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NDA No.21-911C OIiCL..u SaMt

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1'he primary efticacy cmdpoiat for study CIPR.OT lIV03 IA 02 was CliDieal Cure atthe 1est-of;;C.. visit. R.esults in the MPP aDd MITT popuIatiou arc shown in TablelB. 1Il_ MPP populatioD, 148 (IS.1%) patients in the cipRlt1o..poup and 136(11.2%) ill the PNH pup hid CliDical On at the TClHf:.Cln visit. Compared wi.the PNH pup, the proportion ofMPP patients ill the ciJll'Ofto-- poup withSustaiMd CliaiaJ Cure was peate (6seA VI. 56%), IIMlthe propertioD withSUbsIqumt CJiBieaI Cure wu smaller (17% VI. 22%).

In _ MIn popuJaaioft. pmpottioBs ofpatieDts with CIiDicaJ CUN were small« t1taIliD the MPP population, but differences bctwca tr..... poups showed the sametroIlds. 0.. hundnci eipty-four (19.3%) patients in the cipm80ueill poup and 163(1S. J%) ill tbc PNH poup hid CliDical Cure at Visit 4. Com,.. with the PNH...." the pmportioa ofpatients in the eiprofioueiB poup with, S.....ned ClillialC. WIll pater (63% VI. SS%), ... the pmportioa with~ CJiDieal CuRwas smaller (16% vs. 20%). AppmxUnately S% ofpRints in tho ciprofJoxaeiD poup_ 2% ill the PNH poup Wresults•••cdas~.

•·••·•.•··•· .. ·• ... ·c...

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er.-. .Sluiiilit:tlweI.1 I.U ,I T 7.1.1" 7.1.4

The Climca1 CUR .c.1t TctStoOf-CUN visit by eCRnry were simiW to OM another..o~with 1M 0YaaI1 popuIIdioIt NSUIas (Tables J9 and 20).

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1"hI incidence ofCtiftial Cure WII also analyzed by pathoaea. Jncickmce ofClinicalCure wu higher in pIIientI iJlfectcd "Nidi P. tlmIginoM'" in ,.aints iftfeetcd with s.tIIII'efU. 1ft pItients iaf..with P.~ incideacc ofClinical C.... w. It....... inthe ciproOoucirl poup""" in 1M PNH poup. bl p8ticnts inf.-d with So tntTeU.

incicllnce ofClinial Cure was sHPtlY hiPer' in the PNH arouP.... in the ciprofloucinIfOUP (fable 21).

..........

1M....ofClinical Cure 1& Visit 4·"Y COUIItIy........ is .......for the Mr,_MITT IM'p_IliliDftl ill Tables 22 and 23.

n....clawilied" the ovenII,....--tocU JlGPU~1& the Tat f·CiIN visit were abo oIIIerYedia ill US. for ,.. SpIia, ..............110 Ins ne rol,iii.... iIIf widt So ."..,.Spaia was 100 to allowMY'" to heMsIlWlCl.Table n.__,., elCIIIdal Clift .tT......c.n VbIt bJ ....... (IJS).

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CIIeIcaI .,~MICCliftieal retpG_ abo eVIh ~ ciptoftuuciII MJC in ,lIiadS wilh either olebetwe P i_BM or S. ........., for tlcJcJa ..... MPPIIIdMm,..1a1ioas "y widt,itMr ciploftouein or PNH. As ftO&I4 ift Tabla 24and 25 there was .., di.scernib.....ofcJinieal response ilia with incnMiaI

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dJIrofIo..,in MIC in,... tNated with eipioflOXKin otic solution for cidMrP.""";1IGIG or S. tIII1YII8 ia either..MPP or MIlTpopulatiol'ls. HewcYcr, thIN dWappaI'to • possible treneiI town dlcrasilll cfinicall'CSJKll'" with illClaliaaeipfo"in MIC for patients with P.~ trcaied with PNH. No meh 1RIId wunotGd for plIlicnts with S. QII1ftI UoatGd wiCh PNH.

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......,. ••f.I' :~ _ tIaat bIa .,i11I.MICs_'ID'I j 'a · diiI!iaI 'a•••wta-:::l MIC ' witJlPMlt tNDcl_ wIIJa ,.ww.s. iull1 Mrtr'If ,}rd.Willet NI ,..ilJlIt cIiDicIJ n..,.,.,.."............Mm W.MJCa N/ .ccI••IIO"',.........__ MJTr..' MIC.2...,.(~i.._I.te)..

