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`Page 1 of 11
`
`C SL EXHIBIT 1072
`
`Page 1 of 11
`
`CSL EXHIBIT 1072
`
`

`

`
`
`Preventian Qf Hereditary Angieedema
`Attacks with a Snbmtamms €31
`Inhibitor
`
`1‘3 Langém 3:»;WM3333.} {13313.5 31333363116333 333133333383331313;
`A €3,313.th ,9; 339333333 ”LA: 13333313313 13*}. 33331313133311, W33: {3131:1333‘, H. 3:333:33;
`31233 13133233311E3: G1.f§13:353312131 i 3333:0335 M 33153 333:2;11‘1/3311'131131343 313336333,
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`P3: 3159 1,3: 3 K331113313 S N933 {313 {3211}! ML 9:33:23; 3%. {3533323311, LB. $631333
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`37. 333$6303313 M {3133333313 3M {2331131333 A 53,3110" RC: (Acme:
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`ii} P333332:23333 3 P133331“, :3 B L Z‘3333 m3 333‘31CQMFACW 3113933114333033“
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`fi§3€fi§fi<§t3flfi3
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`:33»
`The authors“ 313} names, amsészméc;
`Hereditary angiotfdema is a (Ligabling, gmtemiafly {113211 63313313133311 causec‘i by defieiemcy
`3336953 {W5 “f“‘at‘m'fi a?" £33,391; 5” “"3
`(type I) {13‘ ciysfimction (type 13;} ofthe (3: inhibitor 1330353311, 1311131313133 2 3:33:33, the 11333:
`(1%”
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`336131, 1333131323} 131 51111613031212 Keveis 03131 inhibimr activity 11333333933331 be: sxpecteé to ‘1‘fixthwic3gya3‘zti Pharmacy 31113;». 331 New
`pmvide fif‘fective 31333931333333; {13" attacks:
`3133 $3.. Whitachapez, 3013:3913,
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`611‘ mm: 333.313.313133.311133331131313,mmntymm mmm ifQMPACi)érwc‘stiwmmkprm‘dadin
`3 mmxths befme screemng: We randamiy asszgmd the patients to we <13 four 33633131318231:
`6m: Suppéememary Appendxc 33113313
`sequences in :3 crossover de3ig13, each invaiving ma lG'WQGk 33321131313231: 1312310313: either
`“ “‘3“mg
`31m EU 03‘ 61:) EU 0:” (3531:830 per kilogram of 13033}? 3313133333 twice 31/863631: 3:311:33».st by {313%
`{73.3 1..unghurst,<:3mrds, Craig, 313333 Zuraw
`6321233g er vice 1363521. ’i‘he 9er3 3:33)? 33313333 331361 [3033133333 31133 11313311361‘ at" atsacks sfsaggiw “WWW“ 333333353113 1121511131313».
`edema. Secondary efficacy and points 3133:3333 the 33331136333103: of 31313633133; Wim £12131 :3 313
`3»: 32331; 3333203333631113-331.
`fipL'meB {$6050 reciuctim‘;
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`13313 3212111239: of attacks with ($312239 33 compaz‘eci 331331
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`1323:3173} 21116} the nambsr 331?” 31111163: 331:3: rescue 31136136331331“; 33:13 1133331.
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`1331533533321
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`Of" 3131: 9Q paaients who 31133333333331: mndmnizatian, 3’9 cmnpieted 3313: 33133. Beth 31313125 :1?
