P-1 ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee

P-1

ISTA PharmaceuticalsISTA PharmaceuticalsVitraseVitrase®®

For the treatment of vitreous hemorrhageFor the treatment of vitreous hemorrhage

Food and Drug AdministrationFood and Drug AdministrationDermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs

Advisory CommitteeAdvisory Committee

17 March 200317 March 2003

P-2

ISTAISTA

A specialty pharmaceutical company –A specialty pharmaceutical company –with a focus on ophthalmologywith a focus on ophthalmology

P-3

Vitrase (ovine hyaluronidase) Vitrase (ovine hyaluronidase) Proposed Package LabelProposed Package Label

Indication: treatment of vitreous hemorrhageIndication: treatment of vitreous hemorrhage

To improve visual acuityTo improve visual acuity

To facilitate the physician’s ability to diagnose the To facilitate the physician’s ability to diagnose the underlying retinal pathologyunderlying retinal pathology

P-4

VitraseVitrase

Single intravitreous injectionSingle intravitreous injection

Highly purified Highly purified ovineovine hyaluronidase hyaluronidase

10 years in development10 years in development

Approximately 1,500 patients treated at over Approximately 1,500 patients treated at over 130 sites in 13 countries 130 sites in 13 countries

P-5

Vitrase Development HistoryVitrase Development History

19921992 Preclinical initiatedPreclinical initiated

19961996 US IND submittedUS IND submitted

19981998 Phase II trials completedPhase II trials completed

19981998 Fast-track designationFast-track designation

Sept 2001Sept 2001 Last patient completed Last patient completed Month 3 efficacyMonth 3 efficacy

Throughout 2002Throughout 2002 NDA filed to FDANDA filed to FDA

March 17, 2003March 17, 2003 Advisory committeeAdvisory committee

P-6

ISTA Presentation AgendaISTA Presentation Agenda

IntroductionIntroduction Vicente Anido, Ph.D.Vicente Anido, Ph.D.

Clinical BackgroundClinical Background John W. Chandler, M.D.John W. Chandler, M.D.

Study Design and EfficacyStudy Design and Efficacy Lisa R. Grillone, Ph.D.Lisa R. Grillone, Ph.D.

SafetySafety John W. Chandler, M.D.John W. Chandler, M.D.

Investigators’ PerspectiveInvestigators’ Perspective Baruch D. Kuppermann, M.D.Baruch D. Kuppermann, M.D.Edgar Thomas, M.D.Edgar Thomas, M.D.

Impact on Clinical Practice Impact on Clinical Practice Kirk Packo, M.D.Kirk Packo, M.D.

ConclusionsConclusions Lisa R. Grillone, Ph.D.Lisa R. Grillone, Ph.D.

ConsultantsConsultants

John W. Chandler, M.D.John W. Chandler, M.D.• Ophthalmology ConsultantOphthalmology Consultant

Baruch D. Kuppermann, M.D.Baruch D. Kuppermann, M.D.• Associate Professor of Ophthalmology, UC IrvineAssociate Professor of Ophthalmology, UC Irvine

Edgar Thomas, M.D.Edgar Thomas, M.D.• Vitreo-retinal private practice, Los AngelesVitreo-retinal private practice, Los Angeles

Kirk Packo, M.D.Kirk Packo, M.D.• Rush Medical College, ChicagoRush Medical College, Chicago

Raymond Buck, Ph.D.Raymond Buck, Ph.D.• Statistical Consultant, Cato Research, Ltd.Statistical Consultant, Cato Research, Ltd.

Brooks McCuen, M.D.Brooks McCuen, M.D.• Duke University, DSMB MemberDuke University, DSMB Member

P-7

ISTA PharmaceuticalsISTA Pharmaceuticals

Vicente Anido, Ph.D.Vicente Anido, Ph.D.• President and CEOPresident and CEO

Lisa R. Grillone, Ph.D.Lisa R. Grillone, Ph.D.• VP Clinical Research & Medical AffairsVP Clinical Research & Medical Affairs

Marvin GarrettMarvin Garrett• VP Regulatory Affairs, Quality and ComplianceVP Regulatory Affairs, Quality and Compliance

William Craig, Ph.D.William Craig, Ph.D.• VP Research & Product DevelopmentVP Research & Product Development

Kirk McMullinKirk McMullin• VP OperationsVP Operations

P-8

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Clinical BackgroundClinical Background

John W. Chandler, M.D.John W. Chandler, M.D.

P-10

Vitreous HemorrhageVitreous Hemorrhage

7 new dense spontaneous vitreous hemorrhages 7 new dense spontaneous vitreous hemorrhages per 100,000 population annually (Europe)per 100,000 population annually (Europe)

In US translates to 20,000 new patients entering In US translates to 20,000 new patients entering pool of patients with vitreous hemorrhage each pool of patients with vitreous hemorrhage each yearyear

Reference: Am J Ophthalmol 119:458-465, 1995Reference: Am J Ophthalmol 119:458-465, 1995

P-11


Common causes (most unilateral)Common causes (most unilateral) Proliferative diabetic retinopathyProliferative diabetic retinopathy Posterior vitreous detachment Posterior vitreous detachment

(± retinal tear/detachment)(± retinal tear/detachment) TraumaTrauma Branch or central retinal vein occlusionBranch or central retinal vein occlusion Retinal macroaneurysmRetinal macroaneurysm Age – related macular degenerationAge – related macular degeneration Subarachnoid hemorrhageSubarachnoid hemorrhage

P-12


63% of bilateral vitreous hemorrhages are due to 63% of bilateral vitreous hemorrhages are due to proliferative diabetic retinopathyproliferative diabetic retinopathy

Except for trauma and subarachnoid Except for trauma and subarachnoid hemorrhages, at-risk eyes have pre-existing hemorrhages, at-risk eyes have pre-existing pathologypathology

P-13

Vitreous HemorrhageVitreous HemorrhageMechanismsMechanisms

Tear of normal retinal blood vesselTear of normal retinal blood vessel

Bleed from site of neovascularization or diseased Bleed from site of neovascularization or diseased blood vesselblood vessel

Bleed from other sites such as choroid Bleed from other sites such as choroid

P-14

Vitreous HemorrhageVitreous HemorrhageSequelaeSequelae

Decreases visual acuityDecreases visual acuity

Obstructs visualization of posterior poleObstructs visualization of posterior pole

