1% WW1“
`
`BS
`
`Referequ
`l Bax-in LC}: We?” 33}, lawn 3M! Rum“: wwxufisaim of Wad:
`B virus, (Jam? 2989; i: 881%};
`2 13mins: RH, Samplimt R, Gamay R, Taber E, Kmilm F;
`Nathanwu N. Hcpatitis B Wewcn in hauaetmids «:3?Ms carrim an!
`htputitis B surface mtigm: fmm associated wifix pmmimmc txf
`infecting Am} Win! {$823 111$: 199%] I.
`3 Franks A, 3:731:23, Km: MA, et a}. Emmi: B virus maxim mung
`chfldrm harm is the Unites $34-23 1:: 3mm: Asian rcfizgets. N Eng!
`3 m 1933; 313: 3331-435,
`«1 flied: a, Han-ism £3133;me 31%, SW FE. EWWWme 13¢,
`Ema Me Tmmissian affifipan‘fis 3 firm; fmm magma Asian
`mm us their families rim 3' 9383‘: Hm 1938; 7a: 2649‘
`5 van mixing-fun Thng De Wine—fin Dex Scbnmfi, van hum AM,
`PJM, Yap 3H. Hepatitis B in an institution in: the manual}:
`mega, fiat} was was; £33: 629%”.
`f! myuhi I. Kuhiwagi E; Human H, Kaiigmma W. {Manna H.
`32$: 49 $3:
`Hepmifi; 38 virusMW in amateur Mafia. Amj'mmim' 1983‘;
`
`‘3 Van 33mm: P, Murmurs 3L ficpmifis 13 in mmml mam? hmpimls.
`{sums 193?;E13ML
`S Mufhilfim 3C, Cellini If; Spisland i. Hepatitis B virus taming:
`transmitted {mm retarded children me their families mm; brieflmnm
`mum j’ ,Fkéfasr Gamma? N89 198‘}; 3: £941.
`9 Jeniwn 5n, Lemm am, am: w, mme 1E. anutam anatysis
`af hepatifia B virus mm En mlfm: and 59mm ufWally infecteli
`humustml mm. ,3 53%: Dis 398?; 15G: 29%3917.
`m Emcémfiauo “m a: Medina M, Slam-meg 3,, Vailcdar MI), 3mm“ ER. Fm
`inwmfirmai mka at hmfifis B Mamet m a human 53% tax-tier.
`3? may Bi: 1982; is“: fifizwfié.
`
`
`Departh a! Enldcmlmm ind Community Wm. “disarray
`at mm. mm: Armament. Salaam (? Van namme m.
`M Gramm use». M3 Van De! Mmera. A mum he}: and mama
`Hartman:WW.W {R Mack: 9m}
`MW in: Dr Pietra Van Damme
`
`Respansa ta 3 spasms antlmtmgen
`(EC! 3.32380} in tamoxflemaslstam
`breast canes:
`
`(“gammy Hawefl, Dam? Demand. Jam: fishermen,
`Hagar mama}: Peter Waiter:
`
`
`We Heater; 19 patients with advanced braast cancer
`resistant in tamoxifan with a new specific antiaestmgan
`{H31 182?80) which.
`in animat studies, has rm sgunist
`activity. 13 {89%} amiems mspmdad H had 9mm
`reams and 6
`shnwad nu ahanga} w mamniy
`émramuscum: injections of mi 182110 after grograsssm on
`tamoxifata.
`fur a median duration cf 1S manths with
`minimum side effects. Fretiminary evidence suggests that
`the agent
`is witmm effmts or:
`the
`fiver or
`the
`hypnthalmis—situitary axis‘
`1C1 182?8£} appaam m be a
`premiséng new agent fer treatment of advanced and earfy
`breast gamer.
`
`Lancet 1&9?» 345: 29-«30
`
`i.
`
`Mfimug}: hat? of all parking wim advanced breast cancer
`ham cantata which either regress or remain stabie what:
`mated with maxifm; minean eventually bammc
`resistant aft“ a median dnmtion and” tanfissien at” fifteen
`months. Alfimugh an antaganist with respect
`to the
`canczr, tamaxifm is an wattagenic aganist with respw to
`bone, fiver, and mfiomemum. One came of resistance
`may be the cancer mating w tamaxifan as an aguniat (31'
`that mmmifm is, in acme way, rendered unavailable to
`aestmgen mepmrs so that andagwoua oeatradinl is able:
`as rastimukata cancer gmwth. Tn test this hypathesim we
`mated patients with cancers resistant to tammifen with
`an wfimzmgeu
`(1C!
