EXH IBIT 2
`
`The New Eng:land Journ.d of Medicine
`
`I NHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`HORST 0LSCHEWSICI, M.D., G ERALD SIMONNEAlJ, M.D .. NAZZARENO GAllt, M.D .. TIMOTHY H1GrnBOTTAM, M .0.,
`R OB ERT N AEIJE, M.D., LEWIS J . RUBIN, M.D., SYLVIA NIKKHO, M.0., RUDOLF SPEICH, M.0., MARIUS M . H OEPER, M.D.,
`J URGEN BEHR. M.D .. J bRG WINKLER, M.D., 0UVIER S ITllON, M.D., WLADIMIR POPOV, M.D.,
`H . ARDESCHIR GHOFRANI, M.D., Al ESSANDRA MANES, M.D., DAVID G. KIFLY, M.D., RALPH EWERT, M.D.,
`ANDREAS MEYER, M.0., PAUL A. CORRIS, F.R.C.P., MARION DELCROIX, M.D., M IGUEL GOMEZ-SANCHEZ, M.0.,
`HARALD SIEDENTOP, 01PL.5TAT., AND WERNER SEEGER, M .0.,
`FOR THE A EROSOLIZED ILOPROST RANDOM IZED STUDY GROUP,.
`
`A BSTRACT
`Backgromid Uncont rolled studies suggested that
`aerosolized iloprost, a stable analogue of prostacyclin,
`causes selective pulmonary vasod ilatation and im(cid:173)
`proves hemodynamics and exercise capacity in pa(cid:173)
`tients with pu lmonary hypertension.
`Methods We compared repeated daily inhalations
`of 2.5 or 5.0 µ.g of iloprost (six or n in e times per day;
`median inhaled d ose, 30 µ.g per day) with inhalation
`of placebo. A total of 203 patients with selected forms
`of severe pulmonary arterial hypertension and chronic
`thromboembolic pulmonary hypertension (New York
`Heart Association [NYHAl functional class Ill o r IV)
`were included. The primary end point was met if, af(cid:173)
`ter week 12, the N YHA class and d istance walked in
`six minutes were improved by at least one class and
`al least 10 percent, re:;pectively, in the absence of clin(cid:173)
`ical deterioration according to predefined criteria and
`death.
`R emits The combined clinical end point was met
`by 16.8 percent of the patients receiving iloprost, as
`compared with 4.9 percent of the patients receiving
`placebo (P= 0.007). There were increases in the dis(cid:173)
`tance walked in six minutes of 36.4 m in the iloprost
`group as a whole (P= 0.004) and of 58.8 m in the sub(cid:173)
`group of patients with primary pulmonary hyperten(cid:173)
`sion. Overall, 4.0 percent of patients in the iloprost
`group (including one who died) and 13.7 percent of
`those in the placebo group (including four who died)
`did not complete the study (P= 0.024); the most com (cid:173)
`mon reason for withdrawal was clinical deterioration.
`As compared with base-line values, hemodynamic
`values were significantly improved at 12 weeks when
`measured after iloprost inhalation (P< 0.001). were
`largely unchange d when measured before iloprost
`inhalation, and were significantly wo rse in the placebo
`group. Further significant benef icial effects of iloprost
`treatment included an improvement i n the NYHA class
`(P = 0.03), dyspnea (P= 0.015), and quality of life (P=
`0.026). Syncope occurred with similar frequency in the
`two groups but was more frequently rated as serious
`in the ilo prost group, although this adverse effect was
`not associated with clinical deterioration.
`Concfasions
`Inhaled iloprost is an effective thera(cid:173)
`py for patier1t s with severe pulmonary hypertension.
`(N Engl J Med 2002;347:322-9.)
`Copyright @ 2002 Massachusetts Medical Society.
`
`A CONTINUOUS infusion of prostacyclin
`
`was t he first th erapy shown ro n:ducc mor(cid:173)
`tality in a controlled study of patienrs with
`severe pulmonary hypertension.' However,
`its use is associated with a number of serious draw(cid:173)
`backs. T he l::ick of pulmonary selectivity results in
`svstemic side dkct s, tolerance leads to prog,rcssive
`increases in the dose, :.ind there may be recmrent in(cid:173)
`fections of the intraveno us cathctcr.i As an ;Utcrn;1tivc,
`inhaled nitric oxide possesses pulmonMy sekctivity,
`but it is less potent t han prosracyclin in the pulmo(cid:173)
`nary vasculaturc.3·~ Moreover, an interruption in the
`inhahttion of continuous nitric oxide may cause n!(cid:173)
`bound pulrnonary hypcrt ension.>.11 Designed to com(cid:173)
`bine the beneficial effects of prosr.acyclin with those
`of an inhalational application, aerosolized prostacy(cid:173)
`clin was frmnd to be a potent pulmonary V<\Sodilator
`in patients with acme respiratory failure, exerring
`prctl::rcnrial vasodilatation in well-ventilated lung: rc(cid:173)
`gions.7·10 Simil:ir results were o btained in spontane(cid:173)
`ously b n::arhing patients who had lung fibro~is and
`severe pulmonary hypertension u
`floprost is a stable analogue of prosracyclin that is
`;1ssociared with a longer duration of vasodilarntion.12
`When administered during a short ;1erosolization ma-
`
`From the Dt partmcnt of lnrcrn:t.1 Mt:dicine ll~ tJnivcrsir-y Clinic, Git!S·
`§en, Gemuny (H.O., H .A.G. 1 \ V.S.J; Si:"·ice dt: l'neumolo£tie, H(>pit.11 An(cid:173)
`LOilk' .Rfcli:rt', Cl.m1.m, Fr:uu.:t' (G.S .. O.S.'1; b rituru di C:tn.liolo~iJ., U11iver·
`.~it~ tli Rolng1M, Rolugna, fo'l~ ( N.C.., A M.) ~ Ro~'~1I H;,lb1h.d1ir·c H11 ... pi1al,
`Shctlidd. Unircd 1'.in~dom (TH., lll.G.K.); Dep,1nmem of C.1rdiolngy, tr·
`.1s111c Unlv..:r~i1 ~1 Ho~pi1.1l. Brus.1d"\, Rdgium {R.N.); L'nivn~i1y of Califor·
`11ia M S.m Dl~go /\kdlcal C:.Cmcr, L.t Jolla (L.J.R.); Schcriug~ Berlin, Ga·
`lll.i.I\)' cs.~ .. H.S.); LkparllHCIU o f lt11crnal M.cdiL-it1c, University l lc..)s1~itJI,
`7.urkh~ .<;witzal:.imi. ( R.S., W.11.); I">cr.trt 111cnt of P11curnulog.y, £1,11\oovcr
`M'-"dic.ll S.:hool 1 I Lmnovcr, Gcm1Jnv { ~1.M .11.)~ th..: Division o f Pnlmoll-arv
`l>isc::isc.s, Lfni\•crshy of .\ lunkh-c..;ro15hadern 1 l\hmkh, Gi.:rm:rny (J.B.); Dc·(cid:173)
`par1mc11t o f Pncumology~ Univc.rsi1y CliHi..:, Lc.:ip:cig. Gcrm;my (JJV.); De·
`r,mmcm of Pnc-nmolo>ty .md lnf"ct.:1iot1s Discasc.s. l:msr i\.1oritz Arndt
`l J11in.'.n.i1~. Gu::i.~w.1l1t, c;cn11:111y (R.E ): Fk reil'h P11e11mulu!~M:t Mt:tfr1i11isd1e
`Kcmkli11i t 1111,I Poliklinik. lJniversit.ilsklinikum H.unbur~-El'pcnd<>tf. H.lm·
`burg. (Jc1·m.111y (A.M.); Fn:cm.rn Hospi1.1J, E li!:!-h Hc:~1ton. Ncwca.stk-u1>on(cid:173)
`Ty11l'. United Kinptom (l~A.C.); Dcpartm.:nr of Pncumolo!-!Y· G.uthuislx-rg
`Uni\"Crsity Clinic, Lcm•cn., Bdi;Lum .. (M.D.}; .uui Pulmon:iry Hypcnc1lsion
`U1>it, Hospir.11 12 de Ocrnbre, .ll.1drid ( .\l.G. S.). A,jdress reprint requestS
`rn Dr. Sec~c!'r at the: Dcp.irtrm:.nt o f lmcnul Medicine 11, Un.ivc:-rstty Clinic,
`KJiniksrr. 36, 1).35392 GieSS.r.!ll., Germany, or Jt wt.'r11er.sL•t.:gcr@i11utre.med.
`1111i-gie~1,_de.
`~The rnhcr mcmhers of rhr.:: Acm.wlizcd llopro~t R.Uldomizcd [A.IR)
`m1dy group u c lisr('d i11 rhc App~ndix.
`
`322 · N Engl) Med, Vol. 34 7, N<>. 5 · Au!>USt I. 2002 · www.ncjm.org
`
`rr10 tfow England Joutr.31 cJ Madic~e
`CewtilOel:lii.d frotn n~.ori;i on N1W8'f1tbl!lr l, 201:5. for p&":!Ot'e;l 1.J:!Je on.ty Na o1hef l..'es wit-.:,ut pormi:isiot1.
`Cupjnghl 0 2002 Ma&!oacht.:setls Medic..!11 SCJt:..t&ry. All fiQhts reseNi!d.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01621
`Page 1of92
`
`

`

`IN HA LED ILOPROST FOR S EVERE ~ULMO NA RV HYP ERTEN SI O N
`
`neuvi:r to paricms with pulmonary hypertension, its
`pulmon.u·y vJsodilaLivc potency was. similar to thaL of
`prost<Kyclin, but its ctfocrs lasted for 30 to 90 min(cid:173)
`utes, as compared wirh 15 minures.4·11·13· IS Several
`o pen-label, tmconrrolled st11dies of patients with se(cid:173)
`vere pulmonary hypcrrcnsion suggested that loug(cid:173)
`rcrm use of .1erosolizcd iloprosr resu lts in subst.unial
`dinkal improvcmenr. 11· 1~- 16·10 Our objective in this
`rri.1l was to evaluate rhe effects of inhaled iloprost
`using a rigorous cnd point of clinical cflicacy.
`
`METHOD S
`
`S electio n o f Pirtients
`
`PJri(:lltS w1th prmury pulmon.iry hypcrrcns-1011 .rnd sckctcd ti1rms
`~if 11011pri11ury pulmnn.ary h~pc:rtc11sion were c.tndid.llc:.\ tf,r the
`study. The fonns of 11onp rim.iry pulmonary hypcrtc:n~ion includ·
`cd appetire-supprcs.«rnt- associatcd and sclerodenna-assodatcd
`pulmou:iry hypertension .t~ wdl as inopc.1":lh!c.: d 'l nmk thrnmhocm·
`bo lic pulmo11ary hypcrtcnsiuu. The indusion critcfr.t were 3 1l11.::~n
`puhn011Jry·arrcry pressure greater than 30 mm Hg, rhc ability to
`C<Wi:r b~rween 50 and 500 rn w ithout cncouro.H'.?:Clll l!nt on a six~min­
`utc walk lest." and• New Yo rk Heart Associ~rinn ( NYHA) fonc(cid:173)
`tional dass uf Ill or IV" dcspirc the use uf srandard <Oll\1'ntiunal
`thc;1";1py (antk<JJ~11lants, d iun:tics, di!:(:iT;ilis, c.tlcium.-ch~urnc.:1 blut:k~
`~rs. crnd supplcmcnra~ uxygt:n). Paricnts \••ho \\·en:. fakinJ; invcsri(cid:173)
`tt·•1ion.ll ~ir11~s. pros1.u'Hii,ts, or bi.:.1:i-bl(1ckc.: r.s wen.:: cxdudctt. ·rhc
`doses of c.1ki11111-~-hanrn.:I hluc.:kcrs lud lo he c ons1,tnt for more 1han
`~ix \Wcks hcfore stud y cnrry. Ex...:Jusio11 (ritcri:i , .... ~re .1 pulmo n:uy(cid:173)
`J rtcry wedge.: prt"ssun: at rest of mo re than 15 mm H g, J -.:'.tn.iiac.:
`ind ex .1t n:sr o l" lcss rh.m 1.5 , H. n w rc rh.rn 4 liter~ per minute per
`square m erer of biu..fy--surf.H:e ;trcJ., l.Jl~cding d iso rders, ,1 bilirubin
`le\'d o f more than 3 nig. p<r dt!-ciliter ( 5 1 µ.111n l pc:r liter), i.:rcarininc
`dcorancc bdow 30 ml per nlimttc, J forced ,·itol cJpacity below
`:lO pc:n::_c:m, .1 forced ~xpir:'l.t'ory volunic in one .second rh.it w~s kss
`tlJJn the 1ncln normJ.l v:'l.luc m inus twit::c the stancl:lrd Jcvi::ltio n,
`.tnd dinic~l instabilitv.