Prevents therapy of sight-threatening pathologyPrevents therapy of sight-threatening pathology Retinal and choroidal neovascularizationRetinal and choroidal neovascularization

Causes retinal pathologic changes and Causes retinal pathologic changes and electroretinograph abnormalitieselectroretinograph abnormalities

Large hemorrhages (non-human primates)Large hemorrhages (non-human primates)

Reference: Gaefes Arch Clin Exp Ophthalmol 197:255-267, 1975Reference: Gaefes Arch Clin Exp Ophthalmol 197:255-267, 1975

P-16

Natural History StudiesNatural History Studies

Three StudiesThree Studies

United StatesUnited States

SpainSpain

Diabetic Retinopathy Vitrectomy Study (DRVS)Diabetic Retinopathy Vitrectomy Study (DRVS)

P-17

Natural History StudyNatural History StudyUnited StatesUnited States

Patients with diabetic retinopathy Patients with diabetic retinopathy

85 eyes with untreated large vitreous hemorrhage85 eyes with untreated large vitreous hemorrhage

Visual acuity worse or no better in 70% of eyesVisual acuity worse or no better in 70% of eyesthan 5/200 at 3-10 years follow-upthan 5/200 at 3-10 years follow-up

Reference: Ophthalmology 87: 306-312, 1980Reference: Ophthalmology 87: 306-312, 1980

P-18

Natural History StudyNatural History StudySpainSpain

Compared to baseline visual acuity Compared to baseline visual acuity

At 3 months post massive vitreous hemorrhage At 3 months post massive vitreous hemorrhage with no treatmentwith no treatment

26% improved26% improved 63% unchanged63% unchanged 11% worsened11% worsened

At 2 years with no treatmentAt 2 years with no treatment 49% worse than HM49% worse than HM 21% better than HM21% better than HM

Reference: Retina 8:96-101, 1988Reference: Retina 8:96-101, 1988

P-19

Natural History Study Natural History Study DRVSDRVS

Eyes with severe vitreous hemorrhages (312 eyes) Eyes with severe vitreous hemorrhages (312 eyes)

EligibilityEligibility Onset within 6 months of randomizationOnset within 6 months of randomization Vitrectomy delayed one yearVitrectomy delayed one year Visual acuity at entry 5/200 to LPVisual acuity at entry 5/200 to LP

Outcome (delayed treatment)Outcome (delayed treatment) 22% of patients had hemorrhage clearance at one year and 22% of patients had hemorrhage clearance at one year and

vitrectomy was not requiredvitrectomy was not required 11% vitrectomy for traction retinal detachment11% vitrectomy for traction retinal detachment 5% inoperable (retinal detachment, neovascular glaucoma)5% inoperable (retinal detachment, neovascular glaucoma)

Reference: Arch Ophthalmol 103:1644-1652, 1985Reference: Arch Ophthalmol 103:1644-1652, 1985

P-21

Alternative TherapiesAlternative Therapies

Watchful WaitingWatchful Waiting Poor clearance, inability to diagnose and treatPoor clearance, inability to diagnose and treat

Progression of underlying pathologyProgression of underlying pathology

Poor visual function outcomePoor visual function outcome

There is no pharmaceutical treatment for vitreous There is no pharmaceutical treatment for vitreous hemorrhagehemorrhage

P-22

Alternative TherapiesAlternative Therapies

VitrectomyVitrectomy Major ocular procedureMajor ocular procedure Some eyes/patients poor risksSome eyes/patients poor risks CostsCosts Serious complications (DRVS 30-40%)Serious complications (DRVS 30-40%)

P-23

Goals of New TherapyGoals of New TherapyManagement of Vitreous HemorrhageManagement of Vitreous Hemorrhage

Safe with low risk to treated eyesSafe with low risk to treated eyes

Speeds hemorrhage clearanceSpeeds hemorrhage clearance

Restores visual functionRestores visual function

Allows early therapy of underlying pathologyAllows early therapy of underlying pathology

Does not preclude future vitrectomyDoes not preclude future vitrectomy

Office procedureOffice procedure

P-24

If Vitrase Meets These Goals,If Vitrase Meets These Goals,What Will it Mean to Patients? What Will it Mean to Patients?

Early diagnosis and treatment of underlying Early diagnosis and treatment of underlying conditioncondition

Early return of visual functionEarly return of visual function Unilateral hemorrhage causes significant visual Unilateral hemorrhage causes significant visual

impairmentimpairment Many patients have decreased vision in the other Many patients have decreased vision in the other

eye and become bilaterally impairedeye and become bilaterally impaired

P-25

Vitrase Vitrase

Lyophilized preparation of highly purified ovine Lyophilized preparation of highly purified ovine testicular hyaluronidasetesticular hyaluronidase

Preservative-freePreservative-free

Reconstituted with Sodium Chloride Injection USP Reconstituted with Sodium Chloride Injection USP

P-26

Vitrase: Pharmacokinetics Vitrase: Pharmacokinetics

Intravitreous administration Intravitreous administration Animal studiesAnimal studies

Half-life (plasma): 49 hoursHalf-life (plasma): 49 hours

Highest concentrations: vitreous, retina, sclera Highest concentrations: vitreous, retina, sclera

Half-life (ocular): 60-112 hours Half-life (ocular): 60-112 hours

P-27

Vitrase: Mechanism of Action Vitrase: Mechanism of Action

Cleaves glycosidic bonds of hyaluronan Cleaves glycosidic bonds of hyaluronan

Leads to collapse and liquefaction of vitreous Leads to collapse and liquefaction of vitreous

Facilitates diffusion of molecules including Facilitates diffusion of molecules including proinflammatory chemotactic factors proinflammatory chemotactic factors

Promotes ingress of phagocytic cells and egress Promotes ingress of phagocytic cells and egress of red blood cells and proteins of red blood cells and proteins

P-28

Vitreous Hemorrhage ClearingVitreous Hemorrhage Clearing

P-29

Phase III Trials: Study Phase III Trials: Study Design & Efficacy ResultsDesign & Efficacy Results

Lisa R. Grillone, Ph.D.Lisa R. Grillone, Ph.D.

P-30

Vitrase Phase III Studies Vitrase Phase III Studies

Two Phase III studiesTwo Phase III studies

Double masked, placebo controlledDouble masked, placebo controlled

131 sites contributed patients to the ITT population131 sites contributed patients to the ITT population

12 countries12 countries 7.57.5** IU: IU: 181 patients181 patients 55 IU:55 IU: 365 patients365 patients 75 IU:75 IU: 377 patients377 patients Saline:Saline: 383 patients 383 patients TOTAL Intent to Treat = 1306 patientsTOTAL Intent to Treat = 1306 patients* * North American StudyNorth American Study

P-31

Vit 03 – Ex North AmericaVit 03 – Ex North America

Intent to treat population:Intent to treat population:55 IU: 18655 IU: 18675 IU: 18075 IU: 180Saline: 190Saline: 190 Total: 556Total: 556

Australia (6)Australia (6) Brazil (6)Brazil (6)

Hungary (6)Hungary (6) Italy (3)Italy (3)

Netherlands (3)Netherlands (3) Poland (9)Poland (9)

Spain (4)Spain (4) South Africa (9)South Africa (9)

United Kingdom (12)United Kingdom (12)

Centers:

P-32

Vit 02 - North AmericaVit 02 - North America

Centers:Centers:United StatesUnited States (61) (61)CanadaCanada (9)(9) MexicoMexico (3)(3)

7.5 IU:7.5 IU: 18118155 IU:55 IU: 17917975 IU:75 IU: 197197Saline:Saline: 193193TotalTotal: : 750750

Intent to Treat Population:Intent to Treat Population:

7.5 IU:7.5 IU: 181855 IU:55 IU: 181875 IU:75 IU: 1717WW:WW: 1818TotalTotal:: 7171

P-33

Efficacy PresentationEfficacy Presentation

Study designStudy design

Efficacy measuresEfficacy measures

Patient demographics and baseline characteristicsPatient demographics and baseline characteristics

Efficacy resultsEfficacy results

P-34

Vitrase EfficacyVitrase Efficacy Integrated Phase III - 55 IU & 75 IUIntegrated Phase III - 55 IU & 75 IU

Measurement:Measurement: Month 1Month 1 Month 2Month 2 Month 3Month 3

Reduction in Reduction in Hemorrhage DensityHemorrhage Density

Improvement in BCVAImprovement in BCVA

Outcome by investigatorOutcome by investigator

Surrogate successSurrogate success 55 IU 55 IU OnlyOnly

55 IU 55 IU OnlyOnly

P-35

Study DesignStudy DesignEligibility CriteriaEligibility Criteria

Vitreous hemorrhage for at least 1 monthVitreous hemorrhage for at least 1 month

Severe hemorrhage at entry that obscured Severe hemorrhage at entry that obscured visualization of fundusvisualization of fundus

BCVA worse than 20/200 in study eyeBCVA worse than 20/200 in study eye

P-36

Study DesignStudy DesignEligibility CriteriaEligibility Criteria

Hemorrhage density of Grade 3 or 4 in 12 clock Hemorrhage density of Grade 3 or 4 in 12 clock hours posterior to the equatorhours posterior to the equator

Red reflex is visible but no central retinal detail Red reflex is visible but no central retinal detail (retinal blood vessels) is seen posterior to the (retinal blood vessels) is seen posterior to the equator (Grade 3)equator (Grade 3)

No red reflex (Grade 4)No red reflex (Grade 4)

P-37

Non-Qualifying HemorrhageNon-Qualifying Hemorrhage

Grade 2 – Some blood vessels visible Grade 2 – Some blood vessels visible posterior of the equatorposterior of the equator

P-38

““Headlight in the fog”Headlight in the fog”

Grade 3 Vitreous HemorrhageGrade 3 Vitreous Hemorrhage

P-39

Grade 4 Vitreous HemorrhageGrade 4 Vitreous Hemorrhage

““No red reflex”No red reflex”

P-40

Study DesignStudy DesignExclusion CriteriaExclusion Criteria

Presence or history of retinal detachment, Presence or history of retinal detachment, tears or breakstears or breaks

Ocular traumaOcular trauma

Previous vitrectomyPrevious vitrectomy

Organized hemorrhageOrganized hemorrhage

No light perception in either eyeNo light perception in either eye

P-41

Data Safety Monitoring BoardData Safety Monitoring Board

Reviewed throughout the conduct of the studyReviewed throughout the conduct of the study

Conducted four unmasked interim evaluations for Conducted four unmasked interim evaluations for safety and efficacysafety and efficacy

Made recommendations to continueMade recommendations to continue

P-42

Study DesignStudy DesignRandomizationRandomization

Patients randomly assigned to receivePatients randomly assigned to receive

Single intravitreous injection (50 µL) in one eyeSingle intravitreous injection (50 µL) in one eye

Three or four treatment groupsThree or four treatment groups 7.5 IU* Vitrase7.5 IU* Vitrase 55 IU Vitrase55 IU Vitrase 75 IU Vitrase75 IU Vitrase Saline ControlSaline Control*North American study only*North American study only

P-43

Efficacy MeasuresEfficacy Measures

1.1. Reduction in vitreous hemorrhage densityReduction in vitreous hemorrhage density

2.2. Improvement in BCVA Improvement in BCVA

3.3. Outcome determined by investigator (clearance, Outcome determined by investigator (clearance, diagnosis +/- treatment) diagnosis +/- treatment)

4.4. Surrogate success evaluation (clearance, Surrogate success evaluation (clearance, diagnosis +/- treatment, confirmation)diagnosis +/- treatment, confirmation)

P-44

Surrogate Success EvaluationSurrogate Success Evaluation

Efficacy assessment on or prior to Month 3Efficacy assessment on or prior to Month 3

Hemorrhage clearance sufficient to allow:Hemorrhage clearance sufficient to allow: Diagnosis of underlying condition that caused baseline Diagnosis of underlying condition that caused baseline

hemorrhagehemorrhage

AndAnd Confirmatory documentationConfirmatory documentation that treatment was completed that treatment was completed

(e.g. adequate laser therapy), if required for underlying (e.g. adequate laser therapy), if required for underlying conditioncondition

Or Or Confirmatory documentationConfirmatory documentation (fundus photo) that no further (fundus photo) that no further

treatment requiredtreatment required

P-45

Outcome Determined by InvestigatorOutcome Determined by Investigator

As recorded on the CRF at Months 1, 2 and 3:As recorded on the CRF at Months 1, 2 and 3:

Same as surrogate success evaluationSame as surrogate success evaluation

WithoutWithout confirmatory documentation that treatment confirmatory documentation that treatment was completed or not requiredwas completed or not required

P-46

Reduction in Hemorrhage DensityReduction in Hemorrhage Density

Definition of Grade 0 and 1Definition of Grade 0 and 1

Grade 0:Grade 0: Anatomical details of the retina are visible and Anatomical details of the retina are visible and

pathology is easily treatablepathology is easily treatable

Grade 1:Grade 1: Retinal detail is visible, some hemorrhage may be Retinal detail is visible, some hemorrhage may be

present but laser photocoagulation would still be present but laser photocoagulation would still be possiblepossible

P-47

Grade 0 and Grade 1 Grade 0 and Grade 1 Vitreous HemorrhageVitreous Hemorrhage

Grade 0Grade 0 Grade 1Grade 1

P-48


Success = hemorrhage density reduced from Success = hemorrhage density reduced from Grades 3-4 to Grades:Grades 3-4 to Grades:

0 or 1 in at least 6 clock hours0 or 1 in at least 6 clock hours (All cases, except BRVO)(All cases, except BRVO)

0 or 1 in 3 clock hours (BRVO)0 or 1 in 3 clock hours (BRVO)

P-49


SuccessSuccess = = Three lineThree line improvement measured in improvement measured in LogMAR unitsLogMAR units

• Three lines = 0.3 LogMAR unitsThree lines = 0.3 LogMAR units• Each letter = 0.02 LogMAR unitsEach letter = 0.02 LogMAR units• LP to HM = 1 Line ImprovementLP to HM = 1 Line Improvement

Answers an Important Clinical Question: Answers an Important Clinical Question:

““Is there a meaningful improvement in the patient’s vision Is there a meaningful improvement in the patient’s vision resulting from the hemorrhage density reduction?”resulting from the hemorrhage density reduction?”

Reference: J Ref Surg 13:388-391, 1997Reference: J Ref Surg 13:388-391, 1997

P-50

Efficacy Presentation RoadmapEfficacy Presentation Roadmap

Study SequenceStudy Sequence Vit 03 Ex North AmericaVit 03 Ex North America Vit 02 North AmericaVit 02 North America Integrated Phase IIIIntegrated Phase III

P-51

Patient DemographicsPatient Demographics

Ex-North Ex-North AmericaAmerica(N = 556)(N = 556)

North North AmericaAmerica(N = 750)(N = 750)

Integrated*Integrated*(N = 1125)(N = 1125)

Gender:Gender: Males Males 50.2%50.2% 52.4%52.4% 51.6%51.6%

Age (years):Age (years): Mean (SD) Mean (SD) Min – Max Min – Max

61.9 (12.2)61.9 (12.2)23 – 9323 – 93

61.9 (12.9)61.9 (12.9)25 – 9725 – 97

62.0 (12.4)62.0 (12.4)23 – 9323 – 93

Ethnicity:Ethnicity: Caucasian Caucasian Black Black Asian Asian Other Other

84.0%84.0%9.7%9.7%3.6%3.6%2.7%2.7%

50.8%50.8%5.5%5.5%3.5%3.5%

40.1%40.1%

67.6%67.6%7.7%7.7%3.5%3.5%

21.2%21.2%*does not include 7.5 IU Vitrase*does not include 7.5 IU Vitrase

P-52

Etiology of Baseline Vitreous Etiology of Baseline Vitreous HemorrhageHemorrhage

Probable CauseProbable Cause




Proliferative Diabetic RetinopathyProliferative Diabetic Retinopathy 66.2%66.2% 78.7%78.7% 71.9%71.9%

Central Retinal Vein OcclusionCentral Retinal Vein Occlusion 4.5%4.5% 5.2%5.2% 4.8%4.8%

Branch Retinal Vein OcclusionBranch Retinal Vein Occlusion 5.4%5.4% 3.9%3.9% 4.7%4.7%

Exudative Macular Degeneration Exudative Macular Degeneration

with Choroidal NV Membranewith Choroidal NV Membrane3.6%3.6% 4.4%4.4% 4.4%4.4%

MacroaneurysmMacroaneurysm 0.7%0.7% 0.0%0.0% 0.4%0.4%

Hemorrhagic PVDHemorrhagic PVD 2.3%2.3% 2.0%2.0% 2.2%2.2%

OtherOther 4.0%4.0% 0.7%0.7% 2.4%2.4%

*does not include 7.5 IU Vitrase*does not include 7.5 IU Vitrase

P-53

Duration of Baseline Vitreous Duration of Baseline Vitreous HemorrhageHemorrhage

Duration (Days) Duration (Days) at Entryat Entry




MeanMean 125.3125.3 116.9116.9 120.4120.4

SDSD 113.0113.0 104.6104.6 110.0110.0


P-54

Baseline Diabetic StatusBaseline Diabetic Status




Non-DiabeticNon-Diabetic 28.6%28.6% 17.3%17.3% 23.7%23.7%

DiabeticDiabetic 71.4%71.4% 82.7%82.7% 76.3%76.3%

Type IType I 69.3%69.3% 52.9%52.9% 59.4%59.4%

Type IIType II 30.7%30.7% 47.1%47.1% 40.6%40.6%


P-55

Baseline BCVABaseline BCVA



IntegratedIntegrated(N = 1306)(N = 1306)

Off Chart* at entryOff Chart* at entry 528 528 (95.0%)(95.0%)

652 652 (86.9%)(86.9%)

1180 1180 (90.4%)(90.4%)

*LP, HM, CF for off Chart*LP, HM, CF for off Chart

P-56

Surrogate Success EvaluationSurrogate Success Evaluation

Efficacy assessment on or prior to Month 3Efficacy assessment on or prior to Month 3

Hemorrhage clearance sufficient to allow:Hemorrhage clearance sufficient to allow: Diagnosis of underlying condition that caused study Diagnosis of underlying condition that caused study

hemorrhagehemorrhage

AndAnd Confirmatory documentationConfirmatory documentation that treatment was that treatment was

completed (e.g. adequate laser therapy), if required completed (e.g. adequate laser therapy), if required for underlying conditionfor underlying condition

Or Or Confirmatory documentationConfirmatory documentation (fundus photo) that no (fundus photo) that no

further treatment requiredfurther treatment required

P-57

Surrogate Success EvaluationSurrogate Success EvaluationEx-North AmericaEx-North America

21.6

28.0

25.0

15.3

4.7

19.9

11.3* 13.9

6.7

0

10

20

30

Month 1 Month 2 Month 3

% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-59

Surrogate Success EvaluationSurrogate Success EvaluationNorth AmericaNorth America

38.035.5

6.2

17.1

29.5

25.4

31.5

12.7*

31.3**

15.1*

27.9*

14.2*

0

10

20

30

40


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline7.5 IU55 IU75 IU

*P < 0.05 **P < 0.005

P-61

Surrogate Success EvaluationSurrogate Success EvaluationIntegrated Phase IIIIntegrated Phase III

25.6

5.5

16.2

32.9*

25.5**

13.2**

30.5

21.2

10.6*

0

10

20

30

40


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-63

Outcome Determined by InvestigatorOutcome Determined by Investigator

As recorded on the CRF at Months 1, 2 and 3:As recorded on the CRF at Months 1, 2 and 3:

Same as surrogate success evaluationSame as surrogate success evaluation

WithoutWithout confirmatory documentation that treatment confirmatory documentation that treatment was completed or not requiredwas completed or not required

P-64

Outcome Determined by InvestigatorOutcome Determined by InvestigatorEx-North AmericaEx-North America

25.3

33.9

10.5

18.9

18.8*

30.6*

38.2*

23.3

16.1

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-66

Outcome Determined by InvestigatorOutcome Determined by InvestigatorNorth AmericaNorth America

31.6

23.8

11.9

42.0*

38.7**

26.5**

43.6*40.2**

27.9**28.4**

40.1** 44.2*

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

en

t S

uc

ce

ss


*P < 0.05 **P < 0.005

P-68

Outcome Determined by InvestigatorOutcome Determined by InvestigatorIntegrated Phase IIIIntegrated Phase III

28.5

21.4

11.2

23.3**

35.3**

40.8**

39.3**

22.5**

32.1**

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-70


Success = hemorrhage density reduced from Success = hemorrhage density reduced from Grades 3-4 to Grades:Grades 3-4 to Grades:

0 or 1 in at least 6 clock hours0 or 1 in at least 6 clock hours (All cases, except BRVO)(All cases, except BRVO)

0 or 1 in 3 clock hours (BRVO)0 or 1 in 3 clock hours (BRVO)

P-71

Reduction in Hemorrhage DensityReduction in Hemorrhage DensityEx-North AmericaEx-North America

25.3

33.3

10.5

19.5

19.9*

30.6*36.6*

13.3

23.9

0

10

20

30

40


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-73

Reduction in Hemorrhage DensityReduction in Hemorrhage DensityNorth AmericaNorth America

31.6

35.9

23.3

11.4

24.9**33.1*

20.7*

35.2*

40.8

24.4**

36.0*

42.6*

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

en

t S

uc

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ss


*P < 0.05 **P < 0.005

P-75

Reduction in Hemorrhage DensityReduction in Hemorrhage DensityIntegrated Phase IIIIntegrated Phase III

28.5

11.0

21.4

38.6**

32.9**

20.3** 30.2*

38.2**

19.1**

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-77


SuccessSuccess = = Three lineThree line improvement measured in improvement measured in LogMAR unitsLogMAR units

• Three lines = 0.3 LogMAR unitsThree lines = 0.3 LogMAR units• Each letter = 0.02 LogMAR unitsEach letter = 0.02 LogMAR units• LP to HM = 1 Line ImprovementLP to HM = 1 Line Improvement

Answers an Important Clinical Question: Answers an Important Clinical Question:

““Is there a meaningful improvement in the patient’s vision Is there a meaningful improvement in the patient’s vision resulting from the hemorrhage density reduction?”resulting from the hemorrhage density reduction?”

Reference: J Ref Surg 13:388-391, 1997Reference: J Ref Surg 13:388-391, 1997

P-78

Improvement in BCVAImprovement in BCVAEx-North AmericaEx-North America

32.6

41.7

22.6

28.4

46.2*43.0**

33.3*

23.9

36.1

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-80

Improvement in BCVA Improvement in BCVA North AmericaNorth America

36.3

26.4

17.6

33.7

29.8*

37.039.1*

27.9*

43.640.1*

31.5**

45.2

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

en

t S

uc

ce

ss


*P < 0.05 **P < 0.005

P-82

Improvement in BCVAImprovement in BCVAIntegrated Phase IIIIntegrated Phase III

34.5

20.1

27.4

30.7**

41.1** 44.9**

27.9*

38.2**

43.5*

0

10

20

30

40

50


% o

f P

ts -

Tre

atm

ent

Su

cces

s

Saline

55 IU

75 IU

*P < 0.05 **P < 0.005

P-84

Improvement in BCVA Improvement in BCVA Read Letters “As Is”Read Letters “As Is”Integrated Phase IIIIntegrated Phase III

Saline Saline ControlControl

(N = 383)(N = 383)

55 IU55 IUVitraseVitrase

(N = 365)(N = 365)

75 IU 75 IU VitraseVitrase

(N = 377)(N = 377)

Month 1Month 1 20.4%20.4% 30.7%30.7%p = 0.0013p = 0.0013

27.9%27.9%p = 0.0163p = 0.0163

Month 2Month 2 27.7%27.7% 41.1%41.1%p = 0.0001p = 0.0001

38.2%38.2%p = 0.0021p = 0.0021

Month 3Month 3 34.2%34.2% 44.9%44.9%p = 0.0027p = 0.0027

43.5%43.5%p = 0.0091p = 0.0091

P-85

Conclusions: Vitrase EfficacyConclusions: Vitrase Efficacy Ex-North America - 55 IUEx-North America - 55 IU


Reduction in Reduction in hemorrhage densityhemorrhage density



Surrogate successSurrogate success

P-86

Conclusions: Vitrase EfficacyConclusions: Vitrase Efficacy North America - 55 IU & 75 IUNorth America - 55 IU & 75 IU


Reduction in Reduction in hemorrhage densityhemorrhage density 75 IU 75 IU

OnlyOnly



Surrogate successSurrogate success

P-87

Conclusions: Vitrase EfficacyConclusions: Vitrase Efficacy Integrated Phase III - 55 IU & 75 IUIntegrated Phase III - 55 IU & 75 IU


Reduction in Reduction in Hemorrhage DensityHemorrhage Density



Surrogate successSurrogate success 55 IU 55 IU OnlyOnly

55 IU 55 IU OnlyOnly

P-88

Vitrase Safety Vitrase Safety North America & Ex-North AmericaNorth America & Ex-North America

John W. Chandler, M.D.John W. Chandler, M.D.

P-89

Safety PopulationSafety Population

All patients who received a single intravitreous All patients who received a single intravitreous injection in Phase III Studiesinjection in Phase III Studies

Ex-North America = 551Ex-North America = 551 North America = 740North America = 740

• Original Watchful Waiting Study = 53Original Watchful Waiting Study = 53 Total Safety Populations = 1344Total Safety Populations = 1344

P-93

Summary of Patient Follow-upSummary of Patient Follow-upIntegrated Phase IIIIntegrated Phase III


(N = 378)(N = 378)

7.5 IU 7.5 IU VitraseVitrase

(N = 198)(N = 198)

55 IU 55 IU Vitrase Vitrase

(N = 377)(N = 377)


(N = 391)(N = 391)

Mean daysMean days(SD)(SD)

292.6 292.6 (200.4)(200.4)

348.3 348.3 (245.7)(245.7)

307.7 307.7 (216.4)(216.4)

304.3 304.3 (209.3)(209.3)

Min – MaxMin – Max 5 – 7845 – 784 7 – 9647 – 964 1 – 9721 – 972 6 – 9656 – 965

Patients with:Patients with:

Month 6 Month 6 Follow-up DataFollow-up Data

265 265 (70.1%)(70.1%)

149 149 (75.3%)(75.3%)

273 273 (72.4%)(72.4%)

287 287 (73.4%)(73.4%)

Month 12 Month 12 Follow-up DataFollow-up Data

170 170 (45.0%)(45.0%)

105 105 (53.0%)(53.0%)

186186(49.3%)(49.3%)

186 186 (47.6%)(47.6%)

P-94

Incidence of DeathsIncidence of Deaths

WWWWControlControl



55 IU55 IU Vitrase Vitrase


Ex-North Ex-North AmericaAmerica NANA 5.3%5.3% NANA 3.8%3.8% 6.1%6.1%

North America North America (Saline)(Saline) NANA 3.1%3.1% 3.9%3.9% 5.7%5.7% 5.2%5.2%

North America North America (WW)(WW) 33.3%33.3% NANA 5.6%5.6% 0%0% 0%0%

IntegratedIntegrated 33.3%33.3% 4.2%4.2% 4.0%4.0% 4.5%4.5% 5.4%5.4%

P-95

Safety AnalysisSafety AnalysisNo Light PerceptionNo Light Perception

WWWWControlControl




75 IU 75 IU Vitrase Vitrase P-valueP-value

Ex-North Ex-North AmericaAmerica NANA 0.5%0.5% NANA 0.5%0.5% 1.7%1.7% p=0.459p=0.459

North America North America (Saline)(Saline) NANA 1.6%1.6% 2.8%2.8% 2.3%2.3% 1.5%1.5% p=0.818p=0.818

North America North America (WW)(WW) 5.6%5.6% NANA 22.2%22.2% 5.6%5.6% 17.6%17.6% NANA

IntegratedIntegrated 5.6%5.6% 1.1%1.1% 4.5%4.5% 1.6%1.6% 2.3%2.3% NANA

P-96

Safety AnalysisSafety AnalysisSystemic Adverse EventsSystemic Adverse Events

Ex-North AmericaEx-North America No systemic body systems with No systemic body systems with 10% incidence in 10% incidence in

combined Vitrase groupscombined Vitrase groups

North AmericaNorth America Systemic body systems with Systemic body systems with 10% incidence in 10% incidence in

combined Vitrase groups:combined Vitrase groups:• Infections and infestations (p = 0.680)Infections and infestations (p = 0.680)• Nervous system disorders (p = 0.575)Nervous system disorders (p = 0.575)• Cardiac disorders (p = 0.265)Cardiac disorders (p = 0.265)• Gastrointestinal disorders (p = 0.364)Gastrointestinal disorders (p = 0.364)

P-97

Discontinued Due to Discontinued Due to Serious Adverse EventsSerious Adverse Events

EventEvent Saline Saline ControlControl




Systemic AESystemic AE 00 11 00 33

DeathDeath 11 00 00 11

Retinal DetachmentRetinal Detachment 00 11 00 33

Vitreous HemorrhageVitreous Hemorrhage 00 00 22 11

CataractCataract 00 00 00 00

Increased IOPIncreased IOP 00 11 00 00

P-100

Serious Adverse Events (Incidence Serious Adverse Events (Incidence 5%)5%)Integrated Phase IIIIntegrated Phase III

EventEvent


(N = 378)(N = 378)


(N = 198)(N = 198)


(N = 377)(N = 377)


(N = 391)(N = 391)

Vitreous hemorr. Vitreous hemorr. (rebleed)(rebleed) 14.3%14.3% 25.3%25.3% 17.8%17.8% 18.2%18.2%

Retinal detachmentRetinal detachment 6.3%6.3% 8.1%8.1% 8.0%8.0% 8.7%8.7%

Rubeosis iridisRubeosis iridis 4.0%4.0% 6.6%6.6% 3.4%3.4% 3.1%3.1%

Increased IOPIncreased IOP 3.4%3.4% 11.6%11.6% 4.5%4.5% 5.6%5.6%

P-101

Incidence of Adverse Events Incidence of Adverse Events 10% Reaching 10% Reaching Statistical Significance (p<0.05)Statistical Significance (p<0.05)

Ex - North AmericaEx - North America

Adverse EventAdverse Event


(N = 187)(N = 187)


(N = 184)(N = 184)


(N = 180)(N = 180)

Pts with Pts with 1 Ocular 1 Ocular AEAE 66.3%66.3% 73.4%73.4% 77.8%77.8%

Ocular DisordersOcular Disorders

IritisIritis 19.3%19.3% 40.2%40.2% 43.3%43.3%

HyperemiaHyperemia 24.6%24.6% 37.0%37.0% 39.4%39.4%

PainPain 12.3%12.3% 22.3%22.3% 28.3%28.3%

Overall Generalized Fisher Exact TestOverall Generalized Fisher Exact Test

P-102


Ex - North AmericaEx - North America



(N = 187)(N = 187)


(N = 184)(N = 184)


(N = 180)(N = 180)

Pts with Pts with 1 Ocular AE1 Ocular AE 66.3%66.3% 73.4%73.4% 77.8%77.8%


IritisIritis 19.3%19.3% 40.2%40.2% 43.3%43.3%

HyperemiaHyperemia 24.6%24.6% 37.0%37.0% 39.4%39.4%

PainPain 12.3%12.3% 22.3%22.3% 28.3%28.3%


P-103


North AmericaNorth America



(N = 191)(N = 191)


(N = 180)(N = 180)


(N = 175)(N = 175)


(N = 194)(N = 194)

Pts with Pts with 1 Ocular AE1 Ocular AE 91.1%91.1% 97.2%97.2% 97.1%97.1% 99.0%99.0%


IritisIritis 47.1%47.1% 61.1%61.1% 76.6%76.6% 78.4%78.4%

HyperemiaHyperemia 49.2%49.2% 56.1%56.1% 70.9%70.9% 67.5%67.5%

IrritationIrritation 43.5%43.5% 52.8%52.8% 62.9%62.9% 61.3%61.3%

PainPain 31.9%31.9% 35.0%35.0% 50.3%50.3% 50.5%50.5%

Inc. LacrimationInc. Lacrimation 34.6%34.6% 31.1%31.1% 46.3%46.3% 48.5%48.5%

PhotophobiaPhotophobia 21.5%21.5% 28.9%28.9% 31.4%31.4% 34.5%34.5%

PhotopsiaPhotopsia 7.9%7.9% 11.7%11.7% 19.4%19.4% 14.4%14.4%

VA reducedVA reduced 26.2%26.2% 38.9%38.9% 37.7%37.7% 37.6%37.6%

Vit. Hemorr. (rebleed)Vit. Hemorr. (rebleed) 21.5%21.5% 35.6%35.6% 30.9%30.9% 26.3%26.3%


P-104


North AmericaNorth America



(N = 191)(N = 191)


(N = 180)(N = 180)


(N = 175)(N = 175)


(N = 194)(N = 194)

Pts with Pts with 1 Ocular AE1 Ocular AE 91.1%91.1% 97.2%97.2% 97.1%97.1% 99.0%99.0%


IritisIritis 47.1%47.1% 61.1%61.1% 76.6%76.6% 78.4%78.4%

HyperemiaHyperemia 49.2%49.2% 56.1%56.1% 70.9%70.9% 67.5%67.5%

IrritationIrritation 43.5%43.5% 52.8%52.8% 62.9%62.9% 61.3%61.3%

PainPain 31.9%31.9% 35.0%35.0% 50.3%50.3% 50.5%50.5%

Inc. LacrimationInc. Lacrimation 34.6%34.6% 31.1%31.1% 46.3%46.3% 48.5%48.5%

PhotophobiaPhotophobia 21.5%21.5% 28.9%28.9% 31.4%31.4% 34.5%34.5%

PhotopsiaPhotopsia 7.9%7.9% 11.7%11.7% 19.4%19.4% 14.4%14.4%

VA reducedVA reduced 26.2%26.2% 38.9%38.9% 37.7%37.7% 37.6%37.6%

Vit. Hemorr. (rebleed)Vit. Hemorr. (rebleed) 21.5%21.5% 35.6%35.6% 30.9%30.9% 26.3%26.3%


P-105

Vitrase: Safety Findings Vitrase: Safety Findings

Vitrase administration is associated with Vitrase administration is associated with inflammationinflammation Iritis was frequent, with dose response, but not Iritis was frequent, with dose response, but not

severesevere Frequently self-limited or managed with topical Frequently self-limited or managed with topical

medications medications Also seen in the saline treated eyes but to lesser Also seen in the saline treated eyes but to lesser

extentextent Not a cause of SAEsNot a cause of SAEs Inflammation may help clear vitreous hemorrhageInflammation may help clear vitreous hemorrhage

P-106

Safety Analysis - IritisSafety Analysis - IritisNorth AmericaNorth America

IritisIritis


(N = 191)(N = 191)


(N = 180)(N = 180)


(N = 175)(N = 175)


(N = 194)(N = 194)

AEAE 47.1%47.1% 61.1%61.1% 76.6%76.6% 78.4%78.4%

MildMild 38.7%38.7% 41.7%41.7% 32.0%32.0% 29.9%29.9%

ModerateModerate 6.8%6.8% 15.0%15.0% 32.0%32.0% 30.9%30.9%

SevereSevere 1.6%1.6% 4.4%4.4% 12.6%12.6% 17.5%17.5%

SAESAE 0.5%0.5% 0.6%0.6% 00 1.0%1.0%

Event resolved within:Event resolved within:

0-30 Days0-30 Days 70.7%70.7% 67.1%67.1% 73.4%73.4% 76.7%76.7%

31-60 Days31-60 Days 10.8%10.8% 9.8%9.8% 13.3%13.3% 14.0%14.0%

61-90 Days61-90 Days 3.6%3.6% 4.4%4.4% 5.5%5.5% 2.4%2.4%

P-107

Safety Analysis - Hypopyon Safety Analysis - Hypopyon North AmericaNorth America

HypopyonHypopyon


(N = 191)(N = 191)

7.5 IU7.5 IUVitraseVitrase

(N = 180)(N = 180)


(N = 175)(N = 175)


(N = 194)(N = 194)

AE*AE* 00 0.6%0.6% 1.7%1.7% 7.2%7.2%

SAESAE 00 00 1.1%1.1% 1.5%1.5%

* P = <0.00001* P = <0.00001

P-108

Safety Analysis – Retinal DetachmentSafety Analysis – Retinal DetachmentNorth AmericaNorth America

Retinal Retinal DetachmentDetachment


(N = 191)(N = 191)

7.5 IU7.5 IUVitraseVitrase

(N = 180)(N = 180)


(N = 175)(N = 175)


(N = 194)(N = 194)

AE*AE* 5.8%5.8% 10.6%10.6% 10.3%10.3% 11.9%11.9%

SAESAE 4.2%4.2% 7.2%7.2% 6.9%6.9% 8.2%8.2%

(DRVS 11%)(DRVS 11%)

* P = 0.172* P = 0.172

P-109

Safety ConclusionsSafety Conclusions

Iritis accounted for majority of AE’sIritis accounted for majority of AE’s Higher incidence in Vitrase treated eyesHigher incidence in Vitrase treated eyes Associated with other most common AE’sAssociated with other most common AE’s Self-limited or treated with topical drugsSelf-limited or treated with topical drugs Not a cause of SAE’sNot a cause of SAE’s Sterile hypopyon infrequent and medically treatedSterile hypopyon infrequent and medically treated

NLP not Vitrase relatedNLP not Vitrase related

P-110

Safety ConclusionsSafety Conclusions

Retinal detachmentRetinal detachment rates prior to vitrectomy lowrates prior to vitrectomy low not Vitrase relatednot Vitrase related

Significant SAE’s tended to occur after 90 daysSignificant SAE’s tended to occur after 90 days

The safety profile of Vitrase supports human The safety profile of Vitrase supports human intravitreous administration of Vitrase for the intravitreous administration of Vitrase for the treatment of vitreous hemorrhagetreatment of vitreous hemorrhage

P-111

Clinical Investigators’ Clinical Investigators’ Perspective and Patients’ Perspective and Patients’

ResponseResponse

Baruch D. Kuppermann, M.D. Baruch D. Kuppermann, M.D. Edgar Thomas, M.D.Edgar Thomas, M.D.

P-112

Physicians PerspectivePhysicians Perspective

Clinical practice characteristicsClinical practice characteristics Patient populationPatient population Teaching hospitalTeaching hospital

Goal of vitreous hemorrhage treatmentGoal of vitreous hemorrhage treatment

P-113

Vitrase Impact on a PatientVitrase Impact on a Patient

Patient: Patient: 35 years old35 years old

Diagnosis: DiabeticDiagnosis: Diabetic Severe vitreous hemorrhageSevere vitreous hemorrhage

Treatment: Vitrase 55 IU, single injectionTreatment: Vitrase 55 IU, single injection

P-114

Vitreous Hemorrhage Treatment OptionsVitreous Hemorrhage Treatment Options

Watchful waitingWatchful waiting Natural historyNatural history

• 70% - 80% will never clear70% - 80% will never clear Patient issuesPatient issues Physician issuesPhysician issues

VitrectomyVitrectomy Post “watchful waiting” for at least 3 monthsPost “watchful waiting” for at least 3 months Effective surgeryEffective surgery RiskRisk CostCost

P-115

Vitreous Hemorrhage Treatment OptionVitreous Hemorrhage Treatment Option

VitraseVitrase More effective than “watchful waiting”More effective than “watchful waiting” Less risk than vitrectomyLess risk than vitrectomy Patient: restores QOLPatient: restores QOL Physician: ability to diagnose and treatPhysician: ability to diagnose and treat Summary: a treatment option that will improve our Summary: a treatment option that will improve our

current standard of carecurrent standard of care

P-116

Impact on Impact on Ophthalmology PracticeOphthalmology Practice

Kirk Packo, M.D.Kirk Packo, M.D.

P-117

ConclusionsConclusions

Lisa R. Grillone, Ph.D.Lisa R. Grillone, Ph.D.

P-118

Overall Conclusions Overall Conclusions

A 55 IU dose of Vitrase provides the following A 55 IU dose of Vitrase provides the following benefits:benefits:

1.1. At least a 3-line improvement in BCVAAt least a 3-line improvement in BCVA

2.2. Significant reduction in vitreous hemorrhageSignificant reduction in vitreous hemorrhagedensitydensity allows the physician to visualize, diagnose, and allows the physician to visualize, diagnose, and

treat the underlying cause of the hemorrhagetreat the underlying cause of the hemorrhage

P-119

Overall Conclusions Overall Conclusions

Evidence:Evidence:

Improvement of at least 3 lines of BCVA Improvement of at least 3 lines of BCVA As early as 1 month following treatmentAs early as 1 month following treatment Significance maintained through 3 months Significance maintained through 3 months

Reduction in hemorrhage density Reduction in hemorrhage density As early as 1 month following treatmentAs early as 1 month following treatment Significance maintained through 3 monthsSignificance maintained through 3 months

P-120

Risk Benefit AssessmentRisk Benefit AssessmentVitrase for the Treatment of Vitreous HemorrhageVitrase for the Treatment of Vitreous Hemorrhage

A single intravitreous injection of 55 IU Vitrase A single intravitreous injection of 55 IU Vitrase would provide would provide

The first pharmaceutical treatment with:The first pharmaceutical treatment with:• Early reduction in hemorrhage density andEarly reduction in hemorrhage density and• Significant improvement in BCVASignificant improvement in BCVA

Low incidence of adverse events overall, except for Low incidence of adverse events overall, except for inflammation inflammation

• Iritis, and its associated signs and symptoms, can be Iritis, and its associated signs and symptoms, can be managed with topical therapymanaged with topical therapy

P-121

Does Vitrase Meet the Does Vitrase Meet the Goals for New Therapy?Goals for New Therapy?

Safe with low risk to treated eyesSafe with low risk to treated eyes ++

Speeds hemorrhage clearanceSpeeds hemorrhage clearance ++

Restores visual function Restores visual function ++

Allows early therapy of underlying pathologyAllows early therapy of underlying pathology ++

Does not preclude future vitrectomyDoes not preclude future vitrectomy ++

Office procedureOffice procedure ++

P-122

Indication and UsageIndication and Usage

Proposed package label:Proposed package label:

““Vitrase is indicated for the treatment of vitreous Vitrase is indicated for the treatment of vitreous hemorrhage to improve visual acuity and to hemorrhage to improve visual acuity and to facilitate the physician’s ability to diagnose the facilitate the physician’s ability to diagnose the underlying retinal pathology”underlying retinal pathology”

Documents

P-1 ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee