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Ibrutinib Triple Play

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By Shreya Iyer

uolng Lhlngs ln Lhrees ls ofLen recognlzed as an ouLsLandlng achlevemenL - Lhlnk of haL-Lrlck soccer or a
Lrlple play ln baseball. 1here lsn'L yeL a Lerm for a slngle drug recelvlng Lhree uS lood and urug
AdmlnlsLraLlon (luA) 8reakLhrough 1herapy ueslgnaLlons buL Lhere should be, because lbruLlnlb has
achleved lL. 1he deslgnaLlons are for Lhree dlfferenL 8-cell mallgnancles: (1) relapsed and refracLory
manLel cell lymphoma (MCL), (2) chronlc lymphocyLlc leukemla/small lymphocyLlc lymphoma (CLL/SLL),
and (3) WaldensLrom's macroglobullnemla (WM).

8lchard Þazdur, luA's Cancer Czar and ulrecLor of lLs Cfflce of Cncology and PemaLology ÞroducLs, says
LhaL ºA breakLhrough cancer drug musL be LransformaLlve". 1he luA's crlLerla are LhaL Lhe drug should
ºLreaL a serlous or llfe-LhreaLenlng dlsease or condlLlon" and LhaL ºprellmlnary cllnlcal evldence lndlcaLes
LhaL Lhe drug may demonsLraLe subsLanLlal lmprovemenL over exlsLlng Lheraples on one or more
cllnlcally slgnlflcanL endpolnLs, such as subsLanLlal LreaLmenL effecLs observed early ln cllnlcal

lbruLlnlb ls poLenLlally LransformaLlve ln a number of ways. lL surpasses exlsLlng LreaLmenLs ln Lerms of
convenlence, durablllLy, safeLy, LolerablllLy, and overall efflcacy.

!&! CSC Þaul SLoffels has descrlbed Lhe breakLhrough deslgnaLlon as ºA ma[or leap forward ln
acceleraLlng drug developmenL Llmellnes". 1hls ls supporLed by Lhe facL LhaL new urug AppllcaLlon
(nuA) flllngs for Lwo of Lhe lndlcaLlons (prevlously-LreaLed MCL and prevlously-LreaLed CLL/ SLL) were
recenLly accepLed by Lhe luA, many monLhs early Lhan had been anLlclpaLed.

SLaff members aL !anssen 8&u have been worklng flaL ouL alongslde Lhelr opposlLe numbers aL
Þharmacycllcs, lnc. Lo brlng lbruLlnlb Lo paLlenLs as fasL as ls humanly posslble. 8esLoraLlve ls Lhe word
LhaL comes Lo mlnd when l Lhlnk of lbruLlnlb," says Anll kapur, vlce ÞresldenL and Commerclal Leader of
PemaLology ulsease Area SLronghold. ºWe wanL Lo flnd a way Lo help physlclans geL paLlenLs back Lo
llfe." 1he challenges are greaL, he polnLs ouL, noLlng LhaL currenLly Lhere are no cures for some
lndlcaLlons and a hlgh rlsk for relapsed paLlenLs. ºWe hope," he says, ºLo creaLe a paradlgm shlfL and
replace chemoLherapy alLogeLher."

!"#$%&'"()*'+ &( -$&#
8eLween CcLober, 2012, when Lhe program was esLabllshed, and SepLember 2013, Lhe luA's
8reakLhrough 1herapy ueslgnaLlon program recelved 83 requesLs, of whlch 26 were granLed, lncludlng
Lhe Lhree for lbruLlnlb. 1he program dlffers from Lhe agency's lasL 1rack uevelopmenL program, for
whlch noncllnlcal or cllnlcal daLa can be consldered. 1he developmenL Leam aL !anssen has been
galvanlzed by Lhe speed of progress, wlLh Lhe consLanL need Lo prospecL of [uggle sclenLlflc creaLlvlLy
and lmmedlaLe lmpacL. º1he breakLhrough deslgnaLlon affords us close lnLeracLlon wlLh Lhe luA," sald
Sandy 8aLLay, vlce ÞresldenL, 8egulaLory Affalrs, ºcurrenLly Lhere ls no equlvalenL elsewhere ln Lhe
world." Cf course, he polnLs ouL, Lhe deslgnaLlon does noL guaranLee approval raLher, lL provldes an
lncenLlve LhaL powers Lhe Leam forward every day.

1he blood cancers belng LargeLed wlLh lbruLlnlb are rare and lncurable. 1hey represenL mallgnancy aL
dlfferenL sLages of 8 cell developmenL. Cne of Lhem ls caused by deleLlon of Lhe shorL arm of
chromosome 17 (del 17p) whlch resulLs ln unconLrollable 8 cell prollferaLlon ln Lhe blood and bone
marrow (known as CLL) or ln lymph nodes (known as SLL). uel 17p accounLs for [usL seven percenL of Lhe
roughly 16,000 new cases of CLL dlagnosed ln Lhe uS each year, buL 20 Lo 40 percenL of
relapsed/refracLory paLlenLs have Lhe deleLlon. MCL ls a subLype of 8-cell lymphoma LhaL occurs wlLhln
Lhe manLle zone of Lhe lymph node. llve Lhousand new cases are recorded every year ln Lhe uS and Lhe
flve-year survlval raLe ls [usL 30 percenL for advanced-sLage MCL paLlenLs and 70 percenL for paLlenLs
wlLh llmlLed-sLage dlsease. WM ls caused by unconLrolled clonal prollferaLlon of Lermlnally
dlfferenLlaLed 8 lymphocyLes ln Lhe bone marrow and lymph nodes. 1,300 new cases are reporLed per
year ln Lhe uS, and Lhe dlsease ls currenLly lncurable, buL LreaLable, medlan survlval ls 6.3 years.

lbruLlnlb works ln all Lhree mallgnancles because lL LargeLs and selecLlvely lnhlblLs an enzyme called
8ruLon's Lyroslne klnase (81k). 81k ls a medlaLor of survlval mechanlsms ln cells, lncludlng Lhe regulaLlon
of apopLosls, adheslon, and cell mlgraLlon and homlng. 1hese mechanlsms help mallgnanL 8-cells Lo
survlve and develop. 1he lnLeracLlon wlLh Lhe drug lnhlblLs 81k, lnLerferlng wlLh Lhe ablllLy of Lhe Lumor
cells Lo perslsL. And, slnce lbruLlnlb blnds 81k ln a covalenL manner, LhaL lnhlblLlon ls lrreverslble.
ln Þhase l Lrlals of lbruLlnlb, poslLlve responses of 73 percenL, 78 percenL and 79 percenL were recorded
ln WM, MCL and CLL paLlenLs respecLlvely. Cne Þhase ll sLudy lndlcaLed a 94 percenL evenL-free survlval
aL 12 monLhs. 1o daLe, Len Þhase lll Lrlals have been lnlLlaLed wlLh lbruLlnlb and a LoLal of 40 Lrlals are
currenLly reglsLered on

1he drug also scores hlghly for lLs lmpacL on paLlenLs' quallLy of llfe. lL ls a one-a-day oral medlcaLlon
LhaL does noL need Lo be admlnlsLered ln cllnlcs. Adverse evenLs ln Lhe cllnlcal Lrlals have been mlld,
amounLlng Lo non-hemaLologlc LoxlclLles ln less Lhan 13 percenL of paLlenLs. ln conLrasL, currenL
medlcaLlons such as chemoLherapy musL be admlnlsLered lnLravenously, or by lnLramuscular or
subcuLaneous ln[ecLlon, ln a cllnlc. And, whlle Lhey can work, Lhe slde effecLs are harsh. WlLh currenL
MCL chemoLherapy opLlons, paLlenLs frequenLly relapse and evenLually develop reslsLance.

1he overall lmpacL? ºln hls nearly 30 years of career ln oncology cllnlcal regulaLory affalrs," says !ohn
Season, Senlor ulrecLor, 8egulaLory Affalrs. ºl have never seen daLa Lhls poslLlve."