of cell survival, such as the ones described in Examples of the present disclosure.
  • neural differentiation is understood herein both as differentiation of neural precursor cells, or neural stem cells, and further differentiation of neural cells, such as for example maturation of neuronal cells.
  • An example of such differentiation may be neurite outgrowth from immature neurons, branching of neurites, and also neuron regeneration.
  • the therapeutic agents of the present disclosure may be capable of stimulating of differentiation of neural precursor/stem cells or immature neurons and/or stimulating neurite outgrowth from mature neurons, for examples neurons which were traumatizes but survived and are committed to regenerate damaged processes.
  • differentiation is related to the processes of maturation of neurons and extension of neurites, which take place after the last cell division of said neurons.
  • the therapeutic agents of the present disclosure may be capable of stopping neural cell division and initiating maturation of said cells, such as initiating extension of neurites.
  • “differentiation” is related to initiation of the process of genetic, biochemical, morphological and physiological transformation of neuronal progenitor cells, immature neural cells or embryonic stem cells leading to formation of cells having functional characteristics of normal neuronal cell as such characteristics are defined in the art.
  • Estimation of capability of a candidate compound to stimulate neurite outgrowth may be done by using any known method or assay for estimation of neurite outgrowth, such as the ones described in Examples of the present disclosure.
  • the term “multiple sclerosis” as used herein refers to an auto-immune disease of the central nervous system which is accompanied by one or more of the symptoms described above.
  • the MS is relapsing remitting MS.
  • the MS is a progressive MS. In some embodiments, the progressive MS is secondary progressive MS. In other embodiments, the progressive MS is primary progressive MS. In additional embodiments, the progressive MS is progressive relapsing MS. [159] The term "about” as used herein refers to a range of +/-5% of the specified value. [160] Throughout this specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated.
  • EmtinB is a peptide modeled after the ⁇ -domain of human metallothionein (MT)-II, having the amino acid sequence SAGSCKCKESKSTS (Ambj ⁇ rn et al., 2008; Sonn et al., 2010).
  • a group of peptides including EmtinB was first disclosed in patent application WO 2007/093177 (counterpart U.S. Publication Nos. US 20100166759A1, US 20140179614A1 and US 20170226190A1), the entire contents of which are incorporated herein by reference. In particular, WO 2007/093177 page 6 and pages 9 to 20.
  • Peptides termed “EmtinB or a variant thereof” that are encompassed by the present disclosure comprise a sequence of at most 25 contiguous amino acid residues which comprise an amino acid motif of the formula: S/D/E-(x) n -S/D/E-K/S, wherein (x) n is a sequence of any amino acid residues with an integer n from 4 to 6.
  • (x)n is an amino acid sequence wherein n is 4, in another embodiment n is 6.
  • the amino acid sequence (x) n is a sequence of any amino residues, however, in some preferred embodiments it may comprise at least one of the following amino acid residues: K, S, E or C.
  • EmtinB or a variant thereof is a peptide sequence comprising amino acid residues in the range of 8-25 amino acid residues, such as from 9 to 25 amino acid residues, for example from 10 to 25 amino acid residues.
  • the peptide sequence may be between 11 and 25 amino acid residues, such as between 12 and 25, for example from 13 to 25 amino acid residues.
  • the amino acid sequence may comprise about 15 amino acid residues, such as 14 or 16 amino acid residues, or. it may be about 20 amino acid residues in length, such as from 17 to 19 amino acid residues, or it may comprise from 20 to 25 amino acid residues.
  • EmtinB or a variant thereof is another Emtin peptide such as EmtinAc, EmtinAn, or EmtinBn, or a variant thereof.
  • EmtinB or a variant thereof is a peptide as above wherein the amino acid residue S/D/E at any position of the motif is substituted for amino acid residue C.
  • a peptide as above may for example comprise or consist of an amino acid sequence selected from the following sequences: KKSSCSCSPVGSAK (SEQ ID NO:1) AQGSISKGASDKSS (SEQ ID NO:2) MDPNSSSMGDSST (SEQ ID NO:3) SAGSSKSKESKSTS (SEQ ID NO:4) AQGSICKGASDKSS (SEQ ID NO:5) MDPNCSCMGDSST (SEQ ID NO:6) SAGSCKCKESKSTS (SEQ ID NO:7) KGGEMEAEAEK (SEQ ID NO:8), or be a fragment, or a variant of any of these sequences.
  • EmtinB or a variant thereof may be a peptide which is homologues to a specific subsequence of a selected group of subsequences described above. Sequence homology may be calculated using well known algorithms such as BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM 55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80, BLOSUM 85, or BLOSUM 90.
  • sequence similarity sequence identity
  • sequence homology are used in the present application interchangeably when referred to a number or percentage of identical or similar amino acid residues in two collated amino acid sequences.
  • Similar amino acid residues are amino acid residues de- rived from the same group of “conservative” amino acid residues. The latter groups are discussed further in the application. [173] In the present disclosure the standard one-letter code for amino acid residues is applied as well as the standard three-letter code. Abbreviations for amino acids are in accordance with the recommendations in the IUPAC-IUB Joint Commission on Biochemical Nomenclature Eur. J. Biochem, 1984, vol.184, pp 9-37. Throughout the description and claims, either the three letter code or the one letter code for natural amino acids are used. Where the L or D form has not been specified it is to be understood that the amino acid in question has the natural L form, cf. Pure & Appl. Chem.
  • the peptides formed may be constituted of amino acids of L form, D form, or a sequence of mixed L forms and D forms.
  • the C-terminal amino acid of a peptide described herein exists as a free carboxylic acid, which may also be indicated as "-OH”.
  • the C-terminal amino acid of a compound of the disclosure may be the amidated derivative, which is indicated as "-NH”.
  • the N-terminal amino acid of a polypeptide comprise a free amino group, which may also be indicated as "H-".
  • amino acid can be selected from any amino acid, whether naturally occurring or not, such as alpha amino acids, beta amino acids, and/or gamma amino acids. Accordingly, the group of amino acids comprises but is not limited to: Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Aib, Nal, Sar, Orn, Lysine analogues, DAP, DAPA and 4Hyp.
  • the term “variant thereof” means that the peptides described herein comprise modified amino acids, such as for example glycosylated and/or acetylated amino acids.
  • the term “variant thereof” means that the peptides described herein are modified, for example, by substitution of one or more of the amino acid residues. Both L-amino acids and D-amino acids may be used for substitution. Other modification may comprise derivatives such as esters, sugars, etc. Examples are methyl and acetyl esters.
  • variants of EmtinB may comprise, within the same variant, or fragments thereof or among different variants, or fragments thereof, at least one substitution, such as a plurality of substitutions introduced independently of one another.
  • Variants of the complex, or fragments thereof may thus comprise conservative substitutions independently of one another, wherein at least one glycine (Gly) of said variant, or fragments thereof is substituted with an amino acid selected from the group of amino acids consisting of Ala, Val, Leu, and Ile, and independently thereof, variants, or fragments thereof, wherein at least one alanine (Ala) of said variants, or fragments thereof is substituted with an amino acid selected from the group of amino acids consisting of Gly, Val, Leu, and Ile, and independently thereof, variants, or fragments thereof, wherein at least one valine (Val) of said variant, or fragments thereof is substituted with an amino acid selected from the group of amino acids consisting of Gly, Ala, Leu, and Ile, and independently thereof
  • EmtinB or a variant thereof is a peptide with an amino acid sequence of at least 6 amino acid residues having at least 65% sequence similarity with a sequence selected from the sequences of SEQ ID NOs:1-8, or an amino acid sequence of 6 to 20 contiguous amino acid residues, which has more than 70% sequence similarity with a sequence selected from the sequences of SEQ ID NOs:1-8, such as from 71% to 80% of sequence similarity, from 81% to 85% of sequence similarity, from 86% to 90% of sequence similarity, from 91% to 95% of sequence similarity, or more than 95% of sequence similarity.
  • EmtinB or a variant thereof is a peptide which contains a sequence selected from the sequences of SEQ ID NOs:1-8, said sequence comprising one or more modifications of amino acid residues, such as for example modification described herein.
  • EmtinB or a variant thereof is a fragment of the peptide sequences described herein.
  • the fragment is a fragment of a sequence selected from the sequences of SEQ ID NOs:1-8 which has the length of about 40% of the length of said sequence, or at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the length of said sequence.
  • EmtinB or a variant thereof comprises truncated peptides derived from a sequence selected from the sequences of SEQ ID NOs:1-8.
  • such truncated peptides may comprise 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 amino acids from a sequence selected from the sequences of SEQ ID NOs:1-8.
  • EmtinB or a variant thereof is a mixture containing predominantly a peptide of a sequence selected from the sequences of SEQ ID NOs:1- 8, and one or more truncated peptides derived from a sequence selected from the sequences of SEQ ID NOs:1-8.
