PROL0280722
`
`Founder and Director, Jacksoneye
`
`Mit(:hell A. Jackson, MD
`Cataract Surgery: What Really Matters
`Selecting an NSAI D for
`
`Page 1 of 27
`
`SENJU EXHIBIT 2221
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`
`
`Founder and Director, Jacksoneye
`
`Mit(:hell A. Jackson, MD
`Cataract Surgery: What Really Matters
`Selecting an NSAI D for
`
`Page 1 of 27
`
`SENJU EXHIBIT 2221
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`
`
`N
`
`C")
`
`N r--
`0
`CX)
`N
`0
`_..J
`0
`0::::
`a_
`
`en
`())
`5....
`
`:::J en
`0
`t'\
`~ en ·-
`0
`
`Page 2 of 27
`
`
`
`PROL0280724
`
`3
`
`3. Meekins LC, Afshari NA. Curr Opin Ophthalmol. 2012,23:1-2
`2. www.aces-abes.org/guidelines_for_cataract_practice.htm#chapter7
`1. Allen D. Clin Evidence. 2008; 8(708):1-14.
`
`Medications
`
`Devices, instruments,
`
`Quality of life2
`
`Vision2
`
`and lenses
`
`-:>-: y A''(·-!' <•
`1: ~.;: ,.. r ~ '<·
`
`, , , , ",,.
`
`:•:
`
`"-
`
`amr•o~·-
`
`FEL0.2D
`
`E
`
`o Gloal of cataract surgery is, "-ro restore vision and to improve
`
`quality of life, with minimal adverse effects of treatment"1
`
`Cataract Surgery: The Pursuit of Perfection
`
`H
`10
`9
`e
`7
`EDl'CZ:P 6
`PECFD 5
`LP:E:D 4
`T 0 Z s
`F :P z
`
`Page 3 of 27
`
`
`
`PROL0280725
`
`4
`
`Find I 0. Eur Ophthalmic Rev. 201 0;4:54-59.
`
`tophcal ophthalmic NSAIDs
`o Redluce the risks typical of
`
`inflatmmation and pain
`for sustained control of
`
`o Possess high COX inhibition
`
`therapeutic levels
`rapi~d and sustained
`
`o Penetrate efficiently to allow
`
`An effective topical ophthaln1ic NSAID s,-----h_o_ul_d_: _____ _
`
`NSi\IDS Are an lmportc:Int Tool for Cataract Surgery
`
`Page 4 of 27
`
`
`
`PROL0280726
`
`5
`
`3. ILEVRO [package insert]. Fort Worth, TX; Alcon; 2013.
`2. ACUVAIL [package insert]. Irvine, CA: Allergan; 2011.
`1. PROLENSA[package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2013.
`
`• Guar gum3
`• Carboxymethylcellulose sodium2·3
`Visco!;ity agents
`• Requires enzymatic conversion to active form
`•
`Prodrug3
`• Affects lipophilicity
`Formulation pH1,2
`• lncre~ases lipophilicity
`Halog~enation 1
`
`Improved penetration
`
`Penetration
`
`~ialogenation 1
`Potency
`
`Delivery of NSAIDs
`Various Approaches lJsed to Improve Drug
`
`Page 5 of 27
`
`
`
`PROL0280727
`
`6
`
`-Continue to evolve
`-Require efficient corneal pe~netration to reach site of C()X production
`Inhibit COX-1 and COX-2 and block the production of prostaglandins
`
`-
`
`o NSAIDs are an important tool for cataract surge~(
`
`-Play a key role in postsurgical inflammation and pain
`
`o Prc>staglandins
`
`trauma
`
`-Produce prostaglandins from arachidonic acid as a result of surgical
`-Primarily expressed in Iris and Ciliary body
`
`o Cy(:looxygenase (COX-1 c:tnd COX-2) Enzymes
`
`response that may adver~;ely affect the outcome
`
`o Cataract surgery is comm~on but can lead to infla1mmatory
`Wh«at really matters ...
`
`Page 6 of 27
`
`
`
`1'-
`
`CX)
`
`N r--
`0
`CX)
`N
`0
`_..J
`0
`0::::
`a_
`
`c
`0 ·-+-' co
`:::J E §
`s..... ·-
`0~
`'+- -=
`0
`I
`~en
`(.)
`(.)
`c ·(cid:173)
`co E >-
`"''ro
`co£
`c..c
`rn§-
`e>u
`-~ co
`(.) c
`:::J Q)
`-gE
`s..... 0
`+-'s.....
`.!:.o
`
`~
`I-
`<(
`en
`z
`w
`_J
`0
`(t::
`a...
`
`Page 7 of 27
`
`
`
`PROL0280729
`
`8
`
`4. PROLENSA [package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2013.
`3. BROMDA Y [package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2011.
`2. XIBROM [package insert] Tampa, FL: Bausch & Lomb Incorporated; 2010.
`1. Bronuck [package insert]. Osaka, Japan: Senju Pharmaceutical Co, Ltd.; 2000.
`*In the United States and Japan. Branded bromfenac.
`
`Launched 2011
`
`B&L/CROMA
`
`Launched 2010
`
`Launched 2009
`
`Takeda
`
`Senju
`
`Launched 2005
`
`Bausch ~& Lomb (ISTA)
`
`Launched 2000
`
`Senju
`
`I
`
`I
`
`I
`
`Europe
`
`Thailand
`
`China
`
`USA
`
`Japan
`
`20 Million Patient Uses Over 10 Years*
`
`Extensive Global Safety Record Since 20004
`
`: >
`
`2013
`
`[
`
`2005 ~
`
`L
`
`~00 : >
`
`formulation bromfenac
`
`ophthalmic solution
`
`Approved in the US:
`
`An advanced(cid:173)
`April20134
`
`Postcataract Surgery
`NSAID in the US for
`
`Approved in the US:
`
`First Once-Daily
`October 20103
`
`Postcataract SurgE~ry
`NSAID in the US for
`
`First Twice-Daily'
`
`Approved in the US:
`
`March 20052
`
`Approved in Japan:
`
`B1ronuck
`
`Dosed Twice Daily
`
`Jully 20001
`
`PROLENSATM
`
`BROMDAY®
`
`XIBRQM®
`
`Inflammation Associated With Cataract Surgery
`Bromfenac: A Long History of Treating Ocular
`
`Page 8 of 27
`
`
`
`PROL0280730
`
`9
`
`PROLENSA [package insert]!. Tampa, FL: Bausch & Lomb Incorporated; 2013
`
`-· None
`
`o Contraindications
`
`surgery
`and through the first 14 days post
`surgery, continued on the day of surgery
`once daily beginning 1 day prior to
`
`-· Instill one drop into the affect~ed eye(s)
`
`o Dosage and Administration
`
`who have undergone cataract surgery
`and reduction of ocular pain in patients
`treatment of postoperative inflammation
`solution) 0.07°/o is indicated for the
`
`-· PROLENSA (bromfenac ophthalmic
`
`o lndlications and Usage
`
`PR<)LENSA™ (bromfenc:tc ophthalmic solution) 0.07°/o
`
`Page 9 of 27
`
`
`
`PROL0280731
`
`10
`
`PROLENSA [package insert]!. Tampa, FL: Bausch & Lomb Incorporated; 2013
`
`-Some ocular NSAIDs increase bleeding time due to interference with platelet
`
`aggregation in conjunction with ocular surgery
`
`o Increased bleeding of ocular tissues
`
`-Other NSAIDs
`-Phenylacetic acid derivatives
`-Acetylsalicylic acid
`
`o Potential for cross-sensitivity
`
`may increase potential for healin~~ problems
`
`-Concomitant use of topical NSAIDs and steroids
`-All topical NSAIDs and corticosteroids may slow or delay healing
`
`o Slow or delayed healing
`
`in asthmatics
`
`-Overall prevalence of sulfite sensitivity is unknown, likely low, and n1ore common
`
`symptoms and life-threatening or less severe asthmatic episodes
`
`-Sulfite allergic reactions may occur in susceptible people and include anaphylactic
`-PROLENSA contains sodium sulfite
`
`o Sulfite allergic reactions
`
`PROLENSA™ Warnings and Precautions
`
`Page 10 of 27
`
`
`
`PROL0280732
`
`11
`
`PROLENSA [package insert]!. Tampa, FL: Bausch & Lomb Incorporated; 2013
`
`• Blurred vision
`• Photophobia
`• Eye pain
`• Foreign body sensation
`• Anterior chamber inflammation
`
`-Most common adverse reactions (3o/o-8o/o of patients)
`
`o Post cataract surgery clinical trial experience
`
`-PROLENSA should not be administered while wearing
`
`contact lenses
`
`o Contact lens wear
`
`-These events may be sight threatening
`
`• Corneal thinning, erosion, ulceration, or perforation
`• Epithelial breakdown
`
`In some susceptible patients, use of topical NSAIDs may result in
`
`-
`
`-Use of topical NSAIDs may result in keratitis
`
`o Kel"atitis and corneal reactions
`
`PROLENSATM Warnings and Precautions
`
`Page 11 of 27
`
`
`
`N
`....-
`
`C")
`C'0
`r--
`0
`CX)
`N
`0
`_..J
`0
`0::::
`a_
`
`c
`
`0 ·-+-' ro -:::J
`E s.....
