U.S. patent application number 13/177754 was filed with the patent office on 2012-01-05 for gh secretagogues and uses thereof.
This patent application is currently assigned to THERATECHNOLOGIES INC.. Invention is credited to Thierry Abribat, Soraya Allas, Alcide Chapdelaine, Andre De Villers, Denis Gravel.
Application Number | 20120004174 13/177754 |
Document ID | / |
Family ID | 33480323 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120004174 |
Kind Code |
A1 |
Abribat; Thierry ; et
al. |
January 5, 2012 |
GH SECRETAGOGUES AND USES THEREOF
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.
Inventors: |
Abribat; Thierry;
(St-Foy-Les-Lyon, FR) ; De Villers; Andre;
(Outremont, CA) ; Allas; Soraya; (Iles Des Soeurs,
CA) ; Gravel; Denis; (Saint-Lambert, CA) ;
Chapdelaine; Alcide; (Ile Des Soeurs, CA) |
Assignee: |
THERATECHNOLOGIES INC.
Ville Saint-Laurent
CA
|
Family ID: |
33480323 |
Appl. No.: |
13/177754 |
Filed: |
July 7, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12239712 |
Sep 26, 2008 |
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13177754 |
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11877395 |
Oct 23, 2007 |
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12239712 |
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10969463 |
Oct 20, 2004 |
7316997 |
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11877395 |
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PCT/CA03/00827 |
May 29, 2003 |
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10969463 |
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Current U.S.
Class: |
514/11.2 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 3/00 20180101; A61P 3/04 20180101; A61P 7/00 20180101; A61P
21/06 20180101; A61P 3/06 20180101; A61P 5/48 20180101; A61P 37/00
20180101; A61K 38/25 20130101; A61P 3/08 20180101; C07K 14/60
20130101; A61P 31/18 20180101; A61P 3/10 20180101; A61P 37/04
20180101 |
Class at
Publication: |
514/11.2 |
International
Class: |
A61K 38/25 20060101
A61K038/25; A61P 3/06 20060101 A61P003/06; A61P 7/00 20060101
A61P007/00; A61P 5/48 20060101 A61P005/48; A61P 31/18 20060101
A61P031/18; A61P 3/10 20060101 A61P003/10; A61P 3/08 20060101
A61P003/08; A61P 3/04 20060101 A61P003/04; A61P 3/00 20060101
A61P003/00 |
Claims
1-17. (canceled)
18. A method of altering a first body composition parameter of a
subject having abnormal fat accumulation and a waist circumference
of 95 cm or more if said subject is male or a waist circumference
of 94 cm or more if said subject is female, wherein said method
results in no or substantially no decrease in a second body
composition parameter of said subject, wherein said second body
composition parameter is: (i) subcutaneous fat; (ii) subcutaneous
abdominal tissue (SAT); or (iii) both (i) and (ii); said method
comprising administering to said subject an agent wherein said
agent is: (a) a growth hormone (GH) secretagogue; or (b) a
composition comprising a GH secretagogue and a pharmaceutically
acceptable carrier.
19. The method of claim 18, wherein said GH secretagogue is
GH-releasing factor (GRF) or a GRF analog.
20. The method of claim 19 wherein said GRF analog is a GRF analog
of formula A: X-GRF Peptide (A) wherein; the GRF peptide is a
peptide of formula B (SEQ ID NO: 1); TABLE-US-00012
A1-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-R0 (B)
wherein, A1 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 R0
is NH.sub.2 or NH--(CH.sub.2)n-CONH.sub.2, 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 defining a backbone of 5 to 7
atoms; wherein the backbone can be substituted by C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.6-12 aryl and the backbone comprises
at least one rigidifying moiety connected to at least two atoms of
the backbone; and said moiety is a double bond, triple bond,
saturated or unsaturated C.sub.3-9 cycloalkyl, or C.sub.6-12
aryl.
21. The method of claim 20, wherein X is: ##STR00002## wherein R is
H, CH.sub.3 or CH.sub.2CH.sub.3, and the double bond is cis or
trans; ##STR00003## wherein R is H, CH.sub.3 or CH.sub.2CH.sub.3,
wherein X is in a cis or trans configuration, and wherein said GRF
analog is a racemic mixture or a pure enantiomer; ##STR00004##
wherein R is H, CH.sub.3 or CH.sub.2CH.sub.3, and wherein when R is
CH.sub.3 or CH.sub.2CH.sub.3, X is in a cis or trans configuration;
##STR00005## wherein R is H, CH.sub.3 or CH.sub.2CH.sub.3, wherein
X is in a cis or trans configuration, and wherein said GRF analog
is a racemic mixture or a pure enantiomer; ##STR00006## wherein R
is H, CH.sub.3 or CH.sub.2CH.sub.3, wherein when R is CH.sub.3 or
CH.sub.2CH.sub.3, X is in a cis or trans configuration, and wherein
said GRF analog is a racemic mixture or a pure enantiomer;
##STR00007## wherein R is H, CH.sub.3 or CH.sub.2CH.sub.3, wherein
X is in a cis or trans configuration, and wherein said GRF analog
is a racemic mixture or a pure enantiomer; ##STR00008## wherein R
is H, CH.sub.3 or CH.sub.2CH.sub.3, wherein when R is CH.sub.3 or
CH.sub.2CH.sub.3, X is in a cis or trans configuration, and wherein
said GRF analog is a racemic mixture or a pure enantiomer;
##STR00009## wherein R is H, CH.sub.3 or CH.sub.2CH.sub.3, and
wherein when R is CH.sub.3 or CH.sub.2CH.sub.3, X is in a cis or
trans configuration; ##STR00010## wherein R is H, CH.sub.3 or
CH.sub.2CH.sub.3; ##STR00011## wherein R is H, CH.sub.3 or
CH.sub.2CH.sub.3; ##STR00012## wherein R is H, CH.sub.3 or
CH.sub.2CH.sub.3; ##STR00013## wherein R is H, CH.sub.3 or
CH.sub.2CH.sub.3; or ##STR00014## wherein R is H, CH.sub.3 or
CH.sub.2CH.sub.3, wherein X is in a cis or trans configuration, and
wherein said GRF analog is a racemic mixture or a pure
enantiomer.
22. The method of claim 20, wherein A30 is: (a) a bond; (b) an
amino acid sequence corresponding to positions 30-44 of a natural
GRF peptide, or (c) said amino acid sequence of (b) having a 1-14
amino acid deletion from its C-terminal.
23. The method of claim 20, wherein said GRF peptide is: (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;
or (c) the polypeptide of (a) having a 1 to 14 amino acid deletion
from its C-terminus.
24. The method of claim 20, wherein said GRF analog is (hexenoyl
trans-3)hGRF(1-44)NH.sub.2.
25. The method of claim 18, 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 and (g) any
combination of (a) to (f).
26. The method of claim 18, wherein said abnormal fat distribution
is associated with lipodystrophy, lipohypertrophy, obesity,
dyslipidemia, hypertriglyceridemia or syndrome X.
27. The method of claim 26, wherein said lipodystrophy is
HIV-related lipodystrophy.
28. The method of claim 18, wherein said subject is HIV
positive.
29. The method of claim 28, wherein said subject is receiving
antiviral therapy.
30. The method of claim 18, wherein said subject suffers from
diabetes, glucose intolerance or insulin resistance.
31. The method of claim 20, wherein said GRF analog is administered
at a dose of about 0.0001 to 2 mg.
32. The method of claim 31, wherein said GRF analog is administered
at a dose of about 1 mg or about 2 mg.
33. The method of claim 18, wherein said GH secretagogue or said
composition is administered by an intravenous, oral, transdermal,
subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary,
parenteral, intrarectal or topical route.
34. The method of claim 33, wherein said GH secretagogue or said
composition is administered by a subcutaneous route.
35. The method of claim 18, wherein said alteration of a first body
composition parameter results in an improvement in quality of life
of said subject.
36-88. (canceled)
89. The method of claim 32, wherein said GRF analog is administered
at a dose of about 2 mg.
90. The method of claim 18, wherein said subject has a body mass
index (BMI) of 20 kg/m.sup.2 or more.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of prior application Ser.
No. 12/239,712, filed Sep. 26, 2008, which is a continuation of
prior application Ser. No. 11/877,395, filed Oct. 23, 2007, which
is a continuation of prior application Ser. No. 10/969,463, filed
Oct. 20, 2004, now U.S. Pat. No. 7,316,997, which is a
continuation-in-part of PCT International Patent Application No.
PCT/CA03/00827 filed May 29, 2003. The aforementioned applications
are hereby incorporated herein by reference in their
entireties.
REFERENCE TO SEQUENCE LISTING
[0002] Pursuant to 37 C.F.R. 1.821(c), a sequence listing is
submitted herewith via EFS-Web as an ASCII compliant text file
named "Sequence Listing.txt" that was created on Jul. 7, 2011, and
has a size of 5966 bytes. The content of the aforementioned file
named "Sequence Listing.txt" is hereby incorporated by reference in
its entirety.
FIELD OF THE INVENTION
[0003] The invention relates to growth hormone (GH) secretagogues,
such as GH releasing factor (GRF) and analogs thereof, and uses
thereof.
BACKGROUND OF THE INVENTION
Syndromes Associated with Fat Accumulation
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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 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.
[0008] 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 Clin 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
[0009] 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 decline in GH and IGF-1 observed with aging contribute to
the impaired cognitive function.
[0010] 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 J B, et al.,
Psychoneuroendocrinology 1998 23(1):45-55), and with administration
of IGF-1 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
[0011] 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.
[0012] 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 L A, et al., AIDS 2002
16(8):1103-1111) and in animal models of radiotherapy preceding
bone marrow transplantation (Sun R, et al., BMT Meetings, February
22-26 Orlando, Fla., Abstract 27 2002:68-69).
Catabolism or Muscle Wasting
[0013] 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.
[0014] 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 G
S, 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 A J, 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).
[0015] However, the use of GH to treat conditions such as those
noted above, has been associated with adverse side effects in some
cases.
SUMMARY OF THE INVENTION
[0016] The invention relates to GH secretagogues (e.g. GRF and
analogs thereof) and uses thereof.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] In embodiments, the metabolic condition is associated with
fat accumulation and/or hypercholesterolemia, e.g. obesity,
HIV-related lipodystrophy, metabolic syndrome and syndrome X.
[0035] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] 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);
[0037] FIG. 2 illustrates changes from baseline to day 9 in Pz
amplitude of evoked related potential (P300) during
wakefulness;
[0038] FIG. 3 illustrates mean AUC of antigen-specific
proliferative T cell response;
[0039] FIG. 4 illustrates the percentage of subjects with
protective antibody titers (> 1/40) for B/Victoria; and
[0040] FIG. 5 illustrates the variation of mean IGF-1 levels during
time with placebo, 2 mg/day TH9507, 0.5 mg/day TH9507 and 1 mg/day
TH9507.
[0041] FIG. 6 illustrates a flow diagram of patient disposition in
respect of the studies described in Example 6.
[0042] 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
[0043] In the studies described herein, the effect of (hexenoyl
trans-3)hGRF(1-44)NH.sub.2 (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.
[0044] The studies described herein further demonstrate beneficial
effects on bone markers.
[0045] 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).
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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).
[0051] 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.
[0052] 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.
[0053] 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).
[0054] 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).
[0055] 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).
[0056] 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).
[0057] 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).
[0058] 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.
[0059] In an embodiment, the above-mentioned alteration of a first
body composition parameter results in an improvement of quality of
life of the subject.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] In an embodiment, the above-noted condition characterized by
deficient or decreased bone formation is selected from the group
consisting of osteopenia and osteoporosis.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] In an embodiment, the above-mentioned lipodystrophy is
HIV-related lipodystrophy.
[0069] In an embodiment, the above-mentioned subject is HIV
positive.
[0070] In an embodiment, the above-mentioned subject is receiving
antiviral therapy.
[0071] In an embodiment, the above-mentioned subject suffers from a
condition selected from the group consisting of diabetes, glucose
intolerance and insulin resistance.
[0072] 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 2 mg, in a further embodiment, about 1 mg and
in a further embodiment, about 2 mg.
[0073] 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.
[0074] In an embodiment, the subject is a mammal, in a further
embodiment, a human.
[0075] For the purpose of the present invention the following terms
are defined bellow.
[0076] 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.
[0077] The term "subject" is intended to mean any mammal including,
but not limited to, human, canine, feline, equine, caprine, bovine,
porcine and ovine.
[0078] The term "cognitive function" is intended to mean functions
including, but not limited to thinking, reasoning, memory and
problem solving.
[0079] The term "catabolic/wasting conditions" is intended to mean
condition including, but not limited to, frail bones, low muscular
mass and muscle wasting.
[0080] In the present application, the compound identified as
TH9507 is the [hexenoyl-trans-3-Tyr1]hGRF(1-44)NH.sub.2.
[0081] 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.
[0082] In embodiments, the GH secretagogue is a growth
hormone-releasing factor (GRF; also referred to as growth hormone
releasing hormone [GHRH]) or GRF analog.
[0083] In an embodiment, the GRF is human GRF (hGRF).
[0084] Human growth hormone-releasing factor (hGRF) is a peptide of
44 amino acids with a C-terminal NH.sub.2 modification, referred to
herein as hGRF(1-44)NH.sub.2, and has the following structure:
TABLE-US-00001 (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-NH.sub.2
[0085] Therefore, the amino acid sequence of the just-noted 44
amino acid form is as follows:
TABLE-US-00002 (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
[0086] The minimum active core comprises the first 29 amino acids
of the above sequence, which is referred to herein as
hGRF(1-29)NH.sub.2, and has the following structure:
TABLE-US-00003 (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-NH.sub.2
[0087] Therefore, the amino acid sequence of the just-noted 29
amino acid form is as follows:
TABLE-US-00004 (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
[0088] 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:
TABLE-US-00005 (SEQ ID NO: 6)
Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg- Ala-Arg-Leu
[0089] In an embodiment, the above-mentioned GRF analog is a GRF
analog of formula A:
X-GRF Peptide (A) [0090] wherein; [0091] the GRF peptide is a
peptide of formula B;
TABLE-US-00006 [0091] (SEQ ID NO: 1)
A1-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-R0 (B)
[0092] wherein, [0093] A1 is Tyr or His; [0094] A2 is Val or Ala;
[0095] A8 is Asn or Ser; [0096] A13 is Val or Ile; [0097] A15 is
Ala or Gly; [0098] A18 is Ser or Tyr; [0099] A24 is Gln or His;
[0100] A25 is Asp or Glu; [0101] A27 is Met, Ile or Nle; [0102] A28
is Ser or Asn; [0103] A30 is a bond or amino acid sequence of 1 up
to 15 residues; and [0104] R0 is NH.sub.2 or
NH--(CH.sub.2)n-CONH.sub.2, with n=1 to 12; and [0105] X is a
hydrophobic tail anchored via an amide bond to the N-terminus of
the peptide and the hydrophobic tail defining a backbone of 5 to 7
atoms; [0106] 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 at least two atoms of the
backbone; [0107] said moiety selected from the group consisting of
double bond, triple bond, saturated or unsaturated C3-9 cycloalkyl,
and C6-12 aryl.
[0108] In embodiments, X noted above is selected from the group
consisting of:
##STR00001##
[0109] In embodiments, A30 noted above is selected from the group
consisting of: [0110] (a) a bond; [0111] (b) an amino acid sequence
corresponding to positions 30-44 of a natural GRF peptide, and
[0112] (c) said amino acid sequence of (b) having a 1-14 amino acid
deletion from its C-terminal.
[0113] In embodiments, the above-noted GRF peptide is selected from
the group consisting of: [0114] (a) a polypeptide comprising the
amino acid sequence of SEQ ID NO: 3; [0115] (b) a polypeptide
comprising the amino acid sequence of SEQ ID NO: 5; and [0116] (c)
the polypeptide of (a) having a 1 to 14 amino acid deletion from
its C-terminus.
[0117] In an embodiment, the above-noted GRF analog is (hexenoyl
trans-3)hGRF(1-44)NH.sub.2.
[0118] Methods of preparing the above-described GRF analogs are
described in U.S. Pat. No. 5,861,379 (Ibea et al., Jan. 19, 1999);
No. 6,020,311 (Brazeau et al., Feb. 1, 2000), No. 6,458,764 (Gravel
et al., Oct. 1, 2002) and published US application No. 2004/0171534
A1 (Gravel et al., published Sep. 2, 2004).
[0119] 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.
[0120] 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 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-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 administering or, supervising
the administration of the compositions.
[0121] As used herein "pharmaceutically acceptable carrier" or
"excipient" includes any and all solvents, dispersion media,
coatings, antibacterial and antifungal 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,
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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] Throughout this application, various references are referred
to describe more fully the state of the art to which this invention
pertains. The disclosures of these references are hereby
incorporated by reference into the present disclosure.
EXAMPLES
Example 1
Study Drug
[0129] The compound used in the studies below is (hexenoyl
trans-3)hGRF(1-44)NH.sub.2 (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)NH.sub.2 or Th9507 has the following
structure:
TABLE-US-00007 (SEQ ID NO: 7)
(trans)CH.sub.3--CH.sub.2--CH.dbd.CH--CH.sub.2--CO-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-NH.sub.2
(hexenoyl trans-3)hGRF(1-44)NH.sub.2 was synthesized via the
methods set forth in U.S. Pat. No. 5,861,379 (Ibea et al.; Jan. 19,
1999).
[0130] 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
[0131] 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
[0132] 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 .gtoreq.5), the Walters Criteria for Sleep Maintenance
Insomnia, and the Beck Questionnaire (Score .gtoreq.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.
[0133] 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 the Continuous
Performance Test (CPT) at baseline and at the end of treatment
period.
[0134] 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 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.
Results
[0135] Demographic characteristics by treatment group are displayed
in the following table:
TABLE-US-00008 TABLE 1 Demographic (screening) data by treatment
groups Placebo 0.1 mg 1 mg N = 29 N = 26 N = 27 P value 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)
[0136] 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-1 and IGF-BP3
respectively, ANOVA model on changes from baseline).
[0137] 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.
[0138] 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.
[0139] 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 J B
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
[0140] The present example describes immune findings following an
influenza vaccination challenge in elderly subjects.
Material and Methods
[0141] 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.RTM.
S/F, Shire, Montreal, Canada) containing 15 .mu.g each of A/New
Calcdonia/20/99, A/Panama/2007/99, B/Victoria/504/2000
antigens.
[0142] 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 (.sup.3H) incorporation and
results were log-base 10 transformed prior to analysis. The
antibody titers were determined by standard hemagglutination
inhibition assay and results were log-base 2 transformed prior to
analysis.
[0143] Eighty one (81) subjects completed the study as per
protocol. Subject demographics are shown in the following
table:
TABLE-US-00009 TABLE 2 Subject demographics 1 mg 2 mg Placebo
TH9507 TH9507 All P-value Age 75.9 .+-. 6.5 74.9 .+-. 6.1 73.2 .+-.
4.4 74.6 .+-. 5.8 0.21 (years) Total N 29 29 29 187 0.96 Female 13
13 14 40 Male 16 16 15 47 BMI 27.4 .+-. 5.8 26.9 .+-. 4.2 29.2 .+-.
6.0 27.8 .+-. 5.4 0.26 (kg/m.sup.2) 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
[0144] 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 Calcdonia, P=0.001;
Victoria, P=0.02, (Pairwise comparisons for difference among
treatment groups and ANCOVA analysis for overall treatment
significance).
[0145] 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 Calcdonia strains.
[0146] 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.
[0147] 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.
[0148] 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
[0149] The present example shows the effect of a 7-day
administration of TH9507 on circulating IGF-1 levels in healthy
middle-aged men.
Material and Methods
[0150] 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 placebo, 0.5, 1 or 2 mg of TH9507.
Circulating IGF-1 levels were measured on Days 1 to 7. The 12 hour
GH response and TH9507 PK profile were determined on Day 1 and
7.
Results
[0151] As shown in FIG. 5, IGF-1 increased over baseline values by
8% (placebo), 37% (0.5 mg), 89% (1 mg) 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 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.
[0152] 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 single or repeated treatment with
TH9507.
[0153] 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.
[0154] 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
[0155] The present example illustrates beneficial effects of TH9507
on non-HDL cholesterol levels in a diabetic population.
Material and Methods
[0156] 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
[0157] 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%).
[0158] 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.
[0159] A dose-related increase in the IGF-1 levels was observed at
the end of the treatment period.
[0160] 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
[0161] This study investigated the effects of TH9507, on abdominal
fat accumulation associated with HIV lipodystrophy.
[0162] Design: Randomized, placebo-controlled, multi-center, dose
ranging (placebo, 1 mg or 2 mg SC QD), parallel group, 12-week
study
[0163] Patients: 61 HIV-infected patients (BMI 28.+-.3 [SD]
kg/m.sup.2, 28% diabetic or glucose intolerant) with increased
waist circumference (102 cm.+-.8 [SD]) and waist/hip (1.0.+-.0.1
[SD]).
[0164] Measurements: Body composition was assessed by DXA and
abdominal CT scan; IGF-I, insulin, glucose, lipid, bone turnover,
immunologic, and safety parameters.
[0165] 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, 1
mg, 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, 1 mg, 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, 1 mg, 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,
1 mg, 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.
[0166] 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
[0167] 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 .gtoreq.95 cm for men
and .gtoreq.94 cm for women, and a waist to hip ratio .gtoreq.0.94
for men and .gtoreq.0.88 for women were enrolled. We excluded,
subjects with a BMI .gtoreq.20 kg/m2, CD4 cell count .gtoreq.100
cells/mm3, viral load .gtoreq.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>3.times. upper limit of normal, creatinine >1.5.times.
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 begin antidiabetic medication, use systemic
corticosteroids for >10 days, or begin estrogen or testosterone
preparations during the study.
Study Procedures
[0168] 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 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 the study.
[0169] 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 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
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.
[0170] 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.
[0171] 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
[0172] TH9507 was used in this study, as noted above.
Methods
Biochemical Indices
[0173] 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, Calif.), 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,
Calif.) 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.RTM., Roche diagnostics, Indianapolis, Ind.).
HbAlc was determined by chromatography. PSA was determined using
the Hybritech.RTM. PSA test (Beckman Coulter, Mississauga, Canada).
TSH was measured by microparticle enzyme immunoassay (AxSYM hTSH
II, Abbott Laboratories, Abbott Park, Ill.). NTX (N-terminal
telopeptide of type I collagen; a bone resorption marker) was
measured by ELISA using a commercially available kit
(Osteomark.TM., Ostex International Inc., Seattle, Wash.).
Osteocalcin was measured using a commercially available enzymatic
immunoassay kit (Metra.TM. osteocalcin, Quidel Corporation, San
Diego, Calif.). CD4 and viral load were performed by the individual
site labs by routine methodology.
HOMA was calculated as:
[ .DELTA. Insulin ( 30 min - 0 min ) .DELTA. Glucose ( 30 min - 0
min ) ] Insulin ( 0 min ) . ##EQU00001##
Body Composition
[0174] 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.times.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
[0175] 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
[0176] 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 FIG. 6 for patient disposition and flow
diagram.
[0177] 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 .gtoreq.7.0
mmol/L or 2 h-glucose .gtoreq.11.1 mmol/L) and impaired glucose
tolerance (6.1 mmol/L.ltoreq. fasting glucose .ltoreq.6.9 mmol/L or
7.8 mmol/L .ltoreq.2 h-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-US-00010 TABLE 3 Baseline Characteristics Placebo 1 mg 2 mg 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
[0178] 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, 1 mg, 2 mg, respectively, P<0.01 for change in
2 mg group vs. placebo, P<0.05 for the change in 1 mg group vs.
placebo, Table 3). Total fat 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,
1 mg, 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, 1 mg, 2 mg, respectively, P=0.01 for 2 mg group
vs. placebo) (FIG. 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 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
[0179] 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 2 mg, respectively, P<0.01 for each active group
vs. placebo] (FIG. 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).
[0180] Changes in fasting and 120 minute glucose were not
significant between or within the treatment groups.
Bone Markers
[0181] Osteocalcin increased significantly within the 2 mg group,
whereas no changes with NTX were seen (Table 4).
TABLE-US-00011 TABLE 4 Change from Baseline in Body Composition,
Biochemical and Immunologic Parameters. Week 12 Placebo 1 mg 2 mg P
value P value Baseline .DELTA. Baseline .DELTA. Baseline .DELTA. 2
mg vs. P 1 mg vs. P Body Composition Lean Body 63.9 (9.8) -0.5
(1.6) 64.4 (10.0) 0.7 (2.0) 65.2 (6.9) 1.7 (2.3) * 0.0021 0.0467
Mass (kg) Fat Mass (kg) 22.1 (6.0) 0.3 (1.7) 19.0 (5.7) -0.4 (1.8)
18.1 (7.6) -1.4 (2.0) * 0.0125 0.2962 Trunk Fat (kg) 14.6 (3.4) 0.1
(1.1) 13.1 (3.4) -0.5 (1.4) 12.2 (4.6) -1.1 (1.3) * 0.0144 0.1782
Limb Fat (kg) 6.6 (2.8) 0.1 (0.7) 5.1 (2.6) 0.1 (0.5) 5.1 (3.0)
-0.3 (0.8) 0.1576 1.0000 VAT (cm.sup.2) 190.5 (75.7) -12.0 (32.5)
157.8 (56.6) -11.9 (28.7) 160.2 (53.5) -21.5 (27.9) * 0.6428 1.0000
SAT (cm.sup.2) 237.9 (85.2) -10.5 (31.6) 188.8 (89.0) 6.8 (21.2)
189.8 (124.3) 4.4 (19.8) 0.6919 0.3390 VAT: SAT 0.89 (0.50) -0.01
(0.10) 1.17 (1.25) -0.23 (0.47) * 1.12 (0.74) -0.14 (0.18) * 0.0084
0.0434 Biochemical Indices GH Param- eters.sup.1 IGF-1 (ng/mL)
132.4 (42.4) 18.3 (31.7) 165.3 (62.3) 87.5 (66.9) * 157.0 (41.4)
122.6 (79.1) * 0.0002 0.0042 IGFBP-3 2.7 (0.7) 0.1 (0.4) 2.9 (0.9)
0.6 (0.7) * 2.9 (0.4) 0.6 (0.5) * 0.0007 0.0022 (Mg/L) Lipid
Parameters.sup.1 NONHDL Cholesterol (mmol/L) 4.2 (1.0) 0.3 (0.8)
4.8 (2.1) -0.4 (1.5) 4.0 (1.0) -0.1 (0.7) 0.0770 0.3067 Total
Cholesterol (mmol/L) 5.3 (1.0) 0.4 (0.8) 5.9 (2.3) -0.4 (1.7) 5.2
(1.2) -0.1 (0.8) 0.1822 0.3175 LDL (mmol/L) 3.2 (0.8) 0.5 (0.8) *
3.4 (0.9) 0.1 (0.8) 3.1 (1.0) 0.2 (0.7) 0.9533 0.3695 HDL (mmol/L)
1.1 (0.3) 0.0 (0.1) 1.1 (0.3) 0.0 (0.2) 1.2 (0.3) 0.1 (0.1) *
1.0000 1.0000 Triglycerides (mEq/L) 3.1 (2.5) -0.2 (1.6) 3.9 (4.6)
-1.1 (4.4) 2.8 (1.8) -0.9 (1.3) * 0.0131 0.6146 Chol: HDL 4.9 (1.4)
0.2 (0.8) 5.5 (1.3) -0.3 (0.6) 4.3 (0.7) -0.3 (0.7) 0.0128 0.0508
Glucose Parameters Fasting Glucose (mmol/L) 5.3 (0.6) 0.2 (0.8) 5.3
(0.8) 0.1 (0.5) 5.4 (0.6) 0.1 (0.7) 1.0000 1.0000 HBA.sub.1c (%)
5.1 (0.5) -0.3 (0.5) * 5.2 (0.4) 0.2 (0.4) * 5.2 (0.6) -0.0 (0.5)
Contrasts not done (overall p = 0.008) overall p = 0.0237 Two hour
glucose (mmol/L) 6.4 (2.9) 0.6 (1.8) 6.4 (2.4) 0.1 (2.1) 6.4 (2.1)
0.7 (1.7) 1.0000 1.0000 Fasting Insulin (mUI/L) 15.2 (18.0) 5.1
(15.8) 22.7 (30.7) -2.8 (27.6) 12.1 (12.5) 7.4 (6.2) 1.0000 0.6799
HOMA-R 3.7 (4.6) 2.1 (5.5) 5.5 (7.6) 0.8 (7.0) 3.0 (3.5) 2.0 (1.6)
1.0000 0.8698 Bone Turnover Markers Osteo- 9.2 (4.4) 0.5 (3.9) 8.0
(3.9) 1.5 (4.8) 8.3 (3.8) 3.0 (2.8) * 0.3110 1.0000 calcin (ng/mL)
NTX 36.3 (17.7) -0.8 (20.8) 37.1 (13.4) 4.5 (24.9) 37.2 (23.1) -0.5
(27.7) 1.0000 1.0000 (nMBCE/mM) Immunologic Parameters CD4 540.9
(252.9) 36.9 (107.6) 525.4 (309.1) 24.4 (147.41) 577.0 (327.20)
-23.2 (70.7) Contrasts ND (cells/mm.sup.3) (overall p = 0.3242)
overall p = 0.1259 Viral load No stats available due to
undetectable values .sup.1For GH and lipid parameters, the p-values
presented are obtained from last observation data. Results are mean
