Integrated Phase III Clinical Trials of Low-Concentration, Modified
`Bromfenac
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`Ophthalmic Solution Dosed Once Daily for Cataract
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`J.A. Gow,1 D.F. Goldberg} J.H. Peace,3 T.R. Walters,“ J.P. Gira,5 S.M. KIier,1 T.R. McNa
`for the Low Concentration Bromfenac Ophthalmic Solution Once Daily Study Group
`1Bausch & Lomb Inc, Irvine, CA; 3Wo|stan Eye Associates, Torrance, CA; -‘United Medical Research Institute, Inglewood, CA; *"lexan Eye, Austin, TX; Sophthalmology Consultants, Ltd, St. Louis, MO
`
`Contact iriforriiation:
`Tizr M.
`Ddlls
`
`mi ..
`Baum-h :« Lomb, lric
`53 TEL
`l"f7‘)lQgy Drive
`Irvine», CA ~3‘r>1‘-a
`‘ 788-4383
`
` 0 Phase 3, placebo—control|ecl,
`
`randomized, double-masked, multi-
`
`center study
`0 440 subjecls randomized (222 in the brornfenac group, 218 in the
`placebo group)at 39 clinical sites
`'5 Eligible subjects were scheduled for a unilateral cataract surgery
`(phacoemulsification or extracapsular) with PCIOL implantation
`
`V
`.
`'§¢:reenirtg Phase: Days as to -1’
`
`‘ Sub ects'w,erje‘as'si,gne:d to‘, receive[ei\he} ljromfenac sodium
`‘ ophthalmic solution or placebo c1osedQD '
`‘
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`. Subjects must have met inclusion andexclusion criteria to be
`,
`eligible for <:lini<:al,li’ial
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`Primary efficacy endpoint was clearance of ocular ;
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`inflammationfsummed Ocular Inflammation Score (sols) = .
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`4 Secondary efficacy endpoint-was proportion of subjects pain-
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`Treatment Phase: Day -1 to Day 15
`~ Subjects began dosing on Day -1 (~ 24 hours before surgery)
`subjects returned to the office on Day 1 for evaluation of safety
`and efficacy
`~Sr.il:rjects returned to the office on Day 311 for evaluation of
`safety and efficacy
`-Subjects returned to the office on Day 81:1 for evaluation of
`safety and efficacy
`-Discontinued test agent on day 14 and subjects returned to the
`office on Day 15:l:1 for evaluation of safety and efficacy
`
`
`
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`
`
`Follow—up Phase: Day 22+3 or 7+3 Days After Final Dose
`» Subjects returned to the office an Day mm or 7+3 days after
`discontinuation of test agent for termination evaluation
`
`
`
`Mean
`Early Discoritirurations
`
`91.l21‘l/o
`
`75.98 In
`
`
`
`34 (153%)
`Subjects who discontinuedtest agent early
`
`Due to lack of efficacy
`7 (3.2%)
`
`
`1 *1/c Compliance, : 1031‘ >< riurrzber of Gases‘ is-caved X 1+3
`
`96 (440%)
`52 (23.9%)
`
`Bramfenac
`(tr = 2 12)
`
`Adverse Brent Subjects reporting an AE affeciing
`
`14 (66%)
`the study eye or both eyes
`6 (2.8%)
`Eye Pain
`5 (2.4%)
`Anterior chamber inflammation
`2 (0.9%)
`conjunctiva] hyperemia
`1 (0.5%)
`Photophobia
`1 (0.5%)
`Corneal edema
`1 (0.5%)
`Lacrimation increased
`0
`Foreign body sensation
`O
`Ocular hyperemia
`
`'4 The incidence of CME/ME was 0.5% (1/212) in the bmrnfenac
`group compared with 2.0% (4/204) in the placebo group.
`
`43 (2110/°)
`16 (7.8%)
`11 (5.4%)
`8 (3.9%)
`8 (3.9%)
`5 (2.5%)
`S (2.5%)
`5 (25%)
`4 (2.0%)
`
`l
`..-m..WsW._c......c.u ....J
`
`lowmncentration, modified bromfenac solution dosed QDl
`is safe and effective to treat the inflammation and pain
`associated with cataract surgery.
`
`
`
`
`w-Bromi‘enac
`, ~'Pla'cVe7bVo
`
`
`
`%ofSubjectswithS015:-0
`
`" P < 0.0001
`Day 15
`
`
`
`,................u....u.........................Mean
`
`SO15score
`
`
`
`—-s-Brornfenac
`
`Placebo
`
`Day 1
`
`Day 3
`
`Day 8
`
`* P < 0.0001
`Day 15
`
` ’.r‘~;;;9s:.§.>-:1 To evaluale the efficacy and safety of low-concentration,
`modified bromfenac solution dosed QD for cataract surgery.
` fr-'1
`~. Subjects received either bromfenac (n=222) or placebo
`(n— 18} QD. Dosing began 1 day before cataract surgery and
`continued daily through posbsurgery Day
`14. Primary efficacy
`endpoint was no ocular inflammation by Day 15; secondary efficacy
`endpoint was no ocular pain at Day 1
`to placebo for primary and
`$1:+,oi::::-- Brornfenac was
`superior
`secondary efficacy endpoints (P<0.0001). Compared to placebo,
`bromfenac
`had
`a
`lower
`incidence
`of ocular adverse
`events
`(P: 00m).
`.c--2:-tn)‘. Low-concentration, modified bromfenac solution dosed
`QD is safe and effective to treat the inflammation and pain associated
`with cataract surgery.
`
` sir " 1.5-.':?.§() '2:
`
`'1 Bromfenac is a non-steroidal anti inflammatory drug (NSAID) with
`an extensive history of clinicl efficacy;
`it acts by blocking
`prostaglandin synthesis by inhi
`ting cyclooxygenase 1 and 2 in
`the arachidonic acid pathway 1
`r» The bromine moiety in bromfenac enhances lipophilicity and
`facilitates penetration throughout ocular tissues 3'3
`'- Bronuck® (bromfenac sodium ophthalmic solution) 0.1% was
`initially approved in Japan in July 2000 and was subsequently
`approved for the treatment of blepharitis, conjunctivitis, scleritis
`(including episcleritis) and post-operative inflammation“
`'- Xibromw (lziromfenac ophthalmic solution) 0.09%, administered
`twice daily, was approved by the Food and Drug Administration
`(FDA) on March 24, 2005 for the treatment of patients with post-
`cataract ocular
`inflammation, and in January 2006 for
`the
`treatment of ocular pain following cataract surgery‘
`" Bromday” (bromfenac ophthalmic solution) 0.09% administered
`once daily, was approved by the FDA on October 16, 2010 for the
`treatment of postoperative inflammation and reduction of ocular
`pain in patients who have undergone cataract extraction‘
`'-r Based on extensive posbrnarketing experience and data from
`clinical trials, bromfenac ophthalmic solution has demonstrated a
`favorable safety profile
`0 The modified formulation of brornfenac facilitates
`intraocular
`penetration,
`thereby allowing a
`lower medication load while
`maintaining clinical efficacy with once daily dosing
`
` 0 To evaluate the efficacy and safety of low-concentration, modified
`bromfenac sodium ophthalmic solution dosed once daily for the
`treatment of ocular inflammation and ocular pain associated with
`cataract
`surgery in
`subjects who have undergone cataract
`extraction with posterior chamber intraocular lens implantation
`
`146 (67,095;
`
`Age (vears)
`Mean (so)
`Sex
`
`68.»1(10.7C«)
`
`1.4: (63.5C;
`
`so 5 is es)
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`n (package insert
`is, ca i3"A Ffiartriaceutizals, inc, 23:0
`MB, Tayxry i>
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`~—.a. mar 23, Liinbirc L Moimovrrs, et al «:4; Gncdinan and
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`"l\-jrmam ogioal Basis 0‘ Tlaerao-3 tics. ah ed. New York McC<aw-
`J Uwlar Wharmeool Tlwerapeusics
`nenaersm 61, oamr ‘L, Chanda cc etal
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`lonib inc, lrirrrie, (A. us: cioyees cftlausch a low. inc SH
`Goldberg, JH Peace, und an ‘Era are
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` 5 a former eincloye :fBei
`rants for Sacscr a Lone ir
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`
`
`Presented at the 2012 Annual Meeting of the hrmarican Academy of Ophthalmology, November 10-13, 2012, Chicago, IL
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`Page 1 of 1
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`SENJU EXHIBIT 2227
`LUPIN v. SENJU
`IPR2015-01099