Exhibit 1015
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1015
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`in re Application of:
`8. George Kottayil et al.
`
`Serial No.:
`
`11/698,739
`
`Filed:
`
`January 25, 2007
`
`Atty. Dkt. N0.:
`
`lNS10763PO0O9OUS
`
`\/\z\/-a~«.J\/\/\/
`
`SUBLINGUAL FENTANYL SPRAY
`
`Examiner: Wegert, Sandra
`
`Group Art Unit: 1646
`
`Confirmation No. 4756
`
`DECLARATION OF DR. LARRY DILLAHA TO 37 CFR 1.132
`
`Commissioner For Patents
`P.O. Box 1450
`
`Alexandria, Virginia 22313-1450
`
`Dear Madam:
`
`Your Declarant, Dr. Larry Dillaha, hereby declares and states as follows:
`
`1.
`
`I am currently employed by lnsys Therapeutics, lnc. (“lnsys”), the Assignee of
`
`the present application, as Chief Medical Officer. My duties include overseeing clinical
`
`development, regulatory affairs, medical affairs and the formulation scientists at lnsys.
`
`l
`
`have been continuously employed by lnsys since April 2010.
`
`2.
`
`l have over 10 years of experience in the field of pharmaceutical formulation
`
`development with experience in working on both solid dose and liquid formulation
`
`development.
`
`I have overseen the formulation development of numerous products.
`
`Additionally,
`
`l have worked closely with the U.S. Food and Drug Administration (“FDA”) on
`
`clinical development of such products.
`
`I have been involved with the filing for drug approval
`
`of numerous drugs before the FDA over my career.
`
`3.
`
`l have reviewed the present application, U.S. Pat. Appl. No. 11/698,739, as
`
`well as the last Office Action dated June 8, 2012.
`
`Page 1 of 3
`
`

`
`Declaration of Larry Dillaha
`Serial No. 11/698,739
`
`4.
`
`Fentanyl is a potent, short acting narcotic analgesic used, inter alia, for the
`
`treatment of breakthrough pain in late-stage cancer patients. Such patients are typically
`
`treated for pain with a baseline dosage of a long acting pain medication. However, for
`
`episodes of breakthrough pain, a fast-acting, highly potent pain reliever (e.g., fentanyl) is
`
`desirable. Accordingly, effective treatment for pain in 5 minutes compared to 10 or 15
`
`minutes or longer is significant.
`
`5.
`
`SUBSYS® is-the registered trademark for the lnsys brand of sublingual
`
`fentanyl spray.
`
`SUBSYS® is exemplified and claimed in
`
`the above—noted patent
`
`application. The specific SUBSYS® formulations are as described in Exhibit A.
`
`6.
`
`7
`
`These SUBSYS® formulations were evaluated in Phase lll,
`
`randomized,
`
`double~blind, placebo-controlled, multicenter studies to evaluate the safety and efficacy.
`
`7.
`
`Patients having breakthrough cancer pain began to experience statistically
`
`significant pain relief as early as 5 minutes after dosing. This is consistent with notion that
`
`the claimed dose needs to have a meaningful blood concentration at about 5 minutes. See
`
`SUBSYS® package insert (Figure 1
`
`in Section 12.3) (Exhibit 1) and the Final Study Report
`
`(See efficiency results and conclusion) (Exhibit 2).
`
`8.
`
`No marketed, competitive fentanyl product has been able to show statistically
`
`significant pain relief any earlier than 10 minutes. See Exhibit B and Exhibits 3-7.
`
`9.
`
`These publications, Exhibits 1-7 described above, demonstrate that
`
`the
`
`presently claimed unit dose provides effective pain relief at significantly faster times than
`
`placebo or competitive fentanyl products.
`
`10.
`
`Accordingly, the presently claimed unit dose provides efficacious pain relief at
`
`significantly faster times
`
`relative to other
`
`transmucosal
`
`immediate release fentanyl
`
`formulations, which is both unexpected and, more importantly, a distinct clinical benefit.
`
`Page 2 of 3
`
`

`
`Declaration of Larry Dlilaha
`Serial No. 11/698,739
`
`I hereby declare that all statements made herein of my own knowledge are true and
`
`that all ‘statements made on information and belief are believed to be true; and that these
`
`statements were made with the knowledge that willful false statements and the -like so made
`are punishable by fine or imprisonment, or both. under Section 1001 of Title 18 of the
`
`United States Code, and that such willful false statements may jeopardize the validity of the
`
`application or any patent issuing thereon.
`
`Signed:
`
`’ Z0’ 2’
`
`Dated:
`
`/‘
`
`Page 3 of 3
`
`

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`
`EXHIBIT 2
`
`

`
`Sponsor: ENSYS Therapeutics, inc.
`
`1. TETLE PAGE
`
`TITLE
`
`FINAL STUEEY .ES?;E}’{)’E~’;"E‘
`
`A Randomized, D0ub1e—B1in<:i, Piacebe-Corrtreiled,
`Muiti«Cerrter Study to Evaiuate the Safety and Efficaey
`0fPen“ranyE Sublinguai Spray (Fentanyl SL Spray} for
`the Tr'e-atrnerrt of Breakthrough Cancer Pain.
