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US 2016/0002311 A1 Lau Et Al US 2016.0002311A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002311 A1 Lau et al. (43) Pub. Date: Jan. 7, 2016 (54) NOVEL GLUCAGON ANALOGUES Publication Classification (71) Applicant: NOVO NORDISKA/S, Bagsvaerd (DK) (51) Int. Cl. C07K I4/605 (2006.01) (72) Inventors: Jesper F. Lau, Farum (DK); Thomas A647/48 (2006.01) Kruse, Herlev (DK); Lars Linderoth, A638/28 (2006.01) Alleroed (DK); Henning Thoegersen, A638/26 (2006.01) Farum (DK); Jacob Kofoed, Vaerloese (52) U.S. Cl. (DK); Kirsten Dahl, Smoerum (DK) CPC ............... C07K 14/605 (2013.01); A61K 38/26 (2013.01); A61K 47/48038 (2013.01); A61 K (21) Appl. No.: 14/827,539 38/28 (2013.01) (22) Filed: Aug. 17, 2015 (57) ABSTRACT Related U.S. Application Data The present invention relates to novel peptide compounds (63) Continuation of application No. 136375 filed on which have a protracted profile of action and improved solu Oct. 16, 2012, filed as application No. PCT/EP2011/ bility and stability, to the use of the compounds in therapy, to 054712 on Mar. 28, 2011. methods of treatment comprising administration of the com (60) Provisional application No. 61/319,994, filed on Apr. pounds to patients in need thereof, and to the use of the 1, 2010. compounds in the manufacture of medicaments. The com pounds of the invention are of particular interest in relation to (30) Foreign Application Priority Data the treatment of hyperglycemia, diabetes and obesity, as well as a variety of diseases or conditions associated with hyper Mar. 26, 2010 (EP) .................................. 1 O157901.9 glycemia, diabetes and obesity. Patent Application Publication Jan. 7, 2016 Sheet 1 of 9 US 2016/0002311 A1 6 O 5 O 4.O Vehicle 2 O f Ex. 3, 1000nmol/kg 1030 Ex. 3, 300nmol/kg Ex. 3, 100nmol/kg O O 10 20 30 40 Time (hours) Fig. 2 Patent Application Publication Jan. 7, 2016 Sheet 2 of 9 US 2016/0002311 A1 $2$3$º -- Ex. 4, 300nmol/kg Time (hours) © $2$3$º - Ex. 5, 300nmol/kg Time (hours) Patent Application Publication Jan. 7, 2016 Sheet 3 of 9 US 2016/0002311 A1 1000000 1 O O O 0. O 100 O O 1000 LoC O 20 40 60 80 100 time (hours) x Ex. 3, 25nmol/kg IV, n = 3 - Ex. 3, 50nmol/kg SC, n = 2 Fig. 5 Wehicle HF G3, inmol/kg Vehicle HF pairfed (to 30+1) Ex. 3, 3nmol/kg Ex. 3, 30nmol/kg Ex. 3, 3nmol/kg + G3, 1 nmol/kg Ex. 3, 30nmol/kg + G3, 1 nmol/kg & Wehicle F 600 -5 O 5 10 15 time (days) Fig. 6 Patent Application Publication Jan. 7, 2016 Sheet 4 of 9 US 2016/0002311 A1 o -100 3. an < 200 -300 & s s s s s sy s ess S S S & aV SS s S S * S S * S s\9 aS SS g & b' oos s o' c S.SS S.Sg NN SSSS g ? & ? V Patent Application Publication Jan. 7, 2016 Sheet 5 of 9 US 2016/0002311 A1 1 2 Vehicle HF G3, 1nmol/kg 1 O Vehicle HF pairfed (to 30+1) Ex. 3, 3nmol/kg Ex. 3, 30nmol/kg Ex. 3, 3nmol/kg + G3, 1 nmol/kg Ex. 3, 30nmol/kg+ G3, 1 nmol/kg : Vehicle F Time (hours) Fig. 8 25 Vehicle HF G3, 1 nmol/kg Vehicle HF pairfed (to 30+1) Ex. 3, 3nmol/kg Ex. 3, 30nmol/kg Ex. 3, 3nmol/kg + G3, 1 nmol/kg Ex. 3, 30nmol/kg + G3, nmol/kg s: Vehicle LF Patent Application Publication Jan. 7, 2016 Sheet 6 of 9 US 2016/0002311 A1 300 2 O O Patent Application Publication Jan. 7, 2016 Sheet 7 of 9 US 2016/0002311 A1 Solubility Analogue Fig. 12 Solubility & Stability Area (214 nm, UPC) OOOOOO SOCOCOO -- 4000000 3}}{C} - 2OOOOOO -- COOOO ----- deuexB Analogue Fig. 13 Patent Application Publication Jan. 7, 2016 Sheet 8 of 9 US 2016/0002311 A1 Ø4. ???????????????????????????ºZZZZZZZZZZZZZZZZZ. Ø4. ZZZZZZZZZZZZZZZZZ!) ØA. Recovery(%) Fig. 14 100 200 300 Time (min) Fig. 15 Patent Application Publication Jan. 7, 2016 Sheet 9 of 9 US 2016/0002311 A1 Lag-time - to - 2t to Time Fig. 16 US 2016/0002311 A1 Jan. 7, 2016 NOVEL, GLUCAGON ANALOGUES 0006 Glucagon is however of limited potential use in pharmaceuticals due to fast clearance in human plasma with CROSS-REFERENCE TO RELATED a half life of approximately 5 minutes A high clearance of a APPLICATIONS therapeutic agent is inconvenient in cases where it is desired to maintain a high blood level thereof over a prolonged period 0001. This application is a continuation of U.S. patent of time since repeated administrations will then be necessary. application Ser. No. 13/637,454, filed Oct. 16, 2012 which is In some cases it is possible to influence the release profile of a 35 U.S.C. S371 national stage application of International peptides by applying Suitable pharmaceutical compositions, Patent Application PCT/EP2011/054712 (published as WO but this approach has various shortcomings and is not gener 2011/117415A1), filed Mar. 28, 2011, which claims priority ally applicable. to European Patent Application 10157901.9, filed Mar. 26, 0007 Glucagon is currently available in recombinant 2010; this application further claims priority under 35 U.S.C. form as a freeze-dried formulation, with a short duration of S119 of U.S. Provisional Application 61/319,994, filed Apr. action, restricted to a few hours in spite of a glucagon level 1, 2010; the contents of which are incorporated herein by that peaks at levels far higher than endogenous glucagon reference. levels. There is therefore a need for chemically modified glucagon compounds in order to be delivered at continuous FIELD OF THE INVENTION levels, so that longer biological half-life is achieved, i.e. 0002 The present invention relates to novel glucagon pep modified glucagon peptides with a protracted profile of tide analogues with improved physical stability and solubil action. ity, and with a protracted profile of action, to the use of said 0008 Furthermore, glucagon is not stable for very long peptides in therapy to methods of treatment comprising when dissolved in aqueous solution since physical stability of administration of said peptides to patients, and to the use of glucagonis very poor and solutions of glucagonform gels and said peptides in the manufacture of medicaments. fibrils within hours or days, depending on the purity of the peptide, Salt concentration, pH and temperature. In addition INCORPORATION-BY-REFERENCE OF THE the solubility of human glucagon is very poor at pH 3.5-9.5. SEQUENCE LISTING 0009. Several patent applications disclosing different glu cagon-based analogues and GLP-1/glucagon receptor 0003. In accordance with 37 C.F.R. S.1.52(e)(5), Appli co-agonists are known in the art, such as e.g. patents cants enclose herewith the Sequence Listing for the above WO2008/086086, WO2008/101017, WO2007/056362, captioned application entitled “SeqList 8132 US03', cre WO2008/1524.03 and WO96/29342. Some of the GLP-1/ ated on Aug. 5, 2015. The Sequence Listing is made up of 494 glucagon receptor co-agonists disclosed in these patents refer bytes, and the information contained in the attached to specific mutations relative to native human glucagon. “SeqList 8132 US03” is identical to the information in the Other glucagon analogs disclosed are PEGylated (e.g. specification as originally filed. No new matter is added. WO2007/056362) or acylated in specific positions of native human glucagon (e.g. WO96/29342). Glucagon for preven BACKGROUND OF THE INVENTION tion of hypoglycaemia have been disclosed, as e.g. in patent 0004. The precise control of blood glucose levels is of vital application U.S. Pat. No. 7,314,859. importance to humans as well as other mammals. It is well 0010. The peptides of the present invention provide novel established that the two hormones insulin and glucagon are modified glucagon peptides with a protracted profile of action important for maintenance of correct blood glucose levels. in addition to providing Such modified glucagon peptides in While insulin acts in the liver and peripheral tissues by reduc stable pharmaceutical compositions at physiological pH. ing blood glucose levels via increased peripheral uptake of glucose and reduced glucose output from the liver, glucagon SUMMARY OF THE INVENTION acts mainly on the pancreas and liver, by increasing blood 0011. The present invention relates to novel glucagon pep glucose levels via up-regulation of gluconeogenesis and gly tides with improved physical stability and solubility, to the cogenolysis. Glucagon has also been reported to increase use of said peptides in therapy to methods of treatment com lipolysis, to induce ketosis and to reduce plasma triglyceride prising administration of said peptides to patients, and to the levels in plasma Schade and Eaton, Acta Diabetologica, use of said peptides in the manufacture of medicaments for 1977, 14, 62. use in the treatment of diabetes, eating-disorders, obesity and 0005 Glucagon is an important part of the defence mecha related diseases and conditions. nism against hypoglycaemia and administration of a low dose 0012. The present inventors have surprisingly found a of glucagon may prevent insulin-induced hypoglycaemia or number of positions in human glucagon where acylation with improve the ability to recover from hypoglycaemia. Studies a Substituent comprising a lipophilic moiety and two nega have also shown that glucagon does reduce food intake and tively charged moieties in combination with specific muta body weight in rats and in humans Schulman et al. J. Appl. tions in the glucagon peptide sequence, leads to glucagon Physiol.
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