4128
`
`J. Med. Chem. 2004, 47, 4128-4134
`
`Glucagon-like Peptide-1: The Basis of a New Class of Treatment for Type 2
`Diabetes
`
`Lotte Bjerre Knudsen†
`Discovery Biology Management, Novo Nordisk, DK-2760 Maaloev, Denmark
`
`Received December 24, 2003
`
`Introduction
`Type 2 diabetes is increasingly becoming a worldwide
`epidemic. Currently there is much focus on the gluca-
`gon-like peptide-1 (GLP-1) peptide hormone as the basis
`for a potential new treatment paradigm for type 2
`diabetes. The two major drawbacks of the drugs cur-
`rently utilized in the treatment of type 2 diabetes are
`that (1) during their long-term administration body
`weight increases and (2) the disease progresses over
`time, also evidenced by an increasing loss of (cid:226)-cell
`function.
`GLP-1 was discovered in 1984 and found to be an
`important incretin.1 It is a product of the preprogluca-
`gon gene and is released from the L-cells in the intestine
`upon food intake and potently releases insulin from the
`(cid:226)-cells in the pancreas. Numerous effects other than
`stimulation of insulin release have been ascribed to
`GLP-1. In the pancreas, not only does GLP-1 release
`insulin but it does so in a glucose-dependent manner,2,3
`and it has a number of other functionally important
`effects: stimulation of insulin biosynthesis, restoration
`of glucose sensitivity to the islets, and stimulation of
`increased expression of the glucose transporter GLUT-2
`and glucokinase.4-6 GLP-1 also has a number of effects
`on regulation of (cid:226)-cell mass: stimulation of replication
`and growth and inhibition of apoptosis of existing
`(cid:226)-cells, and neogenesis of new (cid:226)-cells from duct precur-
`sor cells.7,8 GLP-1 inhibits glucagon secretion,9 which
`then leads to reduced hepatic glucose output. In the gut,
`GLP-1 is a potent inhibitor of motility and gastric
`emptying and has also been shown to inhibit gastric acid
`secretion.10 The inhibition of gastric emptying leads to
`decreased food intake and reduced body weight.11,12
`Thus, the current belief is that the GLP-1 compound
`class may be able to control the progression of the type
`2 diabetes disease not only by controlling blood glucose
`but also via several other effects. GLP-1 has also been
`proposed to have direct effects on glucose uptake in
`liver, muscle, and adipose tissue, but the quantitative
`significance of these effects has been questioned.13 New
`publications even suggest that the beneficial effects of
`GLP-1 compounds go beyond the treatment of diabetes.
`There may be specific receptors in the heart that along
`with the benefits of reducing blood glucose may protect
`from cardiovascular complications,14 and GLP-1 stimu-
`lates memory and learning capabilities.15 A comprehen-
`sive review exists on the glucagon-like peptides.13
`Clinically, GLP-1 has been shown to be very effective
`in lowering blood glucose in quite a broad range of
`
`† Phone: +45 44434788. Fax: +45 44663939. E-mail:
`novonordisk.com.
`
`lbkn@
`
`diabetes stages.16 Very importantly, little risk of hy-
`poglycaemia has been observed.2 This is because GLP-
`1, unlike sulfonylureas, only stimulates the natural
`glucose-induced insulin secretion. Up to 6 week studies
`have been performed with natural GLP-1 in a subcu-
`taneous pump. In this study a lowering of body weight
`was also seen.12 The only known pharmacological side
`effect of GLP-1 is nausea and vomiting when adminis-
`tered in high doses. These unwanted effects are medi-
`ated by inhibited gastric emptying. However, the vast
`majority of clinical data indicate that the nausea is
`transient and that efficient glucose control can be
`obtained without this side effect. Thus, from a clinical
`point of view, GLP-1, with its efficacious lowering of
`blood glucose with little risk of hypoglycemia and its
`potential for prevention of disease progression, seems
`ideal for the treatment of type 2 diabetes.
`The GLP-1 receptor was cloned in 1992 and is a
`G-protein-coupled receptor from the B family also
`referred to as the secretin/glucagon family.17 The ligands
`in this family are mainly large peptide hormones. Small-
`molecule antagonists especially for the glucagon recep-
`tor have been described, but no small-molecule agonists
`have been described in the literature. Thus, the GLP-1
`based compound class will most likely be peptides and
`the challenge is that the natural hormone is degraded
`rapidly by the enzyme dipeptidyl peptidase IV (DDP-
`IV) and cleared by the kidneys resulting in a half-life
`of less than 2 min after iv administration and a
`clearance higher than that of the normal cardiac
`output.18-20 GLP-1 exists in two equipotent naturally
`occurring forms, GLP-1(7-37) and GLP-1(7-36)amide,
`the former corresponding to proglucagon(78-108). The
`numbering of GLP-1 starts with 7 because it was
`originally believed that GLP-1(1-37) was the active
`hormone. It was later discovered that the real hormone
`was formed after cleaving off the first 6 N-terminal
`amino acids and then the 7 numbering system begun.
