WO2016066700A1 - New indication for alpha-msh analogues - Google Patents
New indication for alpha-msh analogues Download PDFInfo
- Publication number
- WO2016066700A1 WO2016066700A1 PCT/EP2015/075017 EP2015075017W WO2016066700A1 WO 2016066700 A1 WO2016066700 A1 WO 2016066700A1 EP 2015075017 W EP2015075017 W EP 2015075017W WO 2016066700 A1 WO2016066700 A1 WO 2016066700A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alpha
- msh
- msh analogue
- compound
- use according
- Prior art date
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
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
-
- 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
- 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
- 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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
Definitions
- the present invention is directed to a compound for use in treatment of a human subject with a medical indication, to a method of treating neurodegenerative disorders, and to a use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a human subject.
- CNS Central Nervous System
- the present invention relates to an alpha-MSH analogue for use in treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is between at least 6 weeks and at most 8 weeks.
- the disorder is a juvenile form of the neurodegenerative disorder.
- the neurodegenerative disorder is Multiple Sclerosis.
- the neurodegenerative disorder is dementia.
- the neurodegenerative disorder is Alzheimer's Disease.
- the neurodegenerative disorder is Parkinson's Disease.
- the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS).
- the neurodegenerative disorder is Huntington's Disease.
- the alpha-MSH analogue is administered systemically.
- the alpha-MSH analogue is administered subcutaneously.
- the alpha-MSH analogue is present in the blood plasma of the subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration.
- the alpha-MSH analogue is a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MCIR), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.
- the alpha-MSH analogue is afamelanotide.
- the invention relates to a method of treating neurodegenerative disorders by administering an alpha-MSH analogue to a human subject suffering from
- the invention relates to the use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks and at most 8 weeks.
- the invention allows for effective yet safe and convenient treatment of neurodegenerative disorders using alpha-MSH analogues.
- treatment is defined as encompassing prevention of a disorder.
- alpha-MSH analogues are effective in treatment of CNS disorder of human subjects, preferably neurodegenerative disorders.
- neurodegenerative disorders are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral structures of the nervous system.
- neurodegenerative disorders preferably include the diseases of Multiple Sclerosis, Alzheimer's Disease and other dementias, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS) and which is also called Lou Gehrig's Disease, Huntington's Disease, Degenerative Nerve Diseases, Encephalitis, Epilepsy, Genetic Brain Disorders, Head and Brain Malformations, Hydrocephalus, Stroke, and Prion Diseases.
- the present invention is directed to the above-mentioned neurodegenerative disorders, preferably the juvenile form thereof, each separately and as a group.
- the present invention is directed to Multiple Sclerosis, preferably the juvenile form which is defined according to the invention as occurring before the age of 18 years.
- the present invention is directed to dementia, preferably the juvenile form.
- the present invention is directed to Alzheimer's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 65 years.
- the present invention is directed to Parkinson's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 20 years.
- the present invention is directed to Amyotrophic Lateral Sclerosis (ALS) which is often called Lou Gehrig's Disease, and preferably the juvenile form which is defined according to the invention as occurring before the age of 25 years.
- ALS Amyotrophic Lateral Sclerosis
- the present invention is directed to Huntington's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 20 years.
- the human subject is preferably exposed to alpha-MSH analogue at a blood plasma level of at least 0.01ng/ml, more preferably at least 0.lng/ml, most preferably at least lng/ml and preferably at most 20ng/ml, more preferably at most 15ng/ml, most preferably at most l0ng/ml.
- exposure is for at least 1 day, more preferably at least 2 days, more preferably at least 5 days and preferably at most 30 days, more preferably at most 20 days, most preferably at most 15 days and particularly preferred for at most 10 days, for instance for 7 days or for 10 days.
- alpha-MSH analogue blood plasma levels are achieved after each alpha-MSH analogue administration.
- the alpha-MSH analogue will be present in the blood plasma of the subject at a level and the time period indicated.
- the alpha-MSH analogue is administered in an amount that results in the blood plasma levels indicated. Accordingly, the human subject is subjected to the blood plasma levels indicated.
- the alpha-MSH analogue is administered subcutaneously.
- Preferred systemic administration of the alpha-MSH analogue of the invention is by way of an injection, more preferably by way of a subcutaneously injected implant.
- Preferred systemic administration is by way of a controlled-release formulation.
- the alpha-MSH analogue is at least 2 times administered subsequently to a subject, more preferably at least 3 times, most preferably at least 5 times and for instance up to 20 times.
- the interval between subsequent administrations is at least 2 weeks, more preferably at least 4 weeks, most preferably at least 5 weeks, and most preferably at least 6 weeks and preferably at most 10 weeks, more preferably at most 9 weeks, most preferably at most 8 weeks.
