WO2006133477A1 - Peptides correspondant à l'hormone de croissance humaine - Google Patents

Peptides correspondant à l'hormone de croissance humaine Download PDF

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WO2006133477A1
WO2006133477A1 PCT/AU2005/000828 AU2005000828W WO2006133477A1 WO 2006133477 A1 WO2006133477 A1 WO 2006133477A1 AU 2005000828 W AU2005000828 W AU 2005000828W WO 2006133477 A1 WO2006133477 A1 WO 2006133477A1
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Prior art keywords
peptide
vai
giy
ser
leu arg
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Chris Belyea
Gary Allen Wittert
Caroline Herd
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Metabolic Pharmaceuticals Pty Ltd
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Metabolic Pharmaceuticals Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • This invention relates to peptides corresponding to human growth hormone (hGH) , and more particularly to peptides corresponding to hGH 177-191 and subfragments and analogues thereof .
  • hGH human growth hormone
  • Obesity is an escalating international health problem, and is associated with increased mortality and morbidity risk.
  • Conventional non-pharmacological treatments, based on diet and exercise, are frequently ineffective in promoting sustained weight loss . Consequently, there is a need for pharmacological therapy as an adjunct to diet and lifestyle changes in order to achieve and maintain weight loss .
  • hGH human Growth hormone
  • hGH-deficient state stimulates catecholamine-induced lipolysis in adipose tissue, reduces- fat mass, and increases lean body mass.
  • Pharmacological doses of hGH ( ⁇ 25 ⁇ g/kg/day) have limitations as an obesity treatment as the prolonged use of hGH may be associated with insulin resistance, glucose intolerance, oedema and increases in insulin-like growth factor 1 (IGF- 1) . Prolonged increases in IGF-I may have a range of undesirable effects including an increase in cancer risk.
  • hGH 177-191 synthetic peptide corresponding to amino acid residues 177-191 of the human growth hormone sequence
  • the peptide also enhances lipolysis in human, pig, mouse and rat adipose tissue ex vivo, and increases fat oxidation in obese mice in vivo. Additionally, the peptide increases the expression of ⁇ 3 - ARs in mouse and human cell lines in vitro, and in the adipose tissue of obese mice ex vivo.
  • PCT/AU98/00724 by Metabolic Pharmaceuticals Ltd, discloses analogues of the hGH177-191 peptide which share this activity.
  • PCT/AUOO/01362 (WO01/33977) , discloses the surprising oral activity of all such peptides. The entire disclosures of AU693478,
  • PCT/AU98/00724 and PCT/AUO ⁇ /01362 are incorporated herein by this reference.
  • Peptides corresponding to hGH 177-191 and analogues and subfragments thereof are currently undergoing studies in humans to determine safety, tolerability, weight loss and fat effects.
  • the present invention in a first aspect provides the use of a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone, in a method of modulating lipid metabolism in a human, which method comprises administering the peptide orally to the human at a dose of 0.01-2 mg per day
  • a non-linear dose response to AOD9604 treatment was expected from in vivo and in vitro animal experiments, which show an effective rodent dose of 0.125 to 0.5 mg/kg at the centre of a bell-shaped dose response curve.
  • a 30 mg dose in a 100 kg human is equivalent to 0.3 mg/kg and this was expected to be the most effective dose in humans for promoting lipid metabolism.
  • human trials involving administering 0 (placebo), 1, 5, 10, 20 and 30 mg of an hGH 177-191 analogue indicate that the best activity of the peptide in promoting weight reduction is 1 mg per day.
  • in vitro measurements in our laboratory conducted to understand the activity of the peptide at low dose have revealed a bimodal concentration response, with an unexpected low concentration bell shape equimolar with human growth hormone .
  • the invention provides a dosage unit for use in the first aspect of the invention, the dosage unit comprising 0.01 - 2mg of a peptide corresponding to human growth hormone (hGH) 177- 191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone .
  • hGH human growth hormone
  • the invention provides a method of reducing body weight comprising administering to a human in need thereof an effective amount of a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone, wherein the peptide is administered at a dose of 0.01 - 2 mg per day.
