o

ÍUIOTFAN MFDICINES ACiENCY

' ! t N i rU L i"' ! .. i r . 1 s .i L : I' :S

31 Ma/ 201S
eMA/431 í 11/2015
OommifeLea for Medfdnaí Products Far Humao Use ÍCtIMP)

CHMP extensión of Inclícation varfation assessment report

invented neme: Transíarna

iricemaciónal .non-proprietarv nannie: scaluren

Proceduré Mo. ■EMEA/H/C/002720/II/0037

Marksífng autho-nsatiosi holder (MAH}: PTC Tlierapeutics International

Limited
Table of contents

1. Background Information on the procedure 3

i 1. Type n vanatiori .3
1.2. Steps Laktüi Fo-r Uie ■assessmertL cf üliepraducL. .......... ..4

2. Scientific riíscMssipn •►........i... S

2.1. intrcducticirí -5
Z.2, N-on-dmícal a$pécts ..6
2.3. el laical aspecls 6
2.3.1. inilf-oduclloji ..6
2.3.2. PhormacoSímGtics 6
2.3.3. PhariTtacodvnamlcs. ..,,,.. ,...,,.,.,,23
2.3.4. PK/PD rriodeSIing 23
2.3.5. Dlscusaan dfi cilnieai pkarmdcofogy..... .. 23
2.3.6. Coridusaons on cimical phamacology 24
2,4- C|irll-íal 'afílcscy 24
2.4.1. Maoh síudy 24
2-4.2. DbciJssiioji on cllntcíii officacy .33
2.4.3. Corsduuons en tlio clir»C3l efHcacy 34
ZJ. Cllinkal sefeiy ,..,,,, ,,,.,,., ., ,,34
2.5.1. Dlsoussacn on cliriKa! safeíy 55
2.5.2. Conduaioné en olinic&l safety SS
2.5.3. PSÜRcyde 35
2,6, Rkk manageítieiiii plan..., 5S
2.1. LlpdíitsOÍ &é Preducl InformaiiDíi 5S
2.2.1. .4dd!ítlQnal mónítorJílig 59

3. Bcncfit-Rlsk Batanee... 59

4. Recommondatíons.. 62

5. EPAR changes.. 63

,-i.vüa -i *. 1 'fiih .".f,:

ui i.coic -.en
i'íi fk'ts Ufíiíitt;:! •^¡frúíoa cin-nsírii' tn ííií? fSe'iicf.bf? OÍ' 'n 'iVr'íí'
R&guSaüon 2ÍÍJS/Í72S-
i, Background Information on the procedure

í.J. Type II wariatíon

PursuanL to Artide IQ of Cammlísioa Regulaltan (EC) Na a23'3/200fi, PTC Thsrapsutlcs Intenjatídnal

Limited subriiiEted tü th.a Europaan Píadidiras Agaricy oh 30 AugUst 2ül7 an applicatlcni fora varíatiots.
The foilovíirta variatlon was raqueEted:

V'dHaitiDn rcqwdsteií Typd Ann^xcs

afféctetl
C.I.5.a CJ.S.a - Changeos) to tharapaulic lndicattori(s} - Atodition Type II I snd ms
óf a naw therapáJEIt Indicación ar niodlficaCion of áh
annrciTOci

GxtWiStoti pf Irtijicatiqn fe)fnsli.Jde ■& líppMÍatipiti (ehMi'en fi'em 2 to teíiS thari 5 ytér'S cif age) fel"
Translarna; ss a coníegiifence, sscticos 4,1, 4,¿r 4.B, 5.1 and 5,z of thssmPCans updatea. The
Package Lesflet SRci RMP ('/e'sioh 7.1} is updateci in aKondenice,

The yartatisfi proposed amenílmeints to theSummerv of Product charscterístlcsaiiti Packafs Leaflfá

gnci íO' the Risk Mgrsageiper.t Piaps (RMP),

Trarísleírtii wasílesisnated as-a?» tirphai» metflcL'sel pratiuct Elí/3/D5/27@ en 27 May 20€5, Transterna
víss destgiíeted asan orphar» mecílclnisl produce In Che foitowing rndicahon; tnratment of DuctienuTíe
Muscular Dystrephy.

The new Indicaoon, which Is chesubjeccoí this applicetisfi, feils ^vlchln theato'/ementloned orphan
cíesífnstion.

XnfQfmátrati pn póedíwffr/c reUMrremeñfs

Pursuant to Article 5 of Rí^ulatton (KC) No 1901/2006., the gpplicttloq induded EMA Decisions
P/S3/,JO09i issued on 15 May 2^9, P/123/2010 issued or» 28 July 2010, P/OOSP/SOl J issMed on 4 April
2012, P/0202/2012 fesuedon 30 Aagust 2012, P/0132/2015 ísped on 12 June 2015, P,/aO02/2015
issued on 14 JasuatV 2016,. P/012,2/Z016 issiieá on 29 Apfif 201Ganá P/02B3/Z016 Itsuéd ón 4
No vcmbar 3GT& oí» the gr.intfng of a (product-speciñc) walvor and a cSa-ss wai vor.

At the Bme of submíssion or" the appllcatían. che PtP '.v^s not yec conspleteí as so me measures v/ere
cSéíerréd.

Iftfttrftmtlm ro^fstíng fe orgímn msrkat sKefusivlty

Smihriiy

Punsuant to Arricie o of Regufatíon (ec) Tío. Hi/zooo^ and Articre 3 of commlsslon Regulatíím {á:} No
847/2000, Che apErfIcanc did not submit a crlricai repwrt addngsslnig the possible simüarity vííth
autharised orpban medicinal prcducts because there Is no auChorised orphan medicinal orcduct for a
cmdltion relateil to IhepreposstI ¡ndlcábon.

Ptatai^vt ft^sisi^ncc
The WAH did receive Probo®I Asslstance at tba CHMF in laniuary zoi?
(EMEA/H,'SAí^l8/3/20í6/PA.'SME,ai),

;,t rrticr.tiul Ví''i5:'í "i '«ti'-ie ■

IMAÍ'IJ U11,'ED1E Piac 3,'.:-3
Chiin¡}it^ In ffefe y-.f/svon cotisfeí ¡n the récJncWnS <?/pst&n>iídiítú, lt\ £0i))í?/í.iri7cé V/ifA
Ñsgu^ancm (£U) 2018/Í725
J,2. Steps íalfen for the assússmentof tlm product

Ths Rappcrteur arad LO-Rapcorteur appolnLed by theCHHP wsre:

fepporteur: Johann Lñ<ííswijk Hillege Ca-RspporT'eur: fd,íA

i^lFtnTi'ed date^

Start oF prcced'wne; 16 Saptember 2017 16 S-scttmbera017

CHMP Co-Rapporceur Ássessnisr«t Repart 10 Novembar 2017 Ri/a

CHMP Rüppnrteur Assassriierít Repcrt 10 FJOvembár 20-1.7 14 November 2017

PR«; aappoiteur «.ssessinene Repoit 17 November a-ai7 15 Nevember 201?

PR¿.C mambers commente 22 Novembar 2017 22 November 2017

Updated PRAC Rapporteiir AsseÉSf-ient RapOrt 21 NOiVembar 2017 afá

PRAC Oiílccrní! 30 Mpvombgr 2317 JO Npvómbpr 3017

CHMP memhfirs cem mente 4 D-scember 203 7 d Dececsiber 20]7

ijpdateó CKMP Rjapportear(s)(Jaint) Asssssmsnt 7 Dtfcerriljtjt' 2017 B Deccrsjbtjf 2017

Report

Reqiaestfar Supplemerstary Inforni'satteri (RSl) 14 DsDsmher 2D17 14 Dficamhar 2Ü27

Sybmteáon 22 December 20'17 22 CtecerabEr 2017

PrOSQíáurn Rostcíré 25 Dpc-«!m6c?r 2017 25 C-apamber 3017

CHMP Rspporteur Assessnnent Repcrt 23 Jenuary 2018 24 Japuary 2018

PRA.C flapportfiur AssfissKient Repcírt 26 Jan uarir 2018 £3 larsuarv 2018

PRAC msmbers cpramenis SlJanuary 2018 11 Januar'/ 2018

Updaceá PRAC Rapporteisr Assesemeiic F^eport 01 Feljrwity 2018 iVe

PR.4C Ourcom-p Oa Rfibris?.."!,' 2018 09 Fabrijsry 2012

CHF'IP membars comments 12 Fabruary 2018 .12 Fábru-iPí 201®

UpdíiCnd CHMP BtippQrE:air(s)As-Sr:57iT"i9nif Repnrt 15 Fabasíi.-y 2018 n/á

3nd Rseqisest forSupptemenfcary fniformstisn 22 Fehas&'-jí 2018 22 Febrijgry 2018

Subm ssion. 23 Febmíary 2018 25 February 2018

Pnxesurs, Reetert 26 Febaiarv ZCllS 26 February ,2018

CHMP Rapportaur Assassment Repare 26 March 2018 29 March 2018

PRAC RappartÉor AssesSfnene Réport 28 March 2018 23 Match 2018

PRAC member? comments 04 April 201EÍ 04 Aprii 2019

Updated PRAC Rappartear Asses-sment Report 05 April 201,8 n/a

PR.hC Outcortia 12 Aprii 2018 12 Aprii 2018

CHF'IP mawbísns cptnrrtentp 1-5 April 3018 15 Aprii 2018

Updated CHMP Rapportíjurí&JAssesemerit Report n April 2C18 aO April 2018

3rci P;eque5i for Supplementar}' ínformatLon 26 Aprii 2018 26 April 2018

t'í i .'rsíl-rrr -
1 Li i/::oie
Ci'i.Tírni?? fii rkkr upd'ituo' cpnsípt In íhs redrictía e Qf <íal-3, tn cQmpliííQc:; vrítíi
Reg'jíario¡7(£U)2ÚÍS/í?2S
 Submission 03 May 2018 03 Mav 2018

Prorédufe RésiarC 04 MaV 2018 04 Máv 2018

CHM P Rap pn rte ur fisse&smenit Repc rf 16 May zo l e 17 Mav ZO.tS

CHMP memhfirs commenEs 27, May 20IS 22 May 2018

Updated CPÍMP RapportaUr(S)As-seíHTnenit Réport 24 May 2016 25 May 2018

Opinten 31 May SOIS 1J May 201S

2, scíenitífic díscussion

2.1. JntrQdifctiQn

A.laiurfjn ís ccndi^lánídlv «pprrjvod in l:h« Cwrtjpq.-in Uisian (líU) Sln« 51 íwly ZOH farthc folleyciríg
Irtclicaticni;
"ír^jimsnt 5f(Mjct^snn^ m-usrjjfsr(¿y&opñy rgsvít/ng imv a mnssnss mutíitim in th^ dysuopñifi
se.pe, h ^mhijIswfY par:íSQi~r 5 y^ars aod oidsr."

Atalursn is e first-m-class oral orphani rirug designad toanahle ribcscmal read thrcugh of premature
slcip c-nd'sns, re5ulün.a in Wic fartriaít-sn -sí « fuH-kngth funielranal pnptcípi in paítente wícK nipnscnírfj
niísisticn, feftstjc dlsprd^fs- Atalijrsn te awailabia In graíinles fororal süspiifflsion it» saclists of íliífeimr
sErengtP (125 mg, 2SP fisg, amJ lOOtl mg).

Op 31 Jijly 2014, tf-<e European COTmtesion issneá aconditicns' fvlarl<etmg tocjiorteacioa (MA) fbr
atc-lüren. This impíted that che fdarkecins Aucnorteatior» Hoyer(MAH) hé.d ío wrnptece ongcing stuciíss,
cnd 62 conduct (PTC124-CD-Í120-DMD [Stady 020]) as a Specffic Obligaticñ^ in arder to confirm thac
eho rink-bf^ncfiC híil.sncc In pnsltivr: and la provide addiWonítl date. Thonc düte fgrrmcd thó básb nf tbo
re'keí'íal of rhe cendíiibriai MA, The berifífic/risk hsíi re-eyaluaCsd aysrif),g ciie renevíai proceáureiii
2lHb.[n No'j^raher 20T6, Che CHMP conicteded ií»aC thecobdiCiona! ra-ahíeCíng aultiorisatícin couici he
renevíeí con,5Íiíeri.flg ri-.ar íhe totaiiby of the dinica'' ciara 5yaílBb.':& coriCinued to suppott che pesitive B/R
ofíitalyrefi In the conteict of a oanidipgnal .approval. TbeCon^mittee aisc tcok inco accwntthe race Chat
the MAH, propüsed an updated conFlrrostory study design, bulit upon the raiast currer.t knowlecfge of
thc tlipcHteo ar.d Ite nélur.si prosrcscjipni,, a-s wcil m pn. the dsta g.sthiercd frpm the previeuíf tiúidlesf, «nd
cc:r.slc!e''ed it appiTjpn^ce te see/e as a spiacifo obigaflcn tO' ansv-er íT^e rfimaining tfncerraíniOes in ths
cmtextofcondihonia! marketing authorisati-gn.

Trii the g,arrfintappfication íhe MAH proposes to lowerthe agelimít Origiriaiiy the MAH proposed Do
perfbrm clinical .studlss m chlldren frorn 6 months - 5 vears, Howeye"-, the PDCO conducíed that dueto
pessibia different PK and caffipy concarns, ths dinical stiidias should hespiit ¡nto two difFerant groups;
6 mcn.lhn - 2 vears .;¡n.d 2 - Syearn. Tákíjn iHp írcjn'Scrnn frcrp the POCO ir.te aícaunt IHc MAH h»5
petformee a ciinical .5Cedy ir» 2-5 '/ears. The í.arrent proposel is to chanoe che indioatíon to pacleocs k
évears because, from a dige,5»e patholcgy perspective, that trestraent for DMD wonid he most
efrective whign mitiated as eariy as possibie te the tourse of the disef-ss.

ri-'-T- iiju .hIi '' "I

:• •■Ai'-31 - i i/zoi c r.rjc 5,'.: a
Ifi rhiH bysd.ites' «.rsiício cansfcC in fchc redat^tíño a(p,sr^naíd-iPi», i'n cairípli.KCf; r/i'h
.í?eá¡yj.'a-jni7 í'EL';i 2Ü18/Í72S
In summgfy,thé corrent sufeTnlssicm concerns the resaest fbr the extensión of indicatíoii t® inducie a
rieví papulation (chíídren from 2 to fess than S years of age)fbrTránsfarna fdr tfte treatment oí
Dudienne muscular dyEtnQphy resuiting frtim a nonsense mutación In the dystrophín genein
ansbulatory patlents agacS 2 years and oider.

The propssed recomm^Tuísd doseand schedule oí scaluren im dilMreii 2-5 years of age is Che satpe as
chafe appnoveci for children & 5 vears of age, i.e. 10 mg/kg body weighc in fehe momirtgr 10 mg/ks bociy
víefght at middsY, and 20 mg/tsg bady v/sight In the evaning (for a teta! daily doss of 4Ü mg/kg body
vfetght).

2,2, Non-clmfcsl aspecis

Nú néw ncMi-clinleal dafea have beén submItCsd In Ssis appyc-a*ióft, vyhich is coásiciáred

2.3. címicsi Bspedts

2.3.1. Intrcductíon

ecp

The dinicai trfal supporting fehis appiieation was performed In. acsardance with (KP as claimed by the
eppljcant.

The MAH has provisied a statemenfe feo the effecfe thafe cliatcal criáis wndPetad outsids the cofmmunity
were carried out ín accordance wlch the ethfcel sfcandards of DIrecCive 20Cll/2Q/tC,

2.3.2. Phariiiaeokiiteties

Tha basis of fehli sabaiiissiofi is Stiídy PTC124-GD-030-DMD (study 03€lj - a multípte.'dasef opáñ-íabél
stiídy evaiuatirsg Bia sáfaty and PK ai ataturSTi in pabents ag^ a 2 Lo <5 years oíd wiCíi nmDMD íor a
penad of 28 cfays|4 Víéaks). í n arder bo coliect i'onaar-term saFetv and so me éfTitacy fijnctior.al
endp»inC Imformótiara {l.é. TPTa and NSAA asaesamonts}. a 4S-'.«c5ek ojitonsian ph-ise ivas addPd.
Thé role of thé pharmacokinebí data in thÉs épplication is Lo show comparable atai'jren
pharmaookióétics in childrén. 2-5 yéíirs With thé phormachkinetíGS in óldér children in ordér to briiírté
Che cffh»s,y «.nd íráiotY from chii.yrcn a 5 yoars oí <tgo feo chlidrm 2-5 ycarsof For thet purpos® an
tspdated popPK arsalysis Vías presenled,

StHdy dcíian

Study 030 Vías a Fhasa 2, mulCiple-dose, open-labe! stud'/ evaluahno fche safety and PK cF ataiuireni b
paciente as-sd a2 te <5 veors wiCh nmDMD.thé sftfdy bciwdédn 4-Vi'ée!< screetifn^ perlod, .j 4'Wéék
feri5#tmcnfe pcrlGd bp évalurtósaíéty #nd pharFftScótórfetics,. & la-'ívteck cjítension porlod. and ^
íoltow-up period (eo weeks totóí), Tttg PK evaluación wm conducted ¡n toe Firsc 4 vreeks (d®Y l and
day 28), which atso bcíuded saíeb) asssssmenits.

The resuics rrorfi h párJuldKin PK simuiation ^MpiíórtíáJ that a sfeistly design of 12 paCtents vdtb T-poíni
sannpling aftér the mornmg dose (semple sise and sparse sampJtng stnafeegy) tvowld pra-vide adequate
daba toasséss PK In childrén wííb nmOflDagad 2:2 Lo <S yóárs. Tiiisdssigri was ágraad upon by tfsé

'í.-.n Oí -iii!C5tH-Hi ví-narcT r,5«'.= <ic : r»Mn

•CTt.YffOífS !ri tkh tipéáKd Vjrraóri líonsitrt te íAe íe-dactióñ ef p^nxináf in éómp&íéPü ','fith
Rsgijlaüon(£U)2ÚÍ8/172S
p^diatric Ceromíttee (PDCGÍ sf well as the Modelliríg and Simalation Werking Groap (MS'WG) ttirciígh
a Scientific Advice 'jVorking Party (SAWP) cansuttatían ÍEMA/CHMP/SAíiVP/34612:/2ül7).

Patiencswereadmrtiistered atatare» J-cimes psrcfey (10, 10, 20 mg/kg). The dnjg product lots used
werfl the granutes fbr a<7il suspensión forraulatlon, ivhích ig the.same as the marketed fhrmulattani ln
the European Uatoni <EU), and die ona used u Phasa 2b PTC124-GD-'ü07-DMD and Ptiase 3 PTC124-
GD-02Ü-DMD studies.

aiood samptes were catecbed pre-doEs and at 1, 2, 4, 6, 8, and 10 hours past mormtig da^ on Days 1
and 28 to provfde Informatíon afaout Day I and steady-state ataluren, plasma concentrations.

(^nventloüicil PK parameters of ataluren an Day 1 and 38 were. derived by nísn-compartmentaf anafysis

(NCA), using Phoená WinNonlIn® v6.4 software {Certara, LP, Rrinceton, KJ, USA), PK pararoaters
SLKhi as AUCfl-s, ALfCo ;o,i Cud» (Ü-6 hr), tnaí Í0"6 hr) «era caltulatad as approp ríate for Cay 1
and Dsy 23, the accumulstion ratio fAiS^en Day in, ARíAUC) and AR(Cn,.;,)'werealso calculated,
Lfsing the nreiDMD P.elatjve F Modal(2017)'«th pcoled data from healthy volunteers, patienits vrith
rsmDMD, and patíents from Study OSO, aPaíuren plasma esposuires and athsr PK paracneters suth as
AUCo-hi Cubí, and Ca-erCi/F, end Vsí/F were esfimated artd coraipéreíl wHJi tii^e estimated fot
nmPMO patisnts sged t5 ye^rs vjíio received the same dosing rafimen ístudies PTC1.24-GD-0Q''i^DNID
and Prcl2'5-GD-007-DMD)(as di&cijgssd ln the pspulation PK irsodelting helo'w).

Popufatíi^n PK aitafysis

The popuiatton pharmacokteetíc (PK) roodel foratalurer. hssbesn reflned overíime. hased upen ths
avattehiiitv ef date fnnn. varicus sfesdles. The data froro a recantly cempleted study in patients yííth
nmDMD aged 2-5 yeare (Study 030) and from stuáy 025 (interactton sftidy with rifsmpin) ln heafthy
VQÍunteers wers pooled wlth data fram haaltlsy '/oiunteers(studiss 001 and C02) and patiante with
fsmDMD whc had partidpated ln Studias 004/0Q4e and 007/0070, wíiich had been usedto previousíy
develop a populaban PK modal fa r ataluren (SCPD 00321-2).Tha pcpulatían PK mcdel has been raRned
usIng the popíed data. ]n additibn, several activities were parformed tocomply wlth rdentlficadvíte
that ivas pravided hv theSAWP in January 2017 (Efy!A/CHMP,fSA'Ai?'/34612/20t7}, The primary gc©fe
of the anafysis y/ere as fpüows;
□ Refins the pneuious papulstfon PK modal, bs fraoarparace tha data Frora yaungar pafeents (ages 2 - 5),

□ CwRrro the driver for the decrease in ataluren sxpbiure ydth tí.me (i.e,, ti me-dependent refative
btoaMailabillty or time-dependent clearance),

□ Conduct a cevariate analysis te identify any other patlerít characterisics that are associatecl with the
inter-iníji¥lciual ygTíabifity m atalureni pK CincItnJing cpnfrniatien of the preyfousfy tterived ceefficEents
governing Hte relattanstiip betwean boiiy weíght and clearatiice or volume), and

□ Rsfine the presentation of preriiction-ccrrected visísal predictive check ptots to rotraic those most
ccmmoííly presented in the litensture

Tni the abave nientipi>e.'i 6 studles, atafur©! was administsred praily wi-th doses rangínig fncm 3 to JOO
rpg/kg. PKdata from 76 heaithy voluntsers and 226 nmOf-ID patiei^ts Víere included in theroodel, PK
data from study 15, 24 Japanesa and 24 nan-Japanese healthy valuíiteers adminístared a single tóase
5, 10* or 20 nü^kg of atalureu granulas formulatíois vret^ usad as esbarnial valldatlcn.

PK matíst stfocTúTe

The PKstnjctural modd «sed rich data frcro healthy yolunteers. The primary styucturaf model ivas a
tvro-rampartmerit model wlth fl.'st-crder absorption and linear elirninatlon Thetmpact cf Food en botñ
rRvp £j rff-t Qt niirpriO' ."ri?!::'-'!? "
íMA'-WllM.fteie s.iqD .TK3
Cfiíifís& i'n fjírfe ii>.sr$íúo ccingfef i'n th^ fédíetís.n nf p^rs^nál ln complíapcP Vfítl\
RsguSa-icm (£U) 2ÚÍ3/Í72S
Cfig Fate (ka)snd «xtent (relstip® biasvailaSilto' or F) of absgrpttsflj, m sell as tfw impact ©f dbrnal
variatíoFii {e.g.f fmp&ct of imorning vs. evening doÉng) on CL.i'F, were assass&iJ a prtQrf as part of tim
stractural Pí< modaL

The fitmchiraf mpdel paramerers were tNn re-estimated after paclíng tfte data frem fehe fia^hy
volunteers, nmDMD patients and cyssic ñfcrosis patíehts co aHaTS' Por tssting for pobanBal diFPerances
beCv/ean ths three popolatí-ons. Abscrption race dependent ora dose and reiatíve bioavaiiabíiity
depeitíant on tlm« wlth time), fermtflstwp {day 1), cr diseags state (at steady-state) víere ipcludecí
into Ehe roedei,

Thts populación PK(popPK) riiadeí vías the base modél and reFined váth Che pod®j data from tba fi
stuiies- ÍB heaitlíy ygíuntsers CN= and pmDMO patiente, PK dafe from cystic fibrosis paíents were not
lotrger licluded in order to enrich íhe PK datasec fiar nmDMO paíknts,
The decréase in ataliírén éxposura over Cfrae was evahjated by ttme-dapendénc reteilive biaavsJIabil'lty
and a time deperkent cleáraBcs ruedel. Afn«iel usEng allcmetnte scafipg Fe.0J5 or.cíearinceaníi 1,0
for vcluma oí tbe centta) connpertmenit, was tested b,ut foursd iipstabie,

QJVdn'aíe ünñíysis

Afterupdatíng the Espantfed Model (2013/2014) using thie addilíonal PKdata, a Fcmtal csMariate
analysls was initiaced in NOPIMEM using stepvíiss Fotward saiéctían. Ccntinuous descripCors thaC were
évalUabád faf tháir pct&itlal bü eXpiain a pürtlon at tha Inter-indlVldUal VaríiblllEy in PK paramettsrs
Incíudesi age in y<=ar&, weight in kg, helght Incm,. BSA in BMI In kg/m-, andicáleídafced CLcrfrs
ml./min/l.73 mT Categórica! covariates Chat'Aere evaluatñd Inciude sex, race, padent status {healthy
subjects, nmDMD), FormulatLon, and potenhally scudy íf Víarranted.

StepwÍEe forivard (6..&3S chapsi to the MTOF |<J = O-.M, 1 df) «od besifvvard eiiminatíoís {et íeast s
10.S3 increaseLn the M'i/CF (a = 0.001, 1 df) was appliedtíi setect the coMariates.

Mm'sf Evskmion

Modél evaEüatiani wasassassed by grúphicai eválu-itfbnoF stancfard gooiness^of'rit plóts, ás wéltas

pipts oFthe eb^rved aitd predirted concentrgtlQni-time proFIfeSrexattiioatíon of the predictect
parameter estimates and thet preci'skn (standard error of the reearii} ?.aci compsrisoa ef ¡íiese '/elues
bo hisCorioei resijits. A predIctloni-carrecBad visual prsdictive check (pcVFC) v/as aiso used to assess tha
ability of the fixed and random effects componenCí of the anal PK mcdsf Co adequat^y describía Che
obse-%'ed ataluren concentratíors-time data.

The fit of the time-depenctení refati ve bioavaitsbitity and a tí ms dependent claarance model were
ccmpared by graphicaíi evaluation cFstaadard goadness-oF-fic piots, examination oF Che predlcted
parameter astímates and Lhaír precisión (standard error of the ra^n). Further the mcdels ivere used
to prscfíct tile pfasma conoantritíon-time profiles for the siJbjects from study 025 when ataluren wes
ijfyen in combination with rifampin.

