WO2006108667A2 - Method of treatment using gh antagonist and somatostatin agonist - Google Patents

Method of treatment using gh antagonist and somatostatin agonist Download PDF

Info

Publication number
WO2006108667A2
WO2006108667A2 PCT/EP2006/003438 EP2006003438W WO2006108667A2 WO 2006108667 A2 WO2006108667 A2 WO 2006108667A2 EP 2006003438 W EP2006003438 W EP 2006003438W WO 2006108667 A2 WO2006108667 A2 WO 2006108667A2
Authority
WO
WIPO (PCT)
Prior art keywords
pegvisomant
human
once
somatostatin
subject
Prior art date
Application number
PCT/EP2006/003438
Other languages
French (fr)
Other versions
WO2006108667A3 (en
Inventor
Aart Jan Van Der Lely
Original Assignee
Erasmus University Medical Center Rotterdam
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Erasmus University Medical Center Rotterdam filed Critical Erasmus University Medical Center Rotterdam
Priority to BRPI0609355-8A priority Critical patent/BRPI0609355A2/en
Priority to JP2008505823A priority patent/JP2008535882A/en
Priority to CA002604381A priority patent/CA2604381A1/en
Priority to EP06742584A priority patent/EP1874355A2/en
Priority to AU2006233715A priority patent/AU2006233715A1/en
Priority to US11/918,460 priority patent/US20090215676A1/en
Priority to MX2007012814A priority patent/MX2007012814A/en
Publication of WO2006108667A2 publication Critical patent/WO2006108667A2/en
Publication of WO2006108667A3 publication Critical patent/WO2006108667A3/en
Priority to AU2010257328A priority patent/AU2010257328A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • 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
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones

Definitions

  • the present invention relates to a method and compositions useful for attenuating the effects of elevated levels of growth hormone (GH) in the blood. More particularly, the present invention relates to the reduction of GH levels and/or insulin-like growth factor-1 (IGF-1) levels in the blood by the administration of a combination of a GH antagonist with a somatostatin or somatostatin agonist.
  • GH growth hormone
  • IGF-1 insulin-like growth factor-1
  • Conditions related to GH excess are well known to medical practitioners.
  • One of the best known examples of such conditions, acromegaly is characterized by excessive levels of GH in the blood, often resulting from an adenoma of the anterior pituitary.
  • Acromegaly is associated with significant risk of morbidity (soft-tissue swelling, arthralgia, headache, perspiration, fatigue, CV disorders), insulin resistance and diabetes, vision problems resulting from optic nerve compression by the adenoma, and premature mortality.
  • Most of the biological impacts and symptoms related to GH excess are mediated through IGF-1 , which is secreted by the liver as well as many other target organs as a result of GH receptor activation.
  • GH suppressive drugs Traditional treatment options for acromegaly include surgical removal of the offending tumor with or without follow-on, and normally chronic, medical treatment with GH suppressive drugs.
  • somatostatin analogs such as LANREOTIDE (Ipsen, Paris, France) and OCTREOTIDE (Novartis, Basle, Switzerland) and dopamine agonists such as bromocriptine, cabergoline, and pergolide.
  • dopamine agonists while generally effective at providing symptomatic relief, rarely normalize GH levels.
  • LANREOTIDE and OCTREOTIDE are able to reduce GH and IGF-1 levels in approximately 90% of acromegalic patients.
  • PEGVISOMANT SOMAVERT, Pfizer, Inc., New York, USA
  • PEGVISOMANT comprises a recombinantly produced, 191 amino acid analog of the GH protein to which polyethyleneglycol moieties have been attached (i.e., the protein has been subjected to "pegylation").
  • pegylation a method of producing recombinant proteins, and in particular, growth hormone antagonists, are well known to persons skilled in the art of pharmacy.
  • GH antagonists like PEGVISOMANT are believed to competitively bind to, but not activate, the GH receptor, thereby substantially attenuating most of the effects of high levels of circulating endogenous GH (i.e., normalize IGF-I levels) in most (e.g., 75% - 95%) acromegalics.
  • Pegylation of the GH antagonist protein is intended to improve in vivo half-life and reduce immunogenicity. (Kopchick et al., Endocrine Rev, (2002), 23(5) pp.623-646.)
  • GH antagonist demonstrates that, while this class of therapeutic agent may be generally effective at alleviating most negative effects of high circulating endogenous GH levels, relatively high in vivo concentrations of a GH antagonist are required in order to compete effectively for the GH receptor, hence a high dose must be administered (10 to 40 mg per day or higher in the case of Pegvisomant). Further, while pegylation of the GH antagonist protein offers improved in vivo half-life relative to the non-pegylated form, currently practice with PEGVISOMANT demonstrates that this type of therapeutic agent often needs to be administered on a daily basis in order to assure efficacy.
  • the invention relates to a method for attenuating the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • the invention in a second aspect, relates to a method for reducing the dose of GH antagonist needed to attenuate the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • the invention in a third aspect, relates to a method for reducing the frequency of administration of GH antagonist needed to attenuate the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • the invention in a fourth aspect, relates to a method for normalizing serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • the invention relates to a method for reducing the dose of GH antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTI DE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • the invention relates to a method for reducing the frequency of administration of GH antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
  • said subject is a mammal.
  • said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
  • said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
  • said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
  • said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
  • Figure 1 Normalization of serum IGF-I concentration in 19 acromegalic patients before and after adding once weekly pegvisomant to high-dose monthly somatostatin analogue therapy in a dose finding study with a treatment duration of 42 weeks and dose increments to a maximum of 80 mg of pegvisomant per week.
  • the shaded area indicates the age-dependent normal ranges for IGF-I.
  • octreotide LAR also known as SANDOSTATIN LAR
  • 120 mg of Lanreotide autogel also known as SOMATULINE AUTOGEL
  • Starting dose of pegvisomant was 25 mg per week.
  • Pegvisomant dosage was adjusted until serum IGF-I concentrations were within the age-adjusted normal range.
  • Efficacy was determined at week 42, which was 6 weeks after patients could have reached the maximal allowed dose of 80 mg when necessary. Efficacy parameters were assessed just prior to the next weekly pegvisomant administration. Serum IGF-I concentration were measured by an immunometric assay (Diagnostic Products Corporation; Los Angeles, USA). A Wilcoxon's signed rank test was used for assessing significance of changes from baseline. Statistical significance was accepted at p-values ⁇ 0.05.
  • pegvisomant is needed when there is less GH to compete with, e.g. during co-treatment with a somatostatin analogue.
  • lower insulin levels in the portal vein, with somatostatin analog therapy will decrease the number of available GH receptors at the cell surface of the hepatocytes (7).
  • Somatostatin analogues might also increase pegvisomant levels by unknown mechanisms (4).

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Disclosed is a method for attenuating the effects of growth hormone (GH) in a subject. The method comprises the administration of both a GH antagonist and a somatostatin agonist to said subject, simultaneously or separately, continuously or periodically. In one preferred embodiment of the method an extended release somatostatin agonist composition is administered monthly (such as ocreotide LAR/SANDOSTATIN LAR or Lanreoride autogel/SOMATULINE AUTOGEL) , and a conventional non-extended release GH antagonist composition is administered weekly (such as pegvisomant) .

