D5
`
`‘ilili l..4'h.!*i{.§J:£‘1‘
`
`Rmma “
`1 mm LC}, Wcbcx 1}}, lawn SM. Iiuxismtal Ixanmzissiazz of hcpatitia
`B virus. Lammr "E989; i: 8B‘1'«§3.
`2 Bazmiear RH; Samplimr R, Gamay R, Taber E, Kamfilmn F,
`riathuasuu N. Hepatitis B izxfectécn in hnuaehaids «if chwnic carrimrzi an!
`hnputitis B surface mtigezn: fmsmm associated wizh pmmimcc -3!’
`infection. Am} Emkiemiof @825 1115: 199-21 3.
`3 Pranks A, Bcrsfils Km: M:'&, H 31. 3'!-mntitis B virus irxfiectiw mum;
`children barn in the Unites $123“:-=23 ta Smnmx.-at Asian refugees. 355 Eng!
`3 stm'19s§;a:3: 3301-35,
`at Fwiede flu Haxtisflig iirxhagrashi 3'3-L Shaw FE. fichnwtakwwlfismw 1’£’.:,
`Ema M. Tmnmissfion afimjtarixis E vima fmm ndngztnsi Asian
`chiidncn 2:: their fmniiies rim 3’ fixtaffc Hmrzic 1933; '78.: 26-29.
`5 van ilitzhuz-fsetl Th JM, 120: W5‘iI:te—u':‘1n D2: Sczhn-ME, van [nan AM,
`PJM, Yap SH. Hcpatifin B in an institution in: the mmtaily
`mudafi. Aw} fifafiemfai W88; K33: 629*-53.
`Irfnyuhi I. Kuhiwagi E, Mama: 1!, iiaiig-nun W, Ehcuumz H.
`325: 49
`.
`wgsvims nmmminsian in nursery sciamk. Am gag-,«22.m.*a: 1933:
`
`it
`
`'3
`
`‘fan I}anmm P, Mnrxnm A. ficpasitis 13 in mmml haandkugpa haapimls.
`£.::m-:3 1989; E: 34043.
`S Mufhflfipa K3,, Euliins EC, Spigland I. Htpratitis B virus ixiftattimn
`mtnsmiztcd Ram retarded children :1: their families dmring brinflmme
`zatgruauzc. j’ fixifasr Gmwmmnf N89 19%}; 3: E-9'41.
`9 jeniwn SA, Lemam SM, Balm L.N._. Ncwboki IE. Qmnumtivc anatysis
`af hepatitis 13 ms mm fin saliva and semen uf chrrmicallgs infiectezi
`ham-ussexuai wave. 3 Irgfiist Dis 1987; 15%: 299%?-£17.
`1&3 Emcécrfieuo T1’, 6:: Medina M, Sh-may 1,, vnilcdnr MI), Echifi ER. in
`inmmticmai mzzhreak at hggmiiis B telatsect ca a human Exiting cam‘-tr.
`3? rsgzw Bis 1932; M6: $52-~56.
`
`
`Bnnartnlant as! Egxldcmlu-lazy and cnvnnumlty Medicine. umwmay
`at Antivem. 23113 irmmparn. Baagium (23 van mxmmse an.
`M Gramm ms». 343 Van Der mmera. A Mam;-etza pm}: and Imtlflmcat
`Hyflemmll Eptdaaui-alum Brmasais. Eamon: {R mack: may
`sarrapondamu in: Dr Pietra Van Oamma
`
`than 81 ycarfi aid wit};
`I‘) pirsmzaanpausai patients X4385
`advanced, histnicgicaiiy wrififi, breast cmcacr
`resistant
`to:
`tsmaxifm wen: mated with EC} 182180. The study was
`sppravcd by the ethics vzzommimaw 9’? each clinics} wzcntm.