Genorafíofl of FK Expa^rs:.f-feasu/es

The Individualj Bayesiaii post-hoc PK parameCers from Che most appropriate modeá wers used to
simúlate plasma atalafén concéntratiors-tima profiiesln ordef to ^tímate Day 1 and steady-státe
exposure (CtnaK, AIÍCO'24, and Cave) íorthe patients Irorri Study 030 ¡3:2 ánd <S years age) Included
in the analysfs as ^vell is tsie patients From Study 004 and 007(>5 ye-ars age) vjIip received the same
dcge regiragn ss thpse in Studv OJO (10/10/20 mg/kg). Note that, diie to the sparse sampling
employed in Study OSQj the simuiaCad proFile contained augmeraCed dmas in order to provide a mora
rtíevaniC comparfson to the proFile from patíeats in Study 004, víhc tvere sampled nefatively intensively
on Day I and ac steady-state (e-g., Day 2S),
s .'..n.;-:;!.! Qf .líiimnrs. wisrci e:5,?s:-7ie: -i Rísoft
I2-1A«3 !lH,':-01E fiiail-Q.'G3
Chafí§ti.^ i'n tí').? PpoiAfeo' Víraéri cótisfeií íñ ths esdKtl&n of psrvup.iiií data, In óotnplioQCé with
Rs^ulavson (£U)2018/Í72S
Modsf-Bsssíí Simui&tíons

The finsl pgpBlétraR PK m9ds( wMI be useá as the basfe rór rtisdef-bassd simulations «f PK resulcs Irom
Stuíiy PTC124-SD-O30-DMO ÍStuíly &3<3), a Phase 2, open-labe# stttdy of thesafety, pharfiiasokinetFcs,
anri phsrmarodynaniiicsoFaE'alijnenc in patienrñ '.vlfch nmDMD agftd Pap te five years, Theobjectlve íif
th-e simulBÉton exercises vjil! be bo asssss Ute expscfced sxposura to aCahren tn chüdren a^d bAO ta
(Tve years of age receiviag Che fabalied dait/ dase of 40mgyfcf/doy (as adminisCereJ fn 3 doses of
ID/LO/ao ma/kg)to assure roa: expasure is ccnsisteot across che age continuuEn,

POPPK ANALYSIS RESULTS

Param^er estímate? and associateci standard errors Frcm tiia fit af the nnnDMp Relahve F fvtodel
(2017)to the data from healthy subjects and nmDMD patiencs are pravidad ¡n Table 1. The paranieters
relativa fatoaYaí'iabirity at sCeady-state (FSS)for hsaltfiy subjecte (O^Sfifl or 56.8%) and fcdec(0.0113
hr-.1.)'«re fixed to the final «tímate frorm che healthy swbject models lo the pre'vious raport. An
atcemipt wss made bo Fit th,e vaíue For TSTART bot the respfcsnt v.aiue iva? coosisterit 'Xíith doe prei'lops
estímate of 60 hr and ivas estimatad vílth poor precisioit. Thus,tihi? parameter was aiso Fixed,
Slmllárty, the valúes For FO and FSS far the PCB and granules Forntiulattons 'Aere Fised tiO' the prior
estímates. The ñnat estímate oF FO wss 0.642(64.2%) cor the POS foraiulatíon and 0.SS8(89.&%) For
Cha granules ñormuiabon. The estinnate oF FSS vías 0.568 (56.8%) For baalthy Kibjects, and was
slighcly ioweríFSS ='0.414 or41,4%)fornniDMDpatient?.
Tablé i Parameter éstimatés aiid associated standard errdrsftom the nmDMI>
parameter Fipai esllmate ríSEM
AbsoípKon raía-censiarit, k^ {nr')
kt,(Fer a 70 Kg sudjíci ai'xen 20 mg.'kg) 0.&32 9.72
ha-Do&e power -0' 501 0.770
C'carajics, CUF iL/hr^
CLi'F cocUdeit for tveníngi eítcss and a 7S kg odiili. 3.03 3.29
CUFAVeíght cavier o.&eg ®,9a
Píope-ftional síillt In Cl/P for mornlng or m.aday áosee o.ass 3,3.4
Cent/al 'volurrie oí tlislnbutofi, V^íF iLi
''¡ér coeffiíierT <ior n 70 kg aibjectl 2S.9 7M
ycfi--sVegb( ppwer 0,3.08 2S
Pcríp'nerat'.'nSLfmeof aislribuiion. V^j'F(1) 0.425 «3.5
Oistributíon cicerance, CL/f lü'hr'! 00139 7,13
lailial rela'.ivB bioavatla'ikiity', Fj
Fg for PIB toimula'JCfi ti FIXED"
Fd Far POS íotuudaíiDn 0.042 FIXED'
Fr,for QranUle fñrm-jtab'gfi 0.895 Fixeo^
Rela:l'<?e bÍKivejlabfílty at steacSy-atete Fg^
Fes Fer heaHhy subjects 0.568 FIXEO'
Fes for nniDf® patiena 0.414 FIXED'
Fiíst-erder rata ODnstant for déel:rta in Fj to F»!. k,.Bf ihr"') O.tn 13 FiXÉO'
Dels'f In the on&ei or" itie rfecUne tn Fr. to Fs?., imjim íhr) 60 FIXEO=
''«"isL'r «D.0741 [;27,2 %C"/S Í1,.5
0.267(SL^TICV) 11.2
0,336 (91.4 í-iCV) 22.6
0.161 MO.I %C¥;i 23.-3
W F;". 0.001® (24,.B%C¥) 23.4
ResJ-dusi'N'sriablOtj,'
Log errcí {SDi fer heath-y aiijjeccs 0.172 CO.dlS) 1 .1
Log error(SDj fer renDMD pailanK 0.349(0.531) 0.914
Mole, .Alibfevcaytsosare pro'íáled in Oie áiAreiflaÜon Lhteig.
1 Tnese tíarsmeiers wsre lixed co tíie ínal es^rrates hom ilie previs-isi 0riaíy5l&(IJ.
b T-iis p-ararreter was initfally ñt:o íne updalsd datase: Ttie resif'.lam eelimate nesiíy Ideniisal
to the prevb'ás estfma'e biii ',»,as es:rnaíedv,ií'i pm.t precí-Hisn. Thusihe paiamgís' valué '.■■■as
toed ta Ihe fmaí Eelmiais from ihe ptevlñiia anHl.ysls 111

-h'XP-"J-ilf ."O t:'^ "uif'.nci'.i* nfro^

: '-"'A-'u i L Piian ítf'cn
ChsnSfs tn tkh optFñteef v-^rsvod concfei', in th^ r^daction oF dctía, Fn cotníJi'ÁT,i?GS vdth
Reg'j!a-toi7 (EU) 20Í8/Í72S
ielow are eqiaiíions descrtbing the populatbn meap reJaEíQnshíps for ka, CL/F. Vc/F and relativa
blosvallabiHtv (F)oír íhe titinie<lepsndent relativa braavsilabiHty moiial.

■ ka {hr')= 0.97S*(Dose.'1
• CÜF i;Uhr> = +0.445-AM) wtiBre Aívl = O fot an
evoning dísso aisd 1 for a RsornÍEíg of tnld ífay doae
• ViiiF ílifer) = Z6.S»{'ATKGirO)'^-^
• Réjativá biDavailabi|]ty(F)at any givéfi lime:
1 Wltfiíi TSFD < Ts-mr, F ^ Fd:
= Wben TSFD a Tí.tart. F = S* CFí,s- Fe,).sxp'i-' '''
The prlmar|,< goacfne.ÉS'of'fil: pióte íortha fifi of teesjcistíng poputatiop PK, nrtoáel te'feha-opd&ted daíaset
ons providod In Figure 1,

Fliwre 1 eoodInesE-of-fit ptots for the appTiciation of tiie nmDFlP Roíatlve F Model
(¿Ol7> 'íó the pooíed dstas-et
IíYk}^

rtj' rg?. rr^T' f'-'-Tn^ i fv ñ^s> s rtm "ootTí

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PopuUtiDn ^ítíod ConcantTalicfT ^uqi'mLíi ?ki^D Sirco Pírfft Do^o

The pe-VPC pfote aré prsvldcd h Figure 3,ñQure 3, grtd Rgurc 4 far sil »ubJcck?/paÉlcnter nruDMO
paCisntE oiiiy, and Study 030 pátlente cnl>v ráspecctvaly.

Note Iftok Ihedatá from Ihe óJítehsfoEí étutllés {004® and Q07e) woré nel írsciudéd In thió pc-VPC pióte
tlue to Hié érítrernelv long tteríof tredlrnwt, ^vhich result'!??] m dfoíágB issués, Havrever, Lhese pUíí»
are coñ&icfatéd surricient fdt assessing ths prádlctive áfcélity of Elié mcdél at síéady stáEé as all pallents
tétéivéd at l^st 28 days óF CreatmenL

ri-'V.n a.y,-.-- tif v.,T|?rt1 ."'SOCIC ■ ' RmJ"

rr-w-ij 1 cw/:oie Fcq-j jo/ca
•Cbítfaiif^ In thh fjpd'.ited' 't'^rsiao oonjteí ín ífio re-diíct¡a,t} Qfpsraono^ íFala, tn ¿oiwp.'.'.ífjcs ivif/t
feíPJ/ar/OT .f£ü;i 2Ú1S/1725
Figure 2 Predlctiqn-carrectEci vfewai predietíve check plotfar the final poptilation
p(C tnodel (time-ilependeut reiative hioavaífabilíty) usíng data fraw healthy
vólunteErs and patients with nmOMO

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5 10 15
Time Since Prevtous Dose (hr)
Note: Abbreviaticns are provitíed inifie AiibreviaFion üsting,
Fl-ot.(i#ñii55n' npen citcfis shft'«' Bis ptedicitofl-ooFi^ctíd pbsarv«d aiáluréft p&fietpífskdfis wük thi
is-dlan and 5"V'a5" pÉíd&nüES cil tlie píediciton-daífects-d obs-én/ad data shov^rt |ni solid and da$ted i'ed
linas, raspeetiVÉli.', The red shafiad reglen fe trie 90% psedístion líitsrvai ror ihe «ledlafl sit^uiaíed
írediction-ccjíTecterl Gonc&htrstlons and ítie bli?e siiacted regions are the 90% p-redictloTi friEefvsl fojihe
5'" -and •35''"' perceniiies of the predicticri-coiTected simuliJed'data.

'--..T a. ;fi : I iijic.iiULt"' íí'isre 1 r:'j?'..rTic • rarj-

Fac-3 il/02
in fffte tjfiéiitiíd v?rs/c!fí eonsbt ln ths f^-dóntinfí dA% in :cifr)p¡;\ii^CS VfHh
Ñe^uíation (£U)20JS/Í725
Figure 3 Predíctian'-carrectEdj vidual predictive check pfotforthe final puptilatien
PK modej(time-deperident relstive blcavaifabillty) usfpg data fratn patientis wlth
nmóMp ottiy

-g 100.Ó

■|0 ü

1.0'

0.1

■'ü 23

Time Sin ce Právlous Dose (hrj

Kóle A&biSviaüvnS are prov.ded i¡:i Ihe AbbfevlEi'.rái! LiSting.
Plol úB.ímrÁGn: qpEn ciraiss stioft' bie prEdrctan-correclsd obsanesi aíalpjren concanlraliora 'A.i-h ilis
mecIsiTií and parpr.gnfitjs of ths ,crediclicn^'5crr®;5©;l daía chov.'n in «.olid antídashed rad
linas, rcjpftpgnlivply "Ok; rcKÍ shndntí ingfen ¡í: tha SIDIi prc-ritc:li::-n iPilarerjí fcr üio madinii sits Jíilac
pr9cRjt;on-corr5CiepJ conoar.tations ard rhe blue íhaéad raglons ars- -be &0% pradiirpfcn mier-'sl for hiE
5'^ yrid 96'* peioenr,"■&£ ó? Ihe pi'ed«r.iit--v<;ó!riÉ'í;ted íi'nub.i'éd díilí

■il 'i' idfi , •íí' ■!. í: ■

i'-.vu iii fávj jn/o
fn th/s up-d-ités (i».f,ná'Dí5 ccjnsfei' in ths re.dacfhn af p d-n-j, In cí7fnpi';..fi705 VíVíb
Ragu!s-scn (EU) 2013/Í7ÍS
Figure 4 Predictlqn^ceri'ectefl visual predfctive check pIotfar tFiB final populatiori
PK tnodei (time-dependent relative bioavailability) uslng data fram patiepts wlth
nmDMO enralledl in Study 03P only

1CD 0'-
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Time Since Previoyis Dose (lir)

Note* Abhreviaiions aríi prDV¡d«d in fne Ahbrevialion 1 ísling
Plol d&finitioil coen orclss si'iov..' ths pisdicijoivixífe-cted ebsei"V'&d- ataluien cciosirtraticsis wiHi- ihe
niedisn and parcenriles of (heprssicticn--corr&ctec! o&sen'Oij data shc-vn m solid ond dashedrcd
finas, raspa-rüvaly Tne red shaderi rsgion la ihe 90% nrediniiQn mleroal fnr fng me-dian .ainijlated
pr&Q'ictlDn-corrtcíod concí-nLations antílhe bliie sbadcd re gí-ons are :íig 90% prádiction inian'al Íorího
5"' and 95'" porcartiles. oí iha pred-cticn-csrire'Oled Eimulat&d cata.

External Valldation using singie-dcse adult data In order Co aEsess tha ability of ehe rtmDMO Relative F
Mcdei {¿017) co i:af!rur(istng!;&-ri!05eíle:e obcarinecl frorn dciulcs rjióí wert tiet ¡ncludeí tjte
developraent of the model, a rradlcional '/isusi predi-ccive check (VPC) wan consti'ucCed Ths involved
Cha replícaticn af rhe Sujcív Oi5 da ta ser SOO times in grcliT to simula&a cerncenrrationi-cime pnoflles Fci'
Che 48 scíbiects vvhile incorporsring Che intDar-iridiv.idoaf and residnsi 'jarabiiic/ ñ'om tiiie final pepuladon
PK rnacifil . Tfis rasultanr VPC plata ars provldsd in Figura S.

i.:o3C : í:
Cíiií.'Tpí?? in ri?fe tJia-.V.iffjrt' to.nj.'píj cfjnsíjn' i'n fh^ f«0'nc;tiurj pf .i^iprsip.n.i/íJ'.íí.r, ín catnpiñmc,?. vrífh
R&gv.'arson (£U) 20Í3/Í72S
 (
Figure S Vtsuall predíctíve cbec|< pEats fa r the applícation of the nmDHD Relatfve F
Madef (zcii?) to tfíB data from Stndy OÍS
íkíSH Img/r-gj. ■ii:í\g.n'.y I. 10

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Time Sínce Last Dose {hr]
Nr,!.S AbbJ'i3Vifi3Hjn& aie pí-uviuari ím Uh. Al.iOiuviírtsii LfeUirif
F^ot d®íin!i¡ori. ope-i crcles .5,iicv/ the obsorvsd ataluran concoriL-íitbri:- with Lho mc-dian and
p^.! cerriles Oí 6h5' C'bsetv^sj ;i5,ia shown m scíid nnd rJasímd red lirws, t'éc-pediivply Ths red shsded
región is ih= 90% prediciio-n tní.eiT,'al for ■ih= rreclan simüatec" conDenírahons md Ihe biks ehaded rsgions
are die 4-0% predictton ini&rva! fcr ths S"' and SiC'"' perceutileE. of ihe simulaied daia

Bieanafytícs! assay

The qusnhteüsn ofafalJren ¡n htimai pla-smi? in ttie cliriical studle» was csmed owf using vülidatBá
llnuid ctírcrastogrgph'í-tándem nisss spectromeírv (IX-^IS/MS} ass-to's vílHi higi sensitivio/ and
spsdficity. as prevrouely daKribed fortfie MAü prscadure. The '/alidatían studíes demonsbratad that
íhc prcréduros fer thc detcrminÁttan of .-ttalurcn in human K30DTA and KíEDTA íiro
and reprodúcihle. Tabulare:'! below ische siirnnuarv oí yalictareci bicanaivHcai merhcd usad fc r sfetfy
030. The methicd v/as carhaMy revahdated Co reduce the r.atT,ple aliquot velime from §.lOy mL te
0.0250 mL ín sispport of pediatric studies.

~ "H .r ídb nrM ■■ í r ~!P

k,.";: i.i I.':/!!: j >
CdrirrUf?? in i-kh^ !ip^af:tí3 u^ns-íoi? can^wt in rennctTm nf <í'.tííT, in •ivif'i
Rsg'JÍadon (BU) 2ÚÍS/Í 72S
Tabla 2 Assay Validaban Patamelers for Bloanalvtical MetbadI Us«d to Assay plasma
Sámples Coilected in Atalureíi CUnical Study, PTCi24'GD<030-DMO

inVenrtíw Health
Parameter
Plasma ataluren

Valldfttior» R.ep'srbs ig 183.€17021S«

Method LC-MS/MS

Regressian/ Liiísar,
Vfeighting 1/s®
IS aCalurerj-D4

Sensitivlty ranga 0.5-ZOO pg/mL

U.C-Q 0.5 pe/rnL
Anslyce reotjverv (mean) 35.5%"

IS récovery (mean) 33.4%"

Cal Sktj inter-ttssííy prgqipiiíri {%Q/) 3.75 to &,CjS%

Cal Std tntaf'assay accisracy (SliRE) -2.20 te -3.00%

QC samples 0.500, 1.50, 20.0 and 150 ptj/rnL

QC irttra-sssav pnacísioni(%CV} 1.07 to 14.6%

OC iitCrU'írsSay SCtUrBcy (%RE) -12.2 to 12.3%

QC inte-assay pcedítere (%Qi') IJ2 to 13.6%

QC inter-aggay acaaracy (%RE) -0.367 ta 0.00%

□iluban llnearíty id-FoId (0.1 álluttPn}^

Fraeze/shaw stobillty 4 cycFes at -20 ®C

BenchtPp Étábtllty 23 hours at amblent temp^^ráture

R.eFVigefatiofii stabiIlty/Post- Preparstive 39 hewrs at 5°c
Stafallity

Ljc«ng-tarm stahility ISIÜ days at -ZD'C (KiEDTA)'^

^ PartigI vclrdatian
•"Estabíished during partía! vaíldatlon U3lng"TM>3i9S Ih toVentív Repoit Pto. 5768.0S07'M
Esteblish.ad dürrhgi parEií^' validátí'ón ústñg TM.BSS ín inVénbV Répdrt No. B4S3.073014
Abbreviatlons: CV - coeffidant of variatian; [S - Ijítemal straclsrd; LC-MS/MS - liquld
Gkrgrna.5íifríiphy/tanáet5ii sp'^lrg.pnetrY; LLOQ = tawíir Hmlt oí qMontitatlQn; = ^uatlty ranlrolí
RE = rel.ribvi «fror

Study 030. Human píasisia sampiss ware recáítfsd babiváen. August 31, 20LG and Pabru-irv 2S, 2017.
The^ Irncbded 195 saraple-g for análysis and 1S6 dupltcat-és (1 duplícate sártiple aijaiv'íéd ín píacs óf
primary sampl g oí neo pHmary sa mpio lobo was ompíy), Al! Gt udy ^ampios woro recMsived in acGaptabte
ccnditlon, frozea on dry ice. Study samples,, bíanlíE, standards and QC samples'ware kept at
approximatai v' -ZO^C. The in Larval from First sampEédráVí dale to iast ánalysis data ivas 233 days.
AdaguaSa tting-tépn stábility (ISIO tfaysj nos béan aatablished to Covef the dinicM Sairsplés storága
period (233 savs). In slüdy performance showed a presislon oí S.G to 7.9% arad accuracy withln -4.0

Idlir.nú. r-.-SCI-ne ■ iluJ'";

pjs^í is.'c
Ch,:fn¡i«w Ip rhis i»i»d^tXíd cónsfeí íp (Lite ^(fecfíaj? of p^r&naí éata, ifí cpojjpJIfárít» W«/i
Rsguíatíon (EU) 20Í8/122S
to -2.,5 %,íncuirreiS ssrapte rei:n.gJvsis shovíed thgí s-l ratufss are vílthirs the refjroducibrlity critejia of
tha irrference valúa.

Resufts
Summary stetlstícs oF the .clemQgFaplííc anrl ctiriiggl labóraten.' Information for tbe patients from Study
Q30 are provlded in Tafrie 3 Summaf7 séatistics ofthe canclnuaus demograpbie and clInlcaS taboratory.
The subjects from Studv 030 wera pre'dorainantty CauEasian {11/14, 7S%); the ra^ainilng 3 patíen'ts
wene Asían.

Table 3 Sutnmary statístícs of the continuous demograptiic and clinlcal laborotory

ilrfdrtnatíoti for bealthy sübjects frofnStudy 03Q

Variable H Mean (SD)! Medtat): Mininium Maitirtiyiti

Age (yr'i 14 3.43 {0JS6) 4,00 2,'QO 4.-00

WéJghl(kg) 14 17 0 [3 26) 16.4 132 25.2
BSA (nf) 14 0.671 {0.0734 j 0.660 G.570 0.830
BMI(kgW) 14 17.1 {2,22) ie,s 14 B 22.9
¿■.a. b
CLor{mL''íniai'1,7-3 196 (36,6)
14 201 127 247
Note; Ab;brwi8íL<5n 5 are provided in ih & Abbrevlalion Llsting.
a. Caleulaied for átíuftó ato ybats oí ágs Usiilg Oúc-t&jOít sird GawJS Fc-iniUla áfier subáblullng IBVV
fcr V.TKe if VvTKíS =' IBW ?rid ihen mu'itiptying by BSA/1,73, To prevent «nreasonabi? CLsr
estmates in adults. a valué oF0.7 was substiiulsd far Ser íoi Ihe calcutation of Clcr ií S^r < 0.7.
b. CalciSaisd in p'ediairi^ and adatescents 18 years of age using reviasdl Scftwartg aquatÍQ». Ta
pi6'<fartl tttHeassfíS.ble CLcr eslirnatss (r« 'Ctiildren, a valu® of 0.4 '¡A'bS sübsltiutád íor Str for the
eslculaiien of CLcr i Scj c 0.4

PK aftafysís tiaing NCA ifieth»és in patíents >2 te <S yernta efa^e

All 14 padenís completed the PK pbrtion of tlie study. Mean {SD) plasma ataluren concenitraBan'-ttme
prafiléS áC Day L and Day 28 .are pfesetatéd its Fígiiré 6. Tfié tfiean plasma cPfícentratcfl-time 'tdf'/eS
folloVí a siiullar paLtern an Day 1 and Day 28. Péak concentratfcns bra sean aróiírtd 2 hours pcst tfie
morr.ing dsse and 2 h-oiars post the seccnid dose ñor most patíents, The seaind (mtdday) dose of
ataluren was administered 6 hicrjrs after tha first dase.

,-'i i £if '«fjif MpriBL-c 1

11i'1/zDic iO/uD
Ch.intíi;a ¡ri fhh típ^atss vcrsvoft oonsísf in thn rediKfiasí of psrxx>n>ií dnlei, in cemptinQCs wíth
Rsg>j!a-ion (£U) 2Ü18/172S
Figure 6 Mean (SD) Plasma Atalucen Concentration-Time profiles Foliov/ing Admínistratíon
of AtalurBíi to Pátiants Aged >í to < 5 Years 0!d witli njn&MO (N5il4, Study 030)

riív li • *• i>í.-. ,

» 1

Ibu-.S*...! lAx.;:

fltaiyren PK psrsnrieterr. arg prasantad In "?tte 'i- Mfiar,[5P] fi UCj.c.j AIíQ-iq, a.iri Cu,,. {0-6 hff) for
□ay 1 '/íere 53.03 [30.IS] hr'|jg/mL, 101.64 [5-3.S2] hf^g/mL, and 15.95 [S.Slj gc/niL, respecbvely.
Mean [SD¡ AtlQi-e., AUG;, id. íind Cíi¿,. (O-Otir) for Day 2S at steady staté Were 4],G3 [14.65] hir'yg/mL,
82 13 [27.41] hr^iJQ/rnL, ond 12.54 [^3.41] ua/mL respedively Median t;.-.;, (0-6 hr) v.-ás 3.97 hrs
{1.92 tí5 G.02} an, Qay 1 iir.tí 2.00 ( I.OD l;o G.{l-5¡l on, Dny 78. The .Tncíiri plnnmn ccncBnitratian pra-
cipse (C-.-) al Day 2S v.as 1,929 (.tu/rtiL, dnil Irstílvitlual paliiant Crí, ^■aluíí¡ 'án Da'/ 28 i-ariyáíJ fi'gin 0.66
pa/ml. to 5.29 ng/mL The c-íicumislánon ratifls for AOGi-^. ana Ci„s?(o-6 nrs) ivgre, 9.99 and l 07,
respectivBiy, ir.dicadng no apparer.t drug .ucojraulation up to 6 isoiírs pofI the ra orniing do-ís.

-i I..:!.-ic --'.ji:.*.''
Cfj.jag^y ¡n rkis tjf,íinte;í) censfeí in thn rso'<'>ct¡nr; nf ín sompij.jQcs vníh
.i?ssr,y;flrjb.a (£U) 20Í8/Í72S
3 125 63.^ 83.3 20.1 2.8 2.4 15.5 56.4 j 10.9 l.S Q.56

37.5 •53.9 9r>.2 9-3 6.8 1.6 52.0 95.5 1 13.8 5,4 L.19

5 125 33 5 1 GS 0 8,7 24 0,7 3ii ¿ 56.3 1 14.5 1 .8 1.01

6 125 20.8 1 '19.A u.e 5.9 5.3 42,9 67.2 14,3 4.a 2.07

7 125 2'?.9 1 SO.S 5.9 6.0 2.Q 33.B 71.2 i 3.1 9.1 i.3G
)

g 250 57..) i i'iM.e 2D.5 20,5 1.4 53.5 34.5 j 18,9 9,9 o.g-í

9 250 55.8 1 80.9 13.9 S.D 3.1 63.0 108,8 15.2 7.4 i.ii
1

1 250 83.7 1 1.78,1 18.6 18.6 2.2 1 66.8 1Í7,1 1 15.9 10.0 o.ao

10 250 45.5 ! 102.9 18.B S.O 2.4 15.G 73.3 7.9 4.9 0.76

11 7.50 15.0 /3.I5 7.8 4.2 I.a 15.5 67,7 g.i 7.3 L07.

12 250 105,6 j 170.6 37.5 3.3 2.4 46.3 33.6 1 '9.6 9.4 0.44

33 250 112.3 i 2325 32 32 0.9 41.8 1j4.j 12.2 2,0 037

1

Mean 53.0 i
1
101.6 IG.O 9,1 1.9 1 43.6 S2.1 1 12.5 5.4 0.-99

5<! 30.3 5S.5 9.5 S.9 1.2 i 14.7 27,4 4.4 3.2 0.47
"F.itíonfcr <16.5^5 ^'.-cro dojícd 17.5 mg in mísming nnd al m^díiT/, p.ifcÍGntí?2 1G.5 kg \s'Gra do.'oH 250 mg tn morning and at middav'.

;-I '1 •'

Changss¡n tñís updazed vs/nbi? ca/irfsr/n tha /sdacthn cf;:^rsori3f data, in compUsncs with P.egu/aíson (ElS) 2028/172S

Man Cariron Castro VaMoz

Fecha; ie,f03/2021 0:41:55(UTO
05:00) Bogotá. Lima. Quito. Rio Branco
ID:IDCPE-09918491
Faena: ia/ttl«)2i <] 43 17<UTC-Si 001 Oogoia.Unia. Ouia. Se amen

hitnHcU h(lgi<acvn/oaumanuin'a»ot»FCSMr7C-9eBO-l4ea-AOOF-A<KEC4eF49£
Tsble 5 Summary statistics of patientage and atafuren PK parameier and exposure estímates in patients receikring

Age 25 yf Age to -rS yr

Variable Oocasieii Stiidy ODJ Study oor Pooled 004/007 Síudy 030
fíl=20| ín = 57) (n = rn (rt = 14í
8 5D (20 0) 3,01 (33.2) 8.73 {3D,4) 3 43 (22.0)
Ag« (yr)
5.5af5.00-12.0i 8 00 (5.00 - 20.0) oOC' 13.00-20.01 4.00(2.00 - 4 00)
2.Wf3i.9¡ 3.93(21.0) 3,70 (26,1 (I 2.36(19.6)
Morning
3,0.3 n.91 -e.33, 3,35 (2,53 -6.38) 3 82 11,SI -6.38) 2.31 (1.32-3.33)
Ci íUhri^
Evaning
2.10 {31 9) 2.62 (20.3) 2,47(26.0) 1.56(18 7¡
2.03(t.2S-4.2d¡ 2.5*3 (1,73-4,27) 2 53{1.2a-4.27) 1.4S(1,£l&-2.27)
Vss.'F ¡Li-' 2ñ.9{J6.3) 21.5 21.3(42.8) 13.0(50,5)
■10,3(8.71-44.5; 22,1 í3,4o-5d.o) 21.8(8.71 -54,6) 1 1.6 Í6.7S-31,0)
244 (30.51 302 Í27.3'i 235 (29,5) 253 Í33.0I
Day 1
AUCu.7.J 262)15 i -3S9) 3131103-470) 293(103-470) 254 í 142-418)
Í!ig*hr(mLi 23í (5111 147 Í37.0I 163í40.4'| 1.51 Í3e 5i
Slsady-siató
247 (444-40 Tí 157(58.9-365) 167158.9-4011 153 159.0-244)
10,1 (30.5) 12.6(27.3) 11.9(29.5) 10.6(33.0)
Day í
10.91:6.30-16.2' 13.1 (4.23- 19.31 Í2.2 14.28- 19.6) 10.6(5.92- (7.41
^3ie ÍFQ'rnLJ 6.79 <40.4)
9.64 (31.1) 6.11 (37.0) 6..30Í38.S)
Steady.staíe
iO 3(599- 16 7! B.5s (2,45 - 15 2> 6S612 45- 16 7) 6 23 {2.46 - 10 2)
Day 1 18.6(31 4) Ze.6 ¡32,6) 24.2 (35.7) 23.0(33.2!
18.3(10.9-29.4! 28.7(6,31 -4.3.3) 25.5(6.31 -43 6) 22.7 {137- '35.3)
Cf^,,lM3r'fnLi
14 3 (33.4) 11.5 (4D 3) í2 2 <401) 12 6(44.6)
Stgady-state
15.2(9 05-75 5) 12,4(3.32-7.1 3) 12 6(3.32-25 5) 13 3 {5.2S- 23 3)

Not®: Summary slatstics oíesented as maai (Cyyii and rr.adian fmm. - tna>:,'i forage and gí-omelík maan igecmarric CVÍjj and mad.an ÍFvlin.
- Mas.) fer CL/F, Vs&'F. i.UC,,.-, and
a CLi'F has valúas for morn'ng and evenmg due to Ihe indi/sior, of d.mnaí variation ir. tía modal Vss/F anly has ana valué for esch paiienl

Changa ¡n ínfs L'pdscsil vsrsha ío/isst in the .'SCBCthn of fersana! data, in a>mplancs wíd !tegíJ¡¿tion (£L') lOlS/1 ?2S

Mary Carmen Castro VaMaz

Focha; 18/03/2021 0:41:55 (UTC-
05:00) Bogotá. Lima, Quito. Río Brenco
ID:IDCPE-09918491
Camparisaií betwm'R nmíiMO patiants 3-S years afage aná a J years ofage

Popf'K analysis was «sed to estira ate theetalwren eKposiire in t^e popwtefen of k2 to <S '/ears (stúíly
030) ©nd compare it with the exposwre in tfie popiibtiop of paWepte aged &5 fehidles 004 and 007).
Tabfe 5 suromaris^ atatuneu PKparameteraríd exposure esCimates In pattents recelvína the 10/t0/2&
mg/fcg régimen hy study.The medían steady-stsSe atslareri Cave ín tte 14 paEieniCs from Scudy 010 vías
CsZ! ps/mLr which Es siíghlly ioviCF but b^nswtent '/íllb th&tsosh in thc QÍdcr nmDMP patíenteímodtón
gteadv-State etakaren cave of 10.3 tn Stisdy 004 aocl e,5S íit Sfctacly 0O7),
Visual comparisociE af expcKure ín tita psCientB frerej Study 030, Stwdy 0-04, artd Stady 007 are províded
Hj Rgijhs 7r Ft'fyraí 0, éiid Fi.gure 9,

nmOlilD Palient», lícJaClvG F Modci pnVPC(t&!41t2ttmgí}tg, StieBly.slató, linear Scalé]

WüO.Sin'plícj

g I
^ :
3

«I

29'

10 ÍD
Time Sinee Moínina Oese (hrj

1 sí=í '-lírara >=:.'|i5aK

Figure 7 Atalüreu plasma concetitrations in nmDMD patíents dnseti 10/10/20 mg/kg.

nmDMD patients in Study 004 and 007 worc S 5 years of aa® white paticnts in study
30 were ^ 2 and<S ycars af age.

Ofcsórvcd dáte fe ^.áWn ¡rn cirticS (opijn tírdcs S 5 yCárs of sgOr élñscd ífrclss 2-S ycsrs of ágc. Mcdiani
cí the observeJ daca is síiswn as a black, solld Une. The 5Ch and 95th perceocilea of the observed data
aré thoivn os blatk, díisheci iines. The pertenCllés of tíne símulatéd dafá are shawn as: f-ledlan oí rnétítoh
valúes fóreach replicate: red, soíid Une 90% prédicíion interval around the madíats fine: récij shaded
región fdedian af the Sth./SSth percer.tiies for sacfi replicate: biue, salid line 90% prsdlctíon intervals
.jroíind the Slh/FStti petTenCile ünes: biye^ shárfécí reaians

><} L'i.irrhií!''jaz: * • uDiilDti C.«-l b5Ü • l'-. :cú fí.7qc3rn

r^ilefihciqo 4^%'Jí pocisfmiío tOK-Ti -".fXl
4 <j«ic:S'ii«f'ivía'Oiir v,rt3l:isit» -vt'.'- i .-v-u' nt/«"a-.f.-f?::' '•nainT) r t! n l _rcc-c.4i U»!
versus patient bady waight, cojoitred by study and panelled by p ara mate r and
eceasion (Day 1 and steady-statc}

. n
■•00
3-"" '
:3ri

SiiQ-

B
loa

lU

a
> l&i ri ■* fc -N. ;
E
3
g ui-

CL tí ira

<ih

si » ■^'

ra

in

9Ü CQ ai
Qady "Aíctght ¡kg |

•• C:>Cr ¡JC-I ^ rj^r CÍ5ÚC',- cae-

Hy:£ AL'bf^víiíioírá aíí? (3--ov.d&-J íi.itte Li¿bra. P'K e;.^osuf=!í v^e■■e -íesíveJ ífórn ;lie fítdi
rié- ?u:r'íD?/D ^ Mbáí--' 12017110 ih¿ d¿3áSfeL

> h: I, , iir-ir •■ t -^a' i-'iííi- ^

 r

figufe 9 Boj(-s.n(!-wltisl<ér plots stiowíhg tNcíiistributJons sí atalureti PK exposMre

pararoeter estimiatjesj, stratlfied by sttídy and paaeJed by parameterand accasian
{¡Day i ánd steady-state}
Stoadif-StaiQ

Study

Nísfca: Dátil ÍQr kba 00'? aníl 007 srtwdks are ri^sulte írom patiémteíaS vsarTrof íige) treatod wilb 10, 10,
20 img/tíf. PK GKposures Viene derived from ttie fit of the nnnDMD Reiativs F Modet (2017) ta ths paoled
dataf.et:.
Ptot dsfiniticn: Horisontg' fine ta the medían, box shows the 2p"-7S''' ntsncentifss,arid v/hiskers extend to
tñe 1.S times theinterqyartíle ranga betov and above the 25'^ and 75^ percentiles, respectjvely, Sclid
circles indícate valugs outside of the whiskers.

AbbrcviatíDns: AUC area undar the coñcántraüdn-time curve fram O ea 2d hóurs; Caiü, ávsrage
oartcentnitiDn; Cc-.m, rnaaimísrai observsJ CDrucérstraCíari

rhMi-í!<rar-; c' c»' .^ Itrarf i frritiritic-' sriE^'rijn; -ijccr

2fi5-i jíjTí l
2.3.3v Pharmacodynainics

théteara no phaririaoodyriamics data subnnlttsd by tha applidarat The MAH parformed oniy PK stutíies
atird relied on tba daim of 3 PK-PD correlaticr. from ttíe preMÍoUS study.

2.3.4. PK/PD tnddellirigl

Bassíl on previous PK-PD anaíyses [17],a tarfetatalttran Cave.ssof >£l'.970 snd <17.6 ¡sg/ml is simsd
fbr. AC of the pstients 2-3 years of a^ga had an staluren Cava of >0.970 and pg/mL suggesting xhat
tíiedosecfataiuren 10/10/20 mg/kg is approprióte for nmDMD patients agsd ^2 to <S years.

2.3.5. Otsctission on elmical pharmacology

The bíi?!? >31 Ihkf subriTiIssIon fot thc e^terisran af intlíííítlnn ít? IndudiQ a ncví populíiton {?;,hlldrcn 3 to
tes iban 5 yi^rs cf sfe)for Transíame for the tresiment of nimDuche.-iin§ ra uscyisr dy«Erophy is one
mutijpfe-dose,open-labe! study 030,. eveiuating the ssfety and PK of atalyren in petisnts eged & 2 to <5
vears oíd v/íth nmOWD fcr a pariod of 28 days(4 weeks), Ir v<3s incenided to show comparable ataluren
phsrms^kmeO'a; In children 2-5 years y4th the pharmaookinefcics in glderchiUdren h erderto provMe
bass for 3 cíindiiSinn on ihe expected ths elTlíCtcy feind safeSy in cfiildren 3-5 y-Sírrs of age,
Ataluren i5 mairsiy efirainated by intestlríal and heparicgliucgrcnictatlon. Maturatíon rates of hepatic UGTs
vary hetvíeen theUGTs. hist may extend beyond theageaftvío yeam. UGTlAg Ls tha matn UGT entvfsie
invólved ¡n Saetabo-ilsm clñWtareni, H-ispíikíc U6TIA9 levols feachbd vaíu-e» «H bgfOññtha ogóéf
Pwj years ^Strassbüi'g ét al, 20O2, Míyagl ét al, 203.2), Tberefotej. no age rélated tíiffef''ert:;isSi in
olucurorudasion otterttian dtfferarsce in body sise between paftents ai to <5 years ared as y^rsof age
are to be expected,

FhamxacoklAetrr. dala y/ere colíBcted atday 1 and tfey zb,The treatrnent do-se was 10/19/20 mg/kg (br
iTK3rnlng/midday/even.'ng dose, Using the avaiiabte data on thoobserved plasnna vafu^-rataluren
exposiire appears to be similar in nmDMD patients s2 to <5 years of age cornpareó to tho^ k5 years of
age.

Flatdoslng is reoommended per pnedefined weight groups(SmPC sectlon 4.2). As aconseqisence,

bTilldren <31 ko were dosed 125 mg or 250 mg, dose ranga 7.7 mg/kg to 15,3 mg/kg. Ataluren exposure
varted dose proportlorialiv. hoPce there was considerable vsriabliity betvreen suhiects áue to tiie
dlfferonco ht rfgsing. y.'ring the dosinn roglnnisn, Curtontly propísród (muhíplgg cf soshots gf 325 nnp, 250
rng and lOOC!' ffig),. íhls resultéd In alrnosta 1.6-fsld dirítrens^ij: Irt preitóted ataluren éxpcsuréín nrnDMD
patients 2-S years oíd: patlents 2-5 years oíd wlth Iqw body vreight <17 kg had e lov/er esposare than
nmDMD patients S: 17 kg. FurtHgfj the predicted exposure in pattente <17 E<g was lowercompared to
nmDMD patients; a 5 years ofaga ím study 004 withoittaFi ipyerfsp l.o atsluneni exposure, Additi'on.af data
anaíysis shovred that the trend vj3s not nnh'ersai and íheintersuhject varlfibiiíty m ataluren exposure
gcimnot b.§ fullv .jttributecj to tho diff^irontíipíjirig regtesn, fis body wolpht 'rMoto covorlobo ór» iíte.iriS.-5CT
•rt-nJ» a FJínver ^oeffieiént tes khan 1, a iowér exposurt? Ifí íubjects wltt» a bw brrdy xieight can be éxpectérl
apptying a mg/kg dostng regimep.

Tho MAiH prppppal tp use popPK íínisEysb iva?? to ostimstc tho ataluren exoosure N ihe pepuíation ef S2 to
<5 years and compare It y/kii the exposurefn Cte populeftíon of patients aged gS. However. theCH.MP
conduded tbat there wene too many shortcominos in tíie pnoposed piodel., bringiog abowt üncertarnties
abcut the ability af tho popPK modil to adeciuacelV desc-ifbe the pharmacokinitte o.- ataluren In children
2-5 years of age,

CHMi'r^-Jrirt'S Cí: i/' í^ifiTlCi: ! V^SliriífC-'' 3-""'rfrt3r; '<?¡OC-T

These MncflrtainiUes relsteiJ to. model de'/sropment ano presrantationicf th.e dsta and íncrucifirii R.g.:
e>iternñl i/alidatiQfn ysing singla típsadata in haaífhy votufitraRr? fram study IS indicafK that rha mgdei
doee Psat capture v/ell che dose dependen t el¡ mi naden; s time-deperident broa(íaí lábil¡tj' was incluiied Ln
toe; irtodél pliiltf PK íJaiá fro"! étudy 30 ii^ nmDMD ijauenly 2,-5 yáarS <?!' agt; cJkl npt Irtrjicrtba time
depenéenc pharmKokinetics, ErEpiricali icijcistmencs havefaeen rosde to the morfel ro fittha measured
sceftdv-sisteclsta ivithpuca rHe-chanisdc basis, Oes pite the afforte by d-^e MAH,, ijltiraiatelV the popPK
mad-s! can provide littteadditiohiaf valué over measured plasma cnnicentration datei.

In ternns of the espected pharmacodynignnics oF ataluren, It is plausible to assume that a similar

pharmacodvnamic eiTectirii bovs 2-S ye^ars oíd shoyld beeirpected a» irs pabente >5 vears oíd,, proytóeci
similar exposure te veis are achieve-d. The MAH did not submit new PD data., but rather reterated tl-ie
pasitic n that due to the spedfie ex posare-res ponse b^Tiaviaur of ataluren,, a doss oF lÓ/lO/ifl mg/bg
coLsId b-r; i»ppr<ipriatrí far nmDMD pcitrenls aZ to <5 ycar-íj «>5 i" Ir» assumcdl l.h»l if would i-oswlt in
Cargec concentrattpps of ataluren that are hteñí- to pr<u.'lds the eípected PO effect. In Etieir conclaslani tlia
CHMP agread wfth the preposed appr^ch,

2,3,G,. Cahctusígfis orí cliliica! pháriíiacalá§y

Trsé CMMP coridudéd LhaL thé preseited püpPK model had inheredc flaws not alloeving it ta Sérs'e tha
íniLlally lnte.idleci parpase of démonsttíttinig comparable dtalurén é^posure In patíanls aged 2-5 yaats with
tiütof PiimDMD padenCs aged ¿5 years cf age. DéspiLeall tha el'forts b>« the MAH, tha concernís regatding
toe model remaíri, ánd u'Ümateív it w-as sésn as unabla to provide ádditíorini valué over mensured plasma
cnripnnlrnijon dats, With Ihát In mlnd, l.r,o COmríIHee-ré'.'ló.vcíi the avaliabíe phnrmáfokinétic t^ultS
frgm patídiatrlg Slistl'/ 030 in ikhDMD p.itfí-riLs a-ged >2 Us <5 yeSrS rjltl d<5S«d lO/LD/20 mg/kcj rtt-llurtíii,
arsG corssdersd tisát the analysis dF tha cíjservsd plasma viUés can cónStituLé ancther approach iri
vériíylng the cDmparabíiiCy oí eítposura between the two grcups. Rerogmiing tha potsnbal. uncertaintles
lii Lhis approach, tha Commiltae ulbmaLBiy agreeri that aLaljren espasura appeárs to be similar in
nmOt"1D patiénts ¿2 to <5 veársaf ace cómpareá le Lhose a 5 yeársaí üíje, oíter adminisltaUor. af
lO.FlO/SO' ms/fcg &Ü!>li.!rrjn.

2.4. Clinicaí efficacy

2.4.1, Main study

FTC124-S;D-C!3Í!-DMD ÍSiwdy 030) !s m ni tiple-doy©, cpe."«-I íibel síckSv évólttotjnrf the sofety .índ PKeF
flto lu.riin in n-atlcrits .ígeti 13 to <5 yoOro pid vnth nimDMD tor a perigd pf 29 d.ays (4 isTjeke) In ordor to
cpitect lorig^f-Kim P.^fet,'.' and Funictiíinftl enctpplnt Iriforirnatlon (l.e, TFTs and MSíA asf^smcincs), a -sg-
wesk extensípTi phasewss added, All patientf. received approximstelv id-, lO, 20-mg,i'ki] atalurei 3 times
dgily (TJEj) For 4 weekt dpn.ig cha PK portinn and contínice to receive ths samo doso fnr sn additwnal 4S
weskf. during the ongoing extensión period, Acaipren is adn'iinistered orelly immedistelv aFcerpreparation,

Dunng the rreatrnent peri-od, ep.pi petient returned tothe •clinícel research rpcilit?' disring Week O and
Week 4 ror PK Cesting, and st Week 16, '/«/eek 28 for safety an,d efficacy assessments, SubseQisent vijits
are scheduíed fór Wéék 40 and Wéek 51

The fcilg'.ving rabies summarise the efFicacy results Frcm cheniain scyriíef; supperting theprestint
applícatipn.

ITiir - I ■iCnirtOf ■ í-'VOi t¡' ;

TabfgS^Suttimarv of Effteacvfor triat Sftídy_030
Tille; Studv 030 (:fTC124-GD'030-DMD)
Sbisclv idenWfíer 030(RrC134-í3D-í!30-DMD)
Desifn a phase 2, rnultiple-íiosa.
Dpsn-íabal studv in pabants aped 22 to <5 vearsald (.'«ith nmDMD
Du ratio ii of nn ata phase: 4 vreeks
Durabalí o; Run-irt phase; not applicabie
Duratiora of ExtsnsioFii pliase; 2S-vfeeks
l*lVPcthesi-3 Clinícpl banefitof Atóuran in patíents SZantí! < 5'/earsar aqa
Treatanent? groiips Stiidy a30' 10,to,2fimg/kg Atafuren, JS-week?:,
patíents aged &2 and 5, average age 3 A ,
6 i)a.iji¡sr»is teselved eenostPíldrit steteid
Creatmertc í42.9%'í
Katíonal hístory of DMD 31 patíents, aversge Eige 3.52 , 9 patisrite
Ccoperattae InternaUonal naceived CDiicDmitant steraid Ersatmsnt(29%)
Nhu PDnnüsaila r Rásea tíh
Group (CINRG)
Efidnolnts srid Pwrictionis.1' TFTS
The time taken to run or walfc lO' meters, to
dimb 4 standard stairs, and to stand from a
■definiCisns wbdpolnt fajpine starting po.sition wers assassed

Punclíonal NSA-Si Bilems wereselected (fl59'n aF L'yptceil'r

endpntot
dé'/ébpirtg bcjys are -abie to Fuliy pártortti 8 of
tfie 17 Items)
3 itéms ','iére assássed (100% of bays ^a 3
üra ty'piealiv to Perforrñ thesé),
Results and Analv^sís

Anaiysís ' Prímary Andiysis

1
descriotton
Effee estímate per ! Changes. from CINRG Studv 03!} Mean 5
comparíson ; boserine to vreek n=31 N=12
, 28 _tíme to rür, -0,31 (l.STR) (Mein(SDí) -0.& (1,44) {mean -0.3
; or ivalk 10 metsrs -0.30 (tEádian) (50))
f
-3.6, 4.3 (mtn. max) '0.5 (medto)
-2.. 2 fmlii, rsiajt)
Time ta Climb- 4 Nr-28 N-'ia
Istalrs from Baseiine -1.3 (3,479) Iméan (SD)) -2.1(5.07) (mean -0.8

b Week 28
i
-0.36 (fEstiten) ÍSD})
! -lSr-2.9 (ruin, mgJf) D.í)
-17. 3 rSD)
pbhnigs ini Time te N=25 rí=i2
fróm fl Supine -0,65 (2.010) (mcOTÍSD)) -3..3 (6.70) -2.65
Posítion from -0.35 (median) {mean(5D)}
Basaline to v/eak 23 -9.5, 5,2 (mifí, mas) -Dv5 (median)
i
,_:1S,1 Ímin,maí{)__

ChHPí «t.r-rcr c>' ÜMr-,1 variñtic • 8--'";í'}r (Jf; njc

-'SE- iS'i
 jClíÉifígé ih ESlói'ttíi N-il ^J=12
Star ÁmbalabDFy L.S (1.446)
•Assssment S-item
0.00(1.612)(tii^n(SD)i) +1.
^«ireft^rri Basefine 0.00 (median) (mean(£D))
.tQ Wcék ao -3.0, 3.0 (min, raas) 2.00 (niiadian)
-1.0, 3.0 (min,
iraa:<)

Change in fteth fj=ll y =12

jSter AmbulaCdO'
D.09([í,3Cll5)(fF.efefi(SD)) D,5 (0.7977) i+0.
Assessnnent 3-item
arorefrem Baseline 0,00 (medían) ímeaníSD»
to Wsek 23 0,0,1,0 {min, max) 0,50(medisn)
i -1,0, 2,0(m5Fi,
)
Changó In Msrlh N=ll N=1Z
StarAmbu lator>' 0,64(3:770)(tneanCSD)) 3.4 (4.19) '13
Assessinent boíat 2.00(median) (meani(SD))
Smre Fráib -6.0, 7.Q (rtilrt, max) 4,0 (médían)
Baááli'lié to WéÉk "4,9(mití, taiáX)
28

Mctíjoda- oí Assosslng Hwsoló Function

Muscle futsctfon >fias a-isessed thraiogh titiieá fuiíctton besí's (TFTsl snd tha Narth Star Ambalatory
AssessnrieniC. The time taken to run or i.vaik 10 meCers, to clmb 4 síBRásni stairs,, and to rise froiri supine
has preílicti>« vaii4<3 fcr íllnilca.T¥ meantngful lossof funcffais, Including ambulación, In DMD [^5cO<?nald
2Ü13].

The NSAA is a funttional assessmsnttoo! designed forarobulant patients affected by DMD [Mazzorse
7010] In te crigmc! lom,it consists of 17 actlvioes (indadltíg, for exampte, standlng «prlght, tising to
Etandi-ig frcm a seated positlonr standing oo ene leís, «aiking, rumnin-g, hoppmg, and jynnping) each
scored as O, 1, or 2, vdch a higherscore indicating betvsrfuncíion anda maKimuno total storeof 34. The
fulí 17-(tem S'tale has been 'íalidated for usa in childiT.ni above Che age of 5 years [Mercuri 3016]

Befere Che age ef 4, many cf tíie iCer?5s (for exampte, standmg on one teg attd hoRplng) are not yet
rellabty partormeci hy cypical!v daveiopfng fcoys. At age 3,85% ■of Cypic.ally develcpíoB boys srs abís Co
fully perfomí S oF Che 17 tems and lDü% are abls to peifbrm 3 of tham. Ic is oniy at ag-a 4 that S5% of
tstpfeolly dcvolbpirtg boyo aro aible to acbteve F«tl í:cor<K: in all 17 itoms [Mérs«ri 2015], At? ^result,
cevised rtaaA seniles tfiat includo Che subssB of Items rellably perforrnetí by b-cys In Che a 2 .and < 5 year
age group are the mpst appr'Opriate approach forthis age g/oup, The restdts for these de^loprnentally
approprlaCe 8- and J-lcem scales, as weil m Che IíjII 17-iCGra NSAA scafe, are presented her^s,.

These assessmerite vrere scbeduled to be performed aC basellne (week 0), Weeit 7S, and vyeek 52,
Patiesnt Dcmographies and Baselína Charaeteristics

The patlents and < 5 years of age ¡n Ehe CfNRG sClidy and Che patients in Study ÍISO were sirsiílar
acrosE a rarage of demographíc and baseline characteristics,

The mean, age among patients ín the .sslected age range ofthe CINRC study a^id in Study 030 vim 3,S
years and 3.4 years, respectiveív. Patisnts in Study 030 are stightiy taller and haavier than thsir CEMR.S
counteiparts, but Che 3MI in both groups is comparable.

ChMF-í!,(5eFS'«= &; '31mc-':.| sv>rirt(ic" af-íKir.iji';

Jn Sn,tíiy 030,6 (43%!i patient? (5 of whom are induded in thie evaluaolp popuíation!) renei'/ad
cortirasrernid at bsíelin®,, ín compHn.vün ivith 9- paflfints ira tha ONRcí riatrasc^. Gí'jñn
tneeffecís of chronic administration ofstaroicís on ttiie sl-owing ofdísesse prag^ssion ir. DMD, in Stirdv
030 mviíiiítipators: ivijrii «Ji&puiíicjtfd l," riiainlctin. a;, ijriifgrtn ci il-eroici niyirru^ii dii pri;¡i;ible. Áil 6 patieiity
víluo recsivaó raiticosterpic9s a: b.asslina in 5ti.rdy 030, coniiríued to cío sp coníomiEantiy in r-taDle
retfimens (UsCírq 1ó.2.g.7).

