# Presentation: 498624

## ISTA PharmaceuticalsVitrase®  For the treatment of vitreous hemorrhage

- Food and Drug AdministrationDermatologic and Ophthalmic Drugs Advisory Committee
- 17 March 2003

## ISTA

- A specialty pharmaceutical company –with a focus on ophthalmology

## Vitrase (ovine hyaluronidase) Proposed Package Label

- Indication: treatment of vitreous hemorrhage
- To improve visual acuity
- To facilitate the physician’s ability to diagnose the underlying retinal pathology

## Vitrase

- Single intravitreous injection
- Highly purified ovine hyaluronidase
- 10 years in development
- Approximately 1,500 patients treated at over 130 sites in 13 countries

## Vitrase Development History

**1992****	**Preclinical initiated
**1996**	US IND submitted
**1998**	Phase II trials completed
**1998**	Fast-track designation
**Sept 2001**	Last patient completed 		Month 3 efficacy
**Throughout 2002**	NDA filed to FDA
**March 17, 2003**	Advisory committee

## ISTA Presentation Agenda

**Introduction**	Vicente Anido, Ph.D.
**Clinical Background** 	John W. Chandler, M.D.
**Study Design and Efficacy**	Lisa R. Grillone, Ph.D.
**Safety**	John W. Chandler, M.D.
**Investigators’ Perspective**	Baruch D. Kuppermann, M.D.	Edgar Thomas, M.D.
**Impact on Clinical Practice ****	**Kirk Packo, M.D.
**Conclusions**	Lisa R. Grillone, Ph.D.

## Consultants

- John W. Chandler, M.D.
- Ophthalmology Consultant
- Baruch D. Kuppermann, M.D.
- Associate Professor of Ophthalmology, UC Irvine
- Edgar Thomas, M.D.
- Vitreo-retinal private practice, Los Angeles
- Kirk Packo, M.D.
- Rush Medical College, Chicago
- Raymond Buck, Ph.D.
- Statistical Consultant, Cato Research, Ltd.
- Brooks McCuen, M.D.
- Duke University, DSMB Member

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## ISTA Pharmaceuticals

- Vicente Anido, Ph.D.
- President and CEO
- Lisa R. Grillone, Ph.D.
- VP Clinical Research & Medical Affairs
- Marvin Garrett
- VP Regulatory Affairs, Quality and Compliance
- William Craig, Ph.D.
- VP Research & Product Development
- Kirk McMullin
- VP Operations

- P-

## Clinical Background

- John W. Chandler, M.D.

## Vitreous Hemorrhage

- 7 new dense spontaneous vitreous hemorrhages per 100,000 population annually (Europe)
- In US translates to 20,000 new patients entering pool of patients with vitreous hemorrhage each year

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

## Vitreous Hemorrhage

- Common causes (most unilateral)
- Proliferative diabetic retinopathy
- Posterior vitreous detachment (± retinal tear/detachment)
- Trauma
- Branch or central retinal vein occlusion
- Retinal macroaneurysm
- Age – related macular degeneration
- Subarachnoid hemorrhage

## Vitreous Hemorrhage

- 63% of bilateral vitreous hemorrhages are due to proliferative diabetic retinopathy
- Except for trauma and subarachnoid hemorrhages, at-risk eyes have pre-existing pathology

## Vitreous HemorrhageMechanisms

- Tear of normal retinal blood vessel
- Bleed from site of neovascularization or diseased blood vessel
- Bleed from other sites such as choroid

## Vitreous HemorrhageSequelae

- Decreases visual acuity
- Obstructs visualization of posterior pole
- Prevents therapy of sight-threatening pathology
- Retinal and choroidal neovascularization
- Causes retinal pathologic changes and electroretinograph abnormalities
- Large hemorrhages (non-human primates)

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

## Vitreous HemorrhageCharacteristics

- Rapidly bleeds and disperses
- Clears slowly
- Rate of clearance 1% per day (est.)
- Clearance of large hemorrhage slower

