[-eretta L"NleEsen
`
`trnc.rettn mimetics are a nelv class of pharmacologlcal agents with multiple
`antihypergtrycsnic acfions that rniinic the acdons of tncretin honnones such as
`glucagon-Ul<e pepdde (GLP)-L. Dipepficlyl pepfielase (DPP-TV) inhibitots suppress the
`degradadon of many peptides, including GLP-I, tlrereby extending their bioacdvity"
`$everal incretin mirnefics and DI,P-IV inhibltors are undergolng late-stage ctrinical
`btatrs for l'he treatment of gpe 2 diabetes" These agents appear to have multiple
`rnechanisms of acfion, tncludtng sofire or all of the follovrtng: enh.ancement of
`glucose-etependent fuuultn secre$on; suppression'of inappropriately elevatesl
`glucagon secretion; strolving of gastric emptying; and decreasedfoodintake
`(i.e appetite suppression)" Ba$ed on preltrninary clinical data, incretin rnfunetics
`and DI3P-W inhibiton show potendal for treating type 2 rliabetes.
`
`NType 2 diabetes is charactedzed by the emergence
`of postprandial $ost-meal) and, subsequently, fasting
`hygrerglycemia (fasting plasma glucose >125 mg/dl)
`[1,?], Hlperglycem.ia results ftom pancreaiic p-cells
`secreling inadequate insulin to c.lmpensate for
`itrsulin-resirt;lnce ln periplreral tissues [3,4]. The
`increasing worldwirle prevalence of type 3 riiabetes
`has major ltrplicailons f.or healtlrr:are systems and
`affected individuals, particularlybecause ol: th.e vas-
`cr:lar complications associated witlr thls disease.
`'l'he aim. of phamracological therapy ls to corr.hol
`hyperglycemia. and, ultimatelJz, tr: avert the devas-
`tating complicalions assodated wilh $:stained tissue
`expo$ure t{) excessir,'ely high glucose concentrations.
`However, becnuse of the cotnplex nalrrre of the disease
`and the i:rogres.sive detericration in panr-reafic B-cell
`function, giycemic crrntrr:l in llpe 2 diabetm patierrls
`rernains clifftc-ult. As a resuit, lorrg-temr therapy with
`currerrtly available agurts (Table 1) is often associated
`&'ith an inabiiity to ilratrtailr adequate glycernic con-
`trd [21. I:lere, two new dasses of potential antidiabetic
`agents that are undergoing Lrunan clinical testing
`are discussecl - incretin rrirnetic$ and clipeptidyl
`
`peptidase (DPP)-W inhibitors. These agents elicit
`glucoregulatory actions similar to thr:se of the ino'etin
`hormone glucagon"like peptide (Gl,P)-1 but lhrcrugh
`different medranisms.
`
`!ncrotins
`1lhe otrservatiot] that insulin seffetion frr:ln pan-
`creatic $-cells was more robust after an oral glucose
`b*lus than after an eqttivalent intravenous glucose
`bolrrs led to the elucidation of the role of intestinal
`peptides in the regulation of postprandial insulin
`setretion [51.'lhis'incretin effect' was attributed to
`the irsulinotropic action of gut hormon*, specifi<atly
`glucose-dependent iusr:linol"roJ-ric poLypeptide (GIP)
`and GLP-I. Patients with tvpe ? diabetes generally
`lack tlx ghcose-lo'weringresporrse
`to (ilP. By contmst,
`the,insulirrokropic response to GLP-1 is typically
`irrtact in this patient pergrqlpliot , but circulating
`levels of postpraudial GLP-I iue cteficient. Therefote,
`therapeutic interyentions have focused on exercing
`a pharrnacological GLP-1 effect.