(SD) in SI units
Quality of Life
[0182] 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.
[0183] Study population included 54 men and 7 women. Baseline mean
age was 46.+-.7 [SD], BMI 28.+-.3 [SD] kg/m.sup.2, 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.
[0184] 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
[0185] Discontinuation rates were not different between the groups
(24%, 11%, 29%, placebo, 1 mg, 2 mg 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 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 and/or paresthesias were noted in 19%, 32%
and 52% of the subjects in the placebo, 1 mg 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 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 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.
[0186] Some of the results using a GRF analog in this 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.
[0187] In addition to reducing truncal fat, the 2 mg 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.
[0188] 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.
[0189] 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.
[0190] 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.
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Sequence CWU 1
1
7144PRTArtificial sequenceSynthetic GRF peptide 1Xaa Xaa Asp Ala
Ile Phe Thr Xaa Ser Tyr Arg Lys Xaa Leu Xaa Gln1 5 10 15Leu Xaa Ala
Arg Lys Leu Leu Xaa Xaa Ile Xaa Xaa Arg Xaa Xaa Xaa 20 25 30Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40244PRTHomo
sapiensMISC_FEATURE(44)..(44)Leu residue is capped with an
unsubstituted amide moiety 2Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr
Arg Lys Val Leu Gly Gln1 5 10 15Leu Ser Ala Arg Lys Leu Leu Gln Asp
Ile Met Ser Arg Gln Gln Gly 20 25 30Glu Ser Asn Gln Glu Arg Gly Ala
Arg Ala Arg Leu 35 40344PRTArtificial sequenceAmino acid sequence
of human GRF 3Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val
Leu Gly Gln1 5 10 15Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser
Arg Gln Gln Gly 20 25 30Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg
Leu 35 40429PRTHomo sapiensMISC_FEATURE(29)..(29)Arg residue is
capped with an unsubstituted amide moiety 4Tyr Ala Asp Ala Ile Phe
Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln1 5 10 15Leu Ser Ala Arg Lys
Leu Leu Gln Asp Ile Met Ser Arg 20 25529PRTArtificial sequenceAmino
acid sequence of the minimum active core of human GRF 5Tyr Ala Asp
Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln1 5 10 15Leu Ser
Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg 20 25615PRTArtificial
sequenceAmino acid sequence corresponding to positions 30 to 44 of
human GRF 6Gln Gln Gly Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg
Leu1 5 10 15744PRTArtificial sequenceSynthetic modified GRF peptide
7Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln1 5
10 15Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln
Gly 20 25 30Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu 35
40
* * * * *