I 1111111111111111 11111 1111111111 11111 1111111111 1111111111111111 IIII IIII IIII
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`US008759291B2
`
`(10)Patent No.: US 8,759,291 B2
`c12) United States Patent
`(45)Date of Patent:
`Young et al.
`*Jun. 24, 2014
`
`(54)METHODS OF TREATMENT USING
`
`EXENDIN PEPTIDES OR GLP-1 PEPTIDES
`
`
`7,153,825 B2 12/2006 Young et al.
`
`7,442,680 B2 10/2008 Young et al.
`
`
`7,928,065 B2 * 4/2011 Young et al. 514/6.7
`
`(75)Inventors: Andrew A. Young, Research Triangle
`
`
`Park, NC (US); Will Vine, Poway, CA
`
`
`(US); Kathryn Prickett, Foster City, CA
`WO
`
`
`(US); Nigel R.A. Beeley, Solana Beach,
`WO
`CA (US)
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`
`WO98/05351 2/1998
`
`WO 99/07404 2/1999
`
`OTHER PUBLICATIONS
`
`(73) Assignees: Amylin Pharmaceuticals, LLC, San
`
`
`Barragan at al., Interactions of Exendin-(9-39) with the effects of
`
`
`
`
`
`
`Diego, CA (US); AstraZeneca
`
`
`
`glucagon-like peptide-1-(7-36) amide and of Exendin-4 on arterial
`
`Pharmaceuticals LP, Wilmington, DE
`
`
`
`blood pressure and heart rate in rats, Regulatory Peptides 67:63-68
`
`(US)
`(1996).
`Bhaysar et al., Inhibition of gastric emptying and of food intake
`
`
`
`
`
`( *) Notice: Subject to any disclaimer, the term ofthis
`
`
`
`
`
`
`appear to be independently controlled in rodents, Soc. Neurosci.
`
`
`
`patent is extended or adjusted under 35
`
`
`
`
`Abstr. 21:460 (Abstract 188.8) (1995).
`
`
`U.S.C. 154(b) by 541 days.
`D' Alessio et al., Elimination of the Action ofGlucagon-like Peptide
`
`
`
`
`
`
`
`
`This patent is subject to a terminal dis­
`
`
`
`1 Causes an Impairment of Glucose Tolerance after Nutrient Inges­
`
`
`
`
`tion by Healthy Baboons, J Clin. Invest. 97(1): 133-138 (1996).
`claimer.
`
`
`
`Edwards et al., Cardiovascular and Pancreatic Endocrine Responses
`
`to Glucagon-Like Peptide-1(7-36)Amide in the Conscious Calf, Exp.
`
`
`
`
`P hysiol. 82:709-716 (1997).
`Eissele at al., Rat Gastric Somatostatin and Gastrin Release: Interac­
`
`
`
`
`
`
`
`
`
`tions ofExendin-4 and Truncated Glucagon-Like Peptide-1 (GLP-1)
`Amide, Life Sci. 55(8):629-634 (1994).
`
`
`
`
`Eng et al., Purification and Structure ofExendin-3, a New Pancreatic
`
`
`
`
`Secretagoguge Isolated from Heloderma horridum Venom, J Biol.
`Chem. 265(33):20259-20262 (1990).
`
`
`
`
`Eng et al., Isolation and Characterization ofExendin-4, an Exendin-3
`
`
`
`
`Analogue, from Heloderma suspectum Venom, J Biol. Chem.,
`Related U.S. Application Data
`267(11):7402-7405 (1992).
`(60) Continuation of application No. 12/247,141, filed on
`
`
`
`
`
`
`Fehmann et al., Stable Expression of the Rat GLP-1(7-36)-Amide,
`
`Oct. 7, 2008, now Pat. No. 7,928,065, which is a
`
`Oxyntomodulin, Exendin-4, and Exendin (9-39), Peptides,
`
`
`
`
`
`continuation of application No. 10/656,093, filed on
`
`15(3):453-456 (1994).
`
`
`Sep. 5, 2003, now Pat. No. 7,442,680, which is a
`Ferguson et al., Cell-Surface Anchoring of Proteins via
`
`
`
`
`
`
`Glycosylphosphatidylinositol Structures, Annu. Rev. Biochem.
`
`
`
`division of application No. 09/622,105, filed as
`
`57:285-320 (1988).
`
`
`application No. PCT/US99/02554 on Feb. 5, 1999,
`
`now Pat. No. 6,703,359.
`
`(21)Appl. No.: 13/080,051
`
`
`
`(22) Filed: Apr. 5, 2011
`
`(65)
`
`
`
`Prior Publication Data
`
`
`
`US 2011/0195904Al Aug.11,2011
`
`
`
`(Continued)
`
`
`
`
`
`Provisional application No. 60/075,122, filed on Feb.
`
`
`
`(60)
`13, 1998.
`
`(30)
`
`Primary Examiner - Jeffrey E Russel
`
`
`(74)Attorney, Agent, or Firm - Womble, Carlyle,
`Foreign Application Priority Data
`
`Sandridge & Rice LLP; Mark J. Pino; Alireza Behrooz
`
`
`
`May 24, 2004 (KR) ........................ 10-2004-0036855
`
`(57)
`ABSTRACT
`
`(51)
`Int. Cl.
`A61K 38122
`
`Methods for increasing urine flow are disclosed, comprising
`
`
`
`(2006.01)
`
`
`administration of an effective amount of GLP-1, an exendin,
`
`C07K 141575 (2006.01)
`
`
`
`or an exendin or GLP-1 agonist. Methods for increasing uri­
`
`(52) U.S.Cl.
`
`
`
`
`nary sodium excretion and decreasing urinary potassium con­
`
`
`
`USPC ........ 514/11.7; 514/15.4; 514/15.7; 514/16.4
`
`
`
`centration are also disclosed. The methods are useful for
`
`
`(58) Field of Classification Search
`
`
`
`
`treating conditions or disorders associated with toxic hyper­
`None
`
`
`
`
`volemia, such as renal failure, congestive heart failure, neph­
`
`
`
`
`rotic syndrome, cirrhosis, pulmonary edema, and hyperten­
`
`
`
`
`sion. The present invention also relates to methods for
`
`
`
`
`
`inducing an inotropic response comprising administration of
`
`
`
`
`an effective amount ofGLP-1, an exendin, or an exendin or
`
`
`
`GLP-1 agonist. These methods are useful for treating condi­
`
`
`
`tions or disorders that can be alleviated by an increase in
`
`
`
`
`cardiac contractility such as congestive heart failure. Pharma­
`
`
`
`ceutical compositions for use in the methods of the invention
`are also disclosed.
`
`
`
`
`
`See application file for complete search history.
`
`(56)
`
`
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`
`
`5,424,286 A 6/1995 Eng
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`5,512,549 A 4/ 1996 Chen et al.
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`5,545,618 A 8/ 1996 Buckley et al.
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`5,574,008 A 1111996 Johnson et al.
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`5,955,480 A 9/1999 Chang
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`6,703,359 Bl 3/2004 Young et al.
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`
`7,105,490 B2 9/2006 Beeley et al.
`
`15 Claims, 18 Drawing Sheets
`
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`
`

`

`US 8,759,291 B2
`
`Page 2
`
`125
`
`39
`
`(56)
`
`References
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`Schinzel et al., The Phosphate Recognition Site of Escherichia coli
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`Maltodextrin Phosphorylase, FEES Letters 286: 125-128 ( 1991 ).
`OTHER PUBLICATIONS
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`
`Schjoldager et al., GLP-1 (Glucagon-like Peptide 1) and Truncated
`
`
`
`
`Giike et al., Exedin-4 is a High Potency Agonist and Truncated
`
`
`
`
`GLP-1, Fragments of Human Proglucagon, Inhibit Gastric Acid
`
`
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`Exenin-(9-39)-amide an Antagonist at the Glucagon-like Peptide
`
`
`
`
`
`Secretion in Humans, Digestive Disease and Sciences 34(5):703-708
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`
`
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`1-(7-36)-amide Receptor oflnsulin-secreting fl Cells, J Biol. Chem.
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`268(26): 19650-19655 (1993).
`Singh et al., Use of I-[Y]Exendin-4 to characterize receptors on
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`Knudsen et al., Potent Derivatives of Glucagon-like Peptide-I with
`
`
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`dispersed pancreatic acini and gastric chief cells from guinea pig,
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`Pharmacokinetic Properties Suitable for Once Daily Administration,
`
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`Regulatory Peptides 53:47-59 (1994).
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`J Med. Chem.43:1664-1669 (2000).
`
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`Tang-Christensen et al., Central administration of GLP-1-(7-36)
`
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`Kolligs et al., Reduction of the Incretin Effecty in Rats by the
`
`
`amide inhibits food and water intake in rats, Am. J Physiol.
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`Glucagon-Like Peptide 1 Receptor Angatonist Exendin (9-39)
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`271:R848-R856 (1996).
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`Amide, Diabetes 44:16-19 (1995).
`Thorens et al., Expression cloning of the Pancreatic fl Cell Receptor
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`Malhotra et al., Exendin-4, a new peptide fromHeloderma suspectum
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`
`
`
`
`
`
`for the gluco-incretin hormone glucagon-like peptide 1, Proc. Natl.
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`venom, potentiates cholecystokinin-induced amylase release from
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`Acad. Sci. USA 88:8641-8645 (1992).
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`rat pancreatic acini, Regulatory Peptides 41: 149-156 ( 1992).
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`Thorens et al., Cloning and Functional Expression of the Human Islet
`
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`Montrose-Rafizadeh et al., Structure-Function Analysis ofExendin-4
`
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`
`GLP-1 Receptor, Diabetes 42:1678-1682 (1993).
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`
`/ GLP-1 analogs, Diabetes 45(Suppl. 2):152A (1996).
`
`
`Turton et al., A Role for Glucagon-like peptide-I in the central
`
`
`
`