  • Such mixtures may contain, for example, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, or 80% molar or weight ratio of the peptide of a sequence selected from the sequences of SEQ ID NOs:1-8 to truncated peptides derived from a sequence selected from the sequences of SEQ ID NOs:1-8.
  • EmtinB or a variant thereof is a variant and fragment which has at least one functional activity of a sequence selected from the sequences of SEQ ID NOs:1-8.
  • preferred variants and fragments of the disclosure are functional equivalents/homologues of the amino acid sequence selected from the sequences of SEQ ID NOs:1-8.
  • "Functional equivalent/homologue” in the present context is an amino acid sequence which has at least 65% of homology with a sequence selected from the sequences of SEQ ID NOs:1-8 or a sequence which has at least 40% of the length of a sequence selected from the sequences of SEQ ID NOs:1-8, and which is capable of at least one functional activity of the sequence which it has homology with, or which it is a fragment of, for example it is capable of stimulating neuronal survival, neurite growth, and/or myelin formation.
  • the peptides described above may be naturally occurring, synthetically or recombinantly prepared peptides and peptides prepared by means of enzymatic/chemical cleavage of proteins.
  • the peptides having the amino acid sequences corresponding to subsequences of bigger polypeptides such as for example peptides comprising or consisting of subsequences of the MTs, are derived from the sequences of said bigger polypeptides or proteins.
  • These peptides may be produced either by enzymatic cleavage of proteins or prepared by means of recombinant expression or chemical synthesis.
  • the EmtinB or a variant thereof may contain a single copy of an individual amino acid sequence selected from any of the described above, or it may contain two or more copies of such amino acid sequence.
  • the active therapeutic agent EmtinB or a variant thereof may be formulated as a monomer of a peptide sequence, such as containing a single individual peptide sequence, or it may be formulated as a multimer of a peptide sequence, i.e. containing two or more individual peptide sequences, wherein said individual peptide sequences may be represented by two or more copies of the same sequence or by two or more different individual peptide sequences.
  • a multimer may also comprises a combination of the full-length sequence and one or more fragments thereof.
  • the active therapeutic agent EmtinB or a variant thereof contains two amino acid sequences, and such compound is defined herein as dimer. In another embodiment, the active therapeutic agent EmtinB or a variant thereof contains more than two amino acid sequences, such for example three, four or more sequences. In certain embodiments, the active therapeutic agent EmtinB or a variant thereof contains two or four peptide sequences of the disclosure. However, active agents containing 3, 5, 6, 7, 8 or more sequences are also in the scope of the disclosure. [187] The EmtinB or a variant thereof may be formulated as dimers or multimers comprising more than two copies of individual peptide fragments which may have the identical amino acid sequences or different amino acid sequences.
  • Examples of a compound with different amino acid sequences may be a dimeric peptide containing SEQ ID NO: 1 and SEQ ID NO: 3 or a dimeric peptide containing SEQ ID NO: 1 and SEQ ID NO: 7. Any other combinations of the sequences described herein may be made.
  • the sequences may be connected to each other via peptide bond, or connected to each other through a linker molecule or grouping.
  • EmtinB or a variant thereof may contain two or more copies of a single sequence, such as for example two copies of any of the sequences selected from SEQ ID NOs: 1-8, wherein said two sequences may be connected to each other via a linker molecule or grouping.
  • linking grouping may be an achiral di-, tri- or tetracarboxylic acid. Suitable achiral di-, tri- or tetracarboxylic acids and a method of production such a compound (a ligand presentation assembly method (LPA)) are described in WO0018791 and WO2005014623.
  • LPA ligand presentation assembly method
  • Another example of a possible linker may be the amino acid lysine. Individual peptide sequences may be attached to a core molecule such as lysine forming thereby a dendritic multimer (dendrimer) of an individual peptide sequence(s).
  • EmtinB or a variant thereof is a dendrimeric compound comprising four individual amino acid sequences attached to the lysine core molecule. In some embodiments, at least one of the four individual amino acid sequences comprises an amino acid sequence of the formula defined above.
  • all four individual amino acid sequences of a dendrimeric compound individually comprise an amino acid sequence of the formula defined above.
  • Multimeric compounds described herein include LPA-dimers and Lysin- dendrimers, as well as other types of multimeric compounds comprising two or more individual sequences described above.
  • the EmtinB or a variant thereof may be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the peptide compound) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, oxalic acid, tartaric acid, mandelic acid, and the like.
  • Salts formed with the free carboxyl group may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides
  • organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • Glatiramer acetate is a mixture of polypeptides which do not all have the same amino acid sequence.
  • Glatiramer acetate contains the acetate salts of synthetic polypeptides that contain the four naturally occurring amino acids L-glutamic acid, L- alanine, L-tyrosine, and L-lysine, at average molar fractions of 0.141, 0.427, 0.095 and 0.338, respectively.
  • the average molecule weight of glatiramer acetate is 4,700-11,000 Daltons.
  • glatiramer acetate comprises about 15 to about 100 amino acids.
  • glatiramer acetate (CAS: 147245-92-9) is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: (Glu, Ala, Lys, Tyr) x ⁇ XCH 3 COOH (C5H9NO4 ⁇ C3H7NO2 ⁇ C6H14N2O2 ⁇ C9H11NO3)x ⁇ XC2H4O2 [196] Copaxone ® is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection.
  • Copaxone ® solution contains 20 mg or 40 mg of glatiramer acetate and the following inactive ingredient: 40 mg of mannitol.
  • the pH of the solutions is approximately 5.5 to 7.0.
  • the biological activity of glatiramer acetate is determined by its ability to block the induction of experimental autoimmune encephalomyelitis (EAE) in mice.
  • EAE experimental autoimmune encephalomyelitis
  • an "alternative pharmaceutically acceptable salt" of glatiramer acetate refers to pharmaceutically acceptable salts of the polypeptides that contain the four naturally occurring amino acids L-glutamic acid, L-lysine, L-alanine, and L- tyrosine that make up glatiramer. It is understood by one of ordinary skill in the art that an amino acid can exist in various forms, including, for example, neutral forms, ionized forms (e.g., cationic forms, anionic forms, or zwitterionic forms), or salt forms.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof comprises from about 15 to about 100 amino acids. In some embodiments, the average molecule weight of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof ranges from about 4,000 to about 12,000 Daltons. In some more particular embodiments, the average molecule weight of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof ranges from about 4,700 to about 11,000 Daltons.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof contains the four naturally occurring amino acids L-glutamic acid, L-lysine, L-alanine, and L-tyrosine, with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively.
  • Non-limiting examples of alternative pharmaceutically acceptable salts of glatiramer acetate include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, nitrate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, tocopheryl succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
  • the glatiramer salt is glatiramer acetate.
  • Various formulations of glatiramer salts and methods of preparing glatiramer salts and formulations containing glatiramer salts have been described in, for example, U.S. Patent No.8,399,413, U.S. Patent 8,796, 226, U.S. Patent No.8,859,489, U.S. Patent No.8,920,373, U.S. Patent No.8,921,116, U.S. Patent No.8,969,302, U.S. Patent No.8,993,722, U.S. Patent No.9,018,170, U.S. Patent No.9,029,507, U.S.
  • Pharmaceutical compositions, combinations and formulations [202] In one aspect, the present disclosure relates to a pharmaceutical composition comprising EmtinB (SAGSCKCKESKSTS) or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • Such pharmaceutical composition is capable of promoting survival of neural cells, and/or promoting neurite growth, and/or promoting myelin formation around neurons.
  • the present disclosure also relates to a pharmaceutical composition comprising EmtinB or a variant thereof, wherein the composition is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the present disclosure further relates to a pharmaceutical composition comprising EmtinB or a variant thereof, wherein the composition is formulated to be co-administered with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • EmtinB or a variant thereof and the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are to be administered in combination.
  • Such pharmaceutical compositions advantageously providing a synergistic mixture of the two active therapeutic agents upon co- administration, are capable of promoting survival of neural cells, and/or promoting neurite growth, and/or promoting myelin formation around neurons.
  • the pharmaceutical compositions of the present disclosure may have the described above effects in vitro or in vivo, wherein the composition is administered to a subject.
  • compositions of the disclosure comprise an effective amount of EmtinB or variants thereof, and/or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, as defined above, in combination with pharmaceutically acceptable additives.
  • Such pharmaceutical compositions may suitably be formulated for oral, subcutaneous, percutaneous, intramuscular, intravenous, intracranial, intrathecal, intracerebroventricular, intranasal or pulmonal administration.
  • a pharmaceutical composition of the disclosure is formulated for subcutaneous administration.
  • Strategies in formulation development of medicaments and compositions based on the active therapeutic agents of the present disclosure generally correspond to formulation strategies for any other peptide-based drug product.
