`US009764003B2
`
`c12) United States Patent
`Jensen
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,764,003 B2
`Sep.19,2017
`
`(54) USE OF LONG-ACTING GLP-1 PEPTIDES
`
`(71) Applicant: Novo Nordisk A/S, Bagsvaerd (DK)
`
`(72)
`
`Inventor: Christine B. Jensen, Charlottenlund
`(DK)
`
`(73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`14/409,493
`
`(22) PCT Filed:
`
`Jun. 21, 2013
`
`(86) PCT No.:
`
`PCT/EP2013/063004
`
`§ 371 (c)(l),
`(2) Date:
`
`Dec. 19, 2014
`
`(87) PCT Pub. No.: WO2014/005858
`
`PCT Pub. Date: Jan. 9, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0190474 Al
`
`Jul. 9, 2015
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/694,837, filed on Aug.
`30, 2012, provisional application No. 61/708,162,
`filed on Oct. 1, 2012.
`
`(30)
`
`Foreign Application Priority Data
`
`Jul. 1, 2012
`Oct. 1, 2012
`
`(EP)
`(EP)
`
`12174535
`12186781
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 38/26
`A61P5/50
`A61P3/04
`A61P3/10
`(52) U.S. Cl.
`CPC .................................... A61K 38/26 (2013.01)
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8,129,343 B2
`8,536,122 B2
`2010/0047762 Al
`2010/0292133 Al
`2011/0301080 Al
`
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`9/2013 Lau et al.
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`12/2011 Bush et al.
`
`FOREIGN PATENT DOCUMENTS
`
`CN
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`
`102229668
`102229668 A
`
`11/2011
`11/2011
`
`C07K 14/605
`
`DK
`RU
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO 2006097537 A2 * 9/2006
`2409349 C2
`1/2011
`2413530 C2
`3/2011
`2010/092163 A2
`8/2010
`2011/080103 Al
`7/2011
`2011138421 Al
`11/2011
`2012/016419 Al
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`2012080471 Al
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`2012/130136 Al
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`2012/136790 Al
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`2012177929 A2
`12/2012
`
`OTHER PUBLICATIONS
`
`Kim et al., "Effects of once-weekly dosing of a long-acting release
`formulation of exenatide on glucose control and body weight in
`subjects with type 2 diabetes," Diabetes Care 30:1487-1493
`(2007).*
`Bydureon NDA 022200/S-008 package information, pp. 1-179
`(Feb. 2014).*
`Clinical Trial NCT00696657, entitled "A Randomised Controlled
`Clinical Trial in Type 2 Diabetes Comparing Semaglutide to Pla(cid:173)
`cebo and Liraglutide," pp. 1-5 (Mar. 11, 2015)-accessed Sep. 24,
`2015 at URL clinicaltrials.gov/archive/NCT00696657/2011_03_
`25.*
`Lau et al., "Discovery of the once-weekly glucagon-like peptide-1
`(GLP-1) analogue semaglutide," J. Med. Chem. 58:7370-7380
`(2015).*
`Eperzan assessment report, Euro. Med. Agency, pp. 1-124 (2014)(cid:173)
`accessed Sep. 24, 2015 at URL: ema.europa.eu/docs/en_GB/docu(cid:173)
`ment_library/EPAR_ -_Public_assessment_report/human/
`002735/WC500165119 .pdf. *
`Trulicity assessment report, Euro. Med. Agency, pp. 1-172(2014)(cid:173)
`accessed Sep. 24, 2015 at URL: ema.europa.eu/docs/en_GB/docu(cid:173)
`ment_library/EPAR_ -_Public_assessment_report/human/
`002825/WC500179473.pdf).*
`CDC, "Nathional Health and Nutrition Examination Survey:
`Healthy weitght, overweight, and obesity among U.S. adults,"
`03-0260, pp. 1-2 (Jul. 2003) accessed May 10, 2016 at URL
`cdc. gov/ nchs/ data/nhanes/ databriefs/ adul tweight. pdf. *
`Madsbad S et al. An Overview of once-weekly glucagon-like
`peptide-1 receptor agonists available efficacy and safety data and
`perspectives for the future, Diabetes, Obesity and Metabolism Year
`2011, vol. 13, No. 5, pp. 394-407.