Description

METHOD OF TREATMENT RELATED APPLICATIONS
This application claims priority under 35 U.S.C. section 119 of Application Serial No. 60/670,740, filed April 13, 2005.
DESCRIPTION OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and compositions useful for attenuating the effects of elevated levels of growth hormone (GH) in the blood. More particularly, the present invention relates to the reduction of GH levels and/or insulin-like growth factor-1 (IGF-1) levels in the blood by the administration of a combination of a GH antagonist with a somatostatin or somatostatin agonist.
1. Background of the Invention
Conditions related to GH excess are well known to medical practitioners. One of the best known examples of such conditions, acromegaly, is characterized by excessive levels of GH in the blood, often resulting from an adenoma of the anterior pituitary. Acromegaly is associated with significant risk of morbidity (soft-tissue swelling, arthralgia, headache, perspiration, fatigue, CV disorders), insulin resistance and diabetes, vision problems resulting from optic nerve compression by the adenoma, and premature mortality. Most of the biological impacts and symptoms related to GH excess are mediated through IGF-1 , which is secreted by the liver as well as many other target organs as a result of GH receptor activation.
Traditional treatment options for acromegaly include surgical removal of the offending tumor with or without follow-on, and normally chronic, medical treatment with GH suppressive drugs. Common among such drugs are somatostatin analogs such as LANREOTIDE (Ipsen, Paris, France) and OCTREOTIDE (Novartis, Basle, Switzerland) and dopamine agonists such as bromocriptine, cabergoline, and pergolide. However the dopamine agonists, while generally effective at providing symptomatic relief, rarely normalize GH levels. LANREOTIDE and OCTREOTIDE are able to reduce GH and IGF-1 levels in approximately 90% of acromegalic patients. Of these, approximately one-half to two- thirds are able to reduce their GH and IGF-1 levels to normal levels ("full responders"), while the rest are able to reduce their GH and IGF-1 levels, albeit not to normal levels ("partial responders"). A number of dosage forms for somatostatin analogs are already available for use or are otherwise well known to persons skilled in the art of pharmacy.
For those approximately 10% of acromegalic patients who experience no significant lowering of GH levels in response to somatostatin agonists treatment ("non- responders"), PEGVISOMANT (SOMAVERT, Pfizer, Inc., New York, USA), a representative of a new class of drugs (GH antagonists), has recently been made commercially available. PEGVISOMANT comprises a recombinantly produced, 191 amino acid analog of the GH protein to which polyethyleneglycol moieties have been attached (i.e., the protein has been subjected to "pegylation"). Various methods of producing recombinant proteins, and in particular, growth hormone antagonists, are well known to persons skilled in the art of pharmacy. (By way of example and not limitation, see United States Patent No.'s 5,350,836; 5,681,809; 5,849,535; 5,958,879; 6,057,292; and 6,583,115; United States Patent Publication No.'s 20060026719; 20050214762; 20050123558; 20050059577; and 20040071655. See also Kopchick et al., Endocrine Reviews, (2002), 23(5) pp.623-646.)
Rather than targeting GH secretion, GH antagonists like PEGVISOMANT are believed to competitively bind to, but not activate, the GH receptor, thereby substantially attenuating most of the effects of high levels of circulating endogenous GH (i.e., normalize IGF-I levels) in most (e.g., 75% - 95%) acromegalics. Pegylation of the GH antagonist protein is intended to improve in vivo half-life and reduce immunogenicity. (Kopchick et al., Endocrine Rev, (2002), 23(5) pp.623-646.)
SUMMARY OF THE INVENTION
Experience with the currently available GH antagonist demonstrates that, while this class of therapeutic agent may be generally effective at alleviating most negative effects of high circulating endogenous GH levels, relatively high in vivo concentrations of a GH antagonist are required in order to compete effectively for the GH receptor, hence a high dose must be administered (10 to 40 mg per day or higher in the case of Pegvisomant). Further, while pegylation of the GH antagonist protein offers improved in vivo half-life relative to the non-pegylated form, currently practice with PEGVISOMANT demonstrates that this type of therapeutic agent often needs to be administered on a daily basis in order to assure efficacy.