`The primary metabolite of GLP-1, GLP-1(9-36) amide
`or GLP-1(9-37), has a greatly decreased affinity for the
`GLP-1 receptor and may even be an antagonist or a
`partial agonist. The magnitude and duration of the
`blood glucose lowering ability of natural GLP-1 have
`been shown to be dependent on a continuous supply of
`pharmacological levels.21 Thus, the efficacy of a GLP-
`1-like drug will be dependent on the duration of action
`of the compound or the formulation even though some
`of the long-term benefits of GLP-1 compounds, like
`increasing (cid:226)-cell mass, may not require constantly
`elevated GLP-1 levels. Another potential limitation is
`that the only known pharmacologically induced side
`effect is nausea, occurring via the inhibition of gastric
`
`10.1021/jm030630m CCC: $27.50 © 2004 American Chemical Society
`Published on Web 07/20/2004
`
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`
`Table 1. Overview of GLP-1 Based Compounds in Developmenta
`half-life in
`humans
`4-5 h
`
`principle of protraction
`inherent in exendin-4 amino
`acid sequence
`self-association and
`albumin binding
`
`clinical phase and
`dosing used
`phase 3, twice daily
`
`phase 2 completed,
`once daily
`
`refs
`31, 38, 46
`
`39, 40, 48
`
`11-15 h
`
`compd
`exenatide,
`AC2993
`liraglutide,
`NN2211
`
`CJC-1131
`
`ZP10
`
`structure
`
`exendin-4
`
`((cid:231)-L-glutamyl(N-R-hexa-
`decanoyl))-Lys26Arg34-
`GLP-1(7-37)
`D-Ala8Lys37[2-[2-[2-male
`imidopropionamido
`(ethoxy)ethoxy]acetamide-
`GLP-1(7-37)
`structure not published
`
`10-12 days
`
`in vivo covalent conjugation
`to albumin
`
`phase 1/2, once daily
`
`41
`
`-
`
`-
`
`-
`
`-
`
`inherent in exendin-4 sequence
`and added C-terminal
`stability
`genetic fusion protein
`with albumin
`enzymatically stabilized GLP-1
`analogue
`prodrug of exendin-4
`
`phase 1/2, acute
`dosing only
`
`preclinical
`
`preclinical
`
`42
`
`-
`
`43
`
`preclinical
`
`44
`
`albugon
`
`structure not published
`
`BIM-51077
`
`structure not published
`
`-
`
`(2-sulfo-9-fluorenyl
`methoxycarbonyl)3
`exendin-4
`a Compound names, structure if published, principle of protraction, development phase if known, and dosing frequency used in clinical
`trials if known.
`
`emptying. However, there seems to be tachyphylaxis to
`this side effect so that long-term efficacy can be obtained
`without major gastrointestinal side effects. Neverthe-
`less, this issue of nausea as a side effect is probably the
`most important one to resolve in future clinical trials.
`
`Type 2 Diabetes as a State of Hormonal
`Disorder and Incretin Deficiency.
`At least three hormonal disturbances may be cor-
`rected upon treatment with a GLP-1 compound: de-
`creased effect of Gastric Inhibitory Polypeptide (GIP),
`decreased secretion of GLP-1, and hypersecretion of
`glucagon.
`Type 2 diabetes has been described to be an incretin
`deficiency state because patients have a decreased
`release of GLP-1 upon ingestion of food compared to
`healthy subjects and because the other major incretin,
`GIP, stimulates release of insulin to a much smaller
`extent in type 2 diabetes compared to healthy sub-
`jects.22,23 There is some evidence to support that the
`decreased GLP-1 secretion occurs as a slow deterioration
`with disease progression, since subjects with glucose
`intolerance have a tendency to also have a smaller
`amount released after a meal.24
`GIP was the first known incretin, and it was proposed
`as a treatment for type 2 diabetes in the 1980s.
