P-1 ISTA Pharmaceuticals ISTA Pharmaceuticals Vitrase Vitrase ® ® For the treatment of vitreous For the treatment of vitreous hemorrhage hemorrhage Food and Drug Administration Food and Drug Administration Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee 17 March 2003 17 March 2003
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P-1 ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee.
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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
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
(± 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
Vitreous HemorrhageVitreous Hemorrhage
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
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)
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
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)
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
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
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)
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)
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
Reduction in Hemorrhage DensityReduction in Hemorrhage Density
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
Improvement in BCVAImprovement in BCVA
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?”
Study SequenceStudy Sequence Vit 03 Ex North AmericaVit 03 Ex North America Vit 02 North AmericaVit 02 North America Integrated Phase IIIIntegrated Phase III
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
Month 1 Month 2 Month 3
% 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
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-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
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-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
Month 1 Month 2 Month 3
% o
f P
ts -
Tre
atm
en
t S
uc
ce
ss
Saline7.5 IU55 IU75 IU
*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
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-70
Reduction in Hemorrhage DensityReduction in Hemorrhage Density
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
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-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
Month 1 Month 2 Month 3
% o
f P
ts -
Tre
atm
en
t S
uc
ce
ss
Saline7.5 IU55 IU75 IU
*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
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-77
Improvement in BCVAImprovement in BCVA
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?”
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-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
Overall Generalized Fisher Exact TestOverall Generalized Fisher Exact Test
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
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
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
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 ++
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”