  • lnjectables are usually prepared either as liquid solutions or suspensions, solid forms suitable for solution in, or suspension in, liquid prior to injection. The preparation may also be emulsified.
  • the active ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like, and combinations thereof.
  • the preparation may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or which enhance the effectiveness or transportation of the preparation.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or which enhance the effectiveness or transportation of the preparation.
  • Formulations of the compounds of the disclosure can be prepared by techniques known to the person skilled in the art.
  • the formulations may contain pharmaceutically acceptable carriers and excipients including microspheres, liposomes, microcapsules, nanoparticles or the like.
  • a pharmaceutical composition of the disclosure is formulated for subcutaneous injection.
  • the pharmaceutical composition has a pH in the range of 5.5 to 8.5, or in the range of 5.5 to 7.0.
  • EmtinB or variants thereof, and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof are formulated separately for administration as a combination.
  • EmtinB or variants thereof, or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be formulated on their own, such as, for example, a lyophilized EmtinB or variants thereof, or a lyophilized glatiramer acetate or an alternative pharmaceutically acceptable salt thereof; or as a mixture of EmtinB or variants thereof, or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, with one or more physiologically acceptable carriers, excipients or stabilizers.
  • therapeutic formulations or medicaments can be prepared by mixing EmtinB or variants thereof, or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, having the desired degree of purity, with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) antibody; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine
  • Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral -active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).
  • sHASEGP soluble neutral -active hyaluronidase glycoproteins
  • rHuPH20 HYLENEX®, Baxter International, Inc.
  • Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Publication Nos.2005/0260186 and 2006/0104968.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • additional glycosaminoglycanases such as chondroitinases.
  • Exemplary lyophilized formulations are described in US Patent No.
  • Aqueous formulations include those described in US Patent No.6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.
  • a formulation of EmtinB or variants thereof, or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof as disclosed herein, e.g., sustained- release formulations can further include a mucoadhesive agent, e.g., one or more of polyvinyl pyrrolidine, methyl cellulose, sodium carboxyl methyl cellulose, hydroxyl propyl cellulose, carbopol, a polyacrylate, chitosan, a eudragit analogue, a polymer, and a thiomer.
  • a mucoadhesive agent e.g., one or more of polyvinyl pyrrolidine, methyl cellulose, sodium carboxyl methyl cellulose, hydroxyl propyl cellulose, carbopol, a polyacrylate, chitosan,
  • mucoadhesive agents that can be included in a formulation with EmtinB or variants thereof, or glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, are described in, e.g., Peppas et al., Biomaterials 17(16): 1553-1561, 1996; Kharenko et al., Pharmaceutical Chemistry J. 43(4):200-208, 2009; Salamat-Miller et al., Adv. DrugDeliv. Reviews 57(11): 1666- 1691, 2005; Bernkop-Schnurch, Adv. DrugDeliv. Rev.57(11): 1569-1582, 2005; and Harding et al., Biotechnol. Genet. Eng.
  • formulations and compositions described above may include any one of the following components, or any combination thereof: Acacia, Alginate, Alginic Acid, Aluminum Acetate, an antiseptic, Benzyl Alcohol, Butyl Paraben, Butylated Hydroxy Toluene, an antioxidant.
  • EmtinB sequences may be formulated as comprising isolated individual peptide fragments or multimers or dimers thereof as discussed above.
  • the formulations and compositions described above may suitably be administered by injection, optionally at the site, where the active ingredient is to exert its effect. Additional formulations which are suitable for other modes of administration include suppositories, nasal, pulmonary, and, in some cases, oral formulations.
  • suppositories traditional binders and carriers include polyalkylene glycols or triglycerides.
  • Such suppositories may be formed from mixtures containing the active ingredient(s) in the range of from 0.5% to 10%, preferably 1-2%.
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and generally contain 10-95% of the active ingredient(s), preferably 25-70%. [218] Other formulations are such suitable for nasal and pulmonal administration, e.g. inhalators and aerosols. [219] The formulations and compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective. The quantity to be administered depends on the subject to be treated, including, e.g.
  • Suitable dosage ranges of EmtinB or a variant thereof per kilo body weight are normally of the order of several hundred ⁇ g active ingredient per administration with a preferred range of from about 0.1 ⁇ g to 5000 ⁇ g per kilo body weight.
  • the suitable dosages may be in the range of from 0.1 ⁇ g to 5000 ⁇ g per kilo body weight, such as in the range of from about 0.1 ⁇ g to 3000 ⁇ g per kilo body weight, or in the range of from about 0.1 ⁇ g to 1000 ⁇ g per kilo body weight.
  • the suitable dosages may be in the range of from 0.1 ⁇ g to 1000 ⁇ g per kilo body weight, such as in the range of from about 0.1 ⁇ g to 750 ⁇ g per kilo body weight, or in the range of from about 0.1 ⁇ g to 500 ⁇ g per kilo body weight such as in the range of from about 0.1 ⁇ g to 250 ⁇ g per kilo body weight.
  • the dosage will also depend on the route of administration and will vary with the age and weight of the subject to be treated. For example, when administering nasally, smaller dosages are used than when administering by other routes. Administration may be performed once or may be followed by subsequent administrations.
  • dosage of multimeric forms is in the interval 1 mg to 70 mg per 70 kg body weight.
  • concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is in the range of from 10 mg/mL to 700 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is in the range of from 10 mg/mL to 70 mg/mL, from 70 mg/mL to 150 mg/mL, from 150 mg/mL to 230 mg/mL, from 230 mg/mL to 300 mg/mL, from 300 mg/mL to 380 mg/mL, from 380 mg/mL to 450 mg/mL, from 450 mg/mL to 600 mg/mL, or from 600 mg/mL to 700 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is in the range of from 300 mg/mL to 680 mg/mL, or from 340 mg/mL to 680 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is about 300 mg/mL, about 310 mg/mL, about 320 mg/mL, about 330 mg/mL, about 340 mg/mL, about 350 mg/mL, about 360 mg/mL, about 370 mg/mL, about 380 mg/mL, about 390 mg/mL, about 400 mg/mL, about 410 mg/mL, about 420 mg/mL, about 430 mg/mL, about 440 mg/mL, about 450 mg/mL, about 460 mg/mL, about 470 mg/mL, about 480 mg/mL, about 490 mg/mL, about 500 mg/mL, about
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is about 300 mg/mL, about 310 mg/mL, about 320 mg/mL, about 330 mg/mL, about 340 mg/mL, about 350 mg/mL, about 360 mg/mL, about 370 mg/mL, about 380 mg/mL, about 390 mg/mL, about 400 mg/mL.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is about 550 mg/mL, about 560 mg/mL, about 570 mg/mL, about 580 mg/mL, about 590 mg/mL, about 600 mg/mL, about 610 mg/mL, about 620 mg/mL, about 630 mg/mL, about 640 mg/mL, about 650 mg/m, about 660 mg/mL, about 670 mg/mL, or about 680 mg/mL.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration of from 10 ⁇ g/mL to 200 ⁇ g/mL of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration of from 10 ⁇ g/mL to 20 ⁇ g/mL, from 20 ⁇ g/mL to 30 ⁇ g/mL, from 30 ⁇ g/mL to 40 ⁇ g/mL, from 40 ⁇ g/mL to 50 ⁇ g/mL, from 50 ⁇ g/mL to 60 ⁇ g/mL, from 60 ⁇ g/mL to 70 ⁇ g/mL, from 70 ⁇ g/mL to 80 ⁇ g/mL, from 80 ⁇ g/mL to 90 ⁇ g/mL, from 90 ⁇ g/mL to 100 ⁇ g/mL, from 100 ⁇ g/mL to 110 ⁇ g/mL, from 110 ⁇ g/mL to 120 ⁇ g/mL, from 120 ⁇ g/mL to 130 ⁇ g/mL, from 130 ⁇ g/mL to 140 ⁇ g/
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration of from 50 ⁇ g/mL to 150 ⁇ g/mL of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide from 15 ⁇ g to 250 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide about 15 ⁇ g, about 20 ⁇ g, about 25 ⁇ g, about 30 ⁇ g, about 35 ⁇ g, about 40 ⁇ g, about 45 ⁇ g, about 50 ⁇ g, about 55 ⁇ g, about 60 ⁇ g, about 65 ⁇ g, about 70 ⁇ g, about 75 ⁇ g, about 80 ⁇ g, about 85 ⁇ g, about 90 ⁇ g, about 95 ⁇ g, about 100 ⁇ g, about 105 ⁇ g, about 110 ⁇ g, about 115 ⁇ g, about 120 ⁇ g, about 125 ⁇ g, about 130 ⁇ g, about 135 ⁇ g, about 140 ⁇ g, about 145 ⁇ g, about 150 ⁇ g, about 155 ⁇ g, about 160 ⁇ g, about 165 ⁇ g, about 170 ⁇ g, about 175 ⁇ g, about 180 ⁇ g, about 185 ⁇ g, about
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide from 30 ⁇ g to 70 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain. In some embodiments, the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide from 135 ⁇ g to 170 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation in an amount effective to provide about 30 ⁇ g, about 35 ⁇ g, about 40 ⁇ g, about 45 ⁇ g, about 50 ⁇ g, about 55 ⁇ g, about 60 ⁇ g, about 65 ⁇ g, or about 70 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is present in the pharmaceutical composition or formulation is present in an amount effective to provide about 135 ⁇ g, about 140 ⁇ g, about 145 ⁇ g, about 150 ⁇ g, about 155 ⁇ g, about 160 ⁇ g, about 165 ⁇ g, or about 170 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is 10 to 80 mg; or 12 to 70 mg; or 14 to 60 mg; or 16 to 50 mg; or 18 to 40 mg; or 30 to 40 mg; or 40 mg; or 20 to 30 mg; or 20 mg; or 10 mg.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation may be sufficient to deliver glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the range of from 10 to 600 mg/week; or 100 to 550 mg/week; or 150 to 500 mg/week; or 200 to 450 mg/week; or 250 to 400 mg/week; or 300 to 350 mg/week; or 300 mg/week.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is sufficient to deliver glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the range of from 50 to 150 mg/day; or 60 to 140 mg/day; or 70 to 130 mg/day; or 80 to 120 mg/day; or 90 to 110 mg/day; or 100 mg/day.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation may be sufficient to deliver glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the range of from 10 to 80 mg/day; or 12 to 70 mg/day; or 14 to 60 mg/day; or 16 to 50 mg/day; or 18 to 40 mg/day; or 30 to 40 mg/day; or 40 mg/day; or 19 to 30 mg/day; or 20 mg/day; or 10 to 20 mg/day; or 5 to 15 mg/day, or 5 to 10 mg/day, or 1 to 5 mg/day.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is in the range of from 1 mg/mL to 40 mg/mL, such as for example 20 mg/mL to 40 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is in the range of from 1 mg/mL to 40 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is in the range of from 1 mg/mL to 5 mg/mL, from 5 mg/mL to 10 mg/mL, from 10 mg/mL to 15 mg/mL, from 15 mg/mL to 20 mg/mL, from 20 mg/mL to 25 mg/mL, from 25 mg/mL to 30 mg/mL, or from 35 mg/mL to 40 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is in the range of from 1 mg/mL to 20 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is in the range of from 1 mg/mL to 10 mg/mL or from 10 mg/mL to 20 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 mg/mL.
  • the concentration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the pharmaceutical composition or formulation is about 6 mg/mL or about 12 mg/mL.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration of from 1 ⁇ g/mL to 20 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration of from 1 ⁇ g/mL to 15 ⁇ g/mL, from 2 ⁇ g/mL to 14 ⁇ g/mL, from 2 ⁇ g/mL to 13 ⁇ g/mL, from 2 ⁇ g/mL to 12 ⁇ g/mL, from 2 ⁇ g/mL to 11 ⁇ g/mL, from 2 ⁇ g/mL to 10 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide a concentration about 1 ⁇ g/mL, about 2 ⁇ g/mL, about 3 ⁇ g/mL, about 4 ⁇ g/mL, about 5 ⁇ g/mL, about 6 ⁇ g/mL, about 7 ⁇ g/mL, about 8 ⁇ g/mL, about 9 ⁇ g/mL, or about 10 ⁇ g/mL, about 11 ⁇ g/mL, about 12 ⁇ g/mL, about 13 ⁇ g/mL, about 14 ⁇ g/mL, about 15 ⁇ g/mL, about 16 ⁇ g/mL, about 17 ⁇ g/mL, about 18 ⁇ g/mL, about 19 ⁇ g/mL, or about 20 ⁇ g/mL of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide from 1 ⁇ g to 20 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide from 1 ⁇ g to 15 ⁇ g, from 2 ⁇ g to 14 ⁇ g, from 2 ⁇ g to 13 ⁇ g, from 2 ⁇ g to 12 ⁇ g, from 2 ⁇ g to 11 ⁇ g, from 2 ⁇ g to 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to provide about 1 ⁇ g, about 2 ⁇ g, about 3 ⁇ g, about 4 ⁇ g, about 5 ⁇ g, about 6 ⁇ g, about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, or about 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or formulation in an amount effective to about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, about 10 ⁇ g, about 11 ⁇ g, about 12 ⁇ g, about 13 ⁇ g, about 14 ⁇ g, about 15 ⁇ g, about 16 ⁇ g, about 17 ⁇ g, about 18 ⁇ g, about 19 ⁇ g, or about 20 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • a localised or substantially localised application is preferred.
  • the compositions described herein further comprises pharmaceutically acceptable additives and/or carriers.
  • additives and carriers will be known in the art.
  • Administration may be a continuous infusion, such as intraventricular infusion or administration in more doses such as more times a day, daily, more times a week, weekly, etc.
  • administration of the medicament is initiated before or shortly after the individual has been subjected to the factor(s) that may lead to cell death.
  • the medicament is administered within 8 hours from the factor onset, such as within 5 hours from the factor onset.
  • the compounds exhibit a long term effect whereby administration of the compounds may be conducted with long intervals, such as 1 week or 2 weeks.
  • the administration may be continuous or in small portions based upon controlled release of the active compound(s).
  • precursors may be used to control the rate of release and/or site of release.
  • Other kinds of implants and well as oral administration may similarly be based upon controlled release and/or the use of precursors.
  • the present invention relates to treatment of individuals for inducing differentiation, stimulating regeneration, plasticity and survival of neural cells in vitro or in vivo, said treatment involving administering an effective amount of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof as defined above.
  • Another strategy for administration is to implant or inject cells capable of expressing and secreting EmtinB or variants thereof. Thereby EmtinB or a variant thereof may be produced at the location where it is going to act, while glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be administered in the usual manner.
  • the present disclosure provides methods of treating a subject affected with a neurodegenerative disease or a demyelinating disease, or any disease or condition where the effects of stimulating neural cell proliferation, differentiation and/or survival, and/or stimulating neural plasticity are beneficial for treatment, comprising administering to the subject an effective amount of EmtinB or a variant thereof and an effective amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the present disclosure describes a combination therapy involving administration of an effective amount EmtinB or a variant thereof and an effective amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to a subject.
  • EmtinB or a variant thereof in the manufacture of a medicament for the treatment of a subject affected with a neurodegenerative disease or a demyelinating disease, or any disease or condition where the effects of stimulating neural cell proliferation, differentiation and/or survival, and/or stimulating neural plasticity are beneficial for treatment, wherein the medicament is formulated to be administered in combination with glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the present disclosure also provides uses of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a subject affected with a neurodegenerative disease or a demyelinating disease, or any disease or condition where the effects of stimulating neural cell proliferation, differentiation and/or survival, and/or stimulating neural plasticity are beneficial for treatment, wherein the medicament is formulated to be administered in combination with EmtinB or a variant thereof.
  • the present disclosure also provides uses of a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a subject affected with a neurodegenerative disease or a demyelinating disease, or any disease or condition where the effects of stimulating neural cell proliferation, differentiation and/or survival, and/or stimulating neural plasticity are beneficial for treatment.
  • the present disclosure also provides a combination of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof, for use in the treatment of a subject affected with a neurodegenerative disease or a demyelinating disease, or any disease or condition where the effects of stimulating neural cell proliferation, differentiation and/or survival, and/or stimulating neural plasticity are beneficial for treatment.
  • the subject is a human patient.
  • the terms “combination therapy” or “combination” embrace the administration of EmtinB or a variant thereof described herein and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • the term “co-administration” as used herein will also be understood to refer to the administration of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof in combination with each other.
  • EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof can be formulated as a single composition as described herein or as separate compositions.
  • “combination therapy” or “combination” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, subcutaneous routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered, or formulated to be administered, by subcutaneous or intravenous injection while the other therapeutic agents of the combination may be administered, or formulated to be administered, orally.
  • all therapeutic agents may be administered, or formulated to be administered, orally, subcutaneously, or by intravenous injection.
  • the therapeutic agents are each administered, or formulated to be administered, subcutaneously.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, prior to the administration of the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, prior to the administration of the EmtinB or a variant thereof.
  • the therapeutic agents described herein can be administered to a subject to treat neurodegenerative diseases and disorders.
  • a neurodegenerative disease as suitable for treatment by methods of the present disclosure, can arise from but is not limited to an inherited genetic abnormality, stroke, heat stress, head and spinal cord trauma (blunt or infectious pathology), and/or bleeding that occurs in the brain.
  • the disclosed methods and uses are related to treating neurodegenerative diseases and disorders.
  • a neurodegenerative disease or disorder can include any disease or disorder or symptoms or causes or effects thereof involving the damage or deterioration of neurons.
  • Neurodegenerative diseases and disorders can include, but are not limited to, Alexander Disease, Alper's Disease, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Ataxia Telangiectasia, Canavan Disease, Cockayne Syndrome, Corticobasal Degeneration, Creutzfeldt-Jakob Disease, Huntington Disease, Kennedy's Disease, Krabbe Disease, Lewy Body Dementia, Machado-Joseph Disease, Multiple Sclerosis, Parkinson Disease, Pelizaeus-Merzbacher Disease, Niemann-Pick's Disease, Primary Lateral Sclerosis, Refsum's Disease, Sandhoff Disease, Schilder's Disease, Steele-Richardson-Olszewski Disease, Tabes Dorsalis or any other condition associated with damaged neurons.
  • neurodegenerative diseases and disorders can include or be caused by traumatic spinal cord injury, ischemic spinal cord injury, stroke, traumatic brain injury, and hereditary conditions.
  • the neurodegenerative disease encompassed for treatment by the therapeutic agent described herein can include a demyelinating disease or a myelin related disorder.
  • Demyelinating diseases or myelin related disorders can include any disease, condition (e.g., those occurring from traumatic spinal cord injury and cerebral infarction), or disorder related to demylination, insufficient myelination and remyelination, or dysmyelination in a subject.
  • a myelin related disorder as used herein can arise from a myelination related disorder or demyelination resulting from a variety of neurotoxic insults.
  • “Demyelination” as used herein refers to the act of demyelinating, or the loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative autoimmune diseases, including multiple sclerosis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barre Syndrome.
  • Leukodystrophies are caused by inherited enzyme deficiencies, which cause abnormal formation, destruction, and/or abnormal turnover of myelin sheaths within the CNS white matter.
  • some embodiments of the present invention can include methods for the treatment of neurodegenerative autoimmune diseases in a subject. Remyelination of neurons requires oligodendrocytes.
  • the term “remyelination”, as used herein, refers to the re-generation of the nerve's myelin sheath by replacing myelin producing cells or restoring their function.
  • Demyelinating or myelin related diseases or disorders which may be treated or ameliorated by the methods of the present disclosure include diseases, disorders or injuries which relate to dysmyelination or demyelination in a subject's brain cells, e.g., CNS neurons.
  • Such diseases include, but are not limited to, diseases and disorders in which the myelin which surrounds the neuron is either absent, incomplete, not formed properly, or is deteriorating.
  • diseases include, but are not limited to, multiple sclerosis (MS), neuromyelisits optica (NMO), progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava
  • demyelinating or myelin related diseases or disorders which may be treated or ameliorated by the methods of the present disclosure include leukodystrophies.
  • Leukodystrophies are a group of progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the myelin sheath of the brain. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.
  • Exemeplary leukodystrophies which may be treated or ameliorated by the methods of the present invention include, but are not limited to, adult-onset autosomal dominant leukodystrophy (ADLD), Aicardi-Goutieres syndrome, Alexander disease, CADASIL, Canavan disease, CARASIL, cerebrotendionous xanthomatosis, childhood ataxia and cerebral ypomyelination (CACH)/vanishing white matter disease (VWMD), Fabry disease, fucosidosis, GM1 gangliosidosis, Krabbe disease, L-2-hydroxyglutaric aciduria, megalencephalic leukoencephalopathy with subcortical cysts, metachromatic leukodystrophy, multiple sulfatase deficiency, Pelizaeus-Merzbacher disease (PMD), Pol III-related leukodystrophies, Refsum disease, salla disease (free sialic acid storage disease), Sjogren-Larsson syndrome,
  • Demyelinating or myelin related diseases or disorders which may be treated or ameliorated by the methods of the present disclosure include a disease or disorder characterized by a myelin deficiency. Insufficient myelination in the central nervous system has been implicated in a wide array of neurological disorders. Among these are forms of cerebral palsy in which a congenital deficit in forebrain myelination in children with periventricular leukomalacia, contributes to neurological morbidity (Goldman et al., 2008) Goldman, S. A., Schanz, S., and Windrem, M. S. (2008). Stem cell-based strategies for treating pediatric disorders of myelin. Hum Mol Genet.17, R76-83.
  • myelin loss and ineffective repair may contribute to the decline in cognitive function associated with senescence (Kohama et al., 2011) Kohama, S. G., Rosene, D. L., and Sherman, L. S. (2011) Age (Dordr). Age- related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline. Therefore, it is contemplated that effective compounds and methods of enhancing myelination and/or remyelination may have substantial therapeutic benefits in halting disease progression and restoring function in MS and in a wide array of neurological disorders.
  • the therapeutic agents of the present disclosure can be administered to a subject that does not have, and/or is not suspected of having, a myelin related disorder in order to enhance or promote a myelin dependent process.
  • compounds described herein can be administered to a subject to promote myelination of CNS neurons in order to enhance cognition, which is known to be a myelin dependent process, in cognitive healthy subjects.
  • compounds described herein can be administered, or formulated to be administered, in combination with cognitive enhancing (nootropic) agents.
  • Exemplary agents include any drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals.
  • Non limiting examples include racetams (e.g., piracetam, oxiracetam, and aniracetam), nutraceuticals (e.g., Bacopa monnieri, Panax ginseng, Ginko biloba, and GABA), stimulants (e.g., amphetamine pharmaceuticals, methylphenidate, eugeroics, xanthines, and nicotine), L-Theanine, Tolcapone, Levodopa, Atomoxetine, and Desipramine.
  • racetams e.g., piracetam, oxiracetam, and aniracetam
  • nutraceuticals e.g., Bacopa monnieri, Panax ginseng, Ginko biloba, and GABA
  • stimulants e.g., amphetamine pharmaceuticals, methylphenidate, eugeroics, xanthines, and nicotine
  • L-Theanine Tolcapone
  • the method or use includes administering to the subject, or formulating for administration, a therapeutically effective amount of EmtinB or a variant thereof and glatiramer acetate or an alternative pharmaceutically acceptable salt thereof as described above.
  • MS Multiple sclerosis
  • the demyelination observed in MS is not always permanent and remyelination has been documented in early stages of the disease.
  • methods of the present disclosure can promote myelination of CNS neurons in a subject, therefore leading to preserving, reforming, or enhancing neuronal myelin sheath in the subject.
  • MS disease activity can be monitored by magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses.
  • MRI magnetic resonance imaging
  • multiple sclerosis is a relapsing-remitting multiple sclerosis.
  • the treatment and/or prevention of multiple sclerosis is alleviating a symptom of relapsing-remitting multiple sclerosis in a subject suffering from relapsing-remitting multiple sclerosis or a subject who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis.
  • alleviating a symptom comprises reducing the frequency of relapses.
  • alleviating a symptom comprises reducing the mean cumulative number of Gd-enhancing lesions in the brain of the subject.
  • alleviating a symptom comprises reducing the mean number of new T 2 lesions in the brain of the subject.
  • alleviating a symptom comprises reducing the cumulative number of enhancing lesions on T1- weighted images. In some embodiments, alleviating a symptom comprises reducing brain atrophy in the subject. In some embodiments, alleviating a symptom comprises increasing the time to a confirmed relapse in the subject. In some embodiments, alleviating a symptom comprises reducing the total number of confirmed relapses in the subject. In some embodiments, alleviating a symptom comprises reducing the progression of MRI-monitored disease activity in the subject. In some embodiments, alleviating a symptom comprises reducing total volume of T 2 lesions in the subject.
  • alleviating a symptom comprises reducing the number of new hypointense lesions on enhanced T1 scans in the subject. In some embodiments, alleviating a symptom comprises reducing the total volume of hypointense lesions on enhanced T1 scans. In some embodiments, alleviating a symptom comprises reducing the level of disability as measured by EDSS Score in the subject. In some embodiments, alleviating a symptom comprises reducing the change in EDSS Score in the subject. In some embodiments, alleviating a symptom comprises reducing the change in Ambulation Index in the subject. In some embodiments, alleviating a symptom comprises reducing the level of disability as measured by EuroQoL (EQ5D) questionnaire in the subject.
  • EQ5D EuroQoL
  • alleviating a symptom comprises reducing the level of disability as measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire in the subject.
  • WPAI-GH General Health
  • the present disclosure provides the treatment and/or prevention of a genetic myelin disorder which results from the loss of myelin (demyelination) in a subject.
  • the method or use may further include administering to the subject, or formulating for administration, a therapeutically effective amount of one or more agents(s) that enhance and/or induce accumulation of ⁇ 8,9-unsaturated sterol intermediates of the cholesterol biosynthesis pathway in OPCs.
  • the genetic myelin disorder is a leukodystrophy such as, but not limited to Pelizaeus Merzbacher Disease (PMD).