`However, it was found that GIP only leads to insulin
`secretion in healthy volunteers and not in type 2
`diabetes.22 Recently it has been found that GIP does
`lead to some insulin secretion in type 2 diabetes but that
`it is especially the first-phase secretion that GIP is
`responsible for and that this is lost to a large extent.25
`There is no impaired secretion of GIP in type 2 diabetes
`nor have any receptor mutations been found that could
`be responsible for the lack of effect. By comparison,
`GLP-1 has a full effect on both first- and second-phase
`insulin secretion in type 2 diabetes, and thus, GLP-1
`may substitute the physiological role of GIP that is
`lacking in type 2 diabetes.22
`Dating long ago, glucagon has been described to be
`hypersecreted in type 2 diabetes and glucagon antago-
`
`nists have been proposed as a potential drug class for
`type 2 diabetes.26 Neutralization of glucagon with
`antibodies leads to lowering of blood glucose in several
`animal models.27 Glucagon hypersecretion leads to
`increased hepatic glucose output by increased gluco-
`neogenesis and glycogenolysis and thus contributes to
`elevated blood glucose.28 GLP-1 decreases glucagon
`secretion and thus partly or fully corrects this hyper-
`secretion.
`Thus, treatment with GLP-1 may correct or replace
`three hormonal disturbances in type 2 diabetes. On top
`of that, GLP-1, as mentioned above, has several other
`beneficial effects.
`
`Overview of Compounds in the GLP-1 Class
`(Table 1)
`There are two subclasses of GLP-1 in clinical develop-
`ment. One is natural GLP-1. The other is exendin-4, a
`peptide agonist isolated from the venom of the lizard
`Heloderma Suspectum, also known as the Gila monster.
`There is high structural homology between GLP-1 and
`exendin-4: 53%. The structures of GLP-1 and exendin-4
`are shown in Figure 1. Both exendin-4 and GLP-1 are
`found in the Gila monster. It is not fully understood why
`it has two separate peptides with a large overlap in
`function, but there is a belief that it may be that the
`animal needs two incretins in preparation for large
`infrequent meals. The amino acid sequence of GLP-1 is
`highly preserved across species. Exendin-4 is a very
`potent molecule with a reported potency ranging from
`2-3 to 5-10 times greater than the potency reported
`for GLP-1.29 However, when potency is compared in
`vivo, it is important to take into account the large
`difference in half-life. The apparent potency may seem
`much greater for exendin-4, but when taking into
`account that GLP-1 has a half-life of less than 2 min, a
`valid comparison may be difficult or impossible to
`obtain. As mentioned above, natural GLP-1 has a very
`short half-life because of cleavage by DPP-IV and rapid
`clearance. Other enzymes such as neutral endopeptidase
`(NEP) have also been shown to be involved in the
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`4130 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 17
`
`Figure 1. Amino acid sequence of GLP-1 and exendin-4. Dipeptidyl peptidase IV cleaves between Ala8 and Glu9.
`
`Figure 2. Structures of liraglutide and exenatide, the two first-generation products in the GLP-1 class.
`
`degradation of GLP-1.30 By comparison, exendin-4 is
`much more resistant to proteolytic cleavage by both
`DPP-IV and NEP,31 and its half-life in humans is 26
`min after iv administration. Exendin-4 has a 9 amino
`acid long proline-rich C-terminal tail, which is believed
`to stabilize the agonist conformation, and affinity is
`decreased when the tail is removed.32 Thus, on the basis
`of the exendin-4 sequence, more enzymatically stable
`molecules can be obtained, but it may then be at the
`expense of an immune reaction against the peptide.
`Hitherto, it is clear that therapeutics for the GLP-1
`receptor will be peptides, and thus, the drug discovery
`challenge is to make a stable compound with a long half-
`life. Amino acid sites 7, 10, 12, 13, 15, 28, and 29 have
`previously been shown, in an alanine scan of GLP-1, to
`be sensitive to changes, and it has been proposed that
`the N-terminal part of the peptide is responsible for the
`high-affinity binding to the core of the receptor, whereas
`the C-terminal is more responsible for the selectivity
`by interacting with the large N-terminal of the recep-
`tor.33 A number of early studies aimed at making
`protease stabilized analogues of GLP-1 are available.34,35
`However, none of these GLP-1 analogues have pro-
`ceeded beyond drug candidates presumably because
`they are still rapidly cleared by the kidneys and thus
`require some other form of protraction.34
`Lilly and Amylin are in phase 3 clinical development
`with exenatide (exendin-4, AC2993) as a twice daily
`injection therapy. A large amount of preclinical data on
`exendin-4 have been published from several indepen-
`dent labs, especially a number of reports of exendin-4’s
`ability to stimulate (cid:226)-cell growth, replication, and
`neogenesis.36 Several clinical studies have been pub-
`lished. Side effects have been (as expected for the whole
`class) transient nausea.38 Antibody formation against
`exenatide has been reported.38 Since exenatide is syn-
`thetic exendin-4, no systematic SAR exists from which
`the compound was originally chosen. The companies
`have reported that they are pursuing a slow release
`formulation of exendin-4.
