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`EXHIBIT 3
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 2 of 26 PageID #: 191
`sees TTTTTA
`
`US009764003B2
`
`a2) United States Patent
`US 9,764,003 B2
`(0) Patent No.:
`Sep. 19, 2017
`(45) Date of Patent:
`Jensen
`
`(54) USE OF LONG-ACTING GLP-1 PEPTIDES
`
`(71) Applicant: Novo Nordisk A/S, Bagsvaerd (DK)
`
`(72)
`
`Inventor: Christine B. Jensen, Charlottenlund
`(DK)
`
`WO 2006097537 A2* 9/2006... CO7K 14/605
`DK
`2409349 C2
`1/2011
`RU
`2413530 C2
`3/2011
`RU
`2010/092163 A2
`8/2010
`WO
`2011/080103 Al
`7/2011
`WO
`2011138421 Al
`11/2011
`WO
`2012/016419 Al
`2/2012
`WO
`2012080471 Al
`6/2012
`WO
`2012107476 Al
`8/2012
`WO
`(73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK)
`
`WO 2012/130136 Al=10/2012
`WO
`2012/136790 Al
`10/2012
`1)
`y
`Subject to any disclaimer, the term of this
`Notice:
`*)
`
`WO 2012177929 A2=12/2012
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`OTHER PUBLICATIONS
`
`(21) Appl. No.:
`
` 14/409,493
`
`(22) PCT Filed:
`
`Jun. 21, 2013
`
`(86) PCT No.:
`
`PCT/EP2013/063004
`
`§ 371 (€)(),
`(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) on eeeeeeeeens 12174535
`(EP) onscreen 12186781
`
`(51)
`
`Int. Cl.
`A61K 38/26
`A6ILP 5/50
`A6ILP 3/04
`A6ILP 3/10
`(52) U.S. Cl.
`CPC voices ceeeeteneeeeseeees A61K 38/26 (2013.01)
`(58) Field of Classification Search
`None
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`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
`
`3/2012 Lauet al.
`9/2013 Lauet al.
`2/2010 Button etal.
`11/2010 Spetzleret al.
`12/2011 Bushetal.
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`CN
`
`102229668
`102229668 A
`
`11/2011
`11/2011
`
`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-
`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 assessmentreport, Euro. Med. Agency, pp. 1-124 (2014)—
`accessed Sep. 24, 2015 at URL: ema.europa.eu/docs/en__GB/docu-
`ment_library/EPAR_-_Public_assessment_report/human/
`002735/WC500165119 pdf.*
`Trulicity assessment report, Euro. Med. Agency, pp. 1-172 (2014)—
`accessed Sep. 24, 2015 at URL: ema.europa.eu/docs/en_GB/docu-
`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/adultweight.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.
`Mizutaet 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
`
`Primary Examiner — Julie Ha
`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
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 3 of 26 PageID #: 192
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`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 1 of6
`
`US 9,764,003 B2
`
`Ssemaglutide
`
`Liragiutide
`
`Baseline 8.1
`82
`82
`8.4
`82
`8.1
`8.4
`8.0
`8.1
`Flacebo 0.1 mg G.2mg 0.4 mg 0.6 mg ogg 16mg tamg 1.6 mg
`0.00
`
`
`
`
`0.25
`
`4.00
`
`~1.25
`
`—7.50
`
`~178
`
`~2.00
`
`*p<0.05 vs. placebo
`*o<DDOT ve. placeko
`*Sernagiutide 1.6 rg T superior to Hraglutide 1.2 mg and 1.8 mg
`Data are LS means.
`
`Fig. 1
`
`> ~0.50
`“2-075
`bA
`
`% H
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 4 of 26 PageID #: 193
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 4 of 26 PagelD #: 193
`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 2 of 6
`
`US 9,764,003 B2
`
`i
`eeRe
`
`‘9epanibedios
`
`ocdsiennetthinnnet:
`
`20a
`
`#0-
`
`sO
`
`ao
`
`Ot
`
`1:
`
`g1-9t-
`
`9%
`
`“yqH ul eBueyo
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`Fig. 2
`
`6AeBTBPHatmeen
`
`tau2°epomieiy
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`iBurOTSpAribeuadagen
`
`
`
`“Qepagnileues-p6
`
`Btugyepanpleuas—e.fupgepnn
`
`AEROSmidis
`
`
`
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 5 of 26 PageID #: 194
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 5 of 26 PagelD #: 194
`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 3 of6
`
`US 9,764,003 B2
`
`
`
`Fig. 3A
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 6 of 26 PageID #: 195
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 6 of 26 PagelD #: 195
`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 4 of6
`
`US 9,764,003 B2
`
`es
`
`Fig. 3B
`
`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 7 of 26 PageID #: 196
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 7 of 26 PagelD #: 196
`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 5 of6
`
`US 9,764,003 B2
`
`bh
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`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 8 of 26 PageID #: 197
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 8 of 26 PagelD #: 197
`
`U.S. Patent
`
`Sep. 19, 2017
`
`Sheet 6 of6
`
`US 9,764,003 B2
`
`Poe
`
`_vregiouee BS
`
`SERVOS:
`
`84.9
`
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`

`

`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 9 of 26 PageID #: 198
`Case 1:23-cv-00013-TSK Document 1-3 Filed 01/27/23 Page 9 of 26 PagelD #: 198
`
`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-
`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-
`visional Application 61/708,162; filed Oct. 1, 2012.
`The present invention relates to improved uses of GLP-1
`peptides in therapy.
`
`SEQUENCELISTING
`
`Theinstant 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
`copy,
`created
`on
`Jun.
`17,
`2013,
`is
`named
`8545US01_SeqList.txt and is 7,639 bytes in size.
`
`SUMMARY
`
`In one embodimentthe invention relates to a method for
`a) reduction of HbA1c; b) prevention or treatment of type 2
`diabetes, hyperglycemia,
`impaired glucose tolerance, or
`non-insulin dependent diabetes; or c) prevention or treat-
`mentof obesity, reducing body weight and/or food intake, or
`inducing satiety; wherein said method comprises adminis-
`tration of a GLP-1 agonist to a subject in need thereof,
`wherein said GLP-1 agonist 1) has a half-life of at least 72
`hours, wherein said half-life optionally is determined by
`Assay(IJ); i1) is administered in an amountofat least 0.7 mg
`per week, such an amount equivalent to at least 0.7 mg
`semaglutide per week; and 111) 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 HbA1c; b) the preven-
`tion or
`treatment of type 2 diabetes, hyperglycemia,
`impaired glucose tolerance, or non-insulin dependent dia-
`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 embodimentthe invention relates to a composition
`comprising a GLP-1 agonist for use in a) the reduction of
`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
`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
`less often, and wherein said GLP-1 agonist and/or admin-
`istration optionally is as defined herein.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1 shows change in HbA1c following subcutaneous
`administration of placebo, semaglutide, or liraglutide to
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`humansubjects. *p<0.05 vs. placebo; **p<0.001 vs. placebo
`(based on adjusted means). Baseline values are for infor-
`mation only: data are model-adjusted for baseline HbA1c.
`Data are model-adjusted LS means, FAS LOCF. Theesti-
`mates are from an ANOVA modelwith treatment, country
`and previous treatmentas 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
`treatments are placebo (A); semaglutide 0.1 mg (B, dashed
`line), 0.2 mg (C), 0.4 mg (D), 0.8 mg (EB), 0.8 mg T (F,
`dashed line), 1.6 mg T (G); liraglutide 1.2 mg (H), 1.8 mg
`(1).
`FIG. 3 shows subjects reaching the AACE (FIG. 3A) or
`ADA(FIG.3B) criteria for glycaemic control. The number
`of patients reaching the criteria per treatmentis 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 (EB), 0.8 mg T (F),
`1.6 mg T (G); liraglutide 1.2 mg (H), 1.8 mg (1). *p<0.05 vs.
`placebo; **p<0.001 vs. placebo; ***p<0.0001 vs. placebo
`(based on adjusted means). Data are FAS LOCF. Theesti-
`mates are from a logistic regression model treatment, coun-
`try and previous treatment as fixed effects and baseline
`HbA\lc as covariate. ADA, American Diabetes Association;
`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, dashedline), 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. 5 shows body weight change from baseline at week
`12. **p<0.001 vs. placebo; ***p<0.0001 vs. placebo (based
`on adjusted means. +: Baseline values for information only:
`data are model-adjusted for baseline weight. Data are model-
`adjusted LS means, FAS LOCF. The estimates are from an
`ANOVA model with treatment, country and previoustreat-
`mentas fixed effects and baseline weight as covariate.
`SE: Standard error. FAS: Full analysis set. LOCF: Last
`observation carried forward.
`
`DESCRIPTION
`
`invention relates to an improved use of
`The present
`GLP-1 agonists in therapy. In one embodimentthe 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 HbA1c or b) 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 HbA1c 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 amountof at least 0.7 mg per week, such an
`amount equivalentto at least 0.7 mg semaglutide per week.
`In one embodiment the method is for reduction of HbA1c.
`In one embodiment the method is for prevention or treat-
`ment of type 2 diabetes. In one embodiment the methodis
`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
`
`

`

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`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-
`sion.
`In one embodiment a HbAlec level below 7% is
`achieved. In one embodiment the level of HbAlIc is deter-
`
`mined according to the method defined by the Diabetes
`Control and Complications Trial (DCCT). In one embodi-
`ment the level of HbAlc is determined according to the
`method defined by the International Federation of Clinical
`Chemistry (FCC).
`In one embodimentthe 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 amountofat least 0.7 mg per week, such
`an amount equivalent to at least 0.7 mg semaglutide per
`week. In one embodiment the methodis for prevention or
`treatment of obesity. In one embodiment the methodis for
`reducing body weight and/or food intake. In one embodi-
`ment the methodis for inducing satiety.
`In one embodiment the GLP-1 agonist has a half-life ofat
`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
`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
`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 weekofat least 0.8 mg, at least 0.9 mg, or at
`least 1.0 mg. In one embodiment the GLP-1 agonist is
`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 ofat
`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
`an amount per week equivalentto 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
`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.
`Tn 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
`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 aminoacid residues which
`are not encoded by the genetic code.
`In one embodiment the GLP-1 peptide is a DPPIV pro-
`tected GLP-1 peptide. In one embodiment the GLP-1 pep-
`tide is DPPIVstabilised.
`In one embodiment the GLP-1 agonist has an EC. at or
`below 3000 pM,such as at or below 500 pM orat 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 HbA1c or for use in the
`
`10
`
`15
`
`20
`
`25
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`30
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`35
`
`40
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`45
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`50
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`55
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`60
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`65
`
`4
`prevention or treatment of type 2 diabetes, hyperglycemia,
`impaired glucose tolerance, or non-insulin dependent dia-
`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
`the reduction of body weight and/or food intake, or in the
`induction satiety comprising administering a GLP-1 agonist
`in an amountofat 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 embodimentthe invention relates to a composition
`comprising a GLP-1 agonist and one or more pharmaceuti-
`cally acceptable excipients for use in reduction of HbAlc or
`for prevention or treatment of type 2 diabetes, hyperglyce-
`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 embodimentthe invention relates to a composition
`comprising a GLP-1 agonist and one or more pharmaceuti-
`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 amountof at least 0.7 mg per
`week, such an amount equivalent to at least 0.7 mg sema-
`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 maybe 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 hourperiod, 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-
`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,
`thiazolidinediones, biguanides, meglitinides, glucosidase
`inhibitors, glucagon antagonists, and DPP-IV (dipeptidyl
`peptidase-IV) inhibitors.
`In one embodiment, as used herein, an “amount equiva-
`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. EC,,) within
`+30%, such as within +20% or within +10%, of each other
`optionally determined by Assay (1) 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
`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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`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 managementandcare of a patient for
`the purpose of combating a condition, such as a disease or
`a disorder. In one embodiment
`the term “treatment” or
`
`“treating” is intended to include the full spectrum oftreat-
`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-
`gression of the disease, disorder, or condition;to alleviate or
`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 embodimentpreventionis to be
`understood as the managementandcare of a patient for the
`purpose of combating the disease, condition, or disorder and
`includes the administration of the active compounds to
`prevent the onset of the symptoms or complications.
`In one embodimentthe term “hydrophilic spacer” as used
`herein means a spacer that separates a peptide and an
`albumin binding residue with a chemical moiety which
`comprises at least 5 non-hydrogen atoms where 30-50% of
`these are either N or O.
`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 addedto the peptide. Such addition or deletion of
`amino acid residues can take place at the N-terminal of the
`peptide and/or at the C-terminal of the peptide. A simple
`system is used to describe analogues: For example
`Are**GLP-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 embodimentthe 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-
`
`logue.
`In one embodimentthe term “DPP-IV protected” as used
`herein referring to a polypeptide means a polypeptide which
`has been chemically modified in order to render said com-
`pound resistant to the plasma peptidase dipeptidyl amino-
`peptidase-4 (DPP-IV). The DPP-IV enzyme in plasma is
`knownto 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-
`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-
`ments, the GLP-1 agonist of the invention may be used for
`the following medical treatments:
`(1) 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,
`MODY(maturity onset diabetes of the young), gestational
`diabetes, and/or for reduction of HbA1c;
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`(ii) delaying or preventing diabetic disease progression,
`such as progression in type 2 diabetes, delaying the pro-
`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;
`(i11) 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 (1). In
`a further particular embodiment the indication is (ii). In a
`still further particular embodimentthe 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-
`eases or conditions defined herein. In one embodiment the
`
`indication is (i) and (iii). In one embodimentthe indication
`is (ii) and (111). 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 embodimentthe invention relates to administration
`
`of an effective amount of a GLP-1 agonist.
`In one embodimentas used herein, specific values given
`in relation to numbersor 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-
`tion have a protracted pharmacokinetic profile. Also, or
`alternatively, in a third functional aspect, the GLP-1 agonists
`of the invention are stable against degradation by gastro
`intestinal enzymes.
`Biological Activity (Potency)
`According to the first functional aspect, the GLP-1 ago-
`nists of the invention are biologically active, or potent. In a
`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-
`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 cAMPa functional receptor assay, e.g. based on compe-
`tition between endogenously formed cAMP and exog-
`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
`cAMPAssay, such as the one described in Assay(I).
`In one embodiment
`the term half maximal effective
`
`concentration (EC;,) generally refers to the concentration
`which induces a response halfway between the baseline and
`maximum, by reference to the dose response curve. EC., is
`used as a measure of the potency of a compound and
`represents the concentration where 50% of its maximal
`effect is observed.
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`The in vitro potency of the GLP-1 agonists of the inven-
`tion may be determined as described above, and the EC,, of
`the GLP-1 agonist in question determined. The lower the
`EC,,, the better the potency.
`In a particular embodiment, the medium hasthe following
`composition (final in-assay concentrations): 50 mM TRIS-
`HCl; 5 mM HEPES; 10 mM MgCl,, 6H,O; 150 mM NaCl;
`0.01% Tween; 0.1% BSA; 0.5 mM IBMX; 1 mM ATP; 1 uM
`GTP; pH 7.4.
`In a further particular embodiment, the GLP-1 agonist of
`the invention has an in vitro potency corresponding to an
`EC,, 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 clinicaltrials.
`
`The diabetic db/db mouse is one example of a suitable
`animal model, and the blood glucose lowering effect may be
`determined in such mice in vivo, e.g. as described in Assay
`(IIT), or as described in Example 43 of WO09/030738.
`Also, or alternatively, the effect on food intake in vivo
`may be determined in pharmacodynamicstudies in pigs, e.g.
`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
`(T,,2) in vivo in minipigs after i.v. administration. In addi-
`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
`minipigs after i.v. administration is disclosed in Assay(II).
`Degradation by Gastro Intestinal Enzymes
`the GLP-1
`According to the third functional aspect,
`agonists of the invention are stable, or stabilised, against
`degradation by one or more gastro intestinal enzymes.
`Gastro intestinal enzymesinclude, 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
`gastrointestinal system.
`In a particular embodiment, the GLP-1 agonist of the
`invention has an in vitro half-life (T,,.) in an extract of rat
`small
`intestines, divided by the corresponding half-life
`(T,,2) of GLP-1 (7-37), of at least 1, such as above 1.0, at
`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 (T,,.) of the GLP-1
`agonist in question,
`in an extract of rat small intestines,
`divided by the corresponding half-life (T,,.) of GLP-1
`(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
`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
`of D-histidine, desamino-histidine, 2-amino-histidine, B-hy-
`droxy-histidine, homohistidine, N°-acetyl-histidine, a-fluo-
`romethyl-histidine, o-methyl-histidine, 3-pyridylalanine,
`2-pyridylalanine and 4-pyridylalanine.
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`In one embodiment the GLP-1 peptide is attached to a
`hydrophilic spacer via the amino acid residue in position 23,
`26, 34, 36 or 38 relative to the amino acid sequence of
`GLP-1 (7-37).
`In one embodiment the GLP-1 peptide is exendin-4, an
`exendin-4-analogue, or a derivative of exendin-4.
`In one embodiment the GLP-1 agonist peptide comprises
`the amino acid sequence of the following formula: H-His-
`Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-
`Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH,
`(SEQ ID NO: 2).
`the GLP-1 agonist comprises an
`In one embodiment
`albumin binding residue attached via a hydrophilic spacer to
`the C-terminal amino acid residue of said GLP-1 peptide.
`In one embodiment the GLP-1 agonist comprises a second
`albumin binding residue is attached to an amino ac