  • PMD Pelizaeus Merzbacher Disease
  • Another strategy for treating a subject suffering from a neurodegenerative or demyelinating disease or disorder is to administer a therapeutically effective amount of the active therapeutic agents described herein along with a therapeutically effective amount of additional oligodendrocyte differentiation and/or proliferation inducing agent(s) and/or anti-neurodegenerative disease agent.
  • anti- neurodegenerative disease agents include L-dopa, cholinesterase inhibitors, anticholinergics, dopamine agonists, steroids (e.g.
  • the therapeutic agents described herein can be administered, or formulated to be administered, as part of a combination therapy with adjunctive therapies for treating neurodegenerative and myelin related or demyelinating disorders and diseases, such as, but not limited to, a second and different therapeutic agent and non-drug therapies (e.g., surgery).
  • the therapeutic agents to be administered in a combination therapy described herein can include at least one further anti-neurodegenerative agent.
  • such further anti- neurodegenerative agent is an immunotherapeutic agent.
  • An immunotherapeutic agent for use in the methods of the present invention can include therapies which target the immune component of the disease and/or the acute inflammatory response evidenced during an acute attack in remitting-relapsing multiple sclerosis.
  • therapies which target the immune component of the disease and/or the acute inflammatory response evidenced during an acute attack in remitting-relapsing multiple sclerosis.
  • immunomodulators such as interferon beta-1a and beta-1b (Avonex and Betaseron respectively), natalizumab (Tysabri), or mitoxantrone.
  • the “effective amount” of compounds and derivatives thereof used in the methods and uses of the present disclosure varies depending upon the manner of administration, the age and body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by those skilled in the art.
  • terapéuticaally effective amount refers to an amount (dose) effective in treating a subject, having, for example, a neurodegenerative disease (e.g., Parkinson’s, Alzheimer’s, or Huntington’s disease) such as a demyelinating disease (e.g., multiple sclerosis).
  • a neurodegenerative disease e.g., Parkinson’s, Alzheimer’s, or Huntington’s disease
  • a demyelinating disease e.g., multiple sclerosis
  • the therapeutic agents described herein may be administered, or formulated to be administered, in an amount effective to promote myelination of CNS neurons in a subject by an increase in the myelin sheath area of at least 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, or 1000% as compared to the myelin sheath area of untreated CNS neurons or subject.
  • the therapeutic agents described herein may be administered, or formulated to be administered, in an amount effective to promote survival of CNS neurons in a subject by an increase in the number of surviving neurons of at least 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, or 1000% as compared to the number of surviving neurons in untreated CNS neurons or subject.
  • the therapeutic agents described herein may be administered, or formulated to be administered, in an amount effective enhance growth of CNS neurites in the subject's central nervous system by an increase in the average neurite length of at least 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, or 1000% as compared to the length of neurites in untreated CNS neurites or subject.
  • Suitable dosage ranges of EmtinB or a variant thereof per kilo body weight are normally of the order of several hundred ⁇ g active ingredient per administration with a preferred range of from about 0.1 ⁇ g to 5000 ⁇ g per kilo body weight.
  • the suitable dosages may be in the range of from 0.1 ⁇ g to 5000 ⁇ g per kilo body weight, such as in the range of from about 0.1 ⁇ g to 3000 ⁇ g per kilo body weight, or in the range of from about 0.1 ⁇ g to 1000 ⁇ g per kilo body weight.
  • the suitable dosages may be in the range of from 0.1 ⁇ g to 1000 ⁇ g per kilo body weight, such as in the range of from about 0.1 ⁇ g to 750 ⁇ g per kilo body weight, or in the range of from about 0.1 ⁇ g to 500 ⁇ g per kilo body weight such as in the range of from about 0.1 ⁇ g to 250 ⁇ g per kilo body weight.
  • the dosage will also depend on the route of administration and will vary with the age and weight of the subject to be treated. For example, when administering nasally, smaller dosages are used than when administering by other routes. Administration may be performed once or may be followed by subsequent administrations.
  • dosage of multimeric forms is in the interval 1 mg to 70 mg per 70 kg body weight.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount in the range of from 10 mg to 700 mg.
  • the amount is in the range of from 10 mg to 70 mg, from 70 mg to 150 mg, from 150 mg to 230 mg, from 230 mg to 300 mg, from 300 mg to 380 mg, from 380 mg to 450 mg, from 450 mg to 600 mg, or from 600 mg to 700 mg.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount in the range of from 300 mg to 680 mg, or from 340 mg to 680 mg.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount of about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg,
  • the EmtinB or a variant thereof is administered in an amount of about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg.
  • the concentration of the EmtinB or a variant thereof in the pharmaceutical composition or formulation is about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg/m, about 660 mg, about 670 mg, or about 680 mg.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide from 10 ⁇ g to 200 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide from 10 ⁇ g to 20 ⁇ g, from 20 ⁇ g to 30 ⁇ g, from 30 ⁇ g to 40 ⁇ g, from 40 ⁇ g to 50 ⁇ g, from 50 ⁇ g to 60 ⁇ g, from 60 ⁇ g to 70 ⁇ g, from 70 ⁇ g to 80 ⁇ g, from 80 ⁇ g to 90 ⁇ g, from 90 ⁇ g to 100 ⁇ g, from 100 ⁇ g to 110 ⁇ g, from 110 ⁇ g to 120 ⁇ g, from 120 ⁇ g to 130 ⁇ g, from 130 ⁇ g to 140 ⁇ g, from 140 ⁇ g to 150 ⁇ g, from 150 ⁇ g to 160 ⁇ g, from 160 ⁇ g to 170 ⁇ g, from 170 ⁇ g to 180 ⁇ g, from 180 ⁇ g to 190 ⁇ g, or from 190 ⁇ g to 200 ⁇ g of EmtinB or
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide from 50 ⁇ g to 150 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is administered, for formulated to be administered, in an amount effective to provide from 15 ⁇ g to 250 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide about 15 ⁇ g, about 20 ⁇ g, about 25 ⁇ g, about 30 ⁇ g, about 35 ⁇ g, about 40 ⁇ g, about 45 ⁇ g, about 50 ⁇ g, about 55 ⁇ g, about 60 ⁇ g, about 65 ⁇ g, about 70 ⁇ g, about 75 ⁇ g, about 80 ⁇ g, about 85 ⁇ g, about 90 ⁇ g, about 95 ⁇ g, about 100 ⁇ g, about 105 ⁇ g, about 110 ⁇ g, about 115 ⁇ g, about 120 ⁇ g, about 125 ⁇ g, about 130 ⁇ g, about 135 ⁇ g, about 140 ⁇ g, about 145 ⁇ g, about 150 ⁇ g, about 155 ⁇ g, about 160 ⁇ g, about 165 ⁇ g, about 170 ⁇ g, about 175 ⁇ g, about 180 ⁇ g, about 185 ⁇ g,
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide from 30 ⁇ g to 70 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain. In some embodiments, the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide from 135 ⁇ g to 170 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide about 30 ⁇ g, about 35 ⁇ g, about 40 ⁇ g, about 45 ⁇ g, about 50 ⁇ g, about 55 ⁇ g, about 60 ⁇ g, about 65 ⁇ g, or about 70 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the EmtinB or a variant thereof is administered, or formulated to be administered, in an amount effective to provide about 135 ⁇ g, about 140 ⁇ g, about 145 ⁇ g, about 150 ⁇ g, about 155 ⁇ g, about 160 ⁇ g, about 165 ⁇ g, or about 170 ⁇ g of EmtinB or a variant thereof to the central nervous system or the brain.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be 10 to 80 mg; or 12 to 70 mg; or 14 to 60 mg; or 16 to 50 mg; or 18 to 40 mg; or 30 to 40 mg; or 40 mg; or 20 to 30 mg; or 20 mg, or 10 mg.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be in the range from 10 to 600 mg/week; or 100 to 550 mg/week; or 150 to 500 mg/week; or 200 to 450 mg/week; or 250 to 400 mg/week; or 300 to 350 mg/week; or 300 mg/week.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be in the range from 50 to 150 mg/day; or 60 to 140 mg/day; or 70 to 130 mg/day; or 80 to 120 mg/day; or 90 to 110 mg/day; or 100 mg/day.
