CA2485472C - Gh secretagogues and uses thereof - Google Patents
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- CA2485472C CA2485472C CA2485472A CA2485472A CA2485472C CA 2485472 C CA2485472 C CA 2485472C CA 2485472 A CA2485472 A CA 2485472A CA 2485472 A CA2485472 A CA 2485472A CA 2485472 C CA2485472 C CA 2485472C
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- 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)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/60—Growth-hormone releasing factors (GH-RF) (Somatoliberin)
Abstract
The invention relates to use of a GH secretagogue (e.g. GRF or an analog thereof) for (1) altering a lipid parameter in a subject; (2) altering a body composition parameter in a subject, (3) treating a condition characterized by deficient or decreased bone formation in a subject (4) improving daytime vigilance and/or cognitive function in a subject, (5) improving a metabolic condition in a subject, (6) improving anabolism in a catabolic condition in a subject, and/or (7) improving and/or reconstituting immune function in a subject.
Description
GH SECRETAGOGUES AND USES THEREOF
FIELD OF THE INVENTION
The invention relates to growth hormone (GH) secretagogues, such as GH releasing factor (GRE') and analogs thereof, and uses thereof.
BACKGROUND OF THE INVENTION
Syndromes associated with fat accumulation Physiological systems include a number of lipid compounds /molecules such as triglycerides and sterols (e.g.
cholesterol), and associated carriers/complexes such as HDL, LDL, etc. Adverse levels or metabolism of such molecules is associated with related conditions such as fat accumulation, and associated disease.
Fat accumulation is observed in a range of conditions or syndromes such as obesity, metabolic syndrome, and the recently described HIV-related lipodystrophy syndrome. All these conditions include features which are known to increase the risk of diabetes and/or cardiovascular diseases.
The metabolic syndrome, also known as syndrome X, affect persons with frank obesity as well as those with an increased amount of abdominal fat, and is characterized by insulin resistance, dyslipidemia (hypertriglyceridemia, low serum HDL cholesterol levels, and increased LDL cholesterol levels) and hypertension.
HIV-infected patients treated with highly active antiretroviral therapy (HAART) commonly experience changes in fat distribution that include increased visceral and central fat accumulation (1), as well as loss of extremity
FIELD OF THE INVENTION
The invention relates to growth hormone (GH) secretagogues, such as GH releasing factor (GRE') and analogs thereof, and uses thereof.
BACKGROUND OF THE INVENTION
Syndromes associated with fat accumulation Physiological systems include a number of lipid compounds /molecules such as triglycerides and sterols (e.g.
cholesterol), and associated carriers/complexes such as HDL, LDL, etc. Adverse levels or metabolism of such molecules is associated with related conditions such as fat accumulation, and associated disease.
Fat accumulation is observed in a range of conditions or syndromes such as obesity, metabolic syndrome, and the recently described HIV-related lipodystrophy syndrome. All these conditions include features which are known to increase the risk of diabetes and/or cardiovascular diseases.
The metabolic syndrome, also known as syndrome X, affect persons with frank obesity as well as those with an increased amount of abdominal fat, and is characterized by insulin resistance, dyslipidemia (hypertriglyceridemia, low serum HDL cholesterol levels, and increased LDL cholesterol levels) and hypertension.
HIV-infected patients treated with highly active antiretroviral therapy (HAART) commonly experience changes in fat distribution that include increased visceral and central fat accumulation (1), as well as loss of extremity
2 and subcutaneous fat (especially in the facial fat pads, limbs and buttocks) in association with insulin resistance and dyslipidemia (2, 3). Recent data suggest increased cardiovascular disease and myocardial infarction rates in patients treated with prolonged antiretroviral therapy (ART) (4). In non HIV-infected patients (5) and among HIV-infected patients with changes in fat distribution (6), increased waist to hip ratio (WHR) and central fat accumulation is related to increased metabolic risk indices.
Growth Hormone is known for its lipolytic properties, and its potential role in reversing several of the body fat and associated metabolic abnormalities has been actively studied. Beneficial effects have been shown in GH-deficient individuals (Gotherstrom G. et al., J din Endocrinol Metab 2001 86(10):4657-4665) and non-HIV patients with abdominal obesity (Johannsson G, et al., J Clin Endocrinol Metab 1997, 82(3):727-734). Recent studies also suggest that that GH levels are reduced in HIV-infected patients, and correlate inversely with excess visceral fat accumulation (7, 8). Studies using higher dose, pharmacologic GH administration have resulted in reduced visceral adiposity in this population, but are associated with increased insulin resistance and side effects (9-12).
Cognitive function Cognitive abilities are impaired in a number of conditions including advancing age. Deleterious changes observed with aging affect particularly fluid intelligence, or abilities involving concept formation, rule discovery, planning behavior, and non-verbal reasoning. Conversely, crystallized intelligence, or abilities dependent upon accumulated experience and education is relatively resistant to age-related decline. It has been suggested that the
Growth Hormone is known for its lipolytic properties, and its potential role in reversing several of the body fat and associated metabolic abnormalities has been actively studied. Beneficial effects have been shown in GH-deficient individuals (Gotherstrom G. et al., J din Endocrinol Metab 2001 86(10):4657-4665) and non-HIV patients with abdominal obesity (Johannsson G, et al., J Clin Endocrinol Metab 1997, 82(3):727-734). Recent studies also suggest that that GH levels are reduced in HIV-infected patients, and correlate inversely with excess visceral fat accumulation (7, 8). Studies using higher dose, pharmacologic GH administration have resulted in reduced visceral adiposity in this population, but are associated with increased insulin resistance and side effects (9-12).
Cognitive function Cognitive abilities are impaired in a number of conditions including advancing age. Deleterious changes observed with aging affect particularly fluid intelligence, or abilities involving concept formation, rule discovery, planning behavior, and non-verbal reasoning. Conversely, crystallized intelligence, or abilities dependent upon accumulated experience and education is relatively resistant to age-related decline. It has been suggested that the
3 decline in GH and IGF-1 observed with aging contribute to the impaired cognitive function.
Evidence exists from both animal and human studies that administration of GRF, GH or IGF-1 has significant effect on cognitive functions in conditions where these functions are impaired. For example, this has been demonstrated with GH therapy in GH-deficient adults (Deijen JB, et al., Psychoneuroendocrinology 1998 23(1):45-55), and with administration of IGF-l or GRF in the healthy elderly (Aleman A et al., J Clin Endocrinol Metab 1999 84(2):471-475; Vitiello M.V., et al., Gerontologist 2002 40(Special Issue 1):39).
Immune Function Aging is accompanied by diminished circulating GH
and IGF-1 levels observed in parallel with a declined function of the immune system, particularly affecting the T-cell mediated immunity. The age-related T-cell immune deficiency has been partly attributed to a progressive atrophy of the thymus gland and is considered to be causally related to the increased risk and severity of acquired infections observed in the elderly.
GH and IGF-1 are known to play an integrating role in the development and function of the immune system, as endocrine and/or autocrine/paracrine factors, and their administration has been shown to reverse age-related immune changes. Immune enhancing effects of these factors have been investigated in other immune deficiency states and encouraging results have been observed in HIV-positive patients (Napolitano LA, et al., AIDS 2002 16(8):1103-1111) and in animal models of radiotherapy preceding bone marrow transplantation (Sun R, et al., BMT Meetings, Feb 22-26 Orlando, FL, Abstract 27 2002:68-69).
Evidence exists from both animal and human studies that administration of GRF, GH or IGF-1 has significant effect on cognitive functions in conditions where these functions are impaired. For example, this has been demonstrated with GH therapy in GH-deficient adults (Deijen JB, et al., Psychoneuroendocrinology 1998 23(1):45-55), and with administration of IGF-l or GRF in the healthy elderly (Aleman A et al., J Clin Endocrinol Metab 1999 84(2):471-475; Vitiello M.V., et al., Gerontologist 2002 40(Special Issue 1):39).
Immune Function Aging is accompanied by diminished circulating GH
and IGF-1 levels observed in parallel with a declined function of the immune system, particularly affecting the T-cell mediated immunity. The age-related T-cell immune deficiency has been partly attributed to a progressive atrophy of the thymus gland and is considered to be causally related to the increased risk and severity of acquired infections observed in the elderly.
GH and IGF-1 are known to play an integrating role in the development and function of the immune system, as endocrine and/or autocrine/paracrine factors, and their administration has been shown to reverse age-related immune changes. Immune enhancing effects of these factors have been investigated in other immune deficiency states and encouraging results have been observed in HIV-positive patients (Napolitano LA, et al., AIDS 2002 16(8):1103-1111) and in animal models of radiotherapy preceding bone marrow transplantation (Sun R, et al., BMT Meetings, Feb 22-26 Orlando, FL, Abstract 27 2002:68-69).
4 Catabolism or Muscle Wasting Muscle protein catabolism, or muscle wasting, accompanies many diseases including all critical illness, regardless of the primary cause of disease. It is an important factor for the long-term prognosis and the length of hospital stay and recovery, and may also be a limiting factor for survival. Although many therapeutic tools have been investigated including specific nutritional treatment, there is still a strong need for more effective strategies to counteract protein catabolism.
Previous studies have reported that GH treatment increases muscle mass in older patients. The anabolic effects or abilities of GH to reverse or attenuate muscle wasting have been investigated in several patient groups. GH
has been shown to improve nitrogen balance, an index of net whole-body protein balance, after major gastro-intestinal surgery, burn injury, or major trauma. Anabolic effects have been translated into clinical benefits in COPD patients (improvement of the maximal inspiratory pressure) (Papte GS, et al., Chest 1991 99(6):1495-1500) and elderly patient undergoing surgery following hip fracture (improvement of functional recovery defined as return to independence) (Van der Lely AJ, et al., Eur J Endocrinol 2000 143(5):585-592).
Finally, rGH has been recently approved for management of AIDS-wasting based on results showing increased body weight, lean body mass and functional performance following 12 weeks of treatment (Schambelan M, et al., Ann Intern Med 1996 125(11):873-882).
However, the use of GH to treat conditions such as those noted above, has been associated with adverse side effects in some cases.
Previous studies have reported that GH treatment increases muscle mass in older patients. The anabolic effects or abilities of GH to reverse or attenuate muscle wasting have been investigated in several patient groups. GH
has been shown to improve nitrogen balance, an index of net whole-body protein balance, after major gastro-intestinal surgery, burn injury, or major trauma. Anabolic effects have been translated into clinical benefits in COPD patients (improvement of the maximal inspiratory pressure) (Papte GS, et al., Chest 1991 99(6):1495-1500) and elderly patient undergoing surgery following hip fracture (improvement of functional recovery defined as return to independence) (Van der Lely AJ, et al., Eur J Endocrinol 2000 143(5):585-592).
Finally, rGH has been recently approved for management of AIDS-wasting based on results showing increased body weight, lean body mass and functional performance following 12 weeks of treatment (Schambelan M, et al., Ann Intern Med 1996 125(11):873-882).
However, the use of GH to treat conditions such as those noted above, has been associated with adverse side effects in some cases.
5 SUMMARY OF THE INVENTION
The invention relates to GH secretagogues (e.g.
GRF and analogs thereof) and uses thereof.
Therefore, in a first aspect, the invention provides a method of altering a lipid parameter in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a lipid parameter in a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a lipid parameter in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a lipid parameter in a subject.
In a further aspect, the invention provides a method of altering a first body composition parameter of a subject, the method comprising administering to said subject
The invention relates to GH secretagogues (e.g.
GRF and analogs thereof) and uses thereof.
Therefore, in a first aspect, the invention provides a method of altering a lipid parameter in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a lipid parameter in a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a lipid parameter in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a lipid parameter in a subject.
In a further aspect, the invention provides a method of altering a first body composition parameter of a subject, the method comprising administering to said subject
6 an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a method of treating a condition characterized by deficient or decreased bone formation in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH
secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a first body composition parameter of a subject.
In a further aspect, the invention provides a method of treating a condition characterized by deficient or decreased bone formation in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH
secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with
7 instructions for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for treating a condition characterized by deficient or decreased bone formation in a subject.
In further aspects, the invention relates to a method for (1) stimulating day-time vigilance and/or cognitive functions e.g. in conditions related to aging or mild cognitive impairment, (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (e.g. metabolic conditions including obesity, HIV-related lipodystrophy, metabolic syndrome or syndrome X), (3) improving anabolism in catabolic/wasting conditions (such as those observed in Chronic Renal Failure, congestive heart failure AIDS, following hip fracture, trauma, or major surgery, particularly in elderly subjects), and/or (4) improving immune function or reconstitution of immunodeficient states such as that associated aging, HIV or following high-dose chemotherapy and/or radiotherapy; the method comprising admininistering a GH secretagogue (e.g.
GRF and analogs thereof) or a composition comprising a GH
secretagogue and a pharmaceutically acceptable carrier; to a subject.
In further aspects, the invention relates to uses of a GH secretagogue (e.g. GRF and analogs thereof) or a composition comprising a GH secretagogue and a
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for treating a condition characterized by deficient or decreased bone formation in a subject.
In further aspects, the invention relates to a method for (1) stimulating day-time vigilance and/or cognitive functions e.g. in conditions related to aging or mild cognitive impairment, (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (e.g. metabolic conditions including obesity, HIV-related lipodystrophy, metabolic syndrome or syndrome X), (3) improving anabolism in catabolic/wasting conditions (such as those observed in Chronic Renal Failure, congestive heart failure AIDS, following hip fracture, trauma, or major surgery, particularly in elderly subjects), and/or (4) improving immune function or reconstitution of immunodeficient states such as that associated aging, HIV or following high-dose chemotherapy and/or radiotherapy; the method comprising admininistering a GH secretagogue (e.g.
GRF and analogs thereof) or a composition comprising a GH
secretagogue and a pharmaceutically acceptable carrier; to a subject.
In further aspects, the invention relates to uses of a GH secretagogue (e.g. GRF and analogs thereof) or a composition comprising a GH secretagogue and a
8 pharmaceutically acceptable carrier, for (1) stimulating day-time vigilance and/or cognitive functions e.g. in conditions related to aging or mild cognitive impairment, (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (e.g. metabolic conditions including obesity, HIV-related lipodystrophy, metabolic syndrome or syndrome X), (3) improving anabolism in catabolic/wasting conditions (such as those observed in Chronic Renal Failure, congestive heart failure AIDS, following hip fracture, trauma, or major surgery, particularly in elderly subjects), and/or (4) improving immune function or reconstitution of immunodeficient states such as that associated aging, HIV or following high-dose chemotherapy and/or radiotherapy.
In further aspects, the invention similarly relates to a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue;
and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In further aspects, the invention similarly relates to a use of a GH secretagogue for the preparation of a medicament for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In further aspects, the invention similarly relates to a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue;
and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In further aspects, the invention similarly relates to a use of a GH secretagogue for the preparation of a medicament for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
9 In accordance with the present invention, there is provided a composition for (1) altering a lipid parameter in a subject; (2) altering a body composition parameter in a subject, (3) treating a condition characterized by deficient or decreased bone formation in a subject (4) improving daytime vigilance and/or cognitive function in a subject, (5) improving a metabolic condition in a subject, (6) improving anabolism in a catabolic condition in a subject, and/or (7) improving and/or reconstituting immune function in a subject, the composition comprising an effective amount of a GH secretagogue (e.g. GRF compound or analog thereof) in association with a pharmaceutically acceptable carrier, excipient or diluent.
In embodiments, the metabolic condition is associated with fat accumulation and/or hypercholesterolemia, e.g. obesity, HIV-related lipodystrophy, metabolic syndrome and syndrome X.
In embodiments the catabolic condition is related to one selected from the group consisting of chronic renal failure, AIDS, hip fracture, trauma or major surgery in a subject.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
9a (c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
9b (f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
In another aspect, the present invention provides a composition for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
9c (iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said alteration of a first body composition is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol; and said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
9d (d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
In another aspect, the present invention provides a composition for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL
cholesterol; or (e) any combination of (a) to (d), said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the differences between treatment groups in changes from baseline to week 2 in the mean reaction time of the Continuous Performance Test (CPT);
Fig. 2 illustrates changes from baseline to day 9 in Pz amplitude of evoked related potential (P300) during wakefulness;
Fig. 3 illustrates mean AUC of antigen-specific proliferative T cell response;
Fig. 4 illustrates the percentage of subjects with 5 protective antibody titers (>1/40) for B/Victoria; and Fig. 5 illustrates the variation of mean IGF-l levels during time with placebo, 2mg/day TH9507, 0.5 mg/day TH9507 and 1mg/day TH9507.