  • the method of the third aspect of the invention is performed simultaneously with calorie restriction, at least for an initial period. This serves to optimise the reduction of body weight provided by the method of the third aspect of the invention, as compared to placebo.
  • Calorie restriction may be achieved by a lifestyle modification program, or by additional pharmacological intervention with an appetite suppressant or digestion inhibitor.
  • the invention provides a kit for optimising the reduction of body weight compared to placebo, the kit comprising a peptide corresponding to hGH 177-191 for administering orally at a dose of 0.01 - 2 mg per day, together with information on lifestyle modification capable of enhancing the effect of the peptide in weight reduction.
  • the invention provides the use of a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone, in the treatment of glucose intolerance, or in a method of improving lipid profiles in an animal .
  • hGH human growth hormone
  • the invention provides a method of treating glucose intolerance in an animal, the method comprising administering to the animal an effective amount of a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone.
  • hGH human growth hormone
  • the present invention provides a pharmaceutical formulation for use in treating glucose intolerance in an animal, which formulation comprises a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone a pharmaceutically acceptable carrier.
  • hGH human growth hormone
  • the invention provides a method of improving lipid profiles in an animal, the method comprising administering to the animal an effective amount of a peptide corresponding to human growth hormone (hGH) 177-191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone.
  • hGH human growth hormone
  • the present invention provides a pharmaceutical formulation for use in improving lipid profiles in an animal, which formulation comprises a peptide corresponding to human growth hormone (hGH) 177- 191 or a lipid metabolising subfragment or analogue thereof containing a disulphide bond, with the proviso that the peptide is not intact, full length growth hormone a pharmaceutically acceptable carrier.
  • hGH human growth hormone
  • the use of the fifth aspect, the method of the sixth aspect or the formulation of the seventh aspect may be used to treat or prevent any disorder involving glucose intolerance. Such disorders include diabetes and metabolic syndrome.
  • the use of the fifth aspect, the method of the eighth aspect or the formulation of the ninth aspect may be used to treat or prevent any disorder involving abnormal lipid profiles. Such disorders include hypercholesteraemia and metabolic syndrome.
  • Figure 1 shows a graph plotting weight change (- SEM) over 12 weeks of treatment with AOD 9604 (ITT population, no data imputed) . Difference in adjusted means is from the general linear model adjusting for effects of gender, centre, age and weight before active treatment. * P ⁇ 0.05 (Dunnett's multiple comparisons procedure) , statistically significant for 1 mg AOD9604 female subgroup.
  • Figure 2 shows a graph plotting mean change (-
  • Figure 3 shows a graph plotting changes in lipid profiles in the placebo and AOD9604 treatment groups.
  • Figure 4 shows a graph plotting mean weight change after 12 weeks of treatment for patients who complied or did not comply with diet and lifestyle advice (ITT population, no data imputed) .
  • Compliers were defined as patients who lost > 0 kg in the 2 week placebo run-in period. * P ⁇ 0.05 (Dunnett's multiple comparisons procedure) .
  • Figure 5 shows a graph plotting anthropomorphic measurements of total abdominal fat (mean % change - SEM) after 12 weeks of treatment with AOD9604 (ITT population, no data imputed) . Difference in adjusted means is from the general linear model adjusting for the effects of gender, centre, age and pre-treatment value. * P ⁇ 0.05 (Dunnett's multiple comparisons procedure) .
  • Figure 6 is a graph showing subcutaneous and visceral fat loss for all treatment groups after 12 weeks of treatment with AOD9604 (ITT population, no data imputed) . Difference in adjusted means is from the general linear model adjusting for the effects of gender, centre, age and pre-treatment value. * P ⁇ 0.01 (Dunnett's multiple comparisons procedure) .
  • Figure 8 shows the number of patients diagnosed as diabetic after the trial treatment (non were diagnosed as diabetic before the treatment period as it was an exclusion criterion) .
  • Figure 9 the change in the incidence of IGT or diabetes from prior to trial treatment to the end of the trial treatment .