  • the amount of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be in the range from 10 to 80 mg/day; or 12 to 70 mg/day; or 14 to 60 mg/day; or 16 to 50 mg/day; or 18 to 40 mg/day; or 30 to 40 mg/day; or 40 mg/day; or 19 to 30 mg/day; or 20 mg/day; or 10 to 20 mg/day; or 5 to 15 mg/day, or 5 to 10 mg/day, or 1 to 5 mg/day.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount in the range of from 1 mg to 40 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount in the range of from 20 mg to 40 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount in the range of from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 15 mg, from 15 mg to 20 mg, from 20 mg to 25 mg, from 25 mg to 30 mg, or from 35 mg to 40 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount in the range of from 1 mg to 10 mg or from 10 mg to 20 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount of from 1 mg to 20 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount of about 6 mg or about 12 mg.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount effective to provide from 1 ⁇ g to 20 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount effective to provide from 1 ⁇ g to 15 ⁇ g, from 2 ⁇ g to 14 ⁇ g, from 2 ⁇ g to 13 ⁇ g, from 2 ⁇ g to 12 ⁇ g, from 2 ⁇ g to 11 ⁇ g, from 2 ⁇ g to 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount effective to provide about 1 ⁇ g, about 2 ⁇ g, about 3 ⁇ g, about 4 ⁇ g, about 5 ⁇ g, about 6 ⁇ g, about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, or about 10 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, in an amount effective to provide about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, about 10 ⁇ g, about 11 ⁇ g, about 12 ⁇ g, about 13 ⁇ g, about 14 ⁇ g, about 15 ⁇ g, about 16 ⁇ g, about 17 ⁇ g, about 18 ⁇ g, about 19 ⁇ g, or about 20 ⁇ g of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof to the central nervous system or the brain.
  • the periodic administration of EmtinB or a derivative thereof is effected daily.
  • the EmtinB or a derivative thereof is formulated to be administered daily. In one embodiment, the periodic administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is effected daily. In one embodiment, the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is formulated to be administered daily. [309] In some embodiments, the periodic administration of EmtinB or a derivative thereof is effected twice daily at one half the amount. In some embodiments, the EmtinB or a derivative thereof is formulated to be administered twice daily at one half the amount. In some embodiments, the periodic administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is effected twice daily at one half the amount.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is formulated to be administered twice daily at one half the amount.
  • the periodic administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is effected once every 3 to 11 days; or once every 5 to 9 days; or once every 7 days; or once every 24 hours.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is formulated to be administered once every 3 to 11 days; or once every 5 to 9 days; or once every 7 days; or once every 24 hours.
  • the periodic administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be effected once every 16-32 hours; or once every 18-30 hours; or once every 20-28 hours; or once every 22-26 hours.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is formulated to be administered once every 16-32 hours; or once every 18-30 hours; or once every 20-28 hours; or once every 22-26 hours.
  • the administration of EmtinB or a derivative thereof substantially precedes the administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof.
  • the administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof substantially precedes the administration of EmtinB or a derivative thereof.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof and EmtinB or a derivative thereof may be administered, or formulated to be administered, for a period of time of at least 4 days. In a further embodiment, the period of time may be 5 days to 5 years; or 10 days to 3 years; or 2 weeks to 1 year; or 1 month to 6 months; or 3 months to 4 months.
  • glatiramer acetate or an alternative pharmaceutically acceptable salt thereof and EmtinB or a derivative thereof may be administered, or formulated to be administered, for the lifetime of the subject.
  • the administration, or formulation, of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof and EmtinB or a derivative thereof may each independently be oral, nasal, pulmonary, parenteral, intravenous, intraarticular, transdermal, intradermal, subcutaneous, topical, intramuscular, rectal, intrathecal, intraocular, buccal or by gavage.
  • EmtinB or a derivative thereof may be administered, or formulated to be administered, subcutaneously, intravenously, orally, rectally, transdermally, or parenterally.
  • the preferred route of administration for EmtinB or a derivative thereof is subcutaneous, intravenous or oral. In some embodiments, the preferred route of administration for glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is subcutaneous or oral.
  • the administration of glatiramer acetate or an alternative pharmaceutically acceptable salt thereof may be subcutaneous, intraperitoneal, intravenous, intramuscular, intraocular or oral and the administration of EmtinB or a derivative thereof may be subcutaneous.
  • the administration of both glatiramer acetate or an alternative pharmaceutically acceptable salt thereof and EmtinB or a derivative thereof may be subcutaneous.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, subcutaneously, intraperitoneally, intravenously, intramuscularly, intraocularly or orally.
  • the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof is administered, or formulated to be administered, subcutaneously.
  • the EmtinB or a derivative thereof is administered, or formulated to be administered, subcutaneously.
  • both the glatiramer acetate or an alternative pharmaceutically acceptable salt thereof and the EmtinB or a derivative thereof are administered, or formulated to be administered, subcutaneously.
  • the present disclosure is further described by the following example, which is not intended to limit the scope of the claims.
  • Example 1 Myelination in the CNS involves sequential developmental processes in which OPCs migrate, proliferate, and differentiate into newly formed oligodendrocytes, then those oligodendrocytes (OL) selected by target-dependent survival mechanisms wrap myelin membrane around the axons to form the sheath.
  • Each oligodendrocyte can myelinate many axons, with the number of wraps proportional to the axon diameter and regulated tightly by reciprocal signalling between oligodendrocyte and axons.
  • a reproducible in vitro model of CNS myelination was used based on primary co-cultures of central neurons and OL culturing in 96-well plates and then adapted to high content screening.
  • the aim of this study was to investigate the effect of EmtinB at two concentrations, in combination or not with Copaxone, on myelin formation. For that a usual marker of myelination process by OL, MAG (Myelin Associated Glycoprotein), was quantified.
  • MAP2 antibody Microtubule Associated Protein 2
  • Rat cortical neurons cell culture Rat cortical neurons were cultured as described by Singer (1999). Briefly pregnant female rats of 15 days gestation were killed by cervical dislocation (Rats Wistar; Janvier Lab) and the foetuses were removed from the uterus.
  • the cortex was removed and placed in ice-cold medium of Leibovitz 15 (L15; PanBiotech, Ref P04- 27055, Batch: 8770122) containing 2% of Penicillin-Streptomycin (PS; PanBiotech, ref: P06-07100, Batch: 9300621) and 1% of bovine serum albumin (BSA; PanBiotech, Ref: P06-1391100, Batch: H210914). Cortex were dissociated by trypsinisation for 20 minutes (min) at 37°C (Trypsin EDTA 1X; PanBiotech, Ref: P10-023100, Batch: 3080821).
  • the reaction was stopped by the addition of Dulbecco’s modified Eagle’s medium (DMEM; PanBiotech, Ref: P04-03600, Batch: 4070921) containing DNase I grade II (0.1 mg/ml; PanBiotech, Ref: P60-37780100, Batch: H181015) and 10% of fetal calf serum (FCS; Invitrogen, Ref: 10270106, Batch: 2437712).
  • DMEM Dulbecco’s modified Eagle’s medium
  • FCS fetal calf serum
  • FCS fetal calf serum
  • Cells were then mechanically dissociated by 3 passages through a 10 ml pipette. Cells were then centrifuged at 515 x g for 10 min at 4°C.
  • the supernatant was discarded and the cells pellet was re-suspended in a defined culture medium consisting of Neurobasal (Invitrogen, Ref: 11570556, Batch: 2508186) supplemented with B27 (Invitrogen, ref: 11530536, Batch: 2415372), L-glutamine (2 mM; PanBiotech, Ref: P04-80100, Batch: 7511020), 2% PS and 10 ng/ml of platelet-derived growth factor (PDGF-AA, PanBiotech, Ref: CB-3410010, Batch: H200116). Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test.
  • the cells were seeded at a density of 30000 cells/well in 96-well plates pre-coated with poly-D-lysine (PDL, Greiner, Ref: 655940, Batch: E200933A).
  • PDL poly-D-lysine
  • EmtinB poly-D-lysine
  • End point evaluation Measure of neuron survival, axonal length and total number of OL feet around axon.
  • cells were fixed by a solution of 4% paraformaldehyde (Alpha Aesar, ref J19943, Batch: 211457) for 20 min at room temperature. The cells were then permeabilized and non-specific sites were blocked with a solution of phosphate buffered saline (PBS; PanBiotech; ref: P04-36500, Batch: 8240722) containing 0.1% of saponin (Sigma; ref: S7900, Batch: BCBL8667V) and 1% FCS for 15 min at room temperature.
  • PBS phosphate buffered saline
  • MAG Myelin Associated Glycoprotein polyclonal antibody
  • MAB1567 a rabbit anti-Myelin Associated Glycoprotein polyclonal antibody
  • MAP2 a chicken anti-Microtubule Associated Protein 2
  • All antibodies were diluted in PBS containing 1% FCS, 0.1 % saponin, and will be incubated for 2 hours at room temperature.
  • EmtinB has no significant impact on neurons survival (121% of the control).
  • a treatment of 19 days with Copaxone at 10 ⁇ g/mL and 3 ⁇ g/mL does not modulate the cortical neurons survival (respectively 123% and 129% of the control).
  • EmtinB at 150 ⁇ g/mL, during 19 days induces a slight but non-significant increase of neurites length (130% of the control).