Patient DlsposklÉin
Áil 14 patieríts OTO were enrolleci In Stuér 030 comptsted the 4-ivg#; PK phsse and «ntered Into the 4y-
week gsítensio.i phass- A? ar che 21 Jtily ?017 ast-off dater 2 patisits Iwe completed tbe extensión
phase and no oatients haxe disconcinued prematirelv frcm the study.

pjli'riL»: C iiJi Uífni-tLi' C iNKl» ti l O

"MiílI'- i'
"-■iriBhii.r 10. [ii,. ,:ü:ias ¡Lg
Aóltii ni
II ^ í:i «

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. jJüSí'J-AIÍL ATiAJi...
4 i'i« _ 4 íi
ÍJ 4 MI ; y

13 íi-'í n I nn'Lj üi
•¿¿jnr-.ir'. Li
ai 1.AÓÍ
Áiuíisc.m íi ii. i '.n I] iñ fii
h (JM-U n.'i 4',
iíí: < ¡r'i .13
l'iriüf iotlL aaaL
Mi-.iaiT l!| ...l l,,| il ill lM

i 3 n

u >.T-jri 4>r<i (■' '"n 11 .í>'i41

51 rsla -11 3:'6ü i ■-■AL
Sím Mdt: 1 < :
-^•rr y. 4-
Í.íy>r'>¡L í'ITTi'
ifi i i
i?SDs OSES i íOEí I '"4I .Í.3 2Sí,
u7 _,:n f-Ü 9?

^ ..'iitci MÁU£íA_
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L - ./•
i },'lrnn 4*^01 [TA rrífríiT' t; iJ7" r B '
JAL I b1

i. . ni 7A J 3 US 7^ !!
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„ NHtL 1'I un "TJm J"
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A

'VJ
Results

Time te rwn or waiiN 10 meters

In tfie C[^JP.G naturar hiscorj' datas-at, for the 31, patients íviTh botii baseline and Weak 28 assessmants for
tífie tims to ron ar wafir w meten:", the nn^ean time ini seconds was Eiighíly Improved frann itw 7,32 secprid
bassline, as is e>;per,teá ameng patiens ta this aga graup, witti a meen éscrease af 0.3i s-ecanidá (a
mean impm'j'isrnerstofapproKr.Tiaíel'/ 4% írsm baseline), AmoJig ths iS pstiente in Study 0-30 witfii vafici
fcaseline and 'Week ,?.S assessmRnits, Míe imean Improvement ivas'ü.& secancis írom the fi.7 s&coná
baeeilne, an 3,9% improvamer.t üver basaüne. The relaCive Impravement from baseline cora pared v/ith
thííl, af ptattir&l history data {3,3 vm VtjrSiís. 4%)is 6 vitítírtcft oF cllriical hcjrisjrit aFatainfen in yoiipigei'
patients.

Tahle B Changa in Time to Run or Walk 10 Metars froni Easeline to Week 26 in C1NR6 Natural

I CS31.i>nil[S£ií I Tiiti-,' lü Rciu «1 'tt'.ilk 10 .Meitri iiieraiiil-il

L ■ • é
nr |i t-rxKC, blEuil' ft'O
flj.wlfílñ 1
H
ti 11 jí. 12'
M.-rn i'SI» í "32 C 3Í1'
f,[eJxaii i| 6^7 &ñ

Mín. í.h% J -! i, iJ6 J C

«^.rklS i:
n ¡! n
J.FeiniSEH' f ■ i.'t) '1,! 193' "5-!11 2'3 i'
í'íeJ.ua, ( & -U JC
Muí f 4 i. !-1 -1 5 1
C ii-iisóv fioin Bji'.f'li.tjf !u i
ti t '! I .!
>.Ee.inibí>t 1 -IJ 11 '"i""''.! -fl b ii, l a_¡ |.
í.ííJiUii |! -0 Ji,F ■I) ,r.
Muí. f 5 i. 2

.AisbrevMtiajs: Ct'>.RG~=Co'3pifa:ivc: ír.tni.naticqal ^^c::ialT;üsrJ!a^ fe -ss-'ch Grau'^p ruiural h-rlcrf catiírc':: Max =■■ nraxixium: Nji =
mi ni ra ü 1(1: SD »• 5iaiT¿arü dcviia^iofi.
paüíin: was cxdüdod L-dti ú\k sralv:5 úuq Idí nc-ari^asinc.-1 dcamcc' .nva'd b>" trie iavc^nicaíDr. -ah 'c a i^i-ronc piticr*.
íifí noi; nn.í.'A rerxsíT'Síí ¿b
Time to cíími 4 Stairs

Climcai bsnefir Is furteer suppiprcetl by rhe resmlte r'pr the time to dinrih 4 stairs. ín te e CJMRG nawral
historp' ddtnset, for Lha 2B palients wlth bath baseliné anid Wask 23 asessments for [be .time Lo dlmb 4
Étíiir";, Lhé m-éan tíraé in records Víis Imptovéd frorn tbé 7.30 sétonds át b2«élina te 6.00' SsoPrids it
Week 28 (a meén decresEe oF 1.30 seconds ánd an Improvemenl: oí approxinnaee!y 18% fro—i basélirvs),
Amnr.g tb^i 12 p.itÍJT,t:7 Iri Sfudy OJO V,irtn. V-llid bAOaÜnó .Tinití' WiJók 73 .T.tr:ieÉSrrinr4ü. Cbs me-fln time Ími
tJESKjrüdy ívsí. éísg imprnve.ti frorn flirt 7,4 tréwridi at basailne EO 5-3 atfCTjrids al WejáK 36 {a nirtárs
daoreáse of 2.1 sacbnidsand an imptoVeménC dF approsimately 28% frorn baseiine). Tbe magnitoda oF
te e ralalive irsproií-emení from boaellne ovar natpral Fiistory data (28% versus 13%) Ie íurther evidsnoe
cf cllnilcal benefit.

Ili-ir.' I víi-"nfii' "

- :■)
 Tuniíp utni I ilnfí'l» t liint » "Mlu y H frc imü'iii
Jti'.Üi- t Slíliis 11.1#
Itii -..fiiitp.
n 2S i:
.\5"iu (hDii 7 .Til' 1 '■ I. .iT'j " .1 4 " í'j 1
y-!.?2LBB 4% i ó ; 7

. , ..¿.I®, , ..J.í
ÍS L IS
L1 JS
1 '■i.

.. yíiiMi. .. -i ''!J 1 iJ
Muí KÍJS ; ,f. 117 3 t?.
til.102# fí#!H Ét3i.dlB« lo Viwk id
■V
a i:
-1, -i 1 .1 .1 .Sí'jj . 7 1 ir- .ó;»
■Mr.íijis ■(í ?b 710
•Muí. 5 , .. r i
■=yb".---íicns CC.'>Fiij"0}':i|"^r<'iivr3 S.teítv'Th p-íiuiíiI » i--,imi7!i.ii-i. Mpi -
n nim jm: &D = ;iaricard dcv a:¡Dn.
■c-ne i^a^nt Ivag eíciiids! hum filis SPfSlyss du.? t.Q.r te ?a| r)P,:,;sassriie-.t Ctem?;} riíia^l l.ip thí íi;íe-=;i5a:or. nd '55.5 s—oníí (saeiif
ele no: hsvo rcparsei: funK-ona. asscermonls íit {¡azK 23.

The tima to stand from a supincí position

Thp itma bci slrsná from a pupinfl pa-nition ¡p an Rsíablísiiesi e=5rfy pradicxor of diifRasifl praora&sion m bovs
Viútii DMD over Che age of 7 [Naasone 2016] and ts aiso of important clinEai validity in ycunger bDvs,
si-nce íc Is tJia ñrsc reiMestans w be Icst In DMD patieiCs. In Che CINRG natura.) history dataset, Farthe 25
pattfintí: wirh hoth tasalina and Week ís as5SS-f>nierjc:s; f-gr ctiR -ims tg s&d from ?. supine positicrs, cite
mean cime n s^soond? vías EliglTifly improvedl frnrn the S-éS secpnd beóelinie, w.th a mean ciecrease nf '9.65
seconds, -as is espected -amonf patients in thie a§e grcsup Armong che .12 pstienCs in Studv 0.5':) '«ith vñüc

haseíine sníS V/esk assesspnents, Che nns^n cime in seconds was .siso pnpro'íecl From Che 7,6 seDtnds at
haseilne 'jí 4,1 eeenniL-fí ac Waek 28 f.a mean decresse oF 3.5 ?etonds; and aa improvGmer«c nf
apprpiíiniacely 43'% From base'lnie), The niagnitede oFthe improvement over natural hístory data i435x>
veríus |5 notable.

! . Ti- I '.-.fj.
-'fir

Mary Carmen Castro Valdez

Fecha: 18/03/2021 0:41:55 (UTC-
CologiodoTradJCSDresdcIPcrú 05:00) Bogotá, Lima, Quilo, Rio Branco
ID: IDCPE-099184gi
Focha:18i03/2021Cl:43:17(LrTC«S;00)BogoU.Uina.Ouío.RloBr2nco

ID: 20376744340
Tabte ID Changa in Tima to Stnnd frafn Siigine PosítÍDin fiíúm Baséline ta Week 23 ín
CIURG Nattfral HIstory Datasetand Stmjy D30(Evalúa ble Paptijation)
Tímopaiat Tilín- ta Siiiiil Íí-íiifi Sutií-u* iw-foiidsl '
ííf,l6¡ritk- CIXR'G Stisdi. fiJO 1
i.iEeiirrf"
rl 3.1'
MeüiiS&l 1 €< f7 'fíii !
!Síácfaá:i 5 IP 4s !
Mwi. M.v: n 15 8 1 1
Í\rt4i 19 i
ir 1
Miííi) (■-iD'i 5 OJl f á.7':>r
^'íediaa •1 'TS ■í y !
í.íai. Mas 2,5 1!4 ?. s i
Cliaiju?' frsjin 8:*':flíne 1» tt -ffl; I
IS 1
n H 1 i
"ccjj-I.SDf -J 3 '"6^ '
Mtfdtaifl -13 36 -CO 1
Ms,n Má.-. -."I -IS. 5 J „ J . .... . 1
A3C.feíi,->í<:'.5' a^^■RG■"C(»pSf<íiiVi9 EtSTefnritleiK^i .Ne-ft5rti|ií;,tilrir Bi:í.-?a-rch! Crfoii? M-niríil n-íjwy ííift5.<K; r'!n^ - íf'íixliriiiníi; f-j n -
Kiiinram; SD =• ctan-íard dcvajiion.
'Or-- ptiiieíil wns tíísiiitltd uiij e:«ilvi-3 di>=í ini:«;rrie<fí-sí55n«-il. ífeíin-sii bf Ule -.-ni í « Kíon!? p'tiitil
Ele nDí hüw TEpartcD lE-jictcnii.. asiscsEvTicnts afc VJixk SI.

/VSAA

At 3 yp.ars oF age, at lessr 85% ciF typicalíy dñi'íilnping hoys are able ta reliahiv perform S of rhe 17
FunvWans on Iha íúll N5AA5c.>fí5; Starsd. 30 rr.istors, g-rj frí?m sitking in 4 chai-tei standing,. -ílinnb a
íiíep (wlth Ihe; rrahs íiri-:l lefl foyl.), gtjl; tu ?- SUtirig poyüJ'jri, jwttipr arifl Eurr. [iMtíCUfl ZO'lñ] Iri w-tler-tu
maresoíuratelv f.5-r.«:55 ftinctignal ImrroMement in patüene; SSantí cs yaars «¡r'age,, cties-ltem scalp
basgcüQfTi oHilv ch65€ ftincCionET-Ví'as usad. ín che CTfJRG natural' historv data^ fnr che 11 pgCtents vdth bciCh
baselin-e and Vleak ?.S assassnoenite Fnr che NSAA,- the 8-ltenn score was up-cbianged rrom Che M.DO
fc asfiline. Amnng che ll! pat^ents in Sfiíciy 03Q wirh a yaliri baísFine and Wefik ÍS. assessinnerjf, the mean
WSAA B-hram -ntsaro v^iSs innprovBd frorri th-r IQA?. bíiccline hy L5 píjir.tT,. pr-:?'/ip'incj Furlhísr sUppprt fnr
cliMKjal iwrtiefifc oí atelurcii. In IhlS popuialbn, in a deytjÍpprJiBritíilly ap|:;rOpriate swbssí of fi.!r!.:;l.iOr«S.

! I. ■ iu -It 1
Tabte XI Chaíige in Morth Star Ambulatory AssessmBtit B-item Score from Baselinéto
Week 2S in CINR.6 Natural Hlstory Oataset and Study 030 (Evaluabie PopulaXían)
1 íra.'iHitul lí-fi y-ii,,-iri X"^ %A i
Sinri-ilic VhiiH'íLtlI '
IJ.i'íhtji-
ti
... 1.1".^ __ 1^1 " .J
M'afj! ■'«D-i M ,11.5,1 - 10 J.' II1
Mfrisín 1 1 ifW SU .*••■> 1
Mtli Mj?. l»jy It'O f. y i;-ü' 1'
\\ ,,1.-5: IS
^ 1? i
¡4»á«í4&! 14 Obf 1 03 li 1 a ni |
í.lfdsiJi 14 irr/t _ ! í UO !
_ |.Un ' ü «_J6(:L ■f )i) i,j lli ' !
fh.itiaf íiúüi B.iiébai,' so Wi-t-L 1

l& i

ti J3 1-" !
kí-jj!: %£!, ni>i*i ii! ^1'?! 1 ■•Ó;1 1J(,1
M-tlu.to l'l u J ?fT. ¡
• e j, 01 -1 €' 3 0 j

Thereare 3 ¡tems tiiat 100% üf C>'p:caliv developinq bo'fs are able to perfotm fro.Tii ih-e age of 3 v-ears:
íneablücv co srand, lo reecufs, ft'-sii so frorn sltílns In a oiairco sraindins [^^ercuiv 2016], Ini oriii?rto
njrthe- evHluaüfi ásnctionai improvement Ir» petients snií < 5 vears of ags ín c^6 CINRS clataset: and
StijiJv 030, a 5csle assossing oniíy rheso ¡tems '.V3,í aiso anal'jfseid. In the CTWR.t? natural bistorf'
datas-st, for tbe 11 patien.t5 vuth bodi, bavRlinesnd W&ek 26 assessments fcr tbe MSA6, tbe 3-ítem acore
increased bv O.OQ poínts Fram the baealine cF S.93. Am^ong the 11 patiens in Study 030 '.vith a yaüd
basalina and Week 28 assessraene, tha mean NS.»\A 3-:.tem sccra wae improvei from the 5.33 baselineb'.'
O'.5 palnts.

Whiis the papiíla-ions in íhe A2 and -r S age group in the CJNRiS dacaaetand Study 030- aregenerally
comparable, ciie subsatof 11 CIHRG" pabents Forvíhom NSA,A as seas menta are avalla ble is not
rspresentrab'/e'oFchelargerCJNRG popularon ín rhis ags grotip, All i iciNRG p.abenit.5 with hothbaselinie
and Week 26 assessiTienirs for the NS/¡iA (.vere 4 years oíd at h-ssolíne., en age sC ft-hich st ies-st 85%
typically de'relopirtg a year olds are able tip perFonn gil i7 functioris cif Che fulj NSAA scaie [Memuri 20^6],
The lli pabfints is Sbcdy 030 wlth both bassiineand Week 28 assefitraents indijided 4 patlatts who were
3 years oíd st baseline and 1 patíent who was 2 years oíá at baseiine. Ibis renecced in Che more than 7-
poinc difFarence h Cha baseiine NSAA total stores for tiiis subseC oF CIHFtG patisnts. and tíis 12 patienes in
Study 03U vvith vgiid hg-ielme and week 26 gfíñssraenCff. Cn Che CINRG natural histcry dargset., forthe II
paciente >v¡th hotlo baselujegnd Vl'eek 28 assesaments for die MSAA, cli>e. totgl sccre was slightly imprc/ed
from the 24,00 bc-.;eíine, wlch a mean Incre-ate of 0.64 points, Among "hs 12 p?-Ciencs in Studv 030 vdch
valíd bgcsliraa and 'A'eefc 28 s.t.tetsmflnte. Che mean NSAA total scnre vras Imprai/eri From thee 16.6
basallne by 3.4 polnts. The dltTerence in che improvement In NSAj^ tote! sccrearaong CINRG patiencs and
tile atalureri-traateá pacients In Scudy 030 «¡O.64 po.nts verstss 3.4 poltíCs, raspecCiveiy) is notable,, eespiCe
Cíe limitaticrss of the companconi fci" this erdpoint, and rspresnts anccher inoication oF clinicai benerir.

íi:"ir : t '.Tü'M'fCii
 (
Tahte 12 Changa io píorth star Ambulatnry'AsaésBifleniTataf Bctjrefrom Basetíneto
Week 28 In tUNRG Natural Hfatorv' Oataset and Stndy 030 (Evalaabía Populaticn)
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TU© linear cransfermaclopi of rsiSAA sooref Cc a scalesfa to IQQ ñas aise bean perfcirmed. An, idcrsase q(
-1.0 lineariied urslEs per ysar has besn repcrted ir« the íiLsraCure Icr boys rríLh DM0 prior to age 7 [RicotEI
2015],
Tabfe 13 Changa ¡n Morth Star Ambulatory Assessment Linear Score from Baselíneto
Weck 2S ñt CIMRG Natural HEstory DaCasct and study 030 (Evaiusblci Populación)
T icnrinoülí XE-L\L0WJI SiltiJf
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c.i¡n;:¡n:ii: 'íD - 'ü.iri.Lxr.5 tlí-'. laSiC'-t
Str-'f iji ft-» r ■'x.y, mu -aij ■R'wk TE .n.r„r>:t.írK:i;<": C»j ¡lS-. Iiejai .w.i "'.TÍH.Í c-<i Ír<*>rS< '
¡litrttjUL-if cjltLiiteoíj üJ fe kacii '«ac füií düj inüciü

In theCENBS netisrai hlstory c-ate-ssir, for tiie J1 patienEs'.viih both bs.íieilne and week 25 i-íseesment? for
the NSAA, the rineg'sonre wsf, silghtiv irriRroved from the 66,10 baseline,, vritri cirnean increase or O.-^O
paÍRíts, Amcng the H pctierits in Study '010 Víifh ¡s, valid ba-sfiiine and Wenk 28 a-sj-es.srnenit, ths mean
NSAA llrnear srora vías iranroi/ed from the- 51.7. baseline by S.2 pointK. A,§ain 'witfi che ca'^'sat tiiHt the
age-related olFfarence In baíeline complicatss the cofKp-arlEon,,. thls represants 3 notable arsd poteiicially
rs^Bani'riijful |rií;r43éii,y jii fuiictlciii iii it;iil;ive l.p lh(s c,isctistje artKjrnj Ihij, pahmls iii sfie QNFtG
datasíit,
2.4.2, OísciissfoEi OH clinlcal cfficacy

A phase II, muiti-Jose opán labél síúdy was córeciilctad Cg paríorrn PK ánalysis, The Etudy Inirlüílad
paüants b-etwsen 2 iand 5 years. Psllanbs tvere tfealecl witb 4lJmg/kg/iJap ataíuren for 4 waeks in this
fniüal phAsa, To furlhar fche effícii'tcy and safoty pranieaf prtpdurt ir» thé popylaítorir stody
vtm ejítended to 40 iiteeks. Ais. this study wd?; eriBÍníslIy inte^déí! as ii Pl< siudvr ibere was «o pídcebo-
contrDlísd arra iiicl'jded, and tfsa data are prone to dirrerent Kinds of fa ias becausa af the opan-f-ibsl
^ructura of Lha study.
The WAH has useti hisscnwl data set frem ctNRG c-a pTOÍda for a camparlson oí eificacy. in ieneraír
matar funcüan develop«ent and dissaea progressioís in DMD subjeils áre subject bo significant
varlabiULy. Par thát reas-áh the use of any histarical data En Bie larra >of a treatmentcdatroi group oculd
cnlv bá atcéptad ¡í ths slricl: comparability of the bcludéd padénts fe puafiiteed. In the spadfk: case
heré,. the seleSteti CINRiS pápulatian did nnt différ fróm the patieats incitKtel in study 030 in terms ar
age, Sc>(, hdightand BMA. Impartenüy th-Píigl», the t'wo groupr- shnvfed diffcrcntes In patlent wdght and
Che re&orded liaseline steroid use., .Aíthoíüg'ti a hlgher mean body weíobt (Ud nci" resuít tn a íliffereftcs in
BMt bábrtesi frcüpfe, it canndt bé ejtdutíeci that tt taighk haVe an éfféct an the dóse which éasrh Individual
pacient has raceiveij. la termsafcancomitentsterod use, thers were mere patients in the study 030 that
Were treated wlth sterods (42.9%), tfian those In the CE NRG data aat (29%), Sinos treatmént wlth
Córtirastsrñitis hüs a pfr,''ma eífeet on ciiséívÉé proeiréssfán in DMD (parttcMlPriy nátdbla in the first ysérs
cf trostment), the effeeoy and ssnfety resulte in tha 030 stwdy sulsjtets may he ¡nfluenccíi by Chis, and
should be íntarpreted with cauElan.
Thé oxtsnsran phase li fcr 4.B vveéksr tbé ítildy 0-30 b cUñer4ly engoing índ In the appücatbn tha MAX
has providísl diste aflisr 2i weeks pf treat/stísnt, Iti light ef tt»e deserilj^d inechanism ai actiun ©f atelwten,
arsd the results presanted in the previous pftasé ÜI stildias (007 and 020), thare ia dn increaslrig hcdy of
evidsnce that su^gests thdt lengsr tima may be needed fór any ^Fact of the product ta bé abserved in
dinkai Lerms. Tha affect an the BEd^VT and the TFTs was noL convincing after 4S wseks: In the studies
mentioned above and the CHMP has recoramended 1.5 years phasé ÍII study In order to account for the
foct th.nt clin icol cfféCl may neéd longor pérlóei'G ló bo rabustly deménsferabod. Thérefore Eho prosentjsd 28
weeks' datd an cautd At besfe be «©nsidered as íiupparhve irikumaticn, dr»d »n Itmir cwn wlíí be
IrasulTiciant to pnavídá tha basis fcr a robes!: condusion on the efflcacy oí atalüran In tbe target
populatión.

Ccmsidering the descriE»d meetiantsm of action of atatureiir the naH malntalneil the pasiCton that
favourable efíects of traatmsnt could ba ey.pected on paOant fiinctloning atad less liksiy on nnusde
strength. In suppart of tánLs, the data presentad in this axtensian ct che indicatian applicaUün fdcused on
pararneters and ñndpoints that describe functionlna. II is reccgnlAed that the SM'OT te not .a reil-able
cutcome meosurement toól in ctsildren cSyears, awj therefore in study 030 tti,0. éfílcíicy outcomes vjore
gcfsíCtEd te hé throo mctfSUreC: of dfnod Functicn Cest¿: (TFTs) ánd a revióod versión of thé NSAA,
Althouflh Iri phntíple it fá sgreed that chese may repesenC a nnore apprcíariste yjgy to meastire efficgcy in
this '/DUisg patient pcpulaticin, It has to be kept ín mirtd 6iat tbe clínical relesanoe cf the obsérved
diffárentés shouid ba apprópriátely jesiífiéd. Addilionaliy, the InterpretatiDn afthe dinlcaí vaíiié óf the
cbserved dlfference Is hindsred by tbe short study duratian and tbe látk of án apprópriate control, In the
ferm of a placebo or fiiiiy matchsd hlstorlcnl control grcup, In addiíicn, swpportlue «yiderjce (rom moscle
strcnstfi &nd PP owtecrac mepsures is still conádercd insufficient

Frdiri tbe réSults prasersted for the threé TFTs, it was evldent tbát tftare Wére mi ñor differenceS behveen
dná CtNRG c.or,trol? nnd fcho stwdy 030 papublfar.. Thn effect sise of th<5 afaserved eSiffarence is sueh Lhnt
ft fell withln ilie verieíy rangé ©í b;>6h gr'óyps;, F©r Ijcsif» i;|ie time te ciimb 4 stairs end ihe Clrne te stand
frcm a sspine pcsiüan, a dilference in basáüná leveis was noted, ■Ahich is mare pramrnent in tha stand
frara supine pasition, and may Infíuence the íntérp retaban afthe rasults. As nr.entlaned befare, tbeclinilcal

CHí.1f''.3er>ir-c.t;.r c-' i '."eríPíCic "3cr.-

L -.0
rei'evsnce oF m improvement of 0,3 geoonds fn time ta nin/watk 10 meters gnd sn Improvennent of
Cf.8 síiMnds ín ths time ta descent 4 steirs hes ta be pmperfy justfñedj pnetargbFy by a eiasr corr^lalion ta
íi cJtni'^sal oi/értí; sigrilfVlí^p ti cleOr effact on dlséíjíe pftjgréssión.

Ihe perfdrmed ttie ful! NSAA t<^t and 2 revised swbsets - of 3 aad 8 items, It has ta be highrjghteil
Oiatthé reeults proi/fded representan overtap, sínee íhe 3 ítems are atsa [ncludad ín tha 8 itanns subbest
áftct in the feíl NSM,Teklng the dinicel cxpcrtc' opinfárt Inte éesountr tbe nn^át hsíe'/aiiít test ^>^'ei3ld be the
revteed 8-item NSAA as it «an be perforrned rellably by pacients aged d 'üears (the averege age of Stady
030 poputatiop), Based on this «•/slaation,. the CIWRG patients ^oi.yeíi no Improyenient ordetsrioration,
whiJs for the subjects in study OJO there vms an observeri innprovement af 1.5 pointa, The ¡nterpretatioji
cf this íaestsit should be made víith ceution as tbere are oonfoísnding factors that may bsve sfgniflcancly
contributad ta It,, like the tnhenent variahllit'/ in the disease coursa,, or tbe abovamenaonied difFeretices in
tac p-Btíente' CHiSríKtaristics in the 0r&gp.{f,

The demographjcs of the O siabjecta from CliTRG vmm not pro'/lded, but the fact that thess have a
higher mean MSM scora at bastirse (14.0 versus 10.4) míght suggest that these are oider faüys (i.e. abie
to pertairp ríiofe itefsiS on thé O iterai ^•JSAAll, Thísi ferswrnptión Is aiss SUppórtéd by thé différersSé b»
bacefine m provicleJ on the total N5ÁA - 34,a versirs l6.§ on the tata! score and ss.l '/ersus 51.2 on the
linear scoreTe&pectiveiy. Tbe iack of any improvement fn theClNRS (on the 8 item and the total NSAA)
as Kim pared to seme ímprovement fn the 030 subjecta mfght aiso be dtje ta tbe fact that tbe histon-cal
oantrel greup was not completely maíched. as these were alder boys abte te perforpn more of the ítems
en th4 NSAAj who w«rg -omporad ta yaunger bays stlK .íscsuirins nw.' sklllsand («ncltertsr,

2,4.3, Cbnciusions on the dinical efficacy

Altheogh eha «ffísírey «l&t& ftam 'sfUílv 030 préSer-f a trand i-i feveur ef atídoran tyebtad DMD patients
Bgcd 2-5 yeíirs ald, when wmpflrcd ta é gfSUp óF canitróte, tákén frSñíi thé CIíTRG databsSe,- thcró Bre á
number of inconslstendes In tbe matebing of the hfstaflcal controte were rtoted, and haye to be taken iritj
onfiSldaraCicn ín fiíéevalisatlón óí thé observad dEfférenCsS bel:i.Véan the grotíps. Additlonalfv, EhéáfíecE
ské ánd EES clinlcat feteyarjca remaiñ to bs Fulty asrertAlñácí in Eérms óf théíf impOrtanca fór thá
fünoElonlng of patiénts and the expectsd pctential bsneriE from ataiiireii tréatrasnit Dfepite the
sbo'iiémentianéíi irreguliititiét, it cñnnoh be deniéd that n tratui fBvóuring atídurán wat obsér.'éd whén
ni<;4suring tho funcUaniel párfsrmancepf DMD baysr wslrsg dinicelly Válid and iJstBbkshtíd ifsstromQnter likó
ciie TF=Tsand nsaa and Ks verfants. Altheugh die level of robustness of these cteta ¡s insufflcieniE ts> s&r\'e
ors thelr ov/n os the basi's fcr a conclusión tbat etficacy In DMD patlentSr aged 2-5 years has heas
un^uivccálly deni'DnsSrated, fn the coatest of thá ávallable PK data tbey do pmvidé adcfisionál siipport
that elTicscy Is expected ta be símífar In thess patie,nits and tha ones aoed >5 yeafs, as cfaraonstrated In
tae prevtoysdgvetepment steps.