`Buse B. J. et al., Exenatide once weekly versus liraglutide once
`daily
`in patients with
`type 2 diabetes (DURATION-6): a
`randomised, open-label study, Lancet, 2013, vol. 381, pp. 117-124.
`Mizuta et al. "The Role for GLP-1 in Regulation of Body Weight."
`Progress in Medicine 2008 vol. 28 No. 8 pp. 1909-1912.
`
`* cited by examiner
`
`Julie Ha
`Primary Examiner -
`Assistant Examiner - Kristina M Hellman
`(74) Attorney, Agent, or Firm - Leon Y. Lum
`
`(57)
`
`ABSTRACT
`
`The invention relates to use of long-acting GLP-1 peptides
`in certain dosage regimes for the treatment of type 2
`diabetes, obesity, etc.
`
`6 Claims, 6 Drawing Sheets
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`
`
`U.S. Patent
`
`Sep.19,2017
`
`Sheet 1 of 6
`
`US 9,764,003 B2
`
`Liraglutide
`Semaglutide
`8,0
`8, 1
`8, 1
`8, 1
`8, 1
`8,2
`8,2
`8,2
`Baseline 8, 1
`Placebo0.1 mg 0.2mg 0.4mg 0.8mg 0.8mg 1.6mg 1.2mg 1.8mg
`T
`T
`
`~ ~::: ......... ~-~,....~-
`
`#
`£--0,75
`,c::( £ -1.00
`
`-1.25
`
`-1,50
`
`-1.75
`
`-2.00
`
`-1.18
`
`-1.34
`
`-1.69
`
`"p-<0.05 vs. placebo
`**p<0.001 vs. placebo
`~semagluhde 1.6 mg T superior to liraglutide 1.2 mg and 1.8 mg
`Data are LS means.
`
`Fig. 1
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`~ = = w = N
`
`0--,
`~
`\0
`
`d r.,;_
`
`0 ....
`N
`.....
`rJJ =(cid:173)
`
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`····,:::, ··semagfutide 0.2 mg
`
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`.,,
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`
`
`U.S. Patent
`
`Sep.19,2017
`
`Sheet 3 of 6
`
`US 9,764,003 B2
`
`Fig. 3A
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`
`
`U.S. Patent
`
`Sep.19, 2017
`
`Sheet 4 of 6
`
`US 9,764,003 B2
`
`.
`
`'
`
`.
`
`i ~:-~
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`~-
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`,~ "
`
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`
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`
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`
`~
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`
`Fig. 3 B
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`
`
`U.S. Patent
`
`Sep.19,2017
`
`Sheet 5 of 6
`
`US 9,764,003 B2
`
`N
`-,rl
`
`It'\
`
`tj'
`
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`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`
`
`U.S. Patent
`
`Sep.19,2017
`
`Sheet 6 of 6
`
`US 9,764,003 B2
`
`;.....
`
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`......
`
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`
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`
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`
`Fig. 5
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`
`
`US 9,764,003 B2
`
`1
`USE OF LONG-ACTING GLP-1 PEPTIDES
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a 35 U.S.C. §371 National Stage
`application of International Application PCT/EP2013/
`063004 (WO 2014/005858), filed Jun. 21, 2013, which
`claimed priority of European Patent Application
`12174535.0, filed Jul. 1, 2012 and European Patent Appli(cid:173)
`cation 12186781.6, filed Oct. 1, 2012; this application
`claims priority under 35 U.S.C. §119 of U.S. Provisional
`Application 61/694,837; filed Aug. 30, 2012 and U.S. Pro(cid:173)
`visional Application 61/708,162; filed Oct. 1, 2012.
`The present invention relates to improved uses of GLP-1
`peptides in therapy.
`
`SEQUENCE LISTING
`
`The instant application contains a Sequence Listing which
`has been submitted in ASCII format via EFS-Web and is
`hereby incorporated by reference in its entirety. Said ASCII
`on
`Jun.
`17,
`2013,
`is
`named
`copy,
`created
`8545USOl_SeqList.txt and is 7,639 bytes in size.