- a particularly preferred range for the interval between subsequent administrations of the alpha-MSH analogue is from 6 to 8 weeks. It will be understood that for the purpose of the invention, intervals are separate and subsequent and do not overlap.
- alpha-MSH analogues are directed to alpha-MSH analogues.
- alpha- MSH analogue as used herein is defined as a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1R), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.
- M1R melanocortin-l-receptor
- alpha-MSH analogues include derivatives in which (i) one or more amino acid residues are deleted from the native alpha- MSH molecule at the N-terminal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native alpha-MSH molecule are replaced by another natural, non- natural or synthetic amino acid residue; and/or (iii) an intra-molecular interaction forms as a cyclic derivative.
- Several derivatives of alpha-MSH have been synthesized. In one aspect of the present invention, the alpha-MSH analogues described in US Patents Nos.
- alpha-MSH analogues 4,457,864, 4,485,039, 4,866,038, 4,918,055, 5,049,547, 5,674,839 and 5,714,576 and Australian Patents Nos. 597630 and 618733, which are herein incorporated by reference for their teachings with respect to alpha-MSH analogues and their synthesis thereof, can be used herein.
- the alpha- MSH analogue may be used as such or in the form of a pharmaceutically acceptable salt thereof.
- Preferred examples of such salts are acetate, trifluoroacetate, sulphate, and chloride salts.
- the acetate salt is generally most preferred.
- the alpha-MSH analogue is a non-radiation emitting analogue, i.e. the compound is not radioactive that can be damaging to the body.
- the alpha-MSH analogue emits low and preferably no radiation including alpha, beta and/or gamma radiation at the level or lower than average background radiation levels.
- the alpha-MSH analogue is selected from the group consisting of:
- M is Met, Nle or Lys
- Ri is absent, n-pentadecanoyl, Ac, 4-phenylbutyryl, Ac-Gly-, Ac-Met-Glu, Ac-Nle-Glu-, or Ac-Tyr-Glu-;
- W is -His- or-D-His-;
- X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pN0 2 )D-Phe 7 -;
- Y is -Arg- or -D-Arg-;
- Z is -Trp- or -D-Trp-;
- R 2 is -NH 2 ; -Gly-NH 2 ; or-Gly-Lys-NH 2 , as disclosed in Australian Patent No. 597630.
- alpha-MSH analogue may be a linear analogue as disclosed in US
- the alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
- alpha-MSH analogue is preferably selected from the group consisting of:
- alpha-MSH analogues thereof are selected from the group consisting of:
- the alpha-MSH analogue is a cyclic peptide of formula (I): Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y (I)
- Z is H or an N-terminal group wherein the N-terminal group is preferably a Q to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyi, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain and more preferably is a C 1 to C 7 acyl group;
- Xaa 1 is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and preferably an amino with a side chain including a linear or branched alkyl, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl, and more preferably is an L- or D-isomer of NIe;
- Xaa 4 is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally wherein the ring is substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl, and is preferably D-Phe, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C
- Xaa 5 is L- or D-Pro or an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether and preferably is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap;
- Xaa 7 is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and is preferably an amino acid with a side chain including at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, -O-alky
- Y is a C-terminal group and in another aspect preferably a hydroxyl, an amide, or an amide substituted with one or two linear or branched Q to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.
- Preferred cyclic alpha-MSH analogues are Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH 2 and Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dap)-Trp-NH 2 .
- amino acids are defined in US2013/0296256 pages 5 and 6 which are incorporated herein by reference.
- alkene alkenyl
- alkyl alkyne
- aryl alkyl
- alkyne alkyne
- aryl alkyne
- aralkyl aliphatic
- the most preferred alpha-MSH analogue is [Nle 4 , D-Phe 7 ]- alpha-MSH.
- NDP-MSH NDP-MSH
- It is also generically known as afamelanotide, which is available as an implant formulation under the trademark SCENESSE ® .
- the alpha-MSH analogue is administered in a composition.
- the composition is a slow release formulation, resulting in longer and/or more controlled exposure of the body to the drug.
- the composition is an implant.
- the alpha-MSH analogue is administered in a prolonged release formulation such as described in US2008305152 (equivalent to WO2006/012667), the disclosure of which is included herein by reference.
- the composition preferably comprises at least 5mg of the alpha-MSH analogue, more preferably at least lOmg and preferably at most 30mg, more preferably at most 25mg of the alpha-MSH analogue. Particularly preferred amounts are 20mg or 16mg of the alpha-MSH analogue of which 16mg of the alpha-MSH analogue is the most preferred.
- the composition comprises a controlled release formulation.
- the implant (or rod) comprises a biodegradable polymer, wherein the alpha-MSH analogue is imbedded within the implant.
- the alpha- MSH analogue is encapsulated in an implant composed of poly-(lactide-co-glycolide), poly- (lactide), poly-(glycolide) or a mixture thereof.