Fig. 6 illustrates a flow diagram of patient disposition in respect of the studies described in Example 6.
Fig. 7 illustrates results of dose response of TH9507 on A) IGF-I and B) truncal fat, as measured by DEXA, as described in Example 6. 7A: "ng/ml" represents ng/ml of IGF-1 as measured. 7B: "kg" represents change in truncal fat, with the negative values indicating a decrease in truncal fat.
7A and 7B: "placebo", "1 mg" and "2 mg" correspond to administration of a placebo, 1 mg of Th9507 and 2 mg of Th9507, respectively. Results are mean (SD) . *=P<0.01 vs.
placebo by ANOVA.
DETAILED DESCRIPTION OF THE INVENTION
In the studies described herein, the effect of (hexenoyl trans-3)hGRF(1-44)NH2 (also referred to as TH9507 herein), a growth hormone releasing factor (GRF) analog, was assessed over 12 weeks in HIV-infected men and women with evidence of fat redistribution and increased truncal adiposity. The data herein demonstrate significant effects of TH9507 to increase lean body mass and reduce truncal fat and visceral fat and improve lipid parameters, sparing extremity and subcutaneous fat (Example 6) . These effects were achieved with physiological increases in GH secretion and without adverse effects on blood glucose levels.
The studies described herein further demonstrate beneficial effects on bone markers.
The studies described herein further demonstrate a beneficial effect of Th9507 on daytime vigilance and cognitive function (Example 2), immune response (Example 3), wasting/catabolic conditions (Example 4) and non-HDL
cholesterol (Example 5).
Accordingly, in a first aspect, the invention provides a method of altering a lipid parameter in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier. In an embodiment, the method results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a lipid parameter in a subject.
In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a lipid parameter in a subject. In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a lipid parameter in a subject.
In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In an embodiment, the above-noted the alteration of a lipid parameter is selected from the group consisting of: (a) a decrease in cholesterol; (b) a decrease in non-HDL
cholesterol; (c) a decrease in triglyceride; (d) a decrease in the ratio of total cholesterol:HDL cholesterol; and (e) any combination of (a) to (d).
In an embodiment, the above-noted lipid parameter is associated with a condition selected from the group consisting of lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia and syndrome X.
In a further aspect, the invention provides a method of altering a first body composition parameter of a subject, the method comprising administering to said subject an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In an embodiment, the method results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of: (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT);
and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In an embodiment, the above-mentioned alteration of a first body composition parameter is selected from the group consisting of: (a) an increase in lean body mass; (b) a decrease in trunk fat; (c) a decrease in visceral fat; (d) a decrease in abdominal girth; (e) a decrease in visceral abdominal tissue (VAT); (f) a decrease in VAT:SAT ratio; and (g) any combination of (a) to (f).
In an embodiment, the first body composition parameter is associated with a condition selected from the group consisting of lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia and syndrome X.
In an embodiment, the above-mentioned alteration of a first body composition parameter results in an improvement of quality of life of the subject.
In a further aspect, the invention provides a method of treating a condition characterized by deficient or decreased bone formation or for treating bone dysfunction or defect, in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically 5 acceptable carrier; for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for treating a condition characterized by
In embodiments, the metabolic condition is associated with fat accumulation and/or hypercholesterolemia, e.g. obesity, HIV-related lipodystrophy, metabolic syndrome and syndrome X.
In embodiments the catabolic condition is related to one selected from the group consisting of chronic renal failure, AIDS, hip fracture, trauma or major surgery in a subject.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
9a (c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
9b (f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
In another aspect, the present invention provides a composition for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
9c (iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said alteration of a first body composition is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol; and said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
In another aspect, the present invention provides a use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
9d (d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
In another aspect, the present invention provides a composition for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL
cholesterol; or (e) any combination of (a) to (d), said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the differences between treatment groups in changes from baseline to week 2 in the mean reaction time of the Continuous Performance Test (CPT);
Fig. 2 illustrates changes from baseline to day 9 in Pz amplitude of evoked related potential (P300) during wakefulness;
Fig. 3 illustrates mean AUC of antigen-specific proliferative T cell response;
Fig. 4 illustrates the percentage of subjects with 5 protective antibody titers (>1/40) for B/Victoria; and Fig. 5 illustrates the variation of mean IGF-l levels during time with placebo, 2mg/day TH9507, 0.5 mg/day TH9507 and 1mg/day TH9507.
Fig. 6 illustrates a flow diagram of patient disposition in respect of the studies described in Example 6.
Fig. 7 illustrates results of dose response of TH9507 on A) IGF-I and B) truncal fat, as measured by DEXA, as described in Example 6. 7A: "ng/ml" represents ng/ml of IGF-1 as measured. 7B: "kg" represents change in truncal fat, with the negative values indicating a decrease in truncal fat.
7A and 7B: "placebo", "1 mg" and "2 mg" correspond to administration of a placebo, 1 mg of Th9507 and 2 mg of Th9507, respectively. Results are mean (SD) . *=P<0.01 vs.
placebo by ANOVA.
DETAILED DESCRIPTION OF THE INVENTION
In the studies described herein, the effect of (hexenoyl trans-3)hGRF(1-44)NH2 (also referred to as TH9507 herein), a growth hormone releasing factor (GRF) analog, was assessed over 12 weeks in HIV-infected men and women with evidence of fat redistribution and increased truncal adiposity. The data herein demonstrate significant effects of TH9507 to increase lean body mass and reduce truncal fat and visceral fat and improve lipid parameters, sparing extremity and subcutaneous fat (Example 6) . These effects were achieved with physiological increases in GH secretion and without adverse effects on blood glucose levels.
The studies described herein further demonstrate beneficial effects on bone markers.
The studies described herein further demonstrate a beneficial effect of Th9507 on daytime vigilance and cognitive function (Example 2), immune response (Example 3), wasting/catabolic conditions (Example 4) and non-HDL
cholesterol (Example 5).
Accordingly, in a first aspect, the invention provides a method of altering a lipid parameter in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier. In an embodiment, the method results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a lipid parameter in a subject.
In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a lipid parameter in a subject. In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a lipid parameter in a subject.
In an embodiment, the above-mentioned alteration of a lipid parameter results in no or substantially no increase in blood glucose levels in said subject.
In an embodiment, the above-noted the alteration of a lipid parameter is selected from the group consisting of: (a) a decrease in cholesterol; (b) a decrease in non-HDL
cholesterol; (c) a decrease in triglyceride; (d) a decrease in the ratio of total cholesterol:HDL cholesterol; and (e) any combination of (a) to (d).
In an embodiment, the above-noted lipid parameter is associated with a condition selected from the group consisting of lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia and syndrome X.
In a further aspect, the invention provides a method of altering a first body composition parameter of a subject, the method comprising administering to said subject an agent selected from the group consisting of (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In an embodiment, the method results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of: (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT);
and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for altering a first body composition parameter of a subject. In an embodiment, the above-mentioned alteration of a first body composition parameter results in no or substantially no decrease in a second body composition parameter of the subject, wherein the second body composition parameter is selected from the group consisting of (i) limb fat; (ii) subcutaneous fat; (iii) subcutaneous abdominal tissue (SAT); and (iv) any combination of (i) to (iii).
In an embodiment, the above-mentioned alteration of a first body composition parameter is selected from the group consisting of: (a) an increase in lean body mass; (b) a decrease in trunk fat; (c) a decrease in visceral fat; (d) a decrease in abdominal girth; (e) a decrease in visceral abdominal tissue (VAT); (f) a decrease in VAT:SAT ratio; and (g) any combination of (a) to (f).
In an embodiment, the first body composition parameter is associated with a condition selected from the group consisting of lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia and syndrome X.
In an embodiment, the above-mentioned alteration of a first body composition parameter results in an improvement of quality of life of the subject.
In a further aspect, the invention provides a method of treating a condition characterized by deficient or decreased bone formation or for treating bone dysfunction or defect, in a subject, said method comprising administering to said subject an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue; and (b) a composition comprising a GH secretagogue and a pharmaceutically 5 acceptable carrier; for treating a condition characterized by deficient or decreased bone formation in a subject.
In a further aspect, the invention provides a use of a growth hormone (GH) secretagogue for the preparation of a medicament for treating a condition characterized by
10 deficient or decreased bone formation in a subject.
In an embodiment, the above-noted condition characterized by deficient or decreased bone formation is selected from the group consisting of osteopenia and osteoporosis.
15 In further aspects, the invention relates to uses of a GH secretagogue (e.g. GRF and analogs thereof) or a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier, for (1) stimulating day-time vigilance and/or cognitive functions e.g. in conditions related to aging or mild cognitive impairment, (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (e.g. metabolic conditions including obesity, HIV-related lipodystrophy, metabolic syndrome or syndrome X), (3) improving anabolism in catabolic/wasting conditions (such as those observed in Chronic Renal Failure, congestive heart failure AIDS, following hip fracture, trauma, or major surgery, particularly in elderly subjects), and/or (4) improving immune function or reconstitution of immunodeficient states such as that associated aging, HIV or following high-dose chemotherapy and/or radiotherapy.
In further aspects, the invention similarly relates to a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue;
and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In further aspects, the invention similarly relates to a use of a GH secretagogue for the preparation of a medicament for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In an embodiment, the above-mentioned lipodystrophy is HIV-related lipodystrophy.
In an embodiment, the above-mentioned subject is HIV positive.
In an embodiment, the above-mentioned subject is receiving antiviral therapy.
In an embodiment, the above-mentioned subject suffers from a condition selected from the group consisting of diabetes, glucose intolerance and insulin resistance.
In an embodiment the above-mentioned GH
secretagogue is administered at a dose of about 0.0001 to about 4 mg, in a further embodiment, about 0.0001 to about 2 mg, in a further embodiment, about 1 mg to about 2mg, in a further embodiment, about 1 mg and in a further embodiment, about 2 mg.
In an embodiment, the agent is administered by a route selected from the group consisting of intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal and topical. in an embodiment, the agent is administered by a subcutaneous route.
In an embodiment, the subject is a mammal, in a further embodiment, a human.
For the purpose of the present invention the following terms are defined bellow.
The term "analog" is intended to mean a molecule of different structure but having a biological function similar to the structures of the GRF or to a biologically functional fragment thereof which may include peptidomimetics. Peptidomimetics may be conveniently prepared by direct chemical synthesis using methods well known in the art.
The term "subject" is intended to mean any mammal including, but not limited to, human, canine, feline, equine, caprine, bovine, porcine and ovine.
The term "cognitive function" is intended to mean functions including, but not limited to thinking, reasoning, memory and problem solving.
The term "catabolic/wasting conditions" is intended to mean condition including, but not limited to, frail bones, low muscular mass and muscle wasting.
In the present application, the compound identified as TH9507 is [hexenoyl-trans-3-Tyrl]hGRF(1-44)NH2.
In various aspects, the methods and corresponding uses and packages described herein comprise administering to a subject a growth hormone (GH) secretagogue. "GH
secretagogue" as used herein refers to any compound or molecule, natural or synthetic, which may result in, either directly or indirectly, GH secretion and/or an increase in GH secretion.
In embodiments, the GH secretagogue is a growth hormone-releasing factor (GRF; also referred to as growth hormone releasing hormone [GHRHJ) or GRF analog.
In an embodiment, the GRF is human GRF (hGRF).
Human growth hormone-releasing factor (hGRF) is a peptide of 44 amino acids with a C-terminal NH2 modification, referred to herein as hGRF(1-44)NH2, and has the following structure:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2 (SEQ ID NO: 2) Therefore, the amino acid sequence of the just-noted 44 amino acid form is as follows:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu (SEQ
ID NO: 3) The minimum active core comprises the first 29 amino acids of the above sequence, which is referred to herein as hGRF(1-29)NH2, and has the following structure:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2 (SEQ ID NO: 4) Therefore, the amino acid sequence of the just-noted 29 amino acid form is as follows:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg (SEQ
ID NO: 5) The 1-44 and 1-29 forms differ in that the 1-44 form contains the following additional amino acids, which correspond to positions 30-44 of the 1-44 form:
Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu (SEQ ID NO: 6) In an embodiment, the above-mentioned GRF analog is a GRF analog of formula A:
X-GRF Peptide (A) wherein;
the GRF peptide is a peptide of formula B;
Al-A2-Asp-Ala-Ile-Phe-Thr-A8-Ser-Tyr-Arg-Lys-A13-Leu-A15-Gln-Leu-A18-Ala-Arg-Lys-Leu-Leu-A24-A25-Ile-A27-A28-Arg-A30-RO (B) (SEQ ID NO: 1) wherein, Al is Tyr or" His;
A2 is Val or Ala;
A8 is Asn or Ser;
A13 is Val or Ile;
A15 is Ala or Gly;
A18 is Ser or Tyr;
A24 is Gln or His;
A25 is Asp or Glu;
A27 is Met, Ile or Nle;
A28 is Ser or Asn;
A30 is a bond or amino acid sequence of 1 up to 15 residues; and RO is NH2 or NH- (CH2) n-CONH2i with n=1 to 12; and X is a hydrophobic tail anchored via an amide bond to the N-terminus of the peptide and the hydrophobic tail 10 defining a backbone of 5 to 7 atoms;
wherein the backbone can be substituted by C1-6 alkyl, C3-6 cycloalkyl, or C6-12 aryl and the backbone comprises at least one rigidifying moiety connected to 15 at least two atoms of the backbone;
said moiety selected from the group consisting of double bond, triple bond, saturated or unsaturated C3-9 cycloalkyl, and C6-12 aryl.
In embodiments, X noted above is selected from the group consisting of:
R H C"
H
1 (R=H or CH. or CH2CH,3) GIs or Iran:
2 (R=H or CHI or CH6CH3) R
3 (R=H or C1f or C H 13) co or trans, both as racemic mixtures or pure a nautiomcric pairs R
4 :fit: H, tai, or t i~
cis or trams, both as t is mixtt or p 0nomic pairs .
it oil (R or CU3 or CHrCH;
ens or tom= (when R -A H) /-Oil R
6 QtFff or CHI or CHrCH,) cis or tram, both as tr + ntixam or p e do erk Paks 7 (R-7H or CH, or CH2CH) cis or trans, (when R 4" H) both as racemic mixtures or pure enantiomeric pairs 8 (R-H or (Hr or CH,CCH) cis or trans. both as mcemic mixtures or pure enantiomeric pairs R
9 or CH,3 or H2 R3) cis or ,(when R A H) both as mcemic mixtures or pum a pirs R
1D (R orC, 3orc.co vws& R, IQ
R
it (RrHorC i3orCH ) R
12 (R=U or CH. or CH2CH3) R
13 ( or C11, or C14CH3) In embodiments, A30 noted above is selected from the group consisting of:
(a) a bond;
(b) an amino acid sequence corresponding to positions 30-44 of a natural GRF peptide, and (c) said amino acid sequence of (b) having a 1-14 amino acid deletion from its C-terminus.
In embodiments, the above-noted GRF peptide is selected from the group consisting of:
(a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 3;
(b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 5; and (c) the polypeptide of (a) having a 1 to 14 amino acid deletion from its C-terminus.
In an embodiment, the above-noted GRF analog is (hexenoyl trans-3)hGRF(1-44)NH2.
Methods of preparing the above-described GRF
analogs are described in US patents No. 5,861,379 (Ibea et al., January 19, 1999); No. 6,020,311 (Brazeau et al., February 1, 2000), No. 6,458,764 (Gravel et al., October 1, 2002) and published US application No. 2004/0171534 Al (Gravel et al., published September 2, 2004).
As noted above, in various embodiments, the above-mentioned GH secretagogue may be used therapeutically in formulations or medicaments to effect the above-noted alterations and to prevent or treat the above-noted conditions. The invention provides corresponding methods of medical treatment, in which a therapeutic dose of a GH
secretagogue is administered in a pharmacologically acceptable formulation, e.g. to a patient or subject in need thereof. Accordingly, the invention also provides therapeutic compositions comprising a GH secretagogue and a pharmacologically acceptable excipient or carrier. In one embodiment, such compositions include GH secretagogue in a therapeutically or prophylactically effective amount sufficient to effect the above-noted alterations and to treat the above-noted conditions. The therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.