`
`STUQY mjsmm‘ wrrgerz)
`
`3“
`
`PRGIQCQL NUMBER
`
`5N3~05"001
`
`}:,R‘Li(; pgggycrf
`
`Fentaray} sublinguai spray {Femanyi SI. Spray)
`Active ingredient: Fenianyi base
`Uni‘; strengths: E 005 200, 400, 690, and 800 pg fentanyi
`per aeruatiun (unit dcrse spray device)
`Administered dose strengths: 100, 200, 4%, 603, 800,
`1200 (2x6G0), and 1600 (2x8{)0) gig fentanyi
`
`DRUG SUBS'i"‘ANCE
`
`F©“‘?3“§v" him
`
`INBECA-“QN
`
`Breakthrough cancer pain
`
`SPQNSQR
`
`PRENCEPAL
`1N\jV'ES*'§'*{GA'}f{)R
`
`MEEBICAL 13/E(}NEri~fl:R
`
`Ensys Therapeutics, Inc.
`1022{} S. 5 Est Street, Suite 2
`?h0enix AZ 85044
`A.Eis‘L ofrhe iexieetigators _inve.i\/ed in this etudy, aioeg
`with eimreal site rnierrrratrora, IS meiuded m Appendix
`16.3 .4.
`N§€lLrt‘iCiO .€.’Ia1ere;‘,-, NH)
`Cimrmetrres Research Inc.
`
`STUDY DAT
`
`initiation (First subject enrolled)
`
`18 October 208’?
`
`Compietion (Database leek)
`
`22 February 2010
`
`REPQRT DATE
`
`(33 December 2010 (Version 3.9)
`
`This study was conziuctecii under Good Ciinicai Practice according to the Declarariora of
`Hefisinki (2004).
`
`§§
`
`§
`§
`§
`§
`
`
`
`

`
`Sponsor: ENSYS Therapeutics, inc.
`.....
`,......,.........u“...................w...s..,,......
`.._..,s«««s\.\......................................................................_\....._ ..........“........_......
`P tocolhiumberz Ei\iS—O -091
`
`2. $YNOPSiS
`...
`
`Fcrttanyi suhifira-Fmai spray (Fentzanyi Si, Spray)
`
`
`
`
`._...______,__‘
`..
`E..
`E...
`I...
`
`irisys Thcr'apcu1ics_, Eric.
`
`
`4,,,,,,,,,..
`Name <.~i‘Active
`ingredient
`
`:
`
`.
`
`
`
`: Active ingredient. Fcntzanyl base
`
`Unit strcnggthsz 16%), 200, 4i)i), €300, and 800 pg femanyi per zactuaticm (unit. G036 spray
`device)
`
`Administcrcd dc-sa-3 strengths: 10%, 209, 400, 600, 890, 129-3 (2x(>(§i)), and }6():‘)
`(2.\;3GO) gig; fcrttanyi
`
`
`‘ Indication (phase)
`B.rcaal<;tiu‘ough cancer pain (P‘has:s: I} E)
`
`
`Titie t)f'5§£%I(}}'
`
`E
`
`n.........»..»»_»....»....»»»»....
`.
`....---»‘“....‘§
`A Rzmdc-mized, [)ouhies~i31ir1d, I-‘Eaccbo—C0m‘:ro1Eed, Muiti~Cez3ter Study to Evzziume the
`Safety and }3:ff1c:3cy of Fcrrtanyi Subiinguai Spray (Fcntanyl SL Spray) for the Treatment
`
`0i’B1'eaE<i:hr‘(r-ugh (lancer Pain.
`............................__...._................5....................“.....1‘
`.................r,.........\;.
`
`
`P‘ui>Iic.2zi:im:s
`
`
`
`:E1.:
`
`Nssaatx tn :5
`REPORT PARTICULARS
`::1
`5
`3
`
`93 December 2614‘; (Version 3.0)
`Ifiergrryriz mite
` ..4,,.,,,...
`
`
`
`;;2222 £W
`
`
`
`.,..
`
`E..
`§
`
`g
`
`‘
`
`I.
`
`
`
`Fcriraii rtfsttsxiy
`i~ 13 October 2007 (first subject ctaroiicd) to 2?. 1~‘cbrL:ar_y 20 1 {.3 -(database Bock)
`
`
`
`
`
`:5.r......:1
`
`.
`
`
`
`Sést:s)s1(§;1r'_s' {)3;§egst:ives 3 Es/aiuatc the satay of Fczataziyi SL. Spray in these opicid—tcicra11t suhj ccts.
`Ah athiiiizmzii 0bjc<:iivc was to assess trcatihcitt satisfzicticra with meciiczati-:)t:.
`'H0i}’¢3!..-{R}V
`
`Study Design
`
`
`
`This was 2 Phase iii randomizicd, d0ub}c~biind, p1ac:':bovc<an‘tr0iEcd rriulmcentcr study of
`the ciinicai 1'esg>c-use to Fcrziarayi SL Spray as 2: treatntcnt for breakthrough cancer pain.