  • Tyr-hGH 177-191 In terms of molar amounts, 1 mg of orally dosed Tyr-hGH 177-191 is equivalent to 4 mg of injected human growth hormone, assuming 40% oral availability. This is a typical high level hGH dose in humans, not nowadays given but clearly effective on fat loss . Accordingly the in vitro effect of Tyr-hGH 177-191 which may correspond to this should occur at concentrations roughly equimolar with hGH.
  • the inventors Since the clinical trails results were obtained the inventors have been exploring the 1 nM region and initial experiments have confirmed that around 1 - 10 nM there is a substantial peak in lipolysis from both fat tissue and cultured fat cells, disappearing or flattening at 10 - 100 nM and rising again to 500 - 1000 Nm.
  • the 1 - 10 nM region also corresponds to peaks in relevant intracellular signalling.
  • the inventors therefore propose that 1 mg is near the peak of a bell-shaped effect which is probably the genuine equivalent of hGH effects previously observed in humans. This may involve restoration of adrenaline receptor number in subcutaneous fat tissue, restoring the lipolytic response of that depot to low insulin levels caused by fasting and/or to endogenous adrenaline. 5 mg and 10 mg are well above the top of the peak. Optimal activity in the sub microgram region, being molar equivalent with the highest doses of hGH administered to humans is clearly possible.
  • the inventors also propose that the high dose effect rising at 20 and 30 mg particularly in males may correspond to the direct higher concentration antilipogenic and lipolytic effects observed in fat and the liver. At these higher doses any beneficial effect in non-abdominal fat tissue may disappear or reverse.
  • the preferred dose for weight reduction is the peak of the dose response curve between 0.01 and 2.00 mg. This is expected to be in the region of 0.05-1.50 mg, preferably 0.25-1.25 mg, more preferably 0.25-0.75 mg and most preferably 0.25-0.50 mg.
  • the dose is 0.01, 0.02, 0.03, 0.04,
  • the dose of 0.01 to 2.00 mg is more effective in reducing body weight than higher doses and is active in both genders. Accordingly such a low dose may be used beneficially in methods of promoting weight loss, or overall reduction of body fat.
  • the use of the first aspect, the dosage unit of the second aspect, the method of the third aspect or kit of the fourth aspect of the invention maybe used to treat obesity. Such treatment may also be used to alleviate or prevent conditions related to obesity.
  • "Obesity” refers to a condition whereby a mammal has a Body Mass Index (BMI) , which is calculated as weight (kg) per height. sup.2 (meters), of at least 25.9. Conventionally, those persons with normal weight have a BMI of 19.9 to less than 25.9.
  • BMI Body Mass Index
  • the obesity herein may be due to any cause, whether genetic or environmental.
  • Constants related to obesity refer to conditions which are the result of or which are exasperated by obesity, such as, but not limited to dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary (or cardiovascular) heart disease, particular those cardiovascular conditions associated with high triglycerides and free fatty acids in an individual .
  • dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema
  • exercise intolerance diabetes mellitus
  • insulin resistance hypertension
  • hypercholesterolemia cholelithiasis
  • osteoarthritis orthopedic injury
  • thromboembolic disease cancer
  • coronary (or cardiovascular) heart disease particular those cardiovascular conditions associated with high triglycerides and free fatty
  • the low dose has particular effect in reducing abdominal fat and subcutaneous fat the low dose may be used beneficially in methods of promoting loss of abdominal fat and loss of subcutaneous fat and particularly in the treatment of obesity.
  • the low dose may be used to prevent the risk of heart disease in obese animals with increased abdominal fat.
  • the effect of the peptide in promoting weight loss and modulating lipid metabolism being optimised when the peptide is administered to a subject undergoing calorie restriction was identified by analysing two subgroups of patients in the clinical trial; those who lost weight in the two week placebo run-in period (where all patients received placebo) ("the lifestyle compilers"), and those who did not ("lifestyle non- compliers") . It was found that all of the drug effect is found in the lifestyle compiler group, where the weight loss at the 1 mg dose was 4.2 kg compared to placebo, a highly significant difference and a large difference compared to existing treatments and compared to the group as a whole (2.0 kg) .