`O'Halloran et al., Glucagon-Like Peptide-I (7-36)-NH2: a physi­
`
`
`
`regulation of feeding, Nature 379:69-72 (1996).
`
`
`
`ological inhibitor of gastric acid secretaion in man, J Endocrinology
`
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`Wang et al., Glucagon-like Peptide-I is a Physiological incretin in
`
`126:169-173 (1990).
`
`Rat, J Clin. Invest. 95:417-421 (1995).
`
`
`0rskov et al., Biological Effects and Metabolic Rates ofGlucagon­
`
`
`
`Wettergren et al., Truncated GLP-1 (Proglucagon 78-107-Amide)
`
`
`
`like Peptide-I 7-36 Amide and Glucagonlike Peptide-I 7-37 in
`
`
`
`
`Inhibits Gastric and Pancreatic Functions in Man, Digestive Diseases
`
`
`
`
`
`Healthy Subjects are Indistinguishable, Diabetes 42:658-661 ( 1993).
`
`
`and Sciences 38(4):665-673 (1993).
`
`
`
`Raufman et al., Exendin-3, a Novel Peptide from Heloderma hor­
`Whims et al., Gastric emptying, Glucose Responses, and Insulin
`
`
`
`
`
`
`
`
`ridum Venom, Interacts with Vasoactive Intestinal Peptide Receptors
`
`
`
`
`Secretion after a Liquid Test Meal: Effects of Exogenous Glucagon­
`
`
`and a Newly Described Receptor on Dispersed Acini from Guinea
`
`
`Like Peptide-I (GLP-l-(7-36)Amide iN Type 2 (Noninsulin-Depen­
`
`
`
`Pig Pancreas, J Biol. Chem., 266(5):2897-2902 (1991).
`
`
`
`dent) Diabetic Patietns, J Clin. Endocrinol Metab. 81(1):327-332
`
`
`
`
`
`Raufman et al., Truncated Glucagon-Like Peptide-I Interacts with
`(1996).
`
`
`
`
`Exendin Receptors in Dispersed Acini from Guinea Pig Pancreas, J
`Young et al., Preclinical Pharmacology of Pramlintide in the Rat:
`
`
`
`
`Biol. Chem. 267(30):21432-21437 (1992).
`
`
`
`Comparisons with Human and and Rat Amylin, Drug Development
`
`
`
`Schepp et al., Exendin-4 and Exendin-(9-39)NH: Agonist and
`2
`
`
`Research 37:231-248 (1996).
`
`
`
`
`
`Antagonist, Respectively, at the Rat Parietal Cell Receptor for
`
`
`Glucagon-Like Peptide-l-(7-36)NHi, Eur. J Pharm. 269:183-191
`*cited by examiner
`(1994).
`
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`
`

`

`U.S. Patent
`US 8,759,291 B2
`Sheet 1 of 18
`Jun.24,2014
`
`Response of MAP to GLP-1
`
`Ill
`
`--165 µg GlP1
`---16.61-19 GlP1
`ci 120
`.....-1.65 pg GLP1
`-'f-0.165 pg GlP1
`-o-0.0165 µg GLP1
`-o-saline
`
`� �
`a. 110
`<(
`
`100
`
`11Q14-----.--.....----r---r----,,---;---'---,---,
`-1.5
`1.0 1.5 2.0 2.5
`0.0
`0.5
`hours post lv dose
`
`AGURE1A
`
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`
`

`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 2 of 18
`
`US 8,759,291 B2
`
`Dose-response curve
`MAP to GP-1
`
`300
`
`
`
`EDss 1.2-0.27.u.
`
`logy dose (pg)
`
`FIGURE 1B
`
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`
`

`

`U.S. Patent
`Sheet 3 of 18 US 8,759,291
`B2
`Jun.24,2014
`
`lnotropic effect of GLP-1
`
`140
`
`130
`
`-;-:s
`
`
`cU
`:;i, 120
`0
`!:2
`C
`
`g 110
`
`-0
`
`
`
`-C:
`CD 100
`e CD
`,8:
`- 90
`
`E: "CJ
`8
`
`-ts-80pg
`
`�� eJ.n s.:m· NJoc, � � eJm�
`Tlmeofday
`
`FIGURB2
`
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`

`

`
`U.S. Patent
`Jun.24,2014
`
`Sheet 4 of 18 US 8,759,291 B2
`
`
`
`Response of urine flow to GLP-1
`
`---165 µg GLP1
`-...1s.5 PG GLP1
`---1.65 119 GLP1
`-'f-0.165 J.19GlP1
`-0-0.0165119 GLP1
`-O-saline
`
`2500
`
`_ 2000
`CD
`
`a_ 1500
`
`r;::: 1000
`CD
`
`500
`
`0-+--------,.------.....----.----.--------
`-1.o-0.S p.o 0.5 1.0 1.S
`hows pcm Iv dose
`
`2.0
`
`2.5
`
`FIGURB3A
`
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`