- Lactide/glycolide polymers for drug-delivery formulations are typically made by melt polymerization through the ring opening of lactide and glycolide monomers. Some polymers are available with or without carboxylic acid end groups.
- the end group of the poly-(lactide-co-glycolide), poly-(lactide), or poly- (glycolide) is not a carboxylic acid, for example, an ester, then the resultant polymer is referred to herein as blocked or capped.
- the unblocked polymer conversely, has a terminal carboxylic group.
- linear lactide/glycolide polymers are used; however star polymers can be used as well.
- high molecular weight polymers can be used for medical devices, for example, to meet strength requirements.
- the lactide portion of the polymer has an asymmetric carbon. Commercially racemic DL-, L-, and D-polymers are available.
- the L- polymers are more crystalline and resorb slower than DL- polymers.
- copolymers comprising glycolide and DL-lactide or L-lactide
- copolymers of L-lactide and DL-lactide are available.
- homo-polymers of lactide or glycolide are available.
- the amount of lactide and glycolide in the polymer can vary.
- the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolide, wherein the amount of lactide and glycolide is 100 mole %.
- the biodegradable polymer can be poly-(lactide), 85:15 poly-(lactide-co-glycolide), 75:25 poly-(lactide-co-glycolide), or 65:35 poly-lactide-co-glycolide) where the ratios are mole ratios.
- the biodegradable polymer when the biodegradable polymer is poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide), the polymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30°C.
- the implant preferably comprises alpha-MSH analogue in an amount of from 5% to 60%, more preferably from 10% to 50%, most preferably from 15% to 40%, and in particularly preferred from 15% to 30% by weight of the implant.
- alpha-MSH analogue in an amount of from 5% to 60%, more preferably from 10% to 50%, most preferably from 15% to 40%, and in particularly preferred from 15% to 30% by weight of the implant.
- a preferred implant comprising afamelanotide is available under the name of SCENESSE ® in Italian and Swiss markets.
- the pharmaceutically-acceptable component can include a fatty acid, a sugar, a salt, a water- soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low- molecular- weight porosigen such as polymer or a salt or sugar, or a hydrophobic low- molecular-weight compound such as cholesterol or a wax.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention is directed to alpha-MSH analogues for treatment of neurodegenerative disorders.
Description
NEW INDICATION FOR ALPHA-MSH ANALOGUES
Technical field
The present invention is directed to a compound for use in treatment of a human subject with a medical indication, to a method of treating neurodegenerative disorders, and to a use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a human subject.
Background to the invention
Many studies have been conducted to investigate cause and treatment of Central Nervous System (CNS) disorders. Most studies are based on animal models. However, there remains a need for further improvements, including efficacy and safety aspects.
Summary of the invention
According to the invention, we have found surprising benefits of the particular use of alpha- MSH analogues in treatment and/or prevention of Central Nervous System (CNS) disorders. Accordingly, the present invention relates to an alpha-MSH analogue for use in treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is between at least 6 weeks and at most 8 weeks. Preferably, the disorder is a juvenile form of the neurodegenerative disorder. In one aspect, the neurodegenerative disorder is Multiple Sclerosis. In another aspect, the neurodegenerative disorder is dementia. In another aspect, the neurodegenerative disorder is Alzheimer's Disease. In another aspect, the neurodegenerative disorder is Parkinson's Disease. In another aspect, the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS). In another aspect, the neurodegenerative disorder is Huntington's Disease.
Preferably, the alpha-MSH analogue is administered systemically. Preferably, the alpha-MSH analogue is administered subcutaneously. Preferably, the alpha-MSH analogue is present in the blood plasma of the subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration. Preferably, the alpha-MSH analogue is a
derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MCIR), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Preferably, the alpha-MSH analogue is afamelanotide. In another aspect, the invention relates to a method of treating neurodegenerative disorders by administering an alpha-MSH analogue to a human subject suffering from
neurodegenerative disorder, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks and at most 8 weeks. In another aspect, the invention relates to the use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks and at most 8 weeks. We have surprisingly found that the invention allows for effective yet safe and convenient treatment of neurodegenerative disorders using alpha-MSH analogues.
Details description of the invention
For the purpose of this invention, treatment is defined as encompassing prevention of a disorder.
According to the invention, we have surprisingly found that alpha-MSH analogues are effective in treatment of CNS disorder of human subjects, preferably neurodegenerative disorders. For the purpose of this invention, neurodegenerative disorders are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral structures of the nervous system. According to the invention, neurodegenerative disorders preferably include the diseases of Multiple Sclerosis, Alzheimer's Disease and other dementias, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS) and which is also called Lou Gehrig's Disease, Huntington's Disease, Degenerative Nerve Diseases, Encephalitis, Epilepsy, Genetic Brain Disorders, Head and Brain Malformations, Hydrocephalus, Stroke, and Prion Diseases.
Accordingly, in one aspect, the present invention is directed to the above-mentioned neurodegenerative disorders, preferably the juvenile form thereof, each separately and as a group. In another aspect, the present invention is directed to Multiple Sclerosis, preferably the juvenile form which is defined according to the invention as occurring before the age of 18 years. In another aspect, the present invention is directed to dementia, preferably the juvenile form. In another aspect, the present invention is directed to Alzheimer's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 65 years. In another aspect, the present invention is directed to Parkinson's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 20 years. In another aspect, the present invention is directed to Amyotrophic Lateral Sclerosis (ALS) which is often called Lou Gehrig's Disease, and preferably the juvenile form which is defined according to the invention as occurring before the age of 25 years. In another aspect, the present invention is directed to Huntington's Disease, preferably the juvenile form which is defined according to the invention as occurring before the age of 20 years.
According to the invention, the human subject is preferably exposed to alpha-MSH analogue at a blood plasma level of at least 0.01ng/ml, more preferably at least 0.lng/ml, most preferably at least lng/ml and preferably at most 20ng/ml, more preferably at most 15ng/ml, most preferably at most l0ng/ml. Preferably, exposure is for at least 1 day, more preferably at least 2 days, more preferably at least 5 days and preferably at most 30 days, more preferably at most 20 days, most preferably at most 15 days and particularly preferred for at most 10 days, for instance for 7 days or for 10 days. It will be understood that these alpha-MSH analogue blood plasma levels are achieved after each alpha-MSH analogue administration. As will be understood by a skilled person in the art, after initial alpha-MSH analogue release and absorption by the subject into the blood plasma, the alpha-MSH analogue will be present in the blood plasma of the subject at a level and the time period indicated. Thus, the alpha-MSH analogue is administered in an amount that results in the blood plasma levels indicated. Accordingly, the human subject is subjected to the blood plasma levels indicated.
It is preferred according to the present invention to administer the alpha-MSH analogue systemically. Preferably, the alpha-MSH analogue is administered subcutaneously. Preferred systemic administration of the alpha-MSH analogue of the invention is by way of an injection,
more preferably by way of a subcutaneously injected implant. Preferred systemic administration is by way of a controlled-release formulation.
According to a preferred treatment of the invention, the alpha-MSH analogue is at least 2 times administered subsequently to a subject, more preferably at least 3 times, most preferably at least 5 times and for instance up to 20 times. Preferably, the interval between subsequent administrations is at least 2 weeks, more preferably at least 4 weeks, most preferably at least 5 weeks, and most preferably at least 6 weeks and preferably at most 10 weeks, more preferably at most 9 weeks, most preferably at most 8 weeks. According to the invention, a particularly preferred range for the interval between subsequent administrations of the alpha-MSH analogue is from 6 to 8 weeks. It will be understood that for the purpose of the invention, intervals are separate and subsequent and do not overlap.
According to one aspect, the invention is directed to alpha-MSH analogues. The term "alpha- MSH analogue" as used herein is defined as a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1R), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Such alpha-MSH analogues include derivatives in which (i) one or more amino acid residues are deleted from the native alpha- MSH molecule at the N-terminal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native alpha-MSH molecule are replaced by another natural, non- natural or synthetic amino acid residue; and/or (iii) an intra-molecular interaction forms as a cyclic derivative. Several derivatives of alpha-MSH have been synthesized. In one aspect of the present invention, the alpha-MSH analogues described in US Patents Nos. 4,457,864, 4,485,039, 4,866,038, 4,918,055, 5,049,547, 5,674,839 and 5,714,576 and Australian Patents Nos. 597630 and 618733, which are herein incorporated by reference for their teachings with respect to alpha-MSH analogues and their synthesis thereof, can be used herein. The alpha- MSH analogue may be used as such or in the form of a pharmaceutically acceptable salt thereof. Preferred examples of such salts are acetate, trifluoroacetate, sulphate, and chloride salts. The acetate salt is generally most preferred.
Preferably, according to the invention, the alpha-MSH analogue is a non-radiation emitting analogue, i.e. the compound is not radioactive that can be damaging to the body. In other words, the alpha-MSH analogue emits low and preferably no radiation including alpha, beta and/or gamma radiation at the level or lower than average background radiation levels.
In one aspect of the invention, the alpha-MSH analogue is selected from the group consisting of:
(a) compounds of the formula:
Ac-Ser-Tyr-Ser-M-Gln-His-D-Phe-Arg-Trp-6ly-Lys-Pro-Val-NH2
wherein M is Met, Nle or Lys; and
(b) compounds of the formula:
RrW-X-Y-Z-R2
wherein
Ri is absent, n-pentadecanoyl, Ac, 4-phenylbutyryl, Ac-Gly-, Ac-Met-Glu, Ac-Nle-Glu-, or Ac-Tyr-Glu-;
W is -His- or-D-His-;
X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pN02)D-Phe7-;
Y is -Arg- or -D-Arg-;
Z is -Trp- or -D-Trp-; and
R2 is -NH2; -Gly-NH2; or-Gly-Lys-NH2 , as disclosed in Australian Patent No. 597630.
