Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention generally relates to the treatment of vascular stenosis and associated conditions, and more particularly carotid vascular stenosis and atherosclerosis.
• Vascular stenosis is a condition resulting from the narrowing of blood vessels, which may occur for example as a result of atherosclerosis inside arteries, the vessels which carry blood from the heart to supply the body.
• Atherosclerosis or hardening of the arteries, is a process in which fat, cells and other substances build up inside artery wails forming what are called plaques. These atheromatous plaques make the walls of an artery harder and thicker, and as a result the blood vessel becomes narrower and less flexible, making it more difficult for blood to flow through.
• Vascular stenosis typically affects arteries in the brain, heart and legs and, when severe, causes tissue death, resulting in conditions such as strokes and heart attacks.
• Atherosclerosis is the leading cause of illness and death in the United States and most developed countries. It is estimated that cardiovascular disease, primarily due to coronary artery disease and stroke, affects at least 22 million Individuals in the United States, and causes nearly 900,000 deaths each year.
• the abnormal narrowing of arteries caused by atherosclerosis can affect arteries in the legs, particularly those supplying the calf muscles. This can lead to a condition known as intermittent claudication, where, in the early stages, cramping pains are felt in the calves after walking a certain distance. The pain goes away afte resting for a few minutes. If the disease progresses, the pain is experienced even while resting and leg ulcers, or even gangrene of the toes and feet, may occur.
• Vascular stenosis of arteries in the heart can lead to a condition calied angina, where pain is felt in the chest during exercise, Again, resting usually causes the pain to go away within a short time, although there is the potential for an artery to become completely blocked. In this case the pain becomes heavy and persistent, possibly spreading to the arm or neck, and a heart attack takes place, in which an area of heart muscle dies off.
• vascular stenosis When arteries in the brain are affected by vascular stenosis, this can shut off the blood supply to part of the brain tissue or lead to the rupture of a small blood vessel, with bleeding into the brain. Either of these events results in a stroke, where an area of brain tissue dies off, causing a range of possible symptoms including paralysis, numbness, and problems with speech, sight, movement and balance.
• Carotid artery stenosis which is narrowing of the large arteries in the neck, may also reduce the brain's blood supply and lead to a stroke.
• Vascular stenosis and associated conditions such as atherosclerosis can therefore result in very serious cardiovascular pathologies such as infarction, peripheral vascular disease, stroke, sudden death, cardiac decompensation, cerebral vascular accidents and the like.
• cardiovascular pathologies such as infarction, peripheral vascular disease, stroke, sudden death, cardiac decompensation, cerebral vascular accidents and the like.
• the underlying cause, atherosclerosis is usually quite advanced, having progressed for decades.
• vascular stenosis and associated conditions such as atherosclerosis remain the largest cause of morbidity and mortality in developed countries.
• the present invention provides a method for preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient (GHD) obese subject, said method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-releasing agent.
• GDD growth hormone-deficient
• GH growth hormone
• the present invention provides a growth hormone (GH)-reieasing agent for use in preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient (GHD) obese subject.
• GH growth hormone
• the present invention provides a growth hormone (GH)-reieasing agent for the manufacture of a medicament for use in preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient (GHD) obese subject.
• the present invention provides the use of a growth hormone (GH)- re!easing agent for preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient (GHD) obese subject.
• the present invention provides the use of a growth hormone (GH)- releasing agent for the manufacture of a medicament for preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient obese (GHD) subject.
• GH growth hormone
• the above-mentioned GH-releasing agent is a growth hormone- releasing factor (GRF) or a GRF analog.
• GRF growth hormone- releasing factor
• the above-mentioned GRF analog is a GRF analog of formula
• the GRF peptide is a peptide of formula B:
• A1 is Tyr or His
• A2 is Val or Ala
• A8 is Asn or Ser
• A13 is Val or lie
• A15 is Ala or Gly
• A18 is Ser or Tyr
• A24 is Gin or His
• A25 is Asp or Glu
• A27 is Met, lie or Nie
• A28 is Ser or Asn
• X is a hydrophobic fail anchored via an amide bond to the N-terminus of the GRF peptide and the hydrophobic tail comprising (i) a backbone of 5 to 9 atoms, wherein the backbone can be substituted by d-e alkyl, C 3 - 6 cycloaikyi, or C 6 -i2 aryl and (ii) at least one rigidifying moiety connected to at least two atoms of the backbone; said moiety is a double bond, triple bond, saturated or unsaturated C 3 -9 cycloaikyi, or C 6 -12 aryl, or a pharmaceutically acceptable salt thereof.
• R is H, CH 3 or CH 2 CH 3 , and the double bond is c/s or trans;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , and wherein when R is CH 3 or CH 2 CH 3> X is in a c/s or trans configuration;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , wherein when R is CH 3 or CH 2 CH 3 , X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or GH 2 CH 3 , wherein when R is CH 3 or CH 2 CH 3 , X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , and wherein when R is CH 3 or CH 2 CH 3 , X is in a c/s or trans configuration;
• R is H, CH 3 or CH 2 CH 3 ;
• R is H, CH 3 or CH 2 CH 3 ;
• R is H, CH 3 or CH 2 CH
• R is H, CH 3 or CH9CH ;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein sai:
• GRF analog is a racemic mixture or a pure enantiomer.
• R is CH 3 and the double bond is trans.
• the above-mentioned A30 is: (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.
• the above-mentioned GRF analog is (hexenoyi trans- 3)hGHRH (1 .44;NH 2 (SEQ ID NO: 16).
• the above-mentioned vascular stenosis is carotid stenosis.
• the above-mentioned vascular stenosis and/or associated condition is atherosclerosis.
• FIG. 1 shows the enrollment and outcomes of the subjects studied
• FIG. 2 shows the effects of (hexenoyi trans-3)hGHRH( -4 4 ) NH 2 versus placebo on A)
• IGF-1 vascular endothelial growth factor-1 ; B) abdominal viscera! adipose tissue (VAT) area; C) carotid intima-media thickness (clMT).
• Panel B demonstrates the difference in VAT between treatment groups with (hexenoyi trans-3 ⁇ hGH RH ( 1 . 4 4 ) NH 2 demonstrating a net -19% improvement in VAT compared to placebo.
• Panel C demonstrates the differences in clMT between treatment groups with (hexenoyi trans-3)hGH RH (1 ⁇ 4) NH 2 demonstrating a net -6% improvement in clMT compared to placebo.
• the "T" bars on panel B and C denote the standard error. Statistical significance was determined by longitudinal linear mixed effects modeling with last value carried forward for both panels B and C.
• the present invention provides a method for preventing or treating vascular stenosis and/or associated conditions in a growth hormone-deficient (GH D) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-reieasing agent.
• GH D growth hormone-deficient
• GH growth hormone
• the present invention provides a method for preventing, or reducing the risk of developing, a condition related to vascular stenosis in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-reieasing agent.
• GDD growth hormone-deficient
• GH growth hormone
• the present invention provides a method for reducing vascular stenosis in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)- releasing agent.
• GDD growth hormone-deficient
• GH growth hormone
• growth hormone (GH)-releasing agent refers to an agent that induces the physiological release and increase in plasma levels of endogenous GH in a subject. It excludes GH itself as well as GH variants, fragments, analogues, nucleic acids encoding GH, GH variants or GH fragments.
• the GH-releasing agent is a GH secretagogue.
• Peptides and compounds which are known to stimulate the release of endogenous growth hormone include the growth hormone releasing peptides, ghrelin, GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,41 1 ,890; International Patent Application Publication No. WO 89/071 10; U.S. Patent No. 5,534,494 and international Patent Application Publication No. WO 89/071 1 1 ), and GHRP-2 (described in International Patent Application Publication No. WO 93/04081 and U.S. Patent No. 5,663,146), as well as hexareiin (J. Endocrinol.
• GH secretagogue compounds include, for example:
• Any iigand or agonist of the Growth Hormone (GH) Secretagogue Receptor e.g., GHS-R1 a
• GHS-R1 a Growth Hormone
• the GH-releasing agent is more specific to the GH axis, and does not significantly affect (increase) appetite, blood glucose and/or Cortisol levels.
• the GH-releasing agent is GRF or a GRF analog.
• GHRH GH-releasing hormone
• Native human GRF is a peptide of 44 amino acids having the following structure: Tyr- Aia-Asp-Aia-lie-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Vai-Leu-Giy-Gin-Leu-Ser-Aia-Arg-Lys-Leu-Leu-
• GRF ( . 29) has the following sequence: Tyr-Ala-Asp-Ala-lle-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Giy-Gin-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-lle-Met-Ser-Arg (SEQ ID NO:3).
• GRF ⁇ 1 _ 2 g ⁇ and GRF (1 ⁇ 4) i.e., having the sequence of GRF (1 . 2 9) a the C-terminus of which 1-14 amino acids are added which correspond to residues 30-43 of native human GRF (or other residues), also possess GRF activity.
• GRF variants having one or more amino acid substitutions in the native sequence are known to possess GRF activity.
• GRF or GRF analog as used in the context of the present invention includes, without limitation, human native GRF (1 -4 4) and fragments (1 -40), (1 -29), fragments ranging between 1-29 and the 1 -44 sequence, and any other fragments; GRF from other species and fragments thereof; GRF variants containing amino acid(s) substitutiori(s), addition(s) and/or deietion(s) such that the amino acid sequence of the variant has at least about 90% of identity with the native amino acid sequence, in an embodiment at least about 95% of identity with the native amino acid sequence.
• the above-mentioned fragments/variants retain at least about 10% of the activity of stimulating GH secretion as compared to the native GRF; derivatives or analogs of GRF or fragments or variants thereof having for example an organic group or a moiety coupled to the GRF amino acid sequence at the N-terminus, the C-terminus or on the side-chain (see, e.g., WO2002/062844, US Patent No. 5,792,747); and salts of GRF (human or from other species), as well as salts of GRF fragments, variants, analogs and derivatives.
• the GRF or GRF analog also encompass the GRF molecules currently known in the art, including, without limitation, albumin-conjugated GRF (U.S.
• Patent No. 7,268,1 13 pegylated GRF peptide (U.S. Patent Nos. 7,256,258 and 6,528,485); porcine GRF (1-40) (U.S. Patent No. 8,551 ,996); canine GRF (U.S. patent application no. 2005/0064554); GRF variants of 1 -29 to 1 -44 amino acid length (U.S. Patent Nos. 5,846,936, 5,696,089, 5,756,458 and 5,416,073, and U.S. patent application Nos. 2006/0128615 and 2004/0192593); and Pro°-GHRH peptide and variants thereof (U.S. Patent No. 5,137,872).
• GRF analogs are also disclosed in PCT publications Nos. WO2004/027064, WO2009/009727, WO201 1/153491 and VVO2012/037519. Pharmaceutically acceptable salts of GRF and GRF analogs are also included.
• the GRF analogs also include those described in U.S. Patent Nos. 5,881 ,379 and 5,939,386, which also describe their method of synthesis. More particularly, these GHRH analogs are defined by the following formula A:
• the GRF peptide is a peptide of formula B:
• A1 is Tyr or His
• A2 is Vai or Ala
• A8 is Asn or Ser
• A13 is Val or lie
• A15 is Ala or Gly
• A18 is Ser or Tyr; A24 is G!n or His;
• A25 is Asp or Glu
• A27 is Met, lie or Nie
• A28 is Ser or Asn
• A30 is absent or is amino acid sequence of 1 up to 15 residues.
• X is a hydrophobic tail anchored via an amide bond to the N-terminus of the GRF peptide and the hydrophobic tail comprising (i) a backbone of 5 to 9 atoms, wherein the backbone can be substituted by C -6 aikyi, C 3 . 6 cyc!oaikyi, or C 6 . 12 aryi and (ii) at least one rigidifying moiety connected to at least two atoms of the backbone; said moiety is a double bond, triple bond, saturated or unsaturated C 3 disturb 9 cycioalkyl, or C 6- 12 aryi, or a pharmaceutically acceptable salt thereof.
• X is:
• R is H, CH 3 or CH2CH 3 , and the double bond is c/s or trans;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , and wherein when R is CH 3 or CH 2 CH 3 , X is in a c/s or trans configuration;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , wherein when R is CH 3 or CH 2 CH 3 , X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein sai: GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or CH 2 CH 3 , wherein when R is CH 3 or CH 2 CH 3 , X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer;
• R is H, CH 3 or GH 2 CH 3 , and wherein when R is CH 3 or GH 2 CH 3 , X is in a cis or trans configuration; (ix) wherein R is H, CH 3 or CH 2 CH
• R is H, CH 3 or CH 2 CH 3 , wherein X is in a c/s or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer.
• A30 is: (a) absent; (b) an amino acid sequence corresponding to positions 30-44 of a natural (e.g., human) GHRH peptide; or (c) the amino acid sequence of (b), having a 1 -14 amino acid deletion from its C-terminus.
• A30 is one of the following amino acid sequences (i) to (xv):
• the hydrophobic tail X is a moiety
• the above-mentioned GRF analog is (hexenoyl trans-3)hGHRH ( 1 - 4 4) NH 2 (SEQ ID NO: 16).
• GRF analogs exhibiting agonist properties toward the GRF recepto are disclosed in PCT application No. PCT/CA2012 050242 and U.S. patent No. 8,361 ,964, These GRF analogs are variants of GRF and active fragments and/or variants thereof, comprising a 3 amino acid residue deletion at positions corresponding to residues 21 to 23 (Lys-Leu-Leu in the sequences depicted above) of the native human GRF (
• the GRF analog of the invention may further comprise an alteration of the serine (Ser) corresponding to position 18, preferably a substitution with Lys, L- Ornithine, L-2,4-diaminobutyric acid or L-2,3-diaminopropionic acid, of the native human GRF ( i. 44), its N-terminal fragment GRF (1 _ 29) , or the intermediate forms noted above.
• Ser serine
• X2 is any amino acid, in an embodiment Aia, D-Ala, Ser, Leu, a-aminoisobutyric acid (Aib), Va! or G!y, in a further embodiment Aia or D-A!a;
• X8 is any amino acid, in an embodiment Asn, Asp, Aia, Gin, Ser or Aib, in a further embodiment Aia or Asp, in a further embodiment Asp;
• X9 is any amino acid, in an embodiment Ser, Asp or Ala, in a further embodiment Ser;
• XI I is any amino acid, in an embodiment Arg or L-Homoarginine, in a further embodiment Arg;
• X12 is any amino acid, in an embodiment Lys, L-Ornithine or L-homoarginine, in a further embodiment Lys or L-homoarginine, in yet a further embodiment Lys;
• X13 is any amino acid, in an embodiment Val or Aia, in a further embodiment Vai;
• X15 is any amino acid, in an embodiment Gly or Aia, in a further embodiment Aia;
• X18 is any amino acid, in an embodiment Lys, L-Ornithine, L-2,4-diaminobutyric acid or
• L-2,3-diaminopropionic acid in a further embodiment Lys or L-Ornithine, in yet a further embodiment Lys;
• X19 is Aia or Leu
• X22 is any amino acid, in an embodiment Asp or Giu, in a further embodiment Asp;
• X23 is any amino acid, in an embodiment lie or Leu, in a further embodiment He;
• X24 is any amino acid, in an embodiment Met, He, Nle or Leu, in a further embodiment Met or Leu, in a further embodiment Leu;
• X25 is any amino acid, in an embodiment Ser, Asn, Aib or Ala, in a further embodiment Ala or Ser, in yet a further embodiment Ala;
• X26 is any amino acid, in an embodiment Arg, D-Arg, L-Homoarginine or Lys, in a further embodiment Arg or D-Arg, in yet a further embodiment Arg;
• X27 is any amino acid, in an embodiment Aia, or is absent;
• X28 is any amino acid, in an embodiment Aia, or is absent;
• X29 is any amino acid, in an embodiment Arg, or is absent;
• X30 is any amino acid, in an embodiment Ala, or is absent;
• X31 is any amino acid, in an embodiment Aia or is absent;
• X32 is any amino acid, in an embodiment Arg, or is absent;
• X33 is any amino acid, in an embodiment HoSer, or is absent;
• Representative domains or GRF analogs of formula I include those having the fo!iowing sequences:
• Such GRF analogs may comprise N- and/or C-terminai modifications.
• the amino- terminal modification may be a C C 6 or C 3 -Ci 6 acyl group (linear or branched, saturated or unsaturated), in a further embodiment, a saturated C.-Ce acyl group (linear or branched) or an unsaturated C 3 -C 6 acyl group (linear or branched), in a further embodiment an acetyl group (CH 3 -CO-, Ac).
• the carboxy-terminal modification may be an amidation, for example with an NH 2 residue.
• GRF analogs include those having the following structure:
• a D-Ala
• 0 L-Ornithine
• Aib ⁇ -aminoisobutyric acid
• r D-Arg
• HoSer L-homoserine
• the term "pharmaceutically acceptable salt” refers to salts of compounds that retain the biological activity of the parent compound, and which are not biologically or otherwise undesirable. Such salts can be prepared in situ during the final isolation and purification of the analog, or may be prepared separately by reacting a free base function with a suitable acid. Many of the GRF analogs disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Acid addition salts may be prepared from inorganic and organic acids.
• Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesuifonate, bisulfate, butyrate, camphorate, camphor sulfonate, decanoate, digiuconate, glycerophosphate, hemisuifate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansuifonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, octanoate, oxalate, palmitoate, pectinate, persulfate, 3-phenyipropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyan
• Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Salts derived from organic acids include acetic acid, propionic acid, giycoiic acid, pyruvic acid, oxalic acid, malic acid, maionic acid, succinic acid, maieic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandeiic acid, meihanesulfonic acid, ethanesuifonic acid, p-toiuene-suifonic acid, salicylic acid, and the like.
• acids which can be employed to form pharmaceuticaliy acceptable acid addition salts include, for example, an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid, and an organic acid, e.g., oxalic acid, maleic acid, succinic acid, and citric acid, in an embodiment, the pharmaceutically acceptable salt is acetate.
• an inorganic acid e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid
• an organic acid e.g., oxalic acid, maleic acid, succinic acid, and citric acid
• the pharmaceutically acceptable salt is acetate.
• Basic addition salts also can be prepared by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• Pharmaceuticaliy acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and nontoxic quaternary ammonia and amine cations including ammonium, tetramethyiammonium, tetraethy!ammonium, methylammonium, dimethylammonium, frimethylammonium, triethylammonium, diethylammonium, and ethylammonium, amongst others.
• organic amines useful for the formation of base addition salts include, for example, ethylenediamirie, ethanolamine, diethanoiamine, piperidine, piperazine, and the like.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.
• the GH-re!easing agent may be formulated in a composition ⁇ e.g., a pharmaceutical composition).
• the composition further comprises one or more pharmaceuticaliy acceptable carriers, excipient, and/or diluents.
• pharmaceutically acceptable refers to materials characterized by the absence of (or limited) toxic or adverse biological effects in vivo. It refers to those compounds, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the biological fluids and/or tissues and/or organs of a subject (e. g., human, animal) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carriers, excipient, and/or diluents refers to additives commonly used in the preparation of pharmaceutical compositions and includes, for example, solvents, dispersion media, saline solutions, surfactants, solubi!izing agents, lubricants, emulsifiers, coatings, antibacterial and antifungal agents, chelating agents, pH- modifiers, soothing agents, buffers, reducing agents, antioxidants, isotonic agents, absorption delaying agents or the like (see, e.g., Rowe et ai , Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6 ,h edition, 2009).
• the GH-releasing agent may be formulated for administration via any conventional route, such as intravenous, oral, transdermal, intraperitoneal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral or topical administration.
• routes such as intravenous, oral, transdermal, intraperitoneal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral or topical administration.
• the preparation of such formulations is well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21 st edition, 2005).
• vascular stenosis refers to any conditions resulting from the narrowing of blood vessels, for example atherosclerosis.
• Atherosclerosis means a condition that is associated with, caused by and/or results from the vascular stenosis (e.g., atherosclerosis).
• Such conditions include, for example, thrombosis, high blood pressure, aortic aneurysm, cerebrovascular disease (e.g., cerebrovascular accident (CVA)), transient ischemic attack (TIA), acute myocardial ischemia, myocardial infarction, stroke, limb ischemia (e.g., critical limb ischemia), arterial disease of lower extremities, arterial occlusive diseases (e.g., peripheral artery occlusive diseases), acute coronary syndromes and angina.
• cerebrovascular disease e.g., cerebrovascular accident (CVA)
• TIA transient ischemic attack
• acute myocardial ischemia myocardial infarction
• stroke e.g., limb ischemia
• limb ischemia e.g., critical limb ischemia
• Acute coronary syndromes can be caused by acute destabilization of atherosclerotic plaques (e.g., plaque rupture) that results in acute myocardial ischemia.
• Acute myocardial ischemia is chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease (also called coronary heart disease).
• the rupture of a soft plaque causes the formation of a blood clot (e.g., thrombus) that will rapidly slow or stop blood flow, e.g. 5 minutes, leading to death of the tissues fed by the artery.
• a common endpoint of coronary thrombosis of a coronary artery is a myocardial infarction (i.e., a heart attack).
• Thrombosis and “thrombosis-related disorder” refer to abnormal thrombus formation that causes obstruction of blood vessels and conditions associated with such obstruction.
• the method is for preventing or treating vascular stenosis.
• the above-mentioned method is for preventing or treating one or more of the following vascular stenosis-related conditions in a GHD subject: thrombosis, high blood pressure, aortic aneurysm, cerebrovascular disease (e.g., cerebrovascular accident (CVA)), transient ischemic attack (TIA), acute myocardial ischemia, myocardial infarction, stroke, limb ischemia (e.g., critical limb ischemia), arterial disease of lower extremities, acute coronary syndromes or angina, in an embodiment, the above-mentioned method is for preventing or treating thrombosis in a GHD subject.
• cerebrovascular disease e.g., cerebrovascular accident (CVA)
• TIA transient
• the above-mentioned method is for preventing or treating high blood pressure in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating aortic aneurysm in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating a cerebrovascular disease (e.g., cerebrovascular accident (CVA)) in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating a transient ischemic attack (TIA) in a GHD subject. In an embodiment, the above-mentioned method is for preventing o treating acute myocardial ischemia in a GHD subject.
• CVA cerebrovascular accident
• TIA transient ischemic attack
• the above-mentioned method is for preventing or treating myocardial infarction in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating a stroke in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating limb ischemia (e.g., critical iimb ischemia) in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating arterial disease of lower extremities in a GHD subject. In an embodiment, the above-mentioned method is for preventing or treating a vascular (arterial) occlusive disease in a GHD subject.
• limb ischemia e.g., critical iimb ischemia
• the above-mentioned method is for preventing or treating acute coronary syndromes in a GHD subject, in an embodiment, the above-mentioned method is for preventing or treating angina in a GHD subject. In an embodiment, the above method is for preventing vascular stenosis and/or associated conditions (e.g., one or more of the conditions noted above). In another embodiment, the above method is for treating vascular stenosis and/or associated conditions (e.g., one or more of the conditions noted above).
• the above-mentioned method comprises, prior to the administration, identifying or selecting a subject suffering from vascular stenosis and/or an associated condition, or at risk of suffering from vascular stenosis and/or an associated condition.
• Indicators of atherosclerosis include, fo example, the development of plaques in the arteries, their calcification, the extent of which can be determined by Sudan IV staining, or the development of foam ceils in arteries.
• the narrowing of the arteries (vascular stenosis) can be determined by coronary angioplasty, uitrafast CT, or ultrasound, for example.
• Subjects suitable for treatment according to the methods described herein include those who a medical practitioner has diagnosed as having one or more symptoms of vascular stenosis or atherosclerosis, and particularly those patients who have had or are at risk of an atherosclerotic disease event. Diagnosis may be done by any suitable means known in the art. Methods for diagnosing atherosclerosis are well known in the art, e.g., by measuring systemic atherosclerotic or inflammatory markers such as C-reactive protein, homocysteine, fibrinogen, lipoprotein (a), IL-6, IL-8, or IL-17.
• systemic atherosclerotic or inflammatory markers such as C-reactive protein, homocysteine, fibrinogen, lipoprotein (a), IL-6, IL-8, or IL-17.
• Diagnosis and monitoring can also employ an electrocardiogram, chest X-ray, cardiac catheterization, ultrasound (for the measurement of vessel wall thickness), or measurement of blood levels of CPK, CPK-MB, myoglobin, troponin, homocysteine, or C-reactive protein.
• a subject is diagnosed using computed tomography to detect calcium in the coronary arteries, which is an indicator of plaque progression.
• a patient at risk of development of a vascular stenosis-related condition may have been subjected to the same tests (electrocardiogram, chest X-ray, etc.) or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors (e.g., family history, hypertension, diabetes meilitus, high cholesterol levels, smoking, etc.).
• risk factors e.g., family history, hypertension, diabetes meilitus, high cholesterol levels, smoking, etc.
• Individuals in risk populations can be monitored more rigorously and treatment of vascular stenosis can be started as soon as alterations in the markers or other physiological symptoms can be detected.
• vascular stenosis such as atherosclerosis does not produce symptoms until it narrows the interior of an artery by more than 70%. Symptoms depend on location of the narrowing or blockage, which can occur almost anywhere in the body. Symptoms occur because as an artery is narrowed, the tissues supplied by the artery may not receive enough blood and oxygen. The first symptom of a narrowing artery may be pain or cramps at times when blood flow cannot keep up with the tissues' need for oxygen. Typically, symptoms develop gradually as the stenosis (e.g., atheroma) slowly narrows an artery. However, sometimes the first symptoms occur suddenly because the blockage occurs suddenly, for example, when a blood clot lodges in an artery narrowed by a stenosis (e.g., atheroma), causing a heart attack or stroke.