A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as to effect the above-noted alterations and to reduce the progression of the above-noted conditions. A therapeutically effective amount of a GH secretagogue may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A
therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed 5 by the therapeutically beneficial effects. A
"prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as preventing or inhibiting the rate of onset or progression of the above-10 noted conditions. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. For any particular, subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person 15 administering or supervising the administration of the compositions.
As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal 20 agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, 25 subcutaneous, sublingual or oral administration.
Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art.
Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.
The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, a GH secretagogue can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
Sterile injectable solutions can be prepared by incorporating the active compound (e.g. a GH secretagogue ) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with an alternative aspect of the invention, a GH secretagogue may be formulated with one or more additional compounds that enhance its solubility.
In accordance with another aspect of the invention, therapeutic compositions of the present invention, comprising a GH secretagogue, may be provided in containers, kits or packages (e.g. commercial packages) which further comprise instructions for its use to effect the above-noted alterations and to prevent or treat the above-noted conditions.
Accordingly, the invention further provides a package comprising a GH secretagogue or the above-mentioned composition together with instructions to effect the above-noted alterations and to prevent or treat the above-noted conditions.
The invention further provides a use of a GH
secretagogue to effect the above-noted alterations and to prevent or treat the above-noted conditions. The invention further provides a use of a GH secretagogue for the preparation of a medicament to effect the above-noted alterations and to prevent or treat the above-noted conditions.
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art.
Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way.
Numeric ranges are inclusive of the numbers defining the range. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The following examples are illustrative of various aspects of the invention, and do not limit the broad aspects of the invention as disclosed herein.
EXAMPLES
Example 1: Study drug The compound used in the studies below is (hexenoyl trans-3)hGRF(1-44)NH2 (also referred to as TH9507 herein), which is a synthetic human growth hormone releasing factor analog that comprises the 44-amino acid sequence of human growth hormone releasing factor (hGRF) on which a hexenoyl moiety, a C6 side chain has been anchored on Tyr 1 at the n-terminal. (hexenoyl trans-3)hGRF(1-44)NH2 or Th9507 has the following structure:
(trans) Gly-Ala-Arg-Ala-Arg-Leu-NH2 (SEQ ID NO: 7) (hexenoyl trans-3)hGRF(1-44)NH2 was synthesized via the methods set forth in US 5,861,379 (Ibea et al.; January 19, 1999).
The in vitro half-life of Th9507 is 3-8 hours compared to 0.56 hours for hGRF. Daily 1 and 2 mg doses have been shown to increase IGF-I to the physiological range seen in younger adults (14). The safety profile of TH9507 is generally good. Th9507 has been studied in patients with Type II DM, and was not shown to aggravate overall glycemic control when administered at a daily dose up to 2 mg (15).
Example 2: Administration of TH9507 for improving daytime vigilance in subjects with sleep maintenance insomnia The present example shows the effect of a 14 day-administration of 2 doses of TH9507 (0.1 mg and 1 mg) on vigilance parameters in subjects of 35 to 50 years of age exhibiting sleep maintenance insomnia.
Material and Methods The study involved 82 patients exhibiting sleep maintenance insomnia (20 females, 62 males; mean age 43.2 5.4 years). Patients were selected based on the Pittsburgh Sleep Quality Index (Score ?5), the Walters Criteria for Sleep Maintenance Insomnia, and the Beck Questionnaire (Score -<17). The primary exclusion criteria were other primary sleep disorders and the use of any products affecting sleep or vigilance in the 30 days prior to entering the study.
The study was a randomized, double-blind, placebo-controlled, parallel group and multicenter evaluation of two doses of TH9507 (0.1 mg and 1 mg) administered daily by subcutaneous injection at bedtime for 14 consecutive days.
To evaluate vigilance and the performance in the morning, patients underwent a battery of cognitive tests including 5 the Continuous Performance Test (CPT) at baseline and at the end of treatment period.
The CPT has been described in the literature as a measure of consistency in responding and ability to sustain attention over time (Aleman A, et al., J Clin Endocrinol 10 Metab 1999 84(2):471-475). This test required subjects to press space bar each time the letter "A" was followed by "X". Omission and commission errors, and Mean Reaction Time of correct responses were analyzed.
15 Results Demographic characteristics by treatment group are displayed in the following table:
Table 1 20 Demographic (screening) data by treatment groups Placebo 0,lmg N=26 1 mg N=27 P value N=29 Age (Mean SD) 44.0 5.8 43.2 5.8 42.3 4.5 0.53 (range) (35-56) (34-60) (34-50) (F-test) Gender Males 21 19 22 0.68 Females 8 7 5 chi-square test) Weight(kg) 0.94 (Mean SD) 78.0 14.3 78.2 12.4 79.3 15.3 (F-test) As illustrated in Fig. 1, the Mean Reaction Time of the CPT was significantly and markedly decreased in the 0.1 mg group when compared to placebo. The decrease from baseline to day 9 was 45.85 ms (P=0.023 when compared to placebo as analyzed by an ANOVA model). No significant effect was observed in the 1 mg group. Circulating IGF-1 and IGFBP-3 levels were significantly increased at week 2 in the 1 mg group when compared to placebo (P<0.0001, ANOVA on changes from baseline) As expected the 0.1 mg did not affect these parameters (P=0.07 and P=0.99) for IGF-l and IGF-BP3 respectively, ANOVA model on changes from baseline).
Additional data on effects of TH9507 on vigilance obtained in a previous study are presented in Fig. 2. In this study, TH9507 was administered daily for 7 days in a cross-over design. This study involved 12 healthy subjects aged between 50 to 65 years, exhibiting age-related sleep impairment (Pittsburgh Sleep Quality Index Score from 3 to 7). At the end of the treatment period, daytime vigilance was significantly enhanced when compared to placebo in subjects receiving 1 mg of TH9507, as assessed by P300, an event-related potential test. Changes from Baseline to day 9 in the Pz amplitude of the Evoked Related Potential (P300) observed in the placebo and 1 mg group were as follows:
Placebo, -15%; 1 mg, +55%, P=0.0114, as analyzed by an ANOVA
model.
In both studies, the safety profile of TH9507 was comparable to that of the placebo, except for a higher incidence of reactions at the site of injection observed at 1 mg in the insomnia study.
In summary, these results provide evidence that TH9507 improves daytime vigilance in sleep maintenance insomnia in subjects and would favor a direct mechanism of action of TH9507, not mediated by IGF-1. Data are supported by those obtained by Vitiello et al (Vitiello M.V., et al., Gerontologist 2002 40(Special Issue 1):39-N/A. using hGRF in cognitive tests involving psychomotor and perceptual processing speed (Deijin JB et al, Psychoneuroendocrinology 1998 23(1):45-55) and may support further clinical investigations in subjects with impaired cognitive functions.
Example 3: Effects of TH9507 on the immune response to influenza vaccination in elderly subjects The present example describes immune findings following an influenza vaccination challenge in elderly subjects.
Material and Methods Eighty seven (87) subjects aged 75 years in average were included in a double-bind, randomized, placebo-controlled study. TH9507 or a placebo was administered at a daily dose of 1 or 2 mg by subcutaneous injection for 8 weeks. Follow-up assessments were conducted for 12 weeks after the end of the treatment period. At week 4, in the middle of the treatment period, subjects received the commercial Canadian influenza vaccine (Vaccine Fluviral S/F, Shire, Montreal, Canada) containing 15 pg each of A/New Caledonia/20/99, A/Panama/2007/99, B/Victoria/504/2000 antigens.
Influenza-specific proliferative T cell response and antibody titers were evaluated for each of the 3 strains contained in the vaccine. The proliferative T cell response was assessed by a mitogen assay using tritiated thymidine (3H) incorporation and results were log-base 10 transformed prior to analysis. The antibody titers were determined by standard hemaglutinaion inhibition assay and results were log-base 2 transformed prior to analysis.
Eighty one (81) subjects completed the study as per protocol. Subject demographics are shown in the following table:
Table 2 Subject demographics Placebo 1 mg 2 mg All P-value Age 75.9 74.9 73.2 74.6 0.21 (years) 6.5 6.1 4.4 5.8 Total N 29 29 29 187 0.96 Female 13 13 14 40 Male 16 16 15 47 BMI 27.4 26.9 29.2 27.8 0.26 (kg/m2) 5.8 4.2 6.0 5.4 Data for age and BMI are presented as mean SD. Baseline comparability among treatment groups was tested by ANOVA
(age, BMI) or Pearson's chi-square test (gender).
Results As shown in Fig. 3 the mean AUC calculated for the whole study period including both the treatment and follow-up period (week 0 to week 20) was statistically higher in the 2 mg group when compared with placebo (Panama, P=0.03;
New Caledonia, P=0.001; Victoria, P=0.02, (Pairwise comparisons for difference among treatment groups and ANCOVA
analysis for overall treatment significance).
As illustrated in Fig. 4, administration of TH9507 increased the proportion of patients achieving a protective antibody level for the Victoria antigen when compared to placebo. This observation reached statistical significance at the 2 mg dose and was noted during both the treatment and the follow-up periods (week 6 : P=0.02; Week 8 : P=0.01;
week 12 : P=0.02; week 16 ; P=0.004, week 20 : P=0.01, pairwise comparisons for difference among treatment groups and Pearson chi-square test for overall treatment difference) indicating a sustained effect for up to 16 weeks after cessation of treatment. No statistical difference in the percentage of subjects was observed in the Panama and New Caledonia strains.
A dose-related increase in the mean IGF-1 values was observed during the whole treatment period in both Th9507 groups when compared to baseline. Values returned to baseline following cessation of treatment.
No major difference in the incidence of adverse events was observed between treatment groups except for a dose-related trend in the incidence of reactions at the site of injection.
In summary, the findings observed in this study strongly indicate that TH9507 has a therapeutic potential in immune indications. In particular, its effect of the T-lymphocyte proliferation response following vaccination makes it attractive to develop in clinical situations where the cell-mediated immune'system is depressed, such as viral infections in the elderly and immune-deficient states following HIV infection, high-dose chemotherapy or radiotherapy.
Example 4: ThGRF's benefits in wasting/catabolic conditions The present example shows the effect of a 7-day administration of TH9507 on circulating IGF-l levels in healthy middle-aged men.
5 Material and Methods The study used a randomized, double-blind, placebo-controlled design and was conducted in healthy men, aged 50 to 60 years old. Subjects (8 per group) were injected S.C. once a day for 7 consecutive days with 10 placebo, 0.5, 1 or 2 mg of TH9507. Circulating IGF-l levels were measured on Days 1 to V. The 12 hour GH response and TH9507 PK profile were determined on Day 1 and 7.
Results 15 As shown in Fig. 5, IGF-1 increased over baseline values by 80 (placebo), 370 (0.5 mg), 890 (lmg) and 106% (2 mg); these increases were statistically significant for all 3 doses of TH9507. The 1 mg and 2 mg doses were equally potent and induced a doubling of IGF-1 20 levels up to levels expected for young adults (286 25 and 284 55 ng/ml, respectively), none of the subjects exhibited levels greater than 400 ng/ml. A plateau was reached at Day 4 and 6 for the 1 mg and 2 mg doses, respectively.
25 GH response to TH9507 increased rapidly both on Days 1 and 2. The increase was dose dependent between the 0.5 and 1 mg dose (P<0.01), and was similar at the 1 mg and 2 mg doses. No significant modification in prolactin, ACTH, cortisol, TSH, LH or FSH was observed following 30 single or repeated treatment with TH9507.
PK analysis indicated that Cmax and AUC
parameters increased in function of the dose administered.
The half-life of the TH9507 ranged between 2 and 5 hours.
These results clearly indicate that TH9507 is highly specific on GH= secretion and a powerful IGF-1 inducer, suggesting potential clinical benefits in wasting/catabolic conditions.
Example 5: Effects of GRF on non-HDL cholesterol in patients with type 2 Diabetes The present example illustrates beneficial effects of TH9507 on non-HDL cholesterol levels in a diabetic population.
Material and Methods A double-blind placebo-controlled study was conducted in 53 type II diabetic patients (age = 61 7 [SD]; 34% female) on stable antidiabetic medication (26%
on insulin). Patients were randomized to parallel groups to receive daily subcutaneous administration of a placebo, 1 mg or 2 mg TH9507, respectively.
Results A statistically significant difference was observed at Week 12 between the 3 treatment groups in the mean total cholesterol change from baseline (P=0.04).
Values decreased in the 2 mg group (-11.1 21.9 mg/dl; -6%), as compared to increases in the Placebo (+9.7 22.6 mg/dl; +5%) and 1 mg group (+6.1 16.2 mg/dl; +3%). This effect was accompanied by a decrease in the mean non-HDL
cholesterol values in the 2 mg group (-10.1 19.0 mg/dl;
-7%) and increases in the placebo (+6.8 17.8 mg/dl; +5%) and 1 mg group (+3.8 15.5 mg/dl; +3%).
No statistically significant differences were observed between the three groups during the treatment period in terms of insulin relative response to an oral glucose tolerance test. At Week 12, glycosylated hemoglobin (HbAlc) levels displayed a trend for a decrease in the placebo group, a decrease in the 1 mg group, and no change in the 2 mg group. Clinically relevant changes in antidiabetic medications occurred with a similar incidence in the three treatment groups.
A dose-related increase in the IGF-l levels was observed at the end of the treatment period.
In summary, this study indicates that the repeated administration of TH9507 for 12 weeks decreases the total and non-HDL cholesterol fraction in diabetic subjects and can be safely administered to this population without impairing glucose control. The effects observed on blood lipids and the known lipolytic properties of GH
warrant the investigation of TH9507 for the treatment of syndromes associated with visceral fat accumulation.
Example 6: Effect of GRF analog on lipid profile, body composition and quality of life in HIV-infected patients This study investigated the effects of TH9507, on abdominal fat accumulation associated with HIV
lipodystrophy.
Design: Randomized, placebo-controlled, multi-center, dose ranging (placebo, lmg or 2 mg SC QD), parallel group, 12-week study Patients: 61 HIV-infected patients (BMI 28 3 [SD] kg/mz, 28% diabetic or glucose intolerant) with increased waist circumference (102 cm 8 [SD]) and waist/hip (1.0 0.1 [SD]) Measurements: Body composition was assessed by DXA and abdominal CT scan; IGF-I, insulin, glucose, lipid, bone turnover, immunologic, and safety parameters.
Results: Treatment with TH9507 resulted in a dose-related increase in serum IGF-1 levels within the physiological range [18 (32) ng/mL, 87 (67) ng/mL, 123 (79) ng/mL, mean (SD) for placebo, 1mg, 2 mg, respectively, P<0.01 for change in each active group vs. placebo]. Lean body mass increased significantly in both treatment groups compared to placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg; placebo, lmg, 2 mg, respectively; P<0.01 for 2 mg dose vs. placebo, P<0.05 for the 1 mg group vs. placebo]. Trunk fat decreased in the 2 mg group compared to placebo (0.8%, -4.6% and -9.2%; placebo, lmg, 2 mg, respectively, P=0.01 for 2 mg vs.
placebo), with no significant change in limb fat. Visceral fat decreased most in the 2 mg group (-5.4%, -3.6% and -15.7%; placebo, 1mg, 2 mg, respectively; P=0.03 for change within 2 mg group but P=NS vs. placebo) whereas subcutaneous fat was preserved and did not change between or within groups. The ratio of VAT: SAT improved significantly in both treatment. groups compared to placebo (-0.01 (0.10), -0.23(0.47) and -0.14(0.18), P<0.01 for the 2 mg group vs.
placebo and P<0.05 for the 1 mg group vs. placebo.
Triglyceride and the cholesterol to HDL ratio decreased significantly in the 2 mg treatment group compared to placebo. Treatment was generally well-tolerated without changes in either fasting glucose or 2-hour OGTT.
Conclusion: TH9507 effectively improved body composition and reduced truncal fat by preferentially decreasing visceral fat while preserving subcutaneous fat in patients with HIV
lipodystrophy. TH9507 did not increase glucose levels, even among those with impaired glucose tolerance or diabetes mellitus at baseline, and improved the lipid profile. These data suggest that TH9507, a GRF analog, may be a beneficial treatment strategy for HIV lipodystrophy.
Methods Subjects Eighty-eight subjects were screened between May 2003 and November 2003. Sixty-one subjects were enrolled.
HIV infected males age 18-65 years and non-menopausal females age > 18 years with visceral fat accumulation considered to be part of the HIV lipodystrophy syndrome, waist circumference ? 95 cm for men and ? 94 cm for women, and a waist to hip ratio ? 0.94 for men and >_ 0.88 for women were enrolled. We excluded, subjects with a BMI <-20 kg/m2, CD4 cell count <--100 cells/mm3, viral load >_ 10,000 copies/mL, history of opportunistic infection or HIV-related disease within 3 months of the study, history of prostrate cancer or PSA > 5 ng/ml in male subjects, history of breast cancer or abnormal mammography within 6 months of the study (for these patients without a mammogram within this time frame, one was performed as part of the study) in female subjects, known hypopituitarism or history of pituitary surgery, radiation or significant head trauma, untreated hypothyroidism, prior history of Type I diabetes mellitus (DM), any prior use of GH or GH related products, experimental or marketed, within 6 months of the study, systemic steroid administration or megestrol acetate within 60 days of the study, fasting glucose > 150 mg/dL, SGOT or SGPT > 3x upper limit of normal, creatinine > 1.5x upper limit of normal, or hemoglobin < 9 g/dL. Subjects receiving testosterone or estrogen within the prior six months, with known drug or alcohol dependence or who had participated in another clinical trial with an investigational agent within 30 days were also excluded from the study. All subjects were required to be on a stable antiretroviral regimen for 8 weeks prior to enrollment. Subjects receiving lipid lowering medications were required to be on a stable regimen for 3 months prior to enrollment. Subjects were not permitted to 5 begin antidiabetic medication, use systemic corticosteroids for > 10 days, or begin estrogen or testosterone preparations during the study.
Study Procedures 10 Subjects underwent a screening visit to determine eligibility. All subjects gave written consent to participate in the study, and the study was approved by the Institutional Review Board at each participating site. BMI, anthropometic measurements, TSH and prolactin were 15 performed. Viral load and CD4 count were performed if not previously done within 8 weeks of the study. A PSA was performed in male subjects and a pregnancy test was performed in female subjects. Mammography was also performed in female subjects if not previously done within 6 months of 20 the study.
At the baseline visit, anthropometric measurements were obtained. Total body lean and fat mass as well as regional fat mass in the trunk and extremities were assessed by DEXA.
Abdominal subcutaneous and visceral fat area and the ratio 25 of VAT to SAT were determined by cross-sectional CT at L4-L5. Biochemical parameters including insulin-like growth factor-I, glucose, insulin, lipid profile (cholesterol, HDL, LDL, triglyceride, non HDL and the ratio of cholesterol:HDL), free fatty acids, HbAlC, IGFBP-3, and bone 30 markers (serum osteocalcin and NTX-1), CD4, viral load, and a pregnancy test for female subjects were determined in the fasting state. In addition, insulin and glucose response to a 75 gram standard glucose challenge were assessed and a quality of life questionnaire was administered.
After baseline evaluations were complete subjects were randomized equally to one of three groups, placebo, 1 mg TH9507 or 2 mg TH9507. Randomization was performed by an independent consulting firm, using a permuted block algorithm, with block size equal to 3 and kept confidential in the Theratechnologies Quality Assurance Department until unblinding. Subjects were stratified for gender at the time of treatment assignment. Treatment assignment was blinded to investigators and patients. Active drug and placebo (mannitol) were provided as lyophilized powder in vials of identical appearance, each containing 1.1 mg of material.
Each vial was reconstituted with sterile water immediately prior to injection. Patients were instructed to inject each AM at approximately 0900 h.
Subjects returned for a safety visit at Week 1 to assess adverse events and compliance. Subjects returned at 2 weeks to assess weight, anthropometric measures, lipid profile, free fatty acid, IGFB-1, IGFBP-3, glucose, adverse events and compliance. Subjects returned for a visit at week 6 identical to baseline and a visit at week 9 to assess compliance and adverse events. Subjects returned for a last study visit at week 12 - or, whenever possible, at the time of early termination - identical to the baseline visit.
Study Drug TH9507 was used in this study, as noted above.
Methods Biochemical Indices Clinical laboratory testing was performed by a central lab. Serum IGF-1 was measured after acid-ethanol extraction using the Esoterix RIA kit (Esoterix Inc., Calabasas Hill, CA), with a sensitivity of 10 ng/mL. Intra- and inter-assay coefficients of variation were 4.6-20% and 9-10%, respectively. Serum IGFBP-3 was measured using the Esoterix RIA kit (Esoterix Inc., Calabasas Hill, CA) with a sensitivity of 0.3 mg/mL. Intra- and inter-assay coefficients of variation were 5.1-13% and 5.5-17%, respectively. HDL, LDL, total cholesterol, triglycerides and FFA were determined by enzymatic colorimetric assay. Glucose was measured by enzymatric test (Gluco-quant , Roche diagnostics, Indianapolis, IN). HbAlc was determined by chromatography. PSA was determined using the Hybritech PSA
test (Beckman Coulter, Mississauga, Canada). TSH was measured by microparticle enzyme immunoassay (AxSYM hTSH II, Abbott Laboratories, Abbott Park, IL). NTX (N-terminal telopeptide of type I collagen; a bone resorption marker) was measured by ELISA using a commercially available kit (Osteomark't, Ostex International Inc., Seattle, WA).
Osteocalcin was measured using a commercially available enzymatic immunoassay kit (MetraTM osteocalcin, Quidel Corporation, San Diego, CA). CD4 and viral load were performed by the individual site labs by routine methodology.
HOMA was calculated as:
OInsulin (30min-O min) Insulin (0min) .
A Glucose (30 min- 0min) Body Composition Whole body and regional DEXA (dual energy X-ray absorptiometry) and cross-sectional abdominal CT scans were performed at the individual study sites based on previously established protocols and were standardized across sites.
Digitized images were sent to a central reading center, St.
Lukes Roosevelt Hospital, for analysis by independent experts without knowledge of treatment assignment. Each site was given a procedure manual to follow in obtaining the body composition data and was certified in the proper technique. For the CT scans, parameters were standardized as follows: Tube Voltage = 120 kV, Tube Current = 250 mA, Exposure = 375 mAs, matrix 512 x 512. DFOV was set to include the entire slice into the field of view. For the DEXA scans total body scans were performed with analysis of lean body mass, total fat mass, and regional fat mass in the trunk and extremities as previously described (16) . After analysis the data was transferred to the data management center and incorporated in the study database.
Statistics Body composition endpoints included trunk fat and trunk to limb fat ratio by DEXA and VAT and VAT: SAT by CT
scan. Other endpoints included IGF-I, lipid parameters, glucose and insulin, CD4, viral load, bone markers, and quality of life. A sample size of 20 patients/group was planned to assess a statistically significant change of 10%
or more in intra-group analyses. The planned dropout rate was 25% and therefore 60 patients were enrolled into the study. Baseline data are compared between the groups by F-test based on ANOVA for continuous variables and Chi-Square test for categorical variables. Change over time between groups is compared by ANOVA or the Chi-Square test. Where appropriate, data were rank transformed prior to analysis.
Changes within each group are determined by t-test. The ITT
(intent to treat) population is defined as all subjects who received at least one dose of the study treatment.
Descriptive statistics and analyses for all efficacy and safety analyses are performed on the ITT population. End of study, 12 week, data are used to calculate changes in body composition. For biochemical indices, the last observation available is used to calculate change. Imputation for missing data is not performed. For body composition, end of study data are used to calculate change. Interim analyses were not performed. Results are mean (SD) unless otherwise noted. All statistical tests were performed with a two-sided Type I error level of 0.05.
Results Sixty-one subjects were randomized, 21 to placebo, 19 to TH9507 1 mg and 21 to TH9507 2 mg. Five subjects discontinued in the placebo group, 2 in the 1 mg group and 6 in the 2 mg group, for a 79% completion rate. See Figure 6 for patient disposition and flow diagram.
Baseline demographic for the three study groups are shown in Table 3. At baseline no significant differences were seen between the groups except, including use of antiretroviral therapy. The percentage of patients with diabetes (fasting glucose >- 7.0 mmol/L or 2h-glucose -> 11.1 mmol/L) and impaired glucose tolerance (6.1 mmol/L <- fasting glucose < 6.9 mmol/L or 7.8 mmol/L < 2h-glucose <11.1 mmol/L) was not different between the groups. Among the entire study group, 23% of subjects demonstrated IGT and 5%
demonstrated diabetes mellitus at baseline.
Table 3: Baseline Characteristics Placebo 1mg 2mg P
Age 46.1(7.4) 46.5(6.4) 44.6(7.1) 0.64 Gender Males/Females 18/3 18/1 18/3 NA
Ethnic origin Cauc./Other 18/3 15/4 17/4 0.84 BMI 28.9(2.7) 28.0(3.2) 27.3(4.1) 0.30 WHR 1.0(0.1) 1.0(0.0) 1.0(0.1) 0.65 WC 103.4(8.0) 100.3(6.1) 100.7(9.1) 0.40 IGT-Diabetes 7 4 6 NA
Data are mean (SD). BMI, body-mass index; WHR, waist/hip ratio; WC, waist circumference Body Composition 5 Lean body mass increased in both treatment groups compared to placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg, mean (SD) for placebo, lmg, 2 mg, respectively, P<0.01 for change in 2 mg group vs. placebo, P<0.05 for the change in lmg group vs. placebo, Table 3). Total fat 10 decreased in the 2 mg group compared to placebo [0.3 (1.7) kg, -0.4 (1.8) kg and -1.4 (2.0) kg, placebo, 1mg, 2 mg, respectively, P=0.01 for 2 mg group vs. placebo). Trunk fat decreased in the 2 mg group compared to placebo (0.8%, -4.6%
and -9.2%, placebo, lmg, 2 mg, respectively, P=0.01 for 2 mg 15 group vs. placebo) (Figure 2). VAT tended to decrease more in the 2 mg group (-5.4%, -3.6% and -15.7%, placebo, 1 mg, 2 mg, respectively), (P=NS for comparison of 2 mg vs. placebo, P=0.03 for change within 2 mg group). SAT did not change significantly between the groups and the ratio of VAT:SAT
20 decreased more in the treatment groups compared to placebo [0.01 (0.10), -0.23 (0.47), -0.14 (0.18)] (Table II) (P<0.01 for 2 mg vs. placebo and P=0.04 for 1 mg vs. placebo).
Biochemical Indices 25 IGF-I increased significantly with the 1 and 2 mg dose compared to placebo [18 (32) ng/mL, 87 (67) ng/mL, 123 (79) ng/mL, placebo, 1 mg 2mg, respectively, P<0.01 for each active group vs. placebo] (Figure 3). Triglyceride levels decreased in the 2 mg group compared to placebo (-0.2 (1.3), -0.9 (4.2), -0.9 (1.2), last observation values for placebo, 1 mg, 2 mg, respectively, P<0.05) and the ratio of cholesterol to HDL improved in both treatment groups compared to placebo (0.3 (1.1), -0.3 (0.7), -0.3 (0.6) , last observation values for placebo, 1 mg, 2 mg, respectively, P<0.05).
Changes in fasting and 120 minute glucose were not significant between or within the treatment groups.
Bone Markers Osteocalcin increased significantly within the 2 mg group, whereas no changes with NTX were seen (Table 4).
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b Ln 00i N l0 I
l0r ri (N ri 'H rl ri O N' M M ri N N' Ln Ln m E ^ N 6 ^ k ~' -- co "r co N Ln r ., N' a) (0 O = (N N = O \0 Ol = a) N Ln N' a rt ~--~ rl rl rl N. p () N - O ' M O O O O O
Ln -- = -- N LO - rl N
O I- -i ri co . = 6l rl C) -I N
= 0 0 = --i = O C` C) O r= O
Q (r O I I O I I co N I I O O 1 I O O
C E
E
E Q) o ^ ^ Ln = C^ N' -- l0 Ol N N
O ,0 Ln co l0 r= M Ol M lfl M co N' C r1 Ln M
t6 N co a) M N N O O N' rl O O
d O ri = r a = rl 1` co r 1 M ao 6l N' r= 6l Ln M N
N' dl (n Ln co a) 'C l0 1-1 1-1 Ln ri -i -I .-i N' Ln M r~ M (f) Ln Ln .C
Ln a) o m . = ri r-- i<
l0 ^ ^ N rl ^ ^ ^
C r rl C` M M O r1 N' 00 (0 00 ri (0 ^ ^ (f) 0 41 'H'H O O Ln -i m 0 O 0 0 0 'H = o =y LO -- .~ . p M ' O p p = M ri rl N O = rl M N' Ln O N - -' M
Q. p = ri r1 O W . N N
0 I C) O O I I I ri O O O O O O = O
E . I O O 1 O a) U u is ^ ^
W ^ ^ - p 0 w o0 o N= ^ (n Ln Ln N ^ ^ ^ ^ ^
. co r co N' C- O O CO M Ln N' 110 (n C 6l l0 M p N
(N m N' O N rf rl CD* (D' N ri O O
C Q0 O C- CO N C- o N (n N r1 rl m M ri M N N' = 0) M M
l0 N rl l0 r= N O rl N (D N' Ln M ri M N' (n Ln E tP 'H
0 ~-i 0 Q) L N
tb O ^ rn ^ Xi a) U) m C m -- cr -- v ^ a co ,) w 0 C o(a rn x sT U a - a) m -- a) U
(U x =b E: 0 rt a) a s U 0 .~ .~ ~F'i \ X-. .O' O -i '- \ -H rl U O 1-) ^ ^ .~ 0,- v -c 0 r-1 ri 7-1 as CJ' "0 U) (0 J-) N c N U O O a) a o U) G, M E: E- . v M a u a U^ Q p a ~o O W ro W U U cC v I a >, a x y o- --u x ri a Q - .-I i - ri == -c C ..4 = = F = ' py I ! Y 1 - x O M O tP 0 " rl 4 J0 F v N 1) 1 Ei Ei E' E~ o f"J z E 1-) a s -ri w 0 o ro ~i- xC c5 o o ra ra ro oa awE, 4>M > A I-it-3 z-El axE-I u C7w--x Ln O L17 0 Lf) O Ln -i N N (Y) (N
O co O O M
O m 0 0 O O
O 0 \0 0 0 0 C) ~oo0 00 Q
o o + m a`) z O O O O 0 ,=4, O O 0 =-4 O (n O O O ri O
O O O M O
H H ri O ri U
ao o r {~ N l0 0 N N
H O ri N
O Ln =
r- N O M
CD r0 N M 0 i' ro ro -d Lr) r I r` -H
-~ -N 41 ri N Ln OD M CO Ud N M M - C) N N
=O = O M C) U) = N = C) C) l0 H M OD M Ln 0 U) ri I-- c CC) = N r-I
N ma'r` d' N v 0 H OD Ln Ln 4a N
O I (D H N N -O
ro 0 oo --C) 0) - -o 0 V O l0 61 M M
LI
cr = 0) O 0 N r` N 'C3 (N Ln OJ M Ln -~ N
+) U) O U) P N
co N 0a co - - [) 61 O C) - U) = Ln = N H a) 4 r-I Ln M (D ci Cl) OD 0) H H -P
~o H H LO ,q ro .-I
o l0 ro 5 ~.
O Ln N O I M f Q
rn p H
ro Ln U) m co l0 IT r` N
r4 H. = r-4 -- ro N V' v' 0 4J
N M U) N O
Ln = ~o IT 0 l0 r1 M 0 M Ln Z ro (-a 04 '0 o s~~
H U) o 0) 0 ; =r4 w 04 H > U U U H ro ro m =0 ri -rl - ~I H O - N =-i O +-) H I N N ro ff) O
E~ Ga W O 2 Q if 'J w Lr) O Ln r-A H
Quality of Life A health-related quality of life questionnaire (PLC, Quality of Life Profile for the Chronocally Ill) was self-administered to 61 patients randomized to receive placebo or TH9507 at 1 or 2 mg s.c. daily. The PLC
questionnaire included a general, non-specific part assessing 6 dimensions of global health as well as a disease specific part capturing impact of enlarged abdominal girth, abdominal bloating, tenseness and pain, as well as diarrhea, visible facial changes, visible changes in physical appearance, and the feeling of being recognized as an HIV
positive person.
Study population included 54 men and 7 women.
Baseline mean age was 46 7 [SD] , BMI 28 3 [SD] kg/m2, WC
102 cm 8 [SD] and WHR 1.0 0.1 [SD]. No significant difference between groups was noted for subscales of the main portion of the PLC. Slight changes were observed within the treated groups in the positive mood and social well-being scores but were not considered clinically significant.