`
`SUMMARY
`
`In one embodiment the invention relates to a method for
`a) reduction of HbAlc; b) prevention or treatment of type 2
`diabetes, hyperglycemia, impaired glucose tolerance, or
`non-insulin dependent diabetes; or c) prevention or treat(cid:173)
`ment of obesity, reducing body weight and/or food intake, or
`inducing satiety; wherein said method comprises adminis(cid:173)
`tration of a GLP-1 agonist to a subject in need thereof,
`wherein said GLP-1 agonist i) has a half-life of at least 72
`hours, wherein said half-life optionally is determined by
`Assay (II); ii) is administered in an amount of at least 0.7 mg
`per week, such an amount equivalent to at least 0.7 mg
`semaglutide per week; and iii) is administered once weekly
`or less often.
`In one embodiment the invention relates to a GLP-1
`agonist for use in a) the reduction of HbAlc; b) the preven- 40
`tion or treatment of type 2 diabetes, hyperglycemia,
`impaired glucose tolerance, or non-insulin dependent dia(cid:173)
`betes; or c) the prevention or treatment of obesity, for
`reducing body weight and/or food intake, or for inducing
`satiety; wherein said use comprises administration of said
`GLP-1 agonist in an amount of at least 0.7 mg per week,
`such an amount equivalent to at least 0. 7 mg semaglutide per
`week, and wherein said GLP-1 agonist and/or administration
`optionally is as defined herein.
`In one embodiment the invention relates to a composition
`comprising a GLP-1 agonist for use in a) the reduction of 50
`HbAlc; b) the prevention or treatment of type 2 diabetes,
`hyperglycemia, impaired glucose tolerance, or non-insulin
`dependent diabetes; or c) the prevention or treatment of
`obesity, for reducing body weight and/or food intake, or for
`inducing satiety; wherein said GLP-1 agonist i) has a 55
`half-life of at least 72 hours, wherein said half-life optionally
`is determined by Assay (II); and ii) is administered in an
`amount of at least 0.7 mg per week, such an amount
`equivalent to at least 0.7 mg semaglutide per week; and
`wherein said composition is administered once weekly or 60
`less often, and wherein said GLP-1 agonist and/or admin(cid:173)
`istration optionally is as defined herein.
`
`2
`human subjects. *p<0.05 vs. placebo; **p<0.001 vs. placebo
`(based on adjusted means). Baseline values are for infor(cid:173)
`mation only: data are model-adjusted for baseline HbAlc.
`Data are model-adjusted LS means, FAS LOCF. The esti-
`5 mates are from an ANOVA model with treatment, country
`and previous treatment as fixed effects and baseline HbAlc
`as covariate.
`FIG. 2 shows mean change in HbAlc from baseline
`versus time; data are mean (1.96SE), FAS LOCF. The
`10 treatments are placebo (A); semaglutide 0.1 mg (B, dashed
`line), 0.2 mg (C), 0.4 mg (D), 0.8 mg (E), 0.8 mg T (F,
`dashed line), 1.6 mg T (G); liraglutide 1.2 mg (H), 1.8 mg
`(I).
`FIG. 3 shows subjects reaching the AACE (FIG. 3A) or
`15 ADA (FIG. 3B) criteria for glycaemic control. The number
`of patients reaching the criteria per treatment is indicated in
`each bar. The treatments are placebo (A); semaglutide 0.1
`mg (B), 0.2 mg (C), 0.4 mg (D), 0.8 mg (E), 0.8 mg T (F),
`1.6 mg T (G); liraglutide 1.2 mg (H), 1.8 mg (I). *p<0.05 vs.
`20 placebo; **p<0.001 vs. placebo; ***p<0.0001 vs. placebo
`(based on adjusted means). Data are FAS LOCF. The esti(cid:173)
`mates are from a logistic regression model treatment, coun(cid:173)
`try and previous treatment as fixed effects and baseline
`HbAlc as covariate. ADA, American Diabetes Association;
`25 AACE, American Association of Clinical Endocrinologists.