Although several groups have attempted to extend the dosing schedule, until the present invention it has not been demonstrated that a substantial reduction in the current daily dosing regimen of this highly expensive medication was possible for a significant proportion of acromegalic patients. (See, e.g., Jehle et al., J.Clin. Endo.Metab., 90(3): 1588-1593 (2005); European Public Assessment Report, Scientific Discussion, (available at www.emea.eu.int/humandocs/Humans/EPAR/somavert/somavert.htm.) Thus prior to the present invention there remained a significant need for a method to reduce the dosage and/or the frequency at which a GH antagonist must be administered in order to effect a positive clinical outcome. Such reductions will result in concomtment reduction in the number of painful injections which patients currently must endure, improved quality of life, patient compliance, and
Thus in a first aspect, the invention relates to a method for attenuating the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said first aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said first aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said first aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
In a still more preferred embodiment of said first aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
In another still more preferred embodiment of said first aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
In a second aspect, the invention relates to a method for reducing the dose of GH antagonist needed to attenuate the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said second aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said second aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said second aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
In a still more preferred embodiment of said second aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
In another still more preferred embodiment of said second aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
In a third aspect, the invention relates to a method for reducing the frequency of administration of GH antagonist needed to attenuate the effects of GH in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said third aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said third aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said third aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
In a still more preferred embodiment of said third aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
In another still more preferred embodiment of said third aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
In a fourth aspect, the invention relates to a method for normalizing serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said fourth aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said fourth aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said fourth aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
In a still more preferred embodiment of said fourth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
In another still more preferred embodiment of said fourth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
In a fifth aspect, the invention relates to a method for reducing the dose of GH antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said fifth aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said fifth aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said fifth aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL.
In a still more preferred embodiment of said fifth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month. In another still more preferred embodiment of said fifth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTI DE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
In a sixth aspect, the invention relates to a method for reducing the frequency of administration of GH antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a GH antagonist and a somatostatin or a somatostatin agonist.
In a first embodiment of said sixth aspect said subject is a mammal. Preferably said mammal is a human being, more preferably a human being whose blood plasma level of GH is higher than desired, more preferably still a human being who is suffering from acromegaly or who is at risk of developing acromegaly or symptoms thereof.
More preferably with respect to said first embodiment of said sixth aspect, said subject is a human who suffers from acromegaly and said GH antagonist comprises PEGVISOMANT, wherein said PEGVISOMANT is administered with a frequency of between about once per day and about once every month, inclusive, preferably between about once every 3 days (i.e., about every 2, 3, or 4 days) and about once every 14 days, inclusive, more preferably about once per week, (i.e., about once every 5, 6, 7, 8, or 9 days), most preferably about once every 7 days.
