24
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`To Page No.& ·v
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`806 of 1033
`
`BI Exhibit 1002
`
`

`

`~ ·'
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`I
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`-.._,,;
`
`Project No. __
`Book No. __
`
`'
`
`63
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`Date
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`n---·.,-• \. ...
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`Date ,
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`1
`t:x H 1 B11 B
`
`807 of 1033
`
`BI Exhibit 1002
`
`

`

`INTERLEIJK.IN-2-RECEPTOR BLOCKADE Wll'H DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
`
`·------· -----
`
`lN'fERLEUKIN-2-.RECEPTOR BLOCKADE WlTH DACLIZUMAB TO PREVENT
`ACUTE. REJECl'!ON IN RENAL TRANSPLANTATION
`
`F1....w10 V1NCENn, M.D .. Roa£RT KIRKMAN, M.D .. SUSAN L1GHT, M.D .. GINNY BuMGAADNER, M.D .. PH.D ..
`MARt< Pescov1rz. M.D .. PHILIP HALLORAN, M.O .• PH.0 .. JOHN NEVI.AN, M.D., AlAN WILKINSON. M.D ..
`HENRIK EKBEAG, M .D .. PH.0 .• ROBERT GASTON, M .D .. LARS BACKMAN, M.O .. PH. D .,
`ANO JAMES BuROte", M.D .. FOR THE OAcuZUMAB TR1..u THERAPV' STVov GRoup•
`
`ABSTRACT
`Back91·ound Monoclonal antibodies tl'lat block the
`high·affinity interleukin-2 receptor expressed on al(cid:173)
`toantigen·reactive T lymphocytes may cause selec(cid:173)
`tive immunosuppression. Daclizumab is a genetical(cid:173)
`ly engineered human lgG1 monoclonal antibody that
`binds specifically to the a chain of the interleukin·2
`receptor and may thus reduce the risk of rejection af(cid:173)
`ter renal transplantation.
`Met.hods We administered dacliiumab (1.0 mg per
`lc.ilo9ram of body weight) or placebo intravenously
`before transplantation and once every other week. af(cid:173)
`terward, for a total of five doses. to 260 patients re·
`ceiving first cadaveric lcidney grafts and immuno(cid:173)
`supp'ressive therapy with cyclosporine. azathioprine.
`and prednisone. The patients were followed at regu·
`tar intervels for 12 months. The primary end point
`was the incidence of biopsy-confirmed acute rejec(cid:173)
`tion within six months after transplantation.
`&suits Of the 126 patients given daclizumab. 28
`(22 percent) had biopsy-<:onflrmed episodes of acute
`rejection, as compared with 47 of the 134 patients
`(35 percent) who received placebo (P :..-0.03). Graft
`survival at 12 months was 95 percent in the da·
`clizumab·treated patients. as compared with 90 per·
`cent in the patients given placebo (P =- 0.08). The pa(cid:173)
`tients given dacliiumab did not have any adverse
`reactions to the drug. and at six months, there were
`no significant differences between thfl two groups
`w ith respect to infectious complications or cancers.
`The serum half-life of daclizumab was 20 days, and
`its administration resulted in prolonged saturation of
`interleukin-2u receptors on circulating lymphocytes.
`Conciir.sions Oacliiumab reduces the frequency of
`acute rejection in kidney-transplant recipients. (N Engl
`J Med 1998:338:161-SJ
`c?l1998. Masuc:nuserts Mt:eic:;,I S.:>clerv.
`
`A CUTE rejection is a strong risk factor for
`
`chronic rejection ill recipients of renal
`grafts from cadaveric donors.1 This fact
`has promprcd the development of 11cw
`immunosupprc:ssivc agems designed to reduce the
`incidence and scvcricy of acme rcjecr.ion.2•6 All th~se
`agents, however, achieve reductions in the frequency
`and severity of acute rejection at the price of gcncr·
`alizcd immuuosuppression, with its 3ttendant ri~lcs
`of opporrunistic infection and cancer.
`One potential tarsc~ for more specific immuno·
`suppressive therapy with monoclonal antibodies is
`
`the intcrlcukin-2 rcccpcor.' The higb·affiniry intcr(cid:173)
`lc:ukin-2 receptor is composed uf three uoncovalc:nt·
`ly bound ch.aim: a 55-kd a chain (also referred to
`as CD25 or Tac), a 75-kd f3 chain, and a 64-kd
`'Y cha.in.7 This receptor is prc:setH 01\ ne<lrly all acti(cid:173)
`vated T cells but 11ot on resting T c.ells. The: interac(cid:173)
`tion of imulcukin-2 with this high-affinity receptor
`is required for the clonal expa11sion and continued
`viability of activated T cells. A v:i.ricty of rodent
`monoclonal antibodies dirc:cced against the a chain
`of the: receptor have been used in animals and
`humans to achieve selective immunosuppression by
`targeting only T-ccll don~ responding co the al(cid:173)
`logl"lft.a·tJ Daclizumab, a 1nolc:cularly enginc_c:red
`. /
`hum:rn IgGl incorporating cil;-;fiogen-binding re·
`gions of the parent murine monoclonal antibody, L..
`offers the pocemia1 for greater ~}s.ral?curic use of in·
`tcrlcukin-2-rccepcor bloekad.:.:,.~e compared the
`efficacy of dadizumab with placebo foe die prcvcn·
`tion of acuce rc.jc:crion in renal·mmsplam recipiencs.
