PAGE 1 OF 49
`
`SENJU EXHIBIT 2296
`LUPIN v SENJU
`IPR2015-01105
`
`

`
`Welcome and Opening Remarks
`
`Terry Kim, MD
`
`Director, Ophthalmology Fellowship Programs
`
`Associate Director, Cornea and Refractive
`
`Surgery Services
`
`Duke University Medical Center
`
`Durham, NC
`@2013 Bausch & Lamb lncorporated.
`
`”S’LGX""3’°°92‘2) °"”3
`
`This non-CME seminar is brought to you by
`;:~:.
`._;;.
`.;:~3;;;;,;: »:~:
`COr‘n‘.=lDEh'TIAL rm? :0»? DISTR.‘EUT.’ON.
`
`PAGE 2 OF 49
`
`CONFIDENTIAL
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`2
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`PROLO284794
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`PAGE 2 OF 49
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`

`
`7:00 AM—7:10AM
`
`7:10AM—7:30AM
`
`7:30 AM—7:50 AM
`
`7:50 AM-8:00 AM
`
`AGENDA
`
`Welcome and Opening Remarks
`Terry Kim, MD
`
`Cataract Surgery, inflammation, and NSAIDS:
`What Really Matters?
`John Hovanesian, MD
`
`Bromfenac Ophthalmic Solution 0.07%: Two
`Steps Forward
`Bonnie Henderson, MD
`
`Summary Remarks and Panel Discussion
`Terry Kim, MD
`Bonnie Henderson, MD
`John Hovanesian, MD
`
`C{)I'lFr‘DEI'JTI/xi. N37 FOR OIST1?1E’JT.'O/'4'.
`
`PAGE 3 OF 49
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`CONFIDENTIAL
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`PROLO284795
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`PAGE 3 OF 49
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`

`
`REMINDER
`
`As a courtesy to faculty and your
`colleagues, we ask that you silence
`all mobile devices.
`
`PAGE 4 OF 49
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`CONFIDENTIAL
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`4
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`PROL0284796
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`PAGE 4 OF 49
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`
`USE KEY PADS
`
`During this session you will be
`asked to use interactive keypads
`to respond to questions.
`
`All responses are ANONYMOUS.
`
`PAGE 5 OF 49
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`CONFIDENTIAL
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`5
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`PROLO284797
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`
`HOW TO USE KEYPADS
`
`- Choose your response from the
`keypad buttons.
`
`- You can change your answer by
`simply keying in your new choice.
`
`- The system will only count the last
`
`vote.
`
`PAGE 6 OF 49
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`CONFIDENTIAL
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`5
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`PROL0284798
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`PAGE 6 OF 49
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`

`
`Survey Question
`
`Primary area of specialty? 63%
`
`A. Comprehensive
`
`B. Cornea/External
`
`Disease
`
`C. Cataract
`
`D. Other
`
`C
`CON.=fDEIv'TIAL NET FOR D?STR.‘5’J'.'10/‘I.
`
`PAGE 7 OF 49
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`CONFIDENTIAL
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`7
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`PROL0284799
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`PAGE 7 OF 49
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`

`
`Survey Question
`
`How many cataract surgeries do you perform
`per month?
`
`43%
`
`A. >150
`
`B. 101-150
`
`C. 51-100
`
`D. 25-50
`
`E. <25
`
`PAGE 8 OF 49
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`CONFIDENTIAL
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`8
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`PROL0284800
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`PAGE 8 OF 49
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`

`
`Survey Question
`
`How do you treat postoperative inflammation
`after cataract surgery?
`
`78%
`
`A. Corticosteroids only
`
`B. NSAIDS only
`
`C. Both corticosteroids
`
`and NSAlDS
`
`Speakerto review percentages and avoid off-label commentary.
`
`PAGE 9 OF 49
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`CONFIDENTIAL
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`9
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`PROL0284801
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`PAGE 9 OF 49
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`

`
`Cataract Surgery, lnflammation,
`and NSAlDs: What Really Matters?
`
`John Hovanesian, MD
`
`Harvard Eye Associates
`
`LagunaFmB,CA
`
`Clinical Assistant Professor
`
`UCLA Jules Stein Eye Institute
`
`LosAngebs,CA
`
`PAGE 10 OF 49
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`CONFIDENTIAL
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`10
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`PROL0284802
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`PAGE 10 OF 49
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`

`
`Cataract Surgery Trends
`
`There are an estimated 20.5 million persons 40 years and older with
`cataract in the United States‘?
`
`3.3 million cataract surgeries are performed in the United States
`annually and that number is expected to rise dramatically”
`
`Surgeries in US (miilions)3»“
`
`""""""""""""f"""V’:"""""ff"""""""""""""
`
`1. Williams A, et al. Arch Ophiha/moi.2GO6:§24(9):t308-1314.
`2. Congdon N. et at: Eye Diseases Prevalence Research Group.
`Arch Opnthaimot. 2004‘,l22(4}i487-494
`3 Harmon D, Opfi!I7ar‘m/'c it/larke!Persper:
`9. June 16 2070
`4. American Society
`rgery. Fact sheet. 2006.
`CCNFl‘DEI')'TIAL NC?‘ FOR DtSTR.‘5UT.'O/‘I.
`
`I
`
`There are an estimated 20.5 million persons 40 years and older with cataract in the United
`States. As expected, the prevalence of cataract increases with age, affecting almost half of
`Americans over 75.
`
`Therefore, cataract extraction and intraocular lens (lOL) implantation are a major
`component of ophthalmic surgical volume in the United States, accounting for over 3.3
`million surgeries annually. This number is expected to continue to rise.
`
`References
`
`1. Williams A, et al. Longitudinal rates of cataract surgery. Arch Ophthalmol.
`2006;124(9):1308—1314
`2. Congdon N, et al; Eye Diseases Prevalence Research Group. Arch Ophthalmol.
`2004;122(4):487-4
`3. Harmon D. Q1 2010 US lOL procedures climb 4.6 percent. Ophthalmic Market
`Perspectives, June 16, 2010. Market Scope, LLC, St. Louis, MO.
`4. American Society of Cataract and Refractive Surgery. Fact Sheet—Cataract Surgery &
`Prostate Drug Complications. Fairfax: American Society of Cataract and Refractive
`Surgery, 2006.
`
`PAGE 11 OF 49
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`CONFIDENTIAL
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`11
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`PROL0284803
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`PAGE 11 OF 49
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`