`Novo Nordisk has completed phase 2 clinical trials
`liraglutide((cid:231)-L-glutamoyl(N-R-hexadecanoyl))-
`with
`Lys26,Arg34-GLP-1(7-37) (NN2211) (Figure 2) as a once
`daily injection therapy. Several preclinical and clinical
`studies have been published. Liraglutide is equipotent
`to GLP-1 and has a half-life that is more than 10-fold
`larger that of exendin-4, 8 h vs 26 min after iv
`administration,31,39 respectively. Liraglutide is part of
`
`Figure 3. SAR figure of GLP-1. All sites essential for binding
`from Ala-scan are also conserved between GLP-1 and exendin-
`4. Sites that are possible to modify with fatty acids are only
`color-coded as such. They are all unique for GLP-1 at the same
`time.
`
`a series of acylated derivatives of GLP-1 that are aimed
`at being long-acting via two independent mechanisms,
`self-association and noncovalent binding to plasma
`albumin fatty acid binding sites, resulting in a phar-
`macokinetic profile with slow absorption and a long half-
`life.40 Albumin thus serves as a buffer reservoir for
`liraglutide. GLP-1 can be acylated at multiple sites with
`a hexadecanoyl fatty acid and a (cid:231)-Glu amino acid as a
`spacer, and the acylated GLP-1 exhibits retained po-
`tency and a long half-life after subcutaneous adminis-
`tration. Also, with a slightly shorter fatty acid, dode-
`canoyl, it is possible to attach two fatty acids and still
`have a potent compound with a significantly protracted
`profile. Spacers other than (cid:231)-Glu can be used, e.g.,
`GABA or (cid:226)-Ala. A potency-destroying SAR has also been
`generated in which acylation in the N-terminus position
`8 leads to a compound about 20 times less potent than
`GLP-1. Acylation with two fatty acids on both naturally
`present lysines in positions 26 and 34 destroys potency.
`Last, simultaneous acylation in position 34 combined
`with a modification of the natural histidine in position
`7 (des-aminohistidine) aimed at making the N-terminus
`more resistant to DPP-IV also destroys potency. Thus,
`for acylated derivatives of GLP-1 the SAR is well
`understood.40
`Figure 3 summarizes the limited SAR data that are
`available for GLP-1 and exendin-4.
`
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`Other companies are in the discovery phase or in
`small-scale phase 1/2 clinical development. However,
`very little is published in peer-reviewed journals. Sev-
`eral patent applications claim different analogues of
`mainly exendin-4, but also a few claim analogues of
`GLP-1. The biggest question for these approaches is if
`they can become a convenient product with administra-
`tion once daily or less. To achieve this, the companies
`need to make a slow release formulation in such a way
`that an initial burst can be avoided or they have to build
`some other principle of protraction into the molecule.
`A slow release formulation for peptides without a
`significant initial burst effect has yet to be reported, and
`such a burst effect will no doubt give rise to nausea.
`Conjuchem is developing a reactive analogue of GLP-1
`(CJC-1131) that has also been modified at site 8 to
`protect against DPP-IV degradation and that is de-
`signed to form a covalent bond to albumin after sc
`injection by specific interaction between the Cys34
`moiety of albumin and the C-terminus of the GLP-1
`analogue.41 Thus, in principle the conjugates will have
`the half-life of albumin, which is 19 days in man but
`shorter in rodents. They have reported a very long half-
`life in man, 10-12 days, but so far clinical trials have
`been performed with once daily injections in a relatively
`small number of patients. The challenge for this ap-
`proach is perhaps slightly greater than for the others
`because of the in vivo covalent attachment to albumin.
`On the other hand, this approach does not have the
`challenge of having to invent a protracted formulation.
`Human Genome Sciences is in the discovery phase
`with Albugon, a fusion protein between an analogue of
`GLP-1 and albumin. This approach is similar to that of
`Conjuchem, using covalent binding to albumin as a
`principle of protraction. There is one important differ-
`ence, though: this is an injection of a stable fusion
`protein, whereas Conjuchem is injecting a reactive
`molecule. Human Genome Sciences have reported, but
`not yet published, a half-life of Albugon in monkeys of
`3 days.