`In rnarnmals, GLP:I is deril'ed from tJre proglucagon
`peptide in rnucosal Lcells cif the small intestine [6]
`
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`wtss,*rug{is*sr'.rr}.'!:rxlss-s$!:r 7O3
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`[-Ni€ls€n
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`9360Ton reCentreDrlve,
`Sutte 110,
`9?n Dl€go
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`
`e'ma!l: Inielsen@anrylin,com
`
`MYLAN Ex. 1014, Page 1
`
`

`
`NS\'$$\NS
`
`DDT. Volume lO Number]0. May 2005
`
`TABLE 1
`Overview of type 2 dlabetes therapy
`Phormacologic R6echsnisnrofstion
`traatmsnt rlisr€c
`Avallabla therapeuti€ ag€nts
`Deffease hepatic glucose production
`Biguanides
`Decrease intestinal glucose abrorption
`lncrease glucose uptake by skeletal
`muscle and fat
`
`Stimulate pancreatic Fcell insulin
`secr€tion
`
`Beneficial effEcts ond charocteristic$
`
`Adverse events
`
`Rr-rJuce blood glucose concrntration
`lncrease sensitivity to iniulin
`Reduce blood lipid levels
`Oral administration
`Reduce bloal Elucose concenttation
`Lower riskof hypoglycemla than insulin
`Oral administration
`
`Dianhea
`
`Nausea
`Vomiting
`Can cause lactic acidosis
`
`HypoElycemia
`Weightgain
`
`Nausea
`Vomiting
`Alteration in liverfunction
`indicators
`
`Anemia
`
`Detrimental cardiac effects
`
`Edema
`WeiEhtgnin
`
`Hypoglycemia
`
`Dianhea
`Weightgain
`
`Ab'Jominal pain
`Diarrhea
`
`Flatulence
`Possible elevated I iver
`enxymes
`
`Hypoglycemia
`Weightgoin
`
`TlDs
`
`lmprove target €ell response to insulin
`Decrease hepatlc Alucose output
`Increase insulln-dependent glucose
`uplake in skeletal muscle and fdt
`
`Reduce blocd glucose coh€entration
`Beneffcial alteration of blood lipid levels
`Posslble beneffclal effects on pancreas
`Oral administration
`
`Meglithidesand Stimulateglucose-nrediatedlnsulln
`o-.phenylalanine secretion
`derivatives
`
`tr-Glucosidase
`inhibitors
`
`Inhibit pancreatic a-amylase and
`membrane.bound o'ghrcoddase enzymer
`Deloy glucose absorption by inhiblting
`intestinal disarrharide metabolism
`
`Insulin and
`analogues
`
`Replace or supplement endogenour
`inzulin hormone to correct deficiency
`
`Fotential thorapeutics
`Incretinntimetics Replaceorsupplenrentendogenous
`iclinicaltesting) incretinhormone(s)glucoregulatory
`nctlvity
`
`Reduce blood glucose concentration
`Reduce postprandial glucose excursions
`
`Stimulates insulin secretion
`Oral administration
`Reduce blood glucos€
`€oncentration
`Reduce postprandial glucose excursions
`Stabilize daytime glucose concentrations
`Disperse calories over time
`
`Welght neutral
`
`Oral administration
`Reduce blood glucose concentration
`Suhcutaneous injection
`
`Reduceblood glucoeeconcentration Naugea
`Reduceportprandialglucoeexcursions Vomiting
`Enhance glucose.dependent lnzulln secretion
`Suppress inappropriately eloiated glucagon
`secretion
`Reducefood intake
`Slow gastricemptying
`Weight reduction orweight neutral
`Possible b€neficial effeds.on pancreas and
`insulin sensitivity
`
`DPP-IV inhibitors Inhibit peptide hormorre metabolism by
`(clinicaltesting) DPPiVen4yne,thusincreasingblood
`concentratlons of endogenous bioactive
`forms of GLP-I and other peptides
`
`5ubcutaneous inJection
`Reduce blood glucose concentration
`Weight neutnl
`Possible beneficial effects on insulin sensitivity
`Oral admlnlstratlon
`
`Nat known: awaiting
`Phase lll clinlcal data
`
`and th.e iusulinotropic activity of GLP-1 is mediated
`througlr GLP-1 receptors on parrcreatic $-cells. The release
`of GLP-I in response to a rneal occLrrs rapidly (..within 10
`min) iI} heaithy ildiyiduals iurd is highly correlated with
`irrsulin secTetiorr into the circrlatory systerrl [5]. In indi-
`viduals witlt type 2 diabetes or hnpaired ghtcolre tolerancr
`(praliabetesj, tlds response is defective, rcsulflng in reduced
`
`clrcrrLating concentrations ol: postprandial CiLP-L and a
`blunted trsulin $e(:retory respolne to fo<ld intake [5,7].
`Tlre biologicxl acllvities of GI3-1 [5,7,8] include (i) ntedi
`ating glucose-deperrdent insulin setrefloll to aid plasrna
`ghrcose uptake by tissue; (ii) suppression of postprandial
`glucagon liecretion to reduce hepatic glucose relea$e; (iii)
`regulation of gastdc emptying to avoid oveildlekning the
`
`704
`
`\\.\rN.S ttr$$is{.(\!\\i,$tt\d.-\..{$rrt
`
`MYLAN Ex. 1014, Page 2
`
`

`
`DDT.Volurne lQ Number 10'May t005
`
`!Niv!N\\'$
`
`circulation with gLucose as food is absorbecl from the gug
`ancl (iv) suppression of lbod intake (i.e. appetite). In
`additiort, animal data sugge$t ttrat regulatiorr of malnte-
`nance of pancreatic p-cell mass is a nonrral physiological
`funcllcrn of GLP-I.
`The activity of GLP-1 in controllirry glucose e,{fltr$ions
`in prectinical diabetes models led to a series of f-il,P-L clin-
`icai trials in hulnans [8], In patients with type 2 diabetes,
`continuous irfusion of exogerrous GLP-L via either the
`intraverrous or the subcutaneoltli route was reported to
`nearly nonrralize giycemia hy orharrcing glucose-rnediated
`insulin secretion, suppresdng glucagon secretion arrd slow.