Clinically significant improvements were noted in the enlarged abdominal girth (placebo :-0.13; 1 mg :-0.93, P=0.06 vs baseline; 2 mg :-1.19, P<0.05 vs baseline, NS vs placebo) and bloating scores (placebo : 0.56; 1 mg : -0.50;
2 mg : -0.69, P<0.05 vs. placebo). Improvement in abdominal pain was observed at 1 mg only (P<0.05 vs baseline, NS vs placebo) along with a trend for improvement in tenseness (P=0.07 vs baseline, NS vs placebo). No significant changes were observed in the other disease-specific items.
These data suggest that administration of TH9507, a GRF analog, in HIV patients with abdominal fat accumulation improved QOL with regard to enlarged abdominal girth and related items, consistent with the decrease in truncal and visceral fat observed in this population.
AE's and Discontinuation Discontinuation rates were not different between the groups (24%, 11%, 29%, placebo, 1 mg, 2 mg 5 respectively) . One subject in the placebo group (arthritis), none in the 1 mg group and 3 in the 2 mg group (rash, arhtralgia, paresthesia) experienced AE's leading to treatment discontinuation. Severe AE's were reported in 6%
of the placebo group, 13% of the 1 mg group and 10% of the 2 10 mg group. Musculoskeletal AE's e.g. pain and arthralgias were noted in 24%, 26% and 29% of subjects in the placebo, 1 mg and 2 mg groups respectively. Carpal tunnel symptoms were not noted in any patient. Edema and/or peripheral swelling were noted in 1 patient in the 2 mg group only. Headache 15 and/or paresthesias were noted in 19%, 32% and 52 % of the subjects in the placebo, lmg and 2 mg groups, respectively.
Blood pressure and heart rate did not change between or within the groups. One patient in the placebo group compared to three in the 2 mg group withdrew from the study related 20 to adverse events. Safety laboratory values, including hemoglobin, WBC, LFT's, creatinine did not differ between the groups (data not shown). CPK increased in a greater percentage of the 1 (47%) and 2 mg treated subjects (38%) compared to placebo (19%), but these changes were small and 25 did not result in a greater proportion of abnormal CPK
values between the groups. Anti-TH9507 antibodies were not detected after 12 weeks in any patient. CD4 count and viral load did not change.
Some of the results using a GRF analog in this 30 study are comparable to that seen in response to GHRH 1-29 in a recently published study in men with HIV lipodystrophy, in which truncal fat, but not extremity or subcutaneous fat decreased in response to physiologic increases in GH (13).
The current study extends the findings of Koutkia et al in a larger group of patients, including men and women, using graded doses of a novel 1-44 amino acid GRF analog that is dosed once rather than twice a day. Although the lower of the 2 doses increased IGF-I significantly, this dose did not result in a significant decrease in trunk fat, suggesting that there may be a threshold increase in IGF-I necessary to reduce truncal fat. Visceral fat also decreased significantly by more than 15% over 3 months within the 2 mg group. Of note, the magnitude of this change on a percentage basis is equivalent to that seen with pharmacologic doses of GH (9), suggesting that this strategy is highly effective and potentially very useful because of the general lack of side effects associated with physiologic increases in GH.
In addition to reducing truncal fat, the 2mg GRF
dose significantly improved triglyceride levels and the cholesterol to HDL ratio. This is a significant advantage of a GRF analog, not seen with other treatment strategies for HIV lipodystrophy (17, 18) . Similar beneficial effects on triglyceride were seen with lower, alternating day, but not higher doses of GH in a study reported by Kotler et al.
Growth hormone has been shown to decrease cholesterol and triglycceride levels in GH deficient patients and among otherwise healthy men chosen for abdominal obesity (19, 20).
Taken together, our data suggest that treatment with TH9507 resulted in an improved lipid profile in dyslipidemic, abdominally obese patients with HIV lipodystrophy.
An important issue regarding the use of GH or related strategies in HIV lipodystrophy is glucose control.
Patients with HIV lipodystrophy are often insulin resistant, and a significant percentage, more than a third, may have impaired glucose tolerance (3). In this study, even with the higher dose of 2 mg, there were no significant differences in fasting glucose or 2-hour glucose in response to a standard GTT and no increase in HbAIc.
TH9507 was also associated with other benefits in this study. Osteocalcin, a marker of bone formation increased within the 2 mg group, whereas NTX, a marker of bone resorption did not suggesting a net positive effect on bone turnover. Reduced bone density has been described among patients with HIV disease and among those with lipodystrophy, in inverse association with visceral and truncal adiposity (25, 26). Growth hormone is well known to stimulate bone formation (27). Relative reductions in GH
secretion may therefore contribute to reduced bone density in some patients with lipodystrophy and a positive effect on bone formation, with physiologic increases in GH is an additional benefit of TH9507.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principals of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
REFERENCES
1. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998;351(9106):871-5.
2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
AIDS 1998;12(7):F51-8.
3. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy. Clin Infect Dis 2001;32(1):130-9.
4. Friis-Moller N, Sabin CA, Weber R, et al.
Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349(21):1993-2003.
5. Pouliot MC, Despres JP, Nadeau A. Visceral Obesity in Men: Associations with Glucose Tolerance, Plasma Insulin and Lipoprotein Levels. Diabetes 1992;41:826-34.
6. Meininger G, Hadigan C, Rietschel P, Grinspoon S.
Body-composition measurements as predictors of glucose and insulin abnormalities in HIV-positive men. Am J Clin Nutr 2002;76(2):460-5.
7. Rietschel P, Hadigan C, Corcoran C, et al.
Assessment of Growth Hormone Dynamics in Human Immunodeficiency Virus- Related Lipodystrophy. J Clin Endocrinol Metab 2001;86(2):504-10.
8. Koutkia P, Meininger G, Canavan B, Breu J, Grinspoon S. Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy.
Am J Physiol Endocrinol Metab 2004;286(2):E296-303.
9. Kotler DP, Muurahainen N, Grunfeld C, et al.
Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients. J Acquir Immune Def Syndr 2004;35:239-52.
10. Engelson ES, Glesby MJ, Mendez D, et al. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. J Acquir Immune Defic Syndr 2002;30(4):379-91.
In an embodiment, the above-noted condition characterized by deficient or decreased bone formation is selected from the group consisting of osteopenia and osteoporosis.
15 In further aspects, the invention relates to uses of a GH secretagogue (e.g. GRF and analogs thereof) or a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier, for (1) stimulating day-time vigilance and/or cognitive functions e.g. in conditions related to aging or mild cognitive impairment, (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (e.g. metabolic conditions including obesity, HIV-related lipodystrophy, metabolic syndrome or syndrome X), (3) improving anabolism in catabolic/wasting conditions (such as those observed in Chronic Renal Failure, congestive heart failure AIDS, following hip fracture, trauma, or major surgery, particularly in elderly subjects), and/or (4) improving immune function or reconstitution of immunodeficient states such as that associated aging, HIV or following high-dose chemotherapy and/or radiotherapy.
In further aspects, the invention similarly relates to a package comprising an agent selected from the group consisting of: (a) a growth hormone (GH) secretagogue;
and (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier; together with instructions for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In further aspects, the invention similarly relates to a use of a GH secretagogue for the preparation of a medicament for (1) stimulating day-time vigilance and/or cognitive functions (2) improving metabolic conditions associated with fat accumulation and/or hypercholesterolemia, (3) improving anabolism in catabolic/wasting conditions, and/or (4) improving immune function or reconstitution of immunodeficient states.
In an embodiment, the above-mentioned lipodystrophy is HIV-related lipodystrophy.
In an embodiment, the above-mentioned subject is HIV positive.
In an embodiment, the above-mentioned subject is receiving antiviral therapy.
In an embodiment, the above-mentioned subject suffers from a condition selected from the group consisting of diabetes, glucose intolerance and insulin resistance.
In an embodiment the above-mentioned GH
secretagogue is administered at a dose of about 0.0001 to about 4 mg, in a further embodiment, about 0.0001 to about 2 mg, in a further embodiment, about 1 mg to about 2mg, in a further embodiment, about 1 mg and in a further embodiment, about 2 mg.
In an embodiment, the agent is administered by a route selected from the group consisting of intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal and topical. in an embodiment, the agent is administered by a subcutaneous route.
In an embodiment, the subject is a mammal, in a further embodiment, a human.
For the purpose of the present invention the following terms are defined bellow.
The term "analog" is intended to mean a molecule of different structure but having a biological function similar to the structures of the GRF or to a biologically functional fragment thereof which may include peptidomimetics. Peptidomimetics may be conveniently prepared by direct chemical synthesis using methods well known in the art.
The term "subject" is intended to mean any mammal including, but not limited to, human, canine, feline, equine, caprine, bovine, porcine and ovine.
The term "cognitive function" is intended to mean functions including, but not limited to thinking, reasoning, memory and problem solving.
The term "catabolic/wasting conditions" is intended to mean condition including, but not limited to, frail bones, low muscular mass and muscle wasting.
In the present application, the compound identified as TH9507 is [hexenoyl-trans-3-Tyrl]hGRF(1-44)NH2.
In various aspects, the methods and corresponding uses and packages described herein comprise administering to a subject a growth hormone (GH) secretagogue. "GH
secretagogue" as used herein refers to any compound or molecule, natural or synthetic, which may result in, either directly or indirectly, GH secretion and/or an increase in GH secretion.
In embodiments, the GH secretagogue is a growth hormone-releasing factor (GRF; also referred to as growth hormone releasing hormone [GHRHJ) or GRF analog.
In an embodiment, the GRF is human GRF (hGRF).
Human growth hormone-releasing factor (hGRF) is a peptide of 44 amino acids with a C-terminal NH2 modification, referred to herein as hGRF(1-44)NH2, and has the following structure:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2 (SEQ ID NO: 2) Therefore, the amino acid sequence of the just-noted 44 amino acid form is as follows:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu (SEQ
ID NO: 3) The minimum active core comprises the first 29 amino acids of the above sequence, which is referred to herein as hGRF(1-29)NH2, and has the following structure:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2 (SEQ ID NO: 4) Therefore, the amino acid sequence of the just-noted 29 amino acid form is as follows:
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg (SEQ
ID NO: 5) The 1-44 and 1-29 forms differ in that the 1-44 form contains the following additional amino acids, which correspond to positions 30-44 of the 1-44 form:
Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu (SEQ ID NO: 6) In an embodiment, the above-mentioned GRF analog is a GRF analog of formula A:
X-GRF Peptide (A) wherein;
the GRF peptide is a peptide of formula B;
Al-A2-Asp-Ala-Ile-Phe-Thr-A8-Ser-Tyr-Arg-Lys-A13-Leu-A15-Gln-Leu-A18-Ala-Arg-Lys-Leu-Leu-A24-A25-Ile-A27-A28-Arg-A30-RO (B) (SEQ ID NO: 1) wherein, Al is Tyr or" His;
A2 is Val or Ala;
A8 is Asn or Ser;
A13 is Val or Ile;
A15 is Ala or Gly;
A18 is Ser or Tyr;
A24 is Gln or His;
A25 is Asp or Glu;
A27 is Met, Ile or Nle;
A28 is Ser or Asn;
A30 is a bond or amino acid sequence of 1 up to 15 residues; and RO is NH2 or NH- (CH2) n-CONH2i with n=1 to 12; and X is a hydrophobic tail anchored via an amide bond to the N-terminus of the peptide and the hydrophobic tail 10 defining a backbone of 5 to 7 atoms;
wherein the backbone can be substituted by C1-6 alkyl, C3-6 cycloalkyl, or C6-12 aryl and the backbone comprises at least one rigidifying moiety connected to 15 at least two atoms of the backbone;
said moiety selected from the group consisting of double bond, triple bond, saturated or unsaturated C3-9 cycloalkyl, and C6-12 aryl.
In embodiments, X noted above is selected from the group consisting of:
R H C"
H
1 (R=H or CH. or CH2CH,3) GIs or Iran:
2 (R=H or CHI or CH6CH3) R
3 (R=H or C1f or C H 13) co or trans, both as racemic mixtures or pure a nautiomcric pairs R
4 :fit: H, tai, or t i~
cis or trams, both as t is mixtt or p 0nomic pairs .
it oil (R or CU3 or CHrCH;
ens or tom= (when R -A H) /-Oil R
6 QtFff or CHI or CHrCH,) cis or tram, both as tr + ntixam or p e do erk Paks 7 (R-7H or CH, or CH2CH) cis or trans, (when R 4" H) both as racemic mixtures or pure enantiomeric pairs 8 (R-H or (Hr or CH,CCH) cis or trans. both as mcemic mixtures or pure enantiomeric pairs R
9 or CH,3 or H2 R3) cis or ,(when R A H) both as mcemic mixtures or pum a pirs R
1D (R orC, 3orc.co vws& R, IQ
R
it (RrHorC i3orCH ) R
12 (R=U or CH. or CH2CH3) R
13 ( or C11, or C14CH3) In embodiments, A30 noted above is selected from the group consisting of:
(a) a bond;
(b) an amino acid sequence corresponding to positions 30-44 of a natural GRF peptide, and (c) said amino acid sequence of (b) having a 1-14 amino acid deletion from its C-terminus.
In embodiments, the above-noted GRF peptide is selected from the group consisting of:
(a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 3;
(b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 5; and (c) the polypeptide of (a) having a 1 to 14 amino acid deletion from its C-terminus.
In an embodiment, the above-noted GRF analog is (hexenoyl trans-3)hGRF(1-44)NH2.
Methods of preparing the above-described GRF
analogs are described in US patents No. 5,861,379 (Ibea et al., January 19, 1999); No. 6,020,311 (Brazeau et al., February 1, 2000), No. 6,458,764 (Gravel et al., October 1, 2002) and published US application No. 2004/0171534 Al (Gravel et al., published September 2, 2004).
As noted above, in various embodiments, the above-mentioned GH secretagogue may be used therapeutically in formulations or medicaments to effect the above-noted alterations and to prevent or treat the above-noted conditions. The invention provides corresponding methods of medical treatment, in which a therapeutic dose of a GH
secretagogue is administered in a pharmacologically acceptable formulation, e.g. to a patient or subject in need thereof. Accordingly, the invention also provides therapeutic compositions comprising a GH secretagogue and a pharmacologically acceptable excipient or carrier. In one embodiment, such compositions include GH secretagogue in a therapeutically or prophylactically effective amount sufficient to effect the above-noted alterations and to treat the above-noted conditions. The therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.
A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as to effect the above-noted alterations and to reduce the progression of the above-noted conditions. A therapeutically effective amount of a GH secretagogue may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A
therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed 5 by the therapeutically beneficial effects. A
"prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as preventing or inhibiting the rate of onset or progression of the above-10 noted conditions. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. For any particular, subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person 15 administering or supervising the administration of the compositions.
As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal 20 agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, 25 subcutaneous, sublingual or oral administration.
Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art.
Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.
The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, a GH secretagogue can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
Sterile injectable solutions can be prepared by incorporating the active compound (e.g. a GH secretagogue ) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with an alternative aspect of the invention, a GH secretagogue may be formulated with one or more additional compounds that enhance its solubility.
In accordance with another aspect of the invention, therapeutic compositions of the present invention, comprising a GH secretagogue, may be provided in containers, kits or packages (e.g. commercial packages) which further comprise instructions for its use to effect the above-noted alterations and to prevent or treat the above-noted conditions.
Accordingly, the invention further provides a package comprising a GH secretagogue or the above-mentioned composition together with instructions to effect the above-noted alterations and to prevent or treat the above-noted conditions.
The invention further provides a use of a GH
secretagogue to effect the above-noted alterations and to prevent or treat the above-noted conditions. The invention further provides a use of a GH secretagogue for the preparation of a medicament to effect the above-noted alterations and to prevent or treat the above-noted conditions.
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art.
Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way.
Numeric ranges are inclusive of the numbers defining the range. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The following examples are illustrative of various aspects of the invention, and do not limit the broad aspects of the invention as disclosed herein.