`Zealand is developing an analogue of exendin-4 (ZP10)
`that Aventis recently in-licensed. Neither the structure
`nor the half-life of ZP10 has been published, just the
`fact that it is an amino acid analogue that may be dosed
`twice daily to mice.42 Clinical data have been announced
`but not published. Thus, it is to be expected that this
`compound will have to be dosed twice daily in humans
`unless a protracted formulation can be developed.
`Ipsen is also working on a protease stabilized ana-
`logue of GLP-1, BIM-51077.43 Neither the structure nor
`the receptor potency of the compound has been pub-
`lished, but the compound is referenced to be stabilized
`against both C-terminal and N-terminal enzymatic
`degradation. The development status of this compound
`is preclinical.
`Theratechnologies and ALZA are working on a trans-
`dermal formulation of an analogue of GLP-1 using
`Theratechnologies long-acting peptide technology. The
`structure of the compound has not been published.
`An Israeli group has published a prodrug approach
`on exendin-4 where they attach a 2-sulfo-9-fluorenyl-
`methoxycarbonyl moiety to three amino groups of ex-
`endin-4. The carbonyl moieties are cleaved off in vivo,
`
`Journal of Medicinal Chemistry, 2004, Vol. 47, No. 17 4131
`
`resulting in a pharmacodynamic profile somewhat
`longer than exendin-4 itself in diabetic mice.44
`While a number of companies or institutions have
`programs aimed at identifying new compounds in the
`GLP-1 compound class, very little has been published
`about this except in the patent literature. Several other
`companies have had programs that have not proceeded
`into development, including Watson and Genzyme. Lilly
`has a patent application on fusion proteins. Two com-
`panies Alizyme and Neurogen have had programs aimed
`at finding small-molecule agonists, but both have re-
`ported these programs to be suspended. Novo Nordisk
`has a patent application on small-molecule agonists.
`
`Outlook for the Clinical Promise and
`Challenges of the GLP-1 Class of Drugs
`One of the biggest challenges to the GLP-1 compound
`class is that these compounds are peptides and thus
`have to be injected. This is probably the main reason
`the compound class has been so relatively long on its
`way.
`Alternative delivery forms may be pursued but most
`attempts to make large peptide drugs available by the
`oral, transdermal, or nasal route have failed because of
`either low bioavailability or the toxicity of necessary
`enhancers. Pulmonary administration is currently being
`investigated for insulin by several companies, and if
`successful, it will most likely be investigated as a more
`generally utilized route for other peptides. However,
`because subcutaneous injection always gives some
`protraction that cannot be expected from pulmonary
`administration, a relatively higher dose of a peptide
`would have to be given, which in the case of GLP-1
`might lead to nausea.
`A more specific challenge for a successful GLP-1 drug
`is to have as few gastrointestinal side effects as possible.
`This is a pharmacological side effect and is thus cor-
`related to the pharmacokinetic properties; i.e., nausea
`will occur with peak concentrations. Nausea may best
`be avoided by a long half-life because a long half-life
`gives the smallest needed excursions in plasma concen-
`trations.
