Focus on Zero to Trace Anterior Chamber Inflammation
`
`
`
`
`J.A. Gow1, J.D. Boyce’, H.J. Reiser3, R. Berry4, J.T. Dao5, and S.P. ChandIer1
`for the Low Concentration Bromfenac Ophthalmic Solution Once Daily Study Group
`1Bausch & Lomb Inc., Irvine, CA, 2Orange County Ophthalmology Medical Group, Garden Grove, CA, 3Eye Care Specialists, Kingston, PA, “Eye Care Arkansas PA Little Rock, AR, 5Cornea Consultants of Arizona, Phoenix, AZ
`iii
`
` id Sub-
`
`’! Phase 3, placebo-controlled, randomized, double-masked. multi-
`center study
`" 440 subjects randomized (222 in the bromfenac group, 218 in the
`placebo group)at 39 clinical sites
`'1 Eligible subjects were scheduled for a unilateral cataract surgen/
`(phacoemulsification or extracapsular) with PCIOL implantation
`
`
`
`Screening Phase: Days -8 to v1
`Subjects were assigned to receive either bromfenac
`ophthalmic solution or placebo closed QD
`
`Subjects must have met inclusion and exclusion cri
`eli
`le for clinical trial
`
`Primary efficacy endpoint was clearance of ocular
`inflammation [summed Ocular Inflammation Score (5015) =
`U] lav day 15
`Secondary efficacy endpoint was proportion of subjects with
`trace inflammation (S018: 0-0.5)
`
`
`
`I; Treatment Phase: Day -1 to Day 15
`~Subjec|s began closing on Day -1 (~ 24 hours before surgery)
`~Subjec|s returned to the office on Day 1 for evaluation of
`safety and efficacy
`~Subjec|s returned to the offim on Day 3:l:1 for evaluation of
`safety and efficacy
`-Subjects returned to the office on Day 8:i: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
`
`
`
`Follow-up Phase: Day 22+3 or 7+3 Days After Final Dose
`~ Subjects returned to the office on Day 22+3 or 7+3 days after
`discontinuation of test agent for termination evaluation
`
`146 (67.0%)
`
`684(10 70)
`
`68 5 (9 68)
`
`Age (Vears)
`Mean ('sD)
`
`
`Tt: evaluate in a post—hoc analysis tl—e reduction of ocular irinammatiori
`trace anterior chambe~ inflammation of
`low—concentration, mocitied
`bromrenac ophthalmic solution dosed once daily compared to placebo rollowlng
`cataract surgery in 2 ntegrated clinical trials
`
`V
`:.: subiects undergoing unilateral cataract surgery (phacoemulsiricaticn or
`extiacapsulai cataiatt e><LidLLlUil) witii posteiioi ciiaiiibei
`IDL iiiiplaiitatioii weie
`randomized to ether low—concentration,
`rnodlfed bromfenac ophthalmic solution
`
`(n
`22) or placebo (n—218) once daily dosing began 1 day before cataract
`surgery, continued on the day of surgery, and through post—surgery Day 14 The
`proportion of subiects with trace anterior chamber
`inflammation, defined as a
`Surnrned Ocular Inflammation score (sols) of 0—0 5 (05 cells in the anterior
`chamber anc flare grade of 0:, was assessed a: Days 1, 3, 8, and 15 Safety was
`assessed by the incidence and treouency or ocular and systemic adverse events,
`and ophthalmological eya uations (visual acuity slit lamp examination,
`intraocular
`nressiire,
`and dilated tiinriiiscnnic examination)
`statistical
`signiticance was
`determined using a Fisher s exact test
`A e
`.-:t-;, In the intent—to—treat populat on, subiects had a mean age of 68 0 years,
`were predominantly Caucasian (74 8%), and included a higher percentage of
`female subiects (65 2%) Baseline charac:eristics were similar acrcss treatment
`groups
`A slgl')l:lr:al')tly higher proportion of siibiects
`achieved trace nciilar
`inflammation in the bromfenac group compared to placebo as early as Day 3
`(27 9% ys
`13 8%, p—00003), continued on Day 8 (55 4% ys
`24 3%, p <
`0 0001), and througn Day 15 (712% vs
`39 4%, p < 00001) Cornoared to
`placebo,
`low concent~ation, modited brorrtencc ophthalmic soldtlori dosed once
`daily prcduced a lower overall incidence of ocular adverse events
` Low concentration, mod tied bromrerac ophthalmic solution dosed
`once daily el’fec:lyelv and safely reduced ocular
`lnflarnrnatlor associated with
`cataract surgery
`N.
`ii 1' r-'-dizciiori
`o Bromfenac is a non-steroidal anti
`inflammatory drug (NSAID) with an
`extensive history of clinical efficacy:
`it acts by blocking prostaglandin
`synthesis by inhibiting cyclooxygenase 1 and 2 in the amchidonic acid
`pathway ‘
`s
`The bromine moiety in bromfenac enhances lipophilicity and facilitates
`penetration throughout ocular tissua 2’3
`o Bronucklfl (bromfenac sodium ophthalmic solution) 0.1"/0 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“
`2. xibromw (bromfenac 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“
`0 Bromdayw (bromfenac ophthalmic solution) 0.09% administered once
`daily, was approved by the FDA on October 15, 2010 for the treatment of
`postoperative inflammation and reduction of ocular pain in patients who
`have undergone cataract extraction‘
`9 Based on extensive post—rnarketing experience and data from clinical
`trials, bromfenac ophthalmic solution has demonstrated a favorable
`safety profile
`o The
`advanced
`formulation
`of
`bromfenac
`facilitates
`iniraocular
`penetration, thereby allowing a lower medication load while maintaining
`clinical efficacy with once daily dosing
`-.
`T‘, mr‘
`the reduction of ocular
`a post-hoc analysis
`K To evaluate in
`inflammation to 0 or
`trace anterior chamber
`inflammation of
`advanced formulation,
`|ow—concentration, bromfenac ophthalmic
`solution dosed once daily compared to placebo following cataract
`surgery in 2 integrated clinical trials.
`
`
`
`Anterior Chamber Cells
`
`Anterior Chamber Flare
`
`Cell Cflllhll
`
`Grade
`
`Flare COUHE
`
`0
`1
`
`2
`
`3
`
`4
`
`5
`
`0
`15 cells (trace)
`
`6-15
`
`16-25
`
`26-50
`
`> 50
`
`0
`-
`
`1
`
`2
`
`3
`
`4
`
`Complete absence
`-
`
`Very slight (barely visible)
`
`Moderate (iris and lens clear)
`
`Marked (iris and lens hazy)
`
`Intense (fibrin clot)
`
`100
`<2 Bromfenac 0 07% (n=222)
`
`~izy»Placeb0 (n=218)
`
`9°
`80 —
`
` Grade
`
`
`
`PercentofSuJjectsAchievingTraceInflammation "F < 0.001
`
`*
`71.2
`*9
`
`70 -
`
`60 —
`50 ~
`
`i.
`55.4
`
`
`
`
`
`Bromfenac
`(I1 = 222)
`91. 21%
`
`Percent Com plia nce
`Mea n‘
`Early Discontinuations
`Subjects who discontinued
`34 (15.3%)
`test agent early
`Due to lack of efficacy
`7 (3.2%)
`1 % Compliance : inn >' number of doses received / i 6
`
` Placebo
` Placebo
`
`Adverse Event
`Subjects reporting an AE affecting
`the study eye or both eyes
`Eye Pain
`Anterior chamber inflammation
`Conjunctlval hyperemia
`Photophobia
`Corneal edema
`Lacrimation increased
`Foreign body sensation
`Ocular hyperemia
`
`Bromfenac
`(“ = 212)
`14 (65%)
`6 (2.8%)
`5 (2.4%)
`2 (0.9%)
`1 (0.5%)
`1 (0.5%)
`1 (0.5%)
`Cl
`0
`
`<' The incidence of CME/ME was 0.5% (1/212) in the bromfenac
`group compared with 2.0% (4/204) in the placebo group.
`
`
`low-concentration
`formulation,
`' Advanced
`bromfenac ophthalmic solution dosed once daily
`effectively
`and
`safely
`reduced
`inflammation associated with cataract surgew.