`
`Cataract Surgery
`
`~ Goal of cataract surgery is to restore vision and to improve
`quality of life, with minimal adverse effects of procedure‘
`
`-1‘?
`-TOZ
`-I.PEI>
`‘ FE C2‘D
`.an:cz1>
`<
`rnnorcn
`
`Quality of life?
`
`Devices, instruments.
`and lenses
`
`Medications
`
`1. Alzenll). Olin Ewdence, 2003: 8(708):t~t4.
`4. www.ar:es«ar>es.org/guidetines_§cr_cataract_practice.htm#chapter7
`3. Meekins LC. Afshari NA. Curr Opin Ophthafmo/. 2012. 231-2
`CCNFi‘;',\EI*)'TIr’\L N3?" FOR D)STR.*EUT.'O/‘I.
`
`According to the a recent report in Clinical Evidence, the goal of cataract surgery is to
`restore vision and improve quality of life, with minimal adverse effects of procedure.
`
`Cataract surgery is the most common surgical procedure in the USA and is widely accepted
`as a reliable surgical intervention with gratifying results including improved vision, quality of
`life, etc. Recent developments in the field including femtosecond phacoemulsification, have
`honed surgical technique, advanced the standard of care, and given rise to better patient
`outcomes.
`
`References
`
`1. Alan D. Clin Evidence. 2008; 8(708):1—14.
`2. www.aces-abes.org/guidelines_for_cataract_practice.htm#chapter7
`3.
`l\/leekins LC, Afshari NA. Curr Opin Ophthalmol. 2012, 23:1—2.
`
`PAGE 12 OF 49
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`CONFIDENTIAL
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`
`PROL0284804
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`PAGE 12 OF 49
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`

`
`
`
`Surgical Trauma to Ocular Surface Induces
`inflammatory Response
`
`
`
`
`
`
`
`
`
`- Culminates in the production of inflammatory mediators‘
`— Oxygen-free radicals
`— Proteolytic enzymes
`
`— Cyclooxygenase (1 and 2) metabolites of arachidonic acid:
`prostaglandins, thromboxane, prostacyclin
`
`— Lipoxygenase metabolites of arachidonic acid: ieukotrienes
`
`
`
`
`
`
`- May cause clinical signs‘
`— Perilimbal injection
`— Anterior chamber cells
`~ Anterior chamber flare
`
`- May affect Outcome‘
`— lnflammation—related complications
`— Patient discomfort
`
`- impede recovery of vision
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘i. El-Harazi SM and Feidman RM Curr Opin Ophthalmo/.2001:32(t):4—8.
`CCN.=l9Eh'TlAL rm? :0? DIST:?.‘5UT.'O/2'.
`
`Although rare, sequelae of cataract surgery can compromise patient comfort and impede recovery of
`vision. Surgical trauma to the ocular surface induces inflammatory mediators including oxygen—free
`radicals, proteolytic enzymes, and cyclooxygenase and lipoxygenase metabolites of arachidonic acid.
`Excessive inflammation may cause clinical symptoms of perilimbal injection as well as anterior
`chamber cells and flare. increased inflammation is associated with all the factors listed here.
`
`References
`
`1. El-Harazi SM and Feidman RM. Curr Opin Ophthalmol. 2001 ;12(1):4—8.
`
`PAGE 13 OF 49
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`CONFIDENTIAL
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`PROL0284805
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`PAGE 13 OF 49
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`

`
` -
`
`I, Corlnettiwtc, at al Euru’ Ophtlzalmol. 1995 j5g1}'=$O-47.
`CCNFIDEIJTIAL N3?‘ FOR DtSTR.‘5UT.'O/‘I.
`
`Although rare, sequelae of cataract surgery compromise patient comfort and impede recovery of
`vision. Surgical trauma to the ocular surface induces inflammatory mediators including oxygen-free
`radicals, proteolytic enzymes, and cyclooxygenase and lipoxygenase metabolites of arachidonic acid.
`Excessive inflammation may cause clinical symptoms of perilimbal injection as well as anterior
`chamber cells and flare. Increased inflammation may be associated with all the factors listed here.
`
`References
`
`1. Corbett MC, et al. EurJ Ophthalmo/. 1995;5(1):40-47.
`
`PAGE 14 OF 49
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`CONFIDENTIAL
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`14
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`PROL0284806
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`
`
`Surgical Trauma to Ocular Surface Induces
`Inflammatory Response (cont.)
`
`Increased inflammation may be associated with
`
`— Difficulty of surgery‘
`
`— Prior surgery‘
`
`— Prior intraocular inflammation‘
`
`— Ethnicity (non-Caucasian)‘
`
`— Brown irides‘
`
`PAGE 14 OF 49
`
`