  • This synergistic interaction of the peptide with calorie restriction, preferably by lifestyle modification was unexpected and is unlike that observed with previous obesity drugs.
  • hGH in an obese state or in a hGH-deficient state has been shown to stimulate catecholamine-induced lipolysis in adipose tissue, reduce fat mass and increase lean body mass .
  • the prolonged use of hGH may be associated with insulin resistance, glucose intolerance, oedema possibly associated with increases in insulin-like growth factor 1 (IGF-I) .
  • IGF-I insulin-like growth factor 1
  • the clinical trial undertaken included measurement of glucose levels during an oral glucose tolerance test to determine if peptides corresponding to the hGH C-terminus had the same effect on glucose control as hGH. The results indicated that treatment with Tyr-hGH
  • Tyr- hGH 177-191 does not worsen glucose control or induce insulin resistance.
  • administration of Tyr- hGH 177-191 caused a reduction in patients with impaired glucose tolerance (ITT) and reduced the risk of onset of diabetes as compared to the placebo group.
  • peptides corresponding to human growth hormone (hGH) 177-191 or lipid metabolising subfragments or analogues thereof are capable of controlling glucose metabolism and therefore may be used in the treatment of any disorder involving impaired glucose tolerance, such as metabolic syndrome or diabetes.
  • the inventors also propose that peptides corresponding to human growth hormone (hGH) 177-191 or lipid metabolising subfragments or analogues may be useful in preventing the onset of diabetes.
  • Impaired glucose tolerance refers to a condition that is midway between normal and diabetic. Blood sugar levels on certain tests are higher than normal , but not quite high enough to say the person has diabetes. People with this condition are at higher than average risk for developing diabetes, heart attack, and strokes .
  • Impaired Fasting Glucose IGF
  • Impaired Glucose Tolerance IGT
  • IGT Impaired Fasting Glucose
  • ITT Impaired Glucose Tolerance
  • Impaired Glucose Tolerance ITT is diagnosed when the glucose level is 141 to 199 mg/dL
  • Metabolic syndrome is a common condition that goes by many names (dysmetabolic syndrome, syndrome X, insulin resistance syndrome, obesity syndrome, and
  • Reaven's syndrome It is a set of risk factors that includes: abdominal obesity, a decreased ability to process glucose (insulin resistance) , dyslipidemia
  • Metabolic syndrome is commonly defined as involving three or more of the following: * Central/abdominal obesity as measured by waist circumference [Men - Greater than 40 inches (102 cm) ;
  • prothrombotic blood clotting
  • proinflammatory blood clotting
  • Insulin resistance has a negative effect on lipid production, increasing VLDL (very low-density lipoprotein) , LDL (low-density lipoprotein - the "bad” cholesterol) , and triglyceride levels in the bloodstream and decreasing HDL (high-density lipoprotein - the "good” cholesterol) .
  • VLDL very low-density lipoprotein
  • LDL low-density lipoprotein - the "bad” cholesterol
  • HDL high-density lipoprotein - the "good” cholesterol
  • Insulin resistance also leads to increased insulin and glucose levels in the blood. Excess insulin increases sodium retention by the kidneys, which increases blood pressure and can lead to hypertension. Chronically elevated glucose levels in turn damage blood vessels and organs, such as the kidneys, and may lead to diabetes.
  • Diabetes as used herein encompasses type I, type II and gestational diabetes. Diabetes is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels) , especially after eating. All types of diabetes mellitus share similar symptoms and complications at advanced stages. Hyperglycemia itself can lead to dehydration and ketoacidosis.
  • cardiovascular disease doubled risk
  • chronic renal failure it is the main cause for dialysis
  • retinal damage with eventual blindness
  • nerve damage and and eventual gangrene with probable loss of toes, feet, and even legs in amputation.
  • Diabetes is characterized by either: an inability of the pancreas to produce insulin (type 1 or insulin- dependent diabetes mellitus) or an inability of insulin to exert its normal physiological actions (type 2 or non- insulin dependent diabetes) .