`Bzticnts were included if they had been tmatcd with tammtifen as
`an adiuvam ts: surgery fut mare than twu ycars smi than rczfszpscd
`or taster} with tamaacifen far advxncezfi disease. bati =-1 mmpkete
`or parzial tamissian, :3: an change fear at least six xtxcxsztiw and
`suhsequmdar . Patients were exrziudcd if they had
`serious intermittent diseasz, a WHQ perfurmance sums at
`grzazar tixau 2 and 1: iii: exptcaancy uf lass thaxa 3 mcsmhs, arr had
`received mixer nhemathempy. Que paiiemt had adjmvan: therapy
`for erzmiy 9 months and prugtressed, and was thus :1 pmtmai
`viniatinn but
`is insluciad in the analysis. She had pmgrcssive
`xfistase when {Itasca with K21 182’?8{}. The pmcimzmmt sites ca-f
`disease 131 the time afrténpse an tamuxifen were: bxexstfchtsz wall
`{7}, lymph nmias (1), ‘bane: {:9}, and lungfpleuza {2}. am: giving
`infutmcd rsoascnt,
`all patients underwent baseiine staging
`énvststigazitms bcforc starting Lrwznrtcm with {C1
`i32’?‘8£3;
`including mfiiograghs, liver ultrasnund :3: mmpnted mmugarsspix
`scan (at! awry E-2 manthr-3. and isamp: ban: man {every 6
`mmtha}.
`ICI
`lS3?3i¥ was aéminismrcd as 4 Earns;-acting
`fmrmulatzicm in an
`sazutar
`cvibbased
`xrehicie
`by mcmflalar
`int:-axnumflnr ismfection into at burmck. Far aafazzr appraiaaig the
`first 4 patients received mscnlating xi-uses nf ICI 132780} starting
`with $00 mg the firs: sheath and incrcasing m 25:} mg fr-Lam
`month 2 cmwarzis, fnlinwing cc-nfirnmtiun cf lack at" lcrcal m‘
`systemic drug tuxicity at the 3130 mg dc;-ac. Pavimts Sui? tcceivezd
`2512} mgfrrsunxh fmm flu uuniet. 'I‘k'c:atrx:::m with ICI 382’i’30 was
`contingent until cancer progressicm cecmrrcé. Patients were new
`every 34? days during that first muzz-ntzh ll! monim: mag! and
`systexnic: érug Ix:-Ierflhility and tr: saline! blood samplea far
`pharmamkinefic studies. ‘I‘h-:rea£m:, tevinw was dent mnnthly tn
`evaluate mspanse aid :0 manitm lanai and systcmic cirug
`tn1em‘bi11'*t}'. Bimti samples arm: takcn hcfitzre treatmem mad at
`monahiy Eran-rvais thermfmr far measurement of full taioczd count,
`binchcmimry, scrum h-brmoncs, and lipids. Caxscey respnnse was
`cvaiuated according to UICC aritcria. "Ii: quafifisr far the “no
`change” taztcgurgr, canmr gmwth had ti} stahiiisr: for mart: than
`six manrinsfi
`
`lhipdflia in
`Siam!!! (K4
`Brusflian {Marsha}
`Ii}: 3.E2!‘8a3
`
`Rsespansa tn a spaclflc antlaastmgen
`(EC! :t.32?80} in tamoxrfemasktant
`breast canes:
`
`("“«3Anthnny Haweff, Davis! Defriena‘, Jana fiobertsan,
`Roger arameyg Peter Waftcm
`
`
`we treaieci 19 natients with advanced breast cancer
`resistant to tamoxifen with a new specific antiaestrugen
`{H31 1S§!“r'S0) which.
`in arsimat studies, has an sgunist
`activity‘. 13 {£‘59‘3£} patients saspanded H‘ has? partiai
`respoases
`and 8
`shsrzwed nu ahanga}
`in mamniy
`mzramuscular injections of mi 182‘:'8f} after progression on
`tamoxifen.
`fur a median ziuration cf 13 months with
`minimum side effects. Fretiminary evidence suggests that
`the agent
`is wittmzrt effects on the
`tiver or
`the
`hypathalarnis-aituitary axis.
`ICI :£8E?8{} appears in be a
`prcmising new agfiem fer treatment of advanced and earfy
`breast cancer.
`
`Lancet 1995: 345: 29-60
`
`‘L...
