`Opinion
`
`SeSS
`
`Background
`Medical need
`
`Existing treatment
`
`Current research goals
`
`Competitive environment
`Conclusion
`
`Expert opinion
`
`Review
`
`Emerging GLP-1 receptor agonists
`Asger Lund, Filip K Knop & Tina Vilsboll’
`'Diabetes Research Division, Departmentof Internal Medicine F, Gentofie Hospital, University of
`Copenhagen, Hellerup, Denmark
`
`Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists
`have become available for the treatment of type 2 diabetes. These agents
`exploit the physiological effects of GLP-1, which is able to address several of
`the pathophysiological features of type 2 diabetes. GLP-1R agonists presently
`available are administered once or twice daily, but several once-weekly
`GLP-1R agonists are in late clinical development.
`Areas covered: The present review aims to give an overview of theclinical
`data on the currently available GLP-1R agonists used for treatment of type 2
`diabetes, exenatide andliraglutide, as well as the emerging GLP-1R agonists
`including the long-acting compounds.
`Expert opinion: An emerging therapeutic trend toward initial or early combi-
`nation therapy with metformin- and incretin-based therapy is anticipated for
`patients with type 2 diabetes. GLP-1-based therapy has so far proven safe and
`tolerable. The determination of which incretin-based therapy to choose
`necessitates comparisons between the various GLP-1R agonists. The available
`GLP-1R agonists cause sustained weight loss and clinical relevant improve-
`ment of glycemic control. The long-acting GLP-1R agonists in late develop-
`ment may improve the effects of GLP-1 even further with optimized
`pharmacokinetic profiles resulting in fewer side effects. Meta-analyses have
`shown promising effects on cardiovascular disease and data from ongoing
`multicentertrials with cardiovascular endpoints are expected in 2015.
`
`Keywords: albiglutide, C)C-1134-PC, dulaglutide, exenatide, exenatide once-weekly,
`glucagon-like peptide-1 receptor agonists, liraglutide, lixisenatide, semaglutide, type 2 diabetes
`
`Expert Opin. Emerging Drugs (2011) 16(4):607-618
`
`1. Background
`
`Oral glucose administration elicits a greater insulin response than intravenous (i.v.)
`glucose at identical plasma glucose profiles. This is called the incretin effect, and is
`conveyed bythe two incretin hormones: glucose-dependentinsulinotropic polypep-
`tide (GIP) and glucagon-like peptide-1 (GLP-1) (1). GIP is a 42 amino acid peptide,
`synthesized and released from enteroendocrine K cells mainly located in the duode-
`num and upper jejunum (1). GLP-1 is a 30 aminoacid peptide, a product of proglu-
`cagon gene expression in the intestinal enteroendocrine L cells andis, like GIP,
`secreted after meal
`ingestion (1.2). Together the insulinotropic effect of GIP and
`GLP-1 accounts for up to 70% ofthe insulin secreted after a meal in healthy sub-
`jects, and, thus, plays a very importantrole in postprandial glucose homeostasis(1).
`In patients with type 2 diabetes, the ability of exogenous GIP and GLP-1 to stim-
`ulate insulin secretion is severely diminished when compared with healthy subjects.
`However, the glucose-lowering effect of supraphysiological infusion of GLP-1 is
`preserved (3) while that of GIP is absent(4.5).
`GLP-1 asserts its effects on the beta cells through binding to the GLP-1 receptor
`(GLP-1R), a cell surface receptor highly expressed on the cell membrane of
`pancreatic betacells (2,6). Receptor binding of GLP-1 results in stimulation ofinsu-
`lin secretion in a strict glucose-dependent manner [7,8]. GLP-1 also has potential
`‘effects on beta cell mass as pre-clinical studies have shown:stimulation of beta
`
`10,1517/14728214.2011 616493 © 2011 Informa UK, Ltd,
`ISSN 1472-8214
`607
`All rights reserved: reproduction in whole or in part not permitted
`
`informa
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`Emerging GLP-1 receptor agonists
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`cell proliferation (9.10), differentiation of new beta cells from
`progenitorcells (11| and by inhibition ofbeta cell apoptosis(12).