`Subjects wars to be cvaiuatcii at Screening Visit for the use and rcsponss-3 to opioid. .n
`the previous 24 hours. The Scrccnirxg Visit. was to occur 28 +7 days prior to the Upcn~
`labs! Tifrzaticra Visit.
`
`. Apprcximatciy [30 subjects who expericrxccd -one to foair brcealtthrcaxgh caimcr pain
`:‘
`:':pis:0des each day and who were receiving a stabic
`afschedulcd 24-hour opioids to
`
`_
`
`Inzmagcbaselinepainweretohecntcrzsdintoeatitmgticmpcric:--j"for:3.maxirmsmofili (+5)
`
`days to esiahiisii the cptimai dc:-sc csfiicntztnyl SL Spray required to effectively treat their
`brcahthrsniagh cancer pain. Subj ccts who established an opiimai dose of Fctitanyl SL
`blinds, piacebo—ccnt.ro§E€d pcrica-;i of
`Spray were to be entered into the rzmdcsrriized, double-
`
`
`
`\/ersécn 3.0
`
`CONFEDENTRAL
`
`Version Date: 03 December 2010
`
`: A Eist cfthe iilvcstigaicrrs involved in this study, slang with chnicai site irafcrmaiti-11:2,
`Priracipzsi
`
`
`included in fixpperdix 151.4.
`Im/estigatcr
`ii
`ti}8J.i+:¥;:‘}E‘§‘\<’It«:vEs‘
`
`
`
`,...,
`5.....
`‘Primary Objective
`Assess the citrcacy ofFcntanyi SI. Srsray for {ha treatment of breakthrough cancer‘ pain
`r
`in opioid~t0Ecrant subjects.
`
`
`Er.
`.5
`
`
`

`
`3.
`
`l5....S.............l
`
`I\
`ll.
`
`l
`
`1
`
`Sponsor: ENSYS Therapeutics, inc.
`Protocol Number:
`lNS—G5-001
`
`,_
`
` oftlie selected Fentsinyl SL Spray dose eoinpared to placebo treatment in rnnri .gement of
`
`breakthroiiglt cancer pain. ln the douliledalind period, subjects were to treat ll} episodes
`of l’)}‘(3fils'Z[l1l"CJ-Elgll oarzeer pain using
`blinded study ll}:3(ll.'.'-Ei‘lZl€)‘.’l
`consisting of seven
`Fentanyl SL Spray and three placebo doses placed
`random order. Subjects were to
`complete the pain assessrrients (Pain intensity and Pain Relief) from baseline small 60
`minutes alter dosing and a :~:nl:ije<:l”s Global Evaluation of Study Medication at 30
`minutes and 60 rninutes after eac-li dose of study medication. Subjects were to return for
`9. Final Visit
`+5 days after beginning the doul>le—l>lin<l neriod or within 7 (lays of
`completing 10 double--lallnd treatnienis, wliieliever use-.n'red
`Any subject witlidrawn
`fiom the study was to return for an Early Terniinzttion Visit,
`
`5
`
`
`
`throughout the double—blind period by inc-nitoring laboratory
`Satety was
`changes, Vl“{EEl signs, physical examination elizanges and adverse events. An zieicliti-one! 3{)—
`day safety F'ollow—up Period was to occur after the final Visit.
`
`
`Trezatrraents
`
`.._..,,,......,,.,.,..,................¢........................
`
`In tlie titratic-n perlocl, sulijeets were to begin at the ifill pg dose of Feritanyl SI, Spray
`and their titrate upward until there was sufficient; pain relies" with tolerable side ei‘l‘e<:ts
`established for i:re;>.ling two consecutive episodes ofl3real<.tliro‘ugh cancer pain at the
`same dose level. Fenian)/l Si, Sgsray dose strengths of lilti, 20!), 400, 600, 300, 1290
`(2x6{.lG), and 1600 -(2";x8QiJ_‘; gig were available in the ‘titration §)€‘.1“l()Cl 12:-rlile subject so
`establish 3 dose of}7eii.t2any'l SL Spray that effer:.ti\«'ely treated lareaktlirougli eaneer pain,
`'l‘lie
`ofl"'entanyl SL Spray that successfully treated lsreeldlirougli pain was then to
`he used in the donb‘ie—l3liri<l period. Subjects were to complete it} double~l>lirzd treatmerits
`within the 21 +5 day doulileinliiid periocl. l*‘enianyl was administered as 3 stiblingueil
`spray.
`
`
`l..l
`
`lll
`
`5
`
`r.’\_.
`
`:’;’c’£’/
`
`
`
`
`
`Treatment Duration
`
`Study Drug
`
`days (tiarzition period and
`The planned treatment duration rnay liave been no to
`douhls3—blind period). Subjects may have been enrolled in the study for up to 122 days, as
`lbllows:
`
`Screening Visit to Opemlabel Titration Visit ~ 35 days
`: Titration Period - 26 days (2l +5)
`Dnizablevhlind Period -~ 236 days (21 +5}
`
`+7)
`
`‘<20 5).
`
`Fentanyl subiirignal spray (Fentzinyl Sal. Sprzayj. The reference treatment was a placebo
`aclininistered as 3 suhlingual spray. Foiitaiiyl SL Sprsty dose s:trengi.lr:s of 130, 230, 40-3,
`600, 800. l2‘.-$0 (2xt'§00), and l<‘~Eil(l (iZ.x8(l€)')
`ttg were provided for the titration and dou‘:::le«
`lallncl periods.
`
`Batch Numbers
`
`(xi-2
`Tlie overall batclt number for the clinical pnokagiiig for all efficacy supply was 7:;
`.~,
`
`i:
`.-
`I1.
`
`Sg>.r21§,' used in this study were: Tit)?’ lti-1 (fl =30 ngf),
`{N The batch nuiribers for the Fentanyl
`706(l-49 (‘.200
`706{l5(l (-'l(l€) pg), 706051 {son pg), 705052 (see gig), 705051
`(lfitlti rig, dosed as 2x600 pg}. 706052 and ‘7'(l9r‘i7'7 (_lt’3O=I) gig, dosed as 2x8-(>0 gig).
`The batch E3uE3”.tl3€:1“ For Elie })l£iC€:l3O spray used in this study was 7fio£=46-.
`SUBJECT rornmrron
`
`l Apprct-ximately l3O opioid-tolerant subjects were to he enroiled in the titratiori period of
`the study. it was expected that at least 92 of these sul>_]eets would proceed to the double
`lslind period.
`
`Eénliject: were to have a. documented clinical diagnosis ofearicer with :1 controlled level of i
`beelcgrouncl pain requiring
`stable dose ofsclicduled baseline opioid treatment afar least
`{£0 trig,/clay of rriorpliine, 25 rig/hr ofl.r;3ris<lemi2ail fentanyl, or an equianalgesis: dose of
`ainotlier opioid. The medication for relief ofhreal«;througli pain was to be equivalent to 2:5
`ms
`
`5
`
`
`
`Number Planned
`
`5 Major Inclusion
`Criteria
`
`
`‘
`
`’i}E}§i5}3{‘§i
`
`Version Date: 03 December 2010
`
`

`
`Spenser: ENSYS Therapeutics, inc.
`
`Prolccol Number:
`iNS—05-O01
`
`
`‘~"“"““““"“”“““»”»m"””‘“‘\
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`1’»»‘“''‘““““““
`‘"‘‘~‘»»”""'‘‘“?‘‘‘‘‘““ .
`.
`4
`.
`0X}’C0i1OI1€,
`si§,'di‘s>c0cl<).r1e, or codeine with aceiaminoplieti). Ilse subject was E0 have El
`Sta:-le daily pattern averaging one to 4 lC?!'€Eil~;Eh1‘O'.3gl1 pain episodes during; the 4 day
`
`‘ Screening F’ei‘i<>d,
`
`
`
`0 V Cu.rren‘t use ofcomznei'c.ia ly avzii. alcfe oral shm‘:-acting fentzmyi for b:‘eaktli1‘0ug?i2ii
`pain. Subjects»: previously on Aeti-Cf” O3‘ Ft‘-i1':‘.E)}‘£3® can be enrcalleii iflliey have had a
`day wsishoiit.
`
`
`
`
`
`Maj“. Exdushm
`, Criteria
`1
`
`4*
`
`is
`
`Rapidly iiicreasimg/iiric:s>tiir<)iled pain.
`
`Painful erytiiema, eecicma or ulcers. under the zotigzie,
`
`ASSESSMENTS
`
`
`§
`3
`
`‘
`
`
`
`
`
`Efficacy assessments performed at 5, ‘l0, 35, 30, 45 and 60 minutes after each ti-38$ of
`SEL‘.(‘iy medication iricludeci Pain l'r2ier1si‘ty (P?) and Pain Relief (PR). The Sui>ject’s Global
`5 Evaliiaticm of .‘§au(i_y Medication was ics be XE!3i(l£<) at 30 and 60 minutes after each dose of
`study medication. The prim;i.r_y efficacy endpoint ofthe study
`the Summeci Pain
`Intensity iilifierences (SPEC?) at 39 miY‘1lJl;:3E$ sifiei“ ziosing (SPlDg,g). Tlic secciiclaiy afficaey
`endpoints were ‘Total Pain }'{eliei‘{'l”O'i‘PAR) at 30 minutes :fTO'l"PAR33) after ciosiizg aria‘.
`Sul3j<:ci.’s Global Evaluation of Stiiiiy Meiiication, recorded at 30 minutes after dosing.
`The measurements; cii"l‘()TPAR and SPED were calcuiateai over l)lE€
`iii) rninutes ireatment
`period for each of the 10 doses of siiusiy rtie<lic-mien ilseci to treat breaktlireugh pain in tlie
`doulaie-blind ;.=eri<ae‘.
`
`w.
`A Treatment Satisfaction Qu:«:si‘i0n:iaire for lvledieatioi‘: (TSQM) was completed by
`
`‘
`illfiill‘ satisiact‘
`‘
`l‘ ‘
`'
`‘
`‘
`‘ 431'
`- lien.
`
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`for safety assessment. The effects of
`Adverse events (AE) were recor<i~e<l and 1‘€:‘«}3~Jl‘l€d
`i}‘CE'.i3Tlt‘I‘.'t was vital signs and clinical laboratory measiirerriems were
`i.il:'(3ugllUL1E
`the study. Safety was assessezi on the following criteria:
`
`E
`
`S.-afeiy
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`ABS/'Se.ri-:)iss .r’\-iversc £.i/ems (SAES) OCCUl”l'i1’lgli}fOEJgl)C)E1l£ the study
`l_.eil>orzsioi'y evaluations (serum cliemislry, lzetnamlogy, urln:1lysis;)
`Vital signs assessriicnts (blood gsressiire, heart; féiiiif, rcs_i).ii'a£im‘. rate and
`temperaiure)
`l‘~liys.ic2il exziminzaii-ms
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`S'I',A’I'iS'HCAL METHODS AND ANALYSIS
`
`
`Efficacy
`
`Analyses e>fel":fica<:y were based on the inicnbto-treat population defined as all
`3 randomized subjects who pmvided i'nf<n‘n':eei cciiseni, t-:x3l< siuciy medication semi head :31:
`least one pain rlieasairextiem: following adininistratiosi ofsiudy medication.
`
`The anzalysis of ilic primary endpoiiit, SPIEEQ, was mececled by a data redaicticm
`alga-ritlmi. Within each sii‘:i_ieci., SE-‘,lli);., was summarized over brealgthmu pain
`epissades treated with Fcntamrl SL Spray and (?‘./(?-l‘ episocles treaiezi witli placebo. Tile
`diffcrelice wliihin siiiajetzl. Uftlie two S1-‘ID_:.;;. summaries was then calculated. Aciditioiialiy,
`: wilhin eaicli subject the mean baseline pain intensity was calciiiaied over‘ all brealctlirougir
`pain episodes tteateil with stiicly me<iic:i.i:is)ri =fregar<Eless 0l'tree:ime1ii.‘)i Wiihims 1.Ei)jé3Cl
`
`differences
`SPlD3g were then analyzed using analysis of cg
`ialice (ANCOVA)
`using the \«‘Jiil}lE)~1Sul3j€S3i mean baeeline pain inieiisilty as
`(:0v2a1‘ia‘te.
`
`Tlie secoiiilaijx endpoints 0fT0TPAR30 and Subject Gk:-iaal Evziliiatieii 0fSludy
`f Medicatioai, remrdeii £51.30 mimitezs p0st~<i<>se, were analyzed in a Similar manner. ‘The
`, overall type 1 errei rate for the primary and s;ecr.>ii;ia:"y analyses
`set at (3.05. The p-
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`
`Version Date: 03 Deceriibe: 2010
`
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`;;
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`

`
`Sponsor: lNSYS Therapeutics, lnc.
`Protocol Number:
`iNS—G5-O01
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`»’
`
`
`
`to be considered signi
`primary endpoint was deteraninesi Es‘) be signiiiczint.
`
`
`
`As a sexxsitivitly analysis. the witliir:-subject siirarrriaries ofttealrtietil el’=."et:t were anarlyzetl
`using the Wileexoii signecl rank test. As additi-en-at sensitivity’ analyses, the
`measurements of Pi, Pain intensity Dii‘ference (FED). and SPID were analyzed using 23
`siirgie mixed mmlel in which PI was the dependent varied:-ie. Inference on Pl D and SP1!)
`at all time points, iirelncllrig the 30 minute pl”l1‘fl3.!‘_‘y’
`point, was performed within this
`model, as these. measures are linear e-;>mblna=Lioris of?! at various time points. The fixed
`effects of the rriexlefi were treatment. time, and treatmenmimc irii‘erac£i<m. The rzmclem
`effects were subject and ‘r.=r'ea}xL‘hi'(:-iigli pain episode within subject, and the rnritiorri error
`.
`associated with time gierioci within episode.
`
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`
`Safety
`
`
`
`Demegraphics
`
`= Safety analyses zfliclverse events, labs, and vital signs} were pei'f0rined on the safety
`popuiaati-an, <iefinea‘ as all randosnized subjects Witt) tool«;. at least one close 0l’stu(‘Ey (ling.
`Descriptive statistics were presemetl for denmgrapliics, baseline characteristics,
`siittirtrzny of lziborzitory paraineters. vital sietis anti physicrzai examinations.
`..................... _@_w‘.\\\.\\___ ;
`STUIEY PGPULATION RESULTS
`
`
`
`
`i E213 years (range from 24 to 85 years), with .
`'1'itrs3'tien pespiilation: mean age was
`77% 0f.su‘0ject‘s <65 years of age and 95% of subjects <75 years of age. 53% ofsiibjects
`were femziie and 9E% ol"sLibjeL.ts were Wiraite.
`
`P E3
`3'
`R
`3
`Y
`0 uiatimi: mean age was 54.1 -‘L 11.7 ‘ears ‘ran e from 24 to 85 'ears_. with 83%
`El“?
`of sulijeets <65 years ofage
`97% subjects <75 yearrs of
`54% of subjects were
`femaie and 9 i% of su'ejee-ts were Whitie.
`
`
` A total of l subj sets were
`
`the titration period oftiie study, and
`comprised the safety population. Of these, 93 si3l_vje<:ts (,7S%,‘- were rsmclcirriizecl to the
`deulfle--biiritl period oftiie study. A total 0f35 subjects (27%) in the sefet, popuizitiori
`withdrew from tlie study early, with tile most cumin-an reasc-ns for termination being
`. vciluntary withdrawal (lti subjects or 'i2%) and AB}; ('7 siibjecis or 5%). Cc:-nsicieting only
`i those sulajeets; remci-:>mi;:.ed to the d0ub1e~l:lind period ofthe study, 3 subjects (3%)
`- terminated the study early (cme siitijeci withdrew due to each of an Alli, E3-7)E3-&)Ompliéil’‘t(C€
`‘ arid velntil.ary withdrawal}. There were 95 sulojects (73% ofthe safety poptilation) who
`completed the double~l3iiridl §>ei‘ie>d, and 9-3 subjects (69%) reiletl (t-‘./Eff’ to the safety
`peitioir (if the slutty. Ti3e:'e were 7‘) subjects ((31%) who completed E0 doses ofstiidy
`
`‘
`_<{_ according to he pretoeoi.
`EFFECACY RESULTS
`
`
`
`l he primary e mieacy encipoint for this study was the ev;1liiatl<:-ii of SP1?) Higher SPID
`values indicate imriroveirients in pain intensity’. SPIDH, was signil’ies3nliy improved
`(p<(i.0{it)‘-.) when bre2ii~.tbrei1gb pain episodes were treated with Feiitanyi SL Spi‘-ay
`C(>l‘.’l§)‘.1t”€:d
`to gr-lacelx). Mean (i SD) $33030 scores were 640.3 i 458.8 Ear Fentzmyl Si,
`Spray and 399.6 : 391
`for placebo, with a tiiffereriee <>f240.7 zi: 3ti2.9 between the two
`
`£ treatineirts.SPEDvaluesatalltimepointsweresignificantlyiinprovetiwhenpainwas
`
`treated with Fentanyl SL Spray eoinpared with pl;9.ce'i)c.=. ‘Tin: [)!‘€)§?i)rfiOtl nfsnhjects with
`improved SPED values when trcal<-.<l with Fentanyi SL Spray rssngetl from 60% at S}’l,{),~
`t0
`at
`
`One oi'tw<.= sccerxclary ififfiél‘ cy enzlpoitats for this stiady was the evzeiisatien of 'l"()'l‘}‘Ajl{30.
`. Higher 'l‘O'i‘P/KR vaiues indicate an iinproveinent in total pain relief. For TOTPAE-:;-5
`, TOTPAR was significantly ianprnveci (p<:l).€}0€}l) when 'i>re:akl.iir0ugh pain epistides ‘.‘’€E‘<":
`: treated with l<‘ei1lanj,ri SL Spray compared to piaeebo. Mean ti SD) 'i‘0’l‘PAR;,9 SE3-E)!‘-£35
`were 78.3 :t' 20.4 for‘ Feirtanyl SL Spray and 61.0 :t: 26.8 Fm‘ pi-aeelio, with :1 difference
`127.3 :i: 19.5 between the two tre22l.meiats. 'l‘l".e p—\/alue for '){’{f§'}"F,~°iR3o W5154 33d.l‘~i5%5-*3<i
`'3)?
`
`
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`5
`
`
`
`CONHDENTEAL
`
`VS-’SiO-"i Dali? 03
`
`Subject Disposition
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`Sponsor: JNSYS Therapeutics, inc,
`Protocoi_N'
`bet:
`INS-_O5-001
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`e proportion of subjects withi I U PPAR when treated
`l
`(p'<0.-Wt": E).
`with i<‘entany1 Si, Spray ran from 60% at TOTPAR5 to 84% at ",l‘{f}'i‘I’/ltit_i;0.
`
`
`
`
`
`Subject G-kt-hal ii~]1\ia.‘itaation of Study Medication at 30 minutes was the second seeontlary
`ei"f'icacy endpoint. Higher subject glohai evaiuation values indicate an iniproveinent in
`3 subject perceives the effectiveness of the study medication. At 3t= minutes 3:-0si~
`dose, the subject giohal evaiuzition was significantly irnproved (p<{.3.O€}0‘l) when
`breakthrough pain episodes were treated with Fehtartyl f~}3l_. Etpray compared to placebo.
`Mean -(E SD) subject giohai evaluation scores at 30 minutes were 2.9 Ba 0.8 for Fentanyi
`Si, Spray and 2.0 i (2.8 for niaceho, with a difference oi‘0.3 9: 9.9 between the two-
`treatments. The pr-value for subject global evaiuation scores at ‘;}f= rninutes was adjusted
`for rnuitipliciiy using Hochherg"s method. The adjusted pwaiue remained significant
`{p<'(l.f;l)--It ET)C
`
`Additional efficacy’ endpoints ineiuded TOTPAR at points other than 30 minutes
`poshaiose and giobai evaluation at £50 ntirtntes. "i’tI‘.I'l.‘PA_R, values at all time points were
`signiiiearitiy improved when pain was treated with Fentanyi S1, Spray compared with
`jnlaeeho. Subject giobai evaluation scores at 60 tnintttes were also significantly iniproved
`(_p<0.UO{) it when pain was treated with Fentariyl Si... Spray ernnpareci with nlaeebo.
`
`lnrgrovernents in pain assessments, tneasnred by pain intensity, pain intensity difi'erenee
`and pain reiief, were observed as early as minutes for iientanyl ${.4 Spray on each
`measure, and were durabie through to 60 minutes.
`
`The use oi“ rescue inedication within 60 minutes of treatrncnt was signiiicztntly love
`when pain was treated with i<‘entanyi SL Spray than with piaceho (;)<O.t)(30i). Rescue
`rnedietatioii was required for if;% of episodes treated with Fentanyl SL Spray and for
`23°‘é: of episodes treated with placebo. Conwcrsely, 90% of iCtE‘(fEElt;il11-":‘)t!_gi‘1 pain episodes
`treated with Fenian}/l SL Sr:-ray did not require the use otrescne medication. Within each
`episode, the time to rescue medication usage was cornpttred between treatments using a
`Cox Proportional Hayzards rnodeli accounting for the clustering ofinnltiple episodes with
`subject. The hazard ratio of 0.33 L95‘?/u Ci 0,24, 0.45) indicates there was approxiniately a
`67% reduction i ti the iikeiihood of using rescue pain inedication during treatment of
`...,
`breakthrough cancer pain with Fentanyi Si... 531 tray compared with pl ::ebo_ This ii ding
`was statistieaiiy sigitifiearti ti <('.=.(tt)(}i ).
`
`The 'l";‘:§Qivi was completed at the beginning ofthe titration period (baseline) and at the
`end ofthe titration period (Visit 1 ofthc dcnhie~biind period). Tie TSQl‘s~i domain scores
`For Eiifectiveness, Side Effects, Com/enience, and Overall Sa‘tisfac‘tion
`0 to
`liiii. with higher scores indiczztting greater treatment satisfaction. For each domain, scores
`were higher at the end ofthe titration period as cornparcd to the beginning of the period.
`The greatestdii'i'ei‘ei1ce was seen in the Effectiveriess domain. }i!'t’t§)t‘-:)Vi9rt3t‘:t‘:iS an the end
`of the titration period were also observed for each cfthe individual TSQM questions. At
`
`the end oi‘ the period, 89% ofstihjects were satisfied, very satisfied or e.\;tremcly
`with this medication, ecintaared with 41% otsubjects at haseiine. Sirniiarly, 90% of
`subjects at the end o i‘ the period were at least satisfied with the amount of time it took the
`irtedieaticin to start working, compared with 21% ofsnhjeets at haseiirie, C-zxnparabie
`increases in satisfaction were also seen for the other questions, ineiuding syrnptorn relief,
`coniiders-.;e
`the medication, and convenience ofuse.
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`There were significant Sl‘l.i)3g si:l7_iec‘t—.s;:-ecific treatment differences {ail p-vaiues
`.‘SU.0t}17) for the
`{<65 and 265 years), gender, type oi"‘ar<antni—tlievcioc3-<. pain
`medication
`type oi’ prior breakthrough pain rnedicatinn used and successful dose of
`Fentaityi SL Spray subgroups.
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`
`
`SAFETY RESULTS
`
`Ali Adverse Events
`
`‘ The s ety population consisted of 130 subjects. At least i AE was reported for 78
`i subiccts {6{’:%) in the titratiort peri-zxi and for 47 suhiects €43"/&:_‘,=
`in the doubie-biiri
`“........,....................._,..,....._..._.....____._....._.......,e..
`
`
`Version 3.0
`
`CONFEDENHAL
`
`Version Date: 03 December .2010
`
`: ;
`
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`Sponsor: ENSYS Therapeutics, inc,
`Pretccoi Number: ENS-O5~OO’a
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`srgem class
`period. During the titr tier: period, the most frequently-reported syste
`(SOC) was gasi‘rcihtesi.ihai disorders, for which AES were reported for 36 subjects
`28%). The most frequeutiy—reperte<i AF, was nausea, which was reperted for 17 suhjects
`{13%). Other frequentiy-reported AES included somncierice if i 1 subjects or 9%},
`riizcrirress and vomiting (each repc-rted by ii) sishjects or 3%) and pyrexia ( 3 subjects or
`6‘?/4:). Severe AEs were experienced by 10 subjects (8%) in the titration period. Most
`subjects experienced events asses:se<i its at least possihiy reiated re ‘study drug (51
`suhject:s or 39%). By category‘, 33 subjects (25%) experienced Ailis that were proharhiy
`rehated to study dr'u3_3;, and 1?} suhjerzas {ii %) experienced
`that were pessihiy related.
`
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`
`During the double-hiind period. the most frergiieriti)/-reported SUE was gastrointestinal
`disorders‘ for which [7 suhjects (1795) reported an AB. The mast fi'equehtiy~i'e})oi'ted AF.
`was nausea, which was reported in 7 suiijects er 7‘?/o. Otiaer frequentiydeported
`included hyrierhidrcsis arid oedema peripheral (each reported in 5 subjects or 5%), and
`vornitiri_a, (4 subjects 014%). Severe Aiis were experienced by 5 subjects (5%) in the
`douhie-hiinci pericrir Mes: subjects experienced events assessed as net reiaied to study
`drug (38 subjects or 39%). By cziregciy, 2 subjects (2?/3) experienced AEs that were
`prohshiy reiated to study drug, and 7 subjects cf"/"’/'.'n.j: experienced ABS that were possibly
`related.
`
`
`
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`““— “-“
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`h 1SO(i€S of breekthicu h air: are centrncn er:
`atxents with chronic
`in due to cane
`. Brealrr irouch cancer rash
`3
`
`
`p
`i
`5:»
`;
`is gerieraiiy characteri;z.e<i by 2: rapid onset and a shert duratiorr (up to two hours). Giver: that pa tienis may
`'1 experience severai of these eraisodes en a daily basis, an effective treatment with a rapid onset ofactioit wouid
`: ferrn a significant eempenent efthe overall pain ntanag;erne'rii r'cgirnen. iieiitzahyl
`ii narcciiirr. 2 rraigesic
`in
`, reiieve pain. Feiitarryl Si... Spray is foririulai.eri to deliver ferrtariyi to the oral rruicosa cancer jziatientsi eff-2i'iiig a
`ceriveniem method of deiivery for patients who might o=;herwise have -:iifa"rculiy in adminisi:erin,g erai rnedicaiicris.
`
`A composite suirnrrary <:-f/REIS associated with study drug use or mode of adiriiriistraticn
`W’
`tabulated. There were 33 subjects (2.3%) and 6 suhjec:ts (6%) in the tiirati-:)n and
`-’.iOl1bi3—i?liE}Ci periods, respectively, who experienced an AB related to study drug use.
`Meet of these Aiis occurred in the higher dose groups (3 Gilt)
`fehtartyl). There were 5
`subjects (4%) in the iiEI‘2iiIi£)Kl period who experienced an AB reiated to study drug mode
`of atirninistraticn; no subjects in the douhEe—hiii1(i
`exgieriehc-ed any cfthese AEs,
`
`Three deaths were reccrci-ed in this study, each of which ‘Ném assessed as unrelated tr.-
`study drug. in each czrser the suhject’s death was related to the progression ofthe
`" unde '
`‘rig disease ofcancer. A sirriiiar frequency of.‘*}i.~'\;Es was observed during both
`periods, with 7 subjects (5%) and 6 subjects (6%) reporting SAES in the titration and
`dcuhie—hEihd ericds. res aective! '. in the titration eriod. 5 suhiects 4%" ex ‘rifilihcfiii
`V
`/
`3'
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`,7
`severe SAE.s and 2 subjects (2%) experienced moderate 3s‘A.Es. ln the riciuhle-hirrci period,
`~
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`3 3 subjects (1%) experienced each at moderate and severe SAEs. Ail SAEs were assessed
`5
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`Deaths and Other‘
`Serious Adverse
`Events
`
`1
`3
`
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`
`w
`
`g inthisstudy,subjectstreatedepisodes
`
`breakthroughcancerpaineitherwithFentan)/iSI.
`
`spray. Various pain assessmerits, irrciudihg pain intensity and pain relief, were performed at time points from 5 re
`60 minutes post adruinistrnti-:>n dfsuidy drug. Patients taking Feritanyi SL Spray tc treat breakthrough cancer pain
`'heg2an to experience statistically significant pair: relief as eariy as 5 minutes feilowirig dosirag. “he siggnificarit
`effect ofFehtarryi Si. Spray was ciurahie through 60 minutes, the inst evaiuaticn time point.
`
`'ayoraplacebo
`
`Spray signiiicaritiy reduced breakthrough cancer pain hased on the primary efficacy entipoiht ct"
`5 iientzmyi
`: SPID3¢,, and at every other SPID time point. These resuits were corisisaeht with those obtained ‘or other pain
`evahsationsc including total
`relief and a subject gichai evaiuatieri. At each time point for each pain assessrnerit,
`the effect cfFentar1yi SI, Spray at reiieving i>reai<through cancer pain was signii‘ir:arrtly greaaer than that (1-f!.l’1£')
`placehe spray.
`
`asscsscd with the TSQM, adrninistered at the