`

`
`U.S. Patent
`Jun.24,2014
`
`Sheet 5 of 18 US 8,759,291 B2
`
`Dos&-response curve:
`Urine flow to GLP-1
`
`2000 EDso=Q.71±0.26 t.u.
`
`o.t-=· =::;::::=-"T--�-......------.
`3
`--3 -2
`.,
`0
`1
`2
`tog Iv dose (J.tg)
`
`FlGUR.E3B
`
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`

`

`U.S. Patent
`Sheet 6 of 18
`Jun.24,2014
`
`US 8,759,291 B2
`
`Response of sodium excretion to GLP-1
`
`o _ 2000
`:I CD
`e.,, C) 0
`>< 'tS
`G!,
`e c..
`-=� -c-
`i 1000
`
`-O-saline
`-o-0.0165 µ.g Gl.P1
`-+-0.165 µg GlP1
`_,._1.65µgGLP1
`-+- 16.5 µg GLP1
`-.-155 µgGLP1
`
`hours post Iv dose
`
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`

`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 7 of 18
`
`US 8,759,291 B2
`
`Dose-response Curve:
`Sodium excretion to GLP-1
`
`3000
`
`
`
`2000
`
`ED-0.77+0.05.u.
`
`3
`
`2
`
`s
`
`O
`log tv dose (g)
`
`2
`
`3.
`
`FIGURE 4B
`
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`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 8 of 18
`
`US 8,759,291 B2
`
`Response of trine potassium concentration to GLP-1
`150
`
`25
`
`100
`
`5075
`
`
`
`-- 165g GLP
`-o- 6.5g GP
`--d- 1.65 g GP1
`--0.165pg GP
`-o-0.0185g GLP1
`-O-sans
`
`O
`
`05
`
`t
`OS
`:ours post tv dose
`
`1S
`
`25
`
`FIGURESA
`
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`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 9 of 18
`
`US 8,759,291 B2
`
`Dose-response curve:
`Urine potassium concentration to GLP-1
`
`GO
`
`
`
`ED50.25-0.341.u.
`
`-3
`
`2
`
`-
`log v dose (g)
`
`2
`
`3.
`
`FIGURE 5B
`
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`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 10 of 18
`
`US 8,759,291 B2
`
`Response of MAP to Exendin-4
`
`
`
`140
`g 130
`C f2O
`Cl
`
`10
`s 100
`
`90
`
`--210 pig exendin-4
`-O-21 g exendin-4
`--21 g exendin-4
`A - 0.21 pig exendin-4
`7- 0.02) g exerdin-4
`-- 0.0021 g exendin-4
`-O-Saline
`
`8O
`-10
`
`-0.5
`
`.0
`O.S
`O.O
`hours post iv. dose
`
`5
`
`20
`
`25
`
`FGURE BA
`
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`

`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 11 of 18
`
`US 8,759,291 B2
`
`Dose-Response Curve:
`MAP to Exerdin-4
`
`75
`
`
`
`ED500,240.24.U.
`
`logy dose (g)
`
`FGURE 63
`
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`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 12 of 18
`
`US 8,759,291 B2
`
`lonotropic effect of exendin-4
`
`
`
`1.5
`
`2.0
`
`3.0
`2.5
`Days of treatment
`
`3.5
`
`Figure 7
`
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`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 13 of 18
`
`US 8,759,291 B2
`
`Response of Urine Flow to Exerdin-4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`t
`
`-r-210 g exendin-4
`-O-21 g exendin-4
`-T-2.1 g exendin-4
`A- 0.2 pig extendin-4
`-- 0,021 pig exendin-4
`rt- 0.0021 g exendin1
`-O-Saline
`
`s
`
`-5
`
`O
`S
`1.
`s
`hours post tv dose
`
`2.
`
`25
`
`FGRE8A
`
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`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 14 of 18
`
`US 8,759,291 B2
`
`Dose-Response Curve:
`Urine Flow to Exendit-4
`
`500
`
`
`
`400
`
`E
`w S 300
`SS a si aw
`
`200
`
`e
`t
`s
`
`O
`
`ED50=0.210.8 .i.
`
`FGURE 8B
`
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`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 15 of 18
`
`US 8,759,291 B2
`
`Response of Sodium Excretion to Exendin-4
`
`250
`
`2000
`
`
`
`--210 g exendin-4
`2 g exendin-4
`T-2.1 g exendin-4
`A 021 g exendin-4
`-W-0.021 g exendin-4
`0.0021 pig exendin-4
`-O-Saline
`
`-10
`
`-0.5
`
`0.0
`
`10
`0.5
`hours postiv dose
`
`15
`
`20
`
`2.5
`
`FIGURE 9A
`
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`