`0
`LL
`(]) -.J.....
`I-
`
`Page 12 of 27
`
`
`
`PROL0280734
`
`0~
`
`~~
`~-
`lv~h
`
`S coRNEAL p~
`
`~~
`
`~
`
`v~
`
`~~
`
`penetr·ation
`potency and corneal
`bromine increases
`Halog•~nation with
`
`PROLEN~SA rM Effect
`
`PR<)LENSA-Powere~d for Penetration
`
`Page 13 of 27
`
`
`
`PROL0280735
`
`14
`
`Data on file. Bausch & Lomb Incorporated.
`BROMDA Y [package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2011 ..
`Baklayan GA, et al. J Ocu/ Pharmacal Ther. 2008;24(4):392-398.
`
`Clinical significance of in vitro data is unknown.~
`
`.... ············c~~"~~···· .......................... ~ ·· .. .
`
`0
`
`OH
`
`(
`
`~
`NH2
`
`0 ~
`
`o Not a prod rug
`
`o Fa~cilitates penetration
`
`thr~ough the cornea
`
`o lnc:reases the lipophilicity
`
`o lnc:reases the potency
`
`ag4ainst COX-2
`
`Proven Potency and PE~netration
`
`with bromine
`The lbenefits of halogenatio11
`Bro1mfenac: The Halo~~enation Effect
`
`Page 14 of 27
`
`
`
`PROL0280736
`
`penetration
`which facilitates corneal
`increases lipophilicity
`Lowering 1the pH
`
`0~
`
`~~
`~-
`lv~h
`
`S coRNEAL p~
`
`~~
`
`~
`
`v~
`
`~~
`
`PROLEN~SA rM Effect
`
`PR<)LENSA-Powere~d for Penetration
`
`Page 15 of 27
`
`
`
`PROL0280737
`
`26
`
`st.dution) 0,.07%
`{bro1:r-,1f~n:5c op.lith~tmk;
`PRJ::JLEf'4Sttf
`
`~
`ate D. et aL Expert Opin Drug De/h( 2006;3(2 ):275-287
`
`\~
`
`-
`
`1.,5 7~4
`Tear fluid
`
`7.8
`
`8.3
`
`PR,OLENSA™
`
`BROMDAY'ID
`
`The Effect of pH on Penetration
`
`Page 16 of 27
`
`
`
`PROL0280738
`
`0~
`
`~~
`~-
`lv~h
`
`S coRNEAL p~
`
`~~
`
`~
`
`v~
`
`~~
`
`penetration
`which facilitates corneal
`increases lipophilicity
`Lowering 1the pH
`
`penetr·ation
`potency and corneal
`bromine increases
`Halog•~nation with
`
`PROLEN~SA rM Effect
`
`PR<)LENSA-Powere~d for Penetration
`
`Page 17 of 27
`
`
`
`PROL0280739
`
`18
`
`-· Solution: dose uniformity vvithout the need to shake
`
`-· Convenient once-daily dosing
`
`-· More physiologic pH
`
`-· Lower pH improves corneal penetration, thus lower concentration
`
`o Formulation:
`
`-· Facilitates penetration through the cornea
`
`-· Increases the lipophilicity
`
`-· Increases the potency against COX-2
`
`o Effect of halogenation with t)romine:
`
`Wh«at really matters ...
`
`Page 18 of 27
`
`
`
`(j)
`
`....-
`
`0
`r--
`-.::1'"
`0
`CX)
`N
`0
`_..J
`0
`0::::
`a_
`
`en -ro ·-!.....
`I--ro
`(.) ·-c ·(cid:173)-u
`
`C')
`
`(]) en
`ro
`..c a...
`
`Page 19 of 27
`
`
`
`PROL02807 41
`
`20
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`*Secondary endpoint = pain free; tPrimary endpoint = SOlS grade 0.
`
`[Ocular, topical, inhaled, or oral corticosteroid use within 15 days]
`
`Typical exclusion criteria
`
`discontinued.
`dose if prematun
`+or 1 week after lc
`
`I ~
`
`Day 14
`Final dose
`
`h_
`
`I
`
`1 Drop per Dayr for 16 Days
`
`Day -1
`Start dosing
`
`VehiclE~
`
`PROLENSATM
`I
`
`I
`
`y t
`
`' /
`
`~I
`
`sad of s
`Scree ·
`
`\;;;!;;
`Day 22
`Visit 6
`
`Day 15 (±1)t
`
`Visit 5
`
`(±1)
`DayS
`Visit 4
`
`(±1)
`IDay 3
`Visit 3
`
`Day 1 *
`Visit 2
`
`Study 1 = lEast; Study 2 =West
`
`(Surgery)
`
`Visit 1
`
`DayO
`
`Two Double-Masked, Multicenter, Vehicle-Controlled, Randon1ized Studies
`
`Bro1mfenac 0.07°/o QD Phase 3 Clinicalllrials
`
`§.!~~Y Q~~Ja~
`
`Page 20 of 27
`
`
`
`PROL02807 42
`
`21
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`
`• Visual acuity, slit lamp examination, intraocular pressure~, dilated
`
`-· Ocular comfort on instillation
`
`funduscopic exam
`
`-· Ophthalmologic exam
`-· Ocular and systemic adverse events
`
`o Salfety:
`
`• pain grading of "None" on the Ocular Comfort Grading P~ssessment
`
`-· Day 1 resolution of ocular pain
`
`0 se~condary efficacy endpoint:
`
`• Grade 0 = 0 cells and absence of flare
`Inflammation Score (SOlS) of grade 0)
`
`-· Day 15 clearance of ocular inflammation (Summed Ocular
`
`o Primary efficacy endpoint:
`Study Endpoints
`
`§.!~~Y R!:~Ja~ ,
`
`Page 21 of 27
`
`
`
`PROL02807 43
`
`22
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`toay 15 primary endpoint.
`
`Day 15t
`
`Day 8
`
`Day 3
`
`Day 1
`
`Day ·15t
`
`Day 8
`
`Day 3
`
`Day 1
`
`12.7%
`
`/ 28.2 Yo
`0
`
`//
`
`10
`
`.
`
`"'!" "· • /0
`
`2.70~.···"-6··~~ 5 so/
`
`P<O.O~i
`
`45.5°/o
`P<0.05
`
`Vehicle (n=11 0)
`
`-.-PROLENSA (n=11 0)
`
`O~fo
`
`10°/o
`
`20°/o
`
`30~/o
`
`40°/o
`
`50%
`
`60°/o
`
`P=0.001
`
`45.5~1o
`
`P<0.0001
`
`Vehicle (n=108)
`
`-+-PROLENSA (n=112)
`
`m 40%
`i;: c:
`co
`E 50°/o
`E
`co
`:.;;
`0
`c: 60%
`
`... (.)
`tn 10%
`~
`J: ...
`e co
`
`0 20%
`Q)
`
`'0 30°/o
`0
`(.)
`:::l
`
`en
`:::l QO/o
`:E'
`Q)
`
`I Western Region (S;00124-WR) I
`
`QEastern Region (500124-ER) J
`
`Proportion of Patients with SOlS of Grade 0 ~
`
`[
`
`[ ~~~i~~~y J
`
`Pos~toperative I nflamrr1ation
`PROLENSA TM Is Effective at Eliminating
`
`Page 22 of 27
`
`
`
`PROL02807 44
`
`23
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`toay 15 primary endpoint.
`*P<0.0001.
`
`(n=218)
`Vehicle
`
`(n=222)
`
`PROLENSA
`
`47°/o
`
`80o/o
`*
`
`oo/o
`
`10o/o
`
`20o/o
`
`30°/o
`
`40o/o
`
`50°/o
`
`60°/o
`
`70o/o
`
`80o/o
`
`90°/o
`
`(n=218)
`Vehicle
`j~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~m1
`
`~~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1~1
`
`:;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
`
`20o/o
`
`(n=222)
`
`PROLENSA
`
`46°/o
`*
`
`•
`
`-
`
`-
`
`:
`.. ,
`
`at Day 15 (Pool1ed Data)
`Trace Cells (0-5 cells)
`
`-
`
`SOlS of 0 at Day 15t
`
`(Pooled Data)
`
`·············································
`[ Efficacy J
`
`Have~ Resolution of lnflamm1ation at Day 15
`PR01LENSA rM Treated Patients Are Twice as Likely to
`
`~~ ~ 0 -
`
`90°/o
`
`QO/o
`... (.)
`~ 10S1
`; 20o/o
`0
`Q) 30°/o
`a.. co
`Q)
`'0 40o/o
`0
`(.)
`~ 50o/o
`a.. co
`.E 60°/o
`i;:
`co
`E ?Oo/o
`E
`co
`. 0
`:.;; 80°/(
`0
`c:
`
`:::l en
`:E'
`Q)
`
`:·. 0
`
`tn
`
`Page 23 of 27
`
`
`
`(Yroportion of Subjects Pain Free at Each Study Day (Pooled Data) J
`
`[ ~~~i~~~y J
`
`Reliief [Day 1]
`PR<)LENSA TM Provid~es Rapid Pain
`
`?fl.~ 1 00°/o
`
`_ ...
`
`-.
`
`..
`
`PROL02807 45
`
`24
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`toay 1 secondary endpoint.
`*P<0.0001.
`
`Day 15
`
`DayS
`
`Day 3
`
`Day 1 t
`
`30°/o
`
`:e: 40%
`01
`s:::::
`01 50°/o
`......
`C/JI
`:::::ll 60°/o
`.C!
`Q.ll ·-"
`(JI
`..,.,
`t/ll
`a..
`·-· 80%
`C'Cll
`s:::::
`u..
`90o/o
`.....
`Q.ll
`Q.ll
`
`?QOfo
`
`a..
`.....
`01
`Ct.
`01
`
`Placebo (n=218)
`
`-+-PROLENSA (n==222)
`
`53°/o
`
`SOo/o
`
`167°/o
`
`92~0/o
`
`*
`*
`
`92°/o
`
`*
`*
`
`8~7°/o
`
`*
`""~
`
`79°/o
`
`*
`*
`
`A_
`
`Page 24 of 27
`
`
`
`PROL02807 46
`
`25
`
`Data on file, Bausch & Lomb Incorporated, 2012.
`#Comfort graded on the Ocular Comfort Grading Assessment (OCGA)
`
`
`- ~
`
`- - - - -
`
`~
`
`-
`
`~
`
`~
`
`-
`
`~
`
`~
`
`-
`
`-
`
`~
`
`~
`
`-
`
`~
`
`~
`
`-
`
`-
`
`~
`
`-
`
`-
`
`~
`
`~
`
`Day 15
`
`Day 8
`
`Day 3
`
`Day 1
`
`Improvement Co1mpared to Vehicle in Change from Baseline
`
`(Pooled Data)
`
`Haziness
`
`Eye discharge
`
`Pl1otophobia
`
`sensation
`Foreign body
`
`Itching
`
`Tearing
`
`Ocular pain
`
`Symptom#
`Comfort
`
`PR<)LENSA TM: Comfc>rt Better Than Vet1icle
`
`.·.·.·.··:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·:·.·.·:·:·:·:·:·:·:·:·:···
`
`Safety
`
`Page 25 of 27
`
`
`
`PROL0280747
`
`26
`
`o Sollution: dose uniformity without the need to shake
`
`o Convenient once-daily dosing
`
`o More physiologic pH
`
`o Comfortable
`
`-Anterior chamber inflammation, foreign body sensation, eye pain, photophobia, blurred vision
`
`o Lo\N rate of adverse events (3~Vo-8%)
`
`o Eff~ective treatment for postope~rative inflammation and pain in patients
`PR01LENSA rM provides:
`
`who have undergone cataract surgery
`
`Wh«at really matters ...
`
`Page 26 of 27
`
`
`
`PROL02807 48
`
`US/PR:A/13/0130
`©2013 Bausch & Lomb Incorporated.
`
`All other product/brand names are trademarks of their respective owners.
`®/™ are trademarks of Bausch & Lomb Incorporated or its affiliates.
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`Page 27 of 27
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