`
`Cyclooxygenase Enzymes Produce Prostaglandins
`From Arachidonic Acid as a Result of Surgical Trauma
`
`,
`
`tieliuzar
`m6«m?).'3n~>
`ghosplwlipma
`
`€€Z<Z’z§<:.~‘§ we ~26;
`
`‘fir
`?‘ROS'1‘AGLAN£}iPSXS
`
`Kim SJ, etal SélflIOp17(h ‘mot. "O10: 55{2‘;:10&»l 33.
`CM H. et ai. Olin Ophth
`i. 2
`3:t99~2i0.
`CCNFiDEI‘2'TIr’\i. N3?" FOR OtSTr'<.‘5’o‘T.'O/‘J.
`
`Surgical trauma disrupts cellular phospholipids, activating phospholipase A2, and producing
`arachidonic acid. Arachidonic acid is converted by cyclooxygenases (COX-1 and COX-2) into
`prostaglandin intermediates and subsequently into a variety of eicosanoids that include prostacyclin,
`thromboxane, and most importantly, prostaglandins. As we have discussed, prostaglandins play a key
`role in the manifestation of postsurgical inflammation and pain.
`
`References
`
`1. Kim SJ et al. Surv Ophthalmol. 2010; 55(2):108—133.
`2. Cho H, et al. C/in Ophfhalmol. 2009; 3:199-210.
`
`PAGE 15 OF 49
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`CONFIDENTIAL
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`PROL0284807
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`PAGE 15 OF 49
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`

`
`Survey Question
`
`As a result of trauma from cataract surgery,
`cyclooxygenase production is increased
`primarily in the:
`%
`A. Cornea
`
`B. Iris/Ciliary body
`
`C. Choroid
`
`PAGE 16 OF 49
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`CONFIDENTIAL
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`
`PROL0284808
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`PAGE 16 OF 49
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`

`
` COX Enzymes Are Primarily Expressed in the
`Anterior Segment
`
` COX-1
`
`Cma
`bmi
`..
`COEX1 and:
`v Constitutive enzyme
`
`
`_
`- Homeostatic role-——controls the
`M5
`basal levels of PGS
`COX-1 and -2
`
`.
`
`
`
`
`
`
`
`
`COX-2
`
`
`
`«inducible enzyme—upregulated
`during pathologic conditions
`(eg, injury, inflammation)
`
`-Initiates the synthesis of PGS
`involved in inflammation
`
`
`
` Abuja M. The AAPS Joumai. 2OOS,10(2)’229-241.
`Ch0H. et at. Clin Ophtltalmoi. 2009, 3.199-2'50.
`
`Lawm-x
`Kim SJ, et al. SUN Opillhalnm. 20101 55{2}1iOE—l33,
`
`
`Ram Z. et at. J Ocul Pnarmaco: Tner 20GB;;Z4r2):t4<.—152.
`
`CCNFfDEh'TIr’\L f\.‘3'!' FOR DISTREUTIO/‘I.
`
`
`(eg, PGE2)
`
`Both COX-1 and COX-2 catalyze the biosynthesis of prostaglandins.
`
`COX-1 is a constitutively expressed in a variety of tissues including ocular tissues. Under normal
`conditions it plays a homeostatic role controlling the basal levels of prostaglandins. COX-1 may also
`be increased, and thus increase prostaglandin production, when there is a high level of arachiclonic
`acid such as after cell injury.
`
`COX-2, on the other hand, is an inducible enzyme which is upregulated during pathologic conditions
`such as injury or inflammation. in particular, COX-2 initiates the synthesis of prostaglandins involved
`in severe inflammation including PGE2.
`
`In the anterior segment of the human eye, COX-1 and COX-2 are primarily expressed in the anterior
`uvea, specifically in the nonpigmentepithelium of the ciliary body.
`
`References
`
`1. Ahuja M. The AAPS Journal. 2008;10(2):229-241.
`2. Che H, et al. Clin Ophthalmol. 2009; 3:199-210.
`3. Kim SJ et al. Surv Ophthalmol. 2010; 55(2):108-133.
`4. Radi Z, et al. J Ocul Pharmacol Ther 2008;24(2):141—152.
`
`PAGE 17 OF 49
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`CONFIDENTIAL
`
`17
`
`PROL0284809
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`PAGE 17 OF 49
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`

`
`Prostaglandins (PGS) Play Key Role in
`Postsurgical Inflammation and Pain
`?§*eas§a§§am§§§°ts
`
`LEUKOCYTE
`MIGRAWQN
`
`STIMULATE PAIN
`
`I
`
`vascums
`;’9EaM£Aa;i.nv
`
`J
`
`‘$"
`' Chemosis
`‘ AQUEOW
`humor
`protein‘
`
`=.
`
`7.
`
`I
`
`v
`
`1-
`
`D.iSRUP‘l'tON or
`vasooitanom GCUMWBLOOD
`A
`BARRIERS
`.
`&V
`« Hyperemia
`- Aqueous humor
`protein’
`- Erythemail,
`- queous
`A
`humor
`protein‘
`
`'.
`
`=v
`
`’
`
`'1./-\hLI}3 M. The AAPS Journaf. 2008:lO(2):229-244..
`2. Radi ZA, Ostroski R. !l.lediatorsInfial7:m. 2007;2007'8509t.
`CCNFi‘DEI'2'TI.ki. N37 FOR DISTR.‘5UT,’O/‘I.
`
`Prostaglandins play a key role in the manifestation of postsurgical inflammation and pain. They
`contribute to some of the telltale signs of postoperative cataract surgery inflammation including cell,
`flare, and pain. Prostaglandins are involved in leukocyte recruitmentand migration which may
`contribute cells in the anterior chamber. Prostaglandins stimulate pain, and through their effects on
`the vasculature (eg, permeability and vasodilation), prostaglandins may contribute to protein in the
`aqueous humor, hyperemia and erythema.
`
`References
`
`1. Ahuja M. The AAPS Journal. 2008;10(2):229-241.
`2. Radi ZA, Ostroski R. Mediators lnflamm. 20072007285091.
`
`PAGE 18 OF 49
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`CONFIDENTIAL
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`PROL0284810
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`PAGE 18 OF 49
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`