EXAMPLES
Example 1: Study drug The compound used in the studies below is (hexenoyl trans-3)hGRF(1-44)NH2 (also referred to as TH9507 herein), which is a synthetic human growth hormone releasing factor analog that comprises the 44-amino acid sequence of human growth hormone releasing factor (hGRF) on which a hexenoyl moiety, a C6 side chain has been anchored on Tyr 1 at the n-terminal. (hexenoyl trans-3)hGRF(1-44)NH2 or Th9507 has the following structure:
(trans) Gly-Ala-Arg-Ala-Arg-Leu-NH2 (SEQ ID NO: 7) (hexenoyl trans-3)hGRF(1-44)NH2 was synthesized via the methods set forth in US 5,861,379 (Ibea et al.; January 19, 1999).
The in vitro half-life of Th9507 is 3-8 hours compared to 0.56 hours for hGRF. Daily 1 and 2 mg doses have been shown to increase IGF-I to the physiological range seen in younger adults (14). The safety profile of TH9507 is generally good. Th9507 has been studied in patients with Type II DM, and was not shown to aggravate overall glycemic control when administered at a daily dose up to 2 mg (15).
Example 2: Administration of TH9507 for improving daytime vigilance in subjects with sleep maintenance insomnia The present example shows the effect of a 14 day-administration of 2 doses of TH9507 (0.1 mg and 1 mg) on vigilance parameters in subjects of 35 to 50 years of age exhibiting sleep maintenance insomnia.
Material and Methods The study involved 82 patients exhibiting sleep maintenance insomnia (20 females, 62 males; mean age 43.2 5.4 years). Patients were selected based on the Pittsburgh Sleep Quality Index (Score ?5), the Walters Criteria for Sleep Maintenance Insomnia, and the Beck Questionnaire (Score -<17). The primary exclusion criteria were other primary sleep disorders and the use of any products affecting sleep or vigilance in the 30 days prior to entering the study.
The study was a randomized, double-blind, placebo-controlled, parallel group and multicenter evaluation of two doses of TH9507 (0.1 mg and 1 mg) administered daily by subcutaneous injection at bedtime for 14 consecutive days.
To evaluate vigilance and the performance in the morning, patients underwent a battery of cognitive tests including 5 the Continuous Performance Test (CPT) at baseline and at the end of treatment period.
The CPT has been described in the literature as a measure of consistency in responding and ability to sustain attention over time (Aleman A, et al., J Clin Endocrinol 10 Metab 1999 84(2):471-475). This test required subjects to press space bar each time the letter "A" was followed by "X". Omission and commission errors, and Mean Reaction Time of correct responses were analyzed.
15 Results Demographic characteristics by treatment group are displayed in the following table:
Table 1 20 Demographic (screening) data by treatment groups Placebo 0,lmg N=26 1 mg N=27 P value N=29 Age (Mean SD) 44.0 5.8 43.2 5.8 42.3 4.5 0.53 (range) (35-56) (34-60) (34-50) (F-test) Gender Males 21 19 22 0.68 Females 8 7 5 chi-square test) Weight(kg) 0.94 (Mean SD) 78.0 14.3 78.2 12.4 79.3 15.3 (F-test) As illustrated in Fig. 1, the Mean Reaction Time of the CPT was significantly and markedly decreased in the 0.1 mg group when compared to placebo. The decrease from baseline to day 9 was 45.85 ms (P=0.023 when compared to placebo as analyzed by an ANOVA model). No significant effect was observed in the 1 mg group. Circulating IGF-1 and IGFBP-3 levels were significantly increased at week 2 in the 1 mg group when compared to placebo (P<0.0001, ANOVA on changes from baseline) As expected the 0.1 mg did not affect these parameters (P=0.07 and P=0.99) for IGF-l and IGF-BP3 respectively, ANOVA model on changes from baseline).
Additional data on effects of TH9507 on vigilance obtained in a previous study are presented in Fig. 2. In this study, TH9507 was administered daily for 7 days in a cross-over design. This study involved 12 healthy subjects aged between 50 to 65 years, exhibiting age-related sleep impairment (Pittsburgh Sleep Quality Index Score from 3 to 7). At the end of the treatment period, daytime vigilance was significantly enhanced when compared to placebo in subjects receiving 1 mg of TH9507, as assessed by P300, an event-related potential test. Changes from Baseline to day 9 in the Pz amplitude of the Evoked Related Potential (P300) observed in the placebo and 1 mg group were as follows:
Placebo, -15%; 1 mg, +55%, P=0.0114, as analyzed by an ANOVA
model.
In both studies, the safety profile of TH9507 was comparable to that of the placebo, except for a higher incidence of reactions at the site of injection observed at 1 mg in the insomnia study.
In summary, these results provide evidence that TH9507 improves daytime vigilance in sleep maintenance insomnia in subjects and would favor a direct mechanism of action of TH9507, not mediated by IGF-1. Data are supported by those obtained by Vitiello et al (Vitiello M.V., et al., Gerontologist 2002 40(Special Issue 1):39-N/A. using hGRF in cognitive tests involving psychomotor and perceptual processing speed (Deijin JB et al, Psychoneuroendocrinology 1998 23(1):45-55) and may support further clinical investigations in subjects with impaired cognitive functions.
Example 3: Effects of TH9507 on the immune response to influenza vaccination in elderly subjects The present example describes immune findings following an influenza vaccination challenge in elderly subjects.
Material and Methods Eighty seven (87) subjects aged 75 years in average were included in a double-bind, randomized, placebo-controlled study. TH9507 or a placebo was administered at a daily dose of 1 or 2 mg by subcutaneous injection for 8 weeks. Follow-up assessments were conducted for 12 weeks after the end of the treatment period. At week 4, in the middle of the treatment period, subjects received the commercial Canadian influenza vaccine (Vaccine Fluviral S/F, Shire, Montreal, Canada) containing 15 pg each of A/New Caledonia/20/99, A/Panama/2007/99, B/Victoria/504/2000 antigens.
Influenza-specific proliferative T cell response and antibody titers were evaluated for each of the 3 strains contained in the vaccine. The proliferative T cell response was assessed by a mitogen assay using tritiated thymidine (3H) incorporation and results were log-base 10 transformed prior to analysis. The antibody titers were determined by standard hemaglutinaion inhibition assay and results were log-base 2 transformed prior to analysis.
Eighty one (81) subjects completed the study as per protocol. Subject demographics are shown in the following table:
Table 2 Subject demographics Placebo 1 mg 2 mg All P-value Age 75.9 74.9 73.2 74.6 0.21 (years) 6.5 6.1 4.4 5.8 Total N 29 29 29 187 0.96 Female 13 13 14 40 Male 16 16 15 47 BMI 27.4 26.9 29.2 27.8 0.26 (kg/m2) 5.8 4.2 6.0 5.4 Data for age and BMI are presented as mean SD. Baseline comparability among treatment groups was tested by ANOVA
(age, BMI) or Pearson's chi-square test (gender).
Results As shown in Fig. 3 the mean AUC calculated for the whole study period including both the treatment and follow-up period (week 0 to week 20) was statistically higher in the 2 mg group when compared with placebo (Panama, P=0.03;
New Caledonia, P=0.001; Victoria, P=0.02, (Pairwise comparisons for difference among treatment groups and ANCOVA
analysis for overall treatment significance).
As illustrated in Fig. 4, administration of TH9507 increased the proportion of patients achieving a protective antibody level for the Victoria antigen when compared to placebo. This observation reached statistical significance at the 2 mg dose and was noted during both the treatment and the follow-up periods (week 6 : P=0.02; Week 8 : P=0.01;
week 12 : P=0.02; week 16 ; P=0.004, week 20 : P=0.01, pairwise comparisons for difference among treatment groups and Pearson chi-square test for overall treatment difference) indicating a sustained effect for up to 16 weeks after cessation of treatment. No statistical difference in the percentage of subjects was observed in the Panama and New Caledonia strains.
A dose-related increase in the mean IGF-1 values was observed during the whole treatment period in both Th9507 groups when compared to baseline. Values returned to baseline following cessation of treatment.
No major difference in the incidence of adverse events was observed between treatment groups except for a dose-related trend in the incidence of reactions at the site of injection.
In summary, the findings observed in this study strongly indicate that TH9507 has a therapeutic potential in immune indications. In particular, its effect of the T-lymphocyte proliferation response following vaccination makes it attractive to develop in clinical situations where the cell-mediated immune'system is depressed, such as viral infections in the elderly and immune-deficient states following HIV infection, high-dose chemotherapy or radiotherapy.
Example 4: ThGRF's benefits in wasting/catabolic conditions The present example shows the effect of a 7-day administration of TH9507 on circulating IGF-l levels in healthy middle-aged men.
5 Material and Methods The study used a randomized, double-blind, placebo-controlled design and was conducted in healthy men, aged 50 to 60 years old. Subjects (8 per group) were injected S.C. once a day for 7 consecutive days with 10 placebo, 0.5, 1 or 2 mg of TH9507. Circulating IGF-l levels were measured on Days 1 to V. The 12 hour GH response and TH9507 PK profile were determined on Day 1 and 7.
Results 15 As shown in Fig. 5, IGF-1 increased over baseline values by 80 (placebo), 370 (0.5 mg), 890 (lmg) and 106% (2 mg); these increases were statistically significant for all 3 doses of TH9507. The 1 mg and 2 mg doses were equally potent and induced a doubling of IGF-1 20 levels up to levels expected for young adults (286 25 and 284 55 ng/ml, respectively), none of the subjects exhibited levels greater than 400 ng/ml. A plateau was reached at Day 4 and 6 for the 1 mg and 2 mg doses, respectively.
25 GH response to TH9507 increased rapidly both on Days 1 and 2. The increase was dose dependent between the 0.5 and 1 mg dose (P<0.01), and was similar at the 1 mg and 2 mg doses. No significant modification in prolactin, ACTH, cortisol, TSH, LH or FSH was observed following 30 single or repeated treatment with TH9507.
PK analysis indicated that Cmax and AUC
parameters increased in function of the dose administered.
The half-life of the TH9507 ranged between 2 and 5 hours.
These results clearly indicate that TH9507 is highly specific on GH= secretion and a powerful IGF-1 inducer, suggesting potential clinical benefits in wasting/catabolic conditions.
Example 5: Effects of GRF on non-HDL cholesterol in patients with type 2 Diabetes The present example illustrates beneficial effects of TH9507 on non-HDL cholesterol levels in a diabetic population.
Material and Methods A double-blind placebo-controlled study was conducted in 53 type II diabetic patients (age = 61 7 [SD]; 34% female) on stable antidiabetic medication (26%
on insulin). Patients were randomized to parallel groups to receive daily subcutaneous administration of a placebo, 1 mg or 2 mg TH9507, respectively.
Results A statistically significant difference was observed at Week 12 between the 3 treatment groups in the mean total cholesterol change from baseline (P=0.04).
Values decreased in the 2 mg group (-11.1 21.9 mg/dl; -6%), as compared to increases in the Placebo (+9.7 22.6 mg/dl; +5%) and 1 mg group (+6.1 16.2 mg/dl; +3%). This effect was accompanied by a decrease in the mean non-HDL
cholesterol values in the 2 mg group (-10.1 19.0 mg/dl;
-7%) and increases in the placebo (+6.8 17.8 mg/dl; +5%) and 1 mg group (+3.8 15.5 mg/dl; +3%).
No statistically significant differences were observed between the three groups during the treatment period in terms of insulin relative response to an oral glucose tolerance test. At Week 12, glycosylated hemoglobin (HbAlc) levels displayed a trend for a decrease in the placebo group, a decrease in the 1 mg group, and no change in the 2 mg group. Clinically relevant changes in antidiabetic medications occurred with a similar incidence in the three treatment groups.
A dose-related increase in the IGF-l levels was observed at the end of the treatment period.
In summary, this study indicates that the repeated administration of TH9507 for 12 weeks decreases the total and non-HDL cholesterol fraction in diabetic subjects and can be safely administered to this population without impairing glucose control. The effects observed on blood lipids and the known lipolytic properties of GH
warrant the investigation of TH9507 for the treatment of syndromes associated with visceral fat accumulation.
Example 6: Effect of GRF analog on lipid profile, body composition and quality of life in HIV-infected patients This study investigated the effects of TH9507, on abdominal fat accumulation associated with HIV
lipodystrophy.
Design: Randomized, placebo-controlled, multi-center, dose ranging (placebo, lmg or 2 mg SC QD), parallel group, 12-week study Patients: 61 HIV-infected patients (BMI 28 3 [SD] kg/mz, 28% diabetic or glucose intolerant) with increased waist circumference (102 cm 8 [SD]) and waist/hip (1.0 0.1 [SD]) Measurements: Body composition was assessed by DXA and abdominal CT scan; IGF-I, insulin, glucose, lipid, bone turnover, immunologic, and safety parameters.
Results: Treatment with TH9507 resulted in a dose-related increase in serum IGF-1 levels within the physiological range [18 (32) ng/mL, 87 (67) ng/mL, 123 (79) ng/mL, mean (SD) for placebo, 1mg, 2 mg, respectively, P<0.01 for change in each active group vs. placebo]. Lean body mass increased significantly in both treatment groups compared to placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg; placebo, lmg, 2 mg, respectively; P<0.01 for 2 mg dose vs. placebo, P<0.05 for the 1 mg group vs. placebo]. Trunk fat decreased in the 2 mg group compared to placebo (0.8%, -4.6% and -9.2%; placebo, lmg, 2 mg, respectively, P=0.01 for 2 mg vs.
placebo), with no significant change in limb fat. Visceral fat decreased most in the 2 mg group (-5.4%, -3.6% and -15.7%; placebo, 1mg, 2 mg, respectively; P=0.03 for change within 2 mg group but P=NS vs. placebo) whereas subcutaneous fat was preserved and did not change between or within groups. The ratio of VAT: SAT improved significantly in both treatment. groups compared to placebo (-0.01 (0.10), -0.23(0.47) and -0.14(0.18), P<0.01 for the 2 mg group vs.
placebo and P<0.05 for the 1 mg group vs. placebo.
Triglyceride and the cholesterol to HDL ratio decreased significantly in the 2 mg treatment group compared to placebo. Treatment was generally well-tolerated without changes in either fasting glucose or 2-hour OGTT.
Conclusion: TH9507 effectively improved body composition and reduced truncal fat by preferentially decreasing visceral fat while preserving subcutaneous fat in patients with HIV
lipodystrophy. TH9507 did not increase glucose levels, even among those with impaired glucose tolerance or diabetes mellitus at baseline, and improved the lipid profile. These data suggest that TH9507, a GRF analog, may be a beneficial treatment strategy for HIV lipodystrophy.
Methods Subjects Eighty-eight subjects were screened between May 2003 and November 2003. Sixty-one subjects were enrolled.
HIV infected males age 18-65 years and non-menopausal females age > 18 years with visceral fat accumulation considered to be part of the HIV lipodystrophy syndrome, waist circumference ? 95 cm for men and ? 94 cm for women, and a waist to hip ratio ? 0.94 for men and >_ 0.88 for women were enrolled. We excluded, subjects with a BMI <-20 kg/m2, CD4 cell count <--100 cells/mm3, viral load >_ 10,000 copies/mL, history of opportunistic infection or HIV-related disease within 3 months of the study, history of prostrate cancer or PSA > 5 ng/ml in male subjects, history of breast cancer or abnormal mammography within 6 months of the study (for these patients without a mammogram within this time frame, one was performed as part of the study) in female subjects, known hypopituitarism or history of pituitary surgery, radiation or significant head trauma, untreated hypothyroidism, prior history of Type I diabetes mellitus (DM), any prior use of GH or GH related products, experimental or marketed, within 6 months of the study, systemic steroid administration or megestrol acetate within 60 days of the study, fasting glucose > 150 mg/dL, SGOT or SGPT > 3x upper limit of normal, creatinine > 1.5x upper limit of normal, or hemoglobin < 9 g/dL. Subjects receiving testosterone or estrogen within the prior six months, with known drug or alcohol dependence or who had participated in another clinical trial with an investigational agent within 30 days were also excluded from the study. All subjects were required to be on a stable antiretroviral regimen for 8 weeks prior to enrollment. Subjects receiving lipid lowering medications were required to be on a stable regimen for 3 months prior to enrollment. Subjects were not permitted to 5 begin antidiabetic medication, use systemic corticosteroids for > 10 days, or begin estrogen or testosterone preparations during the study.
Study Procedures 10 Subjects underwent a screening visit to determine eligibility. All subjects gave written consent to participate in the study, and the study was approved by the Institutional Review Board at each participating site. BMI, anthropometic measurements, TSH and prolactin were 15 performed. Viral load and CD4 count were performed if not previously done within 8 weeks of the study. A PSA was performed in male subjects and a pregnancy test was performed in female subjects. Mammography was also performed in female subjects if not previously done within 6 months of 20 the study.