`irrg gastric errptying. The iruulinotropic and glucagon<ls-
`tatic actions of GLP-1 were shown to be giucose<lepetldeut
`(i.e. CLP'I action abated as euglycemia was restored) [8].
`Ttrerefore, long4errtr exogenous GLP-1 therapy would not
`be expeded to induce severe hypoglycemia when admiiris-
`tered alone. Unfortunately, the pharmacokinetic properties
`of GLP-1 llmit the feasibility of this approach, because
`CLP-1 is rapidly degraded by DPP-ff [ralf-life (trrr) of
`<? minJ [9,10.1. Zandet et aL l77') reportrd that although
`subcutaneous infusion of GLP-1 lowered plasma glucose,
`continuous admin!.stration was reouired.
`
`lncretin rnimetics
`Incretiu mimetics are a nerv clasr of pharmacological
`agents wiLh. multiple antihyperglycemic actions that
`mimlc some effecls of endogenous incretin hormones,
`including the glucose-dependent enhancemenl of insulin
`secretioll. Although these agents can exhibit glucoregu-
`latory effects similar to thr:se of GI.P-1, their astions migbt
`not be mediated solely through th.e pancreatic GI-,P-1
`receptor. Therefcrre, the class name'lnuetin mimetic' is
`inlended to emphasize the glucoregulatory and metabolic
`efftctr of these agents, rather than their specificmechanisms
`of action.
`Several GLP-1 analogueslvith resistance to degradation
`by I)PP-IV are cunently undergoing human dinical trials.
`t,iraglutide (Novo Nordsk) and CJC11.31 (ConjuCh.em) have
`utrdergone ttte most extenrive testing to date: liraglutide ts
`expected to stafi Phase lll clinical trialsin ?CI)S or 2(){)6 (www.
`n rrvonordisk,com /investr:rrs/rd_pipeline/rd_pipeline.asp?
`showid=4), Iixe"natide (Anryjin Phannaceuticals and Lli L,illy
`and Comparrg, a syntheticversi.on of tlre naturally occtu-
`ring homrone exendir:.-4 from tlre Gila Nlonster lizard, is
`at a nrore advanced stage of llevelopmenl, recently corrplet-
`hry three pivolal Pluse III clinicat tdals that fonred the basis
`of a n.en'drug applicallon (NDA) submitted. inJune 2004
`to tlre r-DA (http://investors.amylin.comlphoenix.zlrtrnl?c*
`1 0 19 1 1 &p=irol-newsArticle&ID=608 621 &highlight=).
`Another incretirr ntirnetic, ZPL0 (Zealarrcl Phamra and
`Aventis), is currently irr earlpstage ciinical trials (www.
`zp,dk/nervs/ZP 1 0o,/o20Ucersingo/o20dea1_UK9o20veniono,/o
`20{Final).pdf). hr prec'llrrical irrvestlgations, ZP 10 sup-
`pressecl glucose orcursions and enhanced irxulfur secredon
`after oral glucose clullenge tu dbidlt diabetic uiice [1,2].
`
`Llraglutide
`Liraglutide is a GLP-1 derivative synthesized by the
`covalent coupling of a GtP-l analogu.e with a fatty acid
`[131. Liragluticle has been reportecl to trave multiple glu-
`coregulatory aclionr, inclucling reduction of hypergly'cemia
`tlrrough stirnulation of irrsulin sectetion, suppression of
`inappropriate glucagon seuetiorr, slowitg of gastric ernp-
`tying ilrd enhancement of $-cell function and mass
`[1a-Z3h to date, the effect of liraglutide on B-cell ftinc-
`tir:n and rnass has only been sfudied in animal nodels.
`Uraglutide also redr.rced food intake and body weigtrt in
`obese or prediabetic rats [15,16,23], but had no durabie
`effects in obese or diabetic rnice [14]. No long-term data
`liave beerr reported on *ie possible eflerts of liraglrttide
`on food intake and body weight in humans, and short-
`term trials have yielded mlred results I2o,z7)"
`Several Phase I and II studies have reported on liragiu-
`tide administration to humans [77-27,24-26]. In a study
`with L1. subjecls with tlpe 2 diabetes, a single liraglutide
`inJection (10 pSkg) resulted ln the reduction of fasting
`plasma glucose over 12 h, and subsequently suppression
`of glucose srcursions and slowing of gastric emptying
`after a meal [19]; beneficial effects on insulin $ecretion
`and glucagon suppression postmeal were also reported.