`FIG. 4 shows mean body weight change versus time; data
`are mean (1.96SE), FAS LOCF. The treatments are placebo
`(A); semaglutide 0.1 mg (B, dashed line), 0.2 mg (C), 0.4 mg
`(D), 0.8 mg (E), 0.8 mg T (F, dashed line), 1.6 mg T (G);
`30 liraglutide 1.2 mg (H), 1.8 mg (I).
`FIG. 5 shows body weight change from baseline at week
`12. **p<0.001 vs. placebo; ***p<0.0001 vs. placebo (based
`on adjusted means. t: Baseline values for information only:
`data are model-adjusted for baseline weight. Data are model-
`35 adjusted LS means, FAS LOCF. The estimates are from an
`ANOVA model with treatment, country and previous treat(cid:173)
`ment as fixed effects and baseline weight as covariate.
`SE: Standard error. FAS: Full analysis set. LOCF: Last
`observation carried forward.
`
`DESCRIPTION
`
`45
`
`The present invention relates to an improved use of
`GLP-1 agonists in therapy. In one embodiment the invention
`relates to certain dosage regimes of GLP-1 agonists which
`provide improved effect in diseases or conditions, such as
`prevention and/or treatment of type 2 diabetes and obesity.
`In one embodiment the methods of the present invention
`provides surprisingly showed improved reduction of HbAlc
`and reduction of body weight. In one embodiment the
`GLP-1 agonist is administered in an amount which provides
`an improved a) reduction in HbAlc orb) reduction in body
`weight compared to administration of 1.8 mg liraglutide or
`less, such as 0.8 mg liraglutide or less, per day.
`In one embodiment the invention relates to a method for
`reduction of HbAl c or for prevention or treatment of type 2
`diabetes, hyperglycemia, impaired glucose tolerance, or
`non-insulin dependent diabetes, said method comprising
`administration of a GLP-1 agonist to a subject in need
`thereof in an amount of at least 0.7 mg per week, such an
`amount equivalent to at least 0.7 mg semaglutide per week.
`In one embodiment the method is for reduction of HbAlc.
`In one embodiment the method is for prevention or treat(cid:173)
`ment of type 2 diabetes. In one embodiment the method is
`65 for prevention or treatment of hyperglycemia. In one
`embodiment the method is for prevention or treatment of
`impaired glucose tolerance. In one embodiment the method
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1 shows change in HbAlc following subcutaneous
`administration of placebo, semaglutide, or liraglutide to
`
`Novo Nordisk Exhibit 2002
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`
`
`US 9,764,003 B2
`
`3
`is for prevention or treatment of non-insulin dependent
`diabetes. In one embodiment the method of the invention
`comprises delaying or preventing diabetic disease progres(cid:173)
`sion. In one embodiment a HbAlc level below 7% is
`achieved. In one embodiment the level of HbAlc is deter(cid:173)
`mined according to the method defined by the Diabetes
`Control and Complications Trial (DCCT). In one embodi(cid:173)
`ment the level of HbAlc is determined according to the
`method defined by the International Federation of Clinical
`Chemistry (IFCC).
`In one embodiment the invention relates to a method for
`treating or preventing obesity, for reducing body weight
`and/or food intake, or for inducing satiety, said method
`comprising administration of a GLP-1 agonist to a subject in
`need thereof in an amount of at least 0.7 mg per week, such
`an amount equivalent to at least 0.7 mg semaglutide per
`week. In one embodiment the method is for prevention or
`treatment of obesity. In one embodiment the method is for
`reducing body weight and/or food intake. In one embodi(cid:173)
`ment the method is for inducing satiety.
`In one embodiment the GLP-1 agonist has a half-life of at
`least 24 hours, such as at least 48 hours, at least 60 hours,
`or at least 72 hours, or such as at least 84 hours, at least 96
`hours, or at least 108 hours, or optionally at least 120 hours,
`at least 132 hours, or at least 144 hours, wherein said 25
`half-life optionally is determined by Assay (II).
`In one embodiment the GLP-1 agonist is administered
`twice weekly or less often, once weekly or less often, or
`once weekly or less often. In one embodiment the GLP-1
`agonist is administered once every secondly week or less 30
`often, once every third week or less often, or once a month
`or less often.