  • GDM Gestational diabetes mellitus
  • C-terminal growth hormone fragment refers to the C-terminal amino acid sequence of growth hormone.
  • Such a peptide is termed a "C-terminal growth hormone fragment.”
  • C-terminal growth hormone fragment is to be understood to mean a peptide fragment from the carboxy-terminal region of the amino acid sequence of a mammalian growth hormone which is able to reduce lipogenic activity; and, or to stimulate lipolysis.
  • peptide as used herein means any chain of amino acids from 2 to 50 amino acid residues in length, preferably 2 to 20, more preferably about 15 amino acid residues in length. Accordingly the term peptide as used herein also encompasses polypeptides and may be used interchangeably therewith. The only proviso is that any peptide for use in accordance with the present invention does not have the full length sequence of human growth hormone or an analogue thereof from another species and does not modulate IGF-I. Full length growth hormone is capable of modulating lipid metabolism but also modulates IGF-I.
  • the amino acids may include synthetic modifications or the peptide bonds may be modified to enhance stability and/or activity, according to the many methods known in the art .
  • the peptides used in accordance with the present invention have the ability to stimulate the activity of hormone-sensitive lipase, a key enzyme in lipolysis, and/or to inhibit acetyl CoA carboxylase, a key enzyme in lipogenesis.
  • the invention also encompasses the use of peptides which are functional analogues of the native carboxy-terminal sequences of mammalian growth hormones, in that the analogue peptide is capable of modulating lipid metabolism without an appreciable effect on IGF-I.
  • analogues may be derived from natural sources, produced by recombinant DNA technology, or synthesised using conventional peptide synthetic methods. Such peptides synthetic methods are to be understood to include combinatorial methods .
  • Such analogues include a disulphide bond which confers a cyclic configuration on the peptide.
  • all of the active peptides disclosed in AU 693478 and PCT/AU98/00724 are to be understood to be within the scope of this invention, for example :
  • amino acid residue abbreviations used are in accordance with the standard peptide nomenclature:
  • All amino acids, except for glycine, are of the L-absolute configuration, unless indicated as D-absolute configuration. All the above peptides above have a cyclic disulfide bond between Cys(182) and Cys(189) or Pen (182) and Pen (189) as appropriate.
  • the peptides comprises amino acids 182-189 (hGH 182-189) , more preferably amino acids 177-191 of human growth hormone (hGH 177-191) .
  • the peptide is the human growth hormone analogue AOD9604 (Tyr-hGH 177-191) .
  • the invention is also applicable to peptides corresponding to the amino acid sequences of growth hormones of other mammalian species, including but not limited to those of domestic mammals such as cattle, sheep, pigs and horses, companion animals such as cats and dogs, and zoo animals including felids, canids, and non- human primates.
  • Peptides may also be conjugated to a fusion partner to enable easier biosynthesis and/or delivery. They may be incorporated in conventional pharmaceutical compositions, or may be present in a genetically-modified food, such as disclosed in WO 01/33997. The peptides may be administered in pharmaceutical compositions together with a pharmaceutically acceptable carrier for administration.
  • the peptides are preferably administered orally at a dose of 0.01 to 60.00 mg.
  • the animal may be a human, or may be a domestic or companion animal . While it is particularly contemplated that the present invention is used in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as non-human primates, felids, canids, bovids, and ungulates.
  • companion animals such as dogs and cats
  • domestic animals such as horses, cattle and sheep
  • zoo animals such as non-human primates, felids, canids, bovids, and ungulates.
  • the mammal is a human.
  • the human may be a child or an adult .
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent, excipient or vehicle for delivering the growth hormone fragment and/or pharmaceutically-active agent to the subject.
  • the carrier or diluent, and other excipients will depend on the route of administration, and again the person skilled in the art will readily be able to determine the most suitable formulation for each particular case.
  • Analogues of the peptides described herein are included within the scope of the invention, provided that they are functionally active.
  • the terms "functionally active” and “functional activity” in reference to an analogue means that analogue is capable of (or has ability for) modulating lipid metabolism without having an appreciable effect on IGF-I.
  • Analogues as used herein includes amino acid sequence variants of the peptide amino acid sequences provided. Sequence variants include deletions, insertions or substitutions of amino acid residues within the growth hormone fragment amino acid sequence set out above . Any combination of deletion, insertion, and substitution may be made to arrive at an amino acid sequence variant of the growth hormone fragment, provided that the variant possesses the desired functional characteristics described herein; i.e. ability to modulate lipid metabolism without having an appreciable effect on IGF-I.
  • substitutions do not result in loss of functional activity, then more substantial changes, denoted exemplary substitutions in Table 1, or as further described below in reference to amino acid classes, may be introduced, and the resulting variant growth hormone fragment analyzed for functional activity.
  • a person skilled in the art would be able to determine whether a peptide has the ability to modulate lipid metabolisms but has no appreciable effect on IGF-I by methods of the common general knowledge.
  • no appreciable effect means that the effect on IGF-I is not clinically significant and that if any effect of a peptide is registered in an assay it can be considered negligible.
  • a lipolysis assay as described in Example A.
  • obese rats are treated and sacrificed, adipose tissue is obtained from treated and control rats and placed in vials and terbutaline added.
  • the vials are incubated at 37°C for 1 hour, gassed with carbon and assayed in a standard glycerol assay, for example using an assay kit such as Sigma GPO-337.
  • a person skilled in the art may perform an IGF-I assay on a blood sample (for example from a mouse) .
  • a suitable assay kit is available from R & D Systems, Inc., with catalogue number DY791. This is a sandwich ELISA using hamster anti-mouse IGF-I as capture antibody and goat anti-mouse IGF-I as detection antibody.
  • the terms "therapeutically effective amount” and “therapeutic amount” are synonymous, and mean an amount of a peptide of the present invention effective to yield a desired therapeutic response.
  • the specific therapeutically effective amount will obviously vary with such factors as the particular condition being treated, the type of mammal being treated, the physical condition and clinical history of the mammal, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the peptide.
  • the terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing onset of disorders involving impaired glucose or lipid metabolism and/or may be therapeutic in terms of promoting fat loss or correcting impaired glucose metabolism.
  • Treating covers any method of treatment of, or prevention of disease in a mammal, particularly a human, and includes preventing the disease from occurring in a subject who may be predisposed to the disease, but has not yet been diagnosed as having it; inhibiting the disease, i.e., arresting its development; or relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.
  • the first and third aspects of the invention involve oral administration of a peptide.
  • Oral administration may be by the use of tablets, capsules, powders or liquids such as suspensions, solutions, emulsions or syrups .
  • the peptides are orally active it may be possible to administer the peptide as a transgenic foodstuff.
  • conventional excipients e.g. sodium citrate, lactose, macrocrystalline cellulose, starch, etc.
  • lubricating agents e.g. anhydrous silicic acid, hydrolysed castor oil, magnesium stearate, sodium lauryl sulphate, talc, etc.
  • binding agents e.g. starch paste, glucose, lactose, gelatin, mannitol, magnesium trisilicate, etc.
  • conventional liquid carriers can be used.
  • each unit dosage form of the active ingredient can contain from about 5% to about 95% of the same by weight of the entire composition with the remainder comprising conventional pharmaceutical carriers.
  • the dosage unit of the solution may contain 0.05 to about 0.5% of the same by weight of the entire solution.
  • the dosage unit may be of the sustained release type, for example for once daily administration.
  • a suitable sustained or slow release formulation may be achieved, for example, when the peptide is bound to a suitable polymer.
  • the seventh and ninth aspect of the invention includes various pharmaceutical compositions useful for controlling glucose tolerance or improving lipid profiles and therefore preventing or treating disorders involving abnormal glucose metabolism or lipid profiles, such as diabetes, hypercholesteraemia and metabolic syndrome.
  • the pharmaceutical compositions according to one embodiment of the invention are prepared by bringing a peptide corresponding to a C-terminal growth hormone fragment, analogue, variant or salts thereof into a form suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • the pharmaceutical compositions are preferably prepared and administered in- dosage units.
  • Solid dosage units include tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals.
  • the pharmaceutical compositions may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject.
  • dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side effects.
  • An effective amount of the growth hormone fragment to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the subject. Accordingly, it will be necessary for the therapist to titrate the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • a typical daily dosage might range from about 1 ⁇ g/kg to up to 100 mg/kg or more, depending on the mode of delivery.
  • Dosage levels of the growth hormone fragment used for treating glucose intolerance or improving lipid profiles will usually be of the order of about 0.5mcg to about 20mg per kilogram body weight, with a preferred dosage range between about 0.5mcg to about lOmg per kilogram body weight per day (from about 0.5mg to about 3g per patient per day) .
  • the amount of active ingredient which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host to be treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 0.5mg to Ig of an active compound with an appropriate and convenient amount of carrier material, which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 0.5mg to 500mg of active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the term “consisting essentially of” is used herein to indicate that the peptide includes a bioactive lipid metabolic domain of the carboxyl-terminal sequence of a growth hormone, optionally together with other portions of the carboxyl-terminal sequence or other amino acid sequences which do not materially affect the characteristics of the peptide in modulating lipid metabolism, but not other bioactive domains of the growth hormone.
  • AOD9604 STOCK SOLUTION AOD9604 is dissolved in sterile MiIIiQ water at a final concentration of 221 ⁇ M and stored in aliquots at -80 0 C. Immediately before the start of the experiment, single aliquots of the AOD9604 stock solution are thawed on ice and appropriate dilutions of the AOD9604 stock solution are made in KRB/1% BSA/5.5mM D-glucose and immediately added to 3T30L1 cells for the commencement of the 24 hr incubation period as stated above.
  • Body weight and abdominal circumference were measured fortnightly and abdominal fat was assessed by computed tomography (CT) scan at baseline and end of treatment. Abdominal circumference was also assessed with a tape measure. Assessments for safety and tolerability included physical status, adverse event questioning, clinical laboratory tests, oral glucose tolerance test, vital signs and electrocardiograms (ECGs) .
  • CT computed tomography
  • ECGs electrocardiograms
  • the active pharmaceutical ingredient (API) was chemically synthesized by conventional solid-phase synthesis on 4-methyl-benzylhydrylamine resin. Side chain- protected butyloxycarbonyl amino acid derivatives were sequentially added from the C-terminal end to the growing resin-bound peptide chain in the presence of diisopropylcarbodiimide .
  • AOD9604 was dry-mixed with excipients (mannitol and PEG3350) as detailed below.
  • the capsules were a product of Shionogi Qualicaps Co. Ltd. in Japan and distributed by Shionogi Qualicaps, Inc., Whitsett, NC, USA. They were white in colour and composed of hydroxypropylmethylcellulose (USP-grade) , potassium chloride (USP-grade) , carrageenan (USP-grade) , titanium oxide (USP-grade) , carnauba wax (National Formulary (NF) - grade) on the surface as lubricant.
  • USP-grade hydroxypropylmethylcellulose
  • potassium chloride USP-grade
  • carrageenan USP-grade
  • titanium oxide USP-grade
  • carnauba wax National Formulary (NF) - grade
  • the capsules were filled at the VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM, USA. Quality control and stability- testing was shared between the Center and Formatech, Inc., Andover, MA. , USA. The latter developed the pharmaceutical formulation. Results (see Figures) :

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Abstract

L'invention concerne des peptides correspondant à l'hormone de croissance humaine (hGH) 177-191, ou un sous-fragment ou un analogue de celle-ci métabolisant les lipides, contenant un pont disulfure, à condition que le peptide ne soit pas une hormone de croissance de forme intacte et de pleine longueur, et leur utilisation pour moduler le métabolisme des lipides et favoriser la perte de poids lorsqu'ils sont administrés à raison de 0,01 à 2 mg par jour. L'invention concerne également des unités posologiques contenant le peptide. L'invention concerne également l'utilisation des peptides dans le traitement de l'intolérance au glucose et dans l'amélioration des profils lipidiques.
