ExP.ert
`Opinion
`
`1. Background
`2. Medical need
`3. Existing treatment
`4 . Current research goals
`s. Competitive environment
`6. Conclusion
`7. Expert opinion
`
`informa
`
`healthcare
`
`Review
`
`Emerging GLP-1 receptor agonists
`Asgcr Lund, Filip K Knop & Tina Vilsb01J
`D111beta &much Dfri.siorr, Departmrnt •f fnumal Mtdmnr F, Gmrofa Hospira/, UniL'fT'SiJy of
`Coprnhagm, Hrllrrup, DmmarK
`
`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-1 R agonists presently
`available are administered once or twice daily, but several once-weekly
`GLP-1 R agonists are in late clinical development.
`Areas covered: The present review aims to give an overview of the clinical
`data on the currently available GLP-1 R agonists used for treatment of type 2
`diabetes, exenatide and liraglutide, as well as the emerging GLP-1 R agonists
`including the long-acting compounds.
`Expert op inion: An emerging therapeutic trend toward initial or early combi(cid:173)
`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-1 R agonists. The available
`GLP-1 R agonists cause sustained weight loss and clinical relevant improve(cid:173)
`ment of glycemic control. The long-acting GLP-1 R agonlsts in late develop(cid:173)
`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
`multicenter trials with cardiovascular endpoints are expected in 2015.
`
`Kq-words: albiglucide, CJC-1134-PC. dulaglucidc, cxcnacidc:, c,,:enadde oncc-w~kly,
`glucagon-likc pc:pcidc-1 receptor agonim, liraglucidc, lixiscnacidc, semagluride, cype 2 diahcr~
`
`E.xp"t Opin Emerging Drup (201 I) 16(4).607-618
`
`1. Background
`
`OraJ glucose administration elicits a greater insulin response than intravenous (i.v.)
`glucose at identical plasma glucose profiles. This is ca.lied the incretin effect, and is
`conveyed by the two increcin hormones: glucose-<iepcndent insulinotropic polypep(cid:173)
`tide (GIP) and glucagon-like peptide-I (GLP-1} 'I'. GIP is a 42 amino acid peptide,
`synthesized and released from emeroendocrine K cells mainly located in the duode(cid:173)
`num and upper jejunum [IJ. GLP-1 is a 30 amino acid peptide, a produce of proglu(cid:173)
`cagon gene expression in the intestinal enteroendocrine L cells and is, like GIP,
`secreted after meal ingestion [1.21. Together the insulinouopic effect of GIP and
`GLP-1 accounts for up ro 70% of the insulin secreted after a meal in healthy sub(cid:173)
`jects, and, thus, plays a very important role in postprandial glucose homeostasis [IJ.
`In patients with cype 2 diabetes, the ability of exogenous GIP and GLP-1 to stim(cid:173)
`ulate insulin secretion is severdy diminished when compared with. healthy subjcccs.
`However, the glucose-lowering effect of supraphysiologica.l infusion of GLP-1 is
`preserved 13; while that of GIP is absent (4,5) .
`GLP-1 asserts its effects on the be~ cells through binding co the GLP-l receptor
`(GLP-1 R), a cell surface receptor highly expressed on rhe cell membrane of
`pancreatic beta cdls [2.6]. Receptor binding of GLP-1 results in stimulation of insu(cid:173)
`lin secretion in a strict glucose-dependent manner 7,SJ. GLP-1 also has potential
`• effects on beta cell mass as pre-dinicaJ studies have shown: stimulation of beta
`
`10 1517/14728214 2011616493 C 2011 lnforma Ute:. Ltd ISSN 1472-8214
`All rights r=rved reprodvct1011 in whole Of' ,n part not pe,m,tted
`
`607
`
`MPI EXHIBIT 1035 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1035-0001
`
`

`

`Emerging GLP-1 receptor agonists
`
`cdl proliferation 19,101, differentiation of new beta cells from
`progenitor cells ft II and by inhibition of beta ccU apoprosis 11?1.
`Funhcnnore, GLP-1 robusdy inhibits glucagon secretion,
`and the combined effecrs on insulin and glucagon secretion
`results in inhibition of heparic glucose production, which
`contributes significantly ro rhe overall glucose-lowering effea
`of GLP-1 1n1. Additionally, GLP-1 decreases gastrointestinal
`motility 11, and promores satiety 11~1. probably through
`acciv:ation of GLP-1 Rs in the brain in combination with
`GLP-1-induccd decrease in gastric emptying. Chronic admin(cid:173)
`istration of GLP-1 rherefore leads co weight loss (16). All of
`these effects are potentially beneficial in the crearmenc of
`patients with ~ 2 diabetes, and much attcndon have,
`therefore, been given ro the development of pharmacological
`strategies based on the cffccrs of GLP- l.
