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 . 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 u . s . pat . nos . 5 , 350 , 836 ; 5 , 681 , 809 ; 5 , 849 , 535 ; 5 , 958 , 879 ; 6 , 057 , 292 ; and 6 , 583 , 115 ; united states patent publication no .&# 39 ; 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 .) 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 lanreotide , 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 . fig1 : 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 . 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 & gt ; 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 &# 39 ; s signed rank test was used for assessing significance of changes from baseline . statistical significance was accepted at p - values & lt ; 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 fig1 for individual changes ). median dose of weekly pegvisomant necessary to normalize serum igf - i concentration was 60 mg . interestingly , in a phase ii 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 &# 39 ; 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 ≈ c = 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 . 1 . sheppard m c . primary medical therapy for acromegaly . clin . endocrinol . ( oxf ) 2003 ; 58 ( 4 ): 387 - 99 . 2 . trainer p j , drake w m , katznelson l , freda p u , herman - bonert v , van der lely a j et al . treatment of acromegaly with the growth hormone - receptor antagonist pegvisomant . n . engl . j . med . 2000 ; 342 ( 16 ): 1171 - 7 . 3 . van der lely a j , hutson r k , trainer p j , besser g m , barkan a l , 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 lely a j , muller a , janssen j a , davis r j , zib k a , scarlett j a 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 . clin . endocrinol . metab 2001 ; 86 ( 2 ): 478 - 81 . 5 . jehle s , reyes c m , sundeen r e , freda p u . alternate - day administration of pegvisomant maintains normal serum insulin - like growth factor - i levels in patients with acromegaly . j . clin . endocrinol . metab 2005 ; 90 ( 3 ): 1588 - 93 . 6 . drake w m , rowles s v , roberts m e , fode f k , besser g m , monson j p 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 k c , doyle n . ballesteros m , waters m j , ho k k . insulin regulation of human hepatic growth hormone receptors : divergent effects on biosynthesis and surface translocation . j . clin . endocrinol . metab 2000 ; 85 ( 12 ): 4712 - 20 .
disclosed is a method for attenuating the effects of growth hormone 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 , and a conventional non - extended release gh antagonist composition is administered weekly .