Also more preferably with respect to said first embodiment of said sixth aspect, said subject is a human who suffers from acromegaly and said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about five times per day and about once every 6 months, inclusive, preferably between about three times per day and about once every 3 months, inclusive, more preferably between about once per day and about once per month, inclusive, more preferably about once per month. More preferably when said somatostatin agonist is OCTREOTIDE it is provided as OCTREOTIDE LAR, and when said somatostatin agonist is LANREOTIDE it is provided as LANREOTIDE AUTOGEL. In a still more preferred embodiment of said sixth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises OCTREOTIDE, wherein said PEGVISOMANT is administered about once per week and said OCTREOTIDE is administered about once per month.
In another still more preferred embodiment of said sixth aspect, said human subject suffers from acromegaly, said GH antagonist comprises PEGVISOMANT, and said somatostatin agonist comprises LANREOTIDE, wherein said PEGVISOMANT is administered about once per week and said LANREOTIDE is administered about once per month.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 : Normalization of serum IGF-I concentration in 19 acromegalic patients before and after adding once weekly pegvisomant to high-dose monthly somatostatin analogue therapy in a dose finding study with a treatment duration of 42 weeks and dose increments to a maximum of 80 mg of pegvisomant per week. The shaded area indicates the age-dependent normal ranges for IGF-I.
DETAILED DESCRIPTION OF THE INVENTION
Example 1
We examined in a 42-week dose-finding study the efficacy of the combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in 26 patients with active acromegaly. Pegvisomant dose was increased until IGF-I levels normalized or until a weekly dose of 80 mg was reached. IGF-I levels normalized in 25 (95 %) with a median weekly dose of 60 mg pegvisomant. There were no signs of pituitary tumor growth but mild elevations in liver enzymes were observed in 10 patients (38%). The combined therapy might increase compliance, while it can significantly reduce the costs of medical therapy.
Long-acting somatostatin analogues normalize serum IGF-I levels in two-third of patients (1). Pegvisomant normalizes IGF-I levels in > 90% (2;3). We performed an investigator-initiated, 42 weeks, single-centre prospective open label dose-finding study in which 26 acromegalic patients were treated with both a long-acting somatostatin analog and weekly administration of pegvisomant. These patients could not be controlled with long-acting somatostatin analogue monotherapy during at least six months preceding the date of study entrance. The study was approved by the local medical ethical committee and all patients gave their consent. All patients were seen at 6 weeks intervals. Monthly 30 mg of octreotide LAR (also known as SANDOSTATIN LAR) or 120 mg of Lanreotide autogel (also known as SOMATULINE AUTOGEL) therapy was continued. Starting dose of pegvisomant was 25 mg per week. Pegvisomant dosage was adjusted until serum IGF-I concentrations were within the age-adjusted normal range. Efficacy was determined at week 42, which was 6 weeks after patients could have reached the maximal allowed dose of 80 mg when necessary. Efficacy parameters were assessed just prior to the next weekly pegvisomant administration. Serum IGF-I concentration were measured by an immunometric assay (Diagnostic Products Corporation; Los Angeles, USA). A Wilcoxon's signed rank test was used for assessing significance of changes from baseline. Statistical significance was accepted at p-values < 0.05.
Table I shows the baseline characteristics. After 18 weeks treatment with pegvisomant (i.e. with at least 50 mg of pegvisomant per week), normalization of serum IGF-I concentrations could be achieved in 21 of the 26 subjects (81 %). At week 42 (n=19 of 26), IGF-I levels were normalized in 95 %. Mean serum IGF-I decreased from 67.7 ± 29.9 nmol/l at baseline to a lowest value of 24.4 ± 12.0 nmol/l with combined treatment (see figure 1 for individual changes). Median dose of weekly pegvisomant necessary to normalize serum IGF-I concentration was 60 mg. Interestingly, in a phase Il study in the past (unpublished data) a once weekly pegvisomant dose of 80 mg was only effective in normalizing IGF-I in less than one-third of the patients. No signs of pituitary tumor growth were observed on MRI in those subjects who had completed a six-months treatment period (n=19). In 16 % of the patients tumor regression could be demonstrated by an independent neuroradiologist (using the surface to volume summation method), including 18 patients who never had received radiotherapy. Although the data on follow- up with pegvisomant monotherapy to date do not indicate that pegvisomant increases mean tumor size, clinical experience shows that pegvisomant treatment at least does not prevent tumor growth in some patients (4). Mild pegvisomant-dose independent and non-progressive elevations in liver transaminases were observed in 10 patients (38%). There were no drop-outs.
In this proof of principle study we have demonstrated that in patients in whom serum IGF-I levels can not be controlled by monthly long-acting somatostatin analogue monotherapy, normalization of serum IGF-I can be obtained by adding weekly pegvisomant. The observed 95% efficacy is equal to that of daily pegvisomant monotherapy. Weekly instead of daily injections might improve patients' compliance. Also, combined therapy is potentially considerably cheaper than pegvisomant monotherapy, at least in some patients. The average patient treated with pegvisomant monotherapy needs approximately 20 mg daily. We have calculated that combination therapy will be equally expensive as daily 20 mg pegvisomant monotherapy when a weekly pegvisomant dose of 65 mg in the combination treatment regimen is used. Median weekly pegvisomant dosage for normalizing serum IGF-I concentration was 60 mg in our study. In the present study, however, three subjects also participated in one of the former pegvisomant registration studies. Two of them needed 40 mg and one needed 35 mg of pegvisomant daily. In the present study, their IGF-I has normalized with pegvisomant 60 mg and 80 mg weekly, respectively. For patients who need 40 mg of daily pegvisomant monotherapy, the combination therapy could save = € 58 thousand (= UK£ 40.3 thousand; ~ US$ 75.4 thousand ) on an annual basis. Recently, a study was published on alternate day administration of pegvisomant monotherapy (5). This regimen failed to maintain IGF-I within the age-adjusted normal range in 7 of 10 patients. Apparently, most patients treated with pegvisomant monotherapy require daily administration (5). Pegvisomant monotherapy improves insulin sensitivity as compared to somatostatin analogues (6). Although we have not studied this particular issue, one might expect that pegvisomant monotherapy, compared to the combination therapy, has beneficial effects on insulin sensitivity, as somatostatin analogues decrease insulin sensitivity (6).
Less pegvisomant is needed when there is less GH to compete with, e.g. during co-treatment with a somatostatin analogue. Also, lower insulin levels in the portal vein, with somatostatin analog therapy, will decrease the number of available GH receptors at the cell surface of the hepatocytes (7). Somatostatin analogues might also increase pegvisomant levels by unknown mechanisms (4). We conclude that combined treatment with monthly high-dose long-acting somatostatin analogue therapy and weekly subcutaneous pegvisomant administrations is as effective as daily pegvisomant monotherapy.
Reference List
1. Sheppard MC. Primary medical therapy for acromegaly. Clin. Endocrinol. (Oxf)
2003;58(4):387-99.
2. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der LeIy AJ et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N.Engl. J.Med. 2000;342(16): 1171-7.
3. van der LeIy AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L et al.
Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001 ;358(9295): 1754-9.
4. van der LeIy AJ, Muller A, Janssen JA, Davis RJ, Zib KA, Scarlett JA et al. Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J.CIin.Endocrinol.Metab 2001 ;86(2):478-81.
5. Jehle S, Reyes CM, Sundeen RE, Freda PU. Alternate-day administration of pegvisomant maintains normal serum insulin-like growth factor-l levels in patients with acromegaly. J.CIin.Endocrinol.Metab 2005;90(3): 1588-93.
6. Drake WM, Rowles SV, Roberts ME, Fode FK, Besser GM, Monson JP et al. Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant. Eur.J. Endocrinol. 2003;149(6):521-7.
7. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J.CIin.Endocrinol.Metab 2000;85(12):4712-20. Table 1 : Baseline characteristics (n=26)
Mean age 51 yrs (31 - 79 yrs) ( SD 12.6 yrs)
Age distribution
< 40 yrs 5 (19%)
40 - 49 yrs 9 (35%)
50 - 59 yrs 7 (27%)
≥ 60 yrs 5 (19%)
Gender 15 male (58%) 11 female
Baseline IGF-I Mean: 66.7 nmol/L, SD 29.9 nmol/L
Median: 61.1 nmol/L, range 34-122
1 - 2 ULN 12 (46%)
2 - 3 ULN 9 (35%)
> 3 ULN 5 (19%)
Mean: 10.5 μg/L, SD 15.3 μg/L
Baseline GH Median: 5.2 μg/L, range 0.4-69.8
P re-treatment
Both TNH and RTx 8 (31%)
Only TNH 4 (15%)
Neither TNH nor RTx 14 (54%)
Pituitary insufficiency
Panhypopituitarism 6 (23%)
No hypopituitarism 9 (35%)
1 - 2 axes insufficient 11 (42%)
Long-acting SRIF analogs
Lanreotide autosolution 21 (81%)
Octreotide LAR 5 (19%)
Pituitary adenoma size
Macro adenoma 12 (46%)
Micro adenoma 14 (54%)
Baseline characteristics of 26 patients with biochemically active acromegaly, despite long-term treatment with high-dose somatostatin analogues. (ULN = Upper level of normality; TNH = transnasal hypophysectomy; RTx = radiotherapy)

Claims

What is claimed is:CLAIMS
1. A method for attenuating the effects of growth hormone in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
2. A method for reducing the dose of growth hormone antagonist needed to attenuate the effects of growth hormone in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
3. A method for reducing the frequency of administration of growth hormone antagonist needed to attenuate the effects of growth hormone in a human or non-human subject in whom such attenuation is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
4. A method for normalizing serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
5. A method for reducing the dose of growth hormone antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
6. A method for reducing the frequency of administration of growth hormone antagonist needed to normalize the serum IGF-I concentration in a human or non-human subject in whom such normalization is desired, said method comprising administering to said subject both a growth hormone antagonist and a somatostatin or a somatostatin agonist.
7. The method according to any one of claims 1 - 6, wherein said subject is human.
8. The method according to claim 7, wherein said human subject has or is at risk of
16 developing symptoms of acromegaly.
9. The method according to claim 8, wherein said growth hormone antagonist comprises PEGVISOMANT.
10. The method according to claim 9, wherein said somatostatin agonist comprises OCTREOTIDE or LANREOTIDE.
11. The method according to claim 10, wherein said OCTREOTIDE or said LANREOTIDE is administered with a frequency of between about once every day and about once every month.
12. The method according to claim 11 , wherein said OCTREOTIDE or said LANREOTIDE is administered about once every month.
13. The method according to claim 12, wherein said PEGVISOMANT is administered with a frequency of between about once every other day and about once every seven days.
14. The method according to claim 13, wherein said PEGVISOMANT is administered with a frequency of about once every seven days.
15. The method according to claim 14, wherein said OCTREOTIDE is administered as OCTREOTIDE-LAR.
16. The method according to claim 14, wherein said LANREOTIDE is administered as LANREOTIDE AUTOGEL.
17
PCT/EP2006/003438 2005-04-13 2006-04-13 Method of treatment using gh antagonist and somatostatin agonist WO2006108667A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BRPI0609355-8A BRPI0609355A2 (en) 2005-04-13 2006-04-13 use of a growth hormone antagonist and a somatostatin or a somatostatin agonist in the preparation of a composition to attenuate the effects of growth hormone
JP2008505823A JP2008535882A (en) 2005-04-13 2006-04-13 Treatment
CA002604381A CA2604381A1 (en) 2005-04-13 2006-04-13 Use of growth hormone antagonist and somatostatin agonist
EP06742584A EP1874355A2 (en) 2005-04-13 2006-04-13 Method of treatment using gh antagonist and somatostatin agonist
AU2006233715A AU2006233715A1 (en) 2005-04-13 2006-04-13 Method of treatment using GH antagonist and somatostatin agonist
US11/918,460 US20090215676A1 (en) 2005-04-13 2006-04-13 Method of treatment
MX2007012814A MX2007012814A (en) 2005-04-13 2006-04-13 Method of treatment using gh antagonist and somatostatin agonist.
AU2010257328A AU2010257328A1 (en) 2005-04-13 2010-12-20 Method of treatment using GH antagonist and somatostatin agonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67074005P 2005-04-13 2005-04-13
US60/670,740 2005-04-13

Publications (2)

Publication Number Publication Date
WO2006108667A2 true WO2006108667A2 (en) 2006-10-19
WO2006108667A3 WO2006108667A3 (en) 2007-05-03

Family

ID=36968804

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/003438 WO2006108667A2 (en) 2005-04-13 2006-04-13 Method of treatment using gh antagonist and somatostatin agonist

Country Status (10)

Country Link
US (1) US20090215676A1 (en)
EP (1) EP1874355A2 (en)
JP (1) JP2008535882A (en)
CN (1) CN101163505A (en)
AU (2) AU2006233715A1 (en)
BR (1) BRPI0609355A2 (en)
CA (1) CA2604381A1 (en)
MX (1) MX2007012814A (en)
RU (1) RU2397778C2 (en)
WO (1) WO2006108667A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016077620A1 (en) * 2014-11-12 2016-05-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Treatment of hormonal disorders of growth

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103087182B (en) * 2013-02-06 2014-11-05 中国科学院过程工程研究所 N-terminal site-specific modified PEGylated growth hormone antagonist and its preparation method
AU2014280847B2 (en) * 2013-06-13 2019-07-04 Antisense Therapeutics Ltd Combination therapy
KR102167827B1 (en) * 2017-12-20 2020-10-20 주식회사 알테오젠 Novel Growth Hormone Receptor Antagonists and Fusion Proteins Thereof
WO2020014307A1 (en) * 2018-07-11 2020-01-16 Ohio University Peptide-based inhibitors of growth hormone action and methods of the thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021023A1 (en) * 2003-09-02 2005-03-10 Pharmacia & Upjohn Company Therapeutical conversion

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1568772T3 (en) * 1995-09-21 2010-10-18 Genentech Inc Variants of Human Growth Hormone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021023A1 (en) * 2003-09-02 2005-03-10 Pharmacia & Upjohn Company Therapeutical conversion

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FEENSTRA J ET AL: "Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly" LANCET THE, LANCET LIMITED. LONDON, GB, vol. 365, no. 9471, 7 May 2005 (2005-05-07), pages 1644-1646, XP004882310 ISSN: 0140-6736 *
JORGENSEN JENS OTTO LUNDE ET AL: "Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist" JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 90, no. 10, October 2005 (2005-10), pages 5627-5631, XP002425118 ISSN: 0021-972X *
KOPCHICK J J ET AL: "Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly." ENDOCRINE REVIEWS OCT 2002, vol. 23, no. 5, October 2002 (2002-10), pages 623-646, XP002425117 ISSN: 0163-769X cited in the application *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016077620A1 (en) * 2014-11-12 2016-05-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Treatment of hormonal disorders of growth
US10350273B2 (en) 2014-11-12 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Treatment of hormonal disorders of growth
AU2015346277B2 (en) * 2014-11-12 2020-03-26 Centre Hospitalier Universitaire De Liège Treatment of hormonal disorders of growth
AU2020203709B2 (en) * 2014-11-12 2022-09-29 Centre Hospitalier Universitaire De Liège Treatment of hormonal disorders of growth

Also Published As

Publication number Publication date
RU2397778C2 (en) 2010-08-27
US20090215676A1 (en) 2009-08-27
JP2008535882A (en) 2008-09-04
CA2604381A1 (en) 2006-10-19
BRPI0609355A2 (en) 2010-03-30
EP1874355A2 (en) 2008-01-09
MX2007012814A (en) 2008-01-22
WO2006108667A3 (en) 2007-05-03
AU2010257328A1 (en) 2011-01-20
CN101163505A (en) 2008-04-16
AU2006233715A1 (en) 2006-10-19
RU2007141935A (en) 2009-05-20

Similar Documents

Publication Publication Date Title
Elisha et al. Body composition and epicardial fat in type 2 diabetes patients following insulin detemir versus insulin glargine initiation
US11510963B1 (en) Method of treating diseases
US20230201302A1 (en) Oral octreotide administered in combination with other therapeutic agents
Burness et al. Lanreotide Autogel®: A review of its use in the treatment of patients with acromegaly
Puig-Domingo et al. Use of lanreotide in combination with cabergoline or pegvisomant in patients with acromegaly in the clinical practice: The ACROCOMB study
AU2010257328A1 (en) Method of treatment using GH antagonist and somatostatin agonist
KR20150106887A (en) Fusion of human growth hormone and albumin, formulation and uses thereof
KR20090019896A (en) Combination of somatostatin-analogs with dopamine or growth hormone receptor antagonist
Croxtall et al. Lanreotide Autogel®: A review of its use in the management of acromegaly
Paisley et al. Medical treatment in acromegaly
Chanson Emerging drugs for acromegaly
Bronstein Optimizing acromegaly treatment
Frost et al. Growth hormone/insulin-like growth factor axis in human immunodeficiency virus-associated disease
Frara et al. Medical treatment in acromegaly
Nowicka et al. Pegvisomant therapy in acromegalic patient resistant to other treatment: case report
Witek et al. Cushing’s disease: is pasireotide LAR a breakthrough in adjuvant therapy after unsuccessful surgery?
Said et al. Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger–Ellison syndromes: case series and literature review
Rioperez et al. Conn's syndrome in a patient with acromegaly
Meas et al. An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by Octreotide and Pegvisomant
Oyesiku Management of recurrent growth hormone-secreting adenomas
Millner et al. Treatment update on acromegaly
JP2005523915A (en) Treatment of metabolic syndrome

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 561942

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2006233715

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2604381

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2008505823

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/012814

Country of ref document: MX

Ref document number: 200680012348.6

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2006742584

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: DE

ENP Entry into the national phase

Ref document number: 2006233715

Country of ref document: AU

Date of ref document: 20060413

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006233715

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2007141935

Country of ref document: RU

WWP Wipo information: published in national office

Ref document number: 2006742584

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 11918460

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0609355

Country of ref document: BR

Kind code of ref document: A2