`In one embodiment the GLP-1 agonist is administered in
`an amount per week of at least 0.8 mg, at least 0.9 mg, or at
`least 1.0 mg. In one embodiment the GLP-1 agonist is 35
`administered in an amount per week of at least 1.1 mg, at
`least 1.2 mg, or at least 1.3 mg. In one embodiment the
`GLP-1 agonist is administered in an amount per week of at
`least 1.4 mg, at least 1.5 mg, or at least 1.6 mg.
`In one embodiment the GLP-1 agonist is administered in 40
`an amount per week equivalent to at least 0.8 mg, at least 0.9
`mg, or at least 1.0 mg semaglutide. In one embodiment the
`GLP-1 agonist is administered in an amount per week
`equivalent to at least 1.1 mg, at least 1.2 mg, or at least 1.3
`mg semaglutide. In one embodiment the GLP-1 agonist is 45
`administered in an amount per week equivalent to at least
`1.4 mg, at least 1.5 mg, or at least 1.6 mg semaglutide.
`In one embodiment the GLP-1 agonist is selected from the
`group consisting of semaglutide, exenatide, albiglutide, and
`dulaglutide.
`In one embodiment the GLP-1 agonist is administered by
`parenteral administration, such as subcutaneous injection.
`In one embodiment the GLP-1 agonist is a GLP-1 peptide.
`In one embodiment the GLP-1 peptide comprises no more
`than 5, such as no more than 4 or no more than 3, amino acid 55
`residues which have been substituted, inserted or deleted as
`compared to GLP-1 (7-37). In one embodiment the GLP-1
`peptide comprises no more than 4 amino acid residues which
`are not encoded by the genetic code.
`In one embodiment the GLP-1 peptide is a DPPIV pro- 60
`tected GLP-1 peptide. In one embodiment the GLP-1 pep(cid:173)
`tide is DPPIV stabilised.
`In one embodiment the GLP-1 agonist has an EC50 at or
`below 3000 pM, such as at or below 500 pM or at or below
`100 pM, optionally determined by Assay (I).
`In one embodiment the invention relates to a GLP-1
`agonist for use in the reduction of HbAlc or for use in the
`
`4
`prevention or treatment of type 2 diabetes, hyperglycemia,
`impaired glucose tolerance, or non-insulin dependent dia(cid:173)
`betes comprising administering a GLP-1 agonist in an
`amount of at least 0.7 mg per week, such an amount
`equivalent to at least 0.7 mg semaglutide per week. In one
`embodiment the GLP-1 agonist and/or administration is as
`defined herein.
`In one embodiment the invention relates to a GLP-1
`agonist for use in the prevention or treatment of obesity, in
`10 the reduction of body weight and/or food intake, or in the
`induction satiety comprising administering a GLP-1 agonist
`in an amount of at least 0.7 mg per week, such an amount
`equivalent to at least 0.7 mg semaglutide per week. In one
`embodiment the GLP-1 agonist and/or administration is as
`15 defined herein.
`In one embodiment the invention relates to a composition
`comprising a GLP-1 agonist and one or more pharmaceuti(cid:173)
`cally acceptable excipients for use in reduction of HbAlc or
`for prevention or treatment of type 2 diabetes, hyperglyce-
`20 mia, impaired glucose tolerance, or non-insulin dependent
`diabetes, wherein said GLP-1 agonist is administered in an
`amount of at least 0.7 mg per week, such an amount
`equivalent to at least 0.7 mg semaglutide per week. In one
`embodiment the GLP-1 agonist and/or administration is as
`defined herein.
`In one embodiment the invention relates to a composition
`comprising a GLP-1 agonist and one or more pharmaceuti(cid:173)
`cally acceptable excipients for use in the prevention or
`treatment of obesity, in the reduction of body weight and/or
`food intake, or in the induction satiety, wherein said GLP-1
`agonist is administered in an amount of at least 0.7 mg per
`week, such an amount equivalent to at least 0.7 mg sema(cid:173)
`glutide per week. In one embodiment the GLP-1 agonist
`and/or administration is as defined herein.
`In one embodiment the GLP-1 agonist is administered
`with another therapeutic agent. Administration with another
`therapeutic agent may be carried out as administration of the
`GLP-1 agonist and the other therapeutic agent within the
`same therapeutic window ( e.g. within a period of two weeks,
`a period of one week, or in a 96, 72, or 48 hour period, etc.).