`1.822%:
`’Iuwifléfififiyfi
`penmfluampemyimlfimimnnyfi oestra~ 1 .3, §,{ 1 fl)~triene-
`3,1?B~diul) much, in animal studiukt’sJ has bun Shawn to
`have no aganist 3mm:
`ICI 182180 is a amidst] anfimatmgan with an
`Eikfimfiphinyl sida chain in the ?u pasitian‘ There is
`evidence that the side chain prevents ciimarisatian of mm
`malemks
`cf
`the ammgm recepm: which
`is
`a
`prerequisite
`far
`gem: manscriptmn.‘
`In
`contrast;
`tamoxifen, 11kt: Uwcagena, causes tempts: dimerisatian
`ind partly initiates gen: transcription; which is the basis
`of? its pawn! agnnist activity?
`
`I? mmumpwsai pafitnts has than 81 years; aid with
`madman-sec}, hismiogicafiy wrified, breast was: resistant
`to:
`maxifm m mama with {C} 18278&. The 1.»de Was
`31::er by the ethics mmmimxa a? each clinim} centre.
`Paticam were included if they had been 1:3th mm tammcifen as
`an adiuvam m surgery fut mare than Ewan} yam; anti than mispscd
`or mam} with tamoxifen far adamant} disease. hati a mmpkem
`a: partial ramming, a: rm change far at least six Ingmar and
`mksequmfly prefix-eased. Patients ware :xfiufifli
`if they had
`serious intermittent: dism, a WEE} perfumes status at
`gmawr than 2 and a Iift capfimcy 13f was max} 3 months, arr had
`received mixer themanhempy. Gm: patient had adjmn: merapy
`fut tardy 9 months mad pmgtessed, and was thus a prawns}!
`viaiafim but
`is influiiad in the analysis. She had pray-nuke
`éiswse when treated with 3C1 13mm. Themet sites elf
`disuse iii the aims: af aims: an mafia was: bmstfchwt wall
`{7}, lymph mam {1), 2mm: {9), and lungfplema {2}. my 55mg
`infammd magma;
`a}! patients underwent
`inseam staging
`inwstigaziws befom starting wézimcm with {(31 232?83;
`including méiogmghs, liver mtramumi m campmed mmngmph
`was: (at! awry {-2 manthn), and immp: has): man {every 6
`mmthsL ICE ISSYSfl was admmisxmd as a Earns-acting
`Emulatim in a
`stator wflwbased which by math}?
`inmmumkr infectim into a bunack. Far aafsz? appraiaah than
`first 4 patients renewed mcnlating asses nf ICI 132730} starting
`with we mg the first 3'11an and harassing m 25%} mg fwm
`mum}: 2 unwarés, £33}ng ccnfirmntinn 0f lack at“ lanai m
`sysmafic amg await? a: the: :30 mg dent. Fatima 549 received
`2512} mgfimumh {mm the nausea. man-um}: with ICI 332w: was
`contingent mm} cancer progressing. mini. Patients wen mm
`every 3w? days during Ihn first mum w monim: Exam! and
`systemic:
`thug Inlemhfiity and tr: can“: blood samme fur
`pharmamkinafic studies. ‘I‘hemafitr, 17an Was dent mi:an m
`evaluatt saspanse and w mnitm lacs; and We chug
`tniembflin'. Biased samples wm: taken hefme mmem and at
`mmwy Emma mmafier far measurement of full weed mum;
`binchrmimry, serum hmmoncs, and lipidm Cagney mmnse was
`cvsiuamd according to Him: Erimriii. “Ii: quafifir far the “m:
`change” catcgm'y, 2mm:- gawk had we nabiiise for mutt: than
`six mam-m}
`
`Rum in
`mm (in Man {muslin}
`It}: 3321‘”
`
`Partial
`7 [3?)
`MFR 19;. mm: a), fid-gAWL fl“ {PER}
`12mm}, 5 {1293‘ 3mm
`234mm; 18+{MdL 18+{A‘a’1}. ifirémfi 4&5.
`1&1-{A23}. 8- WG 311::
`AH magma magma“ In <38 weeks. 1?:me
`Ifeairmnt mu: tmmxifm M18. A455. NC ‘a‘,
`PR 8. 9. ESL?
`
`Lemar: m brackefs Indicate rename m lemme-n «Mn mm the Manama (smash
`(magma: rmémm mam mange. Pflzprngresswe tam-age} nr eigaven as an
`mum: mast tA}. flumhws t1 brackets Wigwam durath af mama: mm
`lamina.
`
`$3 {32}
`
`a {3:1}
`
`H»: mange
`
`ngwssm
`
`Tabie: Rum m amt durations vi cm in tct 1.32?“
`
`
`InnoPharma Exhibit 1056.0001
`
`

`

`THE WEEK
`
`
`
`19 patients wen: evaluable (table). 13 ((39%)
`A.“
`responded "£0 taxman: for a median. duratian of man:
`than 18 menths.
`*9 are still Impending and caminuing
`treatmmt with ICI 182730 after 16433 manths. Shea of
`response were 501$: tissue {4): bane {7), and lung {3).
`Respanses were: seen in 6 of 9 wmmen who had mag-teased
`whilst receiving tamfixifen fur advanced disease and in '3'
`0f 10 women who had recciwd tamoxifen as adiuvam
`themyy. There appeared to be no associaticm between
`durafinn of treamcm with tamoxifen and subsequent
`response to ICI 183383. No serious drugqelated adverse
`events occurred; minur adverse events were reported by 2
`patients-outransiem bleed—stained vaginal discharge and a
`wbiecti‘ve feeiing of living in a “dream like 5mm” {similar
`in» that she had whflast taking tamam'fen) in one: patient}
`and alteration of body odour (nautical by her husband for
`an: manth), possibly associated with increased hair
`greasiness, in the other. ’I‘hcxe was me alteratian in 1h:
`fiequency of nigh! swam; or hm flushea;
`if alrcady
`present, and none was initiated. None of the patients
`reported vaginal dryncsa or altered libido an direct
`quastionmg at each {mt-patient attendance. ICI 182?80
`appeared we}! tolerated a: the site of iniectian despite the
`relatively large 5 mL volume administered, with £33113“ 3
`patients deveiapimg bruising or arythema on one occasien
`
`each. There were: no clinically sigfificant changes in full
`Maud count <3: unexpected changes: in bicachemical tests.
`Guy study shows that patients with advanced breast
`cancer remand to a specific antioestxogen after failure. of
`mammt with a partial—330mm antiuestrogen. There
`appeared to be no mess resistance Between 101 1821*83
`and tamuxifan in 69% of patients, whereas Studias where
`tamoxifm—resismm: patients ware treated mm another
`triphmylcthykne anfiozaucgan, toremifina, haw reported
`much higher rates of cross resistance.’ The median
`duraticm of rcspcmse to ICI 182780 has not yet been
`reached, but is already lnnger than we might expect imm
`other semnd-linc antics-crime: therapies such as megem‘al
`amtatc.
`
`to act exclusively as an
`ICE 182’330 is thanght
`anfiawsmgm via the (338ng reccpwr.’ Thus response:
`to treatment with Hill 182%?) suggests that oestrogen
`recepwrs remain functianal and that tamoxifen therapy
`fails because cancer
`regrowth is pmduced
`by an
`aeszmgenic stimuius. The cancer may acquire the
`capacity :0 respand to the partial agonist activity 3f
`tamofifen andx‘er
`its. varinus metabolites. This
`is
`suppartad by the ability 0f tamaxifen m atimmat:
`pmliferatien of primary human brgast cancer calls grmxrn
`int-vim" and also by the accasicmal clinical findings 13f
`patients whose
`canccrs mapand to withdrawal of
`tammiifan at the time of treatment failure.‘ Alternatively,
`changag in the inmcelmar handiing of mmoxifan may
`raduca its 332mm: m bios}: oestmgan rempmrs and allow
`stimulaticn m“ cans-3r gmwth by mdagennus acstmgena.
`This. might occur as a result of cancer tails acquiring the
`ability; m inactivate
`tamexifan
`by
`intracellular
`degradatian, intraceiiular sequestratian m pmmins anther
`than oestrogen recaptars. at by increased drug exclusion
`13mm th»: can.“ Our data do mm: distinguish between flame
`resistance mechanisms.
`
`Preiimmary data (net shown) from this :‘study Shaw an
`irfitjal rise in serum ganadcetmpin during the first three
`months 01? Imamem with ICI 182?80 {pmbablgz as a
`new}: of cessation of tammtifen therapy} but no further
`changes thereafter. In View {3f the lad»: af initiation {31'
`
`shawl-inn of hot flushes and hm: sweats men in the study,
`Wt: data suggest that, as was predicted from animal
`studies;
`ICI 182780 may be without effect on the
`hypothalamus and pituitary gland. 1C1 232mg may also
`be peripherally selective with raspezzt to the liver since :10
`significant efi‘ects an semhormone-hinding giohflin and
`iipid havé been seen in the 9mm: study. In primates and
`in shon~mm studies in wamen,” ICI 182’?80 inhibited
`endamen‘ial pmliferation at simiia: serum concmtrafians
`to 11141156 scan in this study. Ifa similar inhibimry efi'ect (3f
`ICI 182780 were sham in longer-term studies,
`this
`wauld be a fun}er therapeutic advantage. of The figfidfic
`mdnesmogen. since mmme is known to be associated
`with pmfiferatim and endometrial cancer.‘
`Our study suggests that ICI 182786 may impmve the
`rate and duration 0f response when used as a first-tine
`tmatmmt far admnccd breast cancczr, sine: ix ham m:
`dmnanstrable agnnist activity. Furtherinorej the back 0f
`toxicity 0: efi'ccr an serum iipids identify ICI 182780 as a
`candidate agent with which to investigate the patential
`benefits of specific antiuestmgens in flit adjuvant setting.
`
`We thank Sisters 3x135: Kiam and Nicki Scat: :fcr sank“ in the clinical
`study; Mr E Ewe, Mr} M T Ewan and Mr R I Williams for mferxing
`pafianm; 1mm Millexftar help with preparing the manuscript; and Emma
`Phamamficals for financial suppazt.
`
`
`Bahamas
`1 Wanting M, Dukes M, Hamlet 3. A pom}! specific pm mfimum
`with ciiniml potmfial. W353 199}; 51: 3863—73.
`3 Fawcl} EB, White R, Ham 5, Sydcnham M, Rage M, E’arker MG.
`Inhihitim of aestmgm mmpmeNA binding by the “pure”
`mtimestmgen 1131 164.38% 31mm to be mediates: by immimi receme
`dimegizafiun. Pm: Max? Ami Sm‘ UM mg}; 87: 15883—331
`3 Em M, Menage:— D, Chamber) P. Rn}: ofIt: two activating clomaim
`on the nmmgen mm: in thecefiqype and pmmotmomcx:
`dependent agonist activity of me; anfimtmgm éwhydmmammdfen.
`.EMBO} 1990; *5: 33114.8.
`4 Hamil A, Madmash I: fonts M. Redfami I, Wagsmfij, Seflwwd RA.
`The defim‘m'san of the ‘Ne changfi categury in patients mica with
`endgame therapy and chi-mum}: 'Fmr advanczé mminnma m” the
`breem. Em} (3mm can Grew? was; 24: ISM—«‘32.
`5 “33:1 CI... filwmazw I. Schnnfeldcr I, Gams 12.32, Green MR.
`Multimmer phase II efficacy trial of mmmificnc in mmax’rfm—mfitanery
`patiemcs 1am}: advanced break: cancer. 33min 022ml 19533; II: 34540.
`:3 DcFrimd 1}}, Ande 13., Bali}, With 33?, West C-ML, iich A.
`Efi'ects a1“ 4~hyémxytammifm and a pure: mfiaestmgm {ICK mama;
`an the danogeuix Wfix a? human breast came: 5:1}: in vim
`3r} Games-199%; 7!}: 2%]:.
`7 Hamel} A, Dodwell {313 Anderson R, Redford I. Response nftc:
`w‘rfluirwai fimmmifan and pmgezsmsms in mm breast tam”.
`3m: (311601199gg3: 61F”.
`A
`8 Osbm‘ne CK, Comméc. E, mm DC, at 3}. Acquired tamexifen
`teammate: canalatjon with refined mam mar Ewcfls at“ tmcxifcn
`and isumasnmrim cf ma~4-hydmxytammdfem
`jNaztf Gamer [mi 1991; 83: 14‘??—32.
`9 Patle E}, Nazism: K.fi Srinivasan 3; c1: 31. Fasiswnce m tamoxifw with
`persisting sensitivity m amen: possihlc mcifiation by excessive
`anfiowmgen binding site activity. Cam-er Re: NQE; SI: 410642.
`L0 “sums E}, Wuhan FL Thnmas NM, Dmetr M The effects af ICT
`XEE’FSQ1 a pure: mtiacstmgen, on the hwadmlamieupinfixamgunxdai-
`axis and an cndflmetrial mnliferafim in gremcmpausal wnmen.
`Hm W 1994; 9; (is: mess}.
`
`
`BRIG Hummus»! of Medina} Oncology, Unwusm a! Manama
`Christie Human Mmchmtm H20 931:, UK {A Hawaii mm};
`Daganment 6f Samar}. unWarsm Rumba! a! Seat}! “gamut.
`Manchester. UK {[3 J mama mes}; 53mm: of Surgery,
`city Naspitat. Naflingham {fme R W manna-y mes,
`3 F Robertsnn PRES}; and lama Pmmmlcais, Macgmsfiam,
`emails, UK {P Walter: Pun)
`
`Garwpondeme ta: fir Mthmy Haw-EH
`
`InnoPharma Exhibit 1056.0002
`
`