`
`An effective topical ophthalmic NSAl,DWshouVlglV;VVVVVVVVVVVVVVVVVVVVVVH
`
` NSAIDS Are an important Post—Operative Tool
`
`
`for Cataract Surgery
`
`
`
`o Penetrate efficiently to allow
`rapid and sustained therapeutic
`levels
`
`0 Possess high COX inhibition for
`sustained control of
`
`inflammation and pain
`
`0 Have a proven safety profile
`
`
`
`Fi:tdlO. Eu: Oplilila/rri av. 2O10.4$.54—5
`CCNFr‘DEI'2'TIAL NET FOR D!STF.*BUT,’ON.
`
`
`
`Given the potential for inflammation after cataract surgery and the importance of controlling that
`inflammation, NSAlDs play a very important role in cataract surgery. An effective topical ophthalmic
`NSAID should offerthe following:
`- Penetrate efficiently into target tissues to allow rapid and sustained achievement of therapeutic
`levels
`
`- Possess high potency of COX inhibition to enable sustained control of inflammation and pain
`- Have a proven safety profile
`
`Reference
`
`1.
`
`Findl 0. Eur Ophthalmic Rev. 2010;4:54-59.
`
`PAGE 19 OF 49
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`CONFIDENTIAL
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`
`PROL0284811
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`PAGE 19 OF 49
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`

`
`Topical Ocular NSAlDs Continue to Evolve
`
`Various Approaches Used to Improve Topical Ocular
`Delivery of NSAIDS
`
`Penetration
`
`Haloge-nation‘
`-
`lncreaseslipophilicity
`
`ll I ll
`
`l
`
`Potency
`Halogenationl
`
`ii 3
`
`l l l i
`
`Formulation pH”
`- Affects lipophiiicity
`
`I
`
`Prodrug3
`°
`improves penetration
`.
`.
`,
`.
`l
`i - Requires enzymatic conversion to active form
`Viscosity agents
`
`- Carboxymethylcellulose sodium“
`
`- Guargum3
`«
`i=Ro«.elisA§aac
`~
`2 AGUVAl‘._ {pack
`3 lLE'vRCi§pact<age Eras
`
`CCNFi‘DEh'TIi<L NOT FOR DISTRi‘E’JT,’O/‘J.
`
`Several strategies have been applied in efforts to improve the delivery and ultimately the efficacy of
`topical NSAlDs for the treatment of inflammation after cataract surgery.
`
`Consistent with the drug development principle of lowest effective dose, the general trend for topical
`ophthalmic NSAID therapy has been molecular and formulation changes that have allowed for:
`— Reduced frequency of administration
`— Reduced drug concentration per dose
`— And ultimately less drug exposure on the ocular surface without compromising clinical
`performance.
`
`References
`1. PROLENSA [package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2013.
`2. ACUVAIL [package insert]. lrvine, CA: Allergen; 2011.
`3. ILEVRO [package insert]. Fort Worth, TX; Alcon; 2013.
`
`PAGE 20 OF 49
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`CONFIDENTIAL
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`
`PROL0284812
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`PAGE 20 OF 49
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`

`
`What really matters...
`
`Cataract surgery is common but can lead to inflammatory response
`that may adversely affect the outcome
`
`Cyclooxygenase (COX-1 and COX-2) Enzymes
`
`— Primarily expressed in lris and Ciliary body
`
`— Produce prostaglaridins from arachidonic acid as a result of surgical
`trauma
`
`Prostaglandins
`
`—- Play a key role in postsurgical inflammation and pain
`
`NSAlDs are an important post-operative tool for cataract surgery
`— Inhibit COX-1 and COX-2 and blockthe production of prostaglanolins
`
`— Require efficient corneal penetration to reach site of COX production
`— Continue to evolve
`
`CCNFlOEI')'TI/w’. NOT FOR D)STFf5’JT,’O/‘I.
`
`PAGE 21 OF 49
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`CONFIDENTIAL
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`
`PROL0284813
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`PAGE 21 OF 49
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`

`
`Bromfenao Ophthalmic Solution 0.07%:
`Two Steps Forward
`
`Bonnie Henderson, MD
`
`Clinical Professor of Ophthalmology
`
`Tufts University School of Medicine
`
`PAGE 22 OF 49
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`CONFIDENTIAL
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`PROLO284814
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`PAGE 22 OF 49
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`

`
`PROLENSA® (bromfenac ophthalmic solution) 0.07%
`
`-
`
`Indications and Usage
`— PROLENSA is indicated for the
`
`treatment of postoperative
`inflammation and reduction of ocular
`
`pain in patients who have undergone
`cataract surgery
`
`- Dosage and Administration
`— Instill one drop into the affected eye(s)
`once daily beginning 1 day prior to
`surgery. continued on the day of
`surgery and through the first 14 days
`post surgery
`
`- Contraindications
`None
`
`PROLENSA[pacKage insert). Tampa, F2. Bauscn & Lamp incorporated; 2013
`CCv"4‘Fr‘DEI'JTIAi. N3?‘ FOR D!STR.‘EUT.’O/‘I.
`
`Reference
`
`1. PROLENSA [package insert]. Tampa, FL: Bausch & Lomb incorporated; 2013.
`
`PAGE 23 OF 49
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`CONFIDENTIAL
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`23
`
`PROLO284815
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`PAGE 23 OF 49
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`

`
`Warnings and Precautions
`
`Sulfite allergic reactions
`PROLENS/Xcontains sodium sulfite
`
`5'-’:"?€I?E.. £§f\4C‘.:§'x-’3i“
`r’bro::4r2>.r.<a:; ophtrzerxrzic
`.'s::n‘i.:tiz3.r>.? 53, 07%
`
`Sulfite allergic reactions may occur in susceptible people and include
`anaphylactic symptoms and life-threatening or less severe asthmatic episodes
`Overall prevalence of sulfite sensitivity is unknown, likely low, and more common
`in asthmatics
`
`Slow or delayed healing
`— All topical NSAlDs and corticosteroids may slow or delay healing
`~ Concomitant use of topical NSAlDs and steroids
`may increase potential for healing problems
`
`Potential for cross-sensitivity
`- Acetylsalicylic acid
`— Phenylacetic acid derivatives
`— Other NSAIDS
`
`increased bleeding of ocular tissues
`— Some ocular NSAlDs increase bleeding time due to interference with platelet
`aggregation in conjunction with ocular surgery
`PROLENSA.{paci<age mserr), Tampa. FL Bausch 8. Lomb incorporated 2013
`CCNFr‘DEI‘)'TIkL I\!3T FOR .DfSTR.‘5’o‘T.'ON.
`
`Reference
`
`1. PROLENSA [package insert]. Tampa, FL: Bausch & Lomb incorporated; 2013.
`
`PAGE 24 OF 49
`
`CONFIDENTIAL
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`24
`
`PROL0284816
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`PAGE 24 OF 49
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`