`(3311330, 238 campamd with 3333mm, reduced the mire ofatmcks aflmrcdimry angimdama
`(mean differencs with 4U 1U, mléE gutzmks 9333111011311; 95% canfidéznce imam} [C11,w338
`m «51.46; anti 333323133 3133332331363 32313333113333.31 333316133 31633111031233; 95% CI, «4.21 30 «2,81;
`373:0{3(31 3233 E10331 cmnmz‘igms} Response 33336:: were 76.3% 515% CI, (12 30 £37) in the MMU
`33331113) and 90315393333333??? £31336) in 3336041? 3153mm. The 33333231 {31333532336 meciimtien W333:
`33333133333 {mm 555 1st3 pi?!’ 332mmmtthe 1332133239 gmup m l 13 125335 @313 11131333}:m 33323
`«3111313 grow anti fmm F3.89 113333 333 3333 placebc gmup m 0.32 1333332; 11633230ch131 the (3841}
`gmup. Advarse 63113133: {1313333 32031131301131? mila1333333331 33311933311: 3336.311 site 3611333331113} {3313:1113er
`in simfiar propoxtians; of patients who received CSI830 123131 3116333: 33330 recewzzd placebos
`Ki‘fiifififififififi
`
`'
`
`In 11331123133 with hereéimry angioedema, the pmphylaétiz: 113:? Si?:1 Submtzmamzs Cl inhibitor
`3333363: 331326333}; significantly mduwd the frequency Mamie 211320133. (1311333.in by (ISL Enabling;
`COMPACT EzzdmC’f number, 2013—00G9‘16—10, 311d {3331316231’3‘3331133503'number, NCTQXWMSM
`
`31 3:133:31; ME?) 33333:
`
`11313333115; mum-s 23 303?
`
`113.1
`
`Page 2 of 11
`
`Page 2 of 11
`
`

`

`I“? ii W ii is? if: 5‘” ,3“: 1‘4 i?
`
`3 {5} E3 R N :"x E :9? {Vi E7. {3 l {25 i“; E;
`
`“La? ”gismfim’mm’ fiNGECNEDlEMA 363 A 1315»
`milling mail mmntialiy fatal condition
`
`characterizeci by itscurmm episecles Oi“
`i
`swelling Witlmut urticaria 0r prurims. The cow
`dizion is flawed by ciei‘iciémcy (Kym: i) (31' dysfmw
`rim} (type ll} of the Cl inhibitm pmwin.‘ Pm
`tients have inaufficient €33
`inhibitor functiim ta
`
`prevent braciykinin production by the contact 53's“
`tam: leading to episodes {if incrmfiszfi capillary
`hyperpermealiiiicy and, swelling. ’i‘lizage episeciea
`manifest clinically as angioeciema attackali’
`Low levels of C1 inhibitor protein antigén 0f
`low functizmal levels iii” C1 inhibiz‘m activity, as:
`well as law levels; Gi'cmriplmiem (34; are (3:21;?
`mastic for hereditary smgimrdema, and baseline
`C1 inhibitor function has been reporleci {a cap
`mlate with disease severityf According m clini»
`cal absmmiims, a Sllfiiéiii‘m‘d tiiriasimlci level (if
`agpmximziteiy 49% functionai Gil. inhibimr actiw
`ity has brim repaired to wafer certain protectian
`against weaken: atmekgfifi
`Regular immvmmm Cl iiiliibimr repiawmmt
`is effective at reducing the frequemy and sever
`ity {if attacks and has: an accapmbiié Safety and
`fiiée—efféct pmfiie. A daublevblind, glaaebswcanw
`swiiec‘l, amamver {trial iiiVGlViilg 22 patients with
`frequent attacks- slmwm a Sam/:3 reciucrimi in the
`frequency anti mverity (ifaztacks with the 113:2 of
`an intraveimui; C1 izshilaitm at a {lease a? 1000 it)
`
`twice “Jammy? ivlowewn iiecauae (affix: tealmiml
`difficulties (3?? regular various accasg, risks with
`film use of indwelling ventral: cathflem, zinci 9:»
`flan: cmmidm‘atifinfi‘“ Kim fievalapxmnt at" a (:1
`inhiifimr cmcantrate wimbig fm regular swim»
`animus admifiistmtimi is ()finmmst.
`
`that adniililstration
`A 13119133: 2 trial 8lIQW€5£l
`23f” {33L83f} {(351 Behring}, a lewwalume, human
`plasmewleriwdj pagteurizafia mummified (.11 iii»
`liilzimr yrepamtian that ii: Suitabia far gubcumw
`nevus injemricam i'ésulteci in a dosafldepenclent 22ml
`cmgmm iz‘mrmge in tmugh 932531313 lavas {if
`fililetimml i3: inhibimr amivizy almva tii)%,‘~5 a
`biacliemicai finding»; impacted m pz‘wide eff‘ew
`hive gimpliylaxis of attacks.