At the baseline visit, anthropometric measurements were obtained. Total body lean and fat mass as well as regional fat mass in the trunk and extremities were assessed by DEXA.
Abdominal subcutaneous and visceral fat area and the ratio 25 of VAT to SAT were determined by cross-sectional CT at L4-L5. Biochemical parameters including insulin-like growth factor-I, glucose, insulin, lipid profile (cholesterol, HDL, LDL, triglyceride, non HDL and the ratio of cholesterol:HDL), free fatty acids, HbAlC, IGFBP-3, and bone 30 markers (serum osteocalcin and NTX-1), CD4, viral load, and a pregnancy test for female subjects were determined in the fasting state. In addition, insulin and glucose response to a 75 gram standard glucose challenge were assessed and a quality of life questionnaire was administered.
After baseline evaluations were complete subjects were randomized equally to one of three groups, placebo, 1 mg TH9507 or 2 mg TH9507. Randomization was performed by an independent consulting firm, using a permuted block algorithm, with block size equal to 3 and kept confidential in the Theratechnologies Quality Assurance Department until unblinding. Subjects were stratified for gender at the time of treatment assignment. Treatment assignment was blinded to investigators and patients. Active drug and placebo (mannitol) were provided as lyophilized powder in vials of identical appearance, each containing 1.1 mg of material.
Each vial was reconstituted with sterile water immediately prior to injection. Patients were instructed to inject each AM at approximately 0900 h.
Subjects returned for a safety visit at Week 1 to assess adverse events and compliance. Subjects returned at 2 weeks to assess weight, anthropometric measures, lipid profile, free fatty acid, IGFB-1, IGFBP-3, glucose, adverse events and compliance. Subjects returned for a visit at week 6 identical to baseline and a visit at week 9 to assess compliance and adverse events. Subjects returned for a last study visit at week 12 - or, whenever possible, at the time of early termination - identical to the baseline visit.
Study Drug TH9507 was used in this study, as noted above.
Methods Biochemical Indices Clinical laboratory testing was performed by a central lab. Serum IGF-1 was measured after acid-ethanol extraction using the Esoterix RIA kit (Esoterix Inc., Calabasas Hill, CA), with a sensitivity of 10 ng/mL. Intra- and inter-assay coefficients of variation were 4.6-20% and 9-10%, respectively. Serum IGFBP-3 was measured using the Esoterix RIA kit (Esoterix Inc., Calabasas Hill, CA) with a sensitivity of 0.3 mg/mL. Intra- and inter-assay coefficients of variation were 5.1-13% and 5.5-17%, respectively. HDL, LDL, total cholesterol, triglycerides and FFA were determined by enzymatic colorimetric assay. Glucose was measured by enzymatric test (Gluco-quant , Roche diagnostics, Indianapolis, IN). HbAlc was determined by chromatography. PSA was determined using the Hybritech PSA
test (Beckman Coulter, Mississauga, Canada). TSH was measured by microparticle enzyme immunoassay (AxSYM hTSH II, Abbott Laboratories, Abbott Park, IL). NTX (N-terminal telopeptide of type I collagen; a bone resorption marker) was measured by ELISA using a commercially available kit (Osteomark't, Ostex International Inc., Seattle, WA).
Osteocalcin was measured using a commercially available enzymatic immunoassay kit (MetraTM osteocalcin, Quidel Corporation, San Diego, CA). CD4 and viral load were performed by the individual site labs by routine methodology.
HOMA was calculated as:
OInsulin (30min-O min) Insulin (0min) .
A Glucose (30 min- 0min) Body Composition Whole body and regional DEXA (dual energy X-ray absorptiometry) and cross-sectional abdominal CT scans were performed at the individual study sites based on previously established protocols and were standardized across sites.
Digitized images were sent to a central reading center, St.
Lukes Roosevelt Hospital, for analysis by independent experts without knowledge of treatment assignment. Each site was given a procedure manual to follow in obtaining the body composition data and was certified in the proper technique. For the CT scans, parameters were standardized as follows: Tube Voltage = 120 kV, Tube Current = 250 mA, Exposure = 375 mAs, matrix 512 x 512. DFOV was set to include the entire slice into the field of view. For the DEXA scans total body scans were performed with analysis of lean body mass, total fat mass, and regional fat mass in the trunk and extremities as previously described (16) . After analysis the data was transferred to the data management center and incorporated in the study database.
Statistics Body composition endpoints included trunk fat and trunk to limb fat ratio by DEXA and VAT and VAT: SAT by CT
scan. Other endpoints included IGF-I, lipid parameters, glucose and insulin, CD4, viral load, bone markers, and quality of life. A sample size of 20 patients/group was planned to assess a statistically significant change of 10%
or more in intra-group analyses. The planned dropout rate was 25% and therefore 60 patients were enrolled into the study. Baseline data are compared between the groups by F-test based on ANOVA for continuous variables and Chi-Square test for categorical variables. Change over time between groups is compared by ANOVA or the Chi-Square test. Where appropriate, data were rank transformed prior to analysis.
Changes within each group are determined by t-test. The ITT
(intent to treat) population is defined as all subjects who received at least one dose of the study treatment.
Descriptive statistics and analyses for all efficacy and safety analyses are performed on the ITT population. End of study, 12 week, data are used to calculate changes in body composition. For biochemical indices, the last observation available is used to calculate change. Imputation for missing data is not performed. For body composition, end of study data are used to calculate change. Interim analyses were not performed. Results are mean (SD) unless otherwise noted. All statistical tests were performed with a two-sided Type I error level of 0.05.
Results Sixty-one subjects were randomized, 21 to placebo, 19 to TH9507 1 mg and 21 to TH9507 2 mg. Five subjects discontinued in the placebo group, 2 in the 1 mg group and 6 in the 2 mg group, for a 79% completion rate. See Figure 6 for patient disposition and flow diagram.
Baseline demographic for the three study groups are shown in Table 3. At baseline no significant differences were seen between the groups except, including use of antiretroviral therapy. The percentage of patients with diabetes (fasting glucose >- 7.0 mmol/L or 2h-glucose -> 11.1 mmol/L) and impaired glucose tolerance (6.1 mmol/L <- fasting glucose < 6.9 mmol/L or 7.8 mmol/L < 2h-glucose <11.1 mmol/L) was not different between the groups. Among the entire study group, 23% of subjects demonstrated IGT and 5%
demonstrated diabetes mellitus at baseline.
Table 3: Baseline Characteristics Placebo 1mg 2mg P
Age 46.1(7.4) 46.5(6.4) 44.6(7.1) 0.64 Gender Males/Females 18/3 18/1 18/3 NA
Ethnic origin Cauc./Other 18/3 15/4 17/4 0.84 BMI 28.9(2.7) 28.0(3.2) 27.3(4.1) 0.30 WHR 1.0(0.1) 1.0(0.0) 1.0(0.1) 0.65 WC 103.4(8.0) 100.3(6.1) 100.7(9.1) 0.40 IGT-Diabetes 7 4 6 NA
Data are mean (SD). BMI, body-mass index; WHR, waist/hip ratio; WC, waist circumference Body Composition 5 Lean body mass increased in both treatment groups compared to placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg, mean (SD) for placebo, lmg, 2 mg, respectively, P<0.01 for change in 2 mg group vs. placebo, P<0.05 for the change in lmg group vs. placebo, Table 3). Total fat 10 decreased in the 2 mg group compared to placebo [0.3 (1.7) kg, -0.4 (1.8) kg and -1.4 (2.0) kg, placebo, 1mg, 2 mg, respectively, P=0.01 for 2 mg group vs. placebo). Trunk fat decreased in the 2 mg group compared to placebo (0.8%, -4.6%
and -9.2%, placebo, lmg, 2 mg, respectively, P=0.01 for 2 mg 15 group vs. placebo) (Figure 2). VAT tended to decrease more in the 2 mg group (-5.4%, -3.6% and -15.7%, placebo, 1 mg, 2 mg, respectively), (P=NS for comparison of 2 mg vs. placebo, P=0.03 for change within 2 mg group). SAT did not change significantly between the groups and the ratio of VAT:SAT
20 decreased more in the treatment groups compared to placebo [0.01 (0.10), -0.23 (0.47), -0.14 (0.18)] (Table II) (P<0.01 for 2 mg vs. placebo and P=0.04 for 1 mg vs. placebo).
Biochemical Indices 25 IGF-I increased significantly with the 1 and 2 mg dose compared to placebo [18 (32) ng/mL, 87 (67) ng/mL, 123 (79) ng/mL, placebo, 1 mg 2mg, respectively, P<0.01 for each active group vs. placebo] (Figure 3). Triglyceride levels decreased in the 2 mg group compared to placebo (-0.2 (1.3), -0.9 (4.2), -0.9 (1.2), last observation values for placebo, 1 mg, 2 mg, respectively, P<0.05) and the ratio of cholesterol to HDL improved in both treatment groups compared to placebo (0.3 (1.1), -0.3 (0.7), -0.3 (0.6) , last observation values for placebo, 1 mg, 2 mg, respectively, P<0.05).
Changes in fasting and 120 minute glucose were not significant between or within the treatment groups.
Bone Markers Osteocalcin increased significantly within the 2 mg group, whereas no changes with NTX were seen (Table 4).
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cr = 0) O 0 N r` N 'C3 (N Ln OJ M Ln -~ N
+) U) O U) P N
co N 0a co - - [) 61 O C) - U) = Ln = N H a) 4 r-I Ln M (D ci Cl) OD 0) H H -P
~o H H LO ,q ro .-I
o l0 ro 5 ~.
O Ln N O I M f Q
rn p H
ro Ln U) m co l0 IT r` N
r4 H. = r-4 -- ro N V' v' 0 4J
N M U) N O
Ln = ~o IT 0 l0 r1 M 0 M Ln Z ro (-a 04 '0 o s~~
H U) o 0) 0 ; =r4 w 04 H > U U U H ro ro m =0 ri -rl - ~I H O - N =-i O +-) H I N N ro ff) O
E~ Ga W O 2 Q if 'J w Lr) O Ln r-A H
Quality of Life A health-related quality of life questionnaire (PLC, Quality of Life Profile for the Chronocally Ill) was self-administered to 61 patients randomized to receive placebo or TH9507 at 1 or 2 mg s.c. daily. The PLC
questionnaire included a general, non-specific part assessing 6 dimensions of global health as well as a disease specific part capturing impact of enlarged abdominal girth, abdominal bloating, tenseness and pain, as well as diarrhea, visible facial changes, visible changes in physical appearance, and the feeling of being recognized as an HIV
positive person.
Study population included 54 men and 7 women.
Baseline mean age was 46 7 [SD] , BMI 28 3 [SD] kg/m2, WC
102 cm 8 [SD] and WHR 1.0 0.1 [SD]. No significant difference between groups was noted for subscales of the main portion of the PLC. Slight changes were observed within the treated groups in the positive mood and social well-being scores but were not considered clinically significant.
Clinically significant improvements were noted in the enlarged abdominal girth (placebo :-0.13; 1 mg :-0.93, P=0.06 vs baseline; 2 mg :-1.19, P<0.05 vs baseline, NS vs placebo) and bloating scores (placebo : 0.56; 1 mg : -0.50;
2 mg : -0.69, P<0.05 vs. placebo). Improvement in abdominal pain was observed at 1 mg only (P<0.05 vs baseline, NS vs placebo) along with a trend for improvement in tenseness (P=0.07 vs baseline, NS vs placebo). No significant changes were observed in the other disease-specific items.
These data suggest that administration of TH9507, a GRF analog, in HIV patients with abdominal fat accumulation improved QOL with regard to enlarged abdominal girth and related items, consistent with the decrease in truncal and visceral fat observed in this population.
AE's and Discontinuation Discontinuation rates were not different between the groups (24%, 11%, 29%, placebo, 1 mg, 2 mg 5 respectively) . One subject in the placebo group (arthritis), none in the 1 mg group and 3 in the 2 mg group (rash, arhtralgia, paresthesia) experienced AE's leading to treatment discontinuation. Severe AE's were reported in 6%
of the placebo group, 13% of the 1 mg group and 10% of the 2 10 mg group. Musculoskeletal AE's e.g. pain and arthralgias were noted in 24%, 26% and 29% of subjects in the placebo, 1 mg and 2 mg groups respectively. Carpal tunnel symptoms were not noted in any patient. Edema and/or peripheral swelling were noted in 1 patient in the 2 mg group only. Headache 15 and/or paresthesias were noted in 19%, 32% and 52 % of the subjects in the placebo, lmg and 2 mg groups, respectively.
Blood pressure and heart rate did not change between or within the groups. One patient in the placebo group compared to three in the 2 mg group withdrew from the study related 20 to adverse events. Safety laboratory values, including hemoglobin, WBC, LFT's, creatinine did not differ between the groups (data not shown). CPK increased in a greater percentage of the 1 (47%) and 2 mg treated subjects (38%) compared to placebo (19%), but these changes were small and 25 did not result in a greater proportion of abnormal CPK
values between the groups. Anti-TH9507 antibodies were not detected after 12 weeks in any patient. CD4 count and viral load did not change.
Some of the results using a GRF analog in this 30 study are comparable to that seen in response to GHRH 1-29 in a recently published study in men with HIV lipodystrophy, in which truncal fat, but not extremity or subcutaneous fat decreased in response to physiologic increases in GH (13).
The current study extends the findings of Koutkia et al in a larger group of patients, including men and women, using graded doses of a novel 1-44 amino acid GRF analog that is dosed once rather than twice a day. Although the lower of the 2 doses increased IGF-I significantly, this dose did not result in a significant decrease in trunk fat, suggesting that there may be a threshold increase in IGF-I necessary to reduce truncal fat. Visceral fat also decreased significantly by more than 15% over 3 months within the 2 mg group. Of note, the magnitude of this change on a percentage basis is equivalent to that seen with pharmacologic doses of GH (9), suggesting that this strategy is highly effective and potentially very useful because of the general lack of side effects associated with physiologic increases in GH.
In addition to reducing truncal fat, the 2mg GRF
dose significantly improved triglyceride levels and the cholesterol to HDL ratio. This is a significant advantage of a GRF analog, not seen with other treatment strategies for HIV lipodystrophy (17, 18) . Similar beneficial effects on triglyceride were seen with lower, alternating day, but not higher doses of GH in a study reported by Kotler et al.
Growth hormone has been shown to decrease cholesterol and triglycceride levels in GH deficient patients and among otherwise healthy men chosen for abdominal obesity (19, 20).
Taken together, our data suggest that treatment with TH9507 resulted in an improved lipid profile in dyslipidemic, abdominally obese patients with HIV lipodystrophy.
An important issue regarding the use of GH or related strategies in HIV lipodystrophy is glucose control.
Patients with HIV lipodystrophy are often insulin resistant, and a significant percentage, more than a third, may have impaired glucose tolerance (3). In this study, even with the higher dose of 2 mg, there were no significant differences in fasting glucose or 2-hour glucose in response to a standard GTT and no increase in HbAIc.
TH9507 was also associated with other benefits in this study. Osteocalcin, a marker of bone formation increased within the 2 mg group, whereas NTX, a marker of bone resorption did not suggesting a net positive effect on bone turnover. Reduced bone density has been described among patients with HIV disease and among those with lipodystrophy, in inverse association with visceral and truncal adiposity (25, 26). Growth hormone is well known to stimulate bone formation (27). Relative reductions in GH
secretion may therefore contribute to reduced bone density in some patients with lipodystrophy and a positive effect on bone formation, with physiologic increases in GH is an additional benefit of TH9507.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principals of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
REFERENCES
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2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
AIDS 1998;12(7):F51-8.
3. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy. Clin Infect Dis 2001;32(1):130-9.
4. Friis-Moller N, Sabin CA, Weber R, et al.
Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349(21):1993-2003.
5. Pouliot MC, Despres JP, Nadeau A. Visceral Obesity in Men: Associations with Glucose Tolerance, Plasma Insulin and Lipoprotein Levels. Diabetes 1992;41:826-34.
6. Meininger G, Hadigan C, Rietschel P, Grinspoon S.
Body-composition measurements as predictors of glucose and insulin abnormalities in HIV-positive men. Am J Clin Nutr 2002;76(2):460-5.