`Furthermore, GLP-1 robustly inhibits glucagon secretion,
`and the combined effects on insulin and glucagonsecretion
`results in inhibition of hepatic glucose production, which
`contributes significantly to the overall glucose-lowering effect
`of GLP-1 {13}. Additionally, GLP-1 decreases gastrointestinal
`motility (14) and promotes satiety 15], probably through
`activation of GLP-1Rs in the brain in combination with
`GLP-1-induced decrease in gastric emptying. Chronic admin-
`istration of GLP-1 therefore leads to weightloss [16). All of
`these effects are potentially beneficial
`in the treatment of
`patients with type 2 diabetes, and much attention have,
`therefore, been given to the development of pharmacological
`strategies based on theeffects of GLP-1.
`One of the major challenges in developing GLP-1-based
`therapy is that native GLP-1 is very rapidly degraded in the
`circulation by the enzyme dipeptidyl peptidase 4 (DPP-4),
`which cleaves off the two N-terminal amino acids and leaves
`the molecule inactive with regard to insulin secretion [17],
`resulting in a half-life of less than 2 min(18). Because of the
`rapid elimination, native GLP-1 is unsuitable for clinical
`use. Two different strategies of circumventing this problem
`have been successful so far. One approach is
`to inhibit
`DPP-4,
`thereby enhancing the survival and therefore the
`effect of endogenously released GLP-1. The other strategy is
`to use GLP-1R agonists thar are resistant to inactivation by
`DPP-4 and modified in a way that prolongs the effect of the
`hormone. In the following sections, the emerging GLP-IR
`agonists are reviewed,
`
`2. Medical need
`
`Type 2 diabetes is a progressive and multifactorial disease.
`There were an estimated 285 million adults with type 2 diabe-
`tes in 2010 worldwide,and,as the westernlifestyle is makingits
`entry into the developing countries, this numberwill continue
`to increase (19). Projections for 2030 show that the prevalence
`of type 2 diabetes is likely to reach almost 450 million {20).
`Type 2 diabetes leads to serious complications that broadly
`can be classified as microvascular (neuropathy, nephropathy
`and retinopathy) or macrovascular (atherosclerosis resulting
`in myocardial infarction and stroke). The ultimate goal of
`diabetes therapy is to prevent these complications in order to
`improve life expectancy and quality oflife. The United
`Kingdom Prospective Diabetes Study (UKPDS) showed that
`improved glycemic control (HbAIc) resulted in less microvas-
`cular complications in patients with type 2 diabetes (21).
`Furthermore,recent follow-up studies from the UKPDShave
`shown thattight glucose control in the early years of disease
`impacts dramatically on the development of complications
`related to the disease (22).
`Despite recognition that type 2 diabetes is a huge public
`health concern, and major efforts to attract attention to the
`importance of tight glycemic control, data from World
`
`the percentage
`show that
`Health Organization (WHO)
`of individuals reaching International Diabetes Federation
`(IDF) treatment goals is still very low (23). Commonbarriers
`to patient adherence include concern about unwanted weight
`gain (24),
`fear of hypoglycemia and perceived inconve-
`nience (25), and these mayall indirectly undermine glycemic
`controlif the prescribed therapy is not followed.
`
`3. Existing treatment
`
`International guidelines for the treatment of patients with
`type 2 diabetes have been suggested by the European Associa-
`tion for the Study of Diabetes (EASD) and the American Dia-
`betes Association (ADA)|26). Based on data from the UKPDS
`it is recommended that metformin should be started in all
`patients with newly diagnosed type 2 diabetes who do not
`have contraindications to metformin treatment (e.g., renal
`disease) [26-29]. However, often metformin is not enough to
`treat the patients with the target HbAlc levels below 7%.
`Therefore, the guidelines suggest additional treatment options
`on which agents to add to metformin treatment (29]. Classical
`therapeutic additives are: i) the insulin secretagogues sulfony-
`lureas (SU), ii) the insulin-sensitizing thiazolidiones (TZD)
`andiii) exogenous insulin. However,all of these agents are
`associated with different adverse effects including risk of
`hypoglycemia (SU and insulin), weight gain (SU,insulin
`and TZD) andincreased risk of bone fractures and even heart
`disease (TZD)(30). Additionally, none of these medications
`are able to correct either the impairment or the progressive
`decline ofbeta cell function. Recently, the incretin-based ther-
`apies including GLP-1R agonists and DPP-4 inhibitors were
`introduced into clinical practice, and these agents are now
`widely used for the treatment of type 2 diabetes (31), with
`the GLP-IR agonists being part of the latest ADA/EASD
`treatmentguidelines (26).
`The development of the GLP-1R agonists is based on two
`different approaches. One strategy exploits the structure of
`native human GLP-1, modified in a way so thatit is resistant
`to degradation by DPP-4,as the backbone for the compounds
`(Figure 1). The other approach uses a naturally occurring
`protein — exendin-4, originally isolated from the saliva of
`the lizard Heloderma suspectum — as the backbone of the
`compounds (Figure 1), Exendin-4 has a 53% sequence homol-
`ogy with human GLP-1 inits first 30 amino acids (32), and
`binds to and activates the GLP-1R with equal potency as
`native GLP-1. Two GLP-1IR agonists have so far been
`approved for the treatment of type 2 diabetes: exenatide,
`based on exendin-4,for twice-daily subcutaneous (s.c.) injec-
`tion andliraglutide, based on the structure of native GLP-1,
`for once-daily s.c. injection.
`
`3.1 Exenatide
`Exenatide (Byetta”, Amylin Pharmaceuticals, Inc., San Diego,
`CA, US/Eli Lilly, Indianapolis, Indiana, US), the first GLP-1R
`agonist to reach the market, was approved by the US Food
`
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`GLP-1 receptor agonists for sc injection
`
`Lund, Knop & Vilsboll
`
`
`
`Semaglutide
`
`clinical use in Europe in 2009 and in the USA in 2010
`(Table 1). In liraglutide, a C-16 acyl chain is linked to amino
`acid 20 via a 'Y-glutamic acid spacer and the lysine in position
`28 of native GLP-1 is exchanged with arginine (Table 2) (41).
`These changes results in a half-life in the range of approxi-
`mately 11 - 15 h after s.c. administration (42), makingit suit-
`able for once-daily dosing (43). The clinical effects of liraglutide
`treatment have been investigated in the Liraglutide Effect and
`Action in Diabetes (LEAD)series of Phase III studies. These
`trials lasting up to 52 weeks, showed that treatmentwith lira-
`glutide both as monotherapy and in combination with metfor-
`min, SU or TZD plus metformin lowered HbAlc and body
`weight. Liraglutide-induced change in HbAlc varied from
`-0.8 to -1.5% (baseline HbAlc of 8.2 - 8.5%) [44-49], reduc-
`tions that in most cases were similar or greater than compared
`with the oral comparator drug (42). Overall, a reduction in
`body weight was seen in all trials in the range of 2 - 3 kg,
`much like other Phase III studies with liraglutide compared
`with placebo, and not different
`from exenatide.
`In the
`LEAD-G study,
`liraglutide and exenatide were compared
`head-to-head (47). A significantly greater reduction in HbAlc
`with liraglutide than with exenatide treatment was observed
`(1.1 vs. 0.8%), as well as greater reduction in FPG (1.6 vs.
`0.6 mM), Greater reductions in triglycerides (0.4 vs. 0.2 mM)
`and free fatty acids (0.17 vs. 0.10 mM) in the liraglutide group
`were observed. Both liraglutide and exenatide caused significant
`decreases in blood pressure. Newly published data from a
`14-week extension of the LEAD-6 Phase IIIb study, where sub-
`jects either continued with liraglutide or switched from exena-
`tide to liraglutide, showed that switching from exenatide to
`liraglutide further and significantly reduced HbAlc (0.3%),
`FPG (0.9 mM), body weight (0.9 kg) and systolic blood
`pressure (3.8 mmHg) (so).
`
`
`
`|ouptased1-based Exendin-4-based
`
`en
`
`Exenatide-
`LAR
`
`se
`
`CJC-1134-PC
`
`Figure 1. Overview of the existing and emerging GLP-1R
`agonists;
`two approaches based on human GLP-1 and
`exendin-4.
`GLP-1R: Glucagon-like peptide-1 receptor.
`
`and Drug Administration (FDA) in April 2005 and by Euro-
`pean Medicines Agency (EMA) in 2007 (Table 1). Exenatide
`is a synthetic version of exendin-4, a 39 amino acid peptide
`(Table 2)(1,32), and is resistant to inactivation by DPP-4. Exena-
`tide is primarily cleared in the kidneys by glomerular filtra-
`tion (33), and the half-life after s.c. injection is approximately
`2 - 3h (34). Exenatide, therefore, has to be administered twice
`daily to achieve 24-h pharmacological plasma concentrations.
`In the early clinical AC2993: Diabetes Management for
`Improving Glucose Outcome (AMIGO)trials, the effects of
`exenatide was investigated in a total of 1446 randomized
`patients (35-37]. Exenatide was given as add-on therapy to met-
`formin, SU or both and these studies reported statistically sig-
`nificant improvement of glycemic control
`in the exenatide
`treatment groups (change of HbAlIc of -1.0% (baseline of
`8.2%) vs. an increase of approximately 0.2% in the placebo
`3.3 Side effects of exenatide and liraglutide
`groups) and change in fasting plasma glucose (FPG) (-0.5
`The side effects during treatment with exenatide and liraglu-
`mM vs. an increase of nearly 1 mM in the placebo groups).
`tide are mild to moderate nausea and vomiting. These side
`Onaverage, the weightloss in the three studies comparing exe-
`effects are dose-dependent and often decline over time (51).
`natide with oral anti-diabetics amounted to 1.6 kg (baseline of
`The incidence of treatment-associated hypoglycemia
`is
`95 kg)
`in the exenatide-treated patients (38). Additionally,
`reported to be low. In fact, occurrence of hypoglycemia dur-
`significant
`reduction in systolic blood pressure compared
`ing exenatide treatment combined with metformin is similar
`with placebo (difference of 2.8 mmHg) orinsulin (difference
`to when metformin is used as monotherapy [52|. However,
`of 3.7 mmHg) have been reported after 6 months oftreatment
`combined with SU therisk of minor hypoglycemic episodes
`with exenatide(39). In 2011, a large retrospective database anal-
`is reported to be in the range of 15 — 36% for exenatide (51)
`ysis looking at the relative incidence of cardiovascular disease
`and 8 -— 25% for liraglutide (53). Approximately 50% of
`(CVD)events in patients with type 2 diabetes either treated
`exenatide-treated patients in long-term, placebo-controlled
`with exenatide twice-daily (n = 39,275) or with other
`studies developed low titres of anti-exenatide antibodies, and
`glucose-lowering agents (n = 381,218) was published (40).
`an additional 6% developed higher levels of antibodies,
`The study reported that
`treatment with exenatide twice-
`during the initial 30 weeks of treatment
`[s1). Among
`daily was associated withasignificantly lower risk of CVD
`liraghutide-treated patients, 4 - 13% developed antibodies
`events than treatmentwith other glucose-lowering agents.
`(low titres) (44-46,49,49|. The exact impact of autoantibodies
`on efficacy and safety in the longer term remains to be estab-
`3.2 Liraglutide
`Liraglutide (Victoza™, Novo Nordisk, Bagsvrd, Copenhagen,
`lished, but patients with high titres seem to have an impaired
`effect on glycemic control[54]. After the approval ofexenatide
`Denmark)is an acylated analog of human GLP-1 (with 97%
`and liraglutide post-marketing reports of several incidents of
`homology with native GLP-1), which was approved for
`
`
`Expert Opin, Emerging Drugs (2011) 16(4)
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`Emerging GLP-1 receptor agonists
`
`Table 1. Overview of the existing and emerging GLP-1R agonists, their state of development and ongoing trials.
`
`Compound
`
`Company
`
`Exenatide
`
`Liraglutide
`
`Eli Lilly/Amylin Pharmaceuticals,
`Inc.
`
`Novo Nordisk
`
`Once-daily
`
`Launched
`
`Formulation
`
`Status of
`development
`
`Twice-daily
`
`Launched
`
`Ongoing trials
`
`Combination with insulin/
`obesity + CVD
`Combination with insulin/
`obesity + CVD
`Combination with insulin’
`obesity
`Phase Ill, GetGoal
`Phase VII
`Phase Ill, Harmony
`Phase Ill, Award
`
`Exenatide once-weekly
`
`Lixisenatide
`
`Eli Lilly/Amylin Pharmaceutical, Inc/
`Alkermes, Inc.
`Zealand Pharma A/S/Sanofi-Aventis
`
`ConjuChem
`GlaxoSmithKline
`Eli Lilly
`
`Once-weekly
`
`Expected 2011
`
`Once-daily
`Once-weekly
`Once-weekly
`Once-weekly
`
`Expected 2011
`Phase VII
`Expected 2012
`Expected 2013
`
`CJC-1134-PC
`Albiglutide
`Dulaglutide
`(LY2189265)
`Phase IlOnce-weekly On hold
`Novo Nordisk
`Semaglutide (NN9535)
`
`
`
`
`
`CVD; Cardiovascular disease; GLP-1R: Glucagon-like peptide-1 receptor
`
`Table 2. Amino acid structures of GLP-1 and the GLP-1R agonists on the marketorin late clinical development
` (published data).
`
`Name
`
`Structure
`
`His-Ala~Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-lle-Ala-Trp-Leu-Val-Lys-
`Gly-Arg
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gin-Ala-Ala-Lys-Glu-Phe-lle-Ala-Trp-Leu-Val-Arg-
`Gly-Arg-Gly
`
`lu-C 16 fatty acid
`(His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gin-Ala-Ala-Lys-Glu-Phe-lle-Ala-Trp-Leu-Val-Lys-
`Gly-Arg), - linked to human albumin
`His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gin-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser
`His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys
`His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-C 13H1906N3 (linker molecule)
`
`|G
`
`Native GLP-1
`
`Liraglutide
`
`Albiglutide
`
`Exenatide
`
`Lixisenatide
`
`CJC-1134-PC
`
`GLP-1: Giucagon-like peptide-1; GLP-1R: Glucagor-like peptide-1 receptor.
`
`acute pancreatitis in patients treated with exenatide andlira-
`glutide have been disclosed (55). However, it is not evident
`that the incidence of acute pancreatitis is higher in those
`receiving exenatide orliraglutide than in the background dia-
`betic population [56]. Still
`it
`is recommended that
`these
`GLP-1R agonists should notbe used in subjects with a history
`ofor increased risk of pancreatitis. Lately, the risk of pancre-
`atic cancer has been discussed in patients treated with exena-
`tide compared with other anti-diabetic medications {57,58}.
`However,
`the EMA recently concluded that a relationship
`between GLP-1R agonists and pancreatic malignancies could
`not yet be confirmed nor excluded {59}. In carcinogenicity
`studies with liraglutide, C cell tumors were observed in thy-
`roid tissue of mice and rats (60). However, recent data identify
`key differences between rodent models, non-human primates
`and humans with regard to this, and the long-term
`
`consequences of sustained GLP-1R activation in the human
`thyroid require further investigation (61), but so far no changes
`in thyroid function have been reported in clinical trials with
`GLP-1R agonists. Furthermore,
`large studies are underway
`aiming to assess and confirm the cardiovascular safety of
`both exenatide and liraglutide.
`
`4. Current research goals
`
`The GLP-1R agonists have already proved to be a valuable
`asset to the treatmentof patients with type 2 diabetes. How-
`ever, despite the many beneficial effects of the GLP-1R ago-
`nists on weight
`loss and improved glycemic control,
`the
`gastrointestinal
`intolerability and daily s.c. administration
`may lead to discontinuation (62), Currently, GLP-1R agonists
`with optimized pharmacokinetic profiles and a lower number
`
`610
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`Lund, Knop & Vilsboll
`
`5. Competitive environment
`
`of adverse events are under development. Most of the emerg-
`ing GLP-1R agonists are for once-weekly s.c. administration.
`The once-weekly regime is thought to improve compliance,
`and to offer an improved throughout-the-day glycemic con-
`trol compared with the currently available GLP-1R agonists
`(exenatide and liraglutide).
`
`studies, exenatide once-weekly
`In all
`twice-daily {64.67}.
`lowered HbAlc and body weight significantly. The HbAlc
`reduction by exenatide once-weekly was up to 1.6%, and in
`most cases this reduction was greater or similar to that of
`the comparator. Overall, a reduction in body weight by exena-
`tide once-weekly was seen in the range of 2.1 — 2.6 kg. Very
`recently,
`the preliminary results from the DURATION-6
`study comparing exenatide once-weekly with liraglutide
`once-daily were reported in a press release [68]. This 26-week
`head-to-head, open-label, study enrolled approximately 900
`5.1 Exenatide once-weekly
`patients with type 2 diabetes who were not achieving adequate
`Exenatide has been developed in a sustained-release formula-
`HbA |c with diet and exercise in conjunction with metformin,
`tion planned for once-weekly s.c. administration by Amylin
`SU, metformin plus a SU or metformin plus a TZD. The
`Pharmaceuticals, Inc., Eli Lilly and Alkermes Inc. (Table 1).
`study revealed that patients receiving exenatide once-weekly
`The exenatide molecules are encapsulated in injectable micro-
`experienced a reduction in HbAlc of 1.3% compared with
`spheres, which consist of a biodegradable medical polymer
`1.5% for liraglutide. Exenatide once-weekly did, therefore,
`also used in other extended-release pharmaceuticals (63). These
`not meet
`the pre-specified primary end point of non-
`microspheres allow gradual drug delivery at a controlled rate
`inferiority to liraglutide with regard to HbAIc reduction since
`by diffusion and erosion of the microspheres. The drug is
`liraglutide was significantly more efficacious than exenatide
`now in late clinical development, and the clinical effects of
`once-weekly. However, exenatide once-weekly did appear to
`exenatide once-weekly have been examined in the ‘Diabetes
`be slightly better tolerated than liraglutide with less gastroin-
`therapy Utilization: Researching changes in HbAlc weight
`testinal side effects (such as nausea and vomiting), alchough
`and other
`factors Through Intervention with exenatide
`more patients experienced local site reactions with exenatide
`Once-weekly’ (DURATION) 1 -6trials (4-69). In DURA-
`compared with liraglutide (68). Data on changes in body
`TION-1, exenatide once-weekly was studied in a head-to-
`weight have notyet been reported.
`head comparison with exenatide twice-daily in 295 patients
`The mostfrequently reported adverse events among exena-
`with type 2 diabetes (HbAIc 8.3 + 1%, weight 103 + 20 kg,
`BMI 35 + 5 kg/m’, diabetes duration 7 + 5 years) over
`tide once-weekly-treated patients in the DURATIONstudies
`were nausea (predominately mild in intensity) (9 - 26%) and
`30 weeks {69}. Exenatide once-weekly was superior to exena-
`vomiting (4 — 11%) \64-70}, Other side effects included diar-
`tide twice-daily in terms of glycemic parameters (HbAlc
`thea (6 - 18%), and injection site adverse effects (pruritus,
`change:
`-1.9 vs.
`-1.5%, proportion of patients reaching
`erythema,
`induration or pain) (10 - 18%) {64-70}. Pooled
`HbAle of 7.0% or
`less: 77 vs. 61%; FPG:
`-2,3 vs.
`data of the safety and tolerability of exenatide once-weekly
`-1.4 mM). Interestingly, glucagon levels decreased signifi-
`from 1095 patients (from the DURATION 1, 2 and 3 stud-
`cantly more with exenatide once-weekly vs. exenatide twice-
`ies) showed that exenatide once-weekly were generally well
`daily, likely contributing to the improvement in FPG levels.
`tolerated, and that
`the overall
`incidence rates of adverse
`Additionally, significandy greater reductions in total choles-
`events, serious adverse events and discontinuations due to
`terol and low-density lipoprotein cholesterol were observed
`serious adverse events were similar
`for exenatide once-
`with the once-weekly exenatide compared with the twice-
`weekly versus the pooled comparators. No major episodes of
`daily exenatide. Equal significant improvements in fasting tri-
`hypoglycemia have been observed and the incidence of mild
`glyceride and systolic and diastolic blood pressures were
`to moderate hypoglycemic events observed with exenatide
`observed with both treatments. No difference in body weight
`once-weekly treatment was lower compared with the pooled
`reduction was observed (3.7 vs. 3.6 kg), and about 75% ofthe
`comparator cohort (16 vs. 22%) (711.
`patients lose weight(69]. A 22-week open-label extension of the
`Recently, a probable correlation between plasma exenatide
`DURATION-1 study, where patients either continued with
`concentrations and changes from baseline in the QT interval
`exenatide once-weekly or switched from exenatide once-
`in healthy subjects was discussed (72). Thus, the FDA recently
`daily to exenatide once-weekly, showed that the improved gly-
`requested a thorough QT interval study with exenatide levels
`cemic control and weightloss were sustained over the 52 weeks
`higher
`than typical
`therapeutic levels of exenatide once-
`of therapy and patients who switched from exenatide twice-
`weekly (73). Additionally, the FDA requested the results of the
`daily to once-weekly achieved a further reduction in HbAIc,
`DURATION-5studyto evaluate theefficacy, safety and effec-
`ending up with the same improvements in glycemic control
`tiveness, of the commercial formulation of exenatide once-
`as the group treated with exenatide once-weekly for the entire
`weekly. Amylin Pharmaceuticals, Inc., Eli Lilly and Alkermes,
`52 weeks {70}.
`Inc. are planning to submit their reply to the FDAby the end of
`studies, exenatide once-
`In the DURATION-2 to 5
`2011. In April 2011, the EMA has issued a positive opinion
`weekly was compared against: a TZD, a DPP-4 inhibitor,
`and exenatide once-weekly will reach the European market
`insulin glargine, metformin and the commercial formulation
`(tradename: Bydureon) by the end of 2011.
`of exenatide once-weekly was compared against exenatide
`
`Expert Opin. Emerging Drugs (2011) 16(4)
`611
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`
`
`Emerging GLP-1 receptor agonists
`
`The ongoing Phase III clinical trial program oflixisenatide is
`called GetGoal and was initiated in May 2008. The program
`has so far enrolled more than 4500 patients and will assess effi-
`cacy andsafety oflixisenatide in patients with type 2 diabetes.
`Theresults from thefirst head-to-head study comparing lixise-
`natide with another GLP-1R agonist
`(GetGoal-X) were
`recently reported in a press release (81). This randomized,
`open-label multicenter study with 639 patients with type 2 dia-
`betes compared theeffect oflixisenatide versus exenatide twice-
`daily as add-on therapy to metformin. The study did meet the
`pre-defined end point of non-inferiority in HbAlc reduction
`oflixisenatide compared with exenatide twice-daily, and signif-
`icantly fewer episodes of hypoglycemia were reported with lixi-
`senatide versus exenatide twice-daily (s1|. The full study and
`additional results from the GetGoal program are expected in
`2011. Furthermore,a large trial evaluating cardiovascular our-
`comes in high-risk patients (i.e., patients with a recent history
`of acute coronary syndrome) has been undertaken, estimated
`study completion date is late 2013. Randomized trials with
`direct comparisons with sitagliptin and liraglutide have been
`completed but no reports are available currendy,
`
`5.2 Lixisenatide
`Lixisenatide is a GLP-1R agonist,in late clinical development
`by Sanofi-Aventis, Paris, France under license from Zealand
`Pharma A/S, Copenhagen, Denmark (Table 1). The peptide
`contains 44 aminoacids andis based on the structure of exen-
`din-4, with the deletion of a proline and an addition ofsix
`lysine residues at the C-terminus (Table 2)
`(74). The affinity
`oflixisenatide to the GLP-1R have been shown to be approx-
`imately four times higher as compared with native GLP-1 (75),
`and half-life in plasma oflixisenatide is reported to be approx-
`imately 3 h (76,77\. Lixisenatide is probably administered as a s.
`c. injection once-daily. Data from a randomized controlled
`trial including 361, drug naive, patients with type 2 diabetes,
`showed that 13 weeks oflixisenatide administration once-
`daily in monotherapy provided significant improvements in
`glycemic control (HbAIc reduction between 0.7 and 0.8%,
`mean FPG reduction between 0.7 and 0.9 mM)(7s). A body
`weight reduction of approximately 2 kg was observed. The
`efficacy oflixisenatide as add-on therapy to metformin was
`evaluated in a dose-finding study of 542 patients with type 2
`diabetes (79). In this 13-week trial, 12 separate arms were initi-
`ated: eight active treatment arms with escalating doses ofs.c.
`5.3 CIC-1134-PC
`lixisenatide (target dose 5, 10, 20 or 30 pg once-daily or
`twice-daily) and four placebo arms. The results showed that
`CJC-1134-PC, Montreal, Canada (ConjuChem) comprises a
`modified exendin-4 molecule and human recombinant albu-
`lixisenatide significantly and dose-dependently lowered mean
`min (Table 1). The exendin-4 derivative includes amino acids
`HbAlc levels from baseline by -0.5 to -0.8% for once-
`
`daily dosing and -0.7 to -0.9% with twice-daily dosing (pla- 1 - 39 of native exendin-4 andalysine residue at position
`40 (Table 2) {82}. Despite being a much larger molecule than
`cebo
`-0.2%). The
`percentage of patients
`achieving
`exendin-4, pre-clinical data have shown that CJC-1134-PC
`HbAIc < 7.0% ranged from 47 to 77% with increasing doses
`retains the ability to bind to and activate the GLP-1R (2). Pre-
`oflixisenatide compared with 32% with placebo. Lixisenatide
`liminary results
`from clinical
`crials
`in patients with
`induced dose-dependent weight
`losses ranging from 2 to
`
`3.9 kg; weight loss in the placebo group was 1.9 kg and, type 2 diabetes indicate that CJC-1134-PC hasahalf-life of
`thus, only in the relatively high-dose lixisenatide groups
`approximately 8 days (like circulating albumin), makingit
`suitable for once-weekly dosing(83). At present, only very lim-
`(20 and 30 pg once-daily and 30 pg twice-daily) the weight
`loss was statistically significant. The conclusion of the
`ited data on the clinical pharmacology of CJC-1134-PC are
`study was that
`lixisenatide 20 pg administered once-daily
`available, and results of Phase | and II studies have been pub-
`demonstrated the best efficacy:tolerability ratio.
`lished solely as abstracts (83.84). A Phase I/II clinical dose-
`finding study (n = 58) with daily administration ofs.c.
`The most commonadverse events to lixisenatide treatment
`were of gastrointestinal origin, much consistent with other
`CJC-1134-PC at doses between 310 and 5000 pg evaluated
`GLP-IR agonists. With lixisenatide as monotherapy (20 pg
`efficacy and safety in patients with type 2 diabetes (#3). Doses
`once-daily), these were reported to be approximately 32 versus
`above 1250 pg produced reductions in mean daily and FPG
`14% in the placebo group with nausea being the most fre-
`levels, persisting for
`1 — 3 weeks after a single s.c. dose.
`quent(78). In the 13-week dose-ranging study (5 - 60 jag) the
`Body weight
`reduction of 2.5 kg (placebo: 1.2 kg) was
`gastrointestinal side effects occurred dose-dependently: nausea
`observed at the 3000 jg dose after 3 weeks (83). The efficacy
`7 - 35% (placebo 5%), vomiting 4 - 19% (placebo 1%) and
`on HbA Ic of CJC-1134-PC compared with placebo was eval-
`diarrhea 6 — 26% (placebo 7%) [79}. No major hypoglycemic
`uated in a 3-month Phase II clinical rial comprising two indi-
`episodes and only few mild to moderate hypoglycemic episodes
`vidual studies with a total of 224 patients with type 2 diabetes
`have been reported,with a similar frequency as during metfor-
`inadequately
`controlled on metformin. CJC-1134-PC
`reduced HbAlc by 0.8% (1.5 - 2 mg once-weekly) and
`min treatment(80). Antibody formation to lixisenatide was fre-
`quentin the only study reporting exact numbers; ranging from
`1.4% (1.5 mg twice-weekly), compared with a 0.4% reduc-
`43 (10 jg once-daily) to 71% (20 pg twice-daily) {79}. No cases
`tion with placebo. Body weight decreased during the 3-month
`of suspected pancreatitis or thyroid tumors have been reported
`treatment period with reductions of 1.2 kg (with 1.5 mg
`during treatment with lixisenatide, but a few emergent adverse
`twice-weekly); however, this difference was notsignificantly
`events have been reported. These include one hypersensitivity
`different
`to the weight
`reductions
`seen with placebo
`reaction and four possible allergic reactions(80).
`(0.4 kg) (84). At present, it is unclear why the CJC-1134-PC
`
`612
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`Expert Opin. Emerging Drugs (2011) 16(4)
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`MPI EXHIBIT 1035 PAGE 6
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`
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`Lund, Knop & Vilsball
`
`compoundseemsto havelittle (or no) effect on body weight
`as compared with most other GLP-1R agonists.