`The true clinical potential of the compound class in
`terms of the extent of the glucose lowering, control of
`body weight, and disease progression still remains to
`be shown. Perhaps the best published study addressing
`this potential to date is with 6 weeks of infusion of
`natural GLP-1 via MiniMed insulin pumps, as shown
`in Figure 4.12 This study demonstrated a potential for
`GLP-1 to rapidly lower fasting blood glucose with 4-5
`mM, mainly with the first week of treatment. This is
`an impressive effect, not met by any other major oral
`drug category available today such as sulfonylureas and
`metformin or insulin sensitizers. This effect is of course
`met by insulin, but there GLP-1 offers a major advan-
`tage in terms of safety because it, unlike insulin, does
`not induce hypoglycemia. The study also showed a
`significant weight lowering effect of treatment with
`GLP-1 compared to vehicle treatment. Another study
`of natural GLP-1 in 55 patients showed that regardless
`of the blood glucose levels of the type 2 diabetic patient,
`GLP-1 administered over a 4 h infusion period markedly
`lowered blood glucose.16 Again, these data indicate that
`glucose control with the GLP-1 compound class may be
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`Figure 4. The 8 h profiles of plasma glucose levels. Data are
`presented as a mean ( SEM. The top panel shows plasma
`glucose levels for patients receiving saline. The panel at the
`bottom shows plasma glucose levels for patients receiving GLP-
`1. For patients receiving saline, fasting plasma glucose levels
`remained unchanged over the 6 weeks, P ) 0.13, and the 8 h
`value throughout the day (8 h mean) remained unaltered, P
`) 0.95. The postprandial glucose excursions (expressed as
`incremental AUC of 0-3 h) remained unaltered, P ) 0.87, as
`did postprandial peak values, P ) 0.3. In the GLP-1 group,
`fasting plasma glucose was reduced by 3.6 CI (2.9-4.3 mmol/L
`(week 1)) and 4.3 CI (2.4-6.2 mmol/L (week 6), P < 0.001; ¢
`values, P < 0.0001. The 8 h mean levels were reduced by 4.9
`CI (4.0-5.7 mmol/L (week 1)) and 5.6 CI (3.7-7.5 mmol/L), P
`< 0.0001, ¢ values P < 0.0001. Postprandial glucose excursions
`decreased, P < 0.001, ¢ values P < 0.0001, as did postprandial
`peak values, P ) 0.003, ¢ values P < 0.0001. Reprinted with
`permission from Lancet.12 Copyright 2002 Elsevier..
`
`significantly better than any of the oral drugs currently
`on the market for type 2 diabetes.
`Also, data of the two compounds in large-scale clinical
`trials, exenatide and liraglutide, are beginning to be-
`come available. Exenatide has a half-life after iv ad-
`ministration of 26 min31 and approximately 4-5 h after
`sc administration. Exenatide has shown a markedly
`improved postprandial profile after 28 days dosing of
`only 0.08 (cid:237)g/kg given twice or three times daily.45
`Independent studies of exendin-4 in man have shown a
`potential for glucose lowering of about of 3-6 mM, but
`the study was performed without a control group,37
`which makes comparison difficult. Liraglutide has been
`shown to have linear dose-dependent pharmacokinetic
`properties in man, with a half-life of 11-15 h and a tmax
`of 9-11 h after sc administration and an absolute
`bioavailability of 55%.39,46 Thus, the half-life should be
`in agreement with full efficacy following once daily
`administration.
`Apart from the control of blood glucose, the potential
`long-term ability of GLP-1 to improve the (cid:226)-cell function
`is a very important point. Indeed, because of the
`combined effects, GLP-1 may even be called a vitamin
`for the (cid:226)-cell. For example, as shown in Figure 5, one
`injection of liraglutide has been shown to restore glucose
`sensitivity to (cid:226)-cells in patients with type 2 diabetes.47
`These data are promising for the potential ability of the
`GLP-1 drug class to delay or perhaps even prevent
`disease progression.
`
`Figure 5. Relationship between insulin secretion rate (ISR)
`and plasma glucose levels during the graded glucose infusion
`protocol in subjects with type 2 diabetes who received lira-
`glutide (“black squares”) or placebo (“white squares”). ISR was
`derived by deconvolution of peripheral C-peptide concentra-
`tions. ISR was substantially increased with liraglutide com-
`pared to placebo over the glucose range 6-12 mmol/L and was
`similar to values in healthy control subjects (“white triangles”)
`who did not receive the drug. Data are the mean ( SE, n )
`10, for each group. Reprinted with permission from Diabetes.47
`Copyright 2003 The American Diabetes Association.
`
`Last, it has been shown in rodents that GLP-1 leads
`to undesirable effects such as increased heart rate and
`blood pressure.48 However, studies with the two com-
`pounds in large-scale clinical trials have not reported
`such important side effects, so it seems that these effects
`are rodent-specific. In fact, it has been suggested that
`GLP-1 may even exert a cardiovascular protecting effect
`either indirectly via lowering of blood glucose and
`plasma lipids or directly via specific GLP-1 receptors
`on the heart.14
`
`Acknowledgment. The author thanks the GLP-1
`discovery and development teams for their entire con-
`tribution. Morten Colding-Jørgensen is thanked for
`fruitful discussions of the principles of protraction.
`Patrick Garibay is thanked for valuable comments on
`the final manuscript.
`
`Biography
`Lotte Bjerre Knudsen obtained her degree in Chemical
`Engineering from the Technical University of Denmark in
`1989. She has been working for Novo Nordisk since 1989 as a
`Scientist in Molecular Pharmacology and as Project Leader of
`the GLP-1 project and is currently Director of the preclinical
`GLP-1 area.
`
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