`The treatment with a GLP-1 agonist according to the present
`invention may be combined with one or more additional
`therapeutic agents, e.g. selected from antidiabetic agents,
`anti obesity agents, appetite regulating agents, antihyperten(cid:173)
`sive agents, agents for the treatment and/or prevention of
`complications resulting from or associated with diabetes and
`agents for the treatment and/or prevention of complications
`and disorders resulting from or associated with obesity;
`examples of these therapeutic agents are: sulphonylureas,
`50 thiazolidinediones, biguanides, meglitinides, glucosidase
`inhibitors, glucagon antagonists, and DPP-IV (dipeptidyl
`peptidase-IV) inhibitors.
`In one embodiment, as used herein, an "amount equiva(cid:173)
`lent to" when used in relation to GLP-1 agonists refers to
`amounts of a first GLP-1 agonist and a second GLP-1
`agonist having GLP-1 receptor potency (i.e. EC50) within
`±30%, such as within ±20% or within ±10%, of each other
`optionally determined by Assay (I) described herein and
`having a half-life within ±30%, such as within ±20% or
`within ±10%, of each other optionally determined by Assay
`(II) described herein.
`In one embodiment an "effective amount" of a GLP-1
`agonist as used herein means an amount sufficient to cure,
`alleviate, or partially arrest the clinical manifestations of a
`65 given disease or state and its complications. An amount
`adequate to accomplish this is defined as "effective amount".
`Effective amounts for each purpose will depend on the
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`5
`severity of the disease or injury as well as the weight and
`general state of the subject. It will be understood that
`determining an appropriate dosage may be achieved using
`routine experimentation, by constructing a matrix of values
`and testing different points in the matrix, which is all within
`the ordinary skills of a trained physician or veterinary.
`In one embodiment the term "treatment" or "treating" as
`used herein means the management and care of a patient for
`the purpose of combating a condition, such as a disease or
`a disorder. In one embodiment the term "treatment" or 10
`"treating" is intended to include the full spectrum of treat(cid:173)
`ments for a given condition from which the patient is
`suffering, such as administration of the active compound to
`alleviate the symptoms or complications; to delay the pro(cid:173)
`gression of the disease, disorder, or condition; to alleviate or 15
`relieve the symptoms and complications; and/or, to cure or
`eliminate the disease, disorder, or condition as well as to
`prevent the condition. In one embodiment prevention is to be
`understood as the management and care of a patient for the
`purpose of combating the disease, condition, or disorder and 20
`includes the administration of the active compounds to
`prevent the onset of the symptoms or complications.
`In one embodiment the term "hydrophilic spacer" as used
`herein means a spacer that separates a peptide and an
`albumin binding residue with a chemical moiety which 25
`comprises at least 5 non-hydrogen atoms where 30-50% of
`these are either N or 0.
`In one embodiment the term "analogue" as used herein
`referring to a polypeptide means a modified peptide wherein
`one or more amino acid residues of the peptide have been
`substituted by other amino acid residues and/or wherein one
`or more amino acid residues have been deleted from the
`peptide and or wherein one or more amino acid residues
`have been added to the peptide. Such addition or deletion of
`amino acid residues can take place at the N-terminal of the 35
`peptide and/or at the C-terminal of the peptide. A simple
`system
`is used to describe analogues: For example
`Arg34GLP-1 (7-37) Lys designates a GLP-1 analogue
`wherein the naturally occurring lysine at position 34 has
`been substituted with arginine and a lysine residue has been
`added to the C-terminal (position 38).
`In one embodiment the term "GLP-1 peptide" as used
`herein means GLP-1 (7-37), a GLP-1 analogue, a GLP-1
`derivative or a derivative of a GLP-1 analogue.
`In one embodiment the term "exendin-4 peptide" as used
`herein means exendin-4 (1-39), an exendin-4 analogue, an
`exendin-4 derivative or a derivative of an exendin-4 ana(cid:173)
`logue.