`
`,
`_
`Warnings and Precautions (cont.)
`
`5'-“ESE; £;"}'\{r‘.§x-’t“
`.s::n‘utiz3.r>.? 53, 07%
`
`- Keratitis and corneal reactions
`
`— Use of topical NSAIDS may result in keratitis
`— in some susceptible patients, use of topical NSAlDs may result in
`~ Epithelial breakdown
`- Corneal thinning, erosion, ulceration. or perforation
`- These events may be sight threatening
`
`~ Contact lens wear
`
`— PROLENSAshould not be administered while wearing
`Contact lenses
`
`- Post cataract surgery clinical trial experience
`— Most common adverse reactions (3%-8% of patients)
`Anterior chamber inflammation
`Foreign body sensation
`Eye pain
`Photophobia
`Blurred vision
`
`Please see full Prescribing information for PROLENSA®
`P&’<OLENSAl_oacz<agemsert}, ramps. FL Bausch 8. Lomb lnccrpo.'ateol,2U13
`CCNFi‘DEI'2'TI/iL N3?" FOR DtSTR.‘5’JT.'O/'4'.
`
`Reference
`
`1. PROLENSA [package insert]. Tampa, FL: Bausch & Lomb incorporated; 2013.
`
`PAGE 25 OF 49
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`CONFIDENTIAL
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`
`PROLO284817
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`PAGE 25 OF 49
`
`

`
`The Formulation
`
`PAGE 26 OF 49
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`CONFIDENTIAL
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`25
`
`PROL0284818
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`PAGE 26 OF 49
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`

`
`Survey Question
`
`Halogenation of amfenac with bromine to
`create bromfenac increases:
`
`A. Potency
`
`B. Penetration
`
`C. Lipophilicity
`
`D. All of the above
`
`PAGE 27 OF 49
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`CONFIDENTIAL
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`27
`
`PROL0284819
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`PAGE 27 OF 49
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`

`
`Bromfenac: The Only Brominated NSAID
`
`Halogenation with bromine:
`
`Proven Potency and Penetration
`
`-
`
`-
`
`Increases the potency
`against COX-2
`
`Increases the Iipophilicity
`
`- Facilitates penetration
`through the cornea
`
`- Not a prodrug
`
`Baklayan GA. et al. J Ocul Pharmacol‘ Ther. 2OOB;24(4‘;:392-398.
`BROMDAY {package insert}. Tampa, Ft. Bausch & Lomb Incorporated: 201 1..
`Data on me. Bausch & Lomb Incorporated
`CCNFl:')EI')'TIl'«L NCT FOR DlSTR.*5UT,’O/‘J.
`
`Halogenation with bromine not only increases the potency of the bromfenac molecule but also
`enhances its lipophilicity, which facilitates corneal penetration.
`
`References:
`
`1. Baklayan GA, Patterson HM, Song CK, et al. 24-hour evaluation of the ocular distribution of
`(14)C-labeled bromfenac following topical instillation into the eyes of New Zealand white
`rabbits. J Ocul Pharmacol Ther. 2008;24(4):392—398.
`2. BROMDAY [package insert]. Tampa, FL: Bausch & Lomb Incorporated; 2011.
`3. Data on file. Bausch & Lomb Incorporated. (Bromfenac 0.07% phase 3 studies.)
`
`PAGE 28 OF 49
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`CONFIDENTIAL
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`28
`
`PROL0284820
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`PAGE 28 OF 49
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`

`
`Bromination Increases Potency
`
`1
`
`Ciinicai significance of in vitro data is unknown.
`
`- Blocks prostaglandin production by inhibiting COX-1 and
`COX-2 enzymes
`
`IC50: Concentration of NSAID that produces 50% inhibition
`of COX-1 and/or COX-2
`
`ICSO COX-1 = 0.086 ;.LM
`
`4
`
`ICSO COX-2: 0.0075 |.tM
`
`2
`
`- Potent inhibitor of COX-2,3 the primary mediator of
`ocular inflammation4
`Int‘ J F/78!’/77 30/ Drug Res. 2010; 2(3): 219-223
`1. Thakrai J, et at.
`2. Kids T. et at. Poster presented at: American Society for Catatact and Refractive
`Surgery {/-KSCRS), April 27-May 2. 2007. San Diego, CA,
`3. Waterbury LD, et al. Curr Med Res Opin. 2006,2Zti3}:’et33-1140,
`4. Waters T. et al. J Cataract Refract SUI‘ 20073311539-1545.
`5 Oka T, et al. Curr Eye Res. 2004:29(t
`-
`CN.=r‘DEIv'TIAL N3?" row ozsmscrxoi-J.
`
`Like other NSAlDs, bromfenac works by blocking prostaglandin production through
`inhibition of the COX enzymes. Bromfenads potency against these enzymes is important to
`consider. Potency is evaluated in laboratory assays that measure the amount of drug
`needed to inhibit 50 percent of the target enzyme activity. The lower the inhibitory
`Concentration 50 or lC5O, the more potent the drug is against the target. You can see on
`this slide that the lC50 values for bromfenac against both COX-1 and COX-2 are very low.
`Bromfenac is an effective inhibitor of COX-2, which is the primary mediator for ocular
`inflammation.
`
`Clinical significance of in vitro data is unknown.
`
`References
`
`lnz‘J Pharm Sci Drug Res. 2010; 2(3): 219-223.
`1. Thakral J, et al.
`2. Kida T, et al. Poster presented at: American Society for Cataract and Refractive Surgery
`(ASCRS). April 27-May 2, 2007. San Diego, CA.
`3. Waterbury LD, et al. Curr Med Res Opin. 2006;22(6):1133-1140.
`4. Walters T, et al. J Cataract Refract Surg. 2007;33:1539-1545.
`5. Oka T, et al. CurrEye Res. 2004;29(1):27—34.
`
`PAGE 29 OF 49
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`CONFIDENTIAL
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`29
`
`PROL0284821
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`PAGE 29 OF 49
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`

`
`Bromination Increases Lipophilicity
`
`Lower Cmgp
`Less lipophilicity
`
`Amfenac1(CLGg,, 2 1.14)
`
`' Log scale:
`I Approx. 10 times greater
`I
`Iipophilicity
`
`V
`
`I—Il O Bromfenacllcmgpz 2.02)
`
`Higher Cmgp
`(More lrpophilicity)
`
`1. Calcufated using Advanced Chemistry Development {ACD/Labs) Software V1 1.02
`(© 19942013 £“«CDrLabs)
`~
`CCN.=£9EIv'TIkL N3?‘ tow OtSTR.*E’JT,’ON.
`
`The human cornea is resistant to penetration by drugs. it is composed of 5 layers. The outermost
`layer, the epithelium, provides a significant barrier (90%) to hydrophilic drugs but little (10%) barrier
`to lipophilic drugs?
`
`Halogenation with bromine increases the lipophilicity (calculated partition coefficient CLQQP: 2.02)
`relative to amfenac (CLOQP: 1.14) by almost 10 times (note it is a log scale)? The greater lipophilicity
`of bromfenac may facilitate penetration through the cornea.
`
`CLOQP = calculated partition coefficient. A partition coefficient is the ratio of concentrations of a
`compound in the 2 phases of a mixture of two immiscible liquids at equilibrium. Normally one of the
`solvents chosen is water while the second is hydrophobic such as octanol. Hence the partition
`coefficient measures of how hydrophilic ("water-loving") or lipophilic (or hydrophobic, "water—fearing")
`a chemical substance is.3 The greaterthe partition coefficient the greater the lipophilicity, usually
`represented with a log scale. Hence a 1 point difference in LogP = 1 order of magnitude or 10 times.
`
`References
`
`1. Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2013
`ACD/Labs)
`2. Ghate D, Edelhauser HF. Expert Opin Drug Deliv. 2006;3(2):275-287.
`3.
`en.wikipedia.org/wiki/Partition_coefticient
`
`PAGE 30 OF 49
`
`CONFIDENTIAL
`
`30
`
`PROLO284822
`
`PAGE 30 OF 49
`
`

`
`Survey Question
`
`The primary reason for lowering the pH of the
`PROLENSA formulation is:
`
`A. Create a greater proportion of
`neutral bromfenac molecules
`
`8. Improve the stability of the
`product
`
`C. Bring the pH of the formulation 13%
`closer to tear fluid
`
`D. Improve the comfort of the
`formulation
`
`PAGE 31 OF 49
`
`CONFIDENTIAL
`
`31
`
`PROL0284823
`
`PAGE 31 OF 49
`
`

`
`Bromfenac 0.09% PRDLENSA5’
`8 3
`_
`7.8
`
`Tear fluid
`7.4
`
`
`
`C~::ate 9.. at at.
`
`o_-am D.»’r'3? £33.’:-x ::czss:s::2:..:225.2:s:I
`
`The pH of a drug determines its degree of ionization (ie, whether it has a charge); a higher proportion
`of nonionized species results in greater corneal penetration.
`
`At high pH, the carboxyi group of bromfenac is not protonated and carries a negative charge (COO—).
`As the pH is lowered, there are more H+ and the COO- becomes protonated (addition of H+) to
`neutralize the negative charge (COOH) of the carboxylic acid. Neutral bromfenac molecules
`(—COOH) results in greater corneal penetration.
`
`References
`
`1. Ghate D, et al. Expert‘ Opin Drug Deliv. 2006;3(2):275-287.
`
`PAGE 32 OF 49
`
`CONFIDENTIAL
`
`32
`
`PROLO284824
`
`PAGE 32 OF 49
`
`

`
`In vivo (Rabbit):
`Persistence in Ocular Tissues
`
`I
`
`Clinical significance of animal data is unknown
`
`:4
`
`Iris/Ciliary Body
`
`Aq Humor
`
`~~:Et£~--Bromfenac 0.0?"/.2 {pH 7.8} Cornea
`~ :1:E~ Bromfenac 0,09% (pi-l 8,3) Cornea
`-A- Sromfenac 0.00% (pH 8.3) iris/Ciliary Body -~a:--Sromfena: 0.07% (pH 7.8) iris/Ciliary Bod»;
`was» Bromtenac 0.09% (pH 8.3) Aqueous Humor -~$&-~Bromfenac 0.07% (r>H 7.8) Aqueous Humor
`
`Comparable tissue levelswith lowerconcentration at lower pH
`
`CCNFr‘DEI*1'TI/\L N.’,"!' FOR D!STR.‘5UT.'OI‘J.
`
`In the cornea, aqueous humor and in the iris-ciliary body, the concentration of bromfenacwas
`comparable for PROLENSA® with 0.07% bromfenac reformulated at pH 7.8 as for bromfenac 0.09%
`formulated at pH 8.3. This suggests that the formulation of PROLENSA can enhance tissue
`penetration and achieve comparable concentration at desired sites of action.
`
`Clinical significance of animal data is unknown.
`
`Reference:
`
`Data on file. Bausch 8. Lomb incorporated.
`
`PAGE 33 OF 49
`
`CONFIDENTIAL
`
`33
`
`PROL0284825
`
`PAGE 33 OF 49
`
`

`
`Designed for Comfort and Convenience
`
`-
`
`l\/lore physiologic pHl=2
`
`Bromfenac 0.09%
`8.3
`
`PROLENSA®
`7.8
`
`8
`
`- Patients reported less foreign body sensation,
`photophobia and had less redness vs. placebo23
`
`- Convenient QD dosing?
`
`- Solution — dose uniformity without the need to shake?
`1. Coffey MJ,e1 at Olin Gphthalmol 2013712990312.
`2. PROLENSA" Prescribing Information. Apfil 2033
`3. Data on file. Eausc-h & Lomb lncorporated.20’x3
`
`COl'.I‘.=l,’)EI‘)'TI/xi. N37 FOR DfSTr?1E’e".'.’O/‘J.
`
`PROLENSA® has a pH (7.8) that is closerto that of tears than bromfenac 0.09% (pH 8.3).
`
`in the phase 3 clinical trials, patients using PROLENSA® reported less foreign body sensation,
`photophobia and had less redness than those using placebo“.
`
`PROLENSA® is administered once a day, and is formulated as a solution that provides dose
`uniformity without the need to shake?
`
`References
`
`1. Coffey MJ, et al. Ciin Ophthalmol. 2013;7:2990312.
`2.
`PROLENSA*’”> Prescribing Information, April 2013
`3. Data on file, Bausch & Lomb incorporated, 2013
`
`PAGE 34 OF 49
`
`CONFIDENTIAL
`
`34
`
`PROL0284826
`
`PAGE 34 OF 49
`
`

`
`What really matters...
`
`~ Effect of halogenation with bromine:
`
`— Increases the potency against COX-2
`
`— Increases the lipophilicity
`
`— Facilitates penetration through the cornea
`
`- Formulation:
`
`Lower pH improves corneal penetration, thus lower
`concentration of bromfenac
`
`More physiologic pH
`
`Convenient once-daily closing
`
`Solution: dose uniformity without the need to shake
`
`CCNFl‘DEI')'TIAL N31" FOR DISTR4‘EUT,’O/‘I.
`
`PAGE 35 OF 49
`
`CONFIDENTIAL
`
`35
`
`PROLO284827
`
`PAGE 35 OF 49
`
`

`
`Phase 3 Clinical Trials
`
`PAGE 36 OF 49
`
`CONFIDENTIAL
`
`35
`
`PROL0284828
`
`PAGE 36 OF 49
`
`

`
`Bromfenac 0.07% QD Phase 3 Clinical Triiaiiliém""""""""
`
`5tud.v.£?.es32.n_
`
`Two Double-Masked, Multicenter, Vehicle-Controlled, Randomized Studies
`Study 1 = East; Study 2 = West
`
`Screening
`:8 cl of surgery
`
`Visit1
`(Surgery)
`Day 0
`
`Visit2
`Day 1*
`
`Visit 3
`Day 3
`(:1)
`
`ViSif4
`Day 8
`(:1)
`
`l
`
`l
`
`l
`
`Sromfenac 0.07%
`
`Vehicle
`
`Visit 5
`Day 15 (:1)?
`
`Visit 6
`Day 22
`(mi
`
`Start dosing
`Day -1
`
`Final close
`Day 14
`
`*or 1 week after last
`dose if prematurely
`discontinued,
`
`1 Drop per Day for 16 Days
`
`Typical exclusion criteria
`[Ocular topical. inhaled. or oral corticosteroid use within 15 clays]
`‘Secondary endpoint = pain free; ‘Primary endpoint = SOIS grade 0.
`Data on file, Bausch & Lomb incorporated 20*2
`CCNFr‘OEI*2'TIAi_ J'\.‘3'!' FOR D(STR.‘5’o‘T,’O/‘J.
`
`The efficacy of PROLENS/\® was demonstrated in two double—masked, multicenter, vehicle—controlled,
`randomized studies, outlined here.
`-
`Studies SOO124—ER and SO0124—WR were conducted at 39 sites to evaluate the safety and efficacy of
`bromfenac 0.07% for the treatment of ocular inflammation and pain associated with cataract surgery.
`Subjects instilled ‘I drop of PROLENSA into the study (operative) eye QD for a total of 16 days. Dosing with
`PROLENSA began 1 day prior to surgery (Day -1) and continued on the day of surgery and for 14 days after
`surgery.
`Subjects had discrete post—study follow-up evaluations for postsurgical inflammation and pain, as well as
`other safety endpoints at Days 0,
`‘l, 3 (:1), 8 (:1), ‘I5 (:1), and 22 (:1).
`Select typical exclusion criteria are also listed here.
`Planned relaxing incisions or other intra-/postoperative procedures
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`-
`-
`
`-
`
`Ocular, topical, inhaled, or oral corticosteroid use within 15 days
`
`Depot corticosteroid use within 45 days
`Ocular, topical, or systemic NSAlDs use within 7 days
`Active corneal pathology
`
`lOP <5 mm Hg or >22 mm Hg
`
`The study demographics were similar between the PROLENSA® group and the vehicle group.
`-
`Subjects assigned to bromfenac 0.07% were similar with respect to age, gender, and race to those subjects
`randomized to receive vehicle.
`
`- There were no significant difference between the studies.
`
`Subject Demographics
`
`llI»»»
`
`800124-er
`
`PROLENSA
`(N=112)
`67.2
`.
`
`_
`.
`l
`§ V°“'°'elN“1°8l
`l
`67.6
`.
`
`l
`
`l
`
`l
`
`E
`5
`g
`
`e
`
`Mean ag
`Gender % female)
`(
`Race
`Caucasian
`Asian
`Black
`Other
`
`S00124-wr
`
`PROLENSA
`(N=110)
`69 6
`
`T
`l
`j
`l
`
`Vehicle
`(n=110)
`69.4
`
`37
`
`CONFIDENTIAL
`
`PROL0284829
`
`PAGE 37 OF 49
`
`

`
` Bromfenac 0.07% was Effective at Eliminating {:?'?'?
`
`
`
`Postoperative inflammation
`
`Proportion of Patients with SOIS of Grade 0
`
`
`5
`
`Iiiiiééisiéiiiiiiiiéiéiiiéiiiii$§§i:i4:E.Blf:i
`gromienack 9,07% {n:1;2)
`--:;:;~Ve.*:ide(n=]08)
`
`P(CD001
`45.5%
`;:::+
`
`SW
`”
`
`40%
`
`LYiiéséiériiiiiéiéiie!iIii${ii§.12Et§l?5ii§iE
`e
`g
`Bmmfenac, 0.07% (n=’.~10)
`~:?:‘:-«Vehicle (n-1110)
`
`P‘O-05
`455%
`
`i
`E
`
`2
`
`F’<0.05
`
`
`
`30%
`
`g
`20% g
`.
`
`30.0%
`
`H
`28.2%
`
`1.8%
`
`5.4%
`
`.
`
`13.0%
`
`10%
`
`12.7%
`
`
`
`
`
`O39Ex
`
`+~
`'6
`£500’
`g
`”°
`.—.
`409;
`L"
`8
`(1333034)
`m
`520%
`E
`
`C C
`
`.31“
`G,
`<33?
`
`§
`
`
`
`i595
`
`0%
`
`65%,
`Day 15*
`oay 3
`‘Day 15 primary endpoint.
`Data on file, Bausch & Lamb incorporated, 2012.
`
`C{)HFi‘9EI'JTIAL N3?‘ FOR DtSTr'<t‘EUT.’O/‘I.
`
`Day 1
`
`Day 3
`
`
`
`Bromfenac ophthalmic solution, 0.07% met its primary endpoint in both Phase 3 studies because a
`significantly higher proportion of patients treated with bromfenac ophthalmic solution, 0.07% had a
`SOIS score of O at Day 15, compared to vehicle. There was also a significant effect at Day 8.
`
`Reference:
`
`Data on file. Bausch 8. Lomb Incorporated.
`
`PAGE 38 OF 49
`
`CONFIDENTIAL
`
`38
`
`PROL0284830
`
`PAGE 38 OF 49
`
`

`
`
`
`Twice as Many Bromfenac 0.07% Treated Patients had {-3
`Resolution of Inflammation at Day 15
`
`
`
`SOIS of 0 at Day 15?
`(Pooled Data)
`
`D
`
`A
`§ 90%
`i
`.9
`<5 80% ,;
`E
`:
`
`9:
`4eo/
`
`
`
`g 70%
`3 60%
`5.
`3
`Ԥ 50% i
`3 40%
`£
`9
`3 30% i
`0
`E
`g 20%
`E 10%
`U
`Q)
`__
`09/
`g
`o
`"’
`
`0
`.
`E
`
`
`
`20%
`
`Vehicie
`{n=218)
`
`,
`
`_
`
`,
`
`V
`
`,
`
`,,,,,,,,,,,,, H
`
`‘
`
`V
`V H
`PROLENSA
`(n=222}
`
`90%
`.
`80%
`
`70% ~
`60% V»
`50%
`40%
`
`30%
`
`20%
`10% 0
`0% ,,
`
`H
`
`Trace Cells (0-5 cells)
`at Day 15 (Pooled Data)
`*
`80%
`
`47%
`
`I_
`PR0fEN5A
`(n-222)
`
`,,
`
`
`
`
`
`"’°<GiO002.
`"Day 15 primary endpoint.
`Data on Vite, Bausch 8: Lomb mcorporated. Z012.
`
`CCNFr‘DEI*JTII3\L NQT FOR DISTRi‘EUT.’O/2'.
`
`
`
`
`The pooled data forthe primary endpoint is shown on the left. Together, the two Phase 3 studies
`achieved a significance of P<0.0001 at Days 8 and 15 on the proportion of patients with SOIS of 0.
`
`On the right is a measurement of trace ceiis (0-5 ceils).
`
`Reference:
`
`Data on file. Bausch & Lomb incorporated.
`
`PAGE 39 OF 49
`
`CONFIDENTIAL
`
`39
`
`PROL0284831
`
`PAGE 39 OF 49
`
`

`
`Bromfenac 0.07% Provided Rapid Pain
`Relief [Day 1]
`
`Proportion of Subjects Pain Free at Each Study Day (Pooied Data)
`
`'3'a\_.
`cu
`Eu.
`EasD.
`
`§9
`
`-.n3U1‘O-r
`.94-’..
`oa
`O3-‘
`n.
`
`oc
`
`*P<O.C|001,
`‘Day 2 secondary endpoint.
`Data on We, Bausch Si Lamb incorporated. 2012.
`
`CCv":‘Fr‘9EI'1'TIAL N37 ‘OR DISTR.‘5UT.’O/‘I.
`
`A difference in percentage of patients reporting no ocular pain was seen with PROLENSA® vs.
`vehicle on Day 1, a secondary efficacy endpoint. This difference was maintained through Day 15
`(P<0.001).
`
`Reference:
`
`Data on file. Bausch 8. Lomb Incorporated.
`
`PAGE 40 OF 49
`
`CONFIDENTIAL
`
`40
`
`PROL0284832
`
`PAGE 40 OF 49
`
`

`
`Vehicle
`(n=102)
`24 (23.5%)
`
`‘
`.
`
`PROLENSA
`(n=103)
`
`18 {16<5%}
`
`Foreign body sensation
`Eve pain
`
`Conjunctival hvperemia
`Increased iOP
`Corneal edema
`lritis
`Increased Iacrimation
`
`Ocuiar hvperemia
`Vitreous floaters
`"""""”""””""”m""”W’".\Ti'a"—"i«iBi7é';§:W&i'"*""""W”m""
`Data on fife, Bausch & Lo b i
`~
`
`CCv'VFr‘DEI'.iTIAi_ N3?" FOR DISTr'<.‘EUT.'O/‘I.
`
`Presented here is a summary of adverse events encountered in the 2 studies.
`
`The adverse events noted in the red