`Nausea was the most common treatment-related adverse
`event noted. In a study with ten patients lvith type 2
`diabe tes, Chang et aL [1 8] demon strated that doling wi th
`7.5 pg/kg lhaglutlde restores the glucose-dependent insirtn
`respollse to glucose i.nlusion. to a level similar to that
`recorded in ten healthyvolunteers subjected to th.e sane
`experimen:tal procedure vvith.out liraglutide. In another
`study, i.3 subjects with type 2 diabetes were dosed witir
`6 pg/kg liraglutide or placeho for 7 days [19], followed by
`physiological assessments using a glucose'clamp' proce-
`dure [27]. This study reported that liraglutide suppressed
`postprandial glucose excursions, reduced fastfurg plasma
`glucose concentrations, enhatrced first-phase insulin
`respense after me;rls and .luppressed pos'fpran.dial plasma
`glucagon concentrations, lvltlt no effect oil the rate of
`gaitric em;:tf ing" HOMA-II analysis [28], a nteasue of
`B-ceJl frmcflon, suggested a beneficial effect on B-cell func-
`Uon during fasting, Liraglutlde had a clealance tr, of -18 h
`[17].]'he three srrbiects with the highest serurn levels of
`liraglutide experietrr:ed u.ausea and abdominal pairl that
`dissipated over ille course of the lxeatment peilorl.
`A 12-week sfudy in 190 patients with type 2 diabetes
`campared liraglutide doses ranging from 0,04.5 to 0.750
`nrg/day cona:rnitantly adnrinistered rt"ith tLre antidiabetic
`sulfony'lurea (SFU) glimepiride or grlacebr: [211. Generally,
`dosedependent redrctions ilr A1.C, which. is the percenta6e
`of glycosylated lrerrioglobin in cirntlatitrg red blood cells',
`reere reporterf hr all but tlte lowest liraglutide dosing group,
`with a ma{nllmr drange of -O.75olo cr:rnpar<l Mthplacebo,
`which was cornparable to ttre results obsened in sublects
`receiving glimepiride treatrnent. I{OMA-B arulysis [?81
`and the proinsulin:insulin ratirr (anerther tneasure of p-cell
`
`-s11t\".{f (rB($i$tr!.*s$trrdsr-..!:{rtr:705
`
`MYLAN Ex. 1014, Page 3
`
`

`
`NE\.\S\-$S
`
`DDT. Volume 1O Number 10. |llay 2005
`
`ftrnction) suggesterl significant improvement in the 0.75
`nrglday lira.glrrtitle group compared n'lth placebo, and
`IIOMA-B irnpror.,ement was sindlar to that observedlvittr
`glimepiride. Mild-to-moderate nausea and headache were
`the rnost cornilton adverse events related t<i liraglutide
`er?osufe in th.is study. Other gastrointe$tinal events (e.g.
`diarrhea, vorniting and constipation) also occurred, but
`at a iower incidence. One subJect treated with [raglutide
`experienced milcl hypogiycrernia cr:rnpared witli four sulr-
`Jects irr tlre glirnepiride group experiencing the sarne
`adyene event.
`In another Plrase II study, 33 patients with q,pe 2 cliabetes
`were dosed wittr liraglutide {0.6 rnglday) or placebo lor 8
`n'eeks [20]. Liragluticle treatnerrt was ass<iciated with a
`decrease in A1C (-0.8o/o; p = 0.028) and fasting seruur
`glucose (-2.2 mmollli p = 0.00?) compared with placebo.
`Furthennore, insr:lin sensitivity, as measured by HOMA-S,
`increased (p = 0.015) and gastric emptylr\q appeared to be
`unaffected. Tlansient episodes of nausea and diarrhea
`$rere the most frequent adverse events associated with
`liraglutide exposure; hlpoglycemia was not obsen'ed.
`In hurnan subJects with type I diabetes, liraglutide sig-
`nificantly reduced body weig?rt after 12 weeks of treatment
`at a dose of 0.45 mg/day', but not at lower (0.045 and
`0.225 mglday) or higher (Ct.60 and 0.75 mg/day) doses
`[21.]. No members of the liraglutide group gahred weighl,
`rvhich is in conlrast to the SIIJ control $oup. In a 33
`patienl studn 8 r,veeks at a dose of 0.6 m$day, liraglutide
`had no apparenl effect on body weight or food intake [20].
`
`CJCI I3T
`CJC11.3I" is a GLP-I analogue conlaining a reactive tinker
`th.at facilitates covalent (imeversible) binding to senrol.
`albumin [29.1. The resultant GLP-I-albumin complex
`relains the activities of G1,P-1, togelher with increased
`resistance t:o D}P-Iv-medi.ated inactivation and prolonged
`duration. of acllon in viw [30]. A study shonrd that ihe
`CJC113l-albumin complex boun.d to Chinese harnster
`owry cells lranlfected evith. hlman recombir:.ant pancreadc
`GLP-1 receptor with a. Kt r:rf 12 n-h{ (cr:mtr-rarerl v,'ith a K, ot
`5.2 nhl fr-rr Gl-P-l) [29]. ln the same assay, tJre LICl1.31.*
`nlbumitr conplex activated cyclic i\MP with an llCro of
`l"l"*13 nM, whicl:. is similar to GL,F-L [39]. Published litera-
`tue indirates that ttre conjugate molecule can reduce basal
`and postprandtal plasrna glucose concen.trations in tlor-
`moglycemic and hyperg{ycrrrric {rliatntic) rrrice. }'ostglucose
`challenge plastna. glucose excursions were not supprersed
`in GLP-1 receptor knockout mir-'e, lvl:.ictr is not the case in
`wiltl-type mice, suggestirrg the dependence of this acttvity
`of CJC11.i31 on a frurctional GLP-L receptor. Ln. tlre same
`
`nNormal healthy human AIC \alues ranEe from 5% to 6% and plovide
`an accurate measure ofaverage blood glucose concentratlons over the
`precedlng 2-3 rronthsHlgher than normal AIC va[.res lndicate polorged
`perlods of ambient hyperglycemta and AIC ralues ln tndil,iduals wlth
`poorty controlled dlabetee (e.those with fluctuaflng blood glumse lerels
`and amblent hyperglycemla rnost o{the day) generally exceed 90.6.