`In one embodiment the term "DPP-IV protected" as used
`herein referring to a polypeptide means a polypeptide which 50
`has been chemically modified in order to render said com(cid:173)
`pound resistant to the plasma peptidase dipeptidyl amino(cid:173)
`peptidase-4 (DPP-IV). The DPP-IV enzyme in plasma is
`known to be involved in the degradation of several peptide
`hormones, e.g. GLP-1, Exendin-4 etc. Thus a considerable
`effort is being made to develop GLP-1 agonists less suscep(cid:173)
`tible to DPP-IV mediated hydrolysis in order to reduce the
`rate of degradation by DPP-IV.
`The present invention also relates to a GLP-1 agonist of
`the invention, for use as a medicament. In particular embodi(cid:173)
`ments, the GLP-1 agonist of the invention may be used for
`the following medical treatments:
`(i) prevention and/or treatment of all forms of diabetes,
`such as hyperglycemia, type 2 diabetes, impaired glucose
`tolerance, type 1 diabetes, non-insulin dependent diabetes, 65
`MODY (maturity onset diabetes of the young), gestational
`diabetes, and/or for reduction of HbAlc;
`
`6
`(ii) delaying or preventing diabetic disease progression,
`such as progression in type 2 diabetes, delaying the pro(cid:173)
`gression of impaired glucose tolerance (IGT) to insulin
`requiring type 2 diabetes, and/or delaying the progression of
`non-insulin requiring type 2 diabetes to insulin requiring
`type 2 diabetes;
`(iii) prevention and/or treatment of eating disorders, such
`as obesity, e.g. by decreasing food intake, reducing body
`weight, suppressing appetite, inducing satiety; treating or
`preventing binge eating disorder, bulimia nervosa, and/or
`obesity induced by administration of an antipsychotic or a
`steroid; reduction of gastric motility; and/or delaying gastric
`emptying.
`In another particular embodiment, the indication is (i). In
`a further particular embodiment the indication is (ii). In a
`still further particular embodiment the indication is (iii). In
`one embodiment the indication is type 2 diabetes and/or
`obesity.
`In one embodiment the method comprises prevention,
`treatment, reduction and/or induction in one or more dis(cid:173)
`eases or conditions defined herein. In one embodiment the
`indication is (i) and (iii). In one embodiment the indication
`is (ii) and (iii). In one embodiment the method comprises
`prevention, treatment, reduction and/or induction in one or
`more diseases or conditions selected from a) and b ), a) and
`c ), b) and c ), or a), b) and c) as defined in claim 1.
`In one embodiment the invention relates to administration
`of an effective amount of a GLP-1 agonist.
`In one embodiment as used herein, specific values given
`in relation to numbers or intervals may be understood as the
`specific value or as about the specific value.
`Functional Properties
`In a first functional aspect, the GLP-1 agonists of the
`invention have a good potency. Also, or alternatively, in a
`second functional aspect, the GLP-1 agonists of the inven(cid:173)
`tion have a protracted pharmacokinetic profile. Also, or
`alternatively, in a third functional aspect, the GLP-1 agonists
`40 of the invention are stable against degradation by gastro
`intestinal enzymes.
`Biological Activity (Potency)
`According to the first functional aspect, the GLP-1 ago(cid:173)
`nists of the invention are biologically active, or potent. In a
`45 particular embodiment, "potency" and/or "activity" refers to
`in vitro potency, i.e. performance in a functional GLP-1
`receptor assay, more in particular to the capability of stimu(cid:173)
`lating cAMP formation in a cell line expressing the cloned
`human GLP-1 receptor.
`The stimulation of the formation of cAMP in a medium
`containing the human GLP-1 receptor may preferably be
`determined using a stable transfected cell-line such as
`BHK467-12A (tk-ts13), and/or using for the determination
`of cAMP a functional receptor assay, e.g. based on compe(cid:173)
`tition between endogenously formed cAMP and exog(cid:173)
`enously added biotin-labelled cAMP, in which assay cAMP
`is more preferably captured using a specific antibody, and/or
`wherein an even more preferred assay is the AlphaScreen
`60 cAMP Assay, such as the one described in Assay (I).
`In one embodiment the term half maximal effective
`concentration (EC50 ) generally refers to the concentration
`which induces a response halfway between the baseline and
`maximum, by reference to the dose response curve. EC50 is
`used as a measure of the potency of a compound and
`represents the concentration where 50% of its maximal
`effect is observed.
`
`30
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`55
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`US 9,764,003 B2
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`7
`The in vitro potency of the GLP-1 agonists of the inven(cid:173)
`tion may be determined as described above, and the EC50 of
`the GLP-1 agonist in question determined. The lower the
`EC50 , the better the potency.
`In a particular embodiment, the medium has the following 5
`composition (final in-assay concentrations): 50 mM TRIS(cid:173)
`HCI; 5 mM HEPES; 10 mM MgCl 2 , 6H2 O; 150 mM NaCl;
`0.01%Tween; 0.1%BSA; 0.5mMIBMX; 1 mMATP; 1 µM
`GTP; pH 7.4.
`In a further particular embodiment, the GLP-1 agonist of 10
`the invention has an in vitro potency corresponding to an
`EC50 at or below 3000 pM, such as below 2000 pM, below
`1000 pM, or below 500 pM, or such as below 200 pM or
`below 100 pM.
`In another particular embodiment the GLP-1 agonist of
`the invention are potent in vivo, which may be determined
`as is known in the art in any suitable animal model, as well
`as in clinical trials.
`The diabetic db/db mouse is one example of a suitable 20
`animal model, and the blood glucose lowering effect may be
`determined in such mice in vivo, e.g. as described in Assay
`(III), or as described in Example 43 of WO09/030738.
`Also, or alternatively, the effect on food intake in vivo
`may be determined in pharmacodynamic studies in pigs, e.g. 25
`as described in Assay (IV).
`Protraction-Half Life In Vivo in Minipigs
`According to the second functional aspect, the GLP-1
`agonists of the invention are protracted. In a particular
`embodiment protraction may be determined as half-life 30
`(T112) in vivo in minipigs after i.v. administration. In addi(cid:173)
`tional embodiments, the half-life is at least 24 hours, such as
`at least 48 hours, at least 60 hours, at least 72 hours, or such
`as at least 84 hours, at least 96 hours, or at least 108 hours.
`A suitable assay for determining half-life in vivo in 35
`minipigs after i.v. administration is disclosed in Assay (II).
`Degradation by Gastro Intestinal Enzymes
`According to the third functional aspect, the GLP-1
`agonists of the invention are stable, or stabilised, against
`degradation by one or more gastro intestinal enzymes.
`Gastro intestinal enzymes include, without limitation, exo
`and endo peptidases, such as pepsin, trypsin, chymotrypsin,
`elastases, and carboxypeptidases. The stability may be tested
`against these gastro intestinal enzymes in the form of
`purified enzymes, or in the form of extracts from the 45
`gastrointestinal system.
`In a particular embodiment, the GLP-1 agonist of the
`invention has an in vitro half-life (T 112) in an extract of rat
`small intestines, divided by the corresponding half-life
`(T112) of GLP-1 (7-37), of at least 1, such as above 1.0, at 50
`least 1.2, at least 2.0, or such as at least 3.0, or at least 4.0.
`In other words, a ratio (SI) may be defined for each GLP-1
`agonist, viz. as the in vitro half-life (T112) of the GLP-1
`agonist in question, in an extract of rat small intestines,
`divided by the corresponding half-life (T 112) of GLP-1 55
`(7-37).
`A suitable assay for determining in vitro half-life in an
`extract of rat small intestines is disclosed in Assay (V).
`GLP-1 Agonists
`In one embodiment the GLP-1 peptide comprises an Aib 60
`residue in position 8.
`In one embodiment the amino acid residue in position 7
`of said GLP-1 peptide is selected from the group consisting
`ofD-histidine, desamino-histidine, 2-amino-histidine, ~-hy(cid:173)
`droxy-histidine, homohistidine, N"'-acetyl-histidine, a-fluo- 65
`romethy I-histidine, a-methy I-histidine, 3-pyridy !alanine,
`2-pyridylalanine and 4-pyridylalanine.
`
`8
`In one embodiment the GLP-1 peptide is attached to a
`hydrophilic spacer via the amino acid resid