`’ Once
`daily
`bromfenac
`ophthalmic
`0.07% was approved on April slit, 2013 by the
`
`U.S. Food and Drug Admi
`stration (FDA) as
`PROLENSA"“5
`
`
`ryine, CA [STA uhamacetticeis, inc, 2010
`Bmrnday“ Lpackage insert)
`Brown HE, Taylor 2
`In Hardinan .c, tinbird LE, N0lln0ffPB, et al eds Goodman anL1Gilrnan’s The
`Pllarrnacoloyicalfiasis arrharaaaurie. oth old Now Vorl< Mi:Crow—Hlll,1UU5 M1—e0
`Baklayan GA Patterson HM, Song i:i<, et al JL7c1/larPhai'rnam:l Therapet/t"r:s2EIEIE,24 392—0
`Henderson BA, cayton .t, chendie» sv at al ophtha/ma/s0y.2011,11b 2120—7
`Dunnerfeld ED, Dunnenfeld A IntE7phthalrnL7lClin. 2005,45 21—40
`PROLENSA“ [peciege insert]
`IN/lVlE,C/1 aatsch 3 Lornh, Inc, 2013
`Financial sJppO’t Bauscr 0 tomb, inc, iryine, CA, use
`Fina .
`ldlsclosures J A (Bow and s P chandler are emplcyees of Dausdn st tomb, inc
`: D Eoyoe, H J Relser, R tser~y, and J ’ Da: are oorisultarts for Bausch &Loml: inc
`
`
`Presented at the 85”‘ Annual Meeting of The Association for Research in Vision and Ophthalmology, Inc.; May 5-9, 2013; Seattle, WA.
`clinical Arrairs, ESat.isd'l at tomb Inc
`30 Technology Drive, Irvine, CA 92618
`
`
`
`SENJU EXHIBIT 2224
`
`LUPIN V. SENJU
`
`IPR2015-01097
`PROLO280756
`
`Page 1 of 1
`
`SENJU EXHIBIT 2224
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`
`J.A. Gow1, J.D. Boyce’, H.J. Reiser3, R. Berry4, J.T. Dao5, and S.P. ChandIer1
`for the Low Concentration Bromfenac Ophthalmic Solution Once Daily Study Group
`1Bausch & Lomb Inc., Irvine, CA, 2Orange County Ophthalmology Medical Group, Garden Grove, CA, 3Eye Care Specialists, Kingston, PA, “Eye Care Arkansas PA Little Rock, AR, 5Cornea Consultants of Arizona, Phoenix, AZ
`iii
`
` id Sub-
`
`’! Phase 3, placebo-controlled, randomized, double-masked. multi-
`center study
`" 440 subjects randomized (222 in the bromfenac group, 218 in the
`placebo group)at 39 clinical sites
`'1 Eligible subjects were scheduled for a unilateral cataract surgen/
`(phacoemulsification or extracapsular) with PCIOL implantation
`
`
`
`Screening Phase: Days -8 to v1
`Subjects were assigned to receive either bromfenac
`ophthalmic solution or placebo closed QD
`
`Subjects must have met inclusion and exclusion cri
`eli
`le for clinical trial
`
`Primary efficacy endpoint was clearance of ocular
`inflammation [summed Ocular Inflammation Score (5015) =
`U] lav day 15
`Secondary efficacy endpoint was proportion of subjects with
`trace inflammation (S018: 0-0.5)
`
`
`
`I; Treatment Phase: Day -1 to Day 15
`~Subjec|s began closing on Day -1 (~ 24 hours before surgery)
`~Subjec|s returned to the office on Day 1 for evaluation of
`safety and efficacy
`~Subjec|s returned to the offim on Day 3:l:1 for evaluation of
`safety and efficacy
`-Subjects returned to the office on Day 8:i: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
`
`
`
`Follow-up Phase: Day 22+3 or 7+3 Days After Final Dose
`~ Subjects returned to the office on Day 22+3 or 7+3 days after
`discontinuation of test agent for termination evaluation
`
`146 (67.0%)
`
`684(10 70)
`
`68 5 (9 68)
`
`Age (Vears)
`Mean ('sD)
`
`
`Tt: evaluate in a post—hoc analysis tl—e reduction of ocular irinammatiori
`trace anterior chambe~ inflammation of
`low—concentration, mocitied
`bromrenac ophthalmic solution dosed once daily compared to placebo rollowlng
`cataract surgery in 2 ntegrated clinical trials
`
`V
`:.: subiects undergoing unilateral cataract surgery (phacoemulsiricaticn or
`extiacapsulai cataiatt e><LidLLlUil) witii posteiioi ciiaiiibei
`IDL iiiiplaiitatioii weie
`randomized to ether low—concentration,
`rnodlfed bromfenac ophthalmic solution
`
`(n
`22) or placebo (n—218) once daily dosing began 1 day before cataract
`surgery, continued on the day of surgery, and through post—surgery Day 14 The
`proportion of subiects with trace anterior chamber
`inflammation, defined as a
`Surnrned Ocular Inflammation score (sols) of 0—0 5 (05 cells in the anterior
`chamber anc flare grade of 0:, was assessed a: Days 1, 3, 8, and 15 Safety was
`assessed by the incidence and treouency or ocular and systemic adverse events,
`and ophthalmological eya uations (visual acuity slit lamp examination,
`intraocular
`nressiire,
`and dilated tiinriiiscnnic examination)
`statistical
`signiticance was
`determined using a Fisher s exact test
`A e
`.-:t-;, In the intent—to—treat populat on, subiects had a mean age of 68 0 years,
`were predominantly Caucasian (74 8%), and included a higher percentage of
`female subiects (65 2%) Baseline charac:eristics were similar acrcss treatment
`groups
`A slgl')l:lr:al')tly higher proportion of siibiects
`achieved trace nciilar
`inflammation in the bromfenac group compared to placebo as early as Day 3
`(27 9% ys
`13 8%, p—00003), continued on Day 8 (55 4% ys
`24 3%, p <
`0 0001), and througn Day 15 (712% vs
`39 4%, p < 00001) Cornoared to
`placebo,
`low concent~ation, modited brorrtencc ophthalmic soldtlori dosed once
`daily prcduced a lower overall incidence of ocular adverse events
` Low concentration, mod tied bromrerac ophthalmic solution dosed
`once daily el’fec:lyelv and safely reduced ocular
`lnflarnrnatlor associated with
`cataract surgery
`N.
`ii 1' r-'-dizciiori
`o Bromfenac is a non-steroidal anti
`inflammatory drug (NSAID) with an
`extensive history of clinical efficacy:
`it acts by blocking prostaglandin
`synthesis by inhibiting cyclooxygenase 1 and 2 in the amchidonic acid
`pathway ‘
`s
`The bromine moiety in bromfenac enhances lipophilicity and facilitates
`penetration throughout ocular tissua 2’3
`o Bronucklfl (bromfenac sodium ophthalmic solution) 0.1"/0 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“
`2. xibromw (bromfenac 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“
`0 Bromdayw (bromfenac ophthalmic solution) 0.09% administered once
`daily, was approved by the FDA on October 15, 2010 for the treatment of
`postoperative inflammation and reduction of ocular pain in patients who
`have undergone cataract extraction‘
`9 Based on extensive post—rnarketing experience and data from clinical
`trials, bromfenac ophthalmic solution has demonstrated a favorable
`safety profile
`o The
`advanced
`formulation
`of
`bromfenac
`facilitates
`iniraocular
`penetration, thereby allowing a lower medication load while maintaining
`clinical efficacy with once daily dosing
`-.
`T‘, mr‘
`the reduction of ocular
`a post-hoc analysis
`K To evaluate in
`inflammation to 0 or
`trace anterior chamber
`inflammation of
`advanced formulation,
`|ow—concentration, bromfenac ophthalmic
`solution dosed once daily compared to placebo following cataract
`surgery in 2 integrated clinical trials.
`
`
`
`Anterior Chamber Cells
`
`Anterior Chamber Flare
`
`Cell Cflllhll
`
`Grade
`
`Flare COUHE
`
`0
`1
`
`2
`
`3
`
`4
`
`5
`
`0
`15 cells (trace)
`
`6-15
`
`16-25
`
`26-50
`
`> 50
`
`0
`-
`
`1
`
`2
`
`3
`
`4
`
`Complete absence
`-
`
`Very slight (barely visible)
`
`Moderate (iris and lens clear)
`
`Marked (iris and lens hazy)
`
`Intense (fibrin clot)
`
`100
`<2 Bromfenac 0 07% (n=222)
`
`~izy»Placeb0 (n=218)
`
`9°
`80 —
`
` Grade
`
`
`
`PercentofSuJjectsAchievingTraceInflammation "F < 0.001
`
`*
`71.2
`*9
`
`70 -
`
`60 —
`50 ~
`
`i.
`55.4
`
`
`
`
`
`Bromfenac
`(I1 = 222)
`91. 21%
`
`Percent Com plia nce
`Mea n‘
`Early Discontinuations
`Subjects who discontinued
`34 (15.3%)
`test agent early
`Due to lack of efficacy
`7 (3.2%)
`1 % Compliance : inn >' number of doses received / i 6
`
` Placebo
` Placebo
`
`Adverse Event
`Subjects reporting an AE affecting
`the study eye or both eyes
`Eye Pain
`Anterior chamber inflammation
`Conjunctlval hyperemia
`Photophobia
`Corneal edema
`Lacrimation increased
`Foreign body sensation
`Ocular hyperemia
`
`Bromfenac
`(“ = 212)
`14 (65%)
`6 (2.8%)
`5 (2.4%)
`2 (0.9%)
`1 (0.5%)
`1 (0.5%)
`1 (0.5%)
`Cl
`0
`
`<' The incidence of CME/ME was 0.5% (1/212) in the bromfenac
`group compared with 2.0% (4/204) in the placebo group.
`
`
`low-concentration
`formulation,
`' Advanced
`bromfenac ophthalmic solution dosed once daily
`effectively
`and
`safely
`reduced
`inflammation associated with cataract surgew.
`’ Once
`daily
`bromfenac
`ophthalmic
`0.07% was approved on April slit, 2013 by the
`
`U.S. Food and Drug Admi
`stration (FDA) as
`PROLENSA"“5
`
`
`ryine, CA [STA uhamacetticeis, inc, 2010
`Bmrnday“ Lpackage insert)
`Brown HE, Taylor 2
`In Hardinan .c, tinbird LE, N0lln0ffPB, et al eds Goodman anL1Gilrnan’s The
`Pllarrnacoloyicalfiasis arrharaaaurie. oth old Now Vorl< Mi:Crow—Hlll,1UU5 M1—e0
`Baklayan GA Patterson HM, Song i:i<, et al JL7c1/larPhai'rnam:l Therapet/t"r:s2EIEIE,24 392—0
`Henderson BA, cayton .t, chendie» sv at al ophtha/ma/s0y.2011,11b 2120—7
`Dunnerfeld ED, Dunnenfeld A IntE7phthalrnL7lClin. 2005,45 21—40
`PROLENSA“ [peciege insert]
`IN/lVlE,C/1 aatsch 3 Lornh, Inc, 2013
`Financial sJppO’t Bauscr 0 tomb, inc, iryine, CA, use
`Fina .
`ldlsclosures J A (Bow and s P chandler are emplcyees of Dausdn st tomb, inc
`: D Eoyoe, H J Relser, R tser~y, and J ’ Da: are oorisultarts for Bausch &Loml: inc
`
`
`Presented at the 85”‘ Annual Meeting of The Association for Research in Vision and Ophthalmology, Inc.; May 5-9, 2013; Seattle, WA.
`clinical Arrairs, ESat.isd'l at tomb Inc
`30 Technology Drive, Irvine, CA 92618
`
`
`
`SENJU EXHIBIT 2224
`
`LUPIN V. SENJU
`
`IPR2015-01097
`PROLO280756
`
`Page 1 of 1
`
`SENJU EXHIBIT 2224
`LUPIN v. SENJU
`IPR2015-01097
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