`

`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 16 of 18
`
`US 8,759,291 B2
`
`Does-Response Curve:
`Sodi
`Excretic to Exeira
`
`
`
`ESO-O.S.S.u.
`
`| -
`
`logy case (pg)
`
`RE8
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1017, p. 18 of 68
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`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 17 of 18
`
`US 8,759,291 B2
`
`Response of trine Potassium Concentration to Exerdin-4
`
`
`
`-er 20 g exerdin-4
`--21 g exercir
`2.1 g exercir-4
`mar (,2: ig exercir
`Yr 8.92 pig exercir-4
`-t-). CO2 ig exerdi-4
`MC-r Saire
`is
`
`to
`
`is
`
`on
`
`is
`to
`as
`Otis post iw iuse:
`
`2
`
`FGURE A
`
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`U.S. Patent
`
`Jun. 24, 2014
`
`Sheet 18 of 18
`
`US 8,759,291 B2
`
`Dose-Response Curve:
`Urine Potassium Concentration to Exendin-4
`
`-2 OO
`
`
`
`ED500,070,26.
`
`logy dose (g)
`
`FIGURE 10B
`
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`US 8,759,291 B2
`
`1.
`METHODS OF TREATMENT USING
`EXENDINPEPTDES OR GLP-1. PEPTDES
`
`RELATED APPLICATIONS
`
`This application is a continuation of U.S. application Ser.
`No. 12/247,141 filed Oct. 7, 2008, issued as U.S. Pat. No.
`7.928,065, which is a continuation of U.S. application Ser.
`No. 10/656,093 filed Sep. 5, 2003, issued as U.S. Pat. No.
`7,442,680, which is a divisional of U.S. application Ser. No.
`09/622,105 filed Sep. 22, 2000, issued as U.S. Pat. No. 6,703,
`359, which is a S371 of PCT/US99/02554 filed Feb. 5, 1999,
`which claims the benefit of U.S. Provisional Application No.
`60/075,122 filed Feb. 13, 1998. All applications are incorpo
`rated herein by reference.
`
`10
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`15
`
`FIELD OF THE INVENTION
`
`2
`GLP-1 did not have this effect. (Tand-Christensen et al., Am.
`J. Physiol., 271:R848-56, 1996). GLP-17-37, which has an
`additional glycine residue at its carboxy terminus, also stimu
`lates insulin secretion in humans (Orskov, et al., Diabetes,
`42:658-61, 1993). A transmembrane G-protein adenylate
`cyclase-coupled receptor believed to be responsible for the
`insulinotropic effect of GLP-1 has been cloned from a f-cell
`line (Thorens, Proc. Natl. Acad. Sci., USA 89:8641-45,
`1992).
`Glucagon and glucagon-like peptides have been found to
`have different cardiovascular effects. Glucagon has been
`reported to have positive inotropic and chronotropic effects,
`produce a slight increase in arterial blood pressure in normal
`individuals, and affect regional blood circulation. GLP-1 has
`been found to produce a moderate increase in both systolic
`and diastolic blood pressure, while GLP-2 has no effect on
`those parameters. GLP-1, administered through the jugular
`vein, has been reported to induce an increase in Systolic and
`diastolic blood pressure and heart rate. (Reviewed in Bar
`ragán, J. M., et al., Regul. Peptides, 67:63-68, 1996).
`Exendins are peptides that are found in the venom of the
`Gila-monster, a lizard endogenous to Arizona, and the Mexi
`can Beaded Lizard. Exendin-3 is present in the venom of
`Heloderma horridum, and exendin-4 is present in the venom
`of Heloderma suspectum (Eng., J., et al., J. Biol. Chen., 265:
`20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267:7402-05,
`1992). The exendins have some sequence similarity to several
`members of the glucagon-like peptide family, with the high
`est homology, 53%, being to GLP-1 (Goke, et al., J. Biol.
`Chem., 268: 19650-55, 1993).
`Exendin-4 is a potentagonist at GLP-1 receptors on insu
`lin-secreting BTC1 cells, at dispersed acinar cells from guinea
`pig pancreas, and at parietal cells from Stomach; the peptide
`also stimulates Somatostatin release and inhibits gastrin
`release in isolated stomachs (Goke, et al., J. Biol. Chem.
`268:19650-55, 1993: Schepp, et al., Eur: J. Pharmacol.,
`69:183-91, 1994: Eissele, et al., Life Sci., 55:629-34, 1994).
`Exendin-3 and exendin-4 were found to be GLP-1 agonists in
`stimulating cAMP production in, and amylase release from,
`pancreatic acinar cells (Malhotra, R., et al., Regulatory Pep
`tides, 41:149-56, 1992; Raufman, et al., J. Biol. Chem. 267:
`21432-37, 1992: Singh, et al., Regul. Pept. 53:47-59, 1994).
`The use of the insulinotropic activities of exendin-3 and exen
`din-4 for the treatment of diabetes mellitus and the prevention
`of hyperglycemia has been proposed (Eng., U.S. Pat. No.
`5,424,286).
`Truncated exendin peptides such as exendin9-39, a car
`boxyamidated molecule, and fragments 3-39 through 9-39
`have been reported to be potent and selective antagonists of
`GLP-1 (Goke, et al., J. Biol. Chem., 268: 19650-55, 1993:
`Raufman, J. P., et al., J. Biol. Chem. 266:2897-902, 1991;
`Schepp, W., et al., Eur: J. Pharm. 269:183-91, 1994; Mon
`trose-Rafizadeh, et al., Diabetes, 45(Suppl. 2): 152A, 1996).
`Exendin9-39 blocks endogenous GLP-1 in vivo, resulting
`in reduced insulin secretion. Wang, et al., J. Clin. Invest.,
`95:417-21, 1995; D'Alessio, et al., J. Clin. Invest., 97:133-38,
`1996). The receptor apparently responsible for the insulino
`tropic effect of GLP-1 has been cloned from rat pancreatic
`islet cells (Thorens, B., Proc. Natl. Acad. Sci. USA 89:8641
`8645, 1992). Exendins and exendin9-39 bind to the cloned
`GLP-1 receptor (rat pancreatic B-cell GLP-1 receptor: Feh
`mann HC, et al., Peptides 15(3): 453-6, 1994; human GLP-1
`receptor: Thorens B, et al., Diabetes 42 (11): 1678-82, 1993).
`In cells transfected with the cloned GLP-1 receptor, exen
`din-4 is an agonist, i.e., it increases cAMP, while exendin9
`39 is an antagonist, i.e., it blocks the stimulatory actions of
`exendin-4 and GLP-1. Id.
`
`25
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`30
`
`35
`
`The present invention relates to methods for increasing
`urine flow comprising administration of an effective amount
`of glucagon-like peptide-1 (7-36 amide (abbreviated “GLP
`7-36NH or simply “GLP-1), an exendin, or an exendinor
`GLP-1 agonist. Methods for increasingurinary Sodium excre
`tion and decreasing urinary potassium concentration are also
`disclosed. The methods are useful for treating conditions or
`disorders associated with toxic hypervolemia, Such as renal
`failure, congestive heart failure, nephrotic syndrome, cirrho
`sis, pulmonary edema, and hypertension. Pharmaceutical
`compositions for use in the methods of the invention are also
`disclosed.
`The present invention also relates to methods for inducing
`an inotropic response comprising administration of an effec
`tive amount of an exendin, GLP-1, or an exendin or GLP-1
`agonist. These methods are useful for treating conditions or
`disorders that can be alleviated by an increase in cardiac
`contractility, such as congestive heart failure.
`The following description Summarizes information rel
`evant to the present invention. It is not an admission that any
`of the information provided herein is prior art to the presently
`claimed invention, nor that any of the publications specifi
`cally or implicitly referenced are prior art to that invention.
`Glucagon-like peptide-1 (7-36 amide (also referred to as
`GLP-1 (7-36NH or GLP-1) is a product of the proglucagon
`gene. It is secreted into plasma mainly from the gut and
`produces a variety of biological effects related to pancreatic
`and gastrointestinal function. The parent peptide, progluca
`gon (PG), has numerous cleavage sites that produce other
`peptide products dependent on the tissue of origin including
`glucagon (PG|32-62) and GLP-17-36NH. (PG|72-107)
`in the pancreas, and GLP-17-37 (PG|78-108) and GLP-1
`7-36NH. (PG 78-107) in the L cells of the intestine where
`GLP-17-36NH (78-107 PG) is the major product.
`GLP-17-36NH, also known as proglucagon 78-107, or
`commonly, just “GLP-1. as used herein, has an insulinotro
`pic effect, Stimulating insulin secretion from pancreatic
`B-cells; GLP-1 also inhibits glucagon Secretion from pancre
`atic C-cells (Orskov, et al., Diabetes, 42:658-61, 1993;
`D’Alessio, et al., J. Clin. Invest., 97:133-38, 1996). GLP-1 is
`reported to inhibit gastric emptying (Williams B, et al., J. Clin
`Endocrinol Metab 81 (1): 327-32, 1996; WettergrenA, et al.,
`Dig Dis Sci 38 (4): 665-73, 1993), and gastric acid secretion.
`(Schjoldager BT, et al., Dig Dis Sci 34 (5): 703-8, 1989;
`O'Halloran DJ, et al., J Endocrinol 126 (1): 169-73, 1990;
`Wettergren A, et al., Dig Dis Sci 38 (4): 665-73, 1993). A
`diuretic, antidypsogenic effect of intracerebroVentricular
`65
`administration of GLP-1 has been reported, however, this
`report claims that a peripheral, intraperitoneal injection of
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`Exendin9-39 also acts as an antagonist of the full length
`exendins, inhibiting stimulation of pancreatic acinar cells by
`exendin-3 and exendin-4 (Raufman, et al., J. Biol. Chem.
`266:2897-902, 1991; Raufman, et al., J. Biol. Chem., 266:
`21432-37, 1992). Exending-39 inhibits the stimulation of
`plasma insulin levels by exendin-4, and inhibits the Soma
`to statin release-stimulating and gastrin release-inhibiting
`activities of exendin-4 and GLP-1 (Kolligs, F., et al., Diabe
`tes, 44:16-19, 1995; Eissele, et al., Life Sciences, 55:629-34,
`1994). Exendin-4, administered through the jugular vein, has
`been reported to induce an increase in Systolic, diastolic and
`mean arterial blood pressure, and in heart rate (Barragán, et
