WO2005014032B1 - Use of secretagogues like ghrelin in cancer cachexia and for stimulating appetite - Google Patents

Use of secretagogues like ghrelin in cancer cachexia and for stimulating appetite

Info

Publication number
WO2005014032B1
WO2005014032B1 PCT/DK2004/000529 DK2004000529W WO2005014032B1 WO 2005014032 B1 WO2005014032 B1 WO 2005014032B1 DK 2004000529 W DK2004000529 W DK 2004000529W WO 2005014032 B1 WO2005014032 B1 WO 2005014032B1
Authority
WO
WIPO (PCT)
Prior art keywords
ghrelin
use according
acyl group
compound
medicament
Prior art date
Application number
PCT/DK2004/000529
Other languages
French (fr)
Other versions
WO2005014032A3 (en
WO2005014032A2 (en
Inventor
Birgitte Holst Lange
Christian Hansen
Henrik Nilsson
Original Assignee
Gastrotech Pharma As
Birgitte Holst Lange
Christian Hansen
Henrik Nilsson
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
Application filed by Gastrotech Pharma As, Birgitte Holst Lange, Christian Hansen, Henrik Nilsson filed Critical Gastrotech Pharma As
Priority to JP2006522237A priority Critical patent/JP2007523048A/en
Priority to US10/567,406 priority patent/US20070037751A1/en
Priority to EP04739026A priority patent/EP1660117A2/en
Publication of WO2005014032A2 publication Critical patent/WO2005014032A2/en
Publication of WO2005014032A3 publication Critical patent/WO2005014032A3/en
Publication of WO2005014032B1 publication Critical patent/WO2005014032B1/en

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
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF] (Somatoliberin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4745—Insulin-like growth factor binding protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/65—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2

Abstract

The present invention relates, in one aspect, to the use of a secretagogue compound for the preparation of a medicament for the prophylaxis or treatment of cancer cachexia in an individual in need of such treatment. In another aspect, the present invention relates to the use of a ghrelin-like compound for the preparation of a medicament for prophylaxis or treatment of cachexia in an individual by administering a subcutaneous dosage of said medicament to the individual. In a further aspect, the present invention relates to the use of a ghrelin-like compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for stimulation of appetite in an individual by administering a subcutaneous dosage of said medicament to the individual. Furthermore, the present invention relates to a number of new ghrelin-like compounds and uses thereof, as well as to pharmaceutical compositions and medical packaging comprising the new ghrelin-like compounds.

Claims

AMENDED CLAIMS [received by the International Bureau on 14 March 2005 (14.03.05); claims 1 and 82 replaced by new claims 1-44 (7 Pages)]
1. Use of a ghrelin-like compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis or treatment of cancer cachexia in an individual in need of such treatment, wherein the ghrelin-like compound comprises a structure defined by formula I
Z1 - (X1)m - (X2) - (X3)n- Z2, wherein Z1 is an optionally present protecting group each X1 is independently selected from an amino acid, wherein said amino acid is selected from naturally occurring and synthetic amino acids, X2 is any amino acid selected from naturally occurring and synthetic amino acids, said amino acid being modified with a bulky hydrophobic group, preferably an acyl group, or a fatty acid, each X3 is independently selected from an amino acid, wherein said amino acid is selected from naturally occurring and synthetic amino acids, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group, preferably an acyl group, or a fatty acid, Z2 is an optionally present protecting group, m is an integer in the range of from 1-10 n is 0 or an integer in the range of from 1-35, and wherein: (a) said ghrelin-like compound or pharmaceuticaly acceptable salt thereof is 27-28 amino acids in length, with the proviso that said ghrelin-like compound is at least 80 % homologous to SEQ ID NO 1, such as at least 85 % homologous to SEQ ID NO: 1 and/or
(b) said ghrelin-like compound is at least 90 % homologous to SEQ ID NO 1.
2. The use according to claim 1 , wherein said ghrelin-like compound is at least 95 % homologous to SEQ ID NO 1.
3. The use according to claim 1 , wherein said ghrelin-like compound is at least 98 % homologous to SEQ ID NO 1.
4. The use according to any of the preceding claims, wherein m is an integer in the range of from 1-9, such as of from 1-8, such as of from 1-7, such as of from 1-6, such as of from 1-5, such as of from 1-4, such as of from 1-3, such as of from 1- 2, such as 2.
5. The use according to any of the preceding claims, wherein X2 is selected from the group of modified Ser, modified Cys and modified Lys, such as wherein X2 is modified Ser. •
6. The use according to any of the preceding claims, wherein the ghrelin-like compound is selected from a compound of formula II Z1 - Gly- (X1)m-1 - (X2) - (X3)n- Z2, formula III Z1 - Gly- Ser - (X2) - (X3)n- Z2, and formula IV Z1 - Gly - (X2) - (X3)n- Z2.
7. The use according to claim 6, wherein the ghrelin-like compound is having formula III.
8. The use according to any of the preceding claims, wherein n is an integer in the range of from 1-25, such as of from 1-24, such as from 1-15, such as of from 1- 10, such as of from 10-25, such as of from 10-24, such as of from 15-25, such as of from 15-24.
138
9. The use according to any of the preceding claims, wherein the acyl group is selected from a C1-C35 acyl group, such as a C1 - C20 acyl group, such as a C1 - C15 acyl group, such as a C6 - C15 acyl group, such as a C6 - C12 acyl group, such as a C8 - C12 acyl group.
10. The use according to any of the preceding claims, wherein the acyl group is selected from the group of C7 acyl group, C8 acyl group, C9 acyl group, C10 acyl group, C11 acyl group, and C12 acyl group.
11. The use according to any of the preceding claims, wherein the acyl group is selected from the group of C8 acyl group, and C10 acyl group.
12. The use according to any of the preceding claims, wherein the acyl group is se- lected from the group of C7 acyl group, C9 acyl group, and C11 acyl group, such as from the group of C9 acyl group and C11 acyl group.
13. The use according to claim 1 , wherein the ghrelin-like compound is ghrelin or a pharmaceutically acceptable salt thereof.
14. The use according to to claim 1 , wherein the ghrelin-like compound has SEQ ID NO: 1 , SEQ ID NO: 2, or SEQ ID NO: 3.
15. The use according to any of the preceding claims, wherein the medicament is in a formulation for subcutaneous administration.
16. The use according to any of the preceding claims, wherein the formulation comprises the ghrelin-like compound or a salt thereof as a lyophilisate and the formulation further comprises a solvent, said lyophilisate and said solvent being in separate compartments until administration.
17. The use according to any of the preceding claims, wherein the formulation is a solution of the ghrelin-like compound or a salt thereof.
18. The use according to claim 16 or 17, wherein the solvent is saline.
19. The use according to any of the preceding claims, wherein the medicament is administered prior to or during a meal.
20. The use according to any of the preceding claims, wherein the medicament is administered in a concentration equivalent to from 10 ng to 10 mg ghrelin per kg bodyweight.
21. The use according to claim 20, wherein the medicament is administered in a concentration equivalent to from 0.1 μg to 1 mg ghrelin per kg bodyweight, such as from 0.5 μg to 0.5 mg ghrelin per kg bodyweight, such as from 1.0 μg to 0.1 mg ghrelin per kg bodyweight, such as from 1.0 μg to 50 μg ghrelin per kg bodyweight, such as from 1.0 μg to 10 μg ghrelin per kg bodyweight.
22. The use according to claim 21 , wherein the medicament is administered in a concentration equivalent to from 0.1 μg to 1 mg ghrelin per kg bodyweight, such as from 0.5 μg to 0.5 mg ghrelin per kg bodyweight, such as from 1.0 μg to 0.1 mg ghrelin per kg bodyweight, such as from 1.0 μg to 50 μg ghrelin per kg bodyweight, such as from 1.0 μg to 10 μg ghrelin per kg bodyweight.
23. The use according to any of the preceding claims, wherein the medicament is administered as a bolus prior to or during a meal, said bolus comprising an amount of the ghrelin-like compound or a salt thereof equivalent to from 0.3 μg to 600 mg ghrelin
24. The use according to claim 23, wherein the medicament is administered as a bolus prior to or during a meal, said bolus comprising an amount of the ghrelin-like compound or a salt thereof equivalent to from 2.0 μg to 200 mg ghrelin, such as from 5.0 μg to 100 nig ghrelin, such as from 10 μg to 50 mg ghrelin, such as from 10 μg to 5 mg ghrelin, such as from 10 μg to 1.0 mg ghrelin.
25. The use according to any of the preceding claims, wherein the medicament is administered from one to three times daily, each administration being during a meal or at the most 180 minutes prior to a meal, such as at the most 90 minutes prior to a meal, e.g. at the most 45 minutes prior to a meal, such as at the most 30 minutes prior to a meal, such as at the most 25 minutes prior to a meal, such as at the most 20 minutes prior to a meal, such as at the most 15 minutes prior to a meal, such as at the most 10 minutes prior to a meal, such as at the most 5 minutes prior to a meal.
26. The use according to claim 25, wherein the medicament is administered three times daily.
27. The use according to any of the preceding claims, wherein the cancer cachexia is caused by a catabolic disorder.
28. The use according to any of claims 1 to 26, wherein the cancer cachexia is caused by an anorectic disorder.
29. The use according to any of claims 1 to 27, where the individual is suffering from a cancer selected from lung cancer, pancreatic cancer, liver cancer, and Gl tract cancers.
30. Use according to any of the preceding claims, wherein said medicament is administered in combination with a chemotherapy medicament.
31. The use according to any of the preceding claims, wherein the treatment or prevention of cancer cachexia leads to stimulation of appetite, stimulation of food in- take, stimulation of weight gain or weight maintenance, and/or increased body fat mass.
32. A method for preventing or treating cancer cachexia, comprising administering to an individual in need thereof an effective amount of a ghrelin-like compound as de- fined in any of claims 1-14.
33. A method for preventing or treating cancer, comprising administering to an individual in need thereof an effective amount of a secretagogue as defined in any of claims 1-14, in combination with an antϊ-neoplastic treatment.
141
34. The method according to claim 33, wherein the antineoplastic treatment is radiotherapy.
35. The method according to claim 33, wherein the antineoplastic treatment is che- motherapy.
36. The method according to any of claims 33-35, wherein the treatment or prevention of cancer cachexia leads to stimulation of appetite, stimulation of food intake, stimulation of weight gain or weight maintenance, and/or increased body fat mass.
37. A method for preventing or treating cachexia, comprising administering to an individual in need thereof an effective amount of a ghrelin-like compound and an effective amount of a NSAID medicament.
38. The method according to claim 37, wherein the ghrelin-like compound is as defined in any of claims 1 to 14.
39. Use of a ghrelin-like compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament, in a formulation for subcutaneous administration, for stimulation of appetite in an individual by administering a subcutaneous dosage of said medicament to the individual, wherein the ghrelin-like compound comprises a structure defined by formula I
Z1 - (X1)m - (X2) - (X3)n- Z2, wherein
Z1 is an optionally present protecting group each X1 is independently selected from an amino acid, wherein said amino acid is selected from naturally occurring and synthetic amino acids,
X2 is any amino acid selected from naturally occurring and synthetic amino acids, said amino acid being modified with a bulky hydrophobic group, preferably an acyl group, or a fatty acid,
142 each X3 is independently selected from an amino acid, wherein said amino acid is selected from naturally occurring and synthetic amino acids, wherein one or more of X1 and X3 optionally may be modified with a bulky hy- i drophobic group, preferably an acyl group, or a fatty acid,
Z2 is an optionally present protecting group, m is an integer in the range of from 1-10 n is 0 or an integer in the range of from 1-35.
40. Use according to claim 39, wherein the ghrelin-like compound is as defined in any of claims 1-14.
41. Use according to claim 40, wherein the formulation is as defined in any of claims 15-19.
42. Use according to claim 41, wherein the solvent is saline.
43. Use according to any of claims 39 to 42, wherein the medicament is administered as defined in any of claims 19-26.
44. Use according to any of claims 39-43, wherein said individual is suffering from lipodystrophy.
143
PCT/DK2004/000529 2003-08-06 2004-08-06 Use of secretagogues like ghrelin in cancer cachexia and for stimulating appetite WO2005014032A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2006522237A JP2007523048A (en) 2003-08-06 2004-08-06 Use of secretagogues
US10/567,406 US20070037751A1 (en) 2003-08-06 2004-08-06 Uses of secretagogues like ghrelin in cancer cachexia and for stimulating appetite
EP04739026A EP1660117A2 (en) 2003-08-06 2004-08-06 Use of secretagogues like ghrelin in cancer cachexia and for stimulating appetite

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
DKPA200301140 2003-08-06
DKPA200301140 2003-08-06
DKPA200301139 2003-08-06
DKPA200301139 2003-08-06
US49481503P 2003-08-14 2003-08-14
US49481603P 2003-08-14 2003-08-14
US60/494,815 2003-08-14
US60/494,816 2003-08-14
DKPA200301283 2003-09-05
DKPA200301283 2003-09-05
DKPA200301570 2003-10-24
DKPA200301570 2003-10-24
DKPA200301569 2003-10-24
DKPA200301569 2003-10-24
DKPA200400570 2004-04-07
DKPA200400570 2004-04-07

Publications (3)

Publication Number Publication Date
WO2005014032A2 WO2005014032A2 (en) 2005-02-17
WO2005014032A3 WO2005014032A3 (en) 2005-03-17
WO2005014032B1 true WO2005014032B1 (en) 2005-04-28

Family

ID=34139992

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2004/000529 WO2005014032A2 (en) 2003-08-06 2004-08-06 Use of secretagogues like ghrelin in cancer cachexia and for stimulating appetite

Country Status (3)

Country Link
EP (1) EP1660117A2 (en)
JP (1) JP2007523048A (en)
WO (1) WO2005014032A2 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097174A2 (en) * 2004-04-07 2005-10-20 Gastrotech Pharma A/S Uses of a combination of ghrelin and somatotropin for the treatment of cachexia
CA2603295A1 (en) * 2004-04-07 2006-10-20 Gastrotech Pharma A/S Use of ghrelin for the treatment of hyperthyroidism
US20080269116A1 (en) * 2004-05-11 2008-10-30 Taub Dennis D Methods of Inhibiting Proinflammatory Cytokine Expression Using Ghrelin
CA2576915A1 (en) * 2004-08-18 2006-03-02 Elixir Pharmaceuticals, Inc. Growth-hormone secretagogues
EP1812044A2 (en) * 2004-10-27 2007-08-01 Gastrotech Pharma A/S Uses of growth hormone secretagogues in the treatment of individuals suffering from renal and/or liver failure
WO2006045314A2 (en) * 2004-10-27 2006-05-04 Gastrotech Pharma A/S Use of a growth hormone secretatogue for increasing or maintaining lean body mass and/or for treatment of chronic obstructive pulmonary disease
WO2006045313A2 (en) * 2004-10-27 2006-05-04 Gastrotech Pharma A/S Uses of secretagogues for treatment of organ transplant patients
US7763707B2 (en) * 2006-03-13 2010-07-27 Liat Mintz Use of ghrelin splice variant for treating cachexia and/or anorexia and/or anorexia-cachexia and/or malnutrition and/or lipodystrophy and/or muscle wasting and/or appetite-stimulation
CN101443358B (en) * 2006-03-13 2016-05-11 利亚特·明茨 The purposes of ghrelin splice variant in treatment cachexia and/or pressure food and/or apocleisis-cachexia and/or malnutrition and/or LD and/or muscle consumption and/or in stimulating appetite
WO2011087102A1 (en) * 2010-01-15 2011-07-21 国立大学法人宮崎大学 Therapeutic agent for promoting recovery of animal under medical treatment
US9486503B2 (en) 2012-10-04 2016-11-08 Shionogi & Co., Ltd. Medicinal agent for suppressing malignant tumor metastasis
EA035578B1 (en) * 2014-09-04 2020-07-09 Хелсинн Хелскеа Са Medical treatment of cancer cachexia based on anamorelin

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JPH04177224A (en) * 1990-11-09 1992-06-24 Sharp Corp Liquid crystal display device
US5798337A (en) * 1994-11-16 1998-08-25 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues
WO2001056592A1 (en) * 2000-02-01 2001-08-09 Novo Nordisk A/S Use of compounds for the regulation of food intake
CA2411667A1 (en) * 2000-05-30 2001-12-06 Merck & Co. Inc. Ghrelin analogs
IL145106A0 (en) * 2000-08-30 2002-06-30 Pfizer Prod Inc Intermittent administration of a geowth hormone secretagogue

Also Published As

Publication number Publication date
EP1660117A2 (en) 2006-05-31
JP2007523048A (en) 2007-08-16
WO2005014032A3 (en) 2005-03-17
WO2005014032A2 (en) 2005-02-17

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