• a stenosis e.g., atheroma
• the term "subject" is intended to mean a human or other mammal, exhibiting, or at risk of developing, vascular stenosis (e.g., atherosclerosis) and/or an associated condition, an inflammatory condition or thrombosis.
• vascular stenosis e.g., atherosclerosis
• Such an individual can have, or be at risk of developing, for example, vascular stenosis (e.g., atherosclerosis) associated with conditions such as thrombosis, coronary heart disease, high blood pressure, myocardial infarction, stroke, critical limb ischemia, angina, peripheral artery disease and the like.
• growth hormone-deficient (GHD) subject refers to a subject having a blunted or decreased GH response (e.g., elevation of GH levels in the blood) to stimulation by a GRF or GRF analog, for example GHRH-arginine.
• the decreased GH response is determined by comparison to the GH response (GH levels) measured in one or more control healthy subjects, or relative to a pre-determined control GH response (e.g., pre-determined "threshold" GH levels in the blood).
• the GH deficiency is measured using a GHRH-arginine stimulation test.
• the GHD subject exhibits a peak blood GH value of about 10 ng/mL (10 pg/L) or less. In another embodiment, the GHD subject exhibits a peak blood GH value of about 9 ng/mL (9 pg/L) or less. In another embodiment, the GHD subject exhibits a peak blood GH value of about 8 ng/mL (8 pg/L) or less, in another embodiment, the GHD subject exhibits a peak blood GH value of about 7 ng/mL (7 pg/L) or less.
• the GHD subject exhibits a peak blood GH value of about 6 ng/mL (8 pg/L) or less, in another embodiment, the GHD subject exhibits a peak blood GH value of about 5 ng/mL (5 pg/L) or less, in another embodiment, the GHD subject exhibits a peak blood GH value of 4 about ng/mL (4 pg/L) or less.
• the above-mentioned method furthe comprises identifying an obese subject having GH deficiency, i.e. exhibiting a peak blood GH value according to one or more of the thresholds defined above.
• the term "obese subject” as used herein refers to a subject having a body mass index (BMi) of about 30 kg/m 2 or more, in an embodiment, the obese subject has a BMI of about 31 kg/m 2 or more. In another embodiment, the obese subject has a BMI of about 32 kg/m 2 or more. In another embodiment, the obese subject has a BMI of about 33 kg/m 2 or more. In another embodiment, the obese subject has a BMI of about 34 kg/m 2 or more. In another embodiment, the obese subject has a BMi of about 35 kg/m 2 or more. In another embodiment, the obese subject has a BMI of about 36 kg/rn ⁇ or more.
• BMi body mass index
• the obese subject has a BMI of about 37 kg/m 2 or more. In another embodiment, the obese subject has a B ! of about 38 kg/m 2 or more. In another embodiment, the obese subject has a BMI of about 39 kg/m or more. In another embodiment, the obese subject has a BMI of about 40 kg/m 2 or more. In another embodiment, the subject is a moderately obese (class 1 ⁇ subject having a BMI of about 30 to about 35 kg/m 2 . In another embodiment, the subject is a severely obese (class II) subject having a BMI of about 35 to about 40 kg/m 2 . In another embodiment, the subject is a very severely obese (class III ⁇ subject having a BMI of more than about 40 kg/m .
• the subject has abdominal obesity. In a further embodiment, the subject is a man and has a waist circumference of about 102 cm (about 40 inches) o more. In another embodiment, the subject is a woman and has a waist circumference of about 88 cm (about 35 inches) or more.
• the subject has one or more of the following features/characterisitics: (I) a hemoglobin concentration of about 12 g/dL or more, (ii) Serum Glutamopyruvate Transferase (SGPT) levels less than about 2.5 times normal, (iii) Serum G!utamooxaloacetate Transferase (SGOT) levels less than about 2.5 times normal, and (iv) creatine levels less than about 1 .5 mg/dL In a further embodiment, the subject has all the features (i) to (iv).
• the subject does not exhibit one or more of the following features: 1 ) obesity due to a known secondary cause (Cushing's syndrome, hypothyroidism, etc.) or a history of gastric bypass procedure; 2) known history of diabetes or use of any antidiabetic drugs; 3) use of any weight lowering drugs; 4) use of estrogen, hormone replacement therapy, oral contraceptives, testosterone, glucocorticoids, anabolic steroids, GHRH, GH or IGF-1 within 3 months; 5) changes in lipid lowering or anti-hypertensive regimen within 3 months; 6) chronic illness including HIV, anemia, chronic kidney disease and liver disease; 7) history of malignancy (except surgically cured basal or squamous cell skin cancers) or history of abnormalities on age appropriate malignancy screen including mammography, colonoscopy, positive fecal occult blood testing, and prostate exam or PSA > 5 ng/mi; 8) history of hypopituitarism, pituitary surgery, pitu
• the growth hormone deficiency is not due to hypopituitarism.
• the subject exhibits increased carotid intima-media thickness (cIMT) relative to a healthy control subject, or relative to a cIMT value measured at an earlier time point in the subject, in another embodiment, the subject is at risk of having an increase in carotid intima-media thickness (cIMT).
• cIMT carotid intima-media thickness
• the present invention provides a method for improving or decreasing cIMT in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-reieasing agent.
• GDD growth hormone-deficient
• GH growth hormone
• the decrease is relative to the cIMT measured prior to administration/treatment). In embodiments, the decrease is of about 0.01 mm or more, in a further embodiment about 0.02 mm or more, (e.g. about 0.03 mm or more). In an embodiment, the decrease is of about 0.01 to 0.05 mm, in a further embodiment of about 0.02 to 0.04 mm, (e.g. about 0.03 mm).
• the decrease in cIMT is relative to a subject (e.g., age and/or gender-matched subject) to whom a GH-reieasing agent has not been administered (e.g., a subject treated with a placebo), in embodiments, the decrease in c!MT is of about 0.01 mm or more, in a further embodiment about 0.02 , 0.03 or 0.04 mm or more, relative to a subject (e.g., age and/or gender-matched subject) not administered with a GH-reieasing agent (e.g., administered with a placebo). In an embodiment, the decrease in cIMT is of about 0.01 to 0.07 mm, in further embodiments of about 0.02 to 0.06 mm (e.g.
• the decrease in cIMT is of about 0.003 to 0.09 mm, in further embodiments of about 0.01 to 0.09 mm (e.g. about 0.05 mm), relative to a subject (e.g., age and/or gender-matched subject) not administered with a GH-releasing agent (e.g., administered with a placebo).
• the decrease in cIMT is of at least about 3%, 4%, 5% or 8%, in further embodiment, from about 3% to about 10%, for example from about 4% to about 8% or about 5% to about 7%.