`
`series of er<periments, ([J1131, sl:n'e.d gasHc ems,tying and
`suppresxd food int.ake in rats, a trait shared with native
`GLP-I [31].
`hr a clinical trial using healthy human vr-rhurteers, single
`subcutaneous irrjections of CJC1131 (t.5-20.5 pg/kg)
`detemrined that the tr, r:f this cottrprtund is 9-15 days,
`with dose-propcirtiorral area under curve [AUC16_*J and
`T,* rangirrg ftom 23 to 76 lr [32]. In a recently reported
`Phase Il dinicai hinl with 206 subiecls, with type 2 diabetes,
`each subjert was injected with a once daily subcutaner:us
`dose of CJC1131 that was escalated periodically during a
`28-day titration (wwwg<lodmedia.com/equicom/con-
`iuctrem/web/presspop. cfnt ?newslD=3 022). Subsecluently,
`subjects rcrere randomized to a&ninistration of CJC1131
`once daily or.'er 56 days at a rate of one, two or three times
`and doses were adJusted individually to maintain
`a
`'veek,
`anundisclosed corrcentration of compound in the blood-
`stream. L,Iild-to-moderate transient nausea and vomiting
`were the most frequent side effects reported in CJC113I"-
`treated subjects and were dose-limiting. Several measures
`of glycemia (A1C and posprandial plasma glucose con-
`centrations) were reduced (as vi'as body weight) to varying
`degrees by the different CJC1L31 treatment regimens. In
`a separate Phase tr tirial, ZZ obese patients with tl?e ?
`diabetes were treated rqith CJC1131 for 14 days at a dose
`c,f ?, 4 or e psiftg day) or for 20 days with 12 pg/(kg day),
`lvith dose-escalation itr s{rme ${,ups to enable lolerance-
`inductlon. to Lhe higher doses [l]31. Mild,to-moderate kan-
`sient nausea and vomiting \{ere again the mtlst frequent
`side effects reported. Overall glycenria was reduced by
`vadable amounts, as was body weight, dependirlg on dose
`and treatment duration. Rechallenge with two subcnta-
`neous injections of CJC1131 (ti weeks aparl) in healthy
`human vr:lunteers exposed to tte Gi,P-l coniugate b-L2
`months earlier was not associated n'ith adverse Immune
`respon.ses, includlng no evidence of neutralieing anti-
`bodies. Th.e absence of neutralirjng antibodies after
`e.xposure to CJC1131 has als* been described in patients
`with type 2 diabetes [34]. ConJuChen is crurentl.y
`explorlng the acflvity of QUl131 ln combinatlou ther-
`apy with metfomiln, thiazolidinediones (TZDs) or SIU;
`(www.goodrnedla.arm/equicom/conluchen/web/prmspctp.
`cfm?newslD=Z887).
`
`Exenatide
`Ilxenatide and GLP-1 share particular glucoregulatory
`a ct ivities, in cludin g gluco se-depend en.t etrhan cemetrt r: f
`insulin secretion, glucost-dependent supprtsion of
`inappropriately high. glucagort secre-tiott, slowing of gastric
`emptyil'rg and reduction af lood intake [11,35*43]. Itt
`addition, exenaticle has Lreen showu to restore first-plrase
`insulin seoefion [4.1,45] and tr: prornote pcell proliferation
`and lslet neogenesis honr precrtrsor cells in in r"ifro arrd
`in vna nodels of diabetes [46].
`Exploratory dose-ranging Phase II clinical trials with
`e.'tenatide identifiecl a clinically useftrl glucose-lowering
`
`706
`
`\\.lr\sdrssdisi:(\s$!'!l$dsr!,i$;$
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`MYLAN Ex. 1014, Page 4
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`DDT. Volume 10, Number 10. May ?005
`
`$s$t$\\rs
`
`dose ranSJe r:f C1.05-t1.20 pg/kg administered suhcutaneously,
`ntth. transient nausea and vr:uriting as the reprlrted dose-
`limitirrg adverse events [37,38]. Phannacoldnetic profiies
`suggested rnirdmal deperidence on trody rveight, support-
`irry Plrase III development of fixed doxrge regimers [37,38].
`In addition, early clidcal experience suggested a Phase III
`stucly desigr strategv for mitigating the ffansierrt nausea
`arid vouriting side effe$s by inc'lu<ling a dose initi.ation
`perictd of L monttr at 5 pg twice daily, followecl b'' a rnain-
`tenanlre dose of 10 pg twice daily [47].
`'Iluee dosing regitnens of exenatide were conrpared to
`placebo in a 28-da1', Phase IL study enrolling J.09 patierrts
`witli type 2 diabetes that were treatecl with rnetfonnin
`and/or a SIU [48]. Patients received 0.08 pg/kg exenatide
`before breakfast and evening meal, before breakfast and
`beddrne or before all 3 events. All exenatide groups had
`significant reductions in AlC compared with placebo
`(p <0.Ct06), rangng frorn -0.7 to -1.19/o. An end.of-study
`41C of <7%o was achleved by 159ztr of exenatide-treated
`subiects, compared with 49zo of placebo-treated subierts.
`In addition, FIOMA-B analysis [28.] revealed increased
`p-cell function at days 14 andZ& compared lvith baseline
`(day -1-) and day 1. llowever, p-cell function n'as unchanged
`in the placebo Foup. The most common adverse events
`reported were mild-to-rnoderate nausea and hypoglycemia,
`Another Phase II study assessed whether glucose-
`dependent in"sulin secretion and the normal physiological
`response to h''pogl]'cemia were preserved during contin-
`uous intravenous infusion of exen.atide or placebo [43].
`F,leven healthy volunteers wete evaluated using a clamp
`procedure [27] to moduiate plasma glucose concel:.lrations.
`lluring euglycemia, althcrugh insulin secretory rates tqere
`significantly higlrer (-.3.5-fo1d) in subjects treated n'itlr
`exenatide compared with those receiving placebo, they
`rapidly decreased as plasma glucose concenhaliolx were
`lowered. Exenatide suppressed inappropriate glucagon
`secretiern during euglycemia, but did not block the coun-
`terregulatory rise in glucagon, cr:rlisol, epinephrlne, n.or-
`epinepb:ine and growtlr hcrmcne during hypoglycemia.
`In addition, fecovery rates after th.e release of the hypo-
`gll,cenlc clamp were equivalenl in e"xenatlde- and placetro-
`treated subjecLs.
`Patien.ts with type 2 diabetes usually have a dramatjc
`reduction in fi.rst-1:hase (i,e. ear:ly pirase) insrrlin secretiorr
`- the insulin nr>nnally $ecreted by pancreatic $-celis
`within 10 min. afler a sudden rise in plilsma ghrco$e con-
`centraLions [49].'lhis defect is in:portant because tl-re first-
`phase cf insr:lin rccretion ls lrcstrdated to have the greatest
`impact on pr:slprandial plasma glucose exr:ursions [49]. In
`subjects with type ? diabetes, treatment with exenatide
`iriueased plasrna irsulirr (p <0,005) durirrg the first (O-10
`ndn) xrd second {L0-120 min) ptrases of glucr:se-stirnulated
`insulirr secretion by a range of 180 to 310o/o and also
`increasedinsulin secretion rates, reiati\re to placebo [451.
`Exenatide-treated patients wittr t'?e ? diabetes trad a
`similar secletory pattBrn to healthy zubiects, The elevation
`
`in plasma insulin. conc€nhations was accompauied by a
`significant lncrease in the glucose disappearance corxtant
`(p = 0.0t131), zupporting the metatrolic actidty of the
`insulin released in this typical tdphasic pattern. ltius,
`exenatide stirnulated troth first- and sec<lrid-phase insulln
`$esetion after glucose challenge in patients with type ?
`diabetes and the rnL)st cornnrort adt'ene events were two
`cases of moderate nausea and oIIe case of mild hypo-
`glycernia,
`More recently, the results of three exerrafide Phase III
`cliniezl trials in subjeds w'ith type 2 cliabetes treated with
`rnetformiri arrdlor an arrtidiabetic SIIU were presented
`[39,50-55l.1tiiriy weeks of exenatide dcising (5 or 10 pg
`twicc daily) significamtiy reduc,ed A1C, fusting plasma glu-
`cose levels and postprandial glucose sxcursiorx, Mean A1C
`reductions hom baseline in the 10 pg exenatide groups
`ranged from -0,9 to -0.8?6 compared n'ith a mean rar\qe
`of +0.1 to +0.?o/o in the placebo group$. FIOIr{A-B and
`proinsulin:insulin ratio indicated improvemeni in the
`exenatide-teated patients. In addition, progesslve reduc-
`tions in body weight were obseled, with means ranging
`from -3.8 to *1.6 kg in the 10 trrg dosing poups after 30
`weeks of treatment, compared rq'it1'r means rarrging frorn
`-0.9 to -0.3 kg in the placebo group (p <0.05). In an
`interim assessment of ongoing, open-label extensions of
`these trials, patients with 52 weeks of 10 ;lg exenatide
`expc,sute had AlC reduction.s of -1.1 t 0.1% (n = 163)
`from baseline, suggesting durability of glycemic control
`in. tlris group [56]. This same patient cohcrrt had weight
`reductions gf -3.6 t 0.5 kg (n = 162) from baseLine, sug-
`gesling that weight loss in this $tlup was progressive.
`I-xenatlde n'as gurerally well-tolerated by patlents co heated
`with metformin and/or an antidiabetic SFU. Mild-to-mod-
`emte nalrsea was the nost conlmon adverse evenl related
`to exenatide ex?ostue and tlre indden.ce of nausea decleaced
`with conlinued ffeatment, l{ild hypoglycemia was most
`commonly observed in patients also trealed with a SFII.
`
`DFP-IV imhihitors
`The enz.yme DPP'IY also knortn as CllZ6, is a trans-
`membrzule and circulating serfule ixotease respcnsible
`fcrl cleavirrg polypeptldes containJng proline or alanine
`residues in. the perrultimate l,.l-tenninal position, thus
`releaslng dipeptidel from the parent molecules and thercby
`altering th.eir biological Junction [5{. As well as being
`firund in biood plasma, DPP-IV is expressed constitulirzely
`on epithelial cells of l:Le kidlrey, inr*tine, Ilver (bite duct)
`and pancreasr on endothelial cells in the vasculahlre, c,t1
`flbroblasts in skin, synovia, an.d. nranrmary gland, on cells
`conlacting ltre cerebrospinal fluid and on subsets of
`irrurnrne cell leukocytes (e.g. T cells, B cells, natural killer
`cel1s and macrophages).
`DPP-IV knockout nrice are fertile and generally healthy,
`wittr nomral lasdng plasma glucose levels [58]. In the irritial
`report on this rrrouse strain, plasrna concentraticirrs of
`iruulin ar,rri Artact ibioaetive) GLP-1 wse elevated cr:rnpared
`
`st{Nr.$r(!${is{,t\rs\.'!:rr*.ly*,r:r:r 7g7
`
`MYLAN Ex. 1014, Page 5
`
`

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`r\U\S$\n$S
`
`DDT.Volume 10, Number 10. May 2005
`
`lvilb w'rld'type nrice L5 mln aftex n$. oral glucose challenge,
`whereas plasnla glucose coo.centratiolls were reduced.
`Orrerall, glucose eJ(clrrsions were suppressed in IIPP-iV
`knrrgkoul ndce after an oral glucose challerrge, lending
`r:redence to DPP-ry as a drug development target for treat-
`turg the Lgperglycernia associated with dialretes. In addition,
`DPP-IV knockout rnice are re$i$tant to diet-induced obesity
`conpared with wild-type rnice [59]. Recluce<l foocl intake,
`irrc:eased energ', e'tpenclinrre and improved insulin sensi-
`tivity are three of the putative rneclranisnrs for this effect,
`coupied with a backgrr-runcl physiolr.rgy of higher circu-
`lating levels of intact GI"P-I and suppression of circ'ulafurg
`glucagorr. DPP-IV knockout rnice were desrribed as being
`less likely to beconre trlperglycemic after streptozotocin-
`induced pancreadc damage, possibly because of the regen-
`erative activity of GLP-1 on pancreatic islets [8]. However,
`as a cautionary note, putative effects on the imrnune
`response have also been reported in this knockout model.
`In particular, IgC production after a primary inununiza-
`ticrn rvith pokeweoJ mitogen rvas only a third of the level of
`the response obsewed in wild-type mice, and vms accom-
`panied by reduced plasma corrcentrations of the cytokines
`interleukin (L)a and IL-3 [60].
`DPP-nt inhibiton suppress the degradation of a v;uiety
`of bioactive peptides, induding GLP-1", ttrereby extending
`their period of action (tuz) [61]. In animals, DPP-ry
`inhibitors have been reported to suppress ttPP-IV activ-
`ity by up to 90o/o [6?.-647, prolong the t1/2 of exogenously
`administered GLP-I [62], increase the plasma conceltkation
`crf endogenous CjLP-1 162441and suppress postprandial
`glucose excursion.s [63-71]. In addition, rats and mice
`with diet-in.duced obesity or genetic predispositions to
`obesity have reduced poslprandial glucose occursions after
`treatment with DI)P'IV inhibitors [66-68]" In one study,
`a shain of Fischer 344 ralr lacking the DPIr-IV enzlmre was
`resistant to the impailed glucose-tolerance that is induced
`in wild-type rats by a high. fat diet [65]. Rat$ and mice
`prone to the development of diabetes nith. age exhjbited
`delays in the onset of hyperglycemla when treated with
`DPP-IV in.hlbitors lrom a youltg age, but generally failed
`to snppre.ss br:dy weight galn and Jbod intake [6164,59,70].
`Irr additlon, DPp-lV inlr"ibitors lailed to slow disease pra-
`gression in older animals [63,64].