`
`Mtimugh haif of all patients: with advanced breast cancer
`ham: cancer; which either rergmss or remain stabie when
`mated with tamaxifen, mmcmrs
`eventually: bezcumc
`resistant aftar a median duration {If tamission cf fifteen
`months. Alzixrmgh an antagonist with respect
`to the
`caucezr, tamaxifcn is an aestrogenic agonist with respect to
`bone, fiver, and amiometrium. {}ne came of rasistance
`may be the cancer macfing ta tammtifan as an aguniat at
`that mm-axifan is, in some way, rendered unavailable to
`aestxogen rcczezptcsrs so that endagmzous cezstradiol is able:
`tn msrixnntata cancer gmwrh. Ta test this hypcthesia, we
`treated patients with cancers resistant to tammtifen with
`an
`wtrimzsarageu
`(ICE
`182?3£!:
`?::-£*3{4,=§.5,5.S
`pentaflur:mpenr5r§s1:1finyi}nnn3:E} oestra~ 1 ,3, §,{1t'3)~:ri-me-
`?z,1’{»*B~diu1) which, in animal studies, has Ewen shcewn to
`have no agzmist acsixrityd
`anti':zc:aI;rc-gsaxz with an
`ICII 182'?8i)
`is a atamidal
`Eikyistfiphinyl side chain in the '33 pcssition. There is
`widens: {hat the side chain prevents. ciimerisaticm of twin
`rnalecszfics
`cf
`the
`aeatmgm rerzcpmr which
`is
`a
`prerequisite
`far
`gem:
`Lranscriptitm.‘
`In
`contrast,
`tamoxifen, like K:-estzmgena, causes :'cCI":pEC.*t dimatisaticm
`and partly initiates gem: transcription; which is the basis
`of‘ its gzarsziai agonist aactivitgn’
`
`7 13?)
`
`13» F321
`
`E :33}
`
`Parka:-:3
`
`H»: change
`
`Psagxessear.
`
`2€I+«IPf¥ 19;. 13-t[I~:»2 E}, i?+§A67), 3?‘ {PER}
`12 {ms}, 5:11.293, 3 :A*.»":';;
`23=+£?«it’38}. 18+{A?-fig, 18+{A?1}. 1Er+{NE 4&5.
`1&1-{A23}. am: 3:11
`am panama gsogresicd In «as weeks. Prwrav-us
`areaimr.-at mil‘: tmmmifen A48, .1485, NC 3‘.
`FR 8. 9. W12
`
`Lemar: in hractcefs rndacate respcmae in tammufm wimn gman for am-annea 6+9-erase
`(PR‘»-‘1f,}8rtfr§‘ rmégaion, mum mange. mzptngresswe disease} at efigax-an as an
`anjuvait mmpy ch}. flumhers £1 bmckats inmate duratic-:1 uf {remnant with
`tanaizhfue.
`
`Tabia: Rupmm mu: amt dnraticms an! umpmsau in E6! xazmo
`
`|nnoPharma Exhibit 10560001
`
`

`

`THE 1.A.N(..'.l:i'1‘
`
`
`
`19 patients wen: evaluable (table). 13 (69%)
`Ali
`responded ‘£0 treaunem for a median duratitm cf more
`than 18 mamhs.
`*9 are still raaponding and ccnlinuing
`treatment with ICI 182730 after 15-23 months. Sites of
`response were 5010: tissue (4), bane {'1'}, and lung (3).
`Respnnses were seen in 6 of 9 women who haii pmgressed
`whilst receiving tamuxifen fur advanced disease and in ‘i’
`at‘ 10 women who had reccivcd tamoxifen as adiuvant
`thtmgty. There appcared to be no associaticzrn bctwecn
`duratinn of treatmcm with tamoxifen and subsequent
`response to ICI 139380. No serious drug~re1at::d adverse
`events occurred; minur adverse events were reported by 2
`patients-wtransieznt bimd—staiz1ed vaginal discharge and 3
`subicctive fceiing of living in a “dream like state?’ {similar
`to» that she had whilst taidng mmmcifenj in one: patient,
`and aitaration of body odour (noticed by her husband for
`com: mimth), passibly associated with increased hair
`greasiness, in the other. ’I‘hc;xe was no alteration in that
`frequency; of nigh: swans or hm: flushes;
`if already
`present, and none was initiated. None of the patients
`reported vaginal drynasa or alterad libido an dime:
`quastioning at each ms:-patient attendance. ICI 18380
`appeared well tolerated at the site of iniecticm despite the
`relatively large 5 ml. volume administered, with cant? 3
`patients dnveiaping bruising or arythema on one occasian
`cash. There were no clinically significant changes in full
`blcoud count <3: unexpected changes in bicachemical tests.