  • EmtinB at 50 ⁇ g/mL, during 19 days induces a significant increase of neurites length (154% of the control, p ⁇ 0.001).
  • a treatment of 19 days with Copaxone at 10 ⁇ g/mL and 3 ⁇ g/mL significantly increases the neurites length (respectively 153% with p ⁇ 0.001 and 167% of the control, p ⁇ 0.0001).
  • EmtinB at 50 ⁇ g/mL is able to increase myelin sheath but not in a statistically significant manner (141% of the control, ns).
  • a treatment of 19 days with Copaxone at 10 ⁇ g/mL significantly increases the myelin sheath area around cortical neurons (167% of the control, p ⁇ 0.05).
  • Copaxone at 3 ⁇ g/mL has no significant impact on myelin sheath area around cortical neurons (137% of the control).
  • a 19-day treatment with Copaxone at 3 ⁇ g/mL and 10 ⁇ g/mL is not able to modulate cortical neurons survival but significantly increase their neurites length as well as the myelin formation around cortical neurons in a significant way for the highest concentration tested of 10 ⁇ g/mL.
  • a 19-day treatment with ⁇ - estradiol at 50nM promotes neurites length and cortical neurons survival as well as the myelin formation around cortical neurons.
  • a treatment with EmtinB, during 19 days, promotes cortical neurons survival and myelin sheath formation with a significant effect at 150 ⁇ g/mL.
  • EmtinB tends to increase neurites length of cortical neurons with a significant effect observed at 50 ⁇ g/mL.
  • Metallothionein and a peptide modeled after metallothionein, EmtinB induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. J Neurochem.2008 Jan;104(1):21-37. [361] Charles P, Hernandez MP, Stankoff B, Aigrot MS, Colin C, Rougon G, Zalc B, Lubetzki C. (2000) Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule, Proc Natl Acad Sci U S A. Jun 20;97(13):7585-90.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions, des combinaisons et des formulations ainsi que des procédés et des utilisations pour améliorer la survie neuronale, la croissance des neurites et la formation de myéline. La présente invention concerne également des procédés et des utilisations pour le traitement de maladies ou de troubles chez des sujets chez lesquels la stimulation de la survie neuronale, de la croissance des neurites, de la myélinisation ou de la remyélinisation est bénéfique.
PCT/AU2023/051207 2022-11-24 2023-11-24 Compositions neuroprotectrices et procédés Ceased WO2024108269A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2022903564 2022-11-24
AU2022903564A AU2022903564A0 (en) 2022-11-24 Neuroprotective compositions and methods

Publications (1)

Publication Number Publication Date
WO2024108269A1 true WO2024108269A1 (fr) 2024-05-30

Family

ID=91194792

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2023/051207 Ceased WO2024108269A1 (fr) 2022-11-24 2023-11-24 Compositions neuroprotectrices et procédés

Country Status (1)

Country Link
WO (1) WO2024108269A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093177A2 (fr) * 2006-02-14 2007-08-23 Vladimir Berezin Fragments de peptides derives de la metallothioneine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093177A2 (fr) * 2006-02-14 2007-08-23 Vladimir Berezin Fragments de peptides derives de la metallothioneine

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AMBJØRN MALENE, ASMUSSEN JOHANNE W., LINDSTAM MATS, GOTFRYD KAMIL, JACOBSEN CHRISTIAN, KISELYOV VLADISLAV V., MOESTRUP SØREN K., P: "Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low‐density lipoprotein receptor family", JOURNAL OF NEUROCHEMISTRY, WILEY-BLACKWELL PUBLISHING LTD., GB, vol. 104, no. 1, 1 January 2008 (2008-01-01), GB , pages 21 - 37, XP093177548, ISSN: 0022-3042, DOI: 10.1111/j.1471-4159.2007.05036.x *
ASMUSSEN, J.W. ; AMBJORN, M. ; BOCK, E. ; BEREZIN, V.: "Peptides modeled after the @a-domain of metallothionein induce neurite outgrowth and promote survival of cerebellar granule neurons", EUROPEAN JOURNAL OF CELL BIOLOGY, WISSENSCHAFLICHE VERLAGSGESELLSCHAFT, STUTTGART,, DE, vol. 88, no. 8, 1 August 2009 (2009-08-01), DE , pages 433 - 443, XP026191667, ISSN: 0171-9335, DOI: 10.1016/j.ejcb.2009.04.001 *
LIDDELOW MATTHEW, LEEDMAN, BRIAN: "EmtinB more effective than Copaxone*) at myelin formation in MS model", ASX ANNOUNCEMENT, 14 July 2020 (2020-07-14), pages 1 - 2, XP093177550, Retrieved from the Internet <URL:https://wcsecure.weblink.com.au/pdf/NSB/02254591.pdf> *
MCKEAGE KATE: "Glatiramer Acetate 40 mg/mL in Relapsing–Remitting Multiple Sclerosis: A Review", CNS DRUGS, ADIS INTERNATIONAL, AUCKLAND, NZ, vol. 29, no. 5, 1 May 2015 (2015-05-01), AUCKLAND, NZ , pages 425 - 432, XP009555098, ISSN: 1172-7047, DOI: 10.1007/s40263-015-0245-z *
PERTH, AUSTRALIA: "Full report from Multiple Sclerosis study: EmtinB significantly increased survival of neuronal cells, axonal regeneration and remyelination in comparison to Copaxone®", ASX ANNOUNCEMENT, NEUROSCIENTIFIC, 4 August 2020 (2020-08-04), pages 1 - 2, XP093177710, Retrieved from the Internet <URL:https://wcsecure.weblink.com.au/pdf/NSB/02262725.pdf> *
SONN KATRIN, PANKRATOVA STANISLAVA, KORSHUNOVA IRINA, ZHARKOVSKY ALEXANDER, BOCK ELISABETH, BEREZIN VLADIMIR, KIRYUSHKO DARYA: "A metallothionein mimetic peptide protects neurons against kainic acid‐induced excitotoxicity", JOURNAL OF NEUROSCIENCE RESEARCH, WILEY-LISS, US, vol. 88, no. 5, 1 April 2010 (2010-04-01), US , pages 1074 - 1082, XP093177549, ISSN: 0360-4012, DOI: 10.1002/jnr.22281 *
ZECCA CHIARA, CAPORRO MATTEO, DISANTO GIULIO, GOBBI CLAUDIO: "Two decades of subcutaneous glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing–remitting multiple sclerosis treatment", PATIENT PREFERENCE AND ADHERENCE, DOVE PRESS LIMITED, pages 1123, XP093177546, ISSN: 1177-889X, DOI: 10.2147/PPA.S68698 *

Similar Documents

Publication Publication Date Title
JP6403062B2 (ja) 組織修復活性組成物及びその利用
HUP0400005A2 (hu) Oszteopontin alkalmazása neurológiai megbetegedések gyógykezelésére és/vagy megelőzésére
KR20170104457A (ko) 신경변성 장애
DK2440225T3 (en) UNKNOWN UNUSED HIP / PAP OR DERIVATIVES THEREOF
CN101534648B (zh) 使用mntf肽及其类似物治疗神经紊乱的方法
KR20050119149A (ko) 말초 신경 질환의 치료 및/또는 예방을 위한 클루스테린의용도
EP2968441A1 (fr) Méthodes de traitement de la sclérose en plaques
WO2024108269A1 (fr) Compositions neuroprotectrices et procédés
CA2716392C (fr) Compositions de facteurs motoneurotrophiques et procedes d&#39;utilisation de ces peptides
US11344607B2 (en) Treatment of disease with relaxin
US20170137483A1 (en) Use of epo-derived peptide fragments for the treatment of inflammatory diseases
KR20180058843A (ko) 짧은 합성 펩티드 및 그의 용도
WO2011053191A1 (fr) Médicament pour le traitement de maladies et de troubles liés à des états de stress et affectant l&#39;être humain et les animaux, et méthode de traitement et/ou de prophylaxie utilisant ce médicament
US20240342238A1 (en) Peptide having obesity and muscle loss inhibitory activities, and use thereof
US10160791B2 (en) Protamine in treatment of neuronal injuries
US10293026B2 (en) Agent for preventing or treating demyelinating disease
US20070148159A1 (en) Use of crotoxin as an analgesic - CIP
JP2021525261A (ja) 代謝疾患の治療におけるｉｇｆｂｐ−２のヘパリン結合ドメイン
KR101615161B1 (ko) 신경질환의 예방 또는 치료를 위한 icam-1의 용도
MX2007010717A (es) Combinacion de egf/ghrp-6 para la neuroregeneracion del sistema nervioso central posterior al dano autoinmune.
CN106456571A (zh) 用于治疗机械性神经元损伤的新组合物
CA2856451A1 (fr) Methode de traitement de la douleur par administration de facteur de croissance du nerf

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23892811

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE