JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTiCS
`Voume 26 Number
`2010
`Mary Arm Liebert
`DO 10.1 089/jop.2009.0091
`
`inc
`
`Topical Cyclosporine OO5% for the Prevention of Dry Eye
`Disease Progression
`
`Sanjay
`
`Rao
`
`Abstract
`
`Purpose To assess the prognosis of dry eye in patients treated with cyclosporine 0.05% or artificial
`using the International Task Force 1TF guidelines
`Methods This was
`trial Dry eye
`prospective randomized longitudinal
`investigator-masked
`single-center
`twice-daily treatment with either cyclosporine 0.05% Restasis Allergan Inc Irvine CA
`patients received
`tears Refresh Endurt Allergan Inc Irvine CA ii
`22 for 12 months Disease severity was
`36 or artificial
`determined at baseline and month 12 according to the consensus guidelines developed by the ITF Dry eye signs
`and symptoms were evaluated at baseline and months 48 and 12
`Results Baseline sign and symptom scores and the proportion of patients with the disease severity level
`or
`0.05 At month 12 34 of 36 cyclosporine patients 94% and 15 of 22 ar
`were comparable in both groups
`tear patients 68% experienced improvements or no change in their disease severity
`0.007 while
`of 36 cyclosporine patients 6% and
`tears patients 32% had disease progression
`001
`of 22 artificial
`Cyclosporine 0.05% improved Schinner
`test scores tear breakup time and Ocular Surface Disease Index scores
`the study with significant
`0.01 differences compared with artificial
`throughout
`tears being observed
`months
`and 12
`Conclusions Treatment with cyclosporine 0.05% may slow or prevent disease progression in patients with dry
`or
`eye at severity levels
`
`tificial
`
`tears by
`
`at
`
`ntroducdon
`
`from ocular
`WITH DRY EYE disease suffer
`irri
`tation often accompanied by vision impairment which
`limits important daily activities and negatively
`impacts
`quality of life QoL.t-3 The prevalence of dry eye disease is
`estimated to be from 5% to 30% The largest US cross-
`sectional survey studies the Womens Health Study WI-IS
`and the Physician Health Study PHS indicated that
`the
`prevalence of dry eye disease among women and men aged
`over 50 years is 78% and 4.3% respectively Using this prev
`alence data 4.9 mfflion Americans aged over 50 years are
`estinrnted to be affected by dry eye disease.67
`The diagnosis and treatment of dry eye is challenging.8
`The Wilmer Eye Institute at Johns Hopkins University re
`Task Force ITF of 17 dry
`cently invited the International
`eye experts to create guidelines for the diagnosis and treat
`ment of dry eye disease by using Delphi consensus tech
`nique.9 The ITF panel categorized dry eye disease severity
`
`tears
`
`with increasing severity from to
`into
`levels Table
`and developed consensus
`treatment guidelines The level of
`disease severity was considered the most important factor in
`determining the appropriate range of therapeutic options.9
`While counseling education and preserved artificial
`were recommended for the management of patients diag
`nosed at severity level
`tears topical
`unpreserved artificial
`and/or corticosteroids were recommended for
`cyclosporine
`Punctal plugs oral
`patients at severity level
`tetracyclines
`systemic immunomodulators and surgery were reserved
`for the management of dry eye patients diagnosed at se
`and 49
`verity levels
`key recommendation
`of the 1TF panel was the use of
`topical anti-inflammatory therapy in patients with clini
`cally apparent ocular surface inflammation.9 This recom
`mendation stemmed from the recent evidence
`indicating
`inflammation plays major role in the disease etiology
`and may be
`unifying mechanism that underlies dry eye
`
`that
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`Lakeside Eye Group Chicago illinois
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`158
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`RAO
`
`TABLE
`
`CRITERIA USED TO DvrImwwE nra LEvns OF DRY EYE Ssvmury AccoRreNc
`
`TO ITF GWDELINE55
`
`Symptoms
`
`Signs
`
`Staining
`
`Level
`
`Mild to moderate
`
`Mild/moderate
`
`conjunctival
`
`None
`
`Level
`
`Level
`
`Level
`
`Moderate to severe
`
`Severe
`
`Severe
`
`signs
`Tear ifim signs visual signs
`Comeal
`ifiamentary keratitis
`Comeal erosions conjunctival
`scarring
`
`Mild punctate corneal and conjunctival
`Central corneal staining
`Severe comeal staining
`
`staining
`
`levels based on the severity of symptoms and signs At least one sign and one symptom
`Disease severity is categorized into
`of each category should be present
`to qualify for the corresponding level assignment
`
`thsease.2 Therefore it was suggested that
`the chronic use
`of safe anti-inflammatory therapies that normalize tear film
`composition early in the disease process may have the po
`tential to slow prevent or reverse dry eye progression3
`0.05% emulsion Restasis
`Ophthalmic cyclosporine
`Allergan Inc Irvine CA is the only anti-inflammatory
`medication approved by the Food and Drug Administration
`lym
`to increase tear production in dry eye patients4 In
`and inhibits
`phocytes cyclosporine binds to cyclophilin
`
`the nuclear
`of
`dephosphorylation
`calcineurin-catalyzed
`factor for T-cell activationMS Cyclosporine thereby inhibits
`IL-2 transcription which upon secretion stimulates T-cell di
`self-propagating autocrine and paracrine loop6
`vision by
`In humans topical administration of cyclosporine 0.05% has
`been shown to decrease the number of activated
`cells and
`expression of inflammatory markers in the conjunctiva of
`topical cy
`dry eye patients.lVS These findings suggest that
`closporine 0.05% targets the underlying inflammatory pro
`cesses in dry eye disease Therefore chronic treatment with
`cyclosporine 0.05% may offer the potential
`to alter the course
`of dry eye disease
`Wilson and Stalling recently evaluated the clinical appli
`cability of the ITF guidelines.3 Physicians participating in
`that study successfully implemented the ITF guidelines for
`diagnosis and treatment of dry eye patients3 Using the ITF
`guidelines this study was designed to assess the prognosis
`of dry eye disease in patients treated with cyclosporine
`0.05% or artificial
`tears
`
`Methods
`
`Study design
`
`identifier
`
`random
`This was
`investigator-masked
`single-center
`longitudinal clinical trial The study was
`ized prospective
`approved by the Western institutional
`review board in
`Olympia WA and was registered with ClinicalTrials.gov
`NCT00567983 Inclusion criteria were of age 18
`years or older diagnosis of dry eye without lid margin dis
`ease or altered tear distribution and clearance and
`disease
`as defined by the 1TF guidelines Table
`severity of level
`or
`1Y Primary exclusion criteria were prior use of topical cyclo
`sporine 0.05% within the last year topical or systemic use of
`anti-inflammatory or anti-allergy medications active ocular
`infection or inflammatory disease or uncontrolled systemic
`disease that can exacerbate dry eye disease Patients who
`wore contact
`lenses were also excluded from the study All
`participating patients signed written consent form before
`initiation of the study-specific procedures
`
`Patients were randomly assigned in 32 ratio to twice-
`daily treatment with either cyclosporine 0.05% or artificial
`tears Refresh EnduraF Allergan Inc Irvine CA in both
`eyes for 12 months The randomization ratio was an empir
`ical estimation due to lack of adequate epidemiological in
`formation to conduct power calculations prior to initiating
`the study Randomization was performed by
`statistical
`program and was overseen by the research coordinator
`Patients were enrolled in the study and initiated therapy
`after screening and randomization on the same day at
`the baseline visit month
`All patients were allowed to
`tears as needed if discomfort was
`utilize rescue artificial
`experienced The primary objective of this study was to
`assess the potential of topical cyclosporine 0.05% therapy
`to halt or slow disease progression relative to control at
`month 12 based on the ITF severity categorization Table
`The secondary outcome variables were the changes
`in
`dry eye signs and symptoms The study was conducted
`the Health Insurance
`in compliance with regulations of
`Portability and Accountability Act and the Declaration of
`Helsinki
`
`Disease severity and dry eye signs
`and symptoms
`
`Disease severity was assessed
`according to the ITF
`consensus guidelines at baseline and month 12 fable
`Patients were evaluated for signs and symptoms of dry eye
`test with anesthesia tear breakup time TBUT
`by Schirmer
`ocular surface staining and Ocular Surface Disease Index
`OSDI at baseline month
`and after receiving the study
`treatments at months 48 and 12 In each study visit TBUT
`was evaluated first
`followed by ocular surface staining and
`The TBUT was measured using
`Schirmer
`test respectively
`fluorescein dye Ocular surface damage was assessed by the
`Oxford method using sodium fluorescein to stain the cornea
`and lissamine green to stain the nasal and temporal bulbar
`conjunctiva.9 The scoring scale for ocular staining was
`and
`in nasal
`in cornea
`in temporal conjunctiva
`to
`to
`representing no staining and
`conjunctiva with
`repre
`senting severe staining These individual scores were then
`summed for the total Oxford score which ranged from to
`15 The change
`from baseline was calculated by subtract
`ing the baseline score from the months
`and 12 scores
`The symptoms of ocular
`irritation and their impact on vi
`sual functioning was assessed by OSDI
`validated 12-item
`questionnaire on
`to 100 with
`scale of
`representing
`asymptomatic and 100 representing severe debilitating dry
`eye disease
`
`to
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`CYCLOSPORINE AGIdNST DRY EYE PROGRESSflON
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`
`Goblet cell density
`
`The density of goblet cells in bulbar conjunctiva was
`evaluated at baseline and month 12 Impression cytology
`was performed in both eyes after evaluation of TBUL oc
`ular staining and Schirmer
`test Goblet cells were collected
`on cellulose acetate ifiters HAWP 304 P0 Millipore Corp
`Billerica MA The filters were fixated in glacial acetic acid
`formaldehyde and 70% ethanol and subsequently stained
`with modified periodic acidSchiff Papanicolaou stain
`400 mm representa
`Goblet cells were counted in
`400
`tive microscopic fields on each fflter.21
`
`Statistical analyses
`
`Patients who completed 12 months of treatment were
`included in the analyses The results were presented as
`SD Intergroup comparisons of categorical variables
`mean
`were performed using the chi-square or Fishers exact
`test
`variables were analyzed using nonparametric
`Continuous
`tests MannWhitney
`tests for between-group comparisons
`and Wilcoxon signed rank tests for within-group compari
`value 0.05 was considered
`sons
`cant difference Statview software SAS Institute Cary NC
`was used for all analyses
`
`statistically signifi
`
`Results
`
`Patient disposition and disease characteristics
`
`Of 74 patients enrolled between February 2006 and
`January2007 58 patients completed the 12-month study and
`were included in the analyses Table
`Forty-one patients
`were female and 17 patients were male The distribution
`or was similar
`of patients with disease severity of level
`in both treatment groups at baseline Approximately two-
`thirds of dry eye patients in both groups were diagnosed
`while one-third of patients was diag
`at severity level
`nosed at severity level
`Table
`There were no significant
`
`0.667 or
`
`differences in the mean age
`between-group
`0.800
`distribution of gender
`Sixteen patients discontinued the study The number of
`discontinuations was significantly higher among patients
`treated with artificial
`tears compared with those treated with
`Of 11 discon
`cyclosporine 005% 11 vs
`0.028 Table
`patients discontin
`tinuations in the artificial
`tear group
`ued the study because of discomfort upon instillation and
`patients were lost to follow-up or moved Seven of these
`patients had disease severity of level
`and patients had
`disease severity of level Of the discontinuations in the cy
`patients discontinued the study because
`dosporine group
`of discomfort upon instillation while were lost to follow-up
`or moved Three of these patients had
`disease severity of
`and
`patients had
`disease severity of level
`level
`
`Disease severity
`
`At month IZ significantly more patients treated with artifi
`dal tears had more severe signs and symptoms of disease than
`did those treated with cyclosporine 0.05% and therefore were
`categorized as progressing to
`higher disease severity level
`patients vs
`of 22
`of 36
`0.007
`respectively
`greater percentage of patients treated with
`In contrast
`Fig
`cyclosporine 0.05% had less severe signs and symptoms of
`disease and were categorized as improving to
`lower disease
`severity level 14 of 3639% patients vs
`of 2218% patients
`respectively This difference however was not statistically
`0.098 When combined with those who did
`significant
`change in the disease severity levels at month 12
`not have
`significantly more patients treated with cyclosporine 0.05%
`had either improvements orno change in disease severity than
`tears 34 of 3694% patients vs
`did those treated with artificial
`15 of 2268% patients respectively
`0.007
`
`Schirmer test scores
`
`test score was 77
`The mean baseline Schirmer
`tears and 7.9
`in patients randomized to artificial
`
`0.6 mm
`1.2 mm
`
`TABLE
`
`PATIFXr5 DisrosmoN AND DIsEAsE CIIutAcmiusncs
`
`Artficia Tear
`
`Cyciosporine 0.05%
`
`Patients it
`Enrolled in study
`Discontinued study
`Completed study
`SD years
`Mean age
`Range
`Gender
`Female
`
`34
`
`Dry eye severity at baseline
`Level
`
`34
`
`Level
`
`33
`IP
`22
`
`41
`
`36
`
`48.2
`6.3
`3959
`
`5.9
`47.5
`3057
`
`1673
`
`15 68
`732
`
`25 69
`
`24 67
`12 33
`
`the study because of discomfort upon instillation Two
`aMine patients discontinued
`patients were lost to follow-up or moved
`0.028 compared to patients who received
`cyclosporine 0.05%
`Two patients discontinued
`the study because of discomfort upon instillation
`Three patients were lost to follow-up or moved
`For patients who completed 12-month study
`0667 compared to the mean age of patients who received artificial
`0.800 compared to the artificial
`tear group
`
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`180
`
`RAO
`
`60
`
`.3
`
`40
`
`20
`
`Ill Artificial Tear
`
`22
`
`Cyclosporine 0.05%
`
`36
`
`Wotened
`
`No Change
`
`Improved
`
`Change in Dry Eye Severity Levels
`
`FIG
`
`Changes in dry eye severity at month 12 compared with baseline Patients were treated with cyclosporine 0.05%
`Task Force ITF consensus
`tears for 12 months Disease severity was assessed according to the International
`or artificial
`guidelines at baseline and month 12 The changes in disease severity levels were categorized as worsened no change or im
`proved when
`patient had
`respectively higher same or lower disease severity level at month 12 compared with baseline
`0.007 compared with the treatment with artificial
`tears
`
`0.625
`
`in patients randomized to cyclosporine 0.05%
`Patients treated with artificial
`tears did not have
`significant
`the study
`test scores throughout
`in their Schirmer
`change
`whereas those treated with cyclosporine 0.05% had increas
`ingly higher mean Schirmer test scores at each follow-up
`visit The mean Schirmer
`test scores of patients treated with
`cyclosporine 0.05% were significantly greater than those of
`1.0mm
`tears at month 89.1
`patients treated with artificial
`1.1 mm
`1.0 mm vs
`0.001 and month 12 9.8
`vs 75
`76
`0.001 Fig
`1.1
`
`TBUT
`
`The mean baseline TBUT was 5.0
`tears and 4.9
`randomized to artificial
`
`0.8
`
`0.8
`
`in patients
`in patients
`
`randomized to cyclosporine 0.05%
`0.550 The mean
`tears slightly de
`TBUT of patients treated with artificial
`creased throughout
`the study whereas patients treated with
`longer mean TBUT
`0.05% had increasingly
`cyclosporine
`The mean TBUT of patients
`at each follow-up visit Fig
`0.05% was significantly longer
`treated with cyclosporine
`tears at months
`than those of patients treated with artificial
`0.001 and 12 6.5
`vs 4.6
`vs
`0.65
`1.4
`6.2
`
`1.1
`
`4.6
`
`0.7s
`
`0.001
`
`Ocular surface staining scores
`
`At baseline patients randomized to cyclosporine 0.05%
`tears had similar mean Oxford staining scores
`or artificial
`
`14
`
`12
`
`Co
`
`H41IIIIIIt.6
`
`Cyciosporine 0.05%
`
`36
`
`Artificial Tear
`
`22
`
`Cyclosporine 0.05%
`22
`
`Artificial Tear
`
`36
`
`lime months
`
`Time months
`
`12
`
`12
`
`FIG
`Schirmer
`test scores Patients were treated with cy-
`tears for 12 months Schinner
`closporine 0.05% or artificial
`test was performed with anesthesia
`indicated study vis-
`at
`0.001 compared with patients treated with artificial
`its
`
`tears
`
`TBUt Patients were treated with cyclosporine
`FIG
`tears for 12 months Tear breakup time
`0.05% or artificial
`Tear breakup time TBUT was measured with fluorescein
`indicated study visits
`0.001 compared with
`dye at
`patients treated with artificial
`
`tears
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`CYCLOSPORft4E AGMNST DRY EYE PROGRESSION
`
`161
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`TABLE
`
`MEAn Ocur.a SURFACE STAmrnsrc Scoaas
`
`Art ficial
`
`tear it
`
`22
`
`1.13 NA
`786
`0.99 0.12
`1.01 0.25
`0.91 0.32
`
`0.64
`
`0.94
`
`0.94
`
`773
`753
`
`754
`
`Baseline
`Month
`Month
`Month 12
`
`8.31
`
`778
`
`728
`
`Cyclosporine 0.05% it
`0.94 NA
`8.44
`0.95 0.13
`0.93 0.64
`1.28 1.19
`
`36
`
`0.35
`
`0.63
`
`1.36
`
`0.056 NA
`
`0.0360.787
`0.576 0.087
`
`0.223 0.011
`
`tears for 12 months Ocular surface
`Patients were treated with cyclosporine 0.05% or artificial
`indicated times by the Oxford method The mean changes from baseline
`damage was assessed at
`and corresponding
`values are indicated in brackets.s The change from baseline was calculated by
`subtracting the baseline score from the month 48 or 12 scores
`NA
`not applicable
`ffhe changes form baseline were paired comparisons If
`baseline was also excluded from that calculation
`
`data point was missing the
`
`1.0
`
`0.9 vs 79 1.1
`At month
`0056 Table
`8.4
`patients
`treated with cyclosporine 0.05% had significantly higher
`mean staining scores than those treated with artificial
`tears
`1.0 vs 77
`0.036 There was no between-
`8.3
`group difference in ocular staining at months
`and 12
`from baseline
`Nonetheless the mean improvement
`Table
`in the ocular staining scores of patients treated with cyclo
`sporine 0.05% was significantly greater than of those treated
`tears at month 12 1.2
`1.4 vs 0.3
`0.9 re
`with artificial
`0.011 Table
`These findings indicate that
`spectively
`cyclosporine 0.05% improved ocular surface staining signif
`icantly more than did artificial
`tears at month 12 compared
`with baseline
`
`OSDI Scores
`
`Patients randomized to artificial
`tears or cyclosporine
`0.05% had similar OSDI scores at baseline
`19.1
`1.9
`0.571 The mean OSDI
`and 18.9
`2.9 respectively
`tears remained
`scores of patients treated with artificial
`unchanged throughout the study Fig
`Patients treated
`with cyclosporine 0.05% however had increasingly lower
`OSDI scores at each study visit with the scores at months
`and 12 being significantly lower than those of patients
`tears 174
`3.4 vs 19.6
`treated with artificial
`1.6 at
`month
`0.011 and 14.9
`4.2 vs 19.7
`2.0 at month
`
`12
`
`0.001
`
`Goblet cell density
`
`At baseline patients randomized to artificial
`tears or cy
`closporine 0.05% had similar mean goblet cell density in
`12.5 cells and 93.6
`9.4 cells re
`bulbar conjunctiva 95.8
`By month 12 goblet cell density
`0.446 Fig
`spectively
`was significantly higher
`in patients treated with cyclo
`sporine 0.05% than those treated with artificial
`tears 116.8
`11.0 cells 0.001
`14.8 cells vs 92.7
`
`Safety
`
`No adverse events attributable to the study medications
`were reported other than discomfort upon instillation dur
`ing the study
`
`DScussion
`
`Dry eye is multifactorial disorder of the tears and the
`ocular surface that results in tear film instability and symp
`toms of discomfort and visual disturbance2 Traditionally
`treatment of dry eye has been palliative and largely based
`on over-the-counter artificial eyedrops and lubricating oint
`ments.n The vast majority of patients seek new therapies
`after using several over-the-counter products over yearsP
`is not known if dry eye severity progresses
`However
`through the course of disease during the years Recently
`clinical standard for
`developed ITF guidelines provide
`
`it
`
`24
`
`20
`
`12
`
`Ocular Surface Disease Index OSDI
`FIG
`scores
`Patients were treated with cyclosporine 0.05% or artificial
`tears for 12 months Dry eye signs and symptoms were
`assessed by the self-reported OSDI questionnaire at indi
`0.011 and
`cated study visits
`0.001 compared
`tears at months
`and
`with
`patients treated with artificial
`12 respectively
`
`Artificial Tear it
`
`22
`
`Cyclosporine 0.05% it
`
`36
`
`Time months
`
`12
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`Artificial Tear
`
`22
`Cyclosporine 0.05%
`
`36
`
`93.6TI
`
`162
`
`.0
`
`La
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`2oL
`
`Baseline
`
`Month 12
`
`FIG
`goblet cell density at baseline and
`Conjunctival
`month 12 Patients were treated with cyclosporine 0.05% or
`tears for 12 months Conjunctival goblet cells were
`artificial
`collected by impression cytology and counted following
`staining with modified periodic acidSchiff Papanicolaou at
`baseline and month 12 J3
`0.001 compared with artificial
`tears at month 12
`
`categorization of dry eye patients based on the disease se
`verity and thereby allow longitudinal studies to evaluate the
`progression of dry eye disease This study not only sought to
`assess the progression of dry eye disease in patients treated
`with artificial
`tears but also evaluated the impact of cyclo
`sporine 0.05% therapy in modulating the course of dry eye
`disease
`Treatment of dry eye patients with cyclosporine 0.05%
`test scores TBUt conjunctival
`improved Schirmer
`goblet
`cell density ocular surface staining scores and OSDI scores
`tears was not
`the study Treatment with artificial
`throughout
`effective in improving the signs and symptoms of dry eye
`disease Similar to these findings several other studies dem
`onstrated that cyclosporine 005% significantly increased
`tear production decreased the intensity of ocular staining
`and decreased
`the severity of symptoms in patients with
`moderate to severe dry eye.2n
`recent prospective study
`indicated that cyclosporine 0.05% therapy significantly fin-
`proved signs and symptoms in patients at all stages of dry
`eye disease mild moderate and severe8 Other studies
`have shown that
`treatment with cyclosporine 0.05% also in
`creased conjunctival goblet cell density in patients with dry
`eye disease.2
`study to develop treat
`Physicians participating in
`ment
`regimens based on the ITF consensus guidelines
`for newly diagnosed dry eye patients chose to treat over
`40% of patients at severity level with the severity level
`treatments ie unpreserved tears and topical cyclosporine
`0.05%3 Hence the use of 1TP guidelines resulted in greater
`focus on treatment of the disease at early stages This shift
`in the patterns of anti-inflammatory therapy use stems
`from the notion that early interruption of
`inflammatory
`in preventing disease progres
`cycles may be instrumental
`sion.13 The impact of dry eye in limiting daily activities and
`causing discomfort is known to become clinically more sig
`nificant as the disease progresses from mild to moderate in
`severity.2
`
`RAO
`
`In addition to alleviating dry eye signs and symptoms
`topical cyclosporine 0.05% therapy appears to be capable
`of slowing the rate of disease progression Reassessment of
`patients at the end of the study period month 12 indicated
`greater number of cyclosporine patients compared
`that
`tear patients 94% vs 68% had improve
`with the artificial
`ments or no change in their disease severity status and far
`fewer 6% vs 32% experienced disease progression These
`findings suggest the progressive nature of dry eye disease
`and indicate that dry eye patients may benefit from cyclo
`sporine 0.05% therapy by achieving disease stabilization or
`slower rate of progression
`retrospective study pro
`recent
`vided evidence
`that cyclosporine 0.05% therapy may change
`the course of dry eye disease In that study
`chronic dry eye
`or were free of signs
`patients diagnosed at severity level
`and symptoms of dry eye disease for minimum of
`year
`6- to 72-month course of cyclosporine
`after completing
`0.05% therapy8
`In some patients dry eye is
`disease that
`difficult-to-treat
`requires long-term anti-inflammatory therapy The safety
`topical anti-inflammatory agent and its suitability
`profile of
`in successful
`for long-term use is therefore
`key factor
`management of dry eye disease Topical corticosteroids have
`been effective in alleviating the signs and symptoms of dry
`eye following short-term use 24 weeks Prolonged ad
`ministration of topical corticosteroids is complicated by the
`associated adverse events including elevation of intraocular
`in visual acuity and fields of vision cat
`pressure defects
`aract formation and increased risk of ocular
`infec Lions.2931
`Topical cyclosporine 0.05% however appears to be safe for
`long-term use Several clinical studies demonstrated that
`cyclosporine 0.05% was well tolerated for up to
`years with
`in nature and mild to
`most adverse events being transient
`moderate in severity.lU2
`number of
`The present study had
`limitations The
`sample size was small as this was pilot study to assess the
`of the study design It should also be noted that
`feasibility
`the differences between the treatment groups reported in
`this study can be applied only to the use of Refresh Endura
`tears may have variable
`as the artificial
`tears Other artificial
`in alleviating the signs and symptoms of dry eye
`Strategies to treat dry eye disease are evolving as our
`tear volume insufficiency
`of dry eye as
`understanding
`condition
`disease of abnormal
`is changing to
`tear ifim
`composition with proinflammatory
`characteristics.bo.n.M
`The findings of the current study are the first evidence
`in
`dicating that dry eye can be progressive in patients treated
`with artificial
`tears alone whereas topical anti-inflamma
`tory therapy with cyclosporine 0.05% may slow or prevent
`the disease progression in patients with dry eye at severity
`Large-scale controlled studies are warranted to
`level
`or
`confirm these findings
`
`efficacies
`
`Acknowedgment
`
`Hadi Moini PhD of Pacific Communications
`editorial assistance
`for this manuscript
`
`provided
`
`Author Disdosure Statements
`
`This study was supported by an unrestricted grant from
`Allergan Inc Irvine CA The author has no proprietary in
`terest in any material or method mentioned in this study
`
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`
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`

`CYCLOSPORINE AGAINST DRY EYE PROGRESSION
`
`163
`
`References
`
`Ishida
`
`continuous
`
`new
`Dogru
`The application of
`Kojima
`et
`functional visual acuity measurement
`system in
`dry eye syndromes Am Ophthalmol 1392532582005
`et al The
`Mertzanis
`Abetz
`Rajagopalan
`relative burden of dry eye in patients lives comparisons
`sample Invest Ophthalmol Vis Sd 464650
`U.S normative
`
`to
`
`2005
`
`Sullivan D.A et al Impact of dry eye
`Dana
`Miljanovic
`life Am Ophthaimoi
`syndrome on vision-related
`quality of
`143409415
`2007
`Lin P.Y Tsai Si Cheng C.Y et al Prevalence of dry eye
`among an elderly Chinese population
`in Taiwan the Shihpai
`Eye Study Ophthalmology 110109611012003
`McCarty C.A Bansal A.K Livingston P.M et aL The epi
`derniology of dry eye in Melbourne Australia Ophthalmology
`10511141119 1998
`Schaumberg D.A Sullivan D.A Buring J.E et aL Prevalence
`of dry eye syndrome among US women Am Ophthalmol
`1363183262003
`Miljanovic B.M et al Association for research in vision and
`ophthalmology Invest Ophthalmol Vis Sd 48E-abstract 4293
`2007
`
`and monitor dry eye disease
`to diagnose
`Methodologies
`Subcommittee of the
`report of
`the Diagnostic Methodology
`international Dry Eye WorkShop 2007 Ocul Surf 5108152
`2007
`
`et
`
`Dysfunctional
`
`Behrens
`tear syn
`Doyle J.J Stern
`drome study group Dysfunctional
`Delphi
`tear syndrome
`recommendations
`Cornea 2590090Z
`approach to treatment
`2006
`10 Pfiugfelder S.C Antiinfiamntatory therapy for dry eye Am
`Ophthalmol 1373373422004
`11 Stern M.E Beuerman R.W Fox K. et aL The pathology of
`dry eye the interaction between the ocular surface and lacrimal
`glands Cornea 17384-5891998
`12 Wilson S.E Inflammation
`unifying theory for the origin of
`dry eye syndrome Manag Care 1214-192003
`13 Wilson S.E and Stulting R.D Agreement of physician treat
`ment practices with the international task force guidelines for
`diagnosis and treatment of dry eye disease Cornea 26284-289
`2007
`14 Restasis
`15 Matsuda
`
`of
`
`cyclosporine
`16 Donnenfeld
`
`insertj Irvine CA Allergan Inc 2004
`Mechanisms
`and Koyasu
`of action
`lmmuno pharmacology 471191252000
`and Pfiugfelder S.C Topical ophthalmic
`pharmacology and clinical uses Surv Ophthalmol
`cyclosporine
`543213382009
`17 Kunert K.S Tisdale A.S Stern M.E et al Analysis of topi
`cal cyclosporine treatment of patients with dry eye syndrome
`lymphocytes Arch Ophthalmol 1181489
`effect on conjunctival
`1496 2000
`Pfiugfelder S.C Ji
`18 Turner
`et al Interleukin-6 levels in
`epithelium of patients with dry eye disease
`the conjunctival
`treated with cyclosporine ophthalmic emulsion Cornea 19492
`4962000
`19 Bron Aj Evans V.E and Smith J.A Grading of corneal and
`staining in the context of other dry eye tests
`conjunctival
`Cornea 226406502003
`
`ophthalmic
`CsA Phase
`25 Stevenson
`
`20 Schiffman R.M Christianson M.D Jacobsen
`et al
`the Ocular Surface Disease Index
`Reliability and validity of
`Arch Ophthalmol 118615621 2001
`21 Pfiugfelder S.C De Paiva C.S Villarreal A.L et al Effects of
`tear and cyclosporine emulsion therapy on
`sequential artificial
`goblet cell density and transforming growth fac
`conjunctival
`tor-beta2 production Cornea 2764692008
`22 The definition and classification of dry eye disease report of the
`Definition and Classification Subcommittee of the International
`Dry Eye WorkShop 2007 Ocul Surf 57592 2007
`23 The Gallup Organization Inc The 2008 Gallup Study of Dry Eye
`Sufferers Princeton NJ Multi-Sponsor Surveys Inc 2008
`Stevenson O.D Mundorf tK et al Two multicenter
`24 Sall
`randomized studies of
`the efficacy and safety of cyclosporine
`emulsion in moderate to severe dry eye disease
`Study Group Ophthalmology 107631-639 2000
`and Reis ILL Efficacy and safety of
`Tauber
`ophthalmic emulsion in the treatment of mod
`cyclosporin
`dose-ranging randomized
`erate-to-severe dry eye disease
`Phase
`trial The Cyclosporin
`Study Group Ophthalmology
`1079679742000
`26 Perry ILD Solomon
`Donnenfeld E.D et
`Evaluation of
`topical cyclospotine for the treatment of dry eye disease Arch
`Ophthalmol 126104610502008
`27 Kunert K.S Tisdale A.S and Gipson LK Goblet cell numbers
`and epithelial proliferation in the conjunctiva of patients with
`dry eye syndrome treated with cyclosporine Arch Ophthalmol
`120330-3372002
`28 Wilson RE and Perry H.D Long-term resolution of chronic
`dry eye symptoms and signs after
`topical cyclosporine treat
`ment Ophthalmology 11476792007
`29 Marsh
`and Pflugfelder S.C Topical nonpreserved methyl
`therapy for keratocorunctivitis sicca in Sjogren
`prednisolone
`syndrome Ophthalmology 1068118161999
`30 Pfiugfelder S.C Maskin S.L Anderson
`double-masked
`placebo-contrulled multicenter
`comparison of
`suspension 0.5% and pla
`etabonate ophthalmic
`loteprednol
`sicca in patients with
`cebo for treatment of keratoconjunctivitis
`delayed tear clearance Am Ophthalmol 1384444572004
`insert Tampa FL Bausch
`31 Lotemax
`Lomb Inc
`
`et aL
`
`randomized
`
`2006
`32 Barber L.D Pflugfelder S.C Tauber
`et al Phase fiT safety
`emulsion adminis
`evaluation of cyclosporine
`0.1% ophthalmic
`tered twice daily to dry eye disease patients for up to
`Ophthalmology 11217901794 005
`33 Baudouin
`The pathology
`of dry eye Surn Ophthalmol
`45Suppl 252115220 2001
`34 Lemp M.A Evaluation and differential diagnosis of keratocon
`junctivitis sicca Rheumatol Suppl 6111142000
`
`years
`
`Received August 21 2009
`Accepted January 31 2010
`
`Address correspondence to
`Dr Sanjay
`Rao
`Lakeside Eye Group SC
`180 Michigan Ste 1900
`Chicago 1L 60601
`
`E-mail sanjayrao@pol.net
`
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`EXHBIT
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`

`The mpact of Dry Eye Disease on Visua Performance
`White Driving
`
`NATHALIE DESCHAMPS XAVIER RICAUD GHISLAINE RABUT ANTOINE LABIlE CHRISTOPHE BAUDOUIN
`AND ALEXANDRE DENOYER
`
`PURPOSE
`
`using
`
`specific simulator was used to assess the
`driving visual performance in patients with dry eye
`disease DED and to determine clinical predictors of
`visual impairments while driving
`DESIGN Prospective
`case-control study
`METHODS The study was conducted
`in the Center
`f