`al., Regul. Pep. 67:63-68, 1996).
`Exendins have recently been found to inhibit gastric emp
`tying (U.S. patent application Ser. No. 08/694,954, filed Aug.
`15
`8, 1996, which enjoys common ownership with the present
`invention and is hereby incorporated by reference). Exendin
`9-39 has been used to investigate the physiological rel
`evance of central GLP-1 in control of food intake (Turton, M.
`D. et al., Nature, 379:69-72, 1996). GLP-1 administered by
`intracerebroventricular (ICV) injection inhibits food intake in
`rats. This satiety-inducing effect of GLP-1 delivered by
`intracerebroventricular injection is reported to be inhibited by
`ICV injection of exendin9-39 (Turton, supra). However, it
`has been reported that GLP-1 does not inhibit food intake in
`mice when administered by peripheral injection (Turton, M.
`D., Nature 379:69-72, 1996; Bhavsar, S. P., Soc. Neurosci.
`Abstr. 21:460 (188.8), 1995). Administration of exendins and
`exendin agonists has also recently been found to reduce food
`intake (U.S. Provisional Patent Application Ser. No. 60/034,
`905, filed Jan. 7, 1997, which enjoys common ownership with
`the present invention and is hereby incorporated by refer
`ence).
`Agents that increase urine flow, or diuretics, are useful for
`treating conditions or disorders that are associated with toxic
`hypervolemic states. Such conditions or disorders include
`renal failure, congestive heart failure, nephrotic syndrome,
`cirrhosis, pulmonary edema, and hypertension. Diuretics are
`also employed to treat conditions in pregnancy, Such as pre
`eclampsia and eclampsia. Further uses of diuretics include
`their use to reduce Volume before some Surgical procedures
`Such as ocular Surgery and neuroSurgery.
`One difficulty encountered with many diuretics such as
`thiazides, loop diuretics, carbonic anhydrase inhibitors, and
`osmotic diuretics, is that although they may be employed to
`45
`increase Sodium excretion, they also result in an increase of
`urinary potassium loss. Examples of the effects of potassium
`loss include muscular weakness, paralysis (including the
`paralysis of respiratory muscles), electrocardiographic
`abnormalities, cardiac dysrhythmia, and cardiac arrest.
`Another difficulty encountered with some diuretics is their
`slow rate of action, which is not conducive to their use in an
`emergency setting.
`Thus, there is a need for a method of increasing urine flow
`that does not deplete potassium concentration in the patient
`and which has a rapid mode of action. Such methods, and
`compounds and compositions which are useful therefore,
`have been invented and are described and claimed herein.
`Compounds that induce inotropic effects (e.g., increase of
`force of contraction of the heart) have been recognized as
`being useful for the treatment of for example, congestive
`heart failure. Congestive heart failure, which is one of the
`most common causes of death and disability in industrialized
`nations, has a mortality rate of about 50% at five years (Good
`man and Gilman's The Pharmacological Basis of Therapeu
`tics, 9th Ed. McGraw Hill, New York, pp. 809-838). Inotropic
`agents currently in clinical use include digitalis, sympatho
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`10
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`4
`mimetic amines and amrinone (Harrison's Principles of Inter
`nal Medicine, 12th Edition, 1991, McGraw Hill, New York,
`pp. 894-899).
`Digotoxin, a cardiac glycoside, an ancient but effective
`therapy for cardiac failure, was initially derived from the
`foxglove leaf, Digitalis purpurea and Digitalis lanata. Cardiac
`glycosides are potent and highly selective inhibitors of the
`active transport of sodium and potassium ions across cell
`membranes (Goodman and Gilman, Supra). Cardiac glyco
`sides have been reported to increase the velocity of shortening
`of cardiac muscle, resulting in an improvement in Ventricular
`function; this effect has been reported to be due to an increase
`in the availability during systole of cytosolic Ca" to interact
`with contractile proteins to increase the velocity and extent of
`sarcomere shortening (Goodman and Gilman, Supra).
`Digotoxin and related cardiac glycosides (e.g. digitoxin)
`have useful durations of action because their excretion,
`mainly via the kidneys, results in plasma t/2 of 1.5-5 days.
`But the therapeutic index of these drugs is very low with
`mildly toxic:minimally-effective dose ratio being 2:1 and
`lethal:minimally-effective dose ratio being between 5:1 and
`10:1. Urinary potassium loss due to use of thiazide and loop
`diuretics may seriously enhance the dangers of digitalis
`intoxication, including Susceptibility to cardiac arrhythmia,
`and potassium-sparing diuretics are often necessary. Slow
`elimination of cardiac glycosides can prolong the period of
`jeopardy during digitalis intoxication, which has been
`reported to occur in 20% of hospital patients on these drugs.
`Absorption and onset of action for all cardiac glycosides
`except ouabain is somewhat prolonged, and this may be a
`disadvantage in emergency cardiac conditions.
`Sympathomimetic amines, which generally include epi
`nephrine, isoproterenol, dopamine and dobutamine, can be
`useful in an acute setting to stimulate myocardial contractil
`ity, but they usually require constant intravenous infusion and
`continuous intensive monitoring of the patient. They typically
`lose their effectiveness after -8 hours, apparently due to
`receptor downregulation.
`Amrinone, a noncatecholamine, non-glycoside agent also
`requires continuous intravenous administration.
`This description of available inotropic agents illustrates the
`need for, and desirability of therapies that are (1) inotropic,
`with (2) rapid onset of action, with (3) prolonged duration of
`action (including a persistent effect, with absence of tachy
`phylaxis), with (4) low toxicity (a high ratio of toxic to thera
`peutic dose), with (5) rapid and profound diuretic effect, with
`(6) a sparing of urinary potassium loss, and with (7) a conve
`nient (non-intravenous) route of administration. We have dis
`covered that exendin and GLP-1 fulfill these criteria.
`
`SUMMARY OF THE INVENTION
`
`The present invention concerns the Surprising discovery
`that exendins, GLP-1, and agonists of these compounds have
`rapid inotropic and diuretic effects. Although GLP-1 has been
`reported to not have a diuretic effect when administered
`peripherally, we have found, surprisingly, that GLP-1 does in
`fact have a diuretic effect after peripheral administration. This
`diuretic effect of exendins, GLP-1, and exendin and GLP-1
`agonists, is accompanied by an increase in urinary Sodium
`concentration. This diuretic effect is also accompanied by a
`decrease in urinary potassium concentration which is unan
`ticipated as many diuretics have been found to cause a pro
`found increase in urinary potassium concentration.
`The present invention is directed to novel methods for
`increasing urine flow comprising the administration of an
`exendin, for example, exendin-3 SEQID NO. 1: His Ser Asp
`
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`US 8,759,291 B2
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`10
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`15
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`25
`
`5
`GlyThr 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 ProPro Ser-NH), orexendin-4SEQID NO.
`2: His Gly Glu GlyThr 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), or other
`compounds which effectively bind to the receptor at which
`exendin exerts its action on increasing urine flow (exendin
`agonists). The present invention is also directed to novel
`methods for increasing urine flow comprising the administra
`tion of GLP-1 SEQID NO. 3: His Ala Glu Gly Thr Phe Thr
`Ser Asp Val Ser Ser Tyr Leu Glu Gly Glin Ala Ala Lys Glu Phe
`Ile Ala Trp Leu Val Lys Gly Arg-NH), or other compounds
`which effectively bind to the receptor at which GLP-1 exerts
`its action on increasing urine flow (GLP-1 agonists).
`In a first aspect, the invention features a method of increas
`ing urine flow in an individual comprising administering to
`the individual atherapeutically effective amount of an exen
`din or an exendin agonist. In one preferred aspect, said exen
`din is exendin-3. More preferably, said exendin is exendin-4.
`By an “exendinagonist' is meanta compound that mimics the
`effects of exendin on increasing urine flow, increasing sodium
`excretion, and/or decreasing urinary potassium concentra
`tion, (the potassium concentration in excreted urine) by bind
`ing to the receptor or receptors where exendin causes this
`effect. Certain novel exendin agonist compounds are
`described in U.S. Provisional Patent Application Ser. No.
`60/055,404, filed Aug. 8, 1997, which was filed as PCT/98/
`16387, on Aug. 6, 1998 and nationalized as U.S. patent appli
`cation Ser. No. 10/181,102, on Jul. 11, 2001 and enjoys com
`30
`mon ownership with the present invention and is hereby
`incorporated by this reference. Certain other novel exendin
`agonist compounds are described in U.S. Provisional Patent
`Application Ser. Nos. 60/066,029 and 60/065,442, both filed
`Nov. 14, 1997, which were filed as PCT/US98/24210, on
`Nov. 13, 1998 and nationalized as U.S. patent application S