2.5. Clinicaí safety

Inimduetfon

Tfie most comman side affects ivldj ataluren (séen in tncfe than 5 in 100 paopla) aré vomiting., dIarrFtoea,
nairsea (feefing 9ck), hÉscteche, stamach ache gnci fíatutence, Side effects are ustiaíly mild or modérate
ín saverity.

Ataluren must not he usad at the sama tinie as certain antibiollts known ás aminoglycosides v/hen thasa
aregiven by injection Lnta.a vein.

rH-lPairfr-í.cí c»' i'iifíitc-.i rafifitiC'' rif-!S-,ni3rrr-i3K.-:~

Patient fijcpogirre

Scuáy 030 bsgan ^vitb a 4-tíeek PK phase a55«sng short-tern^ safetí^ aníl PK, folto'ivecl by a 49-week
extensión phgse to provWeSonp-term sately and erficacy loforanation in this popiatation. Saíety and
pharmarakinetíc date TrofiJ the 4-week PK phase a r« avalla ble ini 5 final PK CSR da&ed 21 April 2<il7, The
cut-<aff data of the PK CSR Vfas 10 Febmary 2017.

This sunnimary presente safety data with a swt-off date ef 21 J«1y 2€17 (che date bv whicli data for the 29
Week '/꣒.C was captured m the datehase for ali IT patients), and Indudes evente with a start date on or
befiore that date.

After the PK CSR aft-off date,, the datehase vías «pdaCed to Inclwde 6 additlonal adverse events
experisnced by 3 pstients durlng the PK ph.Ks not previously ¡reported ín the PK CSft.

IheseTEAEs (¿ pabente vilth eventsof fiattileace, and ene paílent with events of pynexler cghtusion,
OQnsttpBttcifi, and rash) arereflecterS fn this stommarií.

Dunns develgpmení, l doses of atsiuren; 10, 10,. 20 m^'kg per day apd 20, 20,40 ma'kg perday tvere
evaliíateá (Studv 007), While both {toses viere vieM toíerated, dinical benefit was oteenied at the 10, 10,
20 mg/kf dase, which was aelected far the Phase 3 stitdy 020 and 3ubse|uent(y grantsd marketing
authorisation. This adáendum thus summarizes safety data far the 172 paCiants administared the 10, 10,
20 mg/kg ctose frora the t/io pcicied nmDMD prvoéal stuctesin pabents aged hS ¡.'ears(Study DO7 and
Study 020, the Pooled Studies) for the fi rst 29 days 0? treatmefit

Adverse evenCs

Adverse EvenCs Durlng tire First 2:e Days af Treatinent

To ailow for 5 comparison of safeby fn pabents 5 and cícter with tbose < 5 yesrs oíd in the 28-day PK
p hase of the ongoing Studv 030,adverse event data from the first J8 davs nf treatment m Shidy 0fi7 and
020 (tha ttvo raadomized, doubie-blind, placebo-conitrolled, 48-yie^ triáis in patíetits with nmDMD agad
£5 years) víete pooled and sunnmarized, The adverse-event proflle of ataluran tn Study Ü-30 vías
ccmpsrabte to thst of pailencs aged S and oíder In che poaled stirdies.

The Qverall fregueniry of tpaaCment-emergefiit adverse evants ^TEAEs) was slightiy higher araong patienCs
in PKphasa of Study 030(10 patiants; 71.4%) than annang ataluran-treataJ pattants the first 28 daysof
breatment In the Pooled 5titdles(Si pgtiente; 47,l%í,Treatment emergent «Mertts ooBsIdsred to be
reieted to staturen wens infreQuent(n botfi Study 030 and fte Pool®! Studies. Withln the first 28 days of
teeatment In the. Pooled Studies, 3 patlents receivlriig 10, 10, 20 mgi/kg ataluren experienceí TEAEs with s
masinium Cammen Ternriinoiíigy Cnteria for Adverse Events(CTCAE) grade of severe (events sf
coRstípatíon, íleus, and tíls^ss prograssion). All TEtEs fn the PK phase of Study 030 viere míld or
merferate in CTCAE-grede of severfty.

ChMr'edft-fí.ú- c-' ^»'}jrarcT vasii^CíC ■* pr^E-.fí^r: '

J-grr' 15,'f, i
Tábíe 14 Overviev/ Qf Treatment Emergent Adverse EVente by study for First 2B Days
c
of tregtment Reported for More than Oae Pattentin the Pooled studies (Stud-y 007

! Sfntlv (tir fllPi SEiniieí Í10~ iJTh SíSihIí" iJJ-0

! Ptiiiiftli 10. i®. 20 íBS'fcsí ' 10, Pilfl inskg
i PJ;3 i'í.111» Aláluié»

í íX ;= rn (>>-£ 17 €S I4l
' 0 é'-hj'i bsTA :U i^C'l
XtHubs!' llf rE,\.f- )U4 Í9¿ 76
Pálíftisi wirt[ 1, uf muií-; 1, i
TS.-u: 1 o,' i.íü:;i S I f-to i ,1 33 ijl -N
TEAE 'fíJateíl eíi'lafe drae' (' i |
No! ííljTetJ 37i:¡?i ÍJ 12Í Si ? "'.í;» 3 í
Rtfl'ltíá. tTüSTi 37 1,73 ?! :< i}7 "-f
TEAE tra.íEasy to iílí«tsiiJ.aau.iiíiaii n iíi ii 0 ifJCii n is.nii
S.A.I*;. 1; lO.éli fi lií 01
TEAE '.iiih .a simarnnni CrCAIt pmil? of
J.Utí 4? 123 íl yS i 3'^ "t tj (..'7 Í3|!
MotLíifttí ZCi 113 f• ■l |2S hiS
^ ÜjiJ'Üii 3.11 71 a (0 Di,
LiSr-- ihfrll mlMi «E íj íf j ííji ti 70 tJii tt rñ iTi
í-at.-il, Ui'ÜWt u iiO'ii'i fi i I? hi
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TlrAF - a a,1vm# r"-. fu»;
'El íltfíiiir-díiv ¿íií ajcs-^irp-jíñí ¡iiT» luié likí-uiMeflí pckil!!!;íeÍJj.iitü:Lj!jí:o ittuJv tes üp
líiisíi! í'-iaJe tfcrií lifoiKá ti> tin-'í jn i.-rfii?®'.* oí tmieL-ííd ¡Aiiícd-iÍdjioí.? eoon.ifeieil ■ toa rifirró'
JwSe A C£fu£nLrti!íÉlEn¡i-fsa AfertSr fV-ni' (ITEAEii ft j;. itllrifii.¡r; a»Jtli:es*r f-Vnj! duel tuca-, (% títii-.B3i oi
dir jKSisd' «tQülofle ó om íLc fe; £b:í oí ttuJv ánc to o '.rekí fui ik? p3i~-!sil ípoJi-k. t asd 4 iveefci >1 m Síeiís,
••■oi jfe fe |a;4 {!a%-e.iAr-.irt», tfcaj

There wera no áertcus TEi^És aiT¡ong atníuren-treaLerf i3íilÍ62riCs ira the ñrst 23 days oí ths Pcolei Stutííes cr
It» tha PK phase oí Stiidv COO. The mós-t írejuer.uy occurrinp TEAE-a annong psüenLs in the Poolfd Sludies
treistad thís IS, J.O,, 20 ra g/Vj doscs óf otalur'an ciiring tha firpl; 2S dflys ol ír'íaitmgnt mire Víjraftirig
(35.1% vA píit¡Bill3'jv literrbeA (g;.,7".íi .yf patf'jíifei)^ htjfeaíhe (5,íT%. of paelisnLí')^ ria!.e«.a (S.ZTí» oí
patianLí).

■ i.fPt.;
Tabte 15 siítnJtiary of TBAÉb by SDC aab Preférrad term
Talité 17; SraiiuiLin- oíTr#3cisi.pnt-.E!Bíffpnt .Ittversí? EvbqI:? hj- Sy^tf m Orgaii Cksi
.lutl Prtífi'irrtl T«rin EíimtIi-iickI by al Lraií Oiie PUicfba- ar Uj., lU. IB
jMg,,AEji!ui'í'U.-!i»iiHHl PtiS'áeUE tJiiriug liie fLcit 28 Díiy^ af Treíllníñl Eb lltf
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ChMi-0tFt'r-;xí" r»' i»'lnvil.. I varlrétic' s""-!;:.; 13(1; ■•aer.i

eRO-iJLUrixtoa 1 7':
 Slddlf» OC!"/KO Síxidy OSO
SliMty §07/01® W,l&. IDr 10,
Pooled 2fi ingíTr": 2(IlE|fe i
PlJiíttio Afalart'ü AtnfuVeá
System Oi^u Class
(N =172) CN=172I) <7í = l-l) ;
Prtjftrretl Tenu »■ í®®! n D (•%)
Geiterat dtsardírs aarl iidmiiiktratiou site cSrailiíioBS 4Í2J1) a í4.7i^ 5(35.7)
MitJsc 1 íü,¿) OÍM'I Ifll)
PíTí-xia OfOJS SílS'í 4 08.6) ;
DisiaSé flfSaídSíiojl 0 c:ci.©:i 1 fO.S) era.Qi
Ttóra 1 íaffl Ufo 01 ofo.o) ;
Fatíj^e 0 (0,0) 1 íftíl CiW,Ol
Inflfflcii23. likc tibttss 0 fO.O) 1 ca# 0(0,01
■Éiisigy iflcieascíS 1 co.é) OÍO.B) 0 (0.0) ;
Nen-caictiit diesi wm 1 ÍÜ.ÍÍ) ""■ ■efe®" '
InuBMue STstfim disorclet',® »(()#)' 1 fO.él a (0.05
Síasísul aleífisy 0 fü.i) 1 Cflitíi 0,(0®
Inferticms nnri ínfesialicin'í KS (P.ái| iflai.®, . 3 {21.4} '
Ese iafecftKO 0 ÍÓ.Ql 0(0.0) 1 ai)
'KascpliattTiíntts s m) 7(4.1) í (7.1) ,
Rfespaüteri,'' itesct auéiiboii ú (0.0) i (O.é) 1(7 1)
.RMüiíis Q(aci) ?Í1.71 i (7.1.)
Uppcf rcspifarcay ttaa iaíccTÍca lU-2) ! (&.6J 1 (11)
V'trai r,i5ls 0 (0,0) 0(0.0) lí?])
SinsesjIaS 3ÍI.7) 1®.0) 0(0.03
KfifíüíoItLÜl 0 (Q,0) 1 (Oviíl a (0.0)
Gastrocjítmtk 0 (O.O) 2(:i.2| 0 (0,0)
Infltjsnza 1 (m ! (0.<5'J OfO.O)
Toiisitliias ] (Oif) 1 f&.tfl 0(0.0)
Flistífal flíúí iaifoíria:i 0 (Ó.o) líÓO) 0(0 0)
GtnaÉvitis 0 (O.O) 1(0.6) 0 (O.O)
Lc.vít respífatonr íract «n&ctioni 0 (0.0) 1(0 tí) 0 (0.0)
PaiEsiytte 0 (O.O) 1 (O.tí! 0 (0.0) '
Pfaar^Tiiptk. 0(0.0) i Ctttíl 0 (0.0)
Vaíícilla 0 (0.0) i 0(0.01
Slill Eufrclioii 2(1.2) rifO'.ef 0 (0.0)
Ora! licís»i 1 (o.ei Q (0.0) 0(0.®
Otttii media 1 (O.c) 0 ÍO.® 0(0.0) ^
Ptevuíetiii saepEOíeccal 1 íO.d) oía.® 0(0.0)
t?Kcí t!il?cíÍQTi l íO.d) 0(001 0 fG.O)
 Slutliei. IWF'Oirti. Slw-úv ü3íí
,SludviiHjT'iJ20 Ití. Ifl. LO.10.
Pocled 24 utn.'ksi 20 mgdiB
Plaff-brt At.iSarí-n Ac.ihuen
Orgjin C Liss
lis ~ Llí
Proffrs:í<l Tonn IIF"'')) U ffl i «1
fnMHT. poiíoiiiiig..inrt firafí-íIcnTil coinfiliciirtfjti'; 4 l2A5 f li.Oi ]r-1)
CiJsKffi.ic;!! 0 i!'! §) '0 ÍO Od 1 {" i 1
Fail di 1 1 7:i 2 ■! l 21 Q (0 ü,i
Lciiib uMiiiT 1 i'O «) l ÍO ft t OíOOi
Lreamear spmin oion 1 1 0 Dt 0(0 ü:i
SigKM] í:oiTi)3íi?f.í3Cii: fracns'í 0 iO iJ) 1 10 ñ'¡- 0 í-O 0)
P"Jit-miuK30!: i^ain ] 1,0,d) Ü iO 0} 13 (n Dj
to'í'itjf.iHon? 1 (tFfl) I (O.ífl ft (0.0)
DlcKvJ aiíiaime piijípLiraíe tiicref^ií 0 ío.o:i 1 ío.ei 0 (-0 D)
''.Veiglii mcrensc'i 3 (O.d) OíO.Ot- 0(0.01
Mot-íbíiltíin «1114 iujIiíHom r3.is»r<l(-i'=. 1 (».ó) 4 i::ai 2 ci4j:i
3 ÍO ft 'l 3 il 71 1 (7 n
Sfci-ribfílic üCRlcijs-f 0 íO í) 0(^1 1 (7 11
Fluid ccBnitscnt !-> l 0 ¿i-) 1 til ai r) (Ti D,i
.^Iii'íniSQ'.UtrlíMiiÍ! iinti i üsiiiprtni' ti'.'.ijq- íIísíii iIm i .? Cl.T S ft (ILO)
Pam ui exirciíurc 3 lú.é) l '|0 tí-1 0 ifo Oi
!■. ÍValf E<1 0 Íp S) 1 1Ú líl 0 (0 Ú1
Bsd: P3E1 1 íO di 2ÍL 21 0 (0 01
AnliraSsi.i ] iO él i 10 tfl 0 (O 0)
JeLnt STiVetüüS; 0 ÍO 8) l i 0 oí 0(0.0'l
lliisclt nlropíiv ÜíO.e» 1 (Ü.frí (5(0.01
ScoLosis- D i.O.O) 11,1161- 0(0.0.1
TfliduKiís cc'uliacliiEe D l.ó.®) 1 IU.61 ó (0.01
Nfn'ous vy?)iíin disoicíen; .8 {5.:) ij r.6,í 1 r.i)
Héadacbe Si4 71 lOii.Sl 1 (7.51
Pí-^'-dwinatOá h-iperac ü^itv ! 10 4} 11.0. di 0(0.0j
AiuiSüj, 0 íO '31 1 (tirii 0 ÍO.O'i
iÜEtairie 0 íCli) 1 lU.&l 0 (0 Uj
Pí'iiíliiisítií disví tftí 1: í : rl.2) 2 iL2i 11" 11
FmtfSfiii DtOffl 01 fl fii 1 n 31
.■Icrpiitiftii íi^ñf il.'R'.liftaHÍ'.'iív fhíftftfa 0 lO ííj 1 -llj rii fí (0 01
Ab:taiüm3 ts-elavior 0 i.Ü.íi'j 1 lO 6-.1 0(0 Oí
AsJÍ'ÍÉ'.ií.líHl 0 lü iJ'j 1 10 tíi 0 (.0 Oj
Nesamáim 0 Ki.m L ÍO.tií 0(0 en
I'i.&.Cd SWIÜS25 2il2) ÍMQ.01 0 ( 0.0)
.Aflxicrí 1 ÍO.i) 0 (0 Ci '3(0.0,1
Sieep A;-«r(fer 1 ip é) ÍFÓ.Oi CJ (0 i' l
R^prodiieSivi? sv-stcin niud brea?* disflrckrs Ci («.Íp I 10.61 tt IX'.O)
¡■■íTOnu's gietuial 0 (0 íí) [ -lú 6-1 ® ( i) ÍM

!.í -tt 1 '..ru

 Studiés 007J-MI} £tudv03O
Sílidv ÜOTiOIO 10.10. W. 10,.
Pdolud 3# inigdí^ 20 lugila
Placrt# .AtaJurfji Ataíurm
■Sj^tem Orgiin Class
Pi! = J72'| P=172) P." = 14>
J/reférred Teiia u {%) a (f.'b> tt f
teíial ¡tnilTfiitfm' íHiorítc-ns $ íi-"3 4 fSAiS 0 fO.O)
feuresis. 1 fD.él 3(L7) oíoj) :
Uiicfé aÍTíSimíJity l (O.él 1 W.6) O'iíl.t)
0 fixo') l (€.¡5) OlOJ)
StnsHgtoy cito.e) l (0.6) '0;...®:®)
Unn.Tíy feaotoififlcc 110.6:1 oto olü.#)
RpsiJÍinwry, tluítarif autl meílinsiíaal clbotckrs , , .S(4') 10(5.84 l íXl)
CoiigJt 2 «.2:1 1(17) i Ú.Tl
Croptumtigcal pain J{i.71 2 CU) 0 ÍO.#)
NíLsal eengsriai 2{|.21 2(U) ÉffO.i)
EHnaiiliea 0 [o.e) 0 (0.0) ;
Epcsteds 2 [.1.2) 1 (0.63 OCO.O)
SMn aatl snbcofaDeous íissue disordíTs 4 0.35 9 (5.2) 4 f2S.D)
H-tpertricbosts 0 (0.0) Ó (0.0) ! Í7.1)
Ra:,di 2 (1,2) 2(1.2) 3(21,41 .
Rásli «ii'íbaiislPi'.s cr fo.o) 3 (1J) OfO.#)
! fO-,d) 1 (Od) feO.'ff)
Ecdmaosk 0 (0.0) 1 (0.6) OÍOJ)
EaytbíiLü 0 l'O.CO 1 (0.6) 0(,.0.i)
HaA tesiBire.abnoEEsl 0 tO.-Pj 1 (0.6.) OfO.fJ
Ka-atteápilans 0 (Ú.Oj 1 W.6) OíOJ) ■
SfcÍD taminsi aaisaírau 0 (O.O) 1 (•0,6) OI'O.O)
Skin eüüjliaboa 1 [0.6) 0 (0.0.) Otíli)
Tawtilai clisfliiters l£l.l) 0 (0.(1) 0 fO J)
flUSllíEE 2fS.21 Ú (0.0) 0' lOJ)
AtóbreilarloHis: J*M)RA » Medcal Dsaaiw tor R«ilsiaí\' Acávuie: TIAE «'weattaaii'eaffiiaMi sK'ftse
e'ivst.
Safft>- c.-eati for the Saidies weií- codcd Tíssg McdE^ÉLA. vítsioa 15.1. Saítfrt' íar Stud3' OJO ivcrí
e6d«t üícág MedDK4 v&íiai; 19 0. iki ÜK PaoJ«l Simlfe, witfi úie jpfefeñwl 3diu "eawí'ití"' vv'are
cocW av «ciRfhii k litó Rsia] aad Urkuxiy D»ef(tes ifsiauéípH «la^. wMIt ia Siiidv OJO ihesc é venís
iwí-codiíd as ooaimnp ia fe Psj'dsbtnc Di'.ofi!írs ayiteai ofpií» cla&«.
la fiie pienTOi-í siátmsstaj packagc. stie as-trcaídl popTibnca ts iie pop-aJancai foi ssfelj- nsoíyscs
ApMi«u ftii0 cSi?fric3tó«l J fli HS&it eveais witil lie samepieffited lam is coisiled uulj" oace fcr tltal Sena A
psiij-áw ivl50 txpe;i.gria«cl 2 et niareadvese «i-euis wiili itffefftit preíetretUerfai Wi-ilm tlit sastie sysEeífleig.ia
ctass Lí ccMbiled atily eoct la. feat sysácnií osr^aa cíes totaí,
EiffcfeioE TaMí !-f j.Ll l Eid Tabie d 24,l-d2B

Durino che PK phasa cf Study 030,, 4 petlent; I2S.6%) e>:peri6ncsd TEñE; of pyreKfe, 4 paCienCs [28.&Atí)
experienced TEAEsof rash (3 [21.4%] with events wich thepreferred íerm ''rash" and 1 [7.1%] '«ich atii
event vííth Che preferrad term "viral rash") and 2 patíents expsrianíK) TEAEs oF flatuiaíce {14.3%).

In ttse PK phasa of Study 030^ al! 4 s\ients of rash bsgan wlthin Che first 27 days of treatnnentíone event
eacii en Day 6,, Day 12, Day 22, and Day 27) and were mtíd in sevsriCy, <The event with Che preferred
term of "*v1rai raéh" was considerad to be uintikely refatéd ta átaíuren treátrasit.) The 3 évents with á
preferFsd term of "rasti'" vie/e ransiderecf pasfiíhly re teíed to atelursn. Study treabriení npt chenned
ír« rsponse to any of these evente, whtch resol withln l to 15 days,

AN iptherindividpal adverse eyente v/ere experisnced by i patisniteach.

ChMi'aatíüaD" m irlifact •I ra iifltiC'' ST--'E-in-t3i'i laEcr

E'-'.-.;-: j¡ r.i4,' ifi-.íj
Tbere were no destSis to tihe Peoted SEudies or ciy rtng Stady 030 durin'3 the PK ptisse or as of th>e cut-off
dac«r snd n& araluren-treated paHeiítí ajfpsrfencad a serious adversa avene (SAE) during Ehe ñrsr 38 daYs
ef tffe&tmenE ira the Poek-d Síudí® cif in Ihé PK phase af Stuáy 030.

Tai ble 15 OvervieW cf TEAE^

Tablc T-i Ovptti'íí'K' «f Tiwjitrneiat Emargenc í.'i.ílíaríip Ewnii foi" Ui¡o
Ptiarmafokm.ídc Pliaip. Exleiisioii P]íaí,e. aiul Orípal]'íor Snidy OJO
iSüfrtj- Populatiojiji
PK pEiirt» EalfEi<ÍKO.,Plaá!'.i' ' Owiáll
(.%■- lai 1^" ~ I4í
n Q í'jj
Stmljí'r af TEAE Id Jé él
f.itifíin nlth 1 ar
lEilE ii íTl-dl M, i irCi.Q'f
TEilE íehted to cpjdv dnic*
fí« S135 Ti f' ret J'i i/ífriJ»
Puítojed 5 C'JS.T IOJ1 5 (3.5.7 i
rE,3iE líBskcp, to ikíC'jataauiEon éltfüí U cu 6] i ÜKiUll.
■14E ÍJ tftffli OCO'ij 0 jCCU
TEAt wní» a timuauni OfAi pradr bT
MiU tí lí-tí S.i á (4i 9j 7 1 ?Ú 6»
Mefl-iTif 4II28 él 4«F6i 71 '<0 #1
SciTIt ifi (ri.üj i UifiUi
L,r&-t.!:i?;T:ramii «tji.m Oi»#,3 lí^ííO)
Faiid tiO.Qi QCOftl ú fi O.Cif
Afílit eUflfispo*. CrC"i4£ = Cíiiajpal TctacsoJe.ft' Csi-ini;> lis» A<fcin>!r É>irt!». ['.SóííiRA. ~ MnSital ftüipji.áa'*
íra'iRéillitaoy AtbXttisk. T£JiE- ~ lisatsitíc! ftüa fcad silisais? «i si!
'rviñits áíTcifslErríli.» iir.-e-infsiüsí K3ta,».T a |f'is".-ih|i? ra: jTEO.'tt.itür tíhtiraiiip id inofy inia inr conautsed
■rEl.i:;n.r Íijtí.- tár-" ■¡fcifOiírf ía ta'rr rin Unlilflv a unrclisrf reilíSirJiiji ?re rai'aife'íé' tnií Irhííd'
fef3SCK« T.-Hí |-I i I í

Advcfse Evcnts Durtog t3*a Extensión IPhase

As of 21 JmFy 2.017, all H p?¡tiente have con-ipleted the Wsek 20 vísit, Adverse events befínning oo or
bsfore this date are ifidudeí ¡n ttíis subniissiou.

As of tbe c«jt-off date, al! l^i pstienls experienced aC least ana TEAE,. including 10 (71.4%)
patientsvíhs experiencedTEAfe in che PK pha5ean¡d 10 {71,4%| patients wha experiersced TEAfe in che
estensloEi piisse, Tbe m<5»tcorsKnioi5Íy ©ecorring treatraenC-eiTsergeFit «Iverse ©"/ente iverg pyrexia (€
pafcienCs; 41.9%), rash {S pacisnts in toCai, 3 [21.4%] with events witb Che preforred term "rash", 1
[7.1%] with and event with tba prn^rred term "''virai rash", and 1 [7.1%] with an event with che
prefeired terai "rash generafized"); ear ra fe don (4 patients; 28.6%)., rtasopharyngitis p patients;
21.4%), and flstiiieice, vomiting, and cough (2 pa&entseach; 14.3%s). Ai! oCherTEAEs wene experfenced
by 1 (7,1%) petienc each as of the wc-eff date.

rk,Mr-.5írrPS cr &' .-rlítatr. i variíitiC' 3'í;s'';'sri3n: -laof-.s

-'SE""
Talsle 17 suroítiury óf TEAEs far stuáy O^o
Tablc 19: S«in,EKirj- oíTrí*n(Díir!i.f-iax!frEfctf Adver-^s-Etíhíí 'ta bbidy l,OÜ by Spiraa
Oi=ga,ri Class aiitl Pí<etefi'«l Ti-jm in S.nitly 1)30|Saft^iy P«puliítlDu|
TK Pha» Üt.Mldriil;¡"taai- O^'^raD

hy^mx^ Ürgaa r?f=|4t 174 = Mí i7í = Mj

IñiTEriTíd Frrni d("«j Q r.!) o i*.)í

PnÜE^aíi «ifh al 3i?3'^i nn#! TEAE IQ (71-4) 10 f7! 4) UíWOitl

Cta5itiTfÍine33cn¡sl Dí^^nJirs 4rJa.ír :<14.31 fl í4:2.í)
Jíl'íí) 0(iioi Z(H J]
Vaouiia? 0 t;c's) 3i 2 jt4J)
AMamiiiat pazü: !i7 11 OfBlW E «T 5)

i i7:i;i OÍIÍ.W 1 17 *3|

Jinil tÍ3i« á-i5^ f CS5"í J {31.41
£CllÜllÜllÍ9Í

4(130.) JfOi 41 é

l 0(5' WS tí? i;i íl? S|i

1 C? Vi Q l'O'.Dji iP H
fnÍH-riiMí SBfi lTi6««qí«n«s 3(il.4l ?Í.SMI
IziE íril®:2L5ZT3' !ff li Jl7! 4.1 diium

KxirploFwii^ín: 11.7 fi ií.n 41 3 ei..i'i

Sicaadatomal OiO/tti il tfí.ll í ff.S)
Geag'.iiSTií'id" ÍH'IH;) j liíji tii7 !i»

kjctnC'íi?- t) lOii t ii ri 1 t'f #1

Gj;ític>a!::íí3h4 t¡£ijro"jir: Q IDCJ Hí ll insii

HaiifcíJfcan 0 1-3(tí MT.ri E 1.7, Eii

H2a3Tí3nm '&n'r|j!BK:iíCcaS 0í0§,i ¡1 tOÍ) tíT.ll

ResjiífEDiy U3£i ialcíBca Í i7l) ij 0(0.,3) í 0.1)

Riarsftj. !í,7 U O'IB'0') 1 o SI

w-'.jsir^icfv «Krttrtí-fiwra S 7' ll OlftOj 80 í>

1 1 ni 010.01 EO 11

Ipjim',iwi'HjfiBi-; aiiil iijíHiíluial íoiniiHíJifam i r.i.:i

Aiskicip-di bis Oifift 7{1.-| 31 Oít-lil

Coipra^jn 3 (■■ t( Oiif 11) 8 .¡1 i I

Tala:) ibfRsrc 01.0 4) t 7 1,1 S (1S)

Slotiihfrli'Ua ü.ihI Qii lnliaui iliíüaiÍMJi OfWjE I f7J:i .1 <21.41

Orarme i^ppeoa: ! (n.i 1 t)¡;¡>D) Sfl 66

3 Eyf^sáiijníleíaí 0 í iJ E 1? ,11 Sft SI

?i5¿Qbcí|ic acEtep.i 1 o,fa.oj EfJ !fl

Iliraci.'l Ii®f1ri(i0>' S' ■■iniJi!; T.jgo"!

 ,PK Hl.Kf ElIfB-íiMB-iPllfl»
(S-jiirm Orfap ÍV,. 14) (?í <' Mi O"-" 14)
Bi ot®#
fl ■1 ri)

i .17 IT 1 li'iDoo) !
íliÍJSrtr ditoi ifn í r-t) .1 If-Jí 1 it 438

fi fOI't' J 1 iT t) j ti E)

ELOíriti H'tIm BfC.O) .1 1.7 E.5

Ijsmnrii? 1 'T í)
jioií f£i uory dncidem 1 rJi
Osiianutínii ■!íí,0 e-I. ■| Í.T t> i 1.7 »)
teplraf'ff, ilioracif. aicl iiMJja-itíaaJ cbtardHi irJi Jai.4) 4 i:3.8.8
Criijíi K? li 1 <i^ íli l i 1-4 h
IpraBu puK') 1 f.' !j 1 (7 n
.ílaiimíxHj «HJC'Í 1 i-' 15 1 i/í ti
Tüisíillir brpsrtrei&jr iiJiO fi í lí7 £i le? II

Skiiiaiiil lulifaliiufsmi eiii-ji: iIíiíihIh-C! 4 1 42.1; SliJfJ,!!

Pa¿i ? fi l 4) R i.O 0) Ja! 4?

lii,peTBicJii?.n í (7 1} ííW 15| 1 (■ T í.l
?j!¿a ^iKciluaiS i 1,0 CJ. 1 47.1 ¡I I l'l I)
CfílEJED tt 10 irí E? ló' ti
ÁMíiétijilitiiili ?,lFd]>¡1.4. = Mrúsía! Hcdísim* ira fonááiiji.' AeflviUa T¡L4.£ - iFraüirml-miriTircI ísll'n w
asis.
í-jíriy rvroa TiTr? c&bíi CiCífí MsíDlW im'iisiQ ívo
A jKiisná i'.ri» «^jísníorei ? ot ara? ftrrii isiái CiS'Ksmi: pwfoietJ tsna m cmsrJ^^d m£y teKC ira- ItnS Itet» A
pjfcail m ho «paiaiccá 2 ai Cíai5 aái'eri^ s¥eil 4 -aslli iiifefnl jirtteiird fcioa 'atíírai •.bé- Eiirtr p.-ilsuS sirjaa
dsn!?, cisaiifd co) «■ ea.-? la tii t.'i-jfin -ííroi, efe
CiiJ-ftjTílitr- :í Jdv :0}'
Rffcresace: Tatíí l-t J I i 1

All TEAEs In both the PK pba.se and Che effienstsn pbase were mi Id or modérate in ssvsrity. Cf the 10
Í71,^%) pítients who ^perienced TEAEs during the eít.censí"on phas«.. 6 (42,9%} expefiinced TEAB; wich
a rtiaximum CTCAE gradfi of mtid, and 4 {28.6%} íaMperienrad TEAEa ft-ich a mavlmum CTCAE grada of
modérate. Cunnutatívfiiy, of the 14 (100%) patients who experienced a TEAE tíuring che PK phase and the
extensión phase comhined as of the cut-ofifdace, 7 (50.8%} experienced TEAEs v/ith a maKímiim CFCAE
grade af mlld and 7 (5&.Q%) experlenced TEAEs víith a riiaKíñíUm CTCAE grade of mdáeráca.

ChMl-ent'fS.'tr C-' i'liffii:-" i víinsuo' iji-; -jec-.-

Tablé 13 SM-{wnafV t>f TBÁEs bv SDC experieitced by at least í jiatíent sar thefurst
ISíiays flf tfmatmertt»
T3ble 7íi- &í Trcnimcai-rfliUrf Treatana-tif-fniergenr Aah skc E^cnlt Ijv
Sr-stfin OifaM Clti'ís niirl PrefpH'fii Tlprm Eipírieiií-pct hv iif i-pa'Cf Oiie 10,
10, JO mg AtaJiiren.ifpafMl Parifiir nti?liif iFjp Fir«i ÍS Dajt afTrfa.Eiwf-ni
In itii» f'eolpd Síndá^í {StHclj-OP atud Siudv íilfll ot StMÓy 031)(S.aíí?t}-
Psipnljitionl
SUnly
(?l»'''ft2íl Síadifs f'ú'.Cfli) SrsEih'QXi
PcMllF-fl 10, l'fl, 2ñ«a.'te Ifi,
Rarsibi» .Kalui*» «ilalarfo
SpWB Orjao Cb« í?í=ÍTJ,í CV'^Hi
Pi>í'frn"!Í Tí¡re! ,BÍ?íií M"*}
Patí/'.nlí 'aifii al Iffarl rinrrFÍitfrt TfiiC Íflí-Tj i ' píJíí,*^
í|;,ai¡- amS lubTrlailí íl:i®rii«>1i 1 p.t») n{íi»í Oífl.i»
T^Tiífir^ 1 íft® fl ftWJi e»ti)
sp'j 24(lí,Uj íl-NJI
feirrhofJ ripi,i :
Vonúrms: 8MFj OitOj
.Kkjot 01»0 OiIfl.O)
AMasusa]&a 5 tífl n#üj
i'teiikjKc i fei e> •1 il IJ
Alaiemuu].áíKeiti'feí'i, i.É&.ef JiS J'í
■ílíabn-inial m¡A tipiafí ni'dríi s i; 1 75 nftMí
Ásícjiirí^ui ÍÍUI 0 fO «> PiS'O) _ . .
rf-fe'lpflD': bíra-Tíl nt^^Ts^'W, l (ij «(Olii
Gioeral illíoidfTi aiiif ailroinhtraiioa iMí l fíi.ál j n,j5 If'Jí
tomUdoi»
fiSabac V íu y) a tu tí
Fanrr* 0 íu IJí ! tO,®5 UrftO'i
p-mtlú ■n m r/í 1 ÍOdí 0 to m
&!íTTii; wei'í.iTrftl 1 W ísi " "aliltí B (i os
llifíirjhinT aoti liilfsl'asiflnp UlCl.fil ÍÍJ.J!. a par,
G»1iliStJirrfarS fl Cíini 1 fUtfs n Él fi fi
Ló'.'sd !e»4teíaiift' liad'líifcf.'JiSt 0 (Q'.ft) ■| (Q él uio (y
.luurn... fiiÉSínlaa aad DiwC£-Jtiiíil€ajnrElÍ£.ítfoiM ijiiíi.m 1 ÉUííf ÜrtJ.íl
LeIBIi CtTÍET," aciici iíOÉl 1 ruiorji
íais'»ifealleinii Í4II.4Í iiw.tii ■ u «.8»
ñ'fivti rarrc.iEíiS ((0 s> «fóe.í 1 uiifluj
HuWiijoii (Ijuji if:pt íi 1 j fi.-> 0«l.6»
1CÚ « J ti Xs 01.6 B)
JXu?.i.*illciítiílif4j.l :i.i)4 (íiliawwiríí liíiite aílt.in3iri-<. J3«-E> í,íli> D «i.m
BadíMuii OíEi W 1 ftiéí B0O)
iíftMje jQ-^ísv tiifim ! ÍÜ í'í DÉJ0!i
i'ici H ctsraare 0 Cd 81 i, iü cí D»l3j
JÍH-vnB-, ítiioriÍFaTi ñ Dfa.iJt
Jtl.-I ija? tjiRi 0)
lüK 0(0 81 1 (041 01.0' 0.1
S^íVstiíitsiiti 1í"'Jwmi?¥í;\' 1 >.u ei <) 10^ ti ÚPDí

Chí-ft',3(irurs'ú- i>i rlitati-.l wríaíit'> roet:

 PovIhI Ifl. 19. ífl-ms'ka Jft. 10.20 tasiks
Pln«l:'ú .Atnlrntu, .AlílllUíB
Sj■Etrin Oi:e!3 n C íoíí C7í = S-li 1'2)
frcífiTprt iViiii í f hj II !:"«> n ('.al
PsvciuÉilc dtsMderí S i fl.DÍ a to.Oí 0 i'a--oj
Maod ETo'iíiBü. S í«6) íttvi® (1 ti 0)
Seep ckíoíifa J .fO-® DCÚfiS OlSÜ)
fcn-il .tnd iH'iaair?'>rtiwriljn oro.» í fl.'t fl íi.fl)
Cinirí-a'i OW D5 1 Í0"6;i oíeín
PolviOTD 0 í# 8) ttoí;> aiioj
UtUK ahjBtcLÍlEfv Ota oj 1 (0;6i! ore Oí
iRispáMTáiy. iliurrtfk rii»íl uirdlasiiiHíil 1 l W.si 0 p.tj)
dir.m dti's
Cou,ái Op.O) t (0;S} 0 tii)
Epistaxis J#6) (rmm 0 # 0)
Skir fl tiif snísrptanPMií rissisf disniiicni (1 (fl.® za.2i irii.Ai
Eaáb 0 (S tí) I>(i3®í 3.(1141
Rtisb embíjiuímiis 0 Ifi.OJi 2 611) 0 (eclj
Sui bsmlaiE üiKíSifla ota.D) i W-.65 1 0
l'iicdlai iliwsdffí 1 {«.« ft (íl.úl 0 (M)
Fluskatí 3 ».65 5 (O.Oii 0 (f.ín
AíjbiTíiiaíioQs: |;íf.dDJL*\ = Z^CidicaJl Dsriiimaiy fer S^cdaf^xy Acíi'i"i£ies: TEXE ~ tseaniLeta -emsi^eaíS adTsr'ss
tvm
'Eve-ss 'Skenxíí br üt lavesugarcj i.> lint a jKSSiDte of píofcabk relaacsiá-iip to sRiíh' top .ire-coniidetci
rcb-íiT FÍiílf di5« íkrjutd so taví .m imíiieiv: or rarrlircd rtljaijailiip a» íonsidíjed 'lus rebtd'.
Ssttr/ «x-íl3> fe lljf PsoJíd SniiiK varf Wíted ibúís MedCiiS. '.•aí.ica 65 í Safeij «íiír ík %rtitiy ü30 vreic
ccrifiS ijisiisg ríMOÍt-»"!. '.-«rucin !S 'fl
|ij!5licíWP.'knis 5rtei»i(íittiiíiete:ii!r, lijí-'.is-lfe.'Ci-ái.'^iíubtjsa 1.5, ibef^Jiiidaiiíi) Eje «sjtoy
A paüol U'lsi cSpaieucrd 2 os icwc BVitlft widl 'ilic «ite jn c&fíed iwtli ij enJUiíSEil Eaify wrtí fa tliai ictisi. A
UJiisI ivlíjJ «írpéiiaisara 2 ra iiíiif aJí ésáe évEii:i uidi dLQrieül pfffijed tena «.iidán Üa saici ■syw.ías cn,|áQ
íLsií is camlíá >ci!d\- oiu:e á) eltiL oíkbi dass taül
K.-fe-iencf H 3 I 5 nis!Tr.bk'-| í 1
TreatmenC-relaced adverse evsnts are thosG d&emed by the investi^ator 00 ha ve a passible ar probable
relacicniship to süjdv crug. Ir» Che PK phase, 3 events of rasb and 1 avenes oF fiacul&ice vjere consldsred
ralated to aíaluren treatmenc by the InvestIgaCor. In the extensian phase as oí the cuC-oFf date, oneevent
cf ratlguá wás csnsfdered raíátéd to ataFmreni Ireatnisnt by che InvestIgaCor.
No patient to date disccntinuad frotn Cñe sbjdy dtie to a TEAE. En addEtíoíí, thera ware no SAEs or deattw
im the PK phase or ths extenaon phiBe cF Study 030 as of the cut'Off date.
LaboratsiY findings
No clinically meaniñpfül tránds In hematolofy,dlriícal chetiilsCry, or UiinaivEÍs p&rameters were cbsérved
duiing the 28-day PK phase of Stady 030 or Che extetsslon phase as of the oatoff datej and shifts frona
normal valúes at basaline to abnormal valúes at Weak 4 and Week 2:8 v/era ¡nfrequant. Líboratory
abnormalItieE were similar to those eáan In Che Pooied Studias ancS attfíbiitable to the undsriying dfsease.
Duchenne muscular dystrophy is assocíatad with elevaCad total dvolesterol and trig(ycñrieas[Sri vasta va
2O10] in paiC attributafale to the use of cortícosterolds, and changas in llpid proñle are an IdancíRad risk
ásSDciatsd With acalaren creatment for OMD [SrtiPC April 2017]. Most paüents In Study 030 had narmal
valúes for HDL^ LDL, total cholestaraij and triglycerIdéE át baseline and at V/eak 28. At Weék 28, thére
v/eré mean Increases from basaline in cholsterol and HDL leveís of 13%, Vítdie LDL levels irscreased by
18%. iMean triglycaride levels were decreased more than 8% from baseline at Week 28. Shifts firom
normal baseline valyes to abnormal valúes at Week 28 for Lpid parameters were infrequent and
experianced by 4 patlents for total chclesteraf (tvío of v/hom ivere rsceiving concomlcant treatmenc i,vith
sLefolds}, 1 patient for LDL, and 2 patiants for triglyceíides (1 of Víhorn ivas receiylng carccnaitanc steroid
CFéatmánt). In gertétai^ léese pallents had valúes at Che higher end of Cha normal ranga dC basallRé and
éxpériátscéd rétátiVéiy Srinall ihtreases Lts valúes ábova Ihe lappat limit óf normal át Week 28,
C^:Ml'^.'iJyr•x.r.r c' VíiíIhCíC-''
Mary Carmen Castro Valdez
Fecha: 18/03/2021 0:41:55 (UTO-
Cok>gh> do Traductores dol Perú 05:00) Bogotá, Lima, Quilo, ño Branco
ID:IDCPE-0g9ia491
Focha; 1W)3/20210:43:17 (irTC^&OO) Bogoti, Urna, OuUo. Alo Branc»
ID: 20376744940
rinpsy/ctp.instgno.com/docurrenio/val>dar/FCSS077&3EB6-44BB-AO0P-A40CEC4BF43E
Tatole ITI •Mean CÍHingei la LIjíícl J*aa*aui<?£íi'S fmta Batíllfli? as tt'íek 4 ua»! W'«k
2S for .PaUctii'i ovilla Baselíne auJ Pa'St-báfeliDe ^ysf^aníiiís In Sluth' Wl!
(SjJftj» Peipttl,n!lo.B|
SPiatv 0»
LO, 10,. 2.fl ntrl53
AtaJiirpo

Píaianují'tfr rx-W)
Sía tí'.til W«li4 WVo'k IS

Tcrai CLalc-iidol. mtueíi L (0= B) tu- I4;,i

Ba6c2i2W. lüsaai(SDi 43{2ti 1543> .i.AM a.tsís)

PirHto'jeii» mfm CSÜH 4 9Wirl 4|STj- í«=Sít..1«il

Chanfr fea? feselinf, HiMn fSDI #3IH'n65ai 0_59iJfOSI«3|i

Cliantií liian ti-sJanr, ^l-rdiac: ¡jfaaisjr,! U iJti í-O ».I2?]i t 38)

HBL, in- 131. |tai= |.S|

Eíi»Í!iE. jtíEaaiJ'SDt 1.!í5.i0 2?3'7) l Í ?1 iO 14431

Petstowbftí. jücsíi la'D) 3 234 .!,g-J 1491 i,i3(i í,ÍJ MSO-Ji

CriiMHe frain k«¿iin;. nitaa CíiDl 0ifl;'fnoi?jT:i 0 l« fCCií©»
ri'inaé- ftwn taife-) -o©.'af-D >S- n$trr 0 tfr'}.[ 0 l-.s, 0 36}

LDL, miami L (u= J3j Ett- M,3

Biislhsia' itifinitSDi 3 74111 01i1,1 2é.7gilCfíi30i!

Postoictiii;- íüeitt tSÓ^ 3.339(1 I!(315 3 I59«13B74S

riuajif ííC'íD:fciS-dijjí. laíáQ {SD^l & 4fSlí:t 4654,1. 04Sg|C!4j.'aij

ChiiTice ftwn tasírlinr, Medisc 04|í6.®.|1 IOOI 0 4ííli .|,.0 lñ, f 3K!
Tr%toc«iiiSís, ffiincii'L (n- Sil (an i 4}
En^tíími- inraa iSOS 3 5t.&i)fjfíJS7l ;'«Sa|€!f-6ltel
PoabsseLnts. imaas IftDI 3.é£3 ií;0'J6S4,i I S4T i#J5fe?í

ClLinSé ftíTrt Ll-iítoti-, EitrJü iSD'i -0 43.ir0 3f&l:. -Tt tí3 [iO.SS?11
ClLirtfí ffem tovílíH? íiTeíVifi ticiigeí -Ci -lTiJM -55,0 90) -OlSOií-1 74.1 6.5)
..itilirí-müeui. líDl.= !Dtj!i..íferv3.iiy tp^!:C';fí3, LDL = [jjiv-íltoítri,'lijioprtKja. SD =
-»t4r. BaviáiH- n Cr lltí axníimiint licss'ác'i piaí lo tí fii J docí'oí ü&J'f dinp
Efíprrnrf Inhl? I,=í !,fr

ChM''a;¡i.fre;tr ul '"Jicstc ! TOiincic-' s-;--j;F,-.r49t': -eeer;

. -16'IV

Mary Carmen Castro Valdez

Fecha: 18/03/2021 0:41:55(UTC-
Cologio do Traductores do! Perú 05:00) Bogotá, Lima, Quito, Rio Branco
10: IDCPE-09918491
Podra: ia03;202l 0:43:17(UTC-O&OO)Bogotá. Lima. Quilo. Rio Branco

10; 20376744940

tit2ps://Ctp.Ura'gno.eomftlocumoráo^lldai/FC65077C-3E86-4468-AO0F-A40CEC4BP43E
Ta'bte 23: SUíf» lii Stfraiii LipJd Proílto ClLukal l.üiljDM(My.Víseí«ntfeti!i froui
insfliue 1.0 Week é.iii Stiitly 050 {Safel} PopaklittHj
IViai-lia-;('lilip e#']r 4j*
P,ar.nrjr<?r I»! Saiílmé'fesBíE .Lsns" >".anjwl J Hiali
P t«i) 1
Toliil tlujfesterDl(n"1 Jí Loiv OíO't') fiiiOO) 1 & to ft)
■Xctilill, 0 0:1.0.1 0 .fSsi.Jj I 2 05 4.1
Hip.li n ¿i'J) üi Oilil tlj 1 .''0-.i4i
ToiaS n 43 0,1 ptef.'í 1 -1:f3í)í!i
Lütv 2 f'ES.fii i (23 ! 'j f B (Ü fj1
Korsial 8 li'J Ti 7 í53 ÍT í 11 (0
Hlfti 0 í^O.Ol 9fO.05 1 Bi:o.®
tcíial a lííp'fi «i 1 lí ÍO É)
LIJLtii • 13,1 Líit.' (Jipo;! ®Wi)) [ B ua e;i
X-eiijiaJ 0 ÜJ 9 (fi® 2,! 1 i (Í.73
KiSti Ci iiiJOi (tíO.rji 1 IfíMi
Toral O'í'a'Di 9 i'ó9.2,i 1 4,39 Si
Ti-iglj reriibi (ii = 13) Líii-w Ü>iíO fi i fl lüOl 1 Iji(ü6.i
feuiiiJ U tu (.i) S i;ñ3 5 ) 1 tí l U & i
Q lO.Cñ 3 {22 ] j I 2(í5,4j
Tor*l Ci í» Oí 11 m 6] 1 ,?j.|3.4i
HDL - ki-auof l4«jiiKtíft¿, UQL, =• fcí■ík¿_ipi' bf»:qic<cBi
-pcEccnisro:: ot- raiitloLil míi íiu' tSanantiaatai tv me rraraijer of p3í.iratci w-Jei imt ooo-oarjiig v-3¡iif=i ftr Irjiñi
taseíliiit Eid Itj Wfíi 4 [iHi-fctjíííEe-
' Ta-rie í! 3 f

rht.ir-e«-i-; ú' Ij' allrarr i •«ri.-itir

-'fir.i 'Pt'f'.'
 Tatilé 23: SIjíFeí- in i.<}rum Uplcl l*rí>0to Cliiácai labaracory Awwmensi. frAtn
Rii-irbííH' in ^Sciiiy ftAD (\nfrCj PB-ptitr»f3'i>u|i

PaM-luMÜw- Rísüir í\V«b 2Sf

t'.3r2mfíflr ln| Bjií,lisir IííüeIí I r,v, X.-.pnal Hlci,
n i,° tj f ti .f" VI f 11S",!?

1 ulaj CfaalffUí™! fn 14'|. ._i«2W y til 'te . ...Jij'O'/í ip.'.LL,_

lídilMl ft ,'IJ C.f 5)071» 4 0')''^)
Hi.eh 0 íü .üi. U i'üi in .'l:l4 r<

loti] P lÚ «i. Si:'7 If í i'4.' 9)

- - — —

H UI, fn ■ ■ 14,^ Laiv i r í E» d ,"¿b\, Sí rn 0»

' ]VüllIl2] fi lO 'Oí «16!. 5|, tfOfj»

1 íy± PlIj'Üt UlÓÚM «> 111 Ui

i T.r.r.i: 1 i!' In 5 ir? '9i -!! .ni üji

.LTTL líu e J.í> Lé-W ©1,0'-te 0.0) fjj ■B iP 0)

LiunuaJ y ip «1 5cic?:i 5 1 . .!■ 1? ij
Híh"h y lO 'ijl u i.y i«i Mi .-Ü 4)
r-i-ml 0 íl) 'Oj 3üír1 41 4

Tt"íi;li.'.M>iii3M fb ~ l4li Ljm 'D 1*0 ®! 0 i'Mi te r, 10 Oi

XrirgíTjl Ci ífi í 1,1 ? rdfi rij, te 12 te

T4 {
TIL Til ("1 1 ü y» * i.'.l 41 ,te¡2 i,

iOU'l «J 1 ü 0"' 3Úi7l -ü i.iS.Di

A ij te'"', t "i' ' li'üDr.. — fji:e 'i-un-ti:'! 112 L — tír^-'>%r éf- Itj-tEjií
^i'níí-.su^ce 21 'j -cabL-lí-ed '.iü ty.- Ekii-jriiiaiiti s !¡>: icaü'ka C>f ¡.>221:221.'Hb:> LíJ ¡■.•íxi,-cti--j0i; ■^aLte. fúi ttlli
'l-jiatHir sníitr^ \¥«e tli psn-Li-íícif 2'.7.fi2cibs
ivrfrrrtKe Til-"].-: í 'I'

As is char.a<rei1si:lc cf paCienrs wirh OMD ¡Jus íí) Ch« lesk-a-ae í¡f enj'ifrrifts fram the musclfi in tlie siísencí;
gf dyscrasf-km [Tay 2000],, eiP.vHterl te '.¡sis of AST and ALT were commsni at basfiiiniein StíJdy 030, Low
bassiine teveis of hjilr'.ihfni wsre .sise comnnon, ivhileGST te'/eií were typir,ally lormal .al: baseliieand or,
teeatmant. .At Wesk 2S. srnall mean deíreasas In AST aná biilrubin, and sm-all mean Inixeasas in GGT and
ALT were ■^bser^ed, Theaé chíjngeS were noC Gínteilly Sírjnifiíi^nl , Therfj weré r.o paUénts wiíh shlftíi frnm
narrnvtl h«5CÍlno vaiisos t-i» abr«nrm.»l vsktcn fo rALT ®r AST .tt V/ccl: lO, OiG patií.'nt wilh a nnrma! voíwi; «1.
haseline fe rGcr exp^iTericed a síiifc to aiort valyp ígr rhar pa.'arrip.ciarac 'A/neb 13j 2 |iansni:s vjitli nomial
bassfine 'iiakie; for biliruhin glso expenení-gd a shift to la'.v ^'ailles•aC Wsek 28.

i ' if, -il i

r ■
Table 20 Changas Sn hepEitic parameters
34. C luiigif» in HrfKiiiif í'n( ainí-H'í s, (fijiii Bíf-s-IIüi- to i'i'k 4 «mi WWiH
2.S Í0r Parifun n ith Qíi«pIíop .lací PcRí-baít-ljisí- A»•;<'«»fiit? in Siodv OJQ
íSaFi-rv Piftiiijliiriítji)
Sliid' {líO
t i.f I" í I» iB«T k:_<
Al jí.iiii'ííi

Pal iA= ]4i

Vr li U, Pl í áak 2^

IS I, n I In ■ In - 1.'(

f3-"'|i!;¡e nf.iti(STlt '■I? I I ;¡ ií'' í?). 3 T 2 I 1 i {',<• 1 k I

P-' .'"^z .cliai' nií-ia iMJ« vp." Pi, ilPi ^JHt J2t

thüi.;":: í«iü bj^rJal'' al -Jaj i ItiDi ISaSiS; ■3 * ^'1 I' r

Cli.'ipí" liSijLi? ba-rlnlT klAir'ii '!il3iA.~í -ji in-jiiU 3j"iT| . 3£V i ia"> i,', ''ii!)

AJ-1. II L tn -31 i I n " ¡ 41

I n IV í.Aii

Pe r í inr oLOii f Db 12 i' u ^ 1 -v.!; !• M'' J ¡h.vl }■ ] s

i
Cb-'-ii.J'V !í'2iii Í2I-.-.ÜJ! SD' •{ , f "Q ■

í'b-'irt.f 5í«!.u iUM»-- »14 H l,-'F>.'•», A-'b! Si i.-J'ío j4 .1

OIp!, !2 I iU 1 AI In ,Í4i

Be .5-li2i3:í :íií:id { !íB i Ss l 5 931

pi.r.;V.-5>rí mr i\uz<tu f S'l".' í' t> ij! nh' '5 h i 1 eg t

Clmi-'/r íí'jicn b.riClüU'. ihmd i *:?Ds Vía :2\ 1 '' í3 1 6 '

Lii-Cií Jt- ífüeLrj b-J.-liJlT' !*<?] ruLiJíi ír¿ii?r I (i;." ll:f

Bilinilsbíf jtinoB t ! El !) 1 I líí JA

BaAbse» eoV-üuíSSD) e 1.1 5 7|3 5Ó1

3 :mO '"Mt 3 1!«.' '?J I

Chajije ÜQíú baéeiiit?. mt i 30 i s í DO'

CLt.i4i -tr I b.i« M --ií.iíi i I .it, í 1 í [' .. '1 'í 1 i

l.'ílil'jra': AÁ-T - .'íE-ssüv ct,íiLíf!',iii.fr5«-Á' VST ~ ff.irTír.e r.fiuj.-i'K.niiír-i'.-rA Ot.rí ~ 'ísjv^íuj el'TPtíje.ii
AuJl'iíLll'rr
Rff=-i'^-U> í.'.l ^ \'i ■ h

¡•.'•if ( ■ fr e.(if
- 4' ;''
 ío "^A'irrk •! In Sjiiily 0311 iSisfe-tj.' Pojiakirioij}
PMl=liMir1:io« Rrciiíl iW«*|£ 4j
Par-3jgflRr f») BsíoIbi» R«wEt LírtV Xarraal Ritls
o I,*:») n «,*•}
AST ta a lOj Lú-ft # ÍO O) 0 íOj&1( 0(C.0>

Kofawl i RS.O} i ÍD fl
) t «o ®)
ttcb ifO.O) 0(0 flí ,10 í 100 m

TosaE wíÓXil' ti i Ll 'fi'jl -Ifi iSOÚ.Ü'.J

ALT «0 = 01 i Loh i'p.O) # lO tj # íO.fl
Kccnm] i#.ú) i lOJi 1
i E,<0.®5
High B'tü.fi) OílOiO)
1

TomI 3'(fl,D> 0(Q-J'íi 12 CIO» Oí

(jGT 1®= lA] ] Loi'.- iíUO) 117 Tji f(C Of

Keiasd iíO-O]' ITiPZ J) f w Jl

íLÁ ft fiD.ú]. ®(OJl t

Túíijl i ffi 01 13110001 i(|3.®J

Bi.Ki'O-'büii í(i ~ 1]) Lijís' 'J Í16 "ll: 4 136 4f i i;0..®;i

íiOfBlB] 11? !} 2(,!S3l ® CO.S}

Hipli f w ft
Toíal SÍ45SI 1 fi íS.sri tf Cíiiíij
ÁMri I ujijons; Aif = aü^jae KSBsmmo^-t.AST=«pirro:¡aaBXKPHüSwaig.OOJ"= piaE»i cAcosiv)
rf^;4 írri'-r
i::íil:uhís"d tAiiii üi?..rnm:íl^' y hsd EEm-aníi2iM v*3Íik:s £te" húÉt
tasdÍBC iilátfa il'c?ii; ni pJ'í-kl'iCÍiBK' X-^iv-OTlt
SAIrrrKr- Xib!? ,M 1 i

ChMl-'-3íref'S.irF s¡-' .f. 1(rai;í,.| wririeic ^ g^sei 131': -.gcc--

eAV'3iu-i,''o:o =■35-! "úi'i'.'

Mary Carmen Castro Valdez

Fecha: 18/03/2021 0:41:55 (UTC-
Cologio do Traductoros dol Porú 05:00) Bogotá, Lima, Quito, Rio Branco

a
IO:IOCPE-O9918491
PccU: t a«3/20210:43:17 (UTC-O&OO) Bogoli. Uma. QuHo. Rio Branco

10: 20376744940

>inps://ctp.(hslgnacom/docinionlo/val>dar/FC5S077<X3EB6-446B-AO{r-A40CEC4BF43S
 ífj VVctIí 2S ¡n Smdy {SiifriT Püpulíilioii'li
Prnl-lij •,eliDí Rncill {IV eeli JSJ
P,ia-li IB i-lí (■ (ií.l B.liujLÜIr Rí",tiJ[ Lom' ?,orin.iif flitU
o B Itei •O l¡.® iSl

AST ID =" l^i Lw '{TíO gil u >;U' M,j

KchüliI #i'o fii:i U íO ü) tHO.Ol

t IraÍ! a ío rji 0 ijli Oíi 1.21' iff# Os

TtBll §n) Oi| [I (íO C'i t2rlflJ0,i

AL r 1 □ 1jt Lcív «iO 0,! n i.iJ üi iflIÜÜJ

"ÍHJj.tfJ i,HO"!íj (3 iltj.iJS

Hija f{0 0] DíOS'í W íltT.C)

Tcei'I trokji n®»
CrGTtu c ]4:i í-cy: tt i,Ü Oí 1 a tj ijOOi
Vjm-!,,! i/í 1 i JL'f'SStI «jI i 0 0 !i

Hugii #11X0'! U íOJií Oitecu

Tcia.l 0<Qr3>
En=i .iijitj 1» = ] 21 Lija: ?Ml n 5 ri# OI- Ote Oí
Ncnjnl i'llSB 2rt'te ~:i. O'lÜ.Ol
Mioii l'N.OITií fl te c# <0 i.ñ ui
Teiai 7 CX8„B 5í.U ?j. 0 {a.úji
.yíilireiútícsii-í: ALf rj .tlancE; annisí&ijnihmj AAiTaijnrtalí .s^inii-jíanlfa» (jCí!' *- faasno ghtianoyl
Intj'ieaT-if
'PriiiíiPríf-) are taSirAilcíl WiCl te i.ld.j!.-i!¡!£¡u¡fiS3 «; te Ciwiíbn 'U'lisJ itáj i9xi-tsu-"iKij, Tnl'-io Ca bl'líj
.-aá te IVfek -S |Tr.-4 hí soScy s>íii'issi2a3l
ííp|>rnirp TnMf f.S í Añ

Lqw l€vels of serum ereaílninecan be characberisbc óf patients with DMD. sñtice creatiisíne is produced in
skeíflíal muscter arsd pstlenrg ^vith compromisísj músete mass havecorresportílingti' Isw levelsof serum
creaCiniRe [Zhanig 2C3lS],At Wee'< 28,. ttie raeani vslges Por serum creafinfne arrcicystgtin C ivereslightly
mcreased from baseline, These chanfles v/ere not clinically sigi^ificsiit The mean BUN valué yras
unchanged from basefne te Vr'esk 28. All pstíieriiS fiad fign^iaj valuis for cysteüiiHi Cst hoth baselineafid
Waek 28. Five patíenfcs fiad low sarum creatinme vstues at haseline; 3 aiso hsd tow vaíues fa r serum
creatinine at Week 28, white 2 had normal valúes at the latíer tímepoint. Nine patle^üs had normal valúes
for sewrii creaenine eí tesgllrie, 4 of whorn heíl e shíft te 3 low valué ec Week 2S, One pacierrt
experienced a shiftfrom a normal basellne valye to an elsvated BUN valué at Week 28, Creaflnine bveis
and urinélysís were normal for chis pah'ent throughouc che breacmenc. fto patfente had ekvaced valúes fbr
croaciníne Oí crstatin C,

There were no paCients with shfe from normal valúes aC b^eline te ahnormsl yaluos at VJesk 28 for
albiirTiiru^ a-lkaline phospiiatase, calílum,, crestine kinasa,. dírect bifirubin, glucosej fndírect biflrvihin, lactste
dobvciroganasfi. pnqCeinr or soilium.

ChMíteTírí^i-5 cj- c* .-lifrirc ( 5~<:r'r.O!--: '-arír.-

"'firn 5ti''o

Mary Carmen Castro Valdez

Fecha: 18/03/2021 0:41:55 (UTC-
Colegio do Traductóíca del Perú 05:00) Bogotá, Lima, Quito, Rio Branco
ID: IDCPE-Or-
Pocha: 1803/2021 0:43:17 (UTC45'.00) BogoU. Urna. Quilo, Ri

10:20376744940
Tablé 11 Changa® in renaljparama'^rs
Aleaji Clmugi'S iii JíbuíiJ Fai=íiHii!etiíts liwea llnfcUa* w W«fe -1 atttl Weefc
Ta b I e 27:: jg PaileaM wJlü BaM.liaif- aad PB«-bíisfrllne As-s.wtmtiiií üt Smdv #M
{Ssfijy PojíuliiíÉoii)
Sludj- flJO
19, la,30
Ai^Iuíra

l'aiuDiPt»'
Sijiitcic Wor-lí 4 \VV?k 28

Setuai t-i «íi:tiiibitp, iiHnd'C 181-131 lu- 14)

B-uebsE- a;;jn fSD# !9'4 MJi) ISiJtd.OTl

Poí.íJei:<,«-!i:iíc' tílfiae.(SÓj IRá P 63) 3,ísc?sE:t
Ctmn-EP fron» tewiruT ibceti JsU< as 1.5 14] 3 1 I,/o

Cfcairs !i ñni Ípssbáí.?%E£sJian ijfnnafJ 4.0 fii 3.0 {-'5 12)

BCNj mis'jl-L !<I! — l Jl ¡n -14íi

Bcíebof. míM fSD) 4.lfii;LC§J}

PflslikiMrlfrir, riuf^in (S-Ü) i,00 Ij 4 n íi

CíiiMije írQBi ta,?!mí', rain {SíJji 4> ¡-i lO.S4,;j O.ffí (I 337)

Clunr? siam bateíoií. í^frrfmn.í'snnfr) «íoi-n.o?) fl Ofiip? üi 3 2)

CymrtnCiragl. |Q= 14)

lairhi»? Híran(SDí '0 80)(0 1017] fP gCfl-iü.íBiSí)

Pb:-i5M;H.ekof, oif.in CS01 €Í!3íiaifi2S3 lJ9tSi,0 IIIOÍ)

QoilSe ¿üni báisítflí, ££¿221 (,bDji ; •0.07310.1111.1 0.107 (O.flgot:)

:Ctoa..-e ítojQi is3íisl:«2ie'. Median i,,tangís}. 0 tóO «-ti 14 i m 0 llO'POOiOll'i

.Udreiialian.BTiy k íüocá ai>ra -iclEraia
S.í'írsifrtírr T:s'hi? 24 !< ú "

CHí'ir c>' lí^lic-riCi: ,í 'i-arir.oc''

 Tatole as? 5>IiI|[5 Íji Retel.! (.Iltilcnl Laboimfflyjl^stn'íiii-ruts. íl om .BíMcIíov [y U t'ftii 4
luSctulj ÜlüfSiifer^ Psipabrfcu)

i fWfík 4i
PnriTsuifr-M'fu'l Baseltu?. Kii'i-rb >1 1
Liú-w XVintií-kl lliíib
. ii í" a'lJ "«*'I
Sa'UBi are.»rij»iii-pfB ~ B( L<y:i' I 3 O,I'I 1 (3,1) 0(0 e,i
XottMíJ ¡ 3123 1.1 Ci C4|ii 31 fi,iD fjj

HifJl I Ú iiijJ Oí , «■lÚ i) 0.1.0 W.i

¥€-:?! j 03 Su OilJDi

Brvi.0 - ]Jii ¡ II lü Di ; Ó tu (■() 0.(0 Ci.i

NwHiiJ j 01'® Ciii i ll-ttt'il.Ol. (,li.ü IJ,!

Hjí'Is 1 0 h3 úii «HüíO Ü (tj Ul

Tc-ál j U io.i Dii i j. O'IÜIJJ

Ci i'ijtiB C i'i = 3íl L«iní J 1® f'í ' 1,(1 lU 01 0 tó oj

KwbmI ; Ij t'fl Üll IJtilFl.Ói fifüS.í

HjxJi ' 0 í« üi f>fO C>) Olí!) 03
TiA»! ; tí i'ü' Oii i tí tfi 0)
S.3tí.titlOi
Ailitmaiion- SSi-'N => tóbail iíj¿ mBpcm
"Bfícasoj-e. sie cofctfcsd wni Üu éem^nicisr es ihü ir3Sb»r cípsaas:- sfej IekI t¡?a siíX'-iEj'S-aíiií'. íes boils
IrLSííiitf asá átí ®'«k J! ¡m) hsadc# aií^csiaíl
KíiL-fcucc filiít I-I-i' S:-'
rabile Ñ: S'lilfH ta Remal Cllliinil Laboráloi^'A.sieí.iiitraM. tojn Ba.sciiú*! to Wt^eb
IS iii Sftitly OÍO P<r.|jiiiliu,íí.ii>
Pütj-liaiitliBfi Rb^bIi j'3Ví.*k 3.SJ
Paj-ajniíEtir iiil llT.i:i3ieir Ko-.alt Lctr XíOTiiaí i ílffii ;
api'ü.Ja 11"* "i !
Sciniiii í-ff3rt3iise fn - 14) 1 PW i iJT -IJi í ij--l .1) 1 OIOCM i

?íi3Ejn3l 'I fJS ,ftl 3 133 1 0 (0 ri) i

Ftígli 0 ífi B'j e (6 fí| 1 0 (0 ni '
iatí 1 fsa.o. "f iTC" D) I 0 p ni ,
B CS/q al4}. Law Ü p.OI «tfl'tfl 1 0 éO U) i
Nonaal ti» tí) ¡i3{"i:'-W iíioi !
fíigli 0 (O.CÍj 0)8.61 0 ÍO 01 i
latí 0 (M Uj- ¡3iij.y,i 1 !í,7«1 ;
C j'siatm t' fa •- 1-41 La-ií," 0 p t»! «(0.6) u (0 rn ,

íJcifcIn] IJ W líí MCI Olí ,C») ¡ üéO.OI "

HbjJi 0 tO Ü-í O)».0» ; n tú m

Tar-l 0 fij 'íi 1,1 t») ¡ 0 03ITI '

jU.ílaif'ctat.X'i BLU = bLsod ta « nisipjaj
■parsia^-f-s aie caicuhtíá lislb Éa ■ijiaanulxs as éa imolís faí'pitKiitü u-iü- LmI dsi- i=«.'¿aiK 'i ales» Im 6silj
toiíkif salÉr ft'ítk'! pCSr-tj-'-tiilir Mifí-iasíí'
SaSrcsir# : stk Ú 3 á j

ÁE W«ek 28, ííísifts frtJisi isocm«l l.a lovv for bioarbánate diid cliltiride artel fríjrsi rwrmal lo hi9h fór
magnesiüm, poEafSsiüm, arid Urata wére esparíanrad hy 1 paüar«teach. Twc patiarels wiEh normal valúes
aE basáliné had hi^h valúes for pbosfíhátá at Waak 28 (TabJe 14.3.6,Sj. Thésa shlfts ivere niót clirífcally
fnsáñirigíijL

rhi.U'AírHf-, >;r c»' 'iSDfisnc ' ss'-;;-,? iJi-; sTcr.r

syr,-|
Vital Siguí!, PtiysicAl Ffndif!gsai!,d Otíier qfciaeriratioiis Rislateíl to Safetv

There were no din¡cal ly rneanLigrui Crends li» vital sign paramatars in Study 030 as of the ojt-aPf date.

Clectíoca rdiog ranis

Per prot&col,, ECGs are pefformed aC baseline, W&el< 4, and Week 52 or En¡d af Treatment, There víere no
d'inicaliy fiignificani" eip.atrnf.arfliogirBm (0CS) abnormailtias at Irasflline or Weet A in Study 030.

Otiier Stqdies Eíirolling Patients LessThan 5 Years-of Age

Study 012 enríjlled U p^tients >2 ye-sre of ?..ge with nsnsense rriutaOon methylmaioruc acldernlii
(nmMMA)to rec¡slve ata!unín 5, 5, l€ mg/kg fbrg 26 day cycfe, roilop.fjd bv h perlod of 2i ro -iS days
with;5iíit ateiuren treatrnent befare a seccnd cycle of atsíi?reii at a 10, 10, 20 mg/kg dose for 28 dsyj;,

Tbree of toe 11 patients ivere <5 years ofd at toe teme of en rol!raen t; Z padents ivere 3 years of age sraJ
1 p,=5tier»t was 4 ye-ars of age, Atolureni treatment'/res tolerated by toese pabents at both dose le-'/eis.
Vomitíng '/ras tlie mos: freqísently reported TEAB, AH TE^Es '//ere mlld in severic/ and resolved (.vithrpwt
cortcomiCant tr>e.atiTieE!it or dcse modífiístíon. Mo pEtisnts discontínued Creatment dua to a TEAE.

Tabte 22 TlAEs fu ;piatíents < S yeafs of age iri: Patieots witJi Wonsense Mutatjan
MéthyfmalQftfc: AeWemfa
KaLlEÍull«llifl .Irriiio
PjiiíJl! Ailli'iw luéal SíHi>l th' OiHíuiéií
D.KIí' lo -Arsliirvn TsL.'it

1¿ 17 Jai lOl i-
C fjti Jilild fnhk'ly Efliírf Xon." Rp rol vftS
?P lili 20'i 1
i 5 Jul I'fJL!-
fr-.ct Mii-J tnlikcii i'-l-icil Xour P,c ií'_'t> ni
Ifi Jui Iftl l
15 1 íi iiit 2011-
t «ÍUllUlO MJJ L'ükkcíy rclpiriJ X üür RiraOlVriil
12 i-nl IttU.

32 A'iiy
l'll'í 1 V'pindnsc Mi|,1 C'niil-i'iv tíl.r.i.fi.'! X'ppr Ri-.oívrtí
31 Aiir> :CM í

/fijuioun-
C,5t:l Jilild L'nhkeíy coliitd ■Xc-ar 1 JAijoLví-ií
íi.il 2H'll
IG ! Aii,r 301J-
r -jTicifciiis Sil Id ft otaGlv rr1nir.il .>'nnr 1 Sr^d-'.Tií
-1 Au-t .'útil

J Aaij Jte] 1 -
! Auí:l'.u EÍ2;u¡rjiír Idild PoiMibh irtiírd Xonr Rc-aolv-rdl
JOÍl
1 O". JOi l-
Raüi Mild Pr-l ,abll' írL'jíril Xnn.- F-.-íeiívriS
iiOí-E JÓil
'Oc, >d[i-
? (i-i :'&! 1
\'uajii05C ililü .«•lubjUli. ,i«lj::,2j Nour 1 Pai'.cilceJi
9 .'U15 i#31- 1
t? Alivio tí
Ajniilrng Mi Id -jsb'lv jfjatfd Xpnr 1 Brnalvrii
13 1
33j|-
VuSmÍEJil! .MiU L'nhkrSy rfflr.írci Konr 1 R.rnalveíJi
ilí-cr i J'iíll
!

I .•[ I, ■
thé rspcrted adv-Hrsa-'eventsársln lina vvith 6he i^apartad svents for thé patlént pdpulaSlon >5 years,
However, in che ñrsC 28 days of ej;posare the overa!! freiueinicv of TEAEs in SCudy 030 vaes higher than íti
Sie pctálsd sCudiás 007 and 0-20 (10 palients; 71.4% Vérstis 81 patiénts; 47,1%). Thiá higher Iréqtséncj'
saeins to ba driván by a highar fréütiencií of ma!abe(7.1%). p'/raSia (42.9%), ear Iníscü'dn (28,6%) ánd
r-ash (21,4%), whish may' b® 'Con5Íd©r&fi as mar« fnsq«énl: te yoynger chíldrert fn general.

Fór tfie 28 '.veek ast üíf. che fnost corrimon TEA.Es v#ere VóraiCiag, draCrhosa, hsadache, nausea.
Al! patlencs esípertenced at leastona T£A£, howe^er, these viere sí! mild to modérate in niatere,

The labsraiíjiy te&i; analysb an incidas» m ehofeterel and lílglvcerlítes, shiftlng irite Ihe
abnísrmal range, AC 4 iveete 2 patiencs siiiftad fram fiormal co the hifh range. AC 28 v/eeks sn addlttona!
2, Isadlni to a total of 4 paClents shiftsJ to the high range of cho!«terd , Thís could indícate tfiat the
chalestera! lavéis tacrease ovar time. Tbarafore, data írám langar exposure Is rapulre>d. The (ncrease te
tlgíi/cande was observad after 28 vveaks and was not deSeítad yet al 4 v/aeks.
The cholesterol and trlQlycerlde íncrease Is obseri'ed te patients both with atsd wilhout corefcDStanmd
beatmenC. Thís indícate Chat ataluren treatmeríC aloine may resuít In elevabad chaiestero! and
Irio-lycsriHes ratichiñg sbnorront hlgh levéis, ^utthermQpej the rensl pscanietars teslad show ati irtcrease
te bíood ure^ nilrcgtn, Thte cawW Indisate én «ffcct srt rcatsi funsllcr» over tiine. Botb lhc5G sftfcty
concems- ?-ne fnefitlerned fn the srn.f^c and ere psrt of the RMF,

l.s.2. condusíons,am clinicail safelv

Theavailabie data an the safety of ataluren ín Chatarget papuiatton ccnfirm the known safety profila of
Ése prodiict and da ftot ralse any naw concerns. Thay can be usad to suppart the condusiorii that Chara
are reáscns ta belleve Chat(rom a safet'/ pérspectlva, átaluren v/ould bahava simllarly In Df-ID patieals 2-
S-year-okl §s te thase >5 yesrs oíd

2.5.3. PSüRcyde

The PSÜR. cycle retíiains línchenged,

The requframents for submlssion of pencdie ssfety update reports for thís meáicinal pradycc are 5et out m
the líst, of Uíiíon referente fete» (EURD IteC) prowded for under Artfcle I07c(7¡ of Direttiye 2SCil/83/'EC
and gsy swhs^itisic updates pubifsheii on theSifroeean isiedicines víeb-portal.

rhí-ii'a.<rsfjcf 0.; iif-íiKi radritit.' s"-'';'.."!?!*: -.361-

Mary Carmen Castro Valdez

Fecha: 18/03/2021 0:41:55(UTC-
Cologfo do Traductores dot Perú 05:00) Bogotá, Lima, Quito, Rio Branco
ID:IOCPE-O9918491
Focna: ia«3/202l 0;43:t7(IJTC45;00) BopoU. Urna.Quao. RtoBratKO

10: 20378744940

ntlp»7/ctp.inslgna.com/documcrttoAralldarrFCS5077C-3EB6-44eBwADCIF-A40CEC4BF43E
 2,6, Risk management plsn

The CHMP rÉcelvéd the ftjlfawinci Pf^ Advlce on Lhe submitEed Risk NadagáRnent Plan {RMP)í
The PRAC ooFisidereci that the RHP vereton 7,1 dated 23 Febnrary 2D18 Í5 acceptable.

Thé CHMP einlflrs«d thfs advlcé vílEfisul fibánéBS-

Summaty ofs^fety Cí>n€Bms

Ihiportánt
ídentified risKcs * PecenElstl^n of afnlrii3giy<»5lde renal wxieiw

« Long-Eerm cardto'/asoitar effeüs Iñcludirig changas ín Hpid prdfile^

• Hy pertecision ii/iElii use of concern ItatiE systeraic stHtkosteroFds
¡mportant « Renii Wxldty
pptantlal risks
■ Hapalic toKÍcílv
• Hibettiefpa
« Mallnnancies in cseieral
• Eífect üF CQ-sdmintstratiün of atajaren víith nephrotnsk drisgs ctíiier than
Iñrra'/épous nmi nogi lycesldes
• Use In pátáíiLs Vílth nnodérate En savere renal impairmant
• Pobentlal Use In cFlIldrefi frocii 6 fnóriths tó less than 2'/aare
f^issiliig
information^^''* • Ekiciii:letJ feng-toriin í/sfety
• OfF-labali use in patieisEs who do not hare DMD caused hy a nonsense
mutatiofs In íie dysErophm gene
• EtFecE csf co-admirsistratian ofataturan with certaini drugs not ye: evaluated in
formal drug-drug Interactton studjes

-Chanpe m f.íil (srofiie «at. pfsWouíb cíassüled as nn imoorent Isantitied rtgk ticwevef di,-a to Aesiiínf'on.t ovorlop (>?í».6eft ihe r«l(
srJ íiiG iiuporíait p0ic!iHa! irák m Íanp-Mrm. carsÍOTairciílar díoiJ:!:. thc síafc Iras bcea rccSassifisd ajiá is pracntíf cncomirassod víitkiu
BrCilmpHtaiitpDtiiT-lalfiSí.: !c«f-íar.iñ ¡¡aid.avisculEieRacia--
^Uso t-T B^itiaate msí'írafe tr; dcvij-C! hipnt« iniixiTiMat te il?n5í:r ^^snairiciíc-d r^iisaiaf ¡nforr^ijtipr, bsSGíi «rn crhtOTrmiS
irn.1er5laria-iisi 6n>.'gk »-Taj4'GP-S33-Hi¥, asnav ike: e-íS'uateí the »;6r?' aw ¡"K of atríunaii in aatlens wltír írnxiaraS! ío s5-«'6fe
hepaí'c saisajuiarii í^'^AC «coJíiTOairíaies ai PSUSíVCíWlOZVít/soiTO? - 09 Fetnarr iOESJ, Tke sfjdy was ?cií«!icE«! ío devíSop
puiclaxe IDT auiijirsn. tícreliiqi Irs 'Uils flopjiatlBn, airci^ic r,cpdis: Iriiaafj'muní is ars circcj-r^idii Sastíne caniDíSicliX)' aniDiw tunDHD
pa;ic.i¡s. Iko ssud'F camalaterf ra Q120D aad it -ítíiis cc'nckjcixi r.o caiss «¿jiiütTtcnis a.!^ KoiGEarv.
'r.-ie 2K! In ?!at!C3itE iwlirzra DtriJilc a DÍníir thEn Caicaneíi 13 no rcngcr caicdEriscl «TiiSEng infartiiataa shc MAItiias evalítated tfiE
c-iiia'iffi! bs-K! 1.0 dato and Sias ínwnd inc..it!«in:r-í)inl rliBcronra .H ^IFcacv ar caícty, w-ln «te'iircn aM in naánr.ts of noa n ctímc
Dr.'g^i,

'SefeiV "RÍlb Msts w nrtiar'-i.'S •fi+'a éa iwE ¿"ivs BMD cíius^íí aif d üran-üHB'a nnilationi In th-s rfíulrniíiini ge--!! is nsjt estab'-jHí^. íji'i Liieje ms
nci •ifiifíí'j jilan.iísií íi> BV3li.sai» iisa As smé), <jfj=iJbí(i usa a' ttiís ívcs. «■vin íaíntinitsi 5» be snS meaitai^d as nii?5i<»3
litJanratían.

C-i it.1lrarr-| widntiC'' 3S"íS-sr,-iar; -«fi

Ph&rmaeovigHancc pían
SuRiniBryTiiMeof Ongoing and Pianned Atidítional Pharniaeovrgílfifice Actfvttics
Stddy/ortivítv cftluarirl catea orV ObjftCtiWcs Safety 11 StatUc Date far
dMicel-n 1 (ptancied, aufalnisaion oí
a4drefi<:eil | «tartedl iirtarim ar
final tcports
(plann¿díir
actual)

1
Písst-aBproval raqfetry To3Kass ki'iKs /i3 palsitlal Slartod /■njiual repms
toirm safety a nd rlsls atíd startin§ AprJ
Pratec-3l PrCl?:4-0&-é2fei-DMD. "Long-lerm
offoctjvoriCíSs ire (TbisSIn© 2016
Ob^rvatEinai Stisdy ct TranEkir.a Ssíeti? atsd usta]care mrormatlQti Íipril 2023
Efkeüveiiíss In UgMl Cdrc'' fer attilifrei. (ñnal)
Categarv 5

Extensión to Opsn-lateLsaféty and PK stiidy Tci evalúate flie 30 20LV

Potenlitl lÉse Oiigdng
ír cHitóreti 2 yenrs to 5 '/•wts óí óGid, SBidy 6 safoty afiif PK of
ot ttie cirxrenc PiP for !í>'siraphnopaGny sGíEran in chndren In childlreri
f fúni 2 y eii atas ffom Z years
PratOMi PTCl24-GS-é30 DMD, "A Phase 2
7esrs íif «se
Stüdy df thiiSafety, PfíatrnBOPkwctte, «ríd to S yeers of
PteTmaíicitfyiieiiiits of ATiilirscn (PTClífl) In age
Pá.tlan,ts Aged a2 ta <5 fasrs Qld VíJlh
rtonserse Kutation itJysírophlnopathv"

Saroty snd Pk study in pütranlswitk Ta íivaluata tho Uso Irc patÍBala Startcá 20201^
modísrata to severa renal imparrmsnt, safety and Ptí of wTÉi in-sde-ata
ProtQcol PrCl24-(SD-&32-HV, "A Ptíase L, atelitren fn subjests to severa
i^on-labsl. Single Díiot, PareJkjl-Group ra ith •k-SiffwísnC renal
Stud y lú Evaíeaíe t'h.e PliarináCúkiniétidá arid lEfigretS úf teriM ih'ipéinnerit
Safety of ñtaiirran (Prcil4) in Subí«l5 VMittí impalmnent;. !n
Severa Renal Irapaírment and Haalthy ordar lo próvida
piatEhcá Contra! SubjoEÍs" guiii'anco for
ataliiren dcsing in
CategorV 3 psticnte VJíth
modérate to severa
renal ¡rtipíjirjnnnt.
Safdt'í «ikI PK, stody of co-edministretioh of To cvniuisto tbo Cffect ©f W- StartEíí 2Q2O10
¿táliir'cn Oiid á •sütsitive .erebc siíhsfcrate of safety and PK of aifiii.:r.ls!yaCfc)S
0ATP1B3 atóiíren ancífor tite of ataliffen
appropribtei 'AÍtís certain
categury 3 refisitfvc prcbo drugs rtot yot
siitscraie, ir, oitler evalueied in
to p rdv Kfe s'a kfiint:® formal írag»
fortfosfng aialuran dmo
witb tta spiecine inti2racT.iori
concomitEnt Etudies
tacd féaticm,

Study 041: A pJiaee % efflcacy snd safets' l'o coiifirai tlis To confiim ths Startsd filiBl síuóy
stiidy Df «tnlnrcn in pobicnts 'wtN nonstsn.» offteacf and safcty dficacyanrf' roport;
miítetlisrii Ducheinu mi-isculflr íiysftopny nnd pf AtolurBUjín tito wfljiy cf SaplHtnter
opsn -labid- extsnüíon traatfneuto} ataJuren in tba 202i
ambiflaní patients treatmentiof
wiíh nmDKD egcd dtabiifeat
Categorv 2 5 yearr or ©"dor. pátfcnits wfth
nreiDKD aged
§ yoors 0 r
□Uot

CKNPeí<E6riS.Cf »: .1 IIMK I wristic'

 Risk Mimmisation Measures

O, Summary Tabíe ofthe Risk Minimisation Measur^s

Roiftíne RTsb MinimbatíoR Measures Additiüitat

Safcty Concern
rtsK
mtninitsatlon
mea SMros

SniFC secciDn 4.4, 4.B Noiiie pfoposed

Long-term sardiovasasbr uffeis
incUldin® chErtges In Üpid proRlc

SrnPC sscdon 4,S.,4,4,4,S NaiM pKsposed

P^entsal Ícraniilnísgi'i'coslífe renal
tesxKitj-

SmFCscntton *1.4,4.8 fJíiKi ptoppscjd

lílfpa'toriision wifti CTocomitanit
t®n of mrtiroíit^TOd

SmPCsectloiT 4.4, 4.6 ,Mo4a propiTSsd

Ranal cüxteltf

NouiS propcsed None.pro posad

Hepatic toxfcity

Hibemoma
Nons prspc5ixl Mone pf5Pi*5Bd

Nonepropcsed None proppsea

|''L0%Piirt€lB5 ih eup-nral

N&r,0 proposal
Use Qf atEÍisren In nmDMD palíaists lémPC SQrtfen 4.4,4.3
wh-a co-adiiuiiiaerad atsluren with
aaplmitnMle írugs

SmK s^tiah 4.3, 4.4, 5.3 NdRiD piOpCISExl

UsB of «ítwiiaron in nmDPiD píitioists
Mjith modérate to sovano rene!
Iiii|5áirinár>.t

Polsntifcl ii3e ir! citildren fi^m &

SmPc saction 4.1, 4.2, 3.J Therapeudc Indlcatlons rtepp prappsed
ist-Mtliis 10 <2 ysjs oto

rhFiiF-,?iif.í.'Rs;cr o: itiiirairc'i wnsíic 3^'-SE3r,-i3i': -.swr

 E*l(!r.cod lang-tcj-m sfefcty Norse aropoEsd None
pt0.lM^.

Off'iatel useofataluísn. irs

SmPC scctloni 4,1, 4.4 Nor«0
proposed.
pgtteii,C3 pfcg do not h«v« DfcO
hy 0 iMiisense rnutcticn m
the dy.'rtrephin garnj

Kfect or co-admlnstraoon of SjiiPC BOítian 4.4, 4.5

proiKssed-
at«1vrcii i.vtih ccrteln (íniQs not yci
DvekidtGri In form.5l draD-drud
Initor-ictton cpirllas

The MAH fe refTiInded chac, wtóMn 30 calender dars orthe receiptcifttie Clinton, sn «pdated versión of
Afwex I oF th€ RMP tetnpiate, rifieciing the final RMP agreaf at ttíe íltiie oí ehe Opinton süíoiitd be
&íbmitl'fel 'to h-mirmiD-gv^rtterfacofeméa eiirfeBa.eiJ.

2.7. Uptíate oftím Product mformatíon

As a ransequence of tbis new mdical'kjn, sactlocss 4.1, 4.2, 4.B. S.L and 5.2 oFthé SmPCbavebGen
íjpdíited, The Pncfege Lsaflet has beéis ^pduted laí^oMIftQÍy,

2.7.1. Addttiúnal monitoring

P«r5u§nt to Aitícle 23(l}0f Regulation No CEU) 72&/2CI04, Transíanla CAesiuren) is ineudid ín tte
aditicio nal mor.ttoring Ifetas
• It contains a nevj active suhsCance whlch, en 1 Januarj' 2ílll, vías not conitamsd tn anv msditlnai
próduct Aueioíteéd In Che Eb,
■ It is approved under a rarac&ticniflí marketing autharisátloa [REG Art 14^7)]
Tbereíore tbe í.wmrpi^rv of pttufuíC cbai'ae.ten"gfjcs ai»ií Ui'S packíiae tesíleí inelijtfés a stateíisent thal tíés
iTiédiciniá3 product is subject Eó addEioriai fsiónitioriñg and EhaC this will allQW qufck idSfiBfication oí new
sñféty iriíórmaíian. Thé sBaLefnént is preceded by an ifi verted.equi lateral black trianglé.

3, Benefit-Risk Balance

Maiin d in¡cal stndy

The eiteasion of Ehe Ir.cicatbn in chíldrsn aged k 2 to «sS yaars oíd vítth nmDMD is supporteá by data
froro one cllnfeal stsidy - Study &30. This wss 5 Pifase 2, muidple-close,, open-iabei study evsltíadns the
safety, PK, and pharmacc^ynamics(PD)of ataluren In patiénCs agsd S 2 to <5 years with nmDMO.The
áudy indudsd 3 4-víeek screenfng period, a A-vt^eek trestrKenc penbd w evalúate safety and
pharmacolílntócs^ a 48-w6ek exbenston p.eriíid, and a 4-yr6Ek fólow-iip perlod (SO 'weeks total). Tha
proposed dose and scheduie of ataluren in chiidren 2-i years of age vías the same as those approved fcr
children S years of age_, l.e. 10 mg/fcg body vreight in the raorniag, 10 mg/kg body wei§ht at mitidíay,
and 20 mgykg body weight rn the e'.'er^lng (fora total 4aily dose af 4€ m§/ki bedy weight).

Ffivourable effects

The results from Stncty 030 weure usad ta demanstrata áat stafuren plasrra leváis in nmDMD patrients in

Ch.r-ir'-3ír,¡r:.S'(jf; lí' ftlMK l '«riFitiC-- S'ÍSiJX'ír.lír

the age range & 2. te <5 years oW overlapped v/féh íhe steluren pla»rFia lavéis in children a 5 years ef age
(5ti3£iie5 £l'34 and 007) Víhen é?sed aícerdíng ta the reginnen 1I}/10,Í30 f^g/kf. Theíe was completa
tjyeriiip in plasma TOBffsnlraSMs batween poHenes- ^-1 h <S years of age feíUíly 3P} Gcmpored to Ihpss
sS ypars «sí age (stady 007,. pivptel fPr PKPD fcistieashlp) at ési 1 and ai s-lcady-staie, Alteisgh ths
pcpPK, model had Inherervt ñwts v/ht® prevented usa fcr its Initíalty intended parpóse, che plasma level
daca altaved Che CHMP Co posüJvely conduele chac tte aCeluren e)ípo5tare in both age groups ivas
«csi.parab!e

ílfíccitaiaty ín tñe kno%vfetíffe aboat tña .tenefícisl effects

Inioellyr a PppPK analysís v^as to be asad i» isstirníste the ataluren «jípasufe In the- popubij^ft »f a2 t'S <S
years^ arad compárele v/lijn theexpesure in Che.popuiaClon of paCients sgal feS. Koivever, a numberof
uncertafnCíes cvíth Che model hlndered a reliabfe and accuraCe descripción of Che pharmacokinefc of
áfcgluren, Thus tiie data,froin Ifie modellwg alórije were not coasídéred saffrcíint to supporC the proposed
dosieig recci5nmencl3ti€ins ta chtídren 2-5 year? of age.

The MA.H díd not pmvide any PD «lata, lítaC may sapport Che dosfne in nnnDMD patients 52 to <5 ygars.
Henee, there vras no actual conffmnaCron thac steády state levefs In paílenCs 52 co <5 years are sufflcient
Co achieve Che sams magniCude of a PD effsct and 5tihsei|ueniC clfjtfcai tmprovemenC.

Arfdítiongf resuics, describing effects of aCal'uren in tte tangec populación, were províded fdr a creacraent
perlod of 28 víeefei., esslng a comparlson ivich histórica! canCrol daCa from theCINRS (n=T4 and n=l1 to
31 for Che study group aasd hlsCorical data group, respectively). Frcm Chis compan-son. Che resuíCs
ebtatned frorri on 3 ont of 4 pogylljlíf TPTs siíovred a Crend for .stabifisatiein or impreveíiwrtt The
dlSerences were 0,3 ses,, 0.5 sec,, 2,§5 sec., r^pectlvely on hme Co run/ivaiP: 1.0 m, time to dimb 4
staire, time to stand fpgm supine t^ts. A similar crend yras ais® obseryed for the MSAA a.nd the revisé
NSAA results, boch favoijring the ataliiren-treated patients. The cUfferencss observed for che NSAA wrere
2.0 potacs, D.5 poincj- and 3.0 poínts rgspectivafy ots the S-iteini, 3-ltem arsd total WSAAscore.

Wlth repard to efficacy, the rohustness of tice oteerifed resulte and eonduslons ís signíflcantiy affected
from lM>th che open [abe! study d^ian and a companson wlth che externaí control CÍNRS data, The epen
labe! study design mates it susceptible to al! types of btas, knoavn to te presetiC in unblinded scudles,
wt»rie tbe ccmparison to the C3NR6 detja h-as severd knewn dravíbssfe fridudíRS pifcfafis of indirciót
copiparlspris, iange varisbilliy,some basdine diffiergnces betiveen the cv/o groups {e g. treatmsni y4ch
rartioosceraids), and sherc study duratlon,

Atídiliofialtyr Clie effect sise of the observed dlfíerentes an the TFTs and tJSAA sts.>res niake Ife dlfíioull' to
conclude iñíhether Chey y/ere of tnae ciinit&j relevance, and therefore th©se results can onty te interpr^tod
as beíng suppcrtlve for efficae)' fu the ypunf age g mup of 2-5 years, but wilf be insufflcfent on their own
If presentad outade of the contett of the effects obserMed iu Che group of OMD patlente >5 years of age,

misks

tjnfavpuré.ble cffcqts

Mast adverse events as repsrtsd from study 030 are alresdy known from previous sstparifiticetvlth
<!)£pósurc to atalufcsí,

Hpwever, In the tlrsC 20 dsy» of expasure the overaT frequency of TEAEs fn Stiady 030 ivas hífher chan In
tile pooted studies 007 and 02O flQ patients; 71.4% versus 81 patiente; 47.1%), The higher frequéncy
to be driyen by a higher freqi«e!!cy of fiialaise {7,1%), pyrexia (42-9%), ear |rtf<süoh (25,6%)and
rash {21,4%), ivhích may be considerad as morefrequent Iu yoonger chiifdren in general.

For che 28 week rat oif, the mosC ccmmon TEAEs were vamitímg, diarrhoea, headache, nausea. All
paCíenCse*:|>eiieri€ed at least cneTlAB; however, chese wereait milti c» modérate Iu nature.

L>tMl-'a«£.rS.c.F &! ii;iirarí.| vítflritit aíí--;í5n,iar.: '.30c r;

The la&praterv tesc apialYsis ífhevvsd 5Ií IncreiS'S in chotestersl and Eriglvcerides,, shifting Inco the
afanannai range. Change- fn cholegE-eroS tev^s was oh^en/actaE 4 Wf^aks alreadi^, whíle R?r the trlgíiycsrides
- oiily at wsab 2S. Since changes in IFpM pttiFila have baen observed Iti patlenís botfi vjích and wlthout
COrtiDoslérdíl ireahnsnt,- Hii» is lije firíi: ilmtí thaí ll, can ti« eouClucíeci «ilN ciiftalnty alaklréri l/eatmenE
alsae may resulc in elevated ctoiescerol and Englycen'des reachlrtg ahnorroal' lavéis,
llnctsrtalnty inthc kfluwledgealHiuitthc HnfuyaartWe cffc'cteí

Theadditional Bafety data cf eiíposure of the vcsungierage graup fe witti a raaífimnm of 26 wtssks Longer
expos'jre data is missing. Thenefore It Is anceitaln what the long temr» saFety of childnen 1- 5 years v/ould
be,

The obsarv&d alevaEÍon in lipid cholesteroi and trigivceride lavéis are in line iviíh the data from nmDMD
children aged >5 yeare oíd. As it is unknoiivn 'rfhether thesa levels will: continué ta increase, Che nmDMO
chMrefi ^ed 2-5 years ofd fised to he raenitered similarly to the nmOMO children aged >5 yeare.
Furthetmoref altboiiigh renal function seems Iti Eine vdth the data oF nnsDMD chlldrets aged > S years^ the
renal functton neads ta be moultcred In boch agegroupsaa the long terrn effects remaln unknojvrs.

Benefít-ftisk BalancB

Impoitsnce nf favourabla and wnfavouraile effecis

Ataiuren has been aRproved fcr ambulanC children witb DM0 who are sider than 5 years. Due to the
progressiye nsture of ttie diseíser From a bioingicaS and clinical perspeetive, ¡t is agreed thaC ifiivauld he
henafEici to start earfv treatuient In DM0 patieriis, if íhe beneficiaf effects outvvslgh the «nfayourabie
effects. In arder ta espand the indicaban in ycunger childrsn, it vías recommended clinical studíes Ln
children aged 2^5 years shoutd ba parformed, in arder to callect as much PK and clinical: eFricacy and
safet}' data as posslhla in this papulationi. The N,Alíl providad the resuits from sucí» a study (Study OSO)
and ergtfed thet the observed P< behaviour and ttíe pcsitive trends registered tn the measur^ cliniicel
cutcornes, together wilh the benign safety profile of the praduct, wsrrant the e;<tension of the indioatiors
m yaonger OMD patíents. The prcvided dirticel data focused on petieni functioning on^Vr ivithctiC direct
measurement of the eFFects on nntisde strenigth. This may be accepCabla, as the mechanism af actian of
atalursn sugg.K:ts aC best stabilisatian and rfiducticn of tha rate of Icss of Functioti, rather than a dtrect
effect oa muscle strefvgth.

Regarding Che outcome messitras used, It Is aocepted that the 6M'AT is nct a ratiable víay d messuring
effect fn DMD children younger than 5 years, as they are sCill in the de^'elDpment phasa cF tlieir v/alking
ablilty. Thereróre it Is accegt^bte that in study 030 the efñcacy outcome meesures vrere 3 tFTs and a
rsvfeed PISAA tool, Et was dlFTiculE fgr the CHMP fco corsckfde on the Hctual clínica! relevance of the
cbserved differences in. the endpoíntSr birt tíie regisered pcsitivetrenid coyid not be ignored.
Witii regard to the unfavowrahle effKts, some TEAEs have ^vays been o.^ spseial interestr especially ir»
tíiie ccntext of a liFeionig treetment, The safety proffle date fnom study 030 confirms that the alreadv
identified risks related ta treatment with ataiuren in cicíer paíients are also reisvant in patiente 2-5
years ofd. Additionaíly, in Chis study wss the nrst time that suhjetts trested v/ich ataluran oíily stiow a.n
i'ftcreade In glycdrol and trfglyccridcs énd aíter a 20 yíétik o.áipósurc, Thib fe an i'náfeatisn that sfalurm
FTiay ihciease the carcllovasculer rtsk and has to he oonslíered In tlie decisión on che time Co start
treatment in yaung nmOMD boys.

The córjcerns resaiding the suifcahillty d the pupPK wódd tó piovíde relfeble ísuanLiriable estírriaÜo« of
atalucen exposyre remairíj and thus It ivas conclisdecl that the nnodeí couid not be used to support tfje
proposed dssipig In paedíacric patsents to <5 years, ¡nstead Che comparison d atalaren eupesure In
nmDMD patients & 2 to <5 yeam oíd wiTh. thcse a 5 years of ase has been mainly based on ccmparison
of plasma cnncentraticiRE.

ChMPeíri;f"5.tr ry 'Ifr-ir-c"! 'i'arlMfiC'' 8-^"^^rjrp3r; "cev"

 .0

Benefit-fjsk ^lárice

For this extenspofi ^ tte inclfc®tioni to nmDMO cfiifdren agsd 2-5 years, ths sppllcaüit pressnted data from
a single study In the tarpitpopalatran, baildit^ upon theclínkally justífied approKlí that treattng asearly
as posible in a neuro-muscular. pns'gresslve cgaclieion is m^nt to pravide the most bersefft for the
treafcad pjatienCs. Tha appCieariit cóntimues ta defend that based oti the available PK data, ic can bs
róssoriafctv éísuirn^d that sfiíniter-expasatc; ean bi obscrvcd íti'&lderand youngcF DMD paticntír, pp!3¥ldln.g
ftr a similar effíca-iy and safety In totli groups. Addiopnially, tliie obsen/ea positlye crends ín afflcasí data
cara tte as^ed as suppofdve, arad teking into account the generally mild >afet(' profiledf ataluren, cara
jU5tlfya positiva benefit/risk retro concíMsion.

the CHMP eckraortviedged that compretuenslve assessment of etlcaey In cwidren k2 and <5 years of age
fs not feasfble due to the rarlty of diignosed ramDMD patlents <5 veare age. Thus, the Commltíee
agreed 'ivith tíre ab-ove argumentatlon, ooncfuding ttet assamption aboiit Che sirFilíarity' el the efíicac>' arad
safety established ín. nmDMD cbiidren in both groups( &5 years and balcví 5 years of age) can be made,
providéd Chat comparáblo ocpoáura has baen áeiítonstrateií in b-olh age groüps.

The hackground of thls posfeion fe that the dfséase procsss arad pathogeraesis of nmDMD. vvbicli is loss of
muscl'a düe to the absance of dystrophin, Is fníSepandent of age. Aíso the mecbanism of acfelon of
dtelurcHr to onabio ribosomal road-thraugh oí mRNA lati^iñing a premalvira stop cádon, rG$wftf.np (a
producticn of a fulHengOH proteíii (dystropbin), fe expected co be the same In bcsh age progps,
Alíditicriallyr comparableatatwnen asposiira in patients a2 ta <5 years of age with those S:S yeare of age
ostalS be assumedp based crn the observé ful! overiap ira ataltiren plasma ccnceratratiosís ira patients from
fcotb groups,

It was recognised that the reailts from the citntcal data on TFTs arad WSAA as prcvlded, tvere notrobust
era their ow. There are too maray fattors which influence the InterpretstiDni and put ira gueffilon tf^e effect
sfee and clin leal relevance of theohserved resisfts- fJevertheless the observad popitíve tnerads cannot be
[gnored. On the other hand, the prelimiraary sfian: Cerm safety data ^ems in toe with the petient
pflpulatfen «fcred >5 years, arad oprafiitós the generally be^ígra safety ptófílc of the dios, fio majíjr
nne:<pect^ safey rssues were encauntered Ira patierats aged ar2 to <5 yeam, and acaloren Is vfeíl
colerated.

In conctuslon, cakír® ínto aocount the totality of the presented data up cc ttils momerat, che cHMP agreed
Biat they ai-ovi to reasonahiy assume that the efficacy and safety profile 01 ataiuren Ira children wth DMD
2- 5 years oíd cccsld be eirpected to be similar to the one in patients oider than 5 years, thns prsyiding for
a concíuslon on a positi ve B/R ratio in this ccipulatrora.

4. RecommeniJatfons

Outc&m^

Based on the revisv,' of ths submitbsd data,ths CHHP consldsrs tfie foílowíng variation accaptabla and
tberéfare recommánds thevariatian tó the termSofthe Marketing Authorisaticrs, concertiing the fcilowing
change:
Variation accepted Typa AunexBS
affected
C.í.g.a C,I,6,e - Chengafs) to therapeutlc indlcattohís) - Atíditinra Typell i enciniB
of a nevif therepeutte Indicstijsra or modiñcatton cf ara
approved one

ChN^'eíwracj: »' i>1ir,:ir.ci KulntiC-' as-.-'jE'jrmn-aBis:-.-:

p /• • ::/i 1 Cí:O COí'r.-í
Ekísfisíoh of Indicétíoíi to includ© g neiv poputetion (cfiildrera frora 2 to les» chan 5 y«sr5 of for
Trenstema; as a«tisequenee,sectorss^í.I, 42,-i J,5,í and 5,2 cif th« SmPC are upásted ThePa&kage
Leaflet and RMP (yereraru 7,1) is lípciated ini ac&ordanoe.

The variaticn leads to eFmendmeP® to rhe Summap,' of Product Chargcteristics,. Paekage Leaflet arso" to
the Rfsk Management Pten (RNP),

5. £PAR changas
The EPAR will be üpdíited folbwíniB Commléston Decisión for Ihis variatiort. In parlkniter thé ERAR rñDílwla
S "síeps oftsr ífte ímthvrínMúfí"'mV be vpdabsd ^íglloi^;

Scope

Extsnsiau oF Indteatton to inciude a new poputatian (chitdren hora 2 to less than 5 ysárs of agej for
Transiama; asa ccasequence, serticris 4.1, 4.2^4,8, 5.1 and 5J of the SmPC aren p^ated, The Package
L^FIet and RMP (versioni 7,1) is updated in accordance.

Summary

Ploaso refei- to che pisblishád A&iSesófnent Report Transiarnís H-3730-U-37.

Attachments

1- Product rniformatiQn (changrss higlinghted) as adoptad by the CHMP on 31 May 2018

o' '^-iicacc i H^irlr'CíC' x^eprr