- Reference:  Surv Ophthalmol 42:2-39, 1997

## Natural History Studies

- Three Studies
- United States
- Spain
- Diabetic Retinopathy Vitrectomy Study (DRVS)

## Natural History StudyUnited States

- Patients with diabetic retinopathy
- 85 eyes with untreated large vitreous hemorrhage
- Visual acuity worse or no better in 70% of eyesthan 5/200 at 3-10 years follow-up

- Reference: Ophthalmology 87: 306-312, 1980

## Natural History StudySpain

- Compared to baseline visual acuity
- At 3 months post massive vitreous hemorrhage with no treatment
- 26% improved
- 63% unchanged
- 11% worsened
- At 2 years with no treatment
- 49% worse than HM
- 21% better than HM

- Reference: Retina 8:96-101, 1988

## Natural History Study DRVS

- Eyes with severe vitreous hemorrhages (312 eyes)
- Eligibility
- Onset within 6 months of randomization
- Vitrectomy delayed one year
- Visual acuity at entry 5/200 to LP
- Outcome (delayed treatment)
- 22% of patients had hemorrhage clearance at one year and vitrectomy was not required
- 11% vitrectomy for traction retinal detachment
- 5% inoperable (retinal detachment, neovascular glaucoma)

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

## Control Arms

- Delayed vitrectomy arm in DRVS
- Natural history severity analogous for Vitrase studies
- Saline placebo for Vitrase trial
- Involved intravitreous injection
- Controlled for efficacy assessment bias
- Caused intraocular inflammation

## Alternative Therapies

- Watchful Waiting
- Poor clearance, inability to diagnose and treat
- Progression of underlying pathology
- Poor visual function outcome
- There is no pharmaceutical treatment for vitreous hemorrhage

## Alternative Therapies

- Vitrectomy
- Major ocular procedure
- Some eyes/patients poor risks
- Costs
- Serious complications (DRVS 30-40%)

## Goals of New TherapyManagement of Vitreous Hemorrhage

- Safe with low risk to treated eyes
- Speeds hemorrhage clearance
- Restores visual function
- Allows early therapy of underlying pathology
- Does not preclude future vitrectomy
- Office procedure

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

- Early diagnosis and treatment of underlying condition
- Early return of visual function
- Unilateral hemorrhage causes significant visual impairment
- Many patients have decreased vision in the other eye and become bilaterally impaired

## Vitrase 

- Lyophilized preparation of highly purified ovine testicular hyaluronidase
- Preservative-free
- Reconstituted with Sodium Chloride Injection USP

## Vitrase: Pharmacokinetics 

- Intravitreous administration
- Animal studies
- Half-life (plasma): 49 hours
- Highest concentrations: vitreous, retina, sclera
- Half-life (ocular): 60-112 hours

## Vitrase: Mechanism of Action 

- Cleaves glycosidic bonds of hyaluronan
- Leads to collapse and liquefaction of vitreous
- Facilitates diffusion of molecules including proinflammatory chemotactic factors
- Promotes ingress of phagocytic cells and egress of red blood cells and proteins

## Vitreous Hemorrhage Clearing

**Vitreous Hemorrhage Clearing**

## Phase III Trials: Study Design & Efficacy Results

- Lisa R. Grillone, Ph.D.

## Vitrase Phase III Studies 

- Two Phase III studies
- Double masked, placebo controlled
- 131 sites contributed patients to the ITT population
- 12 countries
- 7.5***** IU:	181 patients
- 55 IU:	365 patients
- 75 IU:	377 patients
- Saline:	383 patients
- TOTAL Intent to Treat = 1306 patients
*** **North American Study

## Vit 03 – Ex North America

- Intent to treat population:
- 55 IU:   186
- 75 IU:   180
- _Saline:  190_
- Total:    556

- United Kingdom (12)

- Centers:

## Vit 02 - North America

**Centers:**
- United States	 (61)
- Canada		(9)
-  Mexico		(3)

- 7.5 IU:	181
- 55 IU:	179
- 75 IU:	197
- _Saline:__	__193_
**Total**: 	750

**Intent to Treat Population:**

- 7.5 IU:	18
- 55 IU:	18
- 75 IU:	17
- _WW:__	__18_
**Total**:	71

## Efficacy Presentation

- Study design
- Efficacy measures
- Patient demographics and baseline characteristics
- Efficacy results

## Vitrase Efficacy Integrated Phase III - 55 IU & 75 IU

| Measurement: | Month 1 | Month 2 | Month 3 |
| --- | --- | --- | --- |
| Reduction in Hemorrhage Density |  |  |  |
| Improvement in BCVA |  |  |  |
| Outcome by investigator |  |  |  |
| Surrogate success |  | 55 IU Only | 55 IU Only |

## Study DesignEligibility Criteria

- Vitreous hemorrhage for at least 1 month
- Severe hemorrhage at entry that obscured visualization of fundus
- BCVA worse than 20/200 in study eye

## Study DesignEligibility Criteria

- Hemorrhage density of Grade 3 or 4 in 12 clock hours posterior to the equator
- Red reflex is visible but no central retinal detail (retinal blood vessels) is seen posterior to the equator  (Grade 3)
- No red reflex (Grade 4)

## Non-Qualifying Hemorrhage

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

## Grade 3 Vitreous Hemorrhage

- “Headlight in the fog”

**Grade 3 Vitreous Hemorrhage**

## Grade 4 Vitreous Hemorrhage

**Grade 4 Vitreous Hemorrhage**

- “No red reflex”

## Study DesignExclusion Criteria

- Presence or history of retinal detachment, tears or breaks
- Ocular trauma
- Previous vitrectomy
- Organized hemorrhage
- No light perception in either eye

## Data Safety Monitoring Board

- Reviewed throughout the conduct of the study
- Conducted four unmasked interim evaluations for safety and efficacy
- Made recommendations to continue

## Study DesignRandomization

- Patients randomly assigned to receive
- Single intravitreous injection (50 μL) in one eye
- Three or four treatment groups
- 7.5 IU* Vitrase
- 55 IU Vitrase
- 75 IU Vitrase
- Saline Control
- *North American study only

## Efficacy Measures

- Reduction in vitreous hemorrhage density
- Improvement in BCVA
- Outcome determined by investigator (clearance, diagnosis +/- treatment)
- Surrogate success evaluation (clearance, diagnosis +/- treatment, confirmation)

## Surrogate Success Evaluation

- Efficacy assessment on or prior to Month 3
- Hemorrhage clearance sufficient to allow:
- Diagnosis of underlying condition that caused baseline hemorrhage
**And**
- _Confirmatory documentation_ that treatment was completed (e.g. adequate laser therapy), if required for underlying condition
**Or **
- _Confirmatory documentation_ (fundus photo) that no further treatment required

## Outcome Determined by Investigator

- As recorded on the CRF at Months 1, 2 and 3:
- Same as surrogate success evaluation
- _Without_ confirmatory documentation that treatment was completed or not required

## Reduction in Hemorrhage Density

- Definition of Grade 0 and 1
- Grade 0:
- Anatomical details of the retina are visible and pathology is easily treatable
- Grade 1:
- Retinal detail is visible, some hemorrhage may be present but laser photocoagulation would still be possible

## Grade 0 and Grade 1 Vitreous Hemorrhage

**Grade 0**

**Grade 1**

## Reduction in Hemorrhage Density

- Success = hemorrhage density reduced from Grades 3-4 to Grades:
-  0 or 1 in at least 6 clock hours
- (All cases, except BRVO)
-  0 or 1 in 3 clock hours (BRVO)

## Improvement in BCVA

**Success** = _**Three line**_ improvement measured in LogMAR units
*Three lines = 0.3 LogMAR units*
*Each letter = 0.02 LogMAR units*
*LP to HM = 1 Line Improvement*
- Answers an Important Clinical Question:
- 	“Is there a meaningful improvement in the patient’s vision resulting from the hemorrhage density reduction?”

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

## Efficacy Presentation Roadmap

- Study Sequence
- Vit 03 Ex North America
- Vit 02 North America
- Integrated Phase III

## Patient Demographics

|  | Ex-North America(N = 556) | North America(N = 750) | Integrated*(N = 1125) |
| --- | --- | --- | --- |
| Gender:  Males | 50.2% | 52.4% | 51.6% |
| Age (years):  Mean (SD)  Min – Max | 61.9 (12.2)23 – 93 | 61.9 (12.9)25 – 97 | 62.0 (12.4)23 – 93 |
| Ethnicity:  Caucasian  Black  Asian  Other | 84.0%9.7%3.6%2.7% | 50.8%5.5%3.5%40.1% | 67.6%7.7%3.5%21.2% |

- *does not include 7.5 IU Vitrase

## Etiology of Baseline Vitreous Hemorrhage

| Probable Cause | Ex-North America(N = 556) | North America(N = 750) | Integrated*(N = 1125) |
| --- | --- | --- | --- |
| Proliferative Diabetic Retinopathy | 66.2% | 78.7% | 71.9% |
| Central Retinal Vein Occlusion | 4.5% | 5.2% | 4.8% |
| Branch Retinal Vein Occlusion | 5.4% | 3.9% | 4.7% |
| Exudative Macular Degeneration  with Choroidal NV Membrane | 3.6% | 4.4% | 4.4% |
| Macroaneurysm | 0.7% | 0.0% | 0.4% |
| Hemorrhagic PVD | 2.3% | 2.0% | 2.2% |
| Other | 4.0% | 0.7% | 2.4% |

- *does not include 7.5 IU Vitrase

## Duration of Baseline Vitreous Hemorrhage

| Duration (Days) at Entry | Ex-North America(N = 556) | North America(N = 750) | Integrated*(N = 1125) |
| --- | --- | --- | --- |
| 	Mean | 125.3 | 116.9 | 120.4 |
| 	SD | 113.0 | 104.6 | 110.0 |

- *does not include 7.5 IU Vitrase

## Baseline Diabetic Status

|  | Ex-North America(N = 556) | North America(N = 750) | Integrated*(N = 1125) |
| --- | --- | --- | --- |
| Non-Diabetic | 28.6% | 17.3% | 23.7% |
| Diabetic | 71.4% | 82.7% | 76.3% |
| 	Type I | 69.3% | 52.9% | 59.4% |
| 	Type II | 30.7% | 47.1% | 40.6% |

- *does not include 7.5 IU Vitrase

## Baseline BCVA

|  | Ex-North America(N = 556) | North America(N = 750) | Integrated(N = 1306) |
| --- | --- | --- | --- |
| Off Chart* at entry | 528 (95.0%) | 652 (86.9%) | 1180 (90.4%) |

- *LP, HM, CF for off Chart

## Surrogate Success Evaluation

- Efficacy assessment on or prior to Month 3
- Hemorrhage clearance sufficient to allow:
- Diagnosis of underlying condition that caused study hemorrhage
**And**
- _Confirmatory documentation_ that treatment was completed (e.g. adequate laser therapy), if required for underlying condition
**Or **
- _Confirmatory documentation_ (fundus photo) that no further treatment required

## Surrogate Success EvaluationEx-North America

***P < 0.05  ******P < 0.005**

## Surrogate Success EvaluationEx-North America

|  | Saline Control(N = 190) | 55 IUVitrase(N = 186) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Month 1 | 4.7% | 11.3%p = 0.031 | 6.7%p = 0.564 |
| Month 2 | 15.3% | 19.9%p = 0.296 | 13.9%p = 0.820 |
| Month 3 | 21.6% | 28.0%p = 0.189 | 25.0%p = 0.512 |

## Surrogate Success EvaluationNorth America

***P < 0.05  ******P < 0.005**

## Surrogate Success EvaluationNorth America

|  | Saline Control(N = 193) | 7.5 IU Vitrase(N = 181) | 55 IU Vitrase(N = 179) | 75 IU Vitrase(N = 197) |
| --- | --- | --- | --- | --- |
| Month 1 | 6.2% | 12.7%p = 0.048 | 15.1%p = 0.009 | 14.2%p = 0.015 |
| Month 2 | 17.1% | 25.4%p = 0.065 | 31.3%p = 0.002 | 27.9%p = 0.015 |
| Month 3 | 29.5% | 31.5%p = 0.765 | 38.0%p = 0.106 | 35.5%p = 0.248 |

## Surrogate Success EvaluationIntegrated Phase III

***P < 0.05  ******P < 0.005**

## Surrogate Success EvaluationIntegrated Phase III

|  | Saline Control(N = 383) | 55 IU Vitrase(N = 365) | 75 IUVitrase(N = 377) |
| --- | --- | --- | --- |
| Month 1 | 5.5% | 13.2%p < 0.001 | 10.6%p = 0.010 |
| Month 2 | 16.2% | 25.5%p = 0.002 | 21.2%p = 0.083 |
| Month 3 | 25.6% | 32.9%p = 0.025 | 30.5%p = 0.144 |

## Outcome Determined by Investigator

- As recorded on the CRF at Months 1, 2 and 3:
- Same as surrogate success evaluation
- _Without_ confirmatory documentation that treatment was completed or not required

## Outcome Determined by InvestigatorEx-North America

***P < 0.05  ******P < 0.005**

## Outcome Determined by InvestigatorEx-North America

|  | Saline Control(N = 190) | 55 IU Vitrase(N = 186) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Month 1 | 10.5% | 18.8%p = 0.033 | 16.1%p = 0.153 |
| Month 2 | 18.9% | 30.6%p = 0.012 | 23.3%p = 0.365 |
| Month 3 | 25.3% | 38.2%p = 0.010 | 33.9%p = 0.088 |

## Outcome Determined by InvestigatorNorth America

***P < 0.05  ******P < 0.005**

## Outcome Determined by InvestigatorNorth America

|  | Saline Control(N = 193) | 7.5 IU Vitrase(N = 181) | 55 IU Vitrase(N = 179) | 75 IUVitrase(N = 197) |
| --- | --- | --- | --- | --- |
| Month 1 | 11.9% | 26.5%p = 0.001 | 27.9%p < 0.001 | 28.4%p < 0.001 |
| Month 2 | 23.8% | 38.7%p = 0.003 | 40.2%p = 0.001 | 40.1%p = 0.001 |
| Month 3 | 31.6% | 42.0%p = 0.048 | 43.6%p = 0.023 | 44.2%p = 0.014 |

## Outcome Determined by InvestigatorIntegrated Phase III

***P < 0.05  ******P < 0.005**

## Outcome Determined by InvestigatorIntegrated Phase III

|  | Saline Control(N = 383) | 55 IU Vitrase(N = 365) | 75 IU Vitrase(N = 377) |
| --- | --- | --- | --- |
| Month 1 | 11.2% | 23.3%p < 0.001 | 22.5%p < 0.001 |
| Month 2 | 21.4% | 35.3%p < 0.001 | 32.1%p = 0.001 |
| Month 3 | 28.5% | 40.8%p < 0.001 | 39.3%p = 0.002 |

## Reduction in Hemorrhage Density

- Success = hemorrhage density reduced from  Grades 3-4 to Grades:
-  0 or 1 in at least 6 clock hours
- (All cases, except BRVO)
-  0 or 1 in 3 clock hours (BRVO)

## Reduction in Hemorrhage DensityEx-North America

***P < 0.05  ******P < 0.005**

## Reduction in Hemorrhage DensityEx-North America

|  | Saline Control(N = 190) | 55 IU Vitrase(N = 186) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Month 1 | 10.5% | 19.9%p = 0.017 | 13.3%p = 0.501 |
| Month 2 | 19.5% | 30.6%p = 0.017 | 23.9%p = 0.366 |
| Month 3 | 25.3% | 36.6%p = 0.024 | 33.3%p = 0.111 |

## Reduction in Hemorrhage DensityNorth America

***P < 0.05  ******P < 0.005**

## Reduction in Hemorrhage DensityNorth America

|  | Saline Control(N = 193) | 7.5 IU Vitrase