In another aspect, the alpha-MSH analogue may be a linear analogue as disclosed in US
5674,839, and selected from the group consisting of:
Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2,
Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2,
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2,
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2,
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2,
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH2,
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2,
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH2,
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH2,
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH2,
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH2,
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dpr-NH2,
Ac-Nle-Glu-His-Phe-Arg-Trp-Lys-NH2, and
Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-NH2.
In another aspect, the alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
Ac - NIe - Glu- His- D-Phe -Arg -Trp - Lys - Gly - Pro -Val -NH2,
Ac - NIe- Glu - His - D-Phe - Arg - Trp - Lys-NH2, Ac- NIe - Asp - His - D-Phe - Arg - Trp - Lys-NH2,
Ac- NIe - Asp - His - D-Phe - Arg - Trp - Orn-NH2,
Ac- NIe - Asp - His - D-Phe - Arg - Trp - Dab
Ac- NIe - Asp - His - D-Phe - Arg - Trp -Dpr-NH2,
Ac- Ser -Tyr - Ser- NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH2,
Ac- Ser - Try - Ser -NIe- Asp - His - D-Phe - Arg - Trp - Lys-NH
Ac-Tyr - Ser- NIe -Asp- His - D-Phe - Arg - Trp - Lys-NH2,
Ac- Ser - NIe - Asp - His - D-Phe - Arg - Trp - Lys-NH2,
- NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-NH
Ac- NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-NH2,
Ac - NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH2, and
- Ser - NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH2 wherein Ala = alanine, Arg = arginine, Dab - 2,4-diaminobutyric acid, Dpr = 2,3- diaminopropionic acid, Glu = glutamic acid, Gly = glycine, His = histidine, Lys = lysine, Met = methionine, NIe = norleucine, Orn = ornithine, Phe = phenylalanine, (pN02)Phe =
paranitrophenylalanine, Pig = phenylglycine, Pro = proline, Ser = serine, Trp = tryptophan, TrpFor = N1 formyl-tryptophan, Tyr = tyrosine, Val = valine.
All peptides are written with the acyl-terminal end at the left and the amino terminal end to the right; the prefix "D" before an amino acid designates the D-isomer configuration, and unless specifically designated otherwise, all amino acids are in the L-isomer configuration. n another aspect, the alpha-MSH analogue is preferably selected from the group consisting of:
In another aspect, the alpha-MSH analogue is a cyclic peptide of formula (I):
Z-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Y (I)
or a pharmaceutically acceptable salt thereof, wherein: Z is H or an N-terminal group wherein the N-terminal group is preferably a Q to C17 acyl group, wherein the C1 to C17 comprises a linear or branched alkyl, cycloalkyi, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C1 to C17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C1 to C17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain and more preferably is a C1 to C7 acyl group;
Xaa1 is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and preferably an amino with a side chain including a linear or branched alkyl, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl, and more preferably is an L- or D-isomer of NIe; Xaa2 and Xaa6 are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge, and, preferably, one of Xaa2 and Xaa6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa2 and Xaa6 is an L- or D-isomer of Lys, Orn, Dab or Dap or, in an alternative preferred aspect, Xaa2 and Xaa6 are each Cys, D-Cys, Pen or D-Pen; Xaa3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl,— O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or— O-aryl, or Xaa3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyi, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl and preferably is an L- or D-isomer of His;
Xaa4 is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally wherein the ring is substituted with one or more substituents independently selected from halo, (C1-C10)alkyl-halo, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl, and is preferably D-Phe, optionally substituted with one or more substituents independently selected from halo, (C1-C10)alkyl-halo, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino,
monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;
Xaa5 is L- or D-Pro or an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether and preferably is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap; Xaa7 is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and is preferably an amino acid with a side chain including at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, aryl, or -O-aryl, and more preferably is an L- or D-isomer of Trp, Nal l or l\lal 2; and
Y is a C-terminal group and in another aspect preferably a hydroxyl, an amide, or an amide substituted with one or two linear or branched Q to C17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains. Preferred cyclic alpha-MSH analogues are Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH2 and Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dap)-Trp-NH2.
According to this aspect and in addition to the above defined amino acids, the amino acids are defined in US2013/0296256 pages 5 and 6 which are incorporated herein by reference.
Further, the terms "α,α-disubstttuted amino acid", "N-substituted amino acid", "alkane",
"alkene", "alkenyl", "alkyl", "alkyne", "aryl", "aralkyl", "aliphatic", "acyl", "acylated", "omega amino aliphatic chain", "heteroaryl", "amide", "imide", "amine", "nitrile", and "halogen" are defined on pages 6 and 7 thereof and are also incorporated herein by reference. According to the present invention, the most preferred alpha-MSH analogue is [Nle4, D-Phe7]- alpha-MSH. This preferred compound is sometimes referred to as NDP-MSH. It is also generically known as afamelanotide, which is available as an implant formulation under the trademark SCENESSE®. Preferably, the alpha-MSH analogue is administered in a composition. Preferably, the composition is a slow release formulation, resulting in longer and/or more controlled exposure of the body to the drug. Most preferably, the composition is an implant. In one preferred embodiment, the alpha-MSH analogue is administered in a prolonged release formulation such
as described in US2008305152 (equivalent to WO2006/012667), the disclosure of which is included herein by reference.
The composition preferably comprises at least 5mg of the alpha-MSH analogue, more preferably at least lOmg and preferably at most 30mg, more preferably at most 25mg of the alpha-MSH analogue. Particularly preferred amounts are 20mg or 16mg of the alpha-MSH analogue of which 16mg of the alpha-MSH analogue is the most preferred.
Preferably, the composition comprises a controlled release formulation. In one aspect according to the present invention, the implant (or rod) comprises a biodegradable polymer, wherein the alpha-MSH analogue is imbedded within the implant. In one aspect, the alpha- MSH analogue is encapsulated in an implant composed of poly-(lactide-co-glycolide), poly- (lactide), poly-(glycolide) or a mixture thereof. Lactide/glycolide polymers for drug-delivery formulations are typically made by melt polymerization through the ring opening of lactide and glycolide monomers. Some polymers are available with or without carboxylic acid end groups. When the end group of the poly-(lactide-co-glycolide), poly-(lactide), or poly- (glycolide) is not a carboxylic acid, for example, an ester, then the resultant polymer is referred to herein as blocked or capped. The unblocked polymer, conversely, has a terminal carboxylic group. In one aspect, linear lactide/glycolide polymers are used; however star polymers can be used as well. In certain aspects, high molecular weight polymers can be used for medical devices, for example, to meet strength requirements. The lactide portion of the polymer has an asymmetric carbon. Commercially racemic DL-, L-, and D-polymers are available. The L- polymers are more crystalline and resorb slower than DL- polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are available. Additionally, homo-polymers of lactide or glycolide are available. In the case when the biodegradable polymer is poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide), the amount of lactide and glycolide in the polymer can vary. In one aspect, the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolide, wherein the amount of lactide and glycolide is 100 mole %. In one aspect, the biodegradable polymer can be poly-(lactide), 85:15 poly-(lactide-co-glycolide), 75:25 poly-(lactide-co-glycolide), or 65:35 poly-lactide-co-glycolide) where the ratios are mole ratios.
In one aspect, when the biodegradable polymer is poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide), the polymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30°C.
The implant preferably comprises alpha-MSH analogue in an amount of from 5% to 60%, more preferably from 10% to 50%, most preferably from 15% to 40%, and in particularly preferred from 15% to 30% by weight of the implant. Preferred implants are described in
US2008/0305152 incorporated herein by reference. A preferred implant comprising afamelanotide is available under the name of SCENESSE® in Italian and Swiss markets.
Other pharmaceutically-acceptable components can be encapsulated or incorporated in the composition or in the implant in combination with the alpha-MSH analogue. For example, the pharmaceutically-acceptable component can include a fatty acid, a sugar, a salt, a water- soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low- molecular- weight porosigen such as polymer or a salt or sugar, or a hydrophobic low- molecular-weight compound such as cholesterol or a wax.
Claims
1. Alpha-MSH analogue for use in treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is between at least 6 weeks and at most 8 weeks.
2. Compound for use according to claim 1, wherein the disorder is a juvenile form of the neurodegenerative disorder.
3. Compound for use according to claims 1-2, wherein the neurodegenerative disorder is Multiple Sclerosis.
4. Compound for use according to claim 1-2, wherein the neurodegenerative disorder is dementia.
5. Compound for use according to claim 1-2 or 4, wherein the neurodegenerative disorder is Alzheimer's Disease.
6. Compound for use according to claim 1-2, wherein the neurodegenerative disorder is Parkinson's Disease.
7. Compound for use according to claim 1-2, wherein the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS).
8. Compound for use according to claim 1-2, wherein the neurodegenerative disorder is Huntington's Disease.
9. Compound for use according to claims 1-8, wherein the alpha-MSH analogue is administered system ica I ly.
10. Compound for use according to claims 1-9, wherein the alpha-MSH analogue is administered subcutaneously.
11. Compound for use according to claims 1-10, the alpha-MSH analogue is present in the blood plasma of the subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration.