`L,hE?,37 (Nova:rtis Ph.armaceutirals) is currently the
`nrosl advanced DPP-$ inhihitor undergoing clinical
`de'velopntent. In an exploratrrry 4-lveek dosing Phase II
`study in patients n'ith early.stage tlpe 2 diabetes, 100 mg
`oral LAIr237 administered once daillz 30 min betore hreak-
`f;ut was associated wilh. supl:ressicrr of endogenous DPP.IV
`activity fcrr * 1? h arid surppressiou of postprandial gluc<lse
`excursions (uiean 4 h breakfast prandial glucose: -1.5
`nuuoVl comparecl with placebo; p <.0.C01) [72]. Acldidonally,
`fasting plasula ghrcr:se c'orrcentratiot$ were lr:w,ered (-0.7
`nuroVl cornpared with placebo; p = 0.040), arrd basal and
`postprandial GLP-1 concentrations were increased ccirrr-
`piued with placelxr-treated subiects. Basal and postpmndial
`
`giucagon tevels were reduced, but no change in plasm.a
`insulin concentrations was observed. Given the lower
`ambient glucose concerrtrations, the$e data suggested
`er*ranced iruulin sensltivity in the group rectiving LAI237.
`Tliere lvas no change in bo<!y weight during thls short-
`tenn study, Nasopharyrgitis and nrild headache were the
`rnost corrlrnon adverse events in the L.AF237 group, No
`hlpoglycernia was observed during this trial, as expected
`in patients wittr diet-corttrolled diabetes.
`It4ore recently, Pratley and Galbreath [73] reported on
`a l?-week Phase II stud,v usirrg 25 mg L.4IZ37 twic€ daily
`in obese drug-narve patients witfr type ? diabetes. Baseline
`AIC values averaged 8.Lolo iu this popu.latiorr (mean base-
`line body urass index of 30 kg/rn3), IAF237 treafinent was
`associated with a -0.6 + 0.2Yo decrease in A1C compared
`vvith placebo (p = 0.0010) and 47Ytr of the population with
`baseline ALC >7ozir attained an A1C {7c,/o,The most com-
`mon adverse event related to LAF237 treatment wa$ mild
`hypoglycemia (1070 of subjects), but overall LAF337 was
`generallywell tolerated. A separate lZ-week Phase tr study
`using 50 mg LAF237 once dailf in patients lvitlt tlpe 2
`diabetes taking the antidiabetic dru6; metformin reported
`that LAlz37-treated subiects had a reduction in A1C of
`4.7 *:O.LVo cornparedwith placebo (p <0.0001) [7a]. The
`end-of-study difference from placebo in fasting plasma
`glucose rqas -1.? * 0.4 mmol/l (p = Ct.pC!61 and in peak
`poslprandial plasma glucose was -1.3 t 0.3 mmol/l
`(p <.0.001). LAI?37 was generallywell toleraled; there was
`one ca$e of mild hypoglycemia. In a long-term followup
`(.53 rveeks) ':n thls patlent cohort, 42 subJects receiving
`IAF?.37 and metformin had a change in A1C of +0.01.389/o
`per month, which is not statisticall;r significant, from
`rveeks 12 to 52174,7'l.Twenty-nlne subiects treated with
`placebo and met{nrmin had a change in A1C of +0.05567o
`per mcrnth frc,m $reks 12 to .52, which is significantly
`higher than the LAF237 lreatment grCIup (p <0.0001.).
`There was no difference in body Weight belween the fir'o
`treatment atns, ar.d LAI?37 was generally well-tolerated
`ove.r orle year of e.ryOsure,
`
`Qther DP P-tV i nhi blrors of note
`P93/01 (Probioclrug and OSI Pharmaceuticals) is currently
`in Phase II clinical trials (www.prosidion.conrlmedial
`newsLT-Jun-04.htnrl). A preltminary disclosure on 16
`drug-naive patients with type 2 diabetes reported a sta-
`ti$ticall.v signiflcant suppression of postprandial glucose
`excursion; (p <0.05) with no treatmetrt-related adverse
`e.vents, inclu d i ng n o hypoglycemia (www.probi odrug.
`rle/index.asp?action=swtext&la=5001 &id*438). P32i98
`Probiodrug and Merck and Company) completed lrhase
`I clinical triais (wrvwprobiodrug.delirrdex.asp?attion=
`swtext&1a=500 I &id=402). DPP-W inhitritors hom Merck
`arrd Company (e.g. tvIK-0431) arrd Bristol-Myers Squibb
`entered Phase III cliriical ffials in 2004 (wwlr'.merck.
`com/finance/ anrrualreportlar2003/product-pipeline/;
`index.html).
`www.bms.con/landing/datai
`
`708rr,r.*r"-*{r*gtrdlsl.stsrjisr{..-ryssxr
`
`MYLAN Ex. 1014, Page 6
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`

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`DDT. Volume 10, Number 10. Mav ?005
`
`sisis"ts\Ns
`
`Concludi