7. Rietschel P, Hadigan C, Corcoran C, et al.
Assessment of Growth Hormone Dynamics in Human Immunodeficiency Virus- Related Lipodystrophy. J Clin Endocrinol Metab 2001;86(2):504-10.
8. Koutkia P, Meininger G, Canavan B, Breu J, Grinspoon S. Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy.
Am J Physiol Endocrinol Metab 2004;286(2):E296-303.
9. Kotler DP, Muurahainen N, Grunfeld C, et al.
Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients. J Acquir Immune Def Syndr 2004;35:239-52.
10. Engelson ES, Glesby MJ, Mendez D, et al. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. J Acquir Immune Defic Syndr 2002;30(4):379-91.
11. Wanke C, Gerrior J, Kantaros J, Coakley E, Albrecht M. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS 1999;13(15):2099-103.
12. Lo JC, Mulligan K, Noor MA, et al. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 2001;86(8):3480-7.
13. Koutkia P, Canavan B, Breu J, Toriani M, Kissko J, Grinspoon S. Growth Hormone-releasing Hormone in HIV-infected Men with Lipodystrophy: A Randomized, Controlled Trial. JAMA 2004;292:210-8.
14. Abribat T, Gravel D, Brazeau P. TH9507 A new Growth Hormone-Releasing Factor (GRF) analogue is a powerful Insulin-like Growth Factor-1 (IGF-1) inducer in 50-60 years old healthy subjects : A 7-Day, Randomizeed Multidose Study.
In: The Endocrine Society's 84 rd Annual Meeting; 2001;
Denver; 2001. p. P2-292.
In: The Endocrine Society's 84 rd Annual Meeting; 2001;
Denver; 2001. p. P2-292.
15. Clemmons D, Miller S, De Villers A, et al. Safety assessment and metabolic effects of TH9507, a Growth Hormone Releasing Factor analog(GRF) in patients with Type 2 diabetes mellitus. In: The Endocrine Society's 86 Annual Meeting; 2003; Philadelphia; 2003. p. P2-354.
16. Park YW, Heymsfield SB, Gallagher D. Are dual-energy X-ray absorptiometry regional estimates associated with visceral adipose tissue mass? International Journal of Obesity & Related Metabolic Disorders: Journal of the International Association for the Study of Obesity 2002;26(7):978-83.
17. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV
5 lipodystrophy: A randomized controlled trial. Annals of Internal Medicine 2004;140(10):786-94.
5 lipodystrophy: A randomized controlled trial. Annals of Internal Medicine 2004;140(10):786-94.
18. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA
10 2000;284(4):472-7.
10 2000;284(4):472-7.
19. Johannsson G, Marin P, Lonn L, et al. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab 15 1997;82(3):727-34.
20. Colao A, di Somma C, Cuocolo A, et al. Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab 20 2001;86(5):1874-81.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: THERATECHNOLOGIES INC.
(ii) TITLE OF INVENTION: GH SECRETAGOGUES AND USES THEREOF
(iii) NUMBER OF SEQUENCES: 7 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: SMART & BIGGAR
(B) STREET: 1000 de la Gauchetiere ouest, Suite 3300 (C) CITY: Montreal (D) STATE: Quebec (E) COUNTRY: CANADA
(F) ZIP: H3B 4W5 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: ASCII (text) (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: CA
(B) FILING DATE:
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(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER:
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(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: SMART & BIGGAR
(B) REGISTRATION NUMBER: 85795-75 (C) REFERENCE/DOCKET NUMBER:
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (514)-954-1500 (B) TELEFAX: (514)-954-1396 (2) INFORMATION FOR SEQ ID NO.: 1:
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(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
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(A) ORGANISM: Artificial sequence (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (1)..(1) (C) OTHER INFORMATION: Xaa = Tyr or His (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (2) .. (2) (C) OTHER INFORMATION: Xaa = Val or Ala (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (8)..(8) (C) OTHER INFORMATION: Xaa = Asn or Ser (ix) FEATURE
(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
(B) LOCATION: (15)..(15) (C) OTHER INFORMATION: Xaa = Ala or Gly (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (18) .. (18) (C) OTHER INFORMATION: Xaa = Ser or Tyr (ix) FEATURE
(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
(B) LOCATION: (27) .. (27) (C) OTHER INFORMATION: Xaa = Met or Ile or Nle (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (28) .. (28) (C) OTHER INFORMATION: Xaa = Ser or Asn (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (30)..(30) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (31) .. (31) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (32)..(32) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (33) .. (33) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (34)..(34) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (35)..(35) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (36)..(36) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (37)..(37) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (38)..(38) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (39) .. (39) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
(B) LOCATION: (41)..(41) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (42) .. (42) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (43)..(43) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (ix) FEATURE
(A) NAME/KEY: VARIANT
(B) LOCATION: (44)..(44) (C) OTHER INFORMATION: Xaa = any amino acid or is absent (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 1:
Xaa Xaa Asp Ala Ile Phe Tyr Xaa Ser Tyr Arg Lys Xaa Leu Xaa Gln Leu Xaa Ala Arg Lys Leu Leu Xaa Xaa Ile Xaa Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa (2) INFORMATION FOR SEQ ID NO.: 2:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (44)_.(44) (C) OTHER INFORMATION: Leu residue is capped with an unsubstituted amide moiety (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 2:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 3:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 3:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 4:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 29 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (29)_.(29) (C) OTHER INFORMATION: Arg residue is capped with an unsubstituted amide moiety (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 4:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg (2) INFORMATION FOR SEQ ID NO.: 5:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 29 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence of the minimum active core of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 5:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg (2) INFORMATION FOR SEQ ID NO.: 6:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence corresponding to positions 30 to 44 of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 6:
Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 7:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
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(A) NAME/KEY: MISC FEATURE
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Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: THERATECHNOLOGIES INC.
(ii) TITLE OF INVENTION: GH SECRETAGOGUES AND USES THEREOF
(iii) NUMBER OF SEQUENCES: 7 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: SMART & BIGGAR
(B) STREET: 1000 de la Gauchetiere ouest, Suite 3300 (C) CITY: Montreal (D) STATE: Quebec (E) COUNTRY: CANADA
(F) ZIP: H3B 4W5 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
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(B) FILING DATE:
(C) CLASSIFICATION:
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: SMART & BIGGAR
(B) REGISTRATION NUMBER: 85795-75 (C) REFERENCE/DOCKET NUMBER:
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (514)-954-1500 (B) TELEFAX: (514)-954-1396 (2) INFORMATION FOR SEQ ID NO.: 1:
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(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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(A) NAME/KEY: VARIANT
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Xaa Xaa Asp Ala Ile Phe Tyr Xaa Ser Tyr Arg Lys Xaa Leu Xaa Gln Leu Xaa Ala Arg Lys Leu Leu Xaa Xaa Ile Xaa Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa (2) INFORMATION FOR SEQ ID NO.: 2:
(i) SEQUENCE CHARACTERISTICS
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(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (44)_.(44) (C) OTHER INFORMATION: Leu residue is capped with an unsubstituted amide moiety (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 2:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 3:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 3:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 4:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 29 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (29)_.(29) (C) OTHER INFORMATION: Arg residue is capped with an unsubstituted amide moiety (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 4:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg (2) INFORMATION FOR SEQ ID NO.: 5:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 29 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence of the minimum active core of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 5:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg (2) INFORMATION FOR SEQ ID NO.: 6:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(C) OTHER INFORMATION: Amino acid sequence corresponding to positions 30 to 44 of human GRF
(xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 6:
Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu (2) INFORMATION FOR SEQ ID NO.: 7:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 44 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY:
(ii) MOLECULE TYPE: polypeptide (vi) ORIGINAL SOURCE:
(A) ORGANISM: Artificial sequence (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (1).-(1) (C) OTHER INFORMATION: Tyr residue is linked to an hexenoyl-trans-3 moeity (ix) FEATURE
(A) NAME/KEY: MISC FEATURE
(B) LOCATION: (44)_.(44) (C) OTHER INFORMATION: Leu residue is capped with an unsubstituted amide moiety (xi) SEQUENCE DESCRIPTION: SEQ ID NO.: 7:
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
Claims (41)
1. Use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
2. Use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said use is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol.
3. The use of claim 1 or 2, wherein said alteration of a first body composition parameter is a decrease in visceral abdominal tissue (VAT), a decrease in trunk fat, or both.
4. The use of claim 3, wherein said alteration of a first body composition parameter is a decrease in visceral abdominal tissue (VAT).
5. The use of any one of claims 1 to 4, wherein said second body composition parameter is limb fat, subcutaneous abdominal tissue (SAT), or both.
6. The use of claim 5, wherein said second body composition parameter is subcutaneous abdominal tissue (SAT).
7. The use of any one of claims 1 to 6, wherein said alteration of a lipid parameter is a decrease in triglyceride.
8. The use of any one of claims 1 to 7, wherein said first body composition parameter is associated with lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia or syndrome X.
9. The use of claim 8, wherein said lipodystrophy is HIV-related lipodystrophy.
10. The use of any one of claims 1 to 9, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 0.0001 to 2 mg.
11. The use of claim 10, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 1 mg or about 2 mg.
12. The use of claim 11, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 2 mg.
13. The use of any one of claims 1 to 12, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal or topical administration.
14. The use of claim 13, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for subcutaneous administration.
15. The use of any one of claims 1 to 14, wherein said subject suffers from diabetes, glucose intolerance or insulin resistance.
16. A package comprising (hexenoyl trans-3)hGRF(1-44)NH2 together with instructions for its use as defined in any one of claims 1 to 15.
17. A composition for altering a first body composition parameter of a subject with no or substantially no decrease in a second body composition parameter of said subject and without significantly impairing glucose control in said subject, wherein said alteration of a first body composition parameter is:
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said alteration of a first body composition is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol; and said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
(a) an increase in lean body mass;
(b) a decrease in trunk fat;
(c) a decrease in visceral fat;
(d) a decrease in abdominal girth;
(e) a decrease in visceral abdominal tissue (VAT);
(f) a decrease in VAT:SAT ratio; or (g) any combination of (a) to (f);
wherein said second body composition parameter is:
(i) limb fat;
(ii) subcutaneous fat;
(iii)subcutaneous abdominal tissue (SAT); or (iv) any combination of (i) to (iii);
wherein said alteration of a first body composition is associated with an alteration of one or more of the following lipid parameters:
(I) a decrease in cholesterol;
(II) a decrease in non-HDL cholesterol;
(III) a decrease in triglyceride; or (IV) a decrease in the ratio of total cholesterol:HDL
cholesterol; and said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
18. The composition of claim 17, wherein said alteration of a first body composition parameter is a decrease in visceral abdominal tissue (VAT), a decrease in trunk fat, or both.
19. The composition of claim 18, wherein said alteration of a first body composition parameter is a decrease in visceral abdominal tissue (VAT).
20. The composition of any one of claims 17 to 19, wherein said second body composition parameter is limb fat, subcutaneous abdominal tissue (SAT), or both.
21. The composition of claim 20, wherein said second body composition parameter is subcutaneous abdominal tissue (SAT).
22. The composition of any one of claims 17 to 21, wherein said alteration of a lipid parameter is a decrease in triglyceride.
23. The composition according to any one of claims 17 to 22, wherein said first body composition parameter is associated with lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia or syndrome X.
24. The composition of claim 23, wherein said first body composition parameter is associated with HIV-related lipodystrophy.
25. The composition of any one of claims 17 to 24, wherein said subject suffers from diabetes, glucose intolerance or insulin resistance.
26. Use of (hexenoyl trans-3)hGRF(1-44)NH2 for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
27. Use of (hexenoyl trans-3)hGRF(1-44)NH2 for the preparation of a medicament for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL cholesterol; or (e) any combination of (a) to (d).
28. The use of claim 26 or 27, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 0.0001 to 2 mg.
29. The use of claim 28, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 1 mg or about 2 mg.
30. The use of claim 29, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for administration at a dose of about 2 mg.
31. The use of any one of claims 26 to 30, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal or topical administration.
32. The use of claim 31, wherein said (hexenoyl trans-3)hGRF(1-44)NH2 is adapted for subcutaneous administration.
33. The use of any one of claims 26 to 32, wherein said subject suffers from diabetes, glucose intolerance or insulin resistance.
34. A package comprising (hexenoyl trans-3)hGRF(1-44)NH2 together with instructions for its use as defined in any one of claims 26 to 33.
35. A composition for altering a lipid parameter associated with HIV-related lipodystrophy in a subject without significantly impairing glucose control in said subject, wherein said alteration of a lipid parameter is:
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL
cholesterol; or (e) any combination of (a) to (d), said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
(a) a decrease in cholesterol;
(b) a decrease in non-HDL cholesterol;
(c) a decrease in triglyceride;
(d) a decrease in the ratio of total cholesterol:HDL
cholesterol; or (e) any combination of (a) to (d), said composition comprising (hexenoyl trans-3)hGRF(1-44)NH2 and a pharmaceutically acceptable carrier.
36. The composition of claim 35, wherein said composition is adapted for administration of said (hexenoyl trans-3)hGRF(1-44)NH2 at a dose of about 0.0001 to 2 mg.
37. The composition of claim 36, wherein said composition is adapted for administration of said (hexenoyl trans-3)hGRF(1-44)NH2 at a dose of about 1 mg or about 2 mg.
38. The composition of claim 37, wherein said composition is adapted for administration of said (hexenoyl trans-3)hGRF(1-44)NH2 at a dose of about 2 mg.
39. The composition of any one of claims 35 to 38, wherein said composition is adapted for intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal or topical administration.
40. The composition of claim 39, wherein said composition is adapted for subcutaneous administration.
41. The composition of any one of claims 35 to 40, wherein said subject suffers from diabetes, glucose intolerance or insulin resistance.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2485472A CA2485472C (en) | 2004-10-20 | 2004-10-20 | Gh secretagogues and uses thereof |
| JP2007537087A JP2008516994A (en) | 2004-10-20 | 2005-10-20 | Growth hormone secretagogue and use thereof |
| CN200580043640XA CN101084009B (en) | 2003-05-29 | 2005-10-20 | Gh secretagogues and uses thereof |
| MX2007004682A MX2007004682A (en) | 2004-10-20 | 2005-10-20 | Gh secretagogues and uses thereof. |
| PCT/CA2005/001611 WO2006042408A1 (en) | 2004-10-20 | 2005-10-20 | Gh secretagogues and uses thereof |
| BRPI0516935-6A BRPI0516935A (en) | 2004-10-20 | 2005-10-20 | gh secretagogues and uses thereof |
| EP05797145A EP1812048A4 (en) | 2004-10-20 | 2005-10-20 | Gh secretagogues and uses thereof |
| KR1020077011178A KR101228229B1 (en) | 2004-10-20 | 2005-10-20 | Gh secretagogues and uses thereof |
| AU2005297366A AU2005297366B2 (en) | 2004-10-20 | 2005-10-20 | GH secretagogues and uses thereof |
| NO20072136A NO20072136L (en) | 2004-10-20 | 2007-04-24 | Substance that promotes GH secretion and its use |
| HK08106222.9A HK1115803A1 (en) | 2004-10-20 | 2008-06-04 | Gh secretagogues and uses thereof gh |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2485472A CA2485472C (en) | 2004-10-20 | 2004-10-20 | Gh secretagogues and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2485472A1 CA2485472A1 (en) | 2006-04-20 |
| CA2485472C true CA2485472C (en) | 2011-09-27 |
Family
ID=36242546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2485472A Active CA2485472C (en) | 2003-05-29 | 2004-10-20 | Gh secretagogues and uses thereof |
Country Status (4)
| Country | Link |
|---|---|
| BR (1) | BRPI0516935A (en) |
| CA (1) | CA2485472C (en) |
| HK (1) | HK1115803A1 (en) |
| MX (1) | MX2007004682A (en) |
-
2004
- 2004-10-20 CA CA2485472A patent/CA2485472C/en active Active
-
2005
- 2005-10-20 BR BRPI0516935-6A patent/BRPI0516935A/en not_active Application Discontinuation
- 2005-10-20 MX MX2007004682A patent/MX2007004682A/en active IP Right Grant
-
2008
- 2008-06-04 HK HK08106222.9A patent/HK1115803A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2485472A1 (en) | 2006-04-20 |
| BRPI0516935A (en) | 2008-09-23 |
| HK1115803A1 (en) | 2008-12-12 |
| MX2007004682A (en) | 2007-07-17 |
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