PCT/AU2005/000828 2005-06-14 2005-06-14 Peptides correspondant à l'hormone de croissance humaine Ceased WO2006133477A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013082667A1 (fr) 2011-12-09 2013-06-13 Metabolic Pharmaceuticals Pty Ltd Utilisation de fragments d'hormone de croissance
GB2507341A (en) * 2012-10-29 2014-04-30 Peter Kenny Fat loss composition comprising a prostaglandin F2 alpha analogue and a fragment of amino acids 176-191 of human growth hormone
CN114380902A (zh) * 2021-12-29 2022-04-22 江苏诺泰澳赛诺生物制药股份有限公司 一种hgh(176-191)的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7772794A (en) * 1994-11-10 1996-05-16 Metabolic Pharmaceuticals Limited Treatment of obesity
AU755512B2 (en) * 1997-09-08 2002-12-12 Metabolic Pharmaceuticals Limited Treatment of obesity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7772794A (en) * 1994-11-10 1996-05-16 Metabolic Pharmaceuticals Limited Treatment of obesity
AU755512B2 (en) * 1997-09-08 2002-12-12 Metabolic Pharmaceuticals Limited Treatment of obesity

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FRANCO C. ET AL.: "Growth Hormone Treatment reduces Abdominal Visceral Fat in Postmenopausal Women with Abdominal Obesity: A 12-Month Placebo-Controlled Trial", J CLIN ENDOCRINOL METAB, vol. 90, no. 3, March 2005 (2005-03-01), pages 1466 - 1474, XP003000696 *
LEWIS U. ET AL.: "Structure and Properties of Members of the hGH family: A Review", ENDOCRINE JOURNAL, vol. 47, no. SUPPL, 2000, pages S1 - S8, XP008073462 *
WADE J. ET AL.: "Diabetogenic Action of Human Growth Hormone", INT J PEPTIDE PROT RES, vol. 13, 1979, pages 195 - 200, XP002903354 *
YUEN K. ET AL.: "Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance", EUR J ENDOCRINOL, vol. 151, 2004, pages 39 - 45, XP003000697 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013082667A1 (fr) 2011-12-09 2013-06-13 Metabolic Pharmaceuticals Pty Ltd Utilisation de fragments d'hormone de croissance
JP2015500813A (ja) * 2011-12-09 2015-01-08 メタボリック、ファーマシューティカルズ、プロプライエタリー、リミテッドＭｅｔａｂｏｌｉｃ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｐｔｙ Ｌｔｄ 成長ホルモン断片の使用
US20150079044A1 (en) * 2011-12-09 2015-03-19 Metabolic Pharmaceuticals Pty Ltd Use of growth hormone fragments
EP2788014A4 (fr) * 2011-12-09 2015-10-28 Metabolic Pharmaceuticals Pty Ltd Utilisation de fragments d'hormone de croissance
RU2639474C2 (ru) * 2011-12-09 2017-12-21 Метаболик Фармасьютикалс Пти Лтд Применение фрагментов гормона роста
US10111933B2 (en) 2011-12-09 2018-10-30 Metabolic Pharmaceuticals Pty Ltd Use of growth hormone fragments
CN110448683A (zh) * 2011-12-09 2019-11-15 麦特保利药业有限公司 生长激素片段的用途
KR20190132552A (ko) * 2011-12-09 2019-11-27 메타볼릭 파마슈티칼즈 피티와이 엘티디 성장 호르몬 단편들의 사용
KR102148910B1 (ko) * 2011-12-09 2020-08-28 메타볼릭 파마슈티칼즈 피티와이 엘티디 성장 호르몬 단편들의 사용
US10758593B2 (en) 2011-12-09 2020-09-01 Metabolic Pharmaceuticals Pty Ltd Use of growth hormone fragments
GB2507341A (en) * 2012-10-29 2014-04-30 Peter Kenny Fat loss composition comprising a prostaglandin F2 alpha analogue and a fragment of amino acids 176-191 of human growth hormone
CN114380902A (zh) * 2021-12-29 2022-04-22 江苏诺泰澳赛诺生物制药股份有限公司 一种hgh(176-191)的制备方法

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