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,...__-.-. Taken toIetDer.thae~ ....dlatlllC....,.ediclcIr ofdiaiaI...... at leut hi the cipIdo.aciDUlatIIl_ ana. .

CIIaIIaI+~ ..... fer CIPROT I11I03IA enCliftial + MiaoINoloaieal outcome is summuizcd in Table 2S for .... Mr, and MID~ Clinical + MiaobioJoaicai Cun: and Clift_ +Miaobioloa-_pIOY " End-of..Tmtincnt [EOT] visit and at the Tat-of..c.... (Toe) visitWCN seconduy dIicacy endpoints in the CIPItOT study.

In the MPP population at tho HOT visit, 10%of""" in tho ei......pup Iftd60% • the PNH IfOUP had Clinical + MiclOltioiOlicai CUN. Clinical ;. M"IGfOI!rioJoaieallrApfov....wu observed in 21% ofpdicntl in the ciprotloxacin PNP _ 26% in thePNH...,. At-the Tost-of..c..visit, the piopol1ions ofpatients with CJini$aI +MicNbioJosieal C.., had incRSlMCi to am in tM ciplOtlouein poup and 78% in ....PNH....Tho pmportiofts ofpationts with Clinic81 +M~ IJnJIrov....had~ to J% in .... ciplet10xMift poup and 2% in 1M PNH poup.

1ft the MrrT popaIation. NMIIts were .,...uy similar to .... in .... MPP popuIIIcion.but....'"' haw.n tNa&nNnts wont less f'I'OI'O'BINd. At the EOT visit, 66% of ­......-in_ eiplOfloXIGin ...., and J9% in the PNH pwpW Cliaiotl+M Cure; and 21%1ftCl24%; rapectively, h8d Ctiaical+ M"lCI'OhiotoaialbnfJrov At the Tat-of..Curw visit, the poportions of""'" widl CIiiUuI ...MiGrebio C. had incrcUcd to 19% in .... cipmftoxacin1ft'UP" 75% in 1MPNH...,; poportions;with Clinical'"Mie~ hnpIvvelMlll 11M'*"....Ie 3% ill the cipfofloxtcin pup _ 2% in the PNH poup.

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~"""by COUIIby, die,....ofpltilnts widle + miaobio",aftw• ...,to .... ofthe GOIIIbiMd JIGIlUIlItions. In"US, MPP population........~ C1ftwq 69% for cipot1ouIia_'''' IGrPNHpili11111 at .... EOT visit. In SpUD., 1hc MPP with diniaI +~....cure-'" 70% for IJoCh the ciprot1oucia..PMH At" tat-of'.cuN visit in 1M

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us,..MtP population pili•• sheWIl to ... clinical ... microbio"l CUR was 86%in the ~i...AoXMin arouP..ne" in..PNH poup. In Spain, the cliaical ...m~ cure for the cipmftoxaein_ PNH MPP populationsat" Tat-of..Cunvisit \¥IS Il% IIId I2%, NSJ*tively.

The MITI' population when evaluated by~ specifIC""c~sliPdYtower eliftialllld microbiolopal response ,.. than in the MPP popula&ion but wereSiMilar-to dill .... iIl·the overall MITT population. In Spaift, 1M ~UN rata WIll 72% for..ci~iIIJrOUP and 71% fer die PNII poup It the EOT visit. At the T.-of­Cure visit, ..MITT population ofthe US ~iprot1oucin poup hid·. clinical +microbio cure rate of11%while the PNM IfOUP had a curo '* .74".. 1lIcMm,.,1 at the Tat..f- Cure visit in S....hid clinieal +m~ cure...0182% for the ciprofJoucin poupancl 11% lor the PNH poup (Table 21).'

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Wkn-tynd·.., countIy clWcal+ miavWo .,P..""......s.."... were uclc'liAiaI......... (Tables 21_ 29).111 Table 21, .. US MPP ,.,1 Earvisit ..... cliatiuI ...~ CUN· '"'- of ""lor cipmftoxaeilt...""1%"''' PHH 'or So the dilaigf + 1••_-...It... EOT visit 1% ciJn80._....,. iMpftw.... riIIII WIll

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