`
`ME.TH ODS
`
`Study Oesign
`We p<rformc:d J rmdomizcd, doublc·l>lind, pl:accbo·conuollcd
`trbl ~t 11 t~anspl:inc;itlon cc:nccrs in the Unircd Sruc.:;, 3 in Can·
`~da, and :; in Sweden. Adult$ receiving iim renal :illoi:,-r:i.ft. from
`"1cUV<:1'i.;; do1lOr; were cli~lblc for chc scuJy. ~cicnts were ClCdud(cid:173)
`cd if they wen; r.:cdvini; ;11ultiplc ocs;1n cr11nspl1.1irs or h:ad ~ po~­
`ici,·c: crossm.icch for T· cdl lymphocyte~. The protocol wu :ap·
`proved by the innlcutiC\n:il r<.-vicw boud or ethic$ com111ittce :i.t
`e:i.:h pl1•cicipa1ing ccnrcr, :ind lll p:iticnc£ i;.>.ve written informed
`consent..
`
`lmmunosuppressive Treatment
`A.II pltlenu '""'civcd ~ydosporinc, u.achioprinc;, a11d prcdni·
`sone. The first d.:>sc of i:ydosporinc WH given during the period
`from ll ho1m txfurc to 24 houc5 after transplium1rinn.
`t>.idi¥um:ab (Zc:n1p~ic, Hollinu\1\-~Rochc) or pl:i;ebo w;i.s
`
`-------.... ---
`
`from the Unh·mity of C:ilif<1mi3, San fnnctsi:o (F.V.); Brii;h:;m 1od
`Wo111c11's Hinpitlll. llo11on (R.K.); H<>lfn1a.1111-ul\oc.he. Nutley, N.J.
`(S.l •. ); Ohio Smc Univcniry, Columbus (G.R.); l11cli11u Univenicy, lndi·
`31\•)lOllS (M.~); rhc l..l11ivcriiry oi A.lbccia, E<ln1C>lll01>, Alr;;i .. ~ni:!a
`(r,H.); Emory U11i•cr>i1y, At~rm (J.N.); the: Univcr~ily of C2liti1n1i>, Los
`Ani;clc< (A.W.); M~ln1o> Uni•'CNi1y Huspit~I, M~lino, Sweden (H.E.); the
`Univc:Dil)· :ir l\lil1~1n:1, Blm1inglum (R..G.); Sal1lgri:11~1:J Hospital, Goth·
`cnbnrt:, Swed~ (LB.); l11d )(>Ito.< H11pkiM On.ivcniry, lMtimorc iJ.D.) .
`. '\dd1cs. reprint req11~1.J to Or. Vi11ccnd ~· rhc: ·r,...nspbllt Service. Univct•
`siry of C~li(orn~, San t'nnds.:o, SOS l'~rnusus 11.vc., l\Jn. M884., llo~
`Ull.6, S.m Fnncisco, CJ\ 94143·0116,
`•Other mc111bc:rs Qf the Dadjzum~b Triple 1'h~r•py Srudy (~ruup arc
`listed In <lie Appendh:.
`
`Volum i: 338 Number 3
`
`• 161
`
`808 of 1033
`
`BI Exhibit 1002
`
`

`

`The New England Journal of Medicine
`
`·~~~~~~~~~~~~~~~~~
`
`•
`
`3dn1ini1aert'.J i1ltr.Jvc1H1usly over :i pcri(Jd of IS minurc;.. E.1.ch pa·
`ticnt rc\;civc<1 live doses of either d~..:lizum~b ( l mi; per kll<>s•::i"'
`,,i b,>Jy weight, tn :1 nu!<imum of 100 mi; per do~..:) <>r pl.i.:cbo
`{0.2 n1g of pcil)-surb-.lc 80 per milliliier in 67 mM 1>hosphltc
`bufter). The fim <lose w.i.; :idminisccrcd wi1hin 24 huur~ before
`tr.\Mµl:incalilln, with subsequ..:m dus~s i;i~cn c-.o, (o,,,, six, :ind
`eighr weeks :ifter trJnspl:inr,tiun·.
`
`Primary and Secondary ~nd Points
`·n,e primary end 1"->inr of the study w~ the incidc:ncc of biop·
`s> .. .:onfirmcd :lc11re rejc•"tit>n within the iiM six momln ~fccr
`rr::inspl:mtJtion. All puic•\CS wirh :in unc~pbincd rise in the scrum
`.:re:irininc ..:onccntn.ti<m ,,. •>Ile '" n1ore symptonu of ... cute rc(cid:173)
`jc:.:tiun (fovcr, pl;,, ov.:r the !;lf3ft, or l dccrcuc in urinary vol<unc)
`were rc.quil'l:cl co u11dergC'I :i rcMI biops1· within 24 hours :.i.ti.cr the.
`initiuiun uf ~ntir.:jc\;ttuJ\ thc:r.>py, whic:h consisted initillly uf in·
`U:l\'cnnus lncth)'(prcdnisu(On«. (7 ITIS pct )(itog(ln\ ~( d'.l}') n>r
`three d3)'S. The hinologic dil1'tlO$i$ or rejection ..v~s blSCd (\n the
`prc>cncc oi acurc t11bulitis or v.u..:witii :md wus made by the: i>l ·
`choloi:;i~t :u each instir:utiu11. I'.uirnu were .:onsi.:lcrcd ro hJ\'c
`prcsu~\ptivc t'ejcction if they rcc:cived ~ .:ounc of ailCirejc:,rion
`therapy in the :.i.bsencc: of his101ogic eonfumuion uf n:jcction.
`The diignosi..s of :any subsequent episode$ of rcJccti(ln in p.iticnt~
`prcscnrins; wirh renal dyifum:tiun w~s based on cli1iical eriterh,
`such M the 3bscnc:c of evidence uf t1cplu.>toxici1y or of Ufin~ry
`tract obstruction or infection, wirh a biup:w fur c:ontirm:i.tio11 per·
`fom1cd ar the invcstii:;ator·~ disc.rc:rion.
`Sc::on.S:i•y end points included patient survival )n;i snit sur(cid:173)
`vi"31 lt one yc..1r, the time 10 the first cpi5Uuc of acute rcjc::tion,
`the numbrr of acute reje..:cion episodes per p~ticnt, the m:cd for
`'.lnril}'lTlphocytc ther.r.py (OKT3 Of" 1xilycJonl.1 ant.ithymocyte i;lob·
`.;tin) bec:;1usc uf glucoc:oniroicS·•csisr"nt l'ejcction (dctincu ~~die
`3.t'>scncc of ;. rc~ponse to inrt3'1cnou' mcchylprcdniwlonc puhc
`cher;py), gr.iii: functiun (as indicltcd b)' the icrum crcarininc 1:011·
`.:cnrruion :lnd i;lumcrul~r filcr~cion r.ltc), ~nd the cumului,·c
`dose of prcdnlsune in the iirst $Le mo1\thi 3ltct u:inspbnuciun_
`
`Pharmac:okinetic: Measurements
`Blood ~plcs were .:ollcaed unmediltcly bdurc and lftcr (for
`Hough :ind peak cun.:cnmcions, rcspc:etivdy) the fim ltld filU1
`infusions of d;1clizumab or pl.t;cbo :1.nd on days 70 2nd 84 aFtcc
`rra11:1plinc:uion. A sindwkh c:nzymc-llnk.:d ianmu11<.lsorbc1H "-$$~)'
`w:1s used to mc:ssure dadizum~b in scrum.I•
`Ii\ 20 .:01HC.CU1ivc paricnu It one U.S. ~cnier (University or
`Giliforni:i., S;1n fr:inc;isc:o). lymphocyte ~1uly~i~ w-~$ performed en
`detcm,inc <he urur:idon of the intc:rlcuki11·2-re~cprnr c ch31n.
`with 1h1: use of methods reported pr"-viously."
`
`Gton1erular Filtration Rate
`
`The glumcrulu fillr;\cion rate wa~ mca~urcd in :ill plticnrs with
`func:tioning grafts si,.; monrhs after ITTnspl<int;uion. Mc;1s11rc·
`mcim wc:rc: b.l.<c:d on iohcrol, r~Jioisoropc, or in1.1lin dc:.1r.11nc~ .
`
`Statistic;al Analysis
`
`O ifTcrcncc.s in C3tcgori.:al v~ri:ibtcs beru.·cen the twu i;rt)ups
`wac detefl\\inc:d wirh rhc u$c of the Mantcl-H:icnszd test (with
`steuificuiun lc.:urdi11g ro center). l)j((ercncc~ in the ti1nc ro rhe
`first biup~y·cunfinTJcd episode of rejection were dc:cermi1led with
`the u~c; •>(the lo$·r:inlc rest (with $trnilication :icc0tdini; r(J ccn-
`1er). The log·rlnk resc ''"<l:> 11($0 used m :lllaly:ic the time to i;r~ft
`f~ilurc (or dclth with 11 functio"ing gem) bcciusc: of the S•ll:lll
`number of cvenrs rcporcc:d. l<.apl.1n-Mcicr cscimucs uf the prob·
`:lbility uf p:nii:nt survival :ind graft lurvivil and the cun,ul'iltivc
`probability u(bi~·.:0111irrnc<1 rcjcc:iion were plutrcd over time.
`Ditlcrcnc<.$ in rhe num\xr <)f i>resumptive or biupsy·cunlirin.:d
`rejection cpis.odes per patient in die first silt months were ma·
`l1•nd with 1 norm:il rei;rcssion model. The scrum crc~cininc c:on·
`cc:ntruiuns, i;!omcn.ilar filrr:irion rares, .nd cu1nul:1tivc tln~s ('If
`prcd11isonc ~dminisrercd during rhc fim six months it\cr 1rai1s·
`
`i62
`
`J:inuuy lS, 1998
`
`p1:111!3tinn in the IWO STnUp$ Weft' GUmp;vc.d With th-;: USC Of the.
`Wilcoicon r3nlc-sum rcsr. Lo.,inic:-rc~C$$io11 ~11alysis w~s used co
`.:Utcrminc the effects l) f v:itious fa~ror_, .,,n the probJbility of bi·
`<>pS)'•Cunfinncd rcjc.:tiOO. rrOl)OrtiOll~l·h~7..lrds ~n3Jysas WU UJCd
`11> dercnrnnc rhc cffeHs <'f varimJs ·factors o n the time to biot»Y"
`.:..nlirmcd rcjectiun. The results uf l)'1"pho.:~c :'Ind inccrlcukin-
`2-rc.:c:pt~" l.~ay.1 were cnmp1rcd with rhc u~t of Student's M¢St.
`All st1tisck1I rem wi:rc lwt,·sido.:d.
`J\JI p:iticnr' r.andomly :usl!;ncd to a crum1cnt ~up wen:: in(cid:173)
`cluded in the primvy <Vl~lf$C$ of cffic1cy 31ld s.ifcty, 3eeurt1ini; tt>
`chc; ir\W'ICion·t<>·trc:u vri"ciplc. V~lue.• :a.re: rcp<">ned :u means :SD.
`
`RESULTS
`A total of260 patients were CJlroUed in chc srudy:
`134 patients were assigned to the placebo group,
`atld 126 co rhc dacliwmab group. The cwo groups
`were similar with r.espcct to age:, sex, race, cause of
`end·stagc renal disease, presence or absence of pan·
`cl-reactive ami-HLA antibodics, number of HL:\·
`Olt mhm:uches between donor and recipient, and
`<lur3tion of cold ischcmia for rhe graft (Table 1).
`All pacicms received ar least one dose of the smdy
`drug, a11d 107 of the patients in the placebo group
`(80 percent) and 107 of those in the daclizumab
`group (85 percent) received aU five doses. Gcaft
`funccio11 was dc:layc:d in 39 patieucs i.n the placebo
`group (29 pcrcc:m) and 27 patiems in the: daclizu·
`mab sroup (21 percent). The ~acly use of prophy·
`laccic antil)·mphocyte ther:\py for delayed graft func·
`tio11 led ro the disconcinuacion of the: swdy drug in
`ni11e patients in the placebo grol1p (7 percent) and
`1'itlc: in the daclizumab group ( 7 pc:rcc:nt).
`
`Effic:acy
`Dacli:>.umab prophylaxis resulted in a significam
`reduction in the: incidence of biopsy·documen.ced
`acute rejccrion during the first sill.: months after
`rransplancation (22 percent, vs. 35 percent in the
`placebo group; P _. 0 .03; odds .r.uio, 0.5; 95 percenr
`confidence inrcrva.I, 0.3 to 0.9) (Table 2). The pro(cid:173)
`portion ofp;uiencs ""ith presumptive or biopsy-con(cid:173)
`firmed acme: r:c:jection and the number of rejection
`episod~ per p:lticnr were also lower in the: dadi2u(cid:173)
`mab grOllp, and the: time tO the first rejc:ccion was
`longer. There was a trend tow-ard a reduction i11 the
`number of patients with two or more rej~iot~ epi(cid:173)
`sodes :ind the a.umber rel.'.civing amilymphocyte prep·
`arations for scvcrc: rejection in chc dadizumab group.
`The: beneficial effect of dadizumlb was not infln·
`eoced by delayed graft function, initial use of other
`nntily1nphocytc thcrapit!.S, or exclusion of p:uietns
`who did not receive all five infosio11s of the srudy
`drus (data 1lot shown).
`The patient-survival races ac one year were 98 per·
`cent in the d:iclizumab group and 96 percent in the
`placebo group (Table 3 ). The: graft-survival rates in
`rhc: daclizum:ib and placebo groups were 95 and 90
`percent, respcccively. None of the patients in the da·
`clizumal> group buc three of chose in ~he placebo
`group died of illf~ctions: one each of aspergiUosis,
`
`809 of 1033
`
`BI Exhibit 1002
`
`

`

`INTOLeUKIN-2-RECEPTOR BLOCKADE WITH DACUZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
`-----.. ···---------------------------------
`,. ....
`
`... 1---........
`TA8lL , • Ih.SE· LINE: Cti.111\ht."TtNSTJ<.:S OF Rff".-\1.·At.LOGl(Al'i'
`1Qc1r1?.NTS. •
`
`. ,
`
`C"al\l.CHlllUIC
`
`.'\itc- 1·1·
`1111. 11f 11:nicnu {%)
`S.:1 -
`Mal.:
`Fcm~lc
`l~cc or crlo11ic ttmu1~ -
`Ill" oi p:ui.:111~ {%)
`While
`Blici;
`Or her
`C:4usc of renal f~il'1rc --
`110. of patfcnl.1 (1')
`Glomeruloncphri1is
`l)i~bc!CS m:llillli
`lletcdir.iry or 1)()lycyi1ic kidney disc~sc
`Hypertension
`Other
`l'•ncl·= c:tivc scrum ~11ti6orlic:.-1 -
`no. of p~c.ienu (%)T
`ll-10%
`ll-4?'4
`S0-100'.16
`Ne•. <1fHLA-DR mis1Mcche$ -
`nv. or 1micnu (%Jt
`
`0
`
`2
`GraTI: co,d·~l1cmi:.1 ri.mc. - hr
`
`l'\.Accoo
`IN= 1l41
`
`D•cut.,..MI
`IN=126)
`
`47:::13
`
`+?~13
`
`81 (611)
`53 (40)
`
`74 {59)
`S~ C+l )
`
`Ill (60J
`27 (20)
`26 (19)
`
`.\0 (30)
`29 (22)
`20 (15 )
`19 (14)
`26 (l?)
`
`&+ (<17)
`2+ {l?)
`13 (14)
`
`33 (26)
`31 ; 25}
`24 (19)
`18 {l•)
`19 ( 15)
`
`121 (90)
`10 (7)
`3 (2)
`
`113 (~9)
`Jl (10)
`1 (I )
`
`22 ( 16)
`62 (+6)
`+o (30)
`21:9
`
`19 ( IS )
`49 (39)
`so (40)
`.22:1!
`
`• l"tw.-1ni1lut ,,.,J.h.\ct. :arc l\\calU ":":SD, l~rcenug~::; m:1y not ~"'" n\ l 00
`because <>f rm111dinio.
`f!>Jnd·n:~cri"c ;\ntibodin irt. ~nti·~l.A,.111iburlie1 rim h3'C ~ .:,.toto:.5c
`dfccr Oil lymphocyte!$ ob~inc(i (")"' ~ P•l\cl or donors iro111 the ~cner.tl
`pop11l~tion.
`ioar.i were '"~~ing I\" $<>!UC p•liCJ1U.
`
`TABL£ 2 . ACUTE R!:TECTION Er1s 01>£$ '"' 1'ME Fill.ST S11: MONTHS
`<'F'T''-ll IUNAL TRANSrL'JllTATION 11'1 TH£ rl--'CF,110
`AN:O CACUZUt-v.ll GRours.
`
`R£J£CT10N
`
`One or more biop~y-confinucd
`episodes - ""· nf patients (%)
`011c t'lr n101c biopsy-confim1ed '"
`pn:sumptivc episode$ -
`no. o(
`p~ticnt.s ('.t)
`Twu ur mon: l•inpsf·.:of\l'inncd <>r
`prciump1i<·c cpc4'~11c::s - no. of
`p-.uicm~ (l')
`Mun no. of cph1v1lcs/r.i•ic111
`Ti1\lc 111 fim cplsollc -
`ihyi •
`Episode ruiuirini; 1ncily111pho~)'cc
`110. of puicnu ('6)t
`1he,.~py -
`
`Pl..UHO
`IN=134!
`
`OaCUZUMAI
`!N=126J
`
`p VAlUE
`
`·~ (35)
`
`lS.(22)
`
`o .Ol
`
`52 (39)
`
`32 (25)
`
`0.04
`
`18 ( 13 )
`
`9 P'l
`
`0.08
`
`0 .6
`30:!27
`19 ll4)
`
`0.3
`73:!59
`10 (S)
`
`0.01
`0.008
`0.09
`
`' l'lus-minus vJluc:i arc nlCllM :tSl).
`t "ncll1•mph1-...")tc i:hcrll>Y co1ulm:d of Ol..'T3 .ir )lOlyclon:ll ~ntithy.
`lllO'Y<' ~l<ll.>11li11.
`
`·· c:=-.-
`TABLE 3 , CAUSES or. DEATH .-\ND RfNl\L·GMfT
`Fl\ILUll.f !IT ONr; 'ttl\I\ ,,... THt r1 .... ci.R<>
`/\ND D.'\CLtZl•~\l\B G.11.ow-:>.
`
`-· ·-~·-. -···· -------------
`
`O a CUIUMU
`IN=12BI
`
`1'10. of p)toinrl I'll.I
`
`Dcuh
`ln1t.·uu11 '" lyn•ph1•m'
`C.irJiU'·, ,..:ubr (•""'
`!'11l111011Jry c1nb:>lis111
`lumccrcbr.11 bl~int1
`Sulc;t.tc
`Gr.1(1: l~ilure
`Do ch
`Rfjcctio11
`~rc~hniQI <:a1,,,1sc
`l'rllll~ry lll)llf\11lCliflll
`
`st+)
`3 ( 2 )
`I ( I )
`I ( I)
`0
`0
`13 (10)
`5 (+)
`3 (2)
`4 (.3)
`1 (l)
`
`3 (l)
`l ( I )
`0
`(I
`1 ( I)
`l \I)
`6(S)
`3 (l)
`l (I)
`2 (l)
`0
`
`coccidioidomycosis, 3nd pscudomonas sepsis. One
`patient in the dadizum3b group died of lymphoma.
`The me-Jn scrum crc:acininc conccnuations six
`monrhs after transplantation were the same: in the
`tw<> groups (l.7!:0.7 mg per dedircr [150:::60 µmo!
`per liter)}. The mean glomerular filtration r•\Ce w3s
`$5±23 ll'U per minute in the dadiZlunab group and
`5.2 ±22 ml per n1inurc: in che placebo gto\1p. The av(cid:173)
`erage daily doses of prc:dnisone and cyclosponne did
`1'\or diffi:r between the groups at any rime during the
`srndy, nor was there a difference in the mean trough
`whole-blood c.ydosporine concentrations at any time.
`
`Adver.>e !:vents
`The ldminiscrarion of daclizumab was not associ(cid:173)
`:ued wich an>· immedi.:lre side effcccs. There was no
`significant difference i.n reported adverse: events be·
`tween the two groups (Table: 4). One patient in the:
`placebo group and two patients in the: dadizumab
`group had lymphoma duL"ing the first year after
`transplantation.
`
`Phumac:oklnetic Data
`Pharmacokineric data were available for 92 pa(cid:173)
`tientS in the dadizumab group. The mean scrwn
`half-life of daclizumab was 20 days.
`
`Circulating Peripheral-Blood Lymphocytes
`and lnterhtukin·2 a.Cl'lain Receptor
`There were no differences in absolute lymphoc:yce
`numbers between the pl:iccbo and dacllzumab groups
`before transpla11tation or for six months aft:crv.rard.
`Circulating CD3 + cell c:ooccncrati.01'\S and T·cdl sub(cid:173)
`groups were not measured, because they were not
`affc:ctc:d by dadizumab therapy in an earlier scudy.1'
`There was a :>igil.ificanc decreas~ 111 the percentage
`or circulating lymphocytes that stained with anti-
`
`Volume 338 Number 3
`
`163
`
`810 of 1033
`
`BI Exhibit 1002
`
`

`

`The New England Journal of Medicine
`~-------~-
`---------~ -----~
`
`T .ti.81.,£ 4, ADV?!Ut f;ViNTS /\T S11; MONTHS
`•N TH~ Pt..ACEno AND DACLlZUM.1.11 C11ol11·~.
`
`- -···· .. ·---------~ .... ···-·· ...... , ... _..__
`o .. o.iw..••
`P ..... cuo
`IN; 1Z6l
`tN=1l4J
`
`ADVERSE EVENT&
`
`11~. or p•tienr. ('IOI
`
`Sufa1n c-vcm•
`f<;vcr
`Sepsis ~11d b~.:tcrcmi~
`l'ta1ct1nlOlli~
`Pun~:"I inti:a,nn
`Fu11~cJ11la
`L1>c.tl infcctio11
`L<>ol infccr\01\t
`Ccllulici~ ~nd '~ou11d
`i1,tC .... .,.in11
`Urin:iry rr.i~"t i11feccio11
`Ocher
`/\.ny viral imC<tlont
`Vircmia
`Loc~I infection
`Cr101\lctf1h>vinr~
`i11fcaion
`Vircmia
`Tinuc iniecti1>11
`
`13 (10)
`16 (12)
`9 {7)
`4 ( 3)
`27 (20)
`2 ( 1)
`25 (10)
`70 (5.2)
`+(3)
`
`-44 (33)
`3~ (28)
`32 (21)
`u (9)
`ll (16)
`l+ (10)
`
`10 (7)
`4 i3)
`
`6 <S )
`ll (9)
`.. ( 3)
`3 (2)
`~l (t7)
`0
`21 (17)
`59 (4?)
`7 (6)
`
`3+ (:!7)
`36 {29)
`29 (23)
`12 (10)
`20 (16)
`·~ (l2 )
`
`ll (10)
`3 (2)
`
`"Se1io..s ~dvci~c cv~'" w~rc: defined ~s complic~lio11•
`other thin dc1th or rtjcc,ion dur rn1longcd or required
`ho>pinll~.,~r<,io •n<I wer~ ponibly 0( p11;>wlih· ,.;l.ucd tu tl1e
`nudy drui:.
`tSonlc p~ticr11., lo~d mur<. thin 011t. type ui infe.:tic111.
`
`on accivatc:d T cells. Use of the drug thus spues oth·
`c:r immu11ocompetcnt cclls.7
`Only l 0 percent of d:iclizumab is composed of
`murine sequences, which :lee from the: antigen-bind(cid:173)
`ing regions of the parent antibody. These sequences
`arc insem:d imo human immunoglobuli11 with chc.
`\lse of molecular biologic techniques.'• Our srudy
`highlights the advancages of rhis type of antibody,
`including its prolong~d senun half-life, appro3ching
`thac of human lgG , and die absence o( functional
`immunogcl\iciry associated with irs use.t>.16.l9.2J
`The ~xJ.ct mechanism or mechanisms of action of
`dadi:tum;ib arc noc know11. A !ikdy mechanism is r.hac
`ir binds to circ~llating lymphocytes wirh it~redcukin-2
`cr·chain receptor~ bm does not activate the rccc:pcors,
`and the cells therefore have no free inrc:rkulcin-2
`a-chain rc.:epcors available for activation by intcrlcu(cid:173)
`kin·2. in ~dd.ition, the decline in the perccntasc: of
`circulating lymphocyr<".S e.xpressit~g CD25 (mc3.Sured
`l>y staining with 7g7 antibody) without an accompa·
`nying decrease in the absolme Humber of lympho(cid:173)
`cyt~s suggests char the c:xprc:ssion of u1terkuk.in-2 rc=(cid:173)
`cc:ptors is down·regulated or rhe shedding of the
`daclUumab-bound intcrkukin-2 a chain is increased.
`1n conclusion, when added to therapy wich cyclo·
`sporinc, azathioprine, and p rednisone, dadizun\ab
`reduces the frequency of acure rejection and im(cid:173)
`prov~ short-term gi:afr surviv~l in renal-cransplant
`rcc1p1cms.
`
`CD25 antibody starring 10 hours after r.ransplanta(cid:173)
`cion 3nd lasting up to four momhs in the dac.lizu(cid:173)
`mab group (data uot shown). Simifarly, there was a
`significant decrease in t he pcrc.entasc of circ0ubting
`lymphocytes char sro.iiled with the: fluorescci1) -C01'ju·
`gated antibody 7g7, which binds to an interlcukin-2
`a-chain-receptor cpicop~ disti1'lct from the: cpitopc:
`recognized by dadizumab and rctkcts coral interku(cid:173)
`kin-2a-receptor apression (data not shown).
`
`DISCUSSION
`We found ch:u the p:niems receiving daclizumab
`in addition to inaimena11ce therapy ~~th rhrc:c: ini(cid:173)
`munosupprc:ssive age1'1.ts had a lower frequency of
`biopsy-co nfirmed acute rejection in the first six
`months after transplanucion than the patiencs re·
`ceiving placebo with the three immunosupprcssive
`agencs. In addition, the time to the first episode of
`acute rejection was significant!~· prolonged, and the
`mean number of episodes per p;uicnt significantly
`reduced in chc daclizumab group. These results were
`obc~ioed without a concomitant increase in infec·
`tions complicarions or ca1\cers. The cfficaq· of da·
`clizumab is probably related to it.~ sdcctive target,
`the Q-cbain component of the high-affiniry interku(cid:173)
`lcin-2 rec<:pror, which is ~resent almost exclusivdy
`
`We i:IYe imi&lr.ed "&o DY. 11JWMJ A. W11/J,,,4,..,. fqr hu 'ontrihu(cid:173)
`rio" r~ the rlr:i>eiotmmt of dacli:.u,,mb, An ii t<> Mi. PeJJ!Fl Millnr for
`:,,, a.ssitumce i11 rl1e P"&PA,.a.tio•i of rht 'f1t1111sseript.
`
`APPEND IX
`I 11 '>lldicil•n m chc luthors, th~ fullowing invt~tig:icon participated in chc:
`Ihcli~unul.> Triple Thcnp}' SruJy Crc:>•rp: Vi: .,.rirr Gff.erill HOl['frq!, H4'i(cid:173)
`fi1';, N.S., C"''""" - B. KibcrL: &difi1191 Hv111lt1tl, Hudrfi".IJ<, Sw1d<r1 -
`G. ''fyde11; U>ti~t•rh:;v of Mir.•u.sora, Mi,,-ieapoJ•: · - A. Matu; Be.lb ltr0e.l
`Dtnco"a Mcdi:n/ C:•:rro; ~'" - M . Slt:1pirv; 'f'aJ,,po. G1..ur4/ HDJ'['lra~
`'f.• mJlfl, F/,,, - G. Chw; V«>1fOt/Y1r c • .,., .. 1 HotyirnJ, Vc'l<OhVtt.: R.C.,
`P. J.:.:own; U>Jiv.1~ity afUJifomi11, .v;.1 F>·M1tiuo- M. bnti~
`C:11r1111l1~ -
`Urii>eT'!i11 uf Albtt'tn, &lmtmlo"· .1fo ... C1m .. 1,. - K Sol~; •flt~ Hoff(cid:173)
`,.,,.,.,-La[l.o,,;1~, /Jutl"f, NJ. -·- ,\. Lin. l. Pacr.l, K Nicfordi, .".. Woliczky,
`~n.t J. H~kimi.
`
`REFERENCES
`
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`1t\!;I)' cada,·cri~ renal tl'31llplarH sui'Vi.,.J.I. Cli11 Tn1ispb1il 199-l;8:328-31.
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`cion io prin~ry c~(IJ"cric n:nJl :.llogra.ft rccipicrm. Tr~mpl«nt<\tion 1995:
`60:235·32.
`3. Vin.:<1n1i F, L1->k<ll• 0.-\, N~lon JF, Mendez R, Moto. /\J. One-ye'J.1' (ol·
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`Grn11p, TQn;pl•nmic>n 1996;6l:l576·Sl.
`4, Matti• IU:. M~.:.h:mi~nt> of 3Ctin11 ..>C ,,.,, inu11u11osu1iprcui1·c drug1.
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`5, K.llu11 BD. Sil\llim1u: ~ new ~sent cor cliniQI ~nal tl'JtlJPl~nr:-~cion.
`Trw$J>l:.nc !'rue 1997:lY:4o·SO.
`6. Crnbe< $A, Cll<ln (.; LC, ~n~fa~ OM, M~t""> . .,]. l111m1mc~vppr~<i(ll'I in
`rcml r~.1rupbnr.11i<ln . II. C.mku . .rcrui<1i, ~nril)"tllphocyt< Glo bulin, >!Id
`01'-'"M. Clin Tninspl•nt 1991:5::!19·0~ .
`
`811 of 1033
`
`BI Exhibit 1002
`
`

`

`INTERLIHJKIN·Z-RECEPTOR BL.OCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
`
`7. T:a11i~uch• ·r. Min1111i Y. The IL·l/IL·2 rc..:cp1nr 1y.rcm ; A .:11Hc11t •>-<r•
`,.;,,v ~II l99~:n:S·8.
`8. K11pi<:c·Wci;li11Ski JW, Uia!ll.inmcin T, 1ilucy NL. Suo111 TD. ThcrJr>I'
`whh monodnn"I :111til>Mf 10 inr<rlenkin 2 f<Ccp""r :p•n:o "'r>r•usor
`l' ~ells 1nd prc-·c1111 or r'C\'C~ arntc ;;ll<l):r•fr rcje,-,:lon i11 ·~ts. rmc N~rl
`Acacl s,i lJ S ,\ 1986;83:2614·7,
`9. ~ MH. Sh•piro ME, S1t0111 TH, ct •I. l'rvln11i;:11ion g( 1>1i11i:ac rcn~l
`)ll(lgr.ul ,ur•iv.ll ll)' ~nti·T•c. ~11 :1111i·hunll11 IL·l i.:.:• p:ur monodmul • ••·
`rilt0dy. T~nspl~umion I ~89;'l7:5S·?.
`to. Soulill ..... H?. c~nurovich D. Le M:.iufT n. Cl ~I. ~nclomi~c,l .:un·
`uollcd lliJI of~ 111unudo1ul ancibodr •i;~i11~1 the imulcul.:in·2 rcccpt11r
`!33R~.I) u <•'"'P~"'d with ubbit •111i1hr11•<>eytc 1:1lob11lit1 tC•r pnophy·
`bxis J11Ji111r rcj"1i<•11 uf ren:il ~llo.:,r.u"u. N l!n~l J .Med 1990;322:1l7S.
`82.
`11 . Kirl;1n>"1\ RL. Sha1>i"-' ME, C-irpcn1cr CB. ct ;11. A undon1it«i pm·
`1p:cciv< iriJI uf ~111;·Tac 111u11od<>~ll •nciboJy in lunnin rM1I et1r11pb11~•·
`"'"" Tr~nspl1111luu11 1991;!\1:107-13.
`12. v•u Geld•• T. Zictsc R. M111,1~ "H, cl ~I. I\ •lv111llc·llli11d. pla•cb;i·
`cnnrmlkd •rrnty vimo11nclo1ul :1111i·inrcrlclllt.in·2 rc~<11mc 1ncil>ody
`(llTS63) ld111i11i:.~r~clo11 co prcvcm ~(urc rc]cctiori ,\fic( kiancr 1~111pl1n•
`r•tion. Truispl3ut•riO<l 'l 99S;60:2~8·S2.
`13. lt.edinsR. Vuv.: H, c1c Ville de Goyct J, c1 al. Mono.:lou,I) l1uibodic:$
`in VnJflhyll.:tic in101..nn1u11r•<->'$ic11\ .Utcc li~cr trJ•l$pt,11n<ion: l nn::!o.11·
`
`l~ccl <•nllCC•lled ui1I CumJUri11g OICT3 21\d •11<i·ll....-l receptor 11\0110..•!('lnll
`~111il>o::!y lO·T•~t· I. Tl•rupl>1n3ri<>n t99~:SS:S3-l·O.
`H . Quccl\ C, Sd111ciitcr Wl~ Seli<.lt ·HE, :r •I. A hunu11itcd •nril>ody d•H
`bi1al• '" rl~ lt>tcrlcul.ia\ 2 rcccpror. \'roe N~d /M:ad Sci \.IS A 1989;86:
`10029°33.
`15. HJ~iml ). Mould D. W:ildm11111 T.\, Qucc11 C, AlliJetli C, Lii;hr S. Oc·
`vclop111e1u (liZ.,1 .. ~x: i hu11r.1111~ccl lJl<i·nc intii)(i.iy. In: HuTis WJ •• i\.1:iir
`JR. eds. Anrihv<I>· ch<r3pcuii~. N<>v Yue~; Cru::: Prcu. 1997:277·300.
`16. H.:iki111i I. Chiumiicc !l, Lu~..: Dlt, ct al. Rcduc"1 i111111unos.cnid1y
`•nrl im.,,<'.-~!1 rliJm1~co)cjnc1i.::s uf l111t111nitccl 2nri·Tlc i11 ~-ynomol~llt
`monkC)'$· I Immunol 199l;H?;l35l•!>,
`17. Vi11'"n1i F, L4nu M, Dimb.1u111 I. er al. A pkuc f tri>l ofhulll,ni1cd
`•nti·i111cric11i(i11 J rc.:cptor >lltilwrly in n-11.11 11:11upll111 rcclplcllts. T~IU·
`pl.mmioa\ 1997;63;:53 ·3.
`11. f:l)«r RE, s.,.,; L'r. Dinscr MH, M••1tlcl DR. S~ioh H. Dcmminuinn
`nf h11nw1i:icd ;imi·T~ in humui icrunl I.ii· 1 s.>n<hvich enzyme lint.o.t ;,,...
`mu1101url>au ~~" J fo\111lu1..1I Method• \99S;1S6:•7·S• .
`19. Br\)\,,, I'S Jr. l'~rc111c.1u GL, Dirb:1> FM, cc JI, Nlti·T~~·H, ~ h11n1~n·
`i~cd •nrib?dy n1 die i11rcrlc11kin 2 rcccpcor, f!tvl<Jul($ prlnutc ~rdio~ •l·
`lo~r~rr •l1ri·i\ .. 1, !'roe Nit! r...:a.1 Sci u SA 1991;88:2663·7.
`20. A.niscui C, } ll~1 ] .... w~1Je1U1)11 ·rA, cl ~1. l'tnll\lcoll of ~~'\I~ r.nft·
`vc1"1us·hos1 di=sc wid1 hununizcd 2111i·T>.:: ~•1 ~l\tibody tbat l>inds Cl) chc
`hucrlcukin·! rccq>t''" Blood l99t;&-i:l320·7.
`
`Vol111nc: 338 Numbc:r 3
`
`165
`
`812 of 1033
`
`BI Exhibit 1002
`
`

`

`Interview Summary
`
`.Application No.
`08/146,206
`
`Carter et al
`
`Examiner
`MINH TAM DAVIS
`
`Group Art Unit
`1642
`
`All participants (applicant, applicant's representative, PTO personnel!:
`
`(1) MINH TAM DAVIS
`
`(2) Wendy Lee
`
`Date of Interview ______ D_e_c_1 ~1,_2_00 __ 1 ____ _
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`(3)~------------------
`(4)~----------------~
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`b) D Video Conference
`Type: a) IZl Telephonic
`c) D Personal [copy is given to 1) D applicant 2)0 applicant's representative)
`e) IXI No. If yes, brief description:
`Exhibit shown or demonstration conducted: d) 0 Yes
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`Claim(s) discussed: - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
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`Identification of prior art discussed:
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`Agreement with respect to the claims flD was reached. glD was not reached. hlD N/A .
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`Substance of Interview including description of the general nature of what was agreed to if an agreement was reached , or
`any other comments:
`Pending claims 43-105, 113-131 are allowable.
`
`(A fuller description, if necessary, and a copy of the amendments which the examiner agreed would render the claims
`allowable, if available, must be attached. Also, where no copy of the amendments that would render the claims allowable is
`available, a summary thereof must be attached.)
`
`i)l&l
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`It is not necessary for applicant to provide a separate record of the substance of the interview (if box is checked) .
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`Unless the paragraph above has been checked, THE FORMAL WRITIEN REPLY TO THE LAST OFFICE ACTION MUST
`INCLUDE THE SUBSTANCE OF THE INTERVIEW. (See MPEP section 713.04). If a reply to the last Office action has
`already been filed, APPLICANT IS GIVEN ONE MONTH FROM THIS INTERVIEW DATE TO FILE A STATEMENT OF THE
`SUBSTANCE OF THE INTERVIEW. See Summary of Record of Interview requirements on reverse side or on attached
`
`Examiner Note: You must sign this form unless it is
`an Attachment to a signed Office action.
`
`U. S. Poten