`W5: dascriiye this remits (33“ Elm Clinical Study
`5:): Optimal Managemmi of Previewing Angia»
`(361631333 with Lmvk’oiuma Subcummmmfil~hiliili~
`imr Replawmem: Therapy {COlv’lPiXCT}, a phage 3
`trial testizig the. liypmlmsiii that: 3 twice—wwkly
`auhcutzmeaus .iuiestian Qi'C3L833, as; campared
`with placebo, cuulé Nance {he fi‘equency afav
`
`tilleS 0i? hereditary mgmedema in, pzitients with
`fiequem SitE'Z-Ifllifi.
`
`
`
`TRML QVERSIGHT
`
`Tim trial was jointly designed by the ssponfior
`(CS); Behring) and the smering committee. This
`g‘zmmml, availabk: with the Fail text of this aniclg
`zit Nlilifi‘ixirg, wag zippmvai by rim 31333r0§¥fl€lt€
`regulatory mitlwritiefi and fitlilfis mmmitmes, (3r
`instimtional review lmarcls. All the patienta prov
`videci written iziformeé tangent. An indeger‘idmw
`43am: 323d saf‘esy ummimrlng beard regularly mm—
`itored trial 33 fat}? 23ml pmvided recummenciations
`t0 the Spenser 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~
`mass to {he data anti much its: ”Elli": gamma}? ané
`mmglfitwma of {ha 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. Medimi writing sisal»
`mace, which was paid fan: by“ QSL gaining, writ“;
`pmvidfii‘l by Apalzbefiam.
`
`mnsms
`
`‘12 mam {)5 ages Q2,” {)lilfil‘
`Eligible gamma Wé‘i'fii
`and haul a clinical axial central what-amt); iiisignmw
`sis af‘tyge i {3? ii imredimry angiaaficma (farm
`{Emmi {Eli liiil‘iibimi‘ aétivity {if «353% anfi {343 2211??
`gen kiwi lwlmv aha nm'mal lewi). All (he patiauts
`had hail limr m,“ mam: attackg requiring iiiime~
`diam treatment (if méciical attention or causing
`cliiiimlly gigiiificant functianal impairment 9%:
`a 2*fiiflfi'iil perimi withm 3 maiztiii; Mitre: $€r€EZ€lv
`ing, as ciacumenmfi in the patient‘s. medial few
`orils. Fall, inciiisimi and Exclusiml militia am pm—
`izided in Table 31 in this Supplmlenmry appgiizlix,
`avaziiéiifié a? Militarg.
`Daring the {ML ilk: graham}, was amamiesii m
`iriirlmsie gramme; wim were raceziving Oral/mali—
`cziztimis fin? praghyizixig 0f angiaeciéma attackg,
`if they hail mmiwzci a ambie dams £332“ 3 mamas
`befbre acmening and {31223111516 m camimm
`{limitgimut the: axial. EMEEEI‘IKS Wm had mammal
`an intravenous {31 iizliibimr far mating pram}?
`laxis within 3 manths befmrs: screenéi‘ig were“:
`{axciucifizcl
`
`1132
`
`bi man} man gyi’izm maisaiimm MARCH 23,2331?
`
`Page 3 of 11
`
`Page 3 of 11
`
`

`

`PREVENTION OF H ER {‘231‘5’A ELY AN(EI(31§UIEI\~§§\ ATTACKS
`
`TNAL EESHZSN
`
`COMPACT was an inmmatinml, pmspective,
`malticenmz’, rancimnizesfi, doubiewblixzdg planebcnw
`mnthed, {imwmngmg trial. Afm? ficreming‘
`eiigibia patiems entereé a mark; pfft‘ifld 0f 12;) m
`8 weeks. AH {the patienm has! 21 timings} ciiagz‘msis
`GI," hereditary angiaedema that had been, cam
`firmed by means af‘cemml iabmramry {£56223 arm
`haci hat? at £55233! two attacks, {1:11:ng em}; {2911‘
`secutive 4‘sa’eek: perimi
`an“ :11: 2639:. cm. attack
`during the firs: 2 wreaks 0? Kim mnwiu pariad.
`The pazimts wens madmmiy assigned in a 1:1:153
`mic) by mama of an intemcfiémwegponge 53w;
`Item :13 rece§ve (ZSL830 at 3 {$956 {£40 1U per
`kiiwgmm ofbaciy weight during this fim‘t iGweek
`treatment periad foilmved by Mambo for the? my
`and léweek treatment: pariad m: vice warm (3.9.;
`placebm first and (331.330 seawefi); m (281,830 at a
`dose OHSQ W per kilngmm @11de by placebo
`or vice yams {$3};
`$311. in the Suppiemenmry Ap.
`pendix).
`{’atfiems wlm liar} 12 m’ mam attacks in a can-
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`securive 4waek pariad {excéludi mg the. first f: weeikg
`Gfeach trfiatmem pegiad} mum mag: 3:»; :0 the
`new: treatment permd m" in mg! campiétian a:
`the inwsstigamr’s distreiixm‘ An endwefliriai visit
`was scheduled 1 week after comp/Mien of the:
`gamma! treatment periad a: ifs} pasiem was; Wi£§1~
`(imwn {mm {23:32 trial.
`
`Tammam
`
`CSLét’i-Ei) at 911mm was; afiministered by {316 pav
`than: twim weakéy‘ in ;; daublwbimd crassam'
`manna“ during each treammntpariaé. Elimiaé
`Um meéicatioz’: was pmvidfié as a Eyaghiiimé
`pawder 1:0 be reconstimteci with steriie water: for
`injeciiom rim (103:3 was; mande up m me hear“
`5:3: mififlim per 13% TU, To maintair: the? biisad«
`Eng 1:2}! varying the mimme at? the agfim that
`emh patient receiveé during; tin? two léweek
`treatment {33:16:15, we prwidizci a biggiwaimm:
`placebo (mamhing the vahxme {)f {he 60%:
`{3056 cf CSLBEO) 1:0 patimrzs who remix-’66 the
`4048 dose of (331.830 mm a Emwamme placelm
`(matching the whims oftfie 4041} {1:353 c35CSL830}
`m patiems who maeivmfi
`{£33 {3041.} {fiase m?
`CVSLSW’SG.
`Patienfs ware trained to aémifiiawr the injcw
`rims at home; Injecaism wane m be given by
`mama (fa magma} {SiQW'push mfiiii‘mfi in a aingie
`site in the abfimmiml 3332.1? uniess; the im’ifiitigaw
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`tor timugm an alternative whmmmmm injectkm
`sin: was clinicaliy mare appmpriai’e. i9atie,ntt:~; were
`parmitieci m {256% immveumm {3.1. inhibitm’ cm»
`Ciiflti’élte,
`iczz‘xibam, ecailznxtide, m‘ freghfmxm
`plasma as; a ream“? nmcficatmn far £>z1~émnand
`trezzmmm afamcks at {my time}: during; the triai
`:3: fig: prepmmdumi maphyia xis‘
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`came»; “5555mm:
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`Patients uses} an electmnir: ciiazy an 3 {3:331}; 33:13:22:
`[(3 mean} sympmms, use {if the {riai drug and
`any misc-m: therapy. $316 investigator reviewaci the
`eiacztmnic éiary at. each trial vim and reporteé
`the demiis ohm: 21:12:21; on the: electmnic mew
`
`report $1me Emctéanal {:1 inhibitor activity and
`Cl inhibitor and (24 protein Iewfls were mash
`sated, and clinical iabamtmy assesgments were
`canducted throughmt the trial as: apecifiefi mai
`visits (sea the trial protacol}.
`
`aurcmm MEASURES
`
`The primary efficacy end paint was the number
`0%" attacks 0f angimdema, as repmrfted by the
`imagtigmm Seccmdary efficacy (and paints were
`the gercemage of patiimte‘, Mm had a respmme
`{£50953 reductinn vs. macaw in the: maxim: mi"
`aztackss} and fix: number at” timeg thaé: mama?
`maiiicatim was useri flxpimramry and paints
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`sympmms, Severity m” masks: m, pmpartim of"
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`fCCfiICfEfi
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`{Em} from we attack 0r mere pa! «1-week periaci
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`Qf {ESCRE meéicatian wmsc marmaléxed for the
`
`number afdays that the patient recaived the £20}?