`
`Study Desig n
`
`A HJtJI C1f 203 p:.ui~nrs participated afi:cr 8iviug wricn::n infi)rmt:d
`consent and .lfrcr the sn1ciy had been appro ved by rite loca.1 ethics
`(onunittGcS at 37 Ewropcan spcci:tlisr centers. P:.tk:nrs were ran~
`d o mJy Assigned to rcc..:i\•c iloprosr ( I le 11ncd in, Sch~ring) or placc.:.bo
`.11lcr ""ltili<ation accord in[( to N)'HA ti111c1 ion al class ( Ill or IV)
`.tnd type of pulmonary h)' pt::r tcnsio n ( prim:iry o r nonprim;iry) by
`Ml indcpcnJcm ('Ommitti.::c whose mr.:mbL·rs were unaw(irc of p.-(cid:173)
`ricnts' iLkntitics. A totr.11 ciflOl pMicnu w1·rc randrn11ly .1ssigncd to
`the ilo p rosl gmup, Jlld 102 were Jssigned to the pl.1Cebo group.
`for inh,ll~ttion ~ ilnprost o r plJ.C(bn w~1s diluted with s:iline to a
`cnnccntratinu nf 10 µg per milliliter, and 2 ml \\'.IS '1dded to a neb(cid:173)
`ulizcr ( H alo I.ire, McdicAid ). This device delivered short pulse• uf
`aerosolized par ticles (geo m etric median (:>:SD( aerodynamic diam(cid:173)
`eter of l_)lrtidcs, 4.3:':0.05 µm)"' during thc lirst part of each in(cid:173)
`spiration unril a p redefined total inhaled dose nt 2.5 µg had been
`J ispt:nst=d. Tiu: iuhal:uion wJs then stopped or n:pc-atcJ orn.:c, Lo
`.1<hicvc a tol':\I dose of 5.0 µg, depending on how well the parient
`tolerated chc treatment. After ca<h inhal•rio n. rbc residual volume
`in the m:bulizcr \\:a.s di.sc:uckd. This manc11vc.:r was repeated six or
`nim: rimes d aily, w ith an o vernight break. The ffcllllc11c~r of inha-
`1.itiun and rhc dos.: were individuallv dctcnninc:.d within rhc. tirst
`eight days ofthcr.ipy :icconiing to a predefined dosing algorithm.
`Ri~ht~hc,1rt i.::athctcriz.Hion \\'.\S pcrtOrmcci in .111 p.1ticnt~ at h.t~c
`line.:. .mJ Jl'ri.:r l 2 wcd c::s. The,:. :h.:utc d lCt:ts of inh:1lc.::J iloprost wt::rc
`c·v.1luatcd Jfrcr 12 wl·«ks in all patients, b ut not .it bas.- lim-, to .1wn
`unl>linding. 1\t b.\SC li11c .ind Jfrcr 4, 8, Jnd 12 weeks, pJti<!nts c<>m(cid:173)
`plrr('d ,1 ~i;\'.·minute: ,,,,._tlk tc~t, tht.> J\.bhler Dyspnc..:l lnckx ciucs·
`
`ti<n111.1irc,J" rhc Eun1Qc)I qut:stinrnuirc,?;; .111d tl1c l 2 ~item 1\ll.!'dicJl
`011rcon1c:s Study Shorr~Form <.__icner.1! HeJlth Surv1.:~r. :.o
`PJticnts were n.;mo vcd from the .stud y 1f thcy met t wo c)r m o re
`ot" the fulluwing µn:ddincd criccria fur :J <..ktr.:rior,1rio11 in rl 1c1r ..:on·
`dirio n: refractory systolic Jrrcri~l lwpo rcnsio n (blood pressure, less
`rhan 85 m m H£,}; worsening r ight vcntri~lilar failurL: (i:.g.~ :'IS in ·
`dicared bv rhc dcvclopn1cnt of refractory edema nr .1scitcs); r.lpidly
`pmi;rcssing cantiugrnic, hepatic. or rc1nl failure; a do:.:reasc oLtt
`kasr 30 pcrc~nt in the distance w.dkcd in six minurt!s~ and a d ecline
`in mt:asun:s ofhcmodynamic firnctiun~ su.:h as cctltral veno us pn:s(cid:173)
`s 11n :. ::i.nd mixed \ 't;ll1H1.'\ c1xy~cn S:lf11r:ui11n .
`
`Outcom e Measu res
`The primarv rnd point of the srndy rnnsistcd of .m inncasc of
`,il k'<lSt l U pcn..:t:nl in the dist.:.1111..::l~ w,\\kcd in six minutes ~md .10
`
`T ABLE 1. !l,\s1>- L1~~ Ct1<IRN;rER.1sT1c~ OF Tin; p,niE:-<TS. '
`
`CHARACTERISTIC
`
`kg.
`
`,\ gc - )~r
`\.Yl~igh1 -
`Sex - %.
`l\falc
`Fc111.1Jc
`Un,krlying <lir,i.:asc - no. (%)
`Prim;'l!'Y p11ll11ona1)' h)'pCrn.:nsion
`Nonprimary pulmon.lry hypt.>rtcnsion
`Appetite suppress-.111t&
`Collaµ,~n \'.ts:cul:u diseo.\Sc
`Chronic thrombocmbolic pulmon;uy
`l1ypcrrcnsion
`O r.ti vct.fioctil;1tor t hcr.1py - no.(%}
`NYHA funcrio nJI 'hss - uo. (%)
`rrr
`rv
`i\obhlcr Dysp1it,:.1 lnrlcxt
`6 -Mi11u1c V.""Jlk dis1ancc - m
`l kmndr11:u11il'. \0.ni.1Ck~t
`P11hno 11.try-.u-tcry pressure. - mm H~
`lirc1·s/mi_n
`C.mi i.lil; 0 11tp1tt -
`Pulmonary v.tSCul.1r rcs:isr~rncc -
`tl;·n · scc-;:111- 5
`Systemic \"41.Scular rcsisr:mcc -
`dyn · scc·cni-~
`CenrrJ..I venous prc:s.sun: - mm Hg
`Pulmon~r)'·:lm:ry we-dge pn.-ssur('
`- nun Hg
`Arterial o xyf:!.i:ll s.uur.uion - %
`Mixed vc11flu.s ox~·~cn s.uur.uion - %
`l k.1rr r,m; -
`hcJts/min
`
`ILOPAOST
`G ROUP
`(N = 1011
`
`P LACE&O
`G ROUP
`{N = 102J
`
`5 1.2 ±1 3.2
`71.3 : 14.6
`
`52.8 ~ 12.0
`72.6! I 3.9
`
`.i l.7
`6 S.3
`
`33.3
`66.7
`
`51 (50.5)
`50 (49.5)
`~ ('1.0 )
`13 (11.9)
`33 ( 32.7)
`
`51 (50.0 )
`51 ( 50.0 )
`5 (4 .9 1
`22 (21.6}
`24 (23.SJ
`
`52 ( 51 S)
`
`58 (% .9 )
`
`60 (59.4 )
`~I (40.6)
`4.l{- 1.8
`33.!: 93
`
`:;9 (07.81
`43 (42.2)
`-.i .27±1.8
`3l.5:!:96
`
`5 2.8:!. I L5
`3.8 = 1.I
`l029= 390
`
`53.8: 14. 1
`J.8:!;0 9
`1041:!:493
`
`1872::673
`
`1827 ::503
`
`9.2=5.3
`7.5 : 3.3
`
`8.ESO
`7.6= 3.9
`
`92.6 :!:4.~
`60-4± 7.5
`S3.9:tl2.2
`
`92.2::: 5.0
`60.5;:8.2
`Rl.8 = 15.4
`
`• pil1.~-111i1ms. v.11111:$ .ire mi.::;111~ !.SO. NYHA c..lc11un·s Nl!w York H_t.'~•rt
`Assoc ia1iun. Tht.:n: w·cn:: nu .si~1ilic.1111 dilli:.rt".J1CX:. lit:1wc.1~11 d11t: il11pto.s1 .md
`1h1; lllaccho grOllpS. D.u.1 on dll ~·.ui~hlc."i were J\·.1iL,hlc IOr .ill p-..ui..:nrs cxccp1
`in the following ( J.ICgo rics: pt1hnollJJ)'·;mcry pressure, I p.,ticm_ in c.tch
`f_roup; -.:ou d1J1..' o utpul, I p:.111cn1 in the ilopros1 group .HHJ 6 in 1hc pl.u;c bo
`group; puhnnn.1r~1 \'.1Sl'Ufor rcs1s1:111-.·~. 10 and 6. rc-,spct"11vd r: srsrcmk v.is(cid:173)
`,·uf•r rcsi~t.UK<, 11 '111d !4; ,-cnrr;il \'Cnon< pressure. 5 .rnd 7; pnlmon.m··
`.m·cry wc~ty.e pn::ssnrc, S .md 3; .mc.ri:d O:t\•-~eu sat11r:uiun 1 35 .t11d 31; IHi)'ed
`\'('l)()US OXY~<'Jl S-.UUr:1rioll, 16 .li1<.I 18~ :md he:U't i.lft: 1 2 :mtl 3..
`t0n this 12-poinr ~.lfr, hig.hc:r scnl'es i1\l.tic.uc lc:-ss drspne:i.
`~l':uicms who were rcc.:eiving long-rerrn oxygc.:n th-..·r.lpy r4.."c..:-ivt:d ru.~'d
`lll.~b"t'll -.h1rU1g tht: 111cJ )t1rcme1u ofb;a,se-line hcmody1umic v~uiJ.blcs.
`
`N Engl I i\lcd, Vo l. 347. No. 5 · August l, 2002 · www.ncim.o rg · 323
`
`lhg NfN.· Engl'a.ncf Journal of Madidne
`O<t.wnlondll'.ld from !lCJm cr'Q o"' Nove~r 3. :lilt s FOf'oersona.l ~H only. No other uses.w1the1.1 oismussio.."'I.
`Cooyrlg"ic 0 2002 Mt'l:oJ:S;:ict.usetts ll~ical Soc:;lecy. A.11 rights 1111SONOO.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01621
`Page 2 of 92
`
`

`

`Th e New Eng l.ind Jo urna l of Medicine
`
`improvcmcu r ill thi: N YHA fuw . .:tio11al d .as.s in the Jb~c11cc nf .l
`JL.:tcriur.1riP11 in the tJjn iL.11 co11Jition or tk.1t h durilll!. tile 12 weeks
`of the srudy. Sccond.u-y ctlicacy variables were chJn~;s in the \'alucs
`t<ir 1hc six-minute wolk !'est. the NYHA d :i". M.1hi<r Dyspne:i ln(cid:173)
`ckx scores. hcmuJp1:.11n ic v:1riabks, m d the quJliry or lit<:; d inicJI
`1..k tc.rioratio11: dc~1rh; :'lnd the need for transplanratio n .
`
`Statistical Analysi"
`T he prim:uy 1.:valu::t1·ion of cfiic.u:y im:h1dcd all r.mdomizcd pa(cid:173)
`til'"ntS. D:lt::I :ire pn::scn tcd ;u; llll.:a ns ±Sn, un1es..s nthr;rwisc stated.
`We ind11dcd d.1r.1 on p.uicnrs wh1> prcmm trdy d iswnrinued rhc
`.stu<ly ti.~ing a last-ohs;cr.·ation~c~uric<l·forward .111~llysis for th1..~ six(cid:173)
`mmurc. w.ilk [t.:St'. Patic ms who d ied W\.'rc .1ssi~nr.::d a v.1Ju c of O 111.
`All ~rJti.-;ticd \l"Sls l( u· cflic.Ky variahles \\.l"rt• l\\·O-tJill·J, with J n
`.1lpha level of 0.0 5.
`Tc, .uu l)'i!C the pri1na11' cffic;h:y e nd point .. rnd the improvement
`aitl"'ri.1, we used the ~·1.1111d-H.u:nszel fcsr,n .-.:tr.1rifo~d .tcc.ording rn
`r hc rypt.· o l" pulmonar y liypcrtcnsion ( pri111:.try o r nnupri111~1ry) Jnd
`N YHA class ( 111 or IV). Patients with missing d:i~J o n the primary
`end point at week 12 were ~unsidcred not ro have h~ld a respo nse.
`C h:mgcs: in t he. re.suits tlf the six·minun.: w:.lk w..:rc. cv;1]u:ncd
`wirh use of nonpar~unt:rric analysis of \.'.ovari .. mcc stratitit:d accord(cid:173)
`i11g to rht:. type of pu lmonary hypcrrension. (primary o r nonpri(cid:173)
`m.u-y) and the 1"\'Hf\ cbss (Ill or IV}. with use o f the base-line
`,~.,luc ~ls rh..: i;ovJri;1.tc (.111.1lysis of covari~11Kc), ,rnd the 'Vilcoxon
`~i~ncd-rank (est.
`Ch:ulgcs fro m b~\Se lini.: in hcmodynamk v:llucs Wl!rc analyz.c-d
`'vith r-suristics. Th~ im·csrilGllors h.u1 foll a.cccss to the: darn and
`pcrliirmcd rile w.1lys~s ind:pcmkmly of 1hc sr onsor.
`
`RESULTS
`Base-line demographic an<l hemodvnamic data are
`givrn in 'fable L The mean frequcn..:y o f inh.ilation
`was 7.5 rimes per day. N inety-one pereenr of patients
`received 5.0 µg per inhalation , and 9 percent received
`2.5 µ g, corn::sponding to a median inhaled J ose of
`30 µ,g per day.
`
`Primary Efficacy End Point
`
`l'or the primary end point, we found a significant
`dtcct o f rre:1tment in favor of iloprost ( l'=: 0.007)
`(fiµ: . 1). The estimated o dds of <ln effrcr in the iJo(cid:173)
`prost gro11p, .is compared with the:: placebo group,
`were 3.97 (95 percent <:ontidcncc intcrv.il, 1.47 to
`10.73, by the Mantcl- Hacnszcl rest), with no sigaif:
`ieant heterogeneity among t he four subg roups cate(cid:173)
`gorize d according to type of pulmonary hypcrtc n ·
`sion a.nd NYHA class at b.1sc line (P =0.79 by the
`Breslo w-Day test ). T he secondary analysis of the pri(cid:173)
`mary end point was a logistic-regression rnodd that
`indud.cd trc;1t ment c1ssignmcnt, Jcmo)?;raphic data,
`,md b.1sc-linc d1ar.1etcristics. Only treatment ,issign(cid:173)
`mcnt ( P =: O.Ol) contributed signil·ica.ntly to the prob(cid:173)
`ability of a rc.~ponsc.
`
`Secondary End Points
`
`Six-Minute W11/k Test
`
`The percentage of patients who had an iJicrease of
`<lt least 10 percent in the distance walked in six min(cid:173)
`un:s at week 12 was slightly, but not sign itica.nrly,
`higher in the iloprost gro11p tl1<1n in the pl.iccbo
`group ( P = 0.06) (Table 2 ). T he type of pulmonary
`hypertension h;1d no significant dlcct on the outcome
`in either group (P = 0 .90). A higher percentage o f
`parienrs in the placebo group th;rn in the iloprost
`group h:id a decrease in the distance walked of at least
`10 per cent or did nor complete rhe nudy (Table 2 ) .
`T l1e absolute change in the distance walked in six
`minutes was significantly larger (by 36.4 m ) in the
`
`E
`
`40
`
`20
`
`lloprost
`
`'O
`QJ
`-""
`-;;;
`s
`
`QJ
`
`<t)
`
`QJ
`u
`c:
`<t)
`ti
`Ci
`.:
`°' c
`£ u
`c:
`"' QJ
`~ -40
`
`0
`
`- 20
`
`P = 0.004
`
`Base Line
`
`4Wk
`
`8Wk
`
`12 Wk
`
`Figure 1. Effect of Inhaled Jloprost and Placebo on the Mean (:!:SEJ Change from Base Line in the Dis(cid:173)
`tance Walked in Six Minutes, According to an Intention-to-Treat Ana lysis.
`The P value was obtained with Wilcoxon's test for two independent samples.
`
`324 - N Engl I Med. Vo l. 347, No. 5 · August 1. 2002 · www.ncjm.org
`
`n 9 Nuw Erigr.M JolJtl'llll of IJ.Q(ki,;iQ
`Dow.r.1o&dBd !ft)rYI nojm.org on Nover"lbet 3, 20tS. For pef'$1)f'31 J~lt er.Jy. No c:iuior !J:!;aS w!lho.Jt potm o:iio:n.
`Copyright 0 2002 .'.ta"acnuu-tb t.~edl.::lfll Society . .All ~t-1.5 1os&f\'ed.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01621
`Page 3 of 92
`
`

`

`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`ilnprost group rhan in rhc pbcebo group (P= 0.004)
`( Fig. 1): 58.8 m among those wirh primary pulmo-
`1wry hyper rensio n Jnd 12 111 among those with non(cid:173)
`primary pulmon;uy bypcm :nsion. A parametric analy(cid:173)
`sis of covariance, which induded th<.: ahsohm: v;1luc
`on rhe six-minurc walk rcsr at week 12 as a depcmkm
`v;1ri;1blc and the rre:mnent assignlllent (P = 0.02), t)'pt:
`of pulmonary hypertension (P= 0.06), and disrance
`walked ar base line (P< 0.00 1) d id n or show a sraris(cid:173)
`ticallv significant imernctio n between treatment and
`type 'of pulmonary hypertension ( P = 0. 09 ).
`
`NYHA Class
`More p;1tienrs in rhc iloprosr grm1p rhan in the pla(cid:173)
`cebo group had :rn improvement in the severity of
`lic:m fuilurc, as assessed by the NYHA cbss (P = 0.03)
`(Table 2). T h<.: typ<.: of pulmonary hypcrt<:nsion had
`no dl.cct on rlu: ourwmc in either r;roup (P= 0.39).
`T he pen:cmage ,>f patients with a deterioration in
`:-JYHA dass did nor <lifter significamly betwcrn the
`groups, bur the analysis did lH)t include patients who
`lch: the srud y early owing to death or other reasons.
`A J;1rgcr proporrion o f patienrs in t he placebo group
`rhan in the iloprost group did not cornplct<.: the study
`(Table 2 and Fig. 2). Rcasons indmkd death, d iscon(cid:173)
`tinuation of study rncdicatio n, and w ithdrawal of con-
`
`sent, mosrly owing ro clinkal dercrioration, insutncirnt
`clinical benefit, or both_
`
`Hemodynemics and Gas Exchange
`In the placebo ){rnup, Gudiac o utput, systemic ar(cid:173)
`terial oxygen saturation, and mixed venous OXl'gen
`s;1rurat ion decreased significwtly :1frer 12 weeks .ind
`pulmo nary vascular resistance and right atrial pressure
`increased significwcly (Table 3 ). In rhe iloprost group,
`v;1Jucs ;1ss1.:sscd at 12 wtl:kS, before the first morning
`dose of inhaled iloprost, were largely unchanged from
`base tine, whereas values assessed afrer .inhalation
`w<.:rc s·ignificantly decreased (in the case of pulmonary(cid:173)
`artery pressure, pulmon;iry v;ts<.:ular resisc111ce, system(cid:173)
`ic arterial pressure, and systemic arterial oxygen sarn(cid:173)
`ration ) or increJscd (in rhc case of carbon monoxide
`and pulmonary-artery wedg<.: pressure). At thc com(cid:173)
`pletion of the 12-w.:o.:k study, acute ht:modynamic re(cid:173)
`sponsiveness ro inhaled iloprost was equivalent in the
`phic<.:bo group and the iloprost group, rhoug h rhe lat(cid:173)
`tcr group had bt:en <.:xposcd w daily iloprust inhala(cid:173)
`tion for three months (c..larn not shown ).
`
`Mahler Dyspnea Index
`The me<1n Mahler D yspuea Index transition score
`was signi!icantly better at wcck. 12 in the iluprost
`
`TABLE 2. fa1H ;Ts '"' 12 W EEK' 0 1' T11E1<Al'Y w r 111 INH.~u;1> IL0 1•1<o:>T 0 1< 1'1.A<.liHU
`m i TJIE NEW YuRK H £.\l<:J i\~SOCIATIO>: ( NYHi\) CIA'~ .. IND T IIE SiX· MINL'TE W AJ.K TE ... r.
`
`VARl,A8Lf
`
`llOPMST GROUP
`rxrrn:-.rr.;; wrn1
`(IRJ:!iL\RY
`Pl ',_..tO:>::\R\'
`11rrf.R'fF.:N."ION
`
`,,IJ l'.Vt lf.:"'1°"
`
`r.\Tll!..'\"TS WITJ l
`so:-irru~tAIW
`rtJl-'10SARl'
`
`l{Yrf.A.I f:.:-i.:~! ON
`
`AU. r'.'\'fll~N"J":i.
`
`porcontage of patients
`
`PLACEBO GROUP
`
`r.,l lE.' '1'" w1T11
`r'PJM .. \ l\Y
`['\ ll..\l0 :-.1,\Ry
`I l ll'f.R"rf,:•h !O N
`
`PA1'1i:NTS wrn t
`:-.:o~r1t.1M.;\RJ
`f'\1L\.1U:O-:A;t.'i
`l l\' l' l•. Rll:K"U 1:-.
`
`C l1,.t11!',e! in NYHA d.tss
`l nip1 nvc1I by 2 d .).SSC-S
`lmprovcll by l d .hs
`l.:'ni:ha.n.i::.cd
`\\'o rsc-11cd
`Uar-.t missin~
`Nom.:omplcrion of snid}'
`De.1th
`Olh(!T
`Cli..1nl!·c in 6·111i111ut< w.1lk dist~u1cc
`~ J 0% incrca.ilc
`< 10% iucrea.sc ro <lo~ (frt:rc-dSt
`";;t l 0% dl·etc-.lSc:
`D.11.1 miili.111~
`Combined r.:nd poi111
`
`1.0"
`23.8•
`64.4
`5.9
`1.0
`4.0
`1.0
`3.0t
`
`37.6§
`12.6
`t .;.9
`;:;_9
`
`16.~1
`
`1.9
`22.6
`66 .0
`3 8
`1.9
`3.S
`1.9
`1.9
`
`'191
`37.7
`5 7
`7_;..
`20 R
`
`0.0
`25.0
`62.5
`8.3
`0.()
`4.2
`o.o
`-4.2
`
`25.0
`U .9
`22.9
`4.2
`12.5
`
`0.0
`12.7
`65.7
`7.8
`0.0
`13.7
`3.9
`9 .S+
`
`,, ---::l.:>
`
`.~2.4
`2~.:i
`16.7
`4 _9
`
`0.0
`7.3
`69.I
`10 .9
`0 .0
`12.i
`3.6
`9.1
`
`.W.9
`20.0
`.l2.7
`) (,.4
`s.;;
`
`().0
`19 .l
`61 .7
`4.3
`0 .0
`14.9
`4.3
`1().6
`
`19 .1
`.tt>.S
`17.U
`17 .0
`4 .3
`
`• 11 0.03 IOr the ..:omparison o f r-.l!Cs o f inlproVcn·,e nl {b)' 0 11C or two ,•J..sscs) with the pla.'.cbl> !?roup.
`t Trc<.Hmcm w.1s Ji..~ontinucJ in ,1ll 1hrc.c p.u icnis.
`tTreanntm ""'~ (Hs( ontinu cd in seven p:.ticms, ,\ntl three p.1tienu wirhctrew rhcir ;;on~cnr.
`§ 1'== 0.06 for the ~ump:1rison with 1he p b ccbo proup.
`11'~ 0.007 for 1hc comp.\riso11 wirh rhe ~'bcebo group.
`
`N Engl J i\led, Vo l. 347, No. 5 · August l , 200 2 www.ncj111.org · 325
`
`The New E."Qlal'ld Jou.,,al ol Madic:Wl•
`Ocvtl\lctaded from ri@\m.otg on Nc11embar l , 2~15. For OOrMM!al use o ... !y. No othet u.se-.s 11uilout ~eM'l1uio n..
`Ooo~ll 0 2002 Ma.1i:S.Xhun~ ~·h1llica1 Sociely. All ng"l!s ni~rvad.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01621
`Page 4 of 92
`
`

`

`The Nnv Engla nd journ,d of Med icine
`
`lloprost
`
`Pl«cobo
`
`1.0
`
`0.9
`
`"' E .,
`a:
`"'>
`_-o
`c ::i
`Ol -
`·.;:VJ 0.8
`
`Ol
`.<;;
`.£
`
`"' .,
`0. -5 -
`0 .s
`c
`0
`'§
`a.
`0
`ct
`
`0.7
`
`0.6+-~~r-~-.-~~-.-~~...-~--.~~--.-~~....-~~.--~-.
`30
`80
`90
`10
`20
`40
`50
`60
`0
`70
`Days
`
`Figure 2. Kaplan-Meier Estirn<1tes of the LikP.lihood of Completin g the 12-Week Study.
`fleasons for not completing the study included death, discontinuation of study medication. and
`withdrawal of consent (see Table 2).
`
`T ABLE 3 . MEA:--1 (' SD ) CHANl; E !'ROM BASE LtNI' IN Ht,MOIW.'IA1'11C VA!.UES
`P l ' RJS(i I 2 VVEl-:1',..;; nr Tr lFR.A.P\' WITll I Nl lAJ.En ILOPROST OR Pr.:\ CERO_,.
`
`VAR1AllLE
`
`PlAcuo G ROUP
`
`Pul111011;lry-.1rtcry prl"SSUTl' (mm H~)
`r.1nti:1c i llllfll tl (li1c r.'i/ mi11)
`l'ul1no11.1ry ,·,1scul.u res15t.Ulcc ({iyn·sc.:: ·l·1n ')
`Synemic :u·teri:.1 pres.sun! (nun H~)
`Ri,t.lu .mcri.11 prusurc (mm Ilg)
`l'o bno11J_r y· J.ft l'q' wcdµc: pn:.SSllO: ( llHI\ Ht:·)
`.. \r1r-1i,li rn:ygc;ll .;,;;1111r;uion 1%)
`,\1i~cd \'cnous o~~·~cn S<tnlr .. uiuo r%)
`[ l i.:.u'I r-,111.: th1.·;ns/min}
`
`- 0.2: 6.9
`-0.19 ,-o.:n t
`- '16::32.? t
`- 0.1:: I 2.4
`+ 1.4 !:4.St
`+0.7=3.()
`- 1.(, • 44~
`- 3.2:t6.7t
`-l .2 ~9.5
`
`ILOPROST GROUP
`.\rn:R
`lSHAL/iT!O~
`
`RFI01U~
`IN llt\L\TIO:-..l
`
`me<tn ::. SD
`
`-0.1:!:7.3
`+ 0.05 •·0.80
`9 ::275§
`- 1.i::t12.8
`I 0.5 !:4.6
`+ I.I !:4.7t
`- 0.4 ' .l.7
`- l.l .!-7.6
`- 1.R:t 12.4
`
`-~.6 .t9.3T
`+ 0.'\;i + l.Jt
`- 239::279T
`- 4.3:: I 3.6t
`- 0.8!:4.6
`-'- l.S :t5.3,
`- 1.4 ' 3.7t
`·I l.8.!-R .• l
`-2.25 :! 12.6
`
`• for the ilopros1 )!.roup, brn h prci11hal.i1io11 Jm.i pos1inh,\l,n io11 v,1k1r.:s ,lJ'tcr 12 wcr.:ks .i:rc 4.'.om p<lrcd
`with 1hc ba...-;c.linc \':tlut:s .n s1mly entry.
`tP< 0.001 for the di llt::rcnlX': fro m b:lsc· linc values.
`lP<.0.05 lilr rhr.: difference l"mm b;1se· linc \',th1es.
`§P<.0.01 for t he i:om.p~lrison with t he pl.1i.::ebo ~roup.
`1P< 0.01 for tht' difference from LMSi:·linc ,.·.ttues.
`
`group than in the: placebo group ( dlJ.ngc, + 1.42.:!.:
`2.59 vs. + 0 .30 ± 2.45; P = 0.015). 'The typr:: ofpulmu(cid:173)
`nar)' h ypt:rtt:nsion had nu dkct un. this uutcu1m:.
`
`Quality of Life
`Mean scores on the EuroQol visu al-<maloguc scale
`improved sig,nitic.u1tly (from 46.9 ± 15.9 to 52.8::19.1 )
`in chc iloprost group but wr::re virtually unchanged
`
`in the placebo group (Jrupping from 48.6 ± 16.9 tu
`47.4± 21.l, l'= 0.026 by analysis ufcovari<UKt:). Thr::
`EuroQul hc:alth-statc: score: impruvc:d from 0.49± 0.28
`to 0.5R.::':0.27 in the iloprost group ~ml was un(cid:173)
`changed in the placebo group (0.56± 0 . 29 to 0.56±
`0 .31, l' = O.U by analysis o f rnvariancc). N o ne of the
`other measures of the quality o f li!C were sig nificantly
`ditkrcnt between the groups.
`
`326 · N Engl J Mod, Vol. 347. No.
`
`· August I , 2002 · www.nojm.org
`
`Tho New Er9lllnd Journ'11 of Me<JtC•.,&
`Ool'rioa~ l rutn nejm.cwo on No,·e1n 00t 3. 2015. F0t plilrsonil .tse Ol'fy. f'Joo1•-er u~e~ YollhOut pemiiSsion.
`~01'.10'l M~ll...C"ILl!lens Mi!dlCo'li Soof!ty .AJI r1101ht:5 l e50r\-ed.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01621
`Page 5 of 92
`
`

`

`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSIO N
`
`Clinical Deterioration and Death
`One patiem died in the ilopro~r g ro up during the
`l2-weck 'Ludy, as compan:d with tour patients in the
`placcbu g,ruup (1'= 0.:'17) ("[1blc 2). Critcri;1 for clin(cid:173)
`ical dctcrior;1tio n were met in 4.9 percent o f patients
`in the iloprost gro up and 8.8 percent of those in the
`placebo group (P = U.41). This ind ic;1tcd that fewer
`pariems either died or deteriorated in the iloprost
`group th<Ul iu the pla..:ebo group ( 4.9 percent vs. 11.8
`percent, P = ll.09 ). The type of pulmonary hyperten(cid:173)
`sion had no effect on the o utcome. D uring the study
`period, none of the patients received a lung tran splant.
`
`Safety
`T he total number ofpatiems who had st:rious ad(cid:173)
`verse evems did not ditkr signilicanrly l..H:twecn the
`gruups (13bk 4 ) . R.ighr ventricular foilun: and ede(cid:173)
`ma wen: more th an twice ,\S frequent in the p lacebo
`!;!ro11p as in rhe iluprost group. The Clltal numbt:r of
`syn..:o pal events in each of the two gruups w<1s sim(cid:173)
`ilar (eight in the iloprost group ~111<l five in the pl<i(cid:173)
`cebo group), but rhcse events were more o ti.en con(cid:173)
`sidered serious in rhe iloprost group. Syncope w<is
`not a~sociare<l wilh clinical deterioratio n or prema(cid:173)
`t ure withdrawal from the Sllldy. Syncopal C\'e11ts oc(cid:173)
`curred mun: than two hours alter t he last inhafation
`( ofren afrer an ovc:rnight break), were exercise-induced
`in two patients, were induced by b.ra<lycardia in two
`p:irients (associated with gastroenter itis in one patient
`~md with verapa.mil therapy in the ot her), and resulted
`i.i1 hecid 1rau ma in one [.>atient. l:'lushi.ng and jaw pain
`were more cummon in the ilo prost g.ruup, but these
`ad verse effects were mostly transient ~\nd mild and
`were nor co nsidered to be ser ious in ;my patient.
`
`DISCUSSION
`T he results of this clinical trial demonstrate that
`long-term inhaled administration of aerosolized ilo(cid:173)
`prost, a stable analogue o f prosracvclin, improves a
`clinically important ..:ombined end point consisting
`o f exercise capacity, 'N"YH A class, <llld clinic;1l deteri(cid:173)
`oration in patients with selected forms of pulmonary
`~u:terial hypertension 'md chronic rhromhoemholie
`pulmonary hypertension. Moreover, iloprost improved
`several secondary end points.
`Since intravenous cpoprostenol was shown to im(cid:173)
`prove survival ;unong the most sevcrdy ill p;itients
`with primary pu lmonary h)·perrension , it has heen
`imethical to perform randomized clinical trials among
`patienrs with pulmo nar y hypertension in which sur(cid:173)
`vival is used as an end po int. We chose a combined
`r;nher th;in '' sing le end poinr (e.g., the distance
`walked in six minutes) in order to 1m1ke a more rig(cid:173)
`oro us determination of w hether inhaled iloprosr was
`efficacious. Nc<1rly 40 percent o f all patients who were
`treated with iloprost increased their six-minute walk-
`
`ing distance bv Jt least 10 percent. I lowevcr, only half
`'1s m;m.y patients also had improvement in the N YI lA
`cbss; <.:onvcrsdy, not all patients with <lll improvement
`in NY 1:-lA class had <U1 i.Jicrc::asc of.it k ,ut lO percent in
`the: distance walked in six minutes. Thlls, although
`only 17 percent of p<n icnts in the ilo prost group
`reached the co mbined end point, a substantial mun(cid:173)
`ber of the remaining patients met less strict critnia
`for clinical improvement that would warrant continued
`then1py. l?urtJ1ermorc, significantly fewer pacic11ts in
`the ilo prost group th,in in rhc placebo group prema(cid:173)
`turely discontinued rhc study <lS a result of lack of
`etlic;icv or other reasons, suggestinp; that even w hen
`iloprost therapy docs nor produce substanti<tl improve(cid:173)
`ment, it may staliilizc t h e clinical condition.
`T he me'm inhaled dose o f ilo prost corresponded
`to 0.37 ng per kilogram of body weight per minute,
`which is considerably lower than <ll1 d lective intrave(cid:173)
`nous or su bcutancous dosc:. 2,ix Thus, tarv.etc.d delivery
`of prostanoids ro the pulmonary vasculatu rc by mcan·s
`of iuhab1tio n may substantially reduce t he dru~ re(cid:173)
`quirements.
`
`T ABLE 4 . I Nclllt N<'E o r St!U<>lJS n:-m O THER A n v Eic;E E.vl'.NTs. •
`
`VARIABLE
`
`I LO PROST GROUP PLACUO GROUP
`(N=1011
`IN=1021
`
`p
`VAWE
`
`Serio us ~k<-"rsc: ~vent
`Any C\it:lll'
`Righi \'<:11trK:11l;u foilure
`.rnd '-'dem,,
`Syncope
`Orhcrt
`Adverse t:\'~111!
`Any ...:"'cnt
`(n(rrJ:scd cough
`I k :adachc
`Fl11