• the present invention provides a method for preventing an increase, over time, in cIMT in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)- releasing agent.
• the prevention of the increase is relative to a subject (e.g., age and/or gender-matched subject) not administered with a GH-reieasing agent (e.g., administered with a placebo).
• cIMT may be measured using methods well known in the art, for example ultrasound- based methods (see, e.g., Stein JH et a/., Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force endorsed by the Society for Vascular Medicine.” J Am Soc Echocardiogr. 2008 Feb;21 (2):93-1 1 1 1 ; quiz 189-90).
• the administration of growth hormone (GH)-releasing agent leads to a significant decrease in certain body composition parameters including abdominal visceral adipose tissue (VAT), waist circumference, trunk fat, and total fat, with no significant change in subcutaneous adipose tissue (SAT) (e.g., abdominal SAT), in the subject.
• VAT abdominal visceral adipose tissue
• SAT subcutaneous adipose tissue
• the administration of growth hormone (GH)-releasing agent prevents the increase in certain body composition parameters including abdominal visceral adipose tissue (VAT), waist circumference, trunk fat, and total fat, with no significant change in subcutaneous adipose tissue (SAT) (e.g., abdominal SAT), in the subject.
• SAT subcutaneous adipose tissue
• the present invention provides a method for:
• VAT abdominal visceral adipose tissue
• SAT subcutaneous adipose tissue
• a growth hormone-deficient (GHD) obese subject comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-releasing agent.
• GH growth hormone
• the present invention provides a method for:
• a growth hormone-deficient (GHD) obese subject comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-reieasing agent.
• GH growth hormone
• the present invention further provides a method for decreasing, and/or preventing the increase of, at least one of the following body composition parameters: abdominal VAT, waist circumference, trunk fat, total fat, and the VAT/SAT ratio, without significantly decreasing SAT (e.g., abdominal SAT), in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-releasing agent.
• the GHD obese subject is a GHD abdominally obese subject.
• the body composition paramete is abdominal VAT or the VAT/SAT ratio.
• the body composition parameter is abdominal VAT.
• the body composition parameter is the VAT/SAT ratio.
• the term "without significantly decreasing SAT" as used herein means that the change in SAT between the subject and a control subject or a group of control subjects not administered with a GH-releasing agent, e.g., administered with a placebo, over a given period of time, is not statistically significant as measured by conventional statistical methods, for example those described in the examples below.
• the decrease in the body composition parameter is an absolute decrease in the subject (i.e. relative to the body composition parameter measured prior to administration/treatment ⁇ .
• the body composition parameter is VAT.
• the decrease in VAT is of about 7 to about 23 cm 2 , for example from about 10 to about 20 cm 2 or from about 15 to about 17 cm 2 (e.g., about 16 cm ), in another embodiment, the body composition parameter is waist circumference (WC).
• the decrease in WC is of about 1 to about 3 cm, for example about 2 cm.
• the decrease in the body composition parameter is a decrease relative to a control subject or a group of control subjects not administered with a GH-releasing agent, e.g., administered with a placebo, over a given period of time.
• the body composition parameter is VAT.
• the decrease in VAT is a decrease of about 15% or more, for example of about 16%, 17%, 18%, 19%, 20% or more relative to a control subject or a group of control subjects.
• the decrease in VAT is a decrease of about 12 cm 2 or more, for example about 35 cm 2 or about 40 cm 2 or more, or a decrease of more than 40 cm 2 relative to a control subject or a group of control subjects.
• the decrease in VAT is a decrease of from about 12 cm 2 to about 58 cm', for example from about 20 cm 2 to about 50 cm 2 , from about 25 cm 2 to about 45 cm 2 , from about 30 cm' to about 40 cm 2 (e.g., about 35 cm 2 ), from about 35 cm 2 to about 58 cm 2 or about 40 cm 2 to about 58 cm', of more than 40 to about 58 cm 2 , relative to a control subject or a group of control subjects, in other embodiments, the decrease in VAT is a decrease of about 2 cm 2 or more relative to a control subject or a group of control subjects.
• the decrease in VAT is a decrease of from about 2 cm' to about 63 cm 2 , for example from about 15 cm' to about 50 cm 2 , from about 25 cm 2 to about 40 cm 2 , from about 28 cm 2 to about 36 cm' (e.g., about 32 cm 2 ), relative to a control subject or a group of control subjects.
• the body composition parameter is waist circumference (WC).
• the decrease in WC is of about 0.3 to about 5 or 6 cm, in further embodiments of about 1 to about 5 cm, about 2 to about 4 cm (e.g., about 3 cm). In an embodiment, the decrease in WC is achieved exclusively on reductions in VAT (abdominal VAT), without any significant reduction in SAT (abdominal SAT).
• the administration of growth hormone (GH)-releasing agent also leads to a significant increase in lean body mass. In other embodiments, the administration of growth hormone (GH)-releasing agent prevents the decrease in lean body mass, in the subject.
• the present invention provides a method for:
• a growth hormone-deficient (GHD) obese subject comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-releasing agent.
• GH growth hormone
• the present invention provides a method for:
• a growth hormone-deficient (GHD) obese subject comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-reieasing agent.
• GH growth hormone
• the present invention furthe provides a method fo increasing, and/or preventing the decrease of lean body mass, in a growth hormone-deficient (GHD) obese subject, the method comprising administering to a subject in need thereof an effective amount of a growth hormone (GH)-releasing agent.
• GHD obese subject is a GHD abdominally obese subject.
• the administration of growth hormone (GH)-releasing agent leads to a significant decrease in certain biochemical parameters including triglycerides and C-reactive protein (CRP) in the subject.
• the above-mentioned methods further comprise decreasing, and/or preventing the increase of, triglycerides and/or C-reactive protein levels in the subject.
• the decrease in triglycerides and/or iogC P is relative to the levels measured in the subject prior to administration of the GH-releasing agent.
• the decrease in triglycerides is of about 10 to about 42 mg/dL, for example of about 15 to about 37 mg/dL or about 20 to about 32 mg/dL (e.g., about 26 mg/dL).
• the decrease in CRP determined based on the log-transformed value of C- reactive protein concentration in serum, IogCRP, is of about 0.13 to about 0.21 , for example of about 0.15 to about 0.19 (e.g., about 0.17).
• the decrease is relative to a control subject or a group of control subjects (e.g., aged and/or gender-matched) not administered with a GH-reieasing agent, e.g., administered with a placebo, over a given period of time.
• the decrease in triglycerides is of about 10 to about 30%, for example from about 15 to about 25%, about 17% to about 23% (e.g., about 20%), relative to a control subject or a group of control subjects.