`Guy study shows that patients with advanced breast
`cancer respand to a specific antioestxogen after failure of
`treatment with a partial—agonist antioestrogen. There
`appeared m be no mess resistance Immeen ICI 182?80
`and taxnaxifen in 69% of patients, whereas studies where
`tamoxifen—resistan1: patients were treated with another
`triphenyicthykne antiocsurcgen, toremifizzm, hair: reported
`much higher rates of cross resistance.’ The median
`duraticm of réspcmse to ICI 182780 has not yet been
`reached, but is already longer than we might expect imm
`other second-line, mdocrin: therapies such :35 megeazmul
`acttatc.
`
`to act exclusively as an
`is thcmght
`182’é‘S£)
`ICI
`antioastrcgczn via the oestrugen rzccptcsrx Thus response
`to treatment with ICI 182780 suggests that oestrogen
`receptors remain functicmal and that tamoxifen therapy
`fails because cancer
`regrowth is pmduced
`by an
`cseswrogenic
`stimuius. The cancer may acquire the
`capacity m respcmd to the partial agonist activity sf
`tamoxifexs.
`andfm:
`its varinus metabolites‘ This
`is
`supported by the ability cf tamcsxifen tcze atimidate
`pm-liferatien of primary human breast cancer mils grmxrn
`in-vitro,‘ and also by the cxccasicmal clinical findings af
`patients whose
`canccrs
`rcapand to withdmwal of
`tamaxifm at the time of treatment failure.‘ Altarxzatively,
`changes in the inuaceliular rsandiing of mmoxifen may
`reduce its abiifity ta btock oestr-agen reccptars and allow
`stimulatitm :31" cancer growth by andcagennus mastrogens.
`This might occur as a result of cancer «sails acquiring the
`ability;
`tn
`inactivate
`tamaxifen
`by
`intracellular
`degradatiun, intraceiiular seqnesvtatian to prmeins mixer
`than oeurogen rec-aptarsg or by increased drug exclusion
`from the c:-2:1.“ Our data do mm: distinguish between these
`resistance mechanisms.
`
`Freiiminary data (net shown) from this study Sh-UW an
`initial rise in serum genadcetmpin during the first fiuee
`nmnths of Imatxnent with ICI 182780 iprebablgs as a
`result of cessation of tamcxxifen therapy} but no further
`changes thereafter. In View cf thc lack af initiation or
`
`alteration of hot flushes and hm: sweats men in the study,
`thaw: data suggest that, as was predicted fmm animal
`studies,‘
`ICI 182780 may be withaut effect on the
`hypothalamus and pituitary gland. ICE E82380 may also
`be peripherally selective with respect to the liver since no
`significant efihezts on se2c~horrnone—hinding gioknxlin and
`fipid have been seen in the present study. In primates and
`in shm't~term studies in w0men,‘° ICI 182?80 inhibited
`endcmetrial prcaliferaticm at simiiar sarum conszczatraticms
`to those seen in this study. Ifa similar inhibimry efibct csf
`ICI 182780 were shcswn in longer-«term studies,
`this
`wauld be a furthez therapeutic advantage of the specific
`antinestcogeng since tamoxifen is known to be associated
`with pmliferatim and endometrial cancer.‘
`Our study suggests that ICE 182730 may impmve the
`rate and duration of response: when used as a firm:-Kine
`tmatmtznt for admnccd breast cancer, zinc:
`ix has nan
`dcmanstrable agcrnist activity. Furahemxoreg the back Of
`toxicity or effect on serum iipids identify ICI 182780 as a
`candidate agent with which to investigate the patential
`benefits of specific antic-estrogens in 111: adjuvant setting.
`
`We thank Sisters 31.1352 £€.i¢ma:a:x and Nidd Scat! for scrvicu in the clinical
`study: Mr E Home, Mr} M T Hmvat, and Mr R J Williams fut mferxing
`patienm; jtean Millexfrar help with preparing the manuacriptg and Zeaxecu
`Pharrmweuticals for financial suppart.
`
`Refaranma
`1 Wakafing ELE, Dukes M, Bowler I. A perm: specific pure antiuestrogen
`with ciiniml potmfial. Cmmzrflss IQQI; S1: 336-‘Er'-73.
`2 Fawe.-1} SE, Whiu R, I-‘inure S, fiydcnham M, 13234: M, ?a1-ker MG.
`Inhihitit:-n of aestvagm receptor-DNA birxcting by the “pure”
`mtmesm:-gen IE1 16-{.384 appears to be mediated’ by immimd recepm:
`dimegizatiun. Rm Maxi Assad Sci USA IENO; 87: 6883-8?.
`3 Barry M, Menage: D, Chambcn P. Rn}: ofxhc two activating clomains
`on the cmstrogen rwapmt in the_ce£}»type and pmmoter-context
`dependent agonist activity of me; anfiwestxagen 4-hyclrox3:tammcifen.
`.E;’v£BO5‘ 1991}; *5: 331148.
`4 Hams}! A, Mndntash Is forms M; Redfanti I, Wagstaiifj, Seiiwoo-ti RA‘
`‘The defixtirxian of the ‘Ne <:!:1ange* categury in patients mtmea with
`andm.-tine therapy and ch:-mnzntherap-y far advanczé ztarcitmmn tn” the
`breast. Em} Cancer {Rim Gncai 1088; 24: 156?-3'2.
`5 Vega}: CL, fihemazto I. Schnnfeldcr I, Gama Rh, Green MR.
`Multimsmer phase II cfiicacy trial of mremificnc in ramaxffen-r:£tacxm'y
`patiernts mt}: advanced breast cancer. 3? min Om»! 19533; 11: 34540‘
`:3 DcFri=n-:1 1}}, Anderson I1, Bali}, Wflh DP‘, Wes: C-ML, iiuwcii A.
`Efiects err 4-hydroxytamcssciffln and 2 pure: amiaestrcsgen {ICK Is:-."?80:
`am the clanogeuix gmwzix cad’ Imman breast cantet me.-1}’; in vitxu.
`Sr} Ccmrei-'i9'E1‘é; 7!}: 2Me«-1}.
`'7 1-Immalla, Do-dwell 1313 Anderson E-I, Redford I. Response after
`w‘rfl1x$m‘wai o‘?mmmtEfe:n and pmgezsmgczns in advanced! breast cane;-.1:-,
`firm (I-'nwI1993;3: 61}-13.
`8 Gshomt CK, Gomnaée E, mm: DC, at :1. Acquired tameidfen
`resistance: csanttlation with reéuucd brcaat turner Ecucls at“ tamcxifcn
`and isumasnmrion of tx‘anas~«¥——hydr0:rytamou:ifen.
`j‘N::rf Gama [mt 1991383: 14"?‘}‘-32.
`9 Pavlik E}, Ndsun K4 Srinivasan 3, ct ai. Rxsiszance as mmoxifm with
`persisting sensitivity as asuogen: possible mediation by exc-nssiva
`antiocstmgen binding site acfivity. Cancer Re: P992; S2: 410642.
`£0 'I'homas E}, ‘$53153-tz FL, 'I'hmnas NM, Buwrsetr M. The eficzs af ICT
`XBEVSD, 2 pure: mticoctstmgvn, on the 119parha1amic-pimi:ary«g+::n3da1-
`axis and an cndmmctrial proiifisratiun in ptezncnx:-pausal vmmen.
`Hm-n Rapwd 1994-; 9; (in press}.
`
`
`can napartmsnt of Medina} Oncology, University of Manchester,
`Christie H-nspltai, Mancmvstm M20 EEK, UK (A Hawaii veep};
`Dapactment ef Surgary. lfntvarsity Hospital at‘ Satrth Nlsnchestzer.
`Manchester. UK {[3 1 Demand mes}; Department or surgery,
`city Haspitat. Na1fingham{Pn:>fR W Biaamey mes,
`3 F Robertsnn raw}; and zmeca Pnsmaamamlcais, Nlacalasfieict,
`Gheshire, UK {P walmn Phil‘)
`
`Cunaapondeuce ta: fir afinthmny Hm-‘er!
`
`|nnoPharma Exhibit 10560002
`
`