`One of the major challenges in developing GLP- I-based
`cher.ipy is that native GLP-1 is very rapiclly degraded in the
`circulation by che enzyme dipeptidyl peptidase 4 (DPP-4),
`which cleaves off the two N-rerminal amino acids and leaves
`the molecule inactive with regard to insulin secretion (17),
`resulting in a half-life of less than 2 min 11s1. Because of the
`rapid elimination, nativ<" GLP-1 is unsuitable for clinical
`use. Two different strategics of circumventing chis problem
`have been successful so far. One approach is to inhibit
`DPP-4, tht'rcby enhancing the survival and therefore the
`effect of endogenously rdeascd GLP-1. The other strategy i~
`ro use GLP-1 R agon1srs that arc r<"Smam co ina.ctivacion by
`DPP-4 and modified in a way char prolongs the effect of the
`hormone. In the following sections, the emerging GLP-lR
`agonises arc reviewed.
`
`2. Medical need
`
`Type 2 diabet<"S is a progressive and mulcifactoriaJ disease.
`There were an csomared 285 million adults with ~ 2 diabe(cid:173)
`tes in 20 IO worldwide, and, as rhe western lifestyle is making its
`encry into the developing countries, this number will continue
`ro increase 1191. Projections fur 2030 show that rhe prevalence
`of type 2 diabetes is likely to reach almost 450 million 20.1.
`Type 2 diabetes leads to serious complications that broadly
`can be classified as microvascular (neuropathy, ncphropathy
`and rctinoparhy) or macrovascular (arherosderosis resulting
`in myocardial infarction and stroke). The ultimate goaJ of
`diabetes therapy JS to prevent these complkations in order to
`improve Life expectancy and quality of life. The United
`Kingdom Prospective Diabetes Study (UKPDS) showed that
`improved gJyccm1c conrrol (HbAlc) resulted in less mia-ovas(cid:173)
`cular complicarions in patients with ~ 2 diabetes (11).
`Furthermore, recent follow-up srudics from the UKPDS have
`shown that tight glucose control in the early years of disease
`impacts dramatically on the development of complications
`related to the disease (22J.
`Despite recognition chat type 2 diabetes is a huge publk
`health concern, and ma1or cfforu co attract attention ro the
`imponance of eight glyccmic control, dara from World
`
`Health Organization (WHO) show that rh<" percentage
`of individuals reaching International Diabetes Federation
`(IDF) treatment goaJs is srill very low ,.n . Common barriers
`to patient adherence include concern about unwanted wCJghc
`gain (2◄J, fear of hypoglycemia and perceived inconve(cid:173)
`nience 12~1, and these may all indirectly undermine glyccmic
`control if the prescribed therapy is nor followt'd.
`
`3. Existing treatment
`
`Internacional guidelines for the treatment of patienrs with
`~ 2 diabetes have been suggested by the European Associa(cid:173)
`tion for the Study of Diabetes (EASD) and the American Dia(cid:173)
`betes Association (ADA) (l1>1. B:iscd on cbr2 from the UKPDS
`it is recommended that metformin should be stancd in all
`patients with newly diagnosed type 2 diabetes who do not
`have contraindications to metformin treatment (e.g., renal
`disease) 126-29]. However, often metformin is nor enough to
`treat the patients wirh the target HbA lc levels below 7%.
`Therefore, the guidelines suggest additional treatment options
`on which agents to add co mctformin treatment [291. Classical
`therapeutic additives arc: i) the insulin secrclagogues sulfony(cid:173)
`lurcas (SU), ii) the insulin-sensitizing thiazolidioncs (TZD)
`and iii) exogenous insulin. However, all of these agents arc
`associated with different adverse effeets induding risk of
`hypoglycc.mia (SU and insulin), weight gain (SU. insulin
`and TZD) and increased risk of bone fractures and even hean
`disease (TZD) (30). Additionally, none of these medications
`are able to correct either the impairment or rhe progressive
`decline ofbeca cell function. Recendy, the increrin-bascd ther(cid:173)
`apies including GLP-lR agorusts 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- lR agonises being part of the latest ADNEASD
`rrcacment guidelines [26).
`The development of the GLP-1 R agonisrs is based on rwo
`different approaches. One strategy exploits the Stn.lctUre of
`native human GLP-1, modified in a way so th.at it is resis~nc
`to degradation by DPP-4, as the backbone for the compounds
`(Figure 1). The other approach uses a narurally occurring
`protein - exc.odio-4, originally isolated from the saliva of
`the lizard Hdodcrma suspecrum - as rhe backbone of the
`compounds (Figure I). Excndin-4 has a 53% sequence homol(cid:173)
`ogy with human GLP-1 in its first 30 amino acids 321, and
`binds to and activates the GLP-lR with equal potency as
`native GLP-1. Two GLP-JR agonises have so far been
`approved for the treatment of type 2 diabetes: exenacidc,
`based on exendin-4, for twice-d.tily subcutaneous (s.c.) injec(cid:173)
`tion and liraglutide, based on the strucrurc of narivc GLP-1,
`for once-daily s.c. injection.
`
`3.1 Exenatide
`Excoatide (Byetti\ Amylin Pharmaceuticals, Inc., San Diego,
`CA, US/Eli Lilly, Indianapolis, Indiana. US), rhe first GLP-IR
`agonise to reach the market, was approved by the US Food
`
`608
`
`bpen Optn Emerg,ng Drugs (2011) 16(41
`
`MPI EXHIBIT 1035 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1035-0002
`
`

`

`GLP-1 receptor agonlsts tor sc Injection
`
`GLP-1-based
`
`Exend,n-4-based
`
`Liraglutide
`
`Albiglullde
`
`Exenatide
`
`Exenatide(cid:173)
`LAR
`
`Dulaglutlde
`
`LixisenatJde
`
`CJC-1134-PC
`
`Semaglutide
`
`Figure 1. Overview of the existing and emerging GLP-1R
`agonists; two approaches based on huma n GLP· 1 and
`exendin-4.
`GLP-1 R Glucagon-l1kt' pepltdt'-1 receptor.
`
`and Drug Administr.mon (FDA) in April 2005 and by Euro(cid:173)
`pan Medicines Agency (EMA) in 2007 (Table 1). Exenatide
`is a synthetic version of cxendin-4, a 39 ammo acid peptide
`(Table 2) 11 ,321, and is resistant to inactivation by DPP-4. Exena(cid:173)
`cide 1s primarily cleared in the kidneys by glomcruJar fihra(cid:173)
`oon 133,, .Lnd the half-life after s.c. injccrion is approximately
`2 - 3 h [}4!. Ex.enaride, therefore, has to be administered cwicc
`daily ro achieve 24•h pharmaoological plasma concemr.uioiu.
`In the early clinical AC2993: Diabetes Management for
`Improving Glucose Outcome (AMJGO) rrials, the effects of
`cxenatide was investigated in a total of 1446 randomized
`patients ,s.p •_ Exenacide was given as add-on du~r.i.py to met(cid:173)
`formin, SU or both and these studies reported statisrically sig(cid:173)
`nificant improvement of glycemic control in the exenaride.
`treatment groups (change of HbAlc of -1.0% (baseline of
`8.2%) vs. an increase of approximately 0.2% in the. placebo
`groups) and change in fasting plasma glucose (PPG) (-0.5
`mM vs. an increase of nearly I mM in the placebo groups).
`On average, the weight loss in the chree studies comparing exe(cid:173)
`nacide with oral anti-diabccie3 amounted to 1.6 kg (baseline of
`95 kg) in the cxcnatide-created pacients (381. Additionally,
`significant reduction in systolic blood pressure compared
`with placebo (difference of 2.8 mmHg) or insulin (difference
`of 3.7 mmHg) have been reported after 6 months of ueacment
`with cxenatide J'll. In 2011, a large recrospecrive database anal(cid:173)
`ysis looking ar the relative incidence of cardiovascular disease
`(CVD) ~ents in patients with cypc 2 diabetes either rreaced
`with cxenacide cwicc:-daily (n "' 39,275) or with other
`glucose-lowering agents (n = 381,218) was published (-ioJ.
`The study reported that ucacment with cxenatidc cw1cc:(cid:173)
`daily was associaced with a significantly lower risk of CVD
`~encs than crcatmcnt with ocher glucose-lowering agents.