`respamfing imminent;
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`maliciea in Eabemmry assessments was: RSSeféSfid,
`In additisjn, a preapecified pharmacokimcic
`am} pharmamdynamic ziizaijssis that? was based
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`1133
`
`Page 4 of 11
`
`Page 4 of 11
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`513.2~ z .5352" 5352555-».
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`STfiTISTICAL ANALY$§$
`
`535i} efficacy 32121133383 were perfumed in the irxttew
`tiomtwtreat popalatian. which 55552122525655 2123 the
`maximum; 5va had undergmm s'anciamizatian. Eff}
`may data were included {mm the. beginning 0f
`waek 3 far 6th 51732112155531}: peried £0 accaum for
`:5 mm or 5515553110521? periozi. That primary efficacy
`xnalygis was conducted wittmur impmaticm for
`missing dam. Saf‘aty analyses ware Erased m; the
`safietty papuiatian, which included 5512 the patients
`in the intentionm—xrtaat; population who had re;
`ceived at: least one dose of a study drug.
`We astimamci that a, gamma size 0572 paticnts
`wanld previde a pcwer {JfBWn m detect a reiav
`rive: diffemnce in the primary {and point If 30%
`Immeen the W536 dams cf (ISL-839 and a pawn of
`99% m (Meet a differance betwmn active trim-51‘»
`
`men: and piacebo at an alpha lava} of(3.155, 35555152»
`ing that: patients it:
`the placebs gmup wcuié
`have a mean 515515113521“ of 8.152 zattaakg per day.
`We estimated time 1.06 patients wouid need {a}
`undergascmening on the 22.531551553535313 that 20%
`(if 5115: patienaa weuld be inefigibla m mmr the
`treazrmenz periods after the runvin pix-had {55135 that
`10% 0f the patients win) entered the tremmam
`gerinda wmuid withdraw 1chan Cristi cmnpietiqn.
`Dmcriptive statistics were. used. 17535 the map
`10555in QfEhe number 0? 2155255353 and 5512:: number
`oftimes that 3656513 medicmm was: used, mm
`maliaed far the number afciays that Kim 2351525255:
`receiwé the carrespanciing treatment. 9.
`£51353:—
`squares; mean éifference was estimateé wk};
`95% confidence 555555555525 and :3 wings with the
`
`15353, 53%“ a mimdmfidel aemuming fm‘ the within-
`patiam carrsfiazian. Hy‘pathcm tasfing wag per.»
`formed hierarchical}? m presarve {he pmset Ewe}
`of significance (EROS. Thus, me first tegteci the
`EMU dnse (5f {281.830 versus iawwcaluma placebo,
`and 051.1}! ifthe mil! hypmhfisis was mjscted at an
`alpha level of 0.05 did Wt? {851‘ the: 250455 (15256:
`varsus highwvninme placebo. ”fasting aftha 604E}
`dose versus the 405m dcse was considmread m bi”:
`
`explamtory and W555 always tesmd at an 552535555
`lave} air“ 0.05 far informatianai purpasea. 1351.1 stag
`ziscicai tests were twa—sidczd. 3522555355925} 2525211353523
`were conciucted mm the 1136. Cf SEAS SDfi'Wfii’E,
`53235553051 9.1.3 (31558 Engtitute).
`
`RESU LTS
`
`nwmms
`
`The triai was canductec} from Decamber 2013
`
`through (3525:9138? 201.5. Overafl, 115 patients
`
`were SCI‘Eenfld at. 38 centers: 18 in the Unified
`
`States 551165 20 255217038 Australia, (35155225322. the Cmch
`Republic, Hungary, Israei, 5555255, Ramzmizs, Spain,
`and the: United Kingdmm {Fig S2 in the: Supple—
`mmzm’y Appendix}. Of the 90 23:55tjwts whc
`{55151531551535}: randamizatiofi. 11 dismminuefi 5551'
`variaus 54223555513 (Table 32 in the 82113131525519.225er
`Appandix).