• the decrease in triglycerides is of about 5 to about 67 to 80 mg/dL, for example of about 20 to about 55-60 mg/dL, about 30 to about 45 mg/dL or about 35 to about 40 mg/dL (e.g., about 37 mg/dL), relative to a control subject or a group of control subjects.
• the decrease in logCRP Is of about 10 to about 35%, for example from about 15 to about 30%, about 20% to about 28% (e.g., about 24%), relative to a control subject or a group of control subjects.
• the decrease in logCRP is of about 0.01 to about 0.30, for example of about 0.1 to about 0.2, about 0.13 to about 0.17 (e.g., about 0.15), relative to a control subject or a group of control subjects.
• the above-mentioned administration/treatment results in an increase in IGF-1 levels
• the increase in IGF-1 levels is relative to the levels measured in the subject prior to administration of the GH-releasing agent.
• the increase in IGF-1 levels is of about 60 to about 1 10 g/L, in embodiments of about 65 to about 107 g/L, about 75 to about 100 pg/L, about 80 to about 95 g/L or about 80 to about 90 g/L (e.g. about 86 g/L).
• the increase is relative to a control subject or a group of control subjects (e.g., aged and/or gender-matched) not administered with a GH- releasing agent, e.g., administered with a placebo, over a given period of time.
• a GH- releasing agent e.g., administered with a placebo
• the increase in IGF-1 levels of about 52-54 to about 157 g/L, for example 52 to 132 g/L, in embodiments of about 70 to about 120 g/L, about 80 to about 1 10 g/L, about 92 to about 105 pg/L.
• the administration/treatment is associated with no significant change in blood glucose control in the subject.
• no significant change in blood glucose control means that (i) the difference in blood glucose levels (as measured by conventional assays, e.g.
• a control subject or a group of control subjects to whom a GH-releasing agent has not been administered is not statistically significant as measured by conventional statistical methods, for example those described in the examples below; and/or (ii) that the administration/treatment is not associated with a statistically significant increase (relative to no treatment or placebo) in the frequency of patients developing conditions related to impaired glucose control such as insulin resistance, glucose intolerance and/or diabetes (i.e. no clinically significant effects).
• treatment o "treating” as used herein, is defined as the application or administration of the above-mentioned GH-re!easing agent or a composition comprising same to a subject, or application or administration of the above-mentioned GH-releasing agent or a composition comprising same to an isolated tissue or ceil line from a subject, who has a disorder, a disease, a symptom of disorder or disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, reduce the progression or affect the disorder/disease and/or the symptoms of disorder/disease.
• prevention is defined as the application or administration of the above-mentioned GH-releasing agent or a composition comprising same to a subject, or application or administration of the above-mentioned GH-reieasing agent or a composition comprising same to an isolated tissue or cell line from a subject, who has a predisposition toward a disorder/disease or who is at risk of developing the disorder/disease, with the purpose to prevent o delay the onset of the disease/disorder or of the symptoms, or reduce the severity of the disease/disorder or of the symptoms, when administered prior to the onset/appearance of the disease/disorder or of the symptoms.
• an “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired biological activity and/or the prophylactic/therapeutic result (e.g., prevention and/or treatment of the diseases/disorders noted above).
• a “therapeutically effective amount” refers to an effective amount in the context of therapy; a “prophylacticaily effective amount” refers to an effective amount in the context of prophylaxis.
• An effective amount of a compound of the invention 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 prophylactic/therapeutic response.
• an effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the prophylactic/therapeutic beneficial effects.
• specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
• the GH-releasing agent is administered at a daily dose of about 0.01 mg to about 30 mg, in a further embodiment of about 0.1 mg to about 20 or 25 mg, in a further embodiment of about 0.5 mg to about 20 mg, in a further embodiment at a daily dose of about 1 mg to about 20 mg, for example at a dose of about 1 to about 2 mg (e.g., 1 mg, 1.5 mg or 2 mg).
• the GH-releasing agent or composition comprising same may be administered, or may be for administration, by any conventional route, such as intravenous, oral, transdermal, intraperitoneal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral or topical.
• the GRF analog or pharmaceutically acceptable salt thereof is administered or is for administration by a subcutaneous route.
• the GH- releasing agent or composition comprising same is administered or is for administration by a transdermal route (e.g., using transdermal delivery systems such as transdermal patches).
• the present invention provides a transdermal delivery system, such as a transdermal patch, comprising the above-mentioned GH-reieasing agent or composition comprising same.
• a transdermal delivery system such as a transdermal patch
• Methods and systems for transdermal delivery are well known in the art and are described, for example, in Transdermal Drug Delivery, Second Edition, Marcel Dekker Inc., New York, 2003 and Transdermal and Topical Drug Delivery, Adrian C Williams, Pharmaceutical Press, 2003.
• the GH-releasing agent or composition comprising same is administered or is for administration by the oral route.
• the GH-re!easing agent or composition comprising same is administered or is for administration by a nasal route.
• the above-mentioned prevention and/or treatment comprises administration of the above-mentioned GH ⁇ releasing agent or composition comprising same, in combination with one or more additional active/therapeutic agents.
• the combination of prophylactic/therapeutic agents and/or compositions may be administered or co-administered (e.g. , consecutively, simultaneously, at different times) in any conventional dosage form.
• Co- administration in the context of the present invention refers to the administration of more than one therapeutic in the course of a coordinated treatment to achieve an improved clinical outcome.
• Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
• a first agent may be administered to a patient before, concomitantly, before and after, or after a second active agent is administered.
• the agents may in an embodiment be combined/formulated in a single composition and thus administered at the same time.
• the one or more active agent(s) of the present invention is used/administered in combination with one or more agent(s) currently used to prevent or treat the disorder in question.
• the GH-releasing agent or composition comprising same may be used in combination with drugs used in the treatment of vascular stenosis such as atherosclerosis and associated conditions including anti-atherosclerosis drugs, anti-thrombosis drugs, anti-inflammatory drugs, ACE Inhibitors, cholesterol lowering drugs (e.g., statins), drugs used in the prevention or treatment of cardiovascular diseases such as peripheral antiadrenergic drugs, antihypertensive drugs, drugs affecting renin-angiotensin system, antianginal drugs, cardiac glycosides, inodilators (e.g., aminone, milrinone, enoximone, fenoximone, imazodan, sulmazole), antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, and rezulin.
• drugs used in the treatment of vascular stenosis such as atherosclerosis and associated conditions including anti-atherosclerosis drugs, anti-thrombosis drugs, anti-inflammatory drugs, ACE In
• the above-mentioned administration/treatment is for a period of at least 3 months, in further embodiment of at least 8 months, 9 months or 12 months.
• Eligibility criteria were: 1 ) 18-55 year old men and women; 2) B I 30 kg/m 2 ; 3) waist circumference 102 cm (men) and 88 cm (women): 4) peak stimulated GH ⁇ 9 g/L on standardized GH releasing hormone (GHRH)-arginine stimulation test; 5) hemoglobin >12.0 g/dL, SGOT and SGPT ⁇ 2,5 times normal, and creatinine ⁇ 1.5 mg/dL.
• GHRH GH releasing hormone
• Exclusion criteria for the study were: 1 ⁇ obesity due to a known secondary cause (Cushing's syndrome, hypothyroidism, etc.) or a history of gastric bypass procedure; 2) known history of diabetes or use of any anti-diabetic drugs; 3) current use of any weight lowering drugs; 4 ⁇ use of estrogen, hormone replacement therapy, oral contraceptives, testosterone, glucocorticoids, anabolic steroids, GHRH, GH or IGF-1 within 3 months of enrollment; 5 ⁇ changes in lipid lowering or anti-hypertensive regimen within 3 months of screening; 8 ⁇ chronic illness including HIV, anemia, chronic kidney disease and liver disease; 7) history of malignancy (except surgically cured basal or squamous cell skin cancers) or history of abnormalities on age appropriate malignancy screen including mammography, colonoscopy, positive fecal occult blood testing, and prostate exam or PSA > 5 ng/m!; 8) history of hypopituitarism, pituitary surgery, pituitary
• Subjects were randomized in a 1 :1 fashion to receive 2 mg of the GRF analog (hexenoyl trans-3)hGHRH ⁇ . 4) NH 2 or matching placebo.
• (Hexenoyi trans-3)hGHRH ⁇ 1 .4 4) NH 2 and matching placebo were supplied as a iyophiiized powder and subjects were trained to reconstitute and self-inject the medication subcutaneously daily for one year. The randomization was stratified by gender. Investigators and subjects were blinded to the treatment randomization. Assessment for the primary end point of abdominal VAT and CVD risk factors were performed at baseline, 28 weeks and 52 weeks. Safety parameters including fasting glucose and IGF-1 were also measured at 2 weeks, 4 weeks, 12 weeks and 36 weeks.
• Standardized GHRH-arginine stimulation testing was performed after an overnight fast.
• VAT Abdominal visceral
• SAT subcutaneous adipose tissue
• cIMT Carotid Intima-Media Thickness
• cIMT was measured via ultrasound as previously described (Chan R, et a/., Computers in Cardiology 2000:27:37-40; Makimura H, et al.. J Clin Endocrinol Metab 2009;94:5131 -8). The average cIMT over the length of the measured segments on the right carotid artery is reported.
• Body composition was assessed by dual energy x-ray absorptiometry (DXA, previously
• GH was assessed using a chemi!uminescent immunoassay (Beckman Coulter ⁇ . IGF-1 was measured using the ImmuliteTM 2000 automated immuno-analyzer (Siemens Diagnostics). Lipid profile, glucose and high sensitivity CRP were assessed at the Massachusetts General Hospital (MGH) laboratory using standard methods (Falutz J, et a/., 2007 N Engl J Med 357:2359-2370; Falutz J et a!., 2010 J Acquir Immune Deft Syndr 53:31 1 -322). Compliance:
• Adherence to the study drug was monitored via subject self-reported injection log, as well as a vial count of returned vials at each visit.
• Baseline variables were compared by chi-square test for non-continuous variables, t-test for continuous variables that were normally distributed and Wilcoxon's rank sum test for continuous variables that were not normally distributed.
• Efficacy end points were analyzed using longitudinal linear mixed effects modeling with all available data and the last value carried forward for patients who discontinued and had missing data.
• a secondary analysis was performed using longitudinal linear mixed effects modeling with all available data, without carry forward.
• the reported treatment effect represents estimated differences between (hexenoyl trans-3)hGHRH ( i_44)NH2 and placebo treatment over 12 months in the model.
• the P value was determined from the time x randomization effect in the model.
• Statistical analyses were performed using SAS and J MP 9.0 (SAS Institute). Ail reported P values are two-sided.
• Table 1 Demographic and baseline clinical characteristics of the patients enrolled in the study stratified by treatment group.
• Non-continuous variables are compared using ⁇ 2 test. Results are presented as the mean ⁇ SEM for normally distributed data and analyzed by Student's t-test. For data that is not normally distributed, results are presented as median with interquartile range (25%, 75%) and analyzed using the Wilcoxon rank sum test.
• Medication use includes baseline data as well as initiation of new medications during the course of the study.
• ⁇ Llpid lowering medication use includes subjects using HMG Co-A reductase inhibitors, niacin and fish oil.
• HMG Co-A 3-hydroxy-3-methyl-glutaryl-CoA reductase
• VAT abdominal viscera! adipose tissue area (measured via abdominal computed tomography (CT) scan);
• GH Growth hormone
• GHRH Growth hormone releasing hormone
• IGF-1 insulin-like growth factor-1 .
• Body Composition
• trans-3)hGHRH ( i-44 ) NH 2 increased IGF-1 by 90% and decreased triglycerides by 20% and logCRP by 24% compared to placebo.
• (Hexenoy! trans-3)hGHRH (1 . 44 ⁇ H 2 did not affect total cholesterol, HDL or LDL cholesterol (Table 2). Dietary and Physical Activity Measurements:
• Trunk fat (kg) 23.3+1.3 23.3+1.1 0.53 22.5+1.5 23.5 ⁇ 1.4 22.6 ⁇ 1.7 23.3+2.0
• VAT visceral abdominal adipose tissue area
• SAT SAT
• BSVI! body mass Index
• ALT alanine aminotransferase
• GRF (hexenoyi
• Table 4 Effect of treatment with (hexenoyi irans-3)hGHRH ⁇ 1 , 4 4,NH 2 versus placebo on dietary parameters as assessed by 4-day food record.
• Results are presented as mean + SEM.
• P value from baseline data are obtained by Student ' s t-test for normally distributed variables and VVilcoxon rank sum for non-normally distributed samples.
• Effects size and P values for overall effect was obtained by longitudinal linear mixed effects modeling for each parameter over 12 months.
• TabUe 8 Effect of treatment with (hexenoyl trans-3)hGHRH(i_44 ) NH 2 versus placebo on physical activity as assessed by modified activity questionnaire.

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• 2013
  • 2013-06-21 WO PCT/IB2013/055118 patent/WO2013190520A2/fr not_active Ceased

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