`
`J.2 Liraglutide
`Liraglutidc (Victo1.a ~, Novo Nordisk, Bag.wzrd, Copenhagen,
`Denmark) is an acylated analog of human GLP-1 (with 97%
`homology wirh native GLP-1), which was approved for
`
`Lund, Knop & Vilsboll
`
`clinical use m Europe 1n 2009 and in che USA m lO I 0
`(Table l). In liraglucide, a C-16 acyl cha.in is linked to amino
`acid 20 via a y-glucamic acid spacer and the lysine in position
`28 of nauve GLP-1 1s exchanged with arginine (Table 2) {41 1.
`These changes resuJcs in a half-Life in the: nnge of approxi(cid:173)
`macdy 11 - IS h after s.c. administration (421, making it suit(cid:173)
`able for once-daily dosing [H J. The clinical effcas ofliraglucide
`treatment have been investigated in the Liraglutide Effect and
`Action in Diabetes (LF.AD) series of Phase Ill scudies. These
`uials lasting up co 52 weeks, showed that treatment with lira(cid:173)
`glutide both as monothcrapy and in combination with metfor•
`min, SU or TZD plus mecformin lowered HbA lc and body
`weight. Liraglutide-induccd change m HbAlc varied from
`-0.8 tu -1.5% (ba.-,dine H bAlc of 8.2 - 8.5%) (4·1 •l?J, rcduc-
`1ions chat in most cases were similar or greater than compared
`with the oral comparator drug [421, Overall, a reduction in
`body weight was seen in all rrials in the range of 2 - 3 kg,
`much like other Phase lil srudie.s with li.ragluode compaced
`with placebo, and not different from cx:c:natidc. 1n the
`LEAD-6 srudy, liragluride and exenacide. we.re compared
`head-to-had 1~71. A significandy grcarc:r reduction in HbA le
`with liraglucidc than with eunaride crea_ancnt was observed
`(I.I vs. 0.8%), as wdJ as greater reduction in FPG (1.6 vs.
`0.6 mM). Greater reductions in triglycerides (0.4 vs. 0.2 mM)
`and free fany acids (0.17 vs. 0.10 mM) in che liragluride group
`were observed. Both liraglutide and exenatide caused ,igruliCUlt
`decreases in blood pressure. Newly published data from a
`14-week e)((ension of the LEAD-6 Phase IIIb study, where sub(cid:173)
`jcct:s c:ithcr continued with liragluride or switched from cx:ena(cid:173)
`cide to liraglutide, showed char swirching from e:xc:natide to
`liraglucide funher and s1gnificancly rcduce<l HbAlc {0.3%),
`PPG (0.9 m1n, body WClght (0.9 kg) and systolic blood
`pressure: (3.8 mmHg) ('>OJ.
`
`3.3 Side effects of exenatide and liraglutide
`The side effects during treatment with exenatide and liraglu(cid:173)
`tide are mild to moderate nausea and vomiting. These side
`dfccrs are d~ependenr and often decline over time [~ I).
`The
`incidence of creacment-a.ssociaced hypoglycemia
`is
`reported to be low. In fact, occurrence of hypoglycemia dur•
`ing c:xenacide creacmem combined with mctformin is similar
`to when merformin is used as monotherapy 1~21. How~cr.
`combined with SU the risk of minor hypoglycemic episodes
`is reported ro be in the range of 15 - 36% for exenatide (i 1J
`and 8 - 25% for liraglucide (53). Approximately 50% of
`exenatide-crc::ared patients in long-term, placebo-concroUed
`studies developed low ticre.s of anci-e:xenacide antibodies, and
`an additional 6% developed higher levels of antibodies,
`during the initial 30 weeks of 1reacment [~1 . Among
`liraglutide-treate.d paaencs, 4 - 13% developed antibodies
`{low titres) (-44 ~6.•R,49,. The cxacr impact of autoanobodies
`on efficacy and safety in the longer tc:nn remains 10 be estab(cid:173)
`lished, but patients with high deres seem to have an impaired
`effect on glycemic control r,◄J . After the approval of aenaode
`and liraglutide post-marketing repon:s of several incidents of
`
`Experr Opm Eme«;mg Drugs (2011) 16(4)
`
`609
`
`MPI EXHIBIT 1035 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1035-0003
`
`

`

`Emerging GLP-1 receptor agonists
`
`Table 1. Overview of the existing and emerging GLP-1R agonists. their rtate of development and ongoing trials.
`
`Compound
`
`Company
`
`Exenat1de
`
`L1r aglutide
`
`Eh Lllly/Amylin Pharmaceuticals,
`Inc
`Novo Nordisk
`
`Formulation
`
`Status of
`development
`
`Twice-daily
`
`Launched
`
`Once-daily
`
`Launched
`
`Ongoing trials
`
`Combination with 1nsul1n/
`obesity + CVD
`Combination with insulin/
`obesity + CVD
`Combination with insulin/
`obesity
`Phase 111, GetGoal
`Phase t/11
`Phase 111, Harmony
`Phase Ill, Award
`
`Exenatide once-weekly
`
`L1x1senat1de
`CJC • 1134-PC
`Alb1glut1de
`Dulaglutide
`(L Y218926S)
`Semaglut1de (NN9S35)
`
`Eli U11y/Amyhn Pharmaceutical, lncJ
`Alkermes, Inc.
`Zealand Pharma A/S/Sanof1-Avent1s
`ConiuChem
`GlaxoSmithKline
`Eh L.Jlly
`
`Once-weekly
`
`Expe<:ted 2011
`
`Once-daily
`Once-weekly
`Once-weekly
`Once-weekly
`
`Expected 2011
`Phase t/11
`Expected 2012
`Expected 2013
`
`Novo Nordisk
`
`Once-wee~ly
`
`Phase II
`
`On hold
`
`CVD Cardoova5Cul.u d~ . GLP-1 R Glucagon-1,ke peptide-I receptor
`
`Table 2. Amino acid structures of GLP-1 and the GLP-1R agonists on the market or in late clinical development
`(published data).
`
`Name
`
`Structure
`
`Native GLP-1
`
`l.Jraglut1de
`
`Alb1glut1de
`
`Exenat1de
`
`L1x1senat1de
`
`CJC-1134-PC
`
`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(cid:173)
`Gly-Arg
`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-Arg-
`I
`Gly-Arg-Gly
`Glu•C 16 fatty acid
`(His-Gly-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(cid:173)
`Gly-Arg)i - linked to human albumin
`H 1s-Gly-Glu-Gly-Thr -Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met ·G lu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-T rp-Leu-L ys(cid:173)
`Asn-Gly-Gly-Pro-Ser -Ser -Gly-Ala-Pro-Pro-Pro-Ser
`H 1s-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(cid:173)
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys•lys-l ys•Lys
`H1s-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(cid:173)
`Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-C 13H l 906N3 (linker molecule)
`
`GL.P-1. Glucagon-ltlte peptide-I. GLP-IR. GllJCdOOO-lli pep~l receptor.
`
`acute panacatiris in patiena created with excnatide and lira(cid:173)
`glutide have been disclosed 155!. However, it is not evident
`chat the incidence of acute pancrcacitis is higher in those
`receiving cxcnatide or liraglutide than in the background dia(cid:173)
`betic population IS6J. Still it is recommended that these
`GLP-1 R agonists should nor be used in subjects with a history
`of or increased risk of pancrcatitis. Lately, the risk of pancre(cid:173)
`atic cane.er has been discussed in patients created with exena(cid:173)
`tide compared with other anti-diabetic medications f57.58J.
`However, the EMA recently conduded that a relationship
`between GLP-1 R agonists and pancreatic malignfflcies could
`not yet be confirmed nor excluded [591. In carcinogenicity
`srudies with liraglutide, C cell rumors were observed in thy(cid:173)
`roid tissue of mice and rats 160,. However, recent data identify
`kq differences between rodent models, non-human primates
`and humans with regard co
`this, and
`the
`long-term
`
`consequences of sustained GLP- IR activation m the human
`thyroid require further invcstigacion 161), but so far no changes
`in thyroid function nave been repo"cd in clinical trials with
`GLP-1 R agonises. Funhermore, large studies are underway
`aiming to assess and confirm the cardiovascular safety of
`both c:xcnatidc and liraglutide.
`
`4. Current research goals
`
`The GLP-1 R agonises have already proved to be a valuable
`asset to the treatment of patients with type 2 diabetes. How(cid:173)
`ever, despite the many beneficial effects of the GLP-1 R ago(cid:173)
`nises on weight loss and improved glycemic control. the
`gastrointestinal intolerabi11ty and daily s.c. administration
`may lead to discontinuation (1t21, Currently, GLP-1 R agonists
`with optimized pha.rmacok.inctic profiles and a lower number
`
`610
`
`Expert Opm Emerg,ng Drugs (2011) 16(4)
`
`MPI EXHIBIT 1035 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1035-0004
`
`

`

`Lund, Knop & Vilsbell
`
`of adverse events arc under development. Most of the emerg(cid:173)
`ing GLP-lR agonists arc 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(cid:173)
`trol compared with the currendy available GLP-lR agonists
`(cxcnatidc and liraglutide).
`
`s. Competitive environment
`
`s., Exenatide once-w eekly
`Exenacide has been developed in a sustained-release formula(cid:173)
`tion planned fur oncc-wcddy s.c. adminisuacion by Amyl.in
`Pharmaceuticals, Inc., Eli Lilly and Alkermes Inc. (Table 1).
`The cxenatidc molecules arc encapsulated in injectable micro(cid:173)
`sphcrcs, which consist of a biodegradable medical polymer
`also used in other extended-release pharmaceuticals !6JJ. These
`microsphercs allow gradual drug delivery at a concrolled race
`by diffusion and erosion of the microspheres. The drug is
`now in late clinical development, and the clinical effects of
`cxcnatidc once-weekly have been examined in the 'Diabetes
`therapy Utilization: Researching changes in HbAtc weight
`and other factors Through Intervention with cxenacidc
`Once-weekly' (DURATION) 1 - 6 trials 16-1-691. ln DURA(cid:173)
`TlON-1, cxcnatidc once-weekly was studied in a hcad-ro(cid:173)
`head comparison with cxcnatide rwicc-daily in 295 patients
`with rypc 2 diabetes (HbAl c 8.3 :t 1%, weight 103 :t 20 kg.
`BMI 35 :t 5 kg/m2
`, diabetes duration 7 :t S years) over
`30 weeks (691 . Excnacide once-weekly was superior co cxena(cid:173)
`cidc cwice-daily in terms of glyccmic parameters (HbA le
`change: -1.9 vs. -1.5%, proportion of patients reaching
`HbAlc of 7.0% or less: 77 vs. 61%; FPG: -2.3 vs.
`-1.4 mM). Interestingly, gluc:agon levels decreased signifi(cid:173)
`cancly more with exenacide once-weekly vs. exenacidc cwice(cid:173)
`daily, likely contributing to the improvement in FPG levels.
`Addittonally, significantly greater reductions in coc:aJ choles(cid:173)
`terol and low-density lipoprotcin cholcsrcrol were observed
`with the once-weekly cxenatidc compared with the cwicc(cid:173)
`daily acnacidc. Equal significant improvements in fasting tri(cid:173)
`glyceride and systolic and diascolic blood pressures were
`observed with both treatmencs. No difference in body weight
`reduction was observed (3.7 vs. 3.6 kg), and about 75% of the
`patients lose weight (69J. A 22-wcck open-label extension of the
`DURATION- I study, where patients either continued with
`cxcnatidc once-weekly or switched from cxenatide once(cid:173)
`daily co exenatidc once-weekly, showed that the improved gly(cid:173)
`cemic control and weight loss were susta.ined over the 52 weeks
`of therapy and patients who switched from excnacide twice(cid:173)
`daily co once-weekly achieved a further reduction in HbAJc,
`ending up with the same improvements in glycemic control
`as the group ttt2ted with cxenatide once-wecldy for the entire
`52 weeks (70).
`ln the DURATION-2 to 5 studies, cxenacide once(cid:173)
`weekly was compared against: a TZD, a DPP-4 inhibitor,
`insulin glargine, mccformin and the commercial formulation
`of excnacide once-weekly was compared against cxcnatide
`
`In all srudics, excnatide once-weekly
`cwicc-daily ;"4-071.
`lowered HbAlc and body weight significancly. The HbAJc
`reduction by excnatide once-weekly was up co 1.6%, and in
`most cases this reduction was greater or similar to that of
`the comparator. Overall, a reduction in body weight by cxcna(cid:173)
`tide once-weekly was seen in the range of 2. l - 2.6 kg. V cry
`rcccndy, the preliminary resulrs from the DURATION-6
`study comparing cxenacidc once-weekly with liraglucide
`once-daily were reported in a press release (68). Th~ 26-wcck
`head-co-head, opm-labrl, srudy enrolled approximately 900
`patients with type 2 diabetes who were nor achieving adequate
`HbAlc with diet and exercise in conjunction with mctformin,
`SU, mccformin plus a SU or mecforrnin plus a TZD. The
`srudy revcaJcd that pariencs receiving c:xenatide once-weekly
`experienced a reduction in HbA I c of 1.3% compared with
`1.5% fur liraglucidc. Exenaridc once-weekly did, therefore,
`not meet the pre-specified primary end point of non(cid:173)
`inferiority to liraglucide with regard to HbA 1 c reduction since
`liraglucide was significantly more efficacious than exeoatide
`once-weekly. However, cxcnacide once-weekly did appear co
`be slighdy better tolerated than Liraglutidc with less gastroin(cid:173)
`testinal side effects (such as nausea and vomfring), although
`more patients experienced local site reactions with excnatide
`compared with liraglutide 168). Data on changes in body
`weight have not yet been rcponed.
`The most frequently reported adverse events among aena(cid:173)
`tidc once-wedcly-creaced patients in the DURATION srudics
`were nausea (prcdominacdy mild in intensity) (9 - 26%) and
`vomiting (4 - 11%) ,64-~o:. Other side effects included diar(cid:173)
`rhea (6 - 18%), and mjeccion site adverse dfeccs (prurirus,
`crythema, induration or pain) (10 - 18%) (M-70J. Pooled
`data of the safety and tolcrabilicy of exenaride once-weekly
`from 1095 patients (from the DURATION 1, 2 and 3 stud(cid:173)
`ies) showed that exenatidc oncc-weeldy were generally well
`tolerated, and ch.at the overall incidence r:ues of adverse
`events, scriow adverse events and discontinuations due to
`serious advenc events were similar for cxenacide oncc(cid:173)
`weddy versus che pooled comparators. No major episodes of
`hypoglycemia have been observed and the incidence of mild
`to moderate hypoglycemic events observed with cxenacide
`once-weekly treacmcnc was lower compared with chc pooled
`comparator cohort (16 vs. 22%) 111,.
`Rccencly, a probable correlation between plasma c:xcnaride
`conccocracioru and changes from baseline in the QT interval
`in healthy subjeets was discussed (72). Thus, the FDA recencly
`requested a thorough QT interval study with c:xenacidc levels
`higher than typical therapeutic lcvds of cxenatide once(cid:173)
`weekly (73). Additionally, the FDA requested the results of the
`DURATION-5 scudy co evaluate the efficacy, safety and effec(cid:173)
`tiveness. of che mmmerci.al formulation of cxcnacide oocc(cid:173)
`wcckly. Amylin Pharmaceuticals, Inc., Eli Lilly and Alkermes,
`Inc. are planning to submit their reply to the FDA by the end of
`2011. In April 2011, the EMA has issued a positive opinion
`and cxcnacide once-weekly will reach the European market
`(tradcname: Bydurcon) by the end of 2011.
`
`&pert Opm Emergmg Drugs (201 ll 16(4)
`
`61 1
`
`MPI EXHIBIT 1035 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1035-0005
`
`

`

`Emerging GLP-1 receptor agonists
`
`5.2 Uxisenatide
`Li.xisenacide ss a GLP-1 R ~gonist, in late clmical development
`by Sanofi-Avenris, Paris, France under license from Zeal.uid
`Pharma A/S, Copenhagen, Denmark (Table 1). The peptide
`contains 44 ammo acids and is based on the scructure of cxen(cid:173)
`din-4, wich che deletion of a proline and an addition of six
`lysine residues at che C-tcrmfous (Table 2) r ◄J. The affinity
`of lixisenaride to the GLP-IR have bc:cn shown 10 be :1.pprox(cid:173)
`imacdy four times higher as compared with native GLP-1 1751,
`and half-life in plasm:1. oflixisenatide is reported to be approx(cid:173)
`imatdy 3 h ~<i.'7J. Lixisenatide is probably adminincred a.s as.
`c. injection once-daily. Dara from a randomized controlled
`trial including 36 l, drug naive, patients with rypc 2 diabetes,
`showed that 13 weeks of Iix.iscnacide administration once(cid:173)
`daily in monorhcrapy provided significant improvements in
`glycemic control (HbAlc reduction between 0.7 and 0.8%,
`mean FPG reducoon berwccn 0.7 and 0.9 mM) 1-111. A body
`weight reduaion of appronmacdy 2 kg was observed. The
`efficacy of lixiscnatide as add-on therapy to mcrformin was
`evaluated in a dose-finding srudy of 542 pacienu with type 2
`diabetes •-91, In this 13-wcck crial, 12 separate arms were initi(cid:173)
`ated: eight active treatment arms with esctlacing doses of s.c.
`li.xisenacide (target dose 5, 10, 20 or 30 µg once-daily or
`twice-daily) and four placebo arms. The results showed chat
`lixjsenacide significandy and dose-dependently lowered mean
`HbAlc levels from b.ucline by -0.5 to -0.8% for once(cid:173)
`daily dosing and -0.7 ro -0.9% wirh twice-daily dosing (pla(cid:173)
`cebo
`-0.2%). The pcrcenrage of patients
`.tchicving
`HbAlc < 7.0% ranged from 47 ro 77% with i11creasing doses
`oflixisenatide compared with 32% wirh placebo. Lixiscnatide
`induced dose-dependent weight losses ranging from 2 to
`3.9 kg; weight loss in the placebo group was 1.9 kg and,
`rhus, only in rhc relatively high-dose lixiscnatide groups
`(20 and 30 µg once-daily and .30 µg twice-daily) the weight
`loss was staosticaUy significant. The conclusion of che
`srudy was that lixisenatide 20 µg admjnistered once-daily
`demonstrated the best efficacy:tolerability ratio.
`The most common .tdvcrsc events co lixuenatide treatment
`were of gastrointestinal origin, much consistent with 01her
`GLP-1 R agonises. With lixisenatide as monothcl':lpy (20 µg
`once-daily), these were reported to be approximately 32 versus
`14% in the placebo group with nausea being the mosr fre(cid:173)
`quent [78J. ln the 13-wcck dose-ranging study (5 - 60 µg) che
`gastrointestinal side effects occurred dose-dependently: nausea
`7 - 35% (placebo 5%), vomiting 4 - 19% (placebo 1 %) and
`diarrhea 6 - 26% (placebo 7%) l79J. No major hypoglycemic
`episodes and only few mild ro moderate hypoglycemic episodes
`have been reporced, with a similar frequency as during merfor•
`min treatment 1soJ. Antibody formation to lixisena.cide was fre(cid:173)
`quent in the only study rCPoniog exact numbers; ranging from
`43 ( IO µg once-daily) ro 71 % (20 µg twice-daily) 17'>J. No cases
`of suspected pancreaciris or thyroid rumors have been reported
`during treatment with lixiscnatide, but a few emergent adverse
`cventS have been reported. These include one hypersensitivity
`rcacuon and four possible allergic reactions 1so1.
`
`The ongoing Phase [II clinical rrial program oflixiscnatide is
`called GccGoal and was initiated in May 2008. The program
`has so far enrolled more than 4500 patients and will assess effi(cid:173)
`cacy and safety of lixisenaude in patiems wirh type 2 diabetes.
`The results from the first head-to-head study comparing lixisc-(cid:173)
`nacidc with another GLP-IR agonist (GctGoal-X) were
`recently reported in a press release [SIJ. This random,ttd,
`opro-labe/ multiccorcr study with 639 paciencs with rypc 2 dia(cid:173)
`betes compared the cffecc oflix.iscnatide versus exenatide twice(cid:173)
`daily as add-on thel':lpy to merfonnin. The study did meet the
`pre-defined end point of non-inferiority in HbAJc reduction
`oflimcnatidc compared with cxcnatide twice-daily, and signif(cid:173)
`icanuy fewer episodes of hypoglycemia were rePoned with lixi(cid:173)
`scnaude versus exenatide tw1ce-daily [bl (. The full study and
`additional results from the GetGoal program are expected in
`201 I. Furrhermore, a large trial cvaluaang ardiovascular out(cid:173)
`comes in higb-risl pat.ients (i.e., patients with a recent ruscory
`of acute coronary syndrome) has been undertaken, estimated
`srudy completion date is late 2013. Randomized trials with
`direct comparisons with sicagliprin and liraglutide have been
`completed but no reports arc av.ilable currently.
`
`5.3 CJC-1134-PC
`CJC-1134-PC, Montreal, C:i.nada (ConjuChem) comprises a
`modified cxendin-4 molecule and human recombinant albu(cid:173)
`min (Table 1). The cxendin-4 derivative includes amino acids
`1 - 39 of native cxendin-4 and a lysine residue at position
`40 (Table 2) JR2J. Despite being a much larger molecule than
`cxcndfo-4, pre-clinical data have shown that CJC-1134-PC
`retains the ability to bind to and activate rhe G LP-1 R 11121. Pre(cid:173)
`liminary resulcs
`from clmical
`trials
`in patients with
`type 2 diabetes indicate rhat CJC-1 134-PC has a h