`Deznagraphic anti 53353851552. ciinicai chamcter«
`isrics fifths patients are ahawn in ”125525: 1. In, the
`3 menths; befbre screening, 36% 0f the patienrs
`who received 40 IU of {331.830 p65: kimgmm and
`49% of these who receiveé 60 H.) per kilogram
`had received a pmphylactic {5533351152155 re prevent
`attacks: 01’ afigz’oedema. One at“ these patienm
`centinucé 50 receive om! pmphyiaxig ((33:53:91)
`dusing the Mai. The mam: (3:813) number 535‘" at»
`tacks per mam}; {luring the rux2~i12 pericfi, new
`1555555555555 {’53: the: aumbar a? gays; 2155525 the: patient
`285:5)in the: 99255559052255ng drug {22‘ Mamba, wax
`4.63312 for the 4041} trézatmem sequemag and
`4.61250 fer the 60555 treatmem secgzmnces. The
`mean dm'atian 0f expcxaura was; simiim‘ far 2251
`Irrigatmmts: 16.3i1.6 weeks f0): 40 EU, 16.025223
`wefiks far 60 KL and 13.3t3.3 weaks far mm-
`bingd pimebu.
`
`EFFWACY 52$stst
`
`Amoug patients who received (331.830, the. ram of
`attacks of angioedema was lama): than the ram
`ammng parisms Whi) {waived piaceba. The mean
`differance, as campamd with piaceaba, was «2.42
`azmckr; per 22353551131 {93% mnfidenm 311mm! {CI},
`«3.38 55:: «1.356) with 40 EU and «$.51 2155513258 peg
`manth 693% (33.. ~4.2’1 m «£313 wizh 66 R]
`{135555.05}: {552' both camparisans) ($355326 2). Na sig
`nificant difihmnm wag 352852 bestwaeu {the 4941}
`
`525552 éOdU treatment sequences. T553: {:scm‘mnce
`afaympmms and the: 55253: 01” 5352552115: mmficatim
`in each, patient; durmg each 51253255535621? pariacfi are:
`Shawn in Figare 33515 the Supplementary Apv
`pendix.
`Secandary and explaramry’ end paints are
`313:3 iismcfi in Table 2. in patients with data, that
`€522,515? he 53553151525951 at both (103535. the median
`reductian in the marmalimd 55515255353: afattacks
`
`vergus placebo was; 83.25% (iatezqnartiie ranga,
`69.53 :55 109.03 wk}: 40 1E} 5357(23158303351 95.1%
`(intezfquzsrtfla range, 279.0 to 180.0) with 60 EU.
`The pammmgfi of patienm who 555552 :5 15535125915323
`was 36% in 5:215 41MB gmup am} 9fi%5 in the 60—11}
`gmugp. Overall, 43% 5:55 the? 535153815158 in ("he 40321}
`gmup and 58% (55’? these in the: (SQ-EU group hat?
`
`1134
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`5.; mm.) mm 37:63;
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`5553mm“;
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`5555555525 23 2551.?
`
`Page 5 of 11
`
`Page 5 of 11
`
`

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`315212213: 2 90% reducticm in attacks? and 53% of
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`Patients;
`in, the 60»IU gmup had MM" 222: many
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`Tim average sevmiy (1% aimcks was iower it:
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`chasewad reéhzctian En the nambm‘ af‘atmcks me-
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`gmup, In) patients in the (SO—[U group, and 25
`patiemg in the: piacsba gimp.
`The mam nmmalized number of {imam that
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`both doses; of (181,830 versus placebo (Table 2).
`The rate of use mf rescue medicatimz was 71.7%
`
`Iowa? amang {he patimm in firm {SO-IL? gran?
`than swung thaw in the 404i} gmup. In the
`60% treatment: mqummess {the rate 0?" 133:? 0%"
`teams: mecficatiw was iawer than the rate: of
`attaeks.
`
`Rt screening, rhea iavais Gffimctianal C31 inhibir
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`ciamizatiam 2211mm? biemarkers slxawed a dense»
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`week 3 {Fig 34A, 3&3; 2am} MC in the Supple»
`mermary Appenéix). In Chi? papalatiowbased ex~
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`N EEIGLj Mfifififiilfii Nijfdfiéiifi Méi‘fl‘i 23, 31(21‘?
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`111,35
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`Page 6 of 11
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`Page 6 of 11
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`PREVENTION Oi? H EREDITARY ANGIUIEDEMA ATTACKS
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`Adverse events were repm‘ted by similar pmpc‘m
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`placebo group) and were reporzed by the invest}
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`
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`{me event (umsepsis) in :1 patient wha received
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