12. Compound for use according to claims 1-11, wherein the alpha-MSH analogue is a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1R), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.
13. Compound for use according to claims 1-12, wherein the alpha-MSH analogue is afamelanotide.
14. Method of treating neurodegenerative disorders by administering an alpha-MSH analogue to a human subject suffering from neurodegenerative disorder, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks and at most 8 weeks.
15. Use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a human subject with a neurodegenerative disorder wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks and at most 8 weeks.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/522,260 US20170304406A1 (en) | 2014-10-28 | 2015-10-28 | New indication for alpha-msh analogues |
EP15797607.7A EP3212219A1 (en) | 2014-10-28 | 2015-10-28 | New indication for alpha-msh analogues |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14190766 | 2014-10-28 | ||
EP14190766.7 | 2014-10-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016066700A1 true WO2016066700A1 (en) | 2016-05-06 |
Family
ID=51870838
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/075017 WO2016066700A1 (en) | 2014-10-28 | 2015-10-28 | New indication for alpha-msh analogues |
Country Status (3)
Country | Link |
---|---|
US (1) | US20170304406A1 (en) |
EP (1) | EP3212219A1 (en) |
WO (1) | WO2016066700A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3868395A1 (en) * | 2020-02-23 | 2021-08-25 | Vallaurix Trading Sarl MC | Treatment of medical indication |
WO2021165549A1 (en) * | 2020-02-23 | 2021-08-26 | Vallaurix Trading Sarl Mc | Treatment of medical indication |
US20220135968A1 (en) * | 2018-06-15 | 2022-05-05 | Torrey Pines Law Group, PC | Treatment of synucleinopathy and animal models of synucleinopathy |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4457864A (en) | 1981-10-23 | 1984-07-03 | University Patents, Inc. | Synthetic analogues of α-melanotropin |
US4485039A (en) | 1982-06-11 | 1984-11-27 | University Patents, Inc. | Synthetic analogues of α-melanotropin |
US4866038A (en) | 1986-02-03 | 1989-09-12 | University Patents, Inc. | Method of stimulating integumental melanocytes by topical application of analogs of alpha-msh |
US5049547A (en) | 1988-02-11 | 1991-09-17 | University Patents, Inc. | Composition for stimulating integumental melanocytes |
AU618733B2 (en) | 1987-05-22 | 1992-01-09 | University Patents Inc. | Linear and cyclic analogs of alpha-msh fragments with extraordinary potency |
US5674839A (en) | 1987-05-22 | 1997-10-07 | Competitive Technologies, Inc. | Cyclic analogs of alpha-MSH fragments |
WO2006012667A1 (en) | 2004-08-04 | 2006-02-09 | Clinuvel Pharmaceuticals Limited | Methods of inducing melanogenesis in a subject. |
WO2008031233A1 (en) * | 2006-09-14 | 2008-03-20 | Mondobiotech Laboratories Ag | Compositions and methods for treatment of chronic fatigue syndrome and neurodegenerative diseases |
US20130296256A1 (en) | 2009-11-23 | 2013-11-07 | Palatin Technologies, Inc. | Melanocortin-1 Receptor-Specific Cyclic Peptides |
EP2722340A1 (en) * | 2012-10-19 | 2014-04-23 | TXP Pharma GmbH | Alpha- and gamma-MSH analogues |
-
2015
- 2015-10-28 US US15/522,260 patent/US20170304406A1/en not_active Abandoned
- 2015-10-28 EP EP15797607.7A patent/EP3212219A1/en not_active Withdrawn
- 2015-10-28 WO PCT/EP2015/075017 patent/WO2016066700A1/en active Application Filing
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4457864A (en) | 1981-10-23 | 1984-07-03 | University Patents, Inc. | Synthetic analogues of α-melanotropin |
US4485039A (en) | 1982-06-11 | 1984-11-27 | University Patents, Inc. | Synthetic analogues of α-melanotropin |
US4866038A (en) | 1986-02-03 | 1989-09-12 | University Patents, Inc. | Method of stimulating integumental melanocytes by topical application of analogs of alpha-msh |
US4918055A (en) | 1986-02-03 | 1990-04-17 | Hruby Victor J | Method of stimulating melanocytes by topical application of analogs of alpha-MSH, and compositions for use in same |
AU597630B2 (en) | 1986-02-03 | 1990-06-07 | University Patents Inc. | Method of stimulating melanocytes by topical application of analogs of alpha-msh, and compositions for use in same |
AU618733B2 (en) | 1987-05-22 | 1992-01-09 | University Patents Inc. | Linear and cyclic analogs of alpha-msh fragments with extraordinary potency |
US5674839A (en) | 1987-05-22 | 1997-10-07 | Competitive Technologies, Inc. | Cyclic analogs of alpha-MSH fragments |
US5714576A (en) | 1987-05-22 | 1998-02-03 | Competitive Technologies, Inc. | Linear analogs of alpha-msh fragments |
US5049547A (en) | 1988-02-11 | 1991-09-17 | University Patents, Inc. | Composition for stimulating integumental melanocytes |
WO2006012667A1 (en) | 2004-08-04 | 2006-02-09 | Clinuvel Pharmaceuticals Limited | Methods of inducing melanogenesis in a subject. |
US20080305152A1 (en) | 2004-08-04 | 2008-12-11 | Clinuvel Pharmaceuticals Limited | Methods of Inducing Melanogenesis in a Subject |
WO2008031233A1 (en) * | 2006-09-14 | 2008-03-20 | Mondobiotech Laboratories Ag | Compositions and methods for treatment of chronic fatigue syndrome and neurodegenerative diseases |
US20130296256A1 (en) | 2009-11-23 | 2013-11-07 | Palatin Technologies, Inc. | Melanocortin-1 Receptor-Specific Cyclic Peptides |
EP2722340A1 (en) * | 2012-10-19 | 2014-04-23 | TXP Pharma GmbH | Alpha- and gamma-MSH analogues |
Non-Patent Citations (2)
Title |
---|
CATANIA A ET AL: "Peptide modulation of fever and inflammation within the brain", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK ACADEMY OF SCIENCES, US, vol. 856, 29 September 1998 (1998-09-29), pages 62 - 68, XP002579611, ISSN: 0077-8923 * |
GALIMBERTI D ET AL: "ALPHA-MSH PEPTIDES INHIBIT PRODUCTION OF NITRIC OXIDE AND TUMOR NECROSIS FACTOR-ALPHA BY MICROGLIAL CELLS ACTIVATED WITH BETA-AMYLOID AND INTERFERON GAMMA", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 263, 16 September 1999 (1999-09-16), pages 251 - 256, XP000941934, ISSN: 0006-291X, DOI: 10.1006/BBRC.1999.1276 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220135968A1 (en) * | 2018-06-15 | 2022-05-05 | Torrey Pines Law Group, PC | Treatment of synucleinopathy and animal models of synucleinopathy |
EP3868395A1 (en) * | 2020-02-23 | 2021-08-25 | Vallaurix Trading Sarl MC | Treatment of medical indication |
WO2021165549A1 (en) * | 2020-02-23 | 2021-08-26 | Vallaurix Trading Sarl Mc | Treatment of medical indication |
Also Published As
Publication number | Publication date |
---|---|
US20170304406A1 (en) | 2017-10-26 |
EP3212219A1 (en) | 2017-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2825076T3 (en) | Pharmaceutical compositions | |
CA2416475C (en) | Medicinal uses of mu-opioid receptor agonists | |
KR20110114568A (en) | Dipeptide linked medicinal agents | |
EP3212219A1 (en) | New indication for alpha-msh analogues | |
EA033590B1 (en) | Controlled-release formulations | |
EP3573645B1 (en) | Alpha-msh analogues used in the treatment of xeroderma pigmentosum | |
CN112334477A (en) | Compstatin analogs with increased solubility and improved pharmacokinetic properties | |
US11975040B2 (en) | Plexin binding regulator | |
RU2508295C2 (en) | Synthetic peptides with non-narcotic type of analgetic action | |
CN113412116A (en) | Modified axon growth-attractant factor-1 peptides and compositions for cardioprotection | |
EP3212220A1 (en) | Inflammatory disease | |
US10947274B1 (en) | Synthetic analgesic peptides of RgIA analogs | |
WO2015063102A1 (en) | Alpha-msh analogues for use in bullous disease | |
JPWO2018084311A1 (en) | Preventive or therapeutic agent for inflammatory skin diseases | |
WO2015063099A1 (en) | Alpha-msh analogues for use in the treatment of hailey-hailey disease | |
US10357533B2 (en) | Drug for the effective control of acute and or chronic pain and a method for its administration | |
JP2017525357A (en) | Novel potassium channel blockers and their use in the treatment of autoimmune diseases | |
WO2015067503A1 (en) | Alpha-msh analogues for use in the treatment of psoriasis | |
JP2009502976A (en) | Peptide conjugates for oral delivery of hydrophilic peptide analgesics | |
CN110234334B (en) | Muscle atrophy inhibiting composition | |
WO2021152463A1 (en) | Pharmaceutical composition and method for producing same | |
JP2023529825A (en) | Conformated Constrained α-RGIA Analogs | |
WO2016060190A1 (en) | THERAPEUTIC AGENT FOR COGNITION DISORDER INDUCED BY AMYLOID β-PROTEIN | |
Na | Effect of pH on the formation of acylated octreotides by poly (lactide-co-glycolide) | |
AU2008203708A1 (en) | Use of somatostatin analogs in cluster headache |
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: 15797607 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15522260 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2015797607 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015797607 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |