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`CSL EXHIBIT 1072
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`VOL. 31%?
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`NHL ‘12
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`ESTABLESHEI) HQ 181?.
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`CSL EXHIBIT 1072
`CSL v. Shire
`
`Page 1 of 11
`
`

`

`The authors“ fizii names, améaméc de»
`gmes, and affifiafiarm are Emmi
`in the:
`Appenéix. fiddress reprint requiem: w
`Di, Longhqu at 8am; Heahh NHS Trust.
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`{Si ZES‘
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`Optima)! Management a? Efimvfismmg ism
`gioede'ma with Lm‘nVaiume Summaries»
`mm CMuhibitor Replacemer Thgmpy
`{CQMPACU énvestigatcm $3 pmvéded in
`the? Suppfiememary Append§x, Manama:
`at Niijh‘mrg‘
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`{7:5, Langhurst, Cicmdi, Craig, 3nd} Zuraw
`mmfibmed equaiiy in this amide.
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`if}?R}if?"5' MiaL 3%ii:“ifE {I}
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`3 [
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`E
`
`Preventian Qf Hereditary Angieedema
`Attacks with a Snbmtanems €31
`Inhibitor
`
`M;
`£723 mm}
`H. Langhurgt, Mfljicmdi;103:5;iii, 53min
`£3“, mm; fianfieiyjfi Eai's‘mtemd. Afidm‘sma, W3? imam H. $355485;
`,9
`{23%. Katéfiarig,
`fgutsawaragj.jamm? M,
`Mi: Marmng Hr:me
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`9.}; Keith, 3, Kivéty, 5‘ Her; {‘13. Mary. ML. 83%;}; R. Naman, LB. Schwa
`
`
`T, {Zaiimieyf}, W. Mag! 5‘ Cs'isgam Mi Hernandez, E. fitsggam, M. “t”
`Riiciziég
`i7. éiréhc‘ikovzég M. (Swarm,
`Rfihmgm A: {fianerg‘g
`Qawer,
`
`i3, Eenmwéfiermedyj. EdQEmm‘z, H. frauem "ems? Laway "21 fv’xacirmig.
`ii}. [fiawaakan i. Psagm, m‘
`Zszrawf {m the (TQM PACT Erwegiigaioé‘sfi
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`A BS‘I‘RACT
`
`fiafififififiuflw
`
`Hereditary angiwdema is a ciigabling, gatentiafly {11m} cmditian causec‘i by defieiemcy
`(type I) {31‘ ciysfimction (type II} ofthe (3: inhibitor preterit), In :2 gahase 2 trim, the 11st: (1%”
`CSL83CI, :3 nanofiiter‘eé (33. inhibitor preparation that is suimbie. for subcutanemit; injw
`dim, rezauited Er; fimctienaé Ieveis of {31 inhibimr acfivity that wmfid be: sxpecteé to
`pmvide fif‘fective pmphylzaxisé {3F attacks;
`MEflfi-flfifi
`
`firogyecttive, muificmtém rammmizeé, dozibie’mmd,
`2212 mmmatima},
`We: cgnduciefi
`placebwcmnfirofieé, ééagmangingg phage 3 mg} m m1!me the efficacy 322:5 safety of
`selfiaziminisrared suhcxzmnmus (3311830 in patients. with {we I
`:1)? type 11 hamdimry
`angiflefisma wha had had Ebux‘ m mare attacks in mnsczcmiva 3411031ch pariad within
`3 mnmhs bef'me screening We mum?»me assigned the patients to we Gf'fimr treatment:
`sequences in :: crossover degigfi, each irwaiving m0 léwweek treatment parinds: either
`«am EU 01' 6C) EU 01” (353L830 per kilogram of 130d}? weight twice weekiy feimwed by pk!»
`cebcg er vice versa. ’i‘he pri; nary cffimcy {and point was {hie number at" armcka sfwzmgiax
`edéxm. Secondary efficacy and points wage the prapmtion of gmimsts wim $1231 a my
`gponse {$6050 reéuctim is} the‘ mmber of attacks with ($312239
`compareci wig}:
`Mamba} am} the nambsr 91?” Emma: that rescue nwdicatimz wag aged.
`i? 25 i} {3'35
`
`Of'thc. 9i) paaients who mderwem: madamizatian, 3’9 mmpieted aha trial Beth dimes nf‘
`(331330, as campamd with piawbo, reduced the mire ofatmcks afllez'cdimry angimxiéma
`(mean differencs with 40113, WEAR attzmks gar awash; 95% canfidéznce imam} [(3H,
`m «51.46; anti {1163i} differencg with {313 It: “3.51 attach; per menu); 95% CI, «4.21 {0 «2,831;
`mm: {23: Email cmnparigms'j. Response rates; were 76.3% {€}S% CI, 62 £0 37) in the 40413
`gran}; ami 90% {95% CEy “a”? in $6) if} d a? (3041? gmuga. The mad {a}: :‘fisme meciémtien W352?
`refitmezi {mm 5.55 uses pfif mmth in the piaceba gmup m 1.13 uses gag 11mm}: ii“; the
`4Q¢IU grow anti fmm
`$1353; in me placebc gmup m (3.32 um; per mend; in the (384G
`gmup. Adverse emits {1:19:21 mmmmfly miié am} {ransaéent meal site magmas} {3:111:13er
`in simfiar proportians; of'parienrs who received C-SLSBO ami mess: wim receivad placeba.
`mmzmsxmm
`
`In patiems with hereéimry angioedema, the pmphylamiz: mm (3??:1 Submtzzmmss Cl inhibitor
`twfire weekiy significantly rézducad the fiequeucy ofacute atmckg. (13115:in by (ISL Enabling;
`COMPMZT EudmC’f number, 2013—00G9‘16—10, Md Cliniczii’frizahagm' number, NCTQXWMSM
`
`N mm; Mist» 3%;12 Mummies;
`
`Mfd‘ifj-i 23‘ 201?
`
`113.1
`
`Page 2 ofll
`
`Page 2 of 11
`
`

`

`1“? iii?
`
`l5 2"»? if: in? 1‘4 i}
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`HE} R N :"x
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`1?? M i? D l (J; S
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`.swmcmmama i3 A 1315»
`@"smfimmm'
`milling mail gatezitissliy fatal conditimi
`characterizeci by itscurmm episocles Oi“
`i
`_
`swelling Witlmut urticaria 0r prurims. The cow
`dizion is flawed by ciei‘iciémcy (Kym: i) (31' dygfunw
`rim} (type ll} of the Cl inhibitm pmwin} Pm
`tients have inaufficient €33
`inhibitor functiim ta
`
`tilleS 0i? hereditary afigieedema in, pzitients with
`fiequem SitE'Z-Ifllifi.
`
`TRhRL QVERSIQHT
`
`Tim trial was jointly designed by the ssponfior
`(CS); Behring) and the smering committee. This
`g‘zmmml, availabk: with the Fail text of this anile
`zit Nlilifi‘ixirg, wag zippmvai by rim 313pr0§¥fl€lt€
`regulatory mitlwritiefi and {it‘lilfis mmmitmes, (3r
`instimtional review lmarcls. All the patienta prov
`videci written iziformeé tangent. An indegendem
`43am: 323d saf‘esy mimimrlng beard regularly mm—
`itored trial 33 fat}? 23ml pmvided recummenciations
`t0 the SPOHSGE on szifi?ty—releiwci trial conduct.
`The investigators at each participating mums:
`mfiactm’i the: (lam, which were amaiyzecl by the
`apensm Wild}: input fmm the meeting commitme.
`The mambers {film Steering mmmitme hail ac~
`ems to {he data am? much f0: ihi’: zismmcy ané
`mmglfitwma of film dam and imaiys’es anti fair
`the fizieiizy 05‘ the: trial m the pmmaoi. The
`manuscript was Clmfl’é‘d by the first autimr and
`revigiztfi iiy all that autimzs. Medicai writing sisal»
`mace, which was paid fan: by“ QSL gaining, writ“;
`pmvidfii‘l by Apalzbefiam.
`
`mnmm
`
`prevent braciykinin production by the contact 53's“
`mmz leading to episodes {if incrmfiszfi capillary
`hyperpermealiiiicy and, swelling. ’i‘lizage epism‘iea
`manifest clinically as angioeciema miraclst
`Low levels of C1 inhibitor protein antigan 0f
`low functizmal levels iii” C1 inhibiz‘m activity, as:
`well as law levels; ("IfCCllTiplm’llfth (34; are (1:21;?
`mastic for hereditary smgimrdema, and baseline
`C1 inhibitor function has been reporleci {0 cap
`mlate with disease severityf According m clini»
`cal absmmiims, a Sllfiiéiii‘m‘d tiiriasimlci
`lava} (if
`agpmximziteiy 49% functionai Gil. inhibimr actiib
`ity has brim repaired to wafer certain protectian
`against weaken: atmekgfi‘i
`Regular immwnmm Cl iiiliibimr repiawmmt
`is effective at reducing the frequemy and sever
`ity {if attacks and has: an acmpmbiié Safety and
`fiiée—efféct pmfiie. A daublevblind, glaaebswcanw
`swiiea‘l, armmver {trial iiiVGlViilg 22 patients with
`frequent attacks- slmwm sag/u reciucrimi in the
`fi’fiquency 321:3 mverity Gimmicks with the me of
`an intraveimui; C1 izshibitm at a {lease a? 1900 W
`
`MARCH 23,2131?
`
`twice weekin ivlowewn iiecauae (affix: mammal
`difficulties (3?? regular WHOBS accasa risks with
`film use of indwelling ventral: cathflem, zinci 9:»
`flan: cmmidm‘atifing,“ Kim fievalapxmm at" a (:1
`inhiifimr cmcantrate Suitabia fm regular swim»
`animus admifiistmtimi is ()finmmst.
`
`that adniililstration
`A 13119133: 2 trial 8lIQW€5£l
`alt” {33L83f} {(351 Behring}, a lewwalume, human
`plasmewleriwdj pagteurizafia xiamf’limmd (1:1 iii»
`liilzimr yrepamtian that ii: Suitabia far gubcumw
`nevus injemriam i'ésulteci in a dosafldepenclent 22ml
`cmgmm iz‘mrmge in tmugh 932531313 lamb {if
`filiitt‘timml i3: inhibimr amivizy almva @i)%,‘-% a
`biacliemicai finding; impacted m pz‘wide effiaw
`hive gimpliylaxis of attacks.
`W5: dascriiye this remits (33“ Elm Clinical Study
`5:): Optimal Managemmi of Previewing Augia»
`(361631333 with Lmvk’oiuma Subcummmis;fikinlxilr
`imr Replawmem: Therapy {COMMCT}, a phage 3
`trial testizig the. liypmlmsiii that: 3 twice—wefi<ly
`auhcutzmeaus .iuiestian Qi'C3L833, as; campared
`with placebo, cuulé Nance {he fi‘equency Gigi?
`
`‘12 yeam {lf ages Q2,” 9165::
`Eligible gamma Wé‘i'fii
`and haul a clinical axial central what-awry iiisignmw
`sis af‘tyge i {3? ii imredimry angiaaficma (funcw
`{Emmi {Eli iriliibimr aétivity {if «353% anfi {343 2211??
`gen kiwi lwlmv aha nm'mal lewi). All (he patiauts
`had hail limr m,“ film‘s? attackg requiring iiiime~
`diam treatment (if mczciical attention or causing
`cliiiimlly gigiiificant functianal impairment 9%:
`a 2*fiiflfifil perimfl withm 3 maiztiii; Mitre: $€r€EZ€lv
`ing, as ciacumenmfi in the patient‘s. medial few
`orils. Fall, inciiisimi and Exclusiml cfiteriii am pm—
`izided in Table 31 in this Supplmlenmry appgiizlix,
`avaziiéiifié a? Militarg.
`Daring the amt ilk: graham}, was ammuiesii m
`infilde gramme; wim were raceziving Oral/mali—
`castimis fin? praghyizixig 0f angiaeciéma attackg,
`if they hail gamma, 2 ambie dams £332“ 3 mamas
`bi:me acieening and {31223111516 m camimm
`{limitgimut the: axial. Ifligientg Wm had mammal
`an intravenous {31 iizl’iibimr far mating pragili?
`laxis within ‘3 manths befmré screenéi‘ig were“:
`{'ZXCllléififCl.
`
`N emu; max) gyflzm
`
`Page 3 of 11
`
`

`

`PREVENTION OF H liRl‘lfil‘l’r’l ELY ANGHM‘ZUHMS“ ATTACKS
`
`TRlAL DESK???)
`
`COMPACT was an lnmmatimml, pmspective,
`malticenmz’, razlclmnizesfi, doublewblilldl planebcnw
`mntmlled, {lagemanging trial. AM? ficreming‘
`eligibla patiems animal a mark; Wriod 0f 12;) m
`8 weeks. All {the patienm had 21 clialml cilagz‘msis
`all? hereditary angiaedema that had been, cam
`firmed by means af‘cemml lalmzratmy {£56223 algal
`hacl hail at law! we attacks, {liifillg em}; {2911‘
`secutive claim}: periml
`an“ :11: 2639: cm. attack
`during the firs: 2 wreaks 0? ma: Elmle garland.
`The {mamas wens madmmly assigned in a 1:1:153
`mic) by mama of an intemclfivawegponge
`Item :16 recelve (ZSL830 at 3 {less {£40 1U per
`lcilcagmm oflmcly weight during this fim iéwveek
`treatment periad follmved by placebo for Elk? my
`and léweek treatment: pariad m: vice warm (3.9.;
`placebm firm; and (331.330 seagull); m (281,830 at a
`dose OHSQ lU per kilagmm fallawezl Izzy placebo
`or vice llama {$3};
`$311. in the Supplementary Ap.
`pendix).
`l’atlems wlm haul 12 m’ mam attacks in a can-
`
`securive 4wael< pariad {excéludi mg the. first fl weeilcg
`Gfeach trfiatmem pegmd} {:mllcl mag:
`m the
`new: treatment periml m in mm camplétim} a:
`the immistigamr’s distreiixml An endwciflirial visit
`was scheduled 1 week after complfition of the:
`56mm treatment periad {31* if}; palm): W213 WM?
`(imwn {mm {23:2 trial.
`
`mammm
`
`CSLét’i-li) at 911mm was; afiministerecl by {316 pav
`than: twim weakly in ;; (laublewlfilnd crasswm
`manna“ during each treammntpariaé. Elimlacl
`Ulal meclicaliozl was maximal as
`lyaghillmcl
`pawcler 1:0 be reconstimteci with sterile water: for
`injeciiml; Elm (103:3 was; rmmcled up in tile near“
`:33: mlllllim per 13% IU, To maintair: the! bliml«
`lug 1:2}! varying the mlume at? the 235332;}: that
`will patient resell-‘22:} during; tin? two Maxwell"
`treatment {33:16:15, we pmvidizci a higlwalmm:
`placebo (mamlxing‘
`the valume {)f {be (low
`close 0f CSLBEO) 1:0 patimrzs who remix-’66 the
`4048 dose of (331.830 zle a lmwalmm placelm
`(matching the valume oftlw 4041} {1:353 c35CSL830}
`m pmlems who maximal
`film (3041} @562 at"
`(331530.
`Patienfs ware trained to aémifiiawr the illicit»
`rims at home; lujecaism wane m be given by
`mama (fa maximal filmy-push mellmcl in a alngie
`site in the abalmmlml 3332.1? unless; the humming
`
`tor tlmuglat an alternative Slthllllélnffmlfi injectiml
`site was clinically mare appmprlai’e. l?atiemtt:~; were
`permitieci m {256% lmraveumm {3.1. inhibimr can»
`cammt‘e, icaiilmm, ecallamide, m‘ freglvfmxm
`plasma as; a ream“? meclicatirgm far £>z1~clmnand
`trezzmmm afamcks at {my time}: during; the trial
`:3: fig: prepmmduml lamphyla xisl
`
`cammm. “5555mm:
`
`(Sally magi»:
`Patients usecl 2m electrmliit (filmy an
`m mean} sympmms, use {if the {rial drug? and
`any misc-m: therapy. ’li‘he investigator reviewaci the
`elasrmnic (liary at. each trial vial: and reporteé
`the details (film 21mm; on the: electmfiic mew
`
`report lme Eanctéanal {:1 inhibitor activity and
`(:1 inhibitor and (24 protein levels were mam
`sated, and clinical iabamtmy assesgments were
`camlucted throughvut the trial as: apecifiefi trial
`visits (sea the trial promcol}.
`
`aurwm MEASURES
`
`The primary efficacy end palm. was the number
`05 attacks 0f angimdema, as rapmlfted by the
`lavagtigamn Semmlary efficacy (and paints were
`the gercemage of patiimte‘, wlm had a respmme
`{£50953 reductinn vs. placelm in the: mafia: ml”
`aztackss} and ma number at” timeg tlm‘g mama?
`mafilcatim} was {$6351 fixplmamr}! and paints
`inelasz tilt: maniac}:
`(3%” {MES (3‘? zmgioedema
`sympmms, Severity 53f masks: m, pmpartlm of"
`gazltziems
`in Wham {ha number (3f Miami; was
`fCClLlleEQl
`ti} 36338 than (me 3133th per 4~weak glee
`rim} from we attack 0r mere
`ell-week periacl
`with placebo. The 'numl‘mm 0%" amelcs anal uses
`elf {ESCRE meélcatlan zximsc marmaléxed for the
`
`number 0f? that the patient recaived the £20}?
`raspamling imminent;
`‘
`3:466:35 and the”: sideeafllvzct prefile were: mimiw
`waxed {Maugham thfi trial. film-arse: avents‘ gsrlmxs
`adverse events‘ solicited legal site reactions (112v
`dueling dificamflam swelling, bruising 0r itch»
`ing at {he injection aim), the presence {sf lnlzibl~
`Cary 2mii»Cl inhilaimr mmibadim results mfvirzzl
`serwlagic mama, and clinically signil‘lcmfi: 11131101,»
`maliciaa in labemlmy assessments WW6 afiSififéSfid,
`In additisjn, a preapecifieil plmrmacokimclc
`am} pharmamdynamic zlizaljssis that? was based
`0;: am lntervalwensured repeated time—m—evmt
`medal wag {tenstmcted m Liiz'ectly “slate 5mm
`@9113:
`(33. inhébiwr gczlvil‘y m [11$ attack (:2? aw
`gimdezm‘
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`
`1133
`
`Page 4 ofll
`
`Page 4 of 11
`
`

`

`aw N939)
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`z) wasx a :3?" mum ,
`
`STfiTISTICAL ANALY$§$
`
`Ail efficacy mmiyses were perfumed in the irxttew
`tiomtwtreat popalatiang which includeé ail the
`patienté; “416 had undergmm s'anciamizatian. Eff}
`may data were included {mm the. beginning 0f
`wmk 3 far 6th umtmem peried £0 accaum for
`a mam or waghout periozi. That primary efficacy
`malygis was conducted witfmur impuratian for
`missing dam. Saf‘aty analyses ware Erased 0n the
`safietty papuiatian, which included 31?, the patients
`in the intentmnm—xréafi population who had re;
`ceived at: least one dose of a study drug.
`We astimamci that a, gamma size 0572 patients
`wanld previde a pcwer Mam m detect a reiav
`rive: diffemnce in the primary {and point If 30%
`hemeen the ma dams cf (ISL-839 and a pflwer of
`99% m (Meet a differance betwaten active tram»
`
`men: and piacebo at an alpha lava} of(3.135, 35521112»
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`the placebs gmup wauié
`have a mean :mmber of 8.152 zittatkfi per day.
`We estimated time 1.06 patients wouid need {a}
`undergascmening on the assumgatim that 29%
`(if rm: patienaa weuld be inefigibla in (mm the
`treazrmenz periods after the runvin perimd ané that
`10% 0f the patients win) entered the treatment
`gerinda wmuid withdraw 1chan Cristi cmnpietiqn,
`Désscriptive statistics were used. Pay the camp
`parin cafrhe number efatmcks and this: number
`oftimes that {856113 medicmsn was: used, mm
`maliaed far the number m" (£31315 that Kim mama:
`receiwé the carrespanciing treatment a Mass:—
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`Page 5 ofll
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`Page 5 of 11
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`Page 6 ofll
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`Page 6 of 11
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`1136
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`Page 7 ofll
`
`Page 7 of 11
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`

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`PREVENTION 037' H ERPLDITARY ANGIUIEDEMA ATTACKS
`
`
`
`
`
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`WWW
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`% Madereée
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`smrgrv mm suns spams
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`Adverse events were repm‘ted by similar pmpc‘m
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`patients in the 4045;} gmup, 76% ofthose in the
`60—IU group, and 8.3% ofrhose in the combined
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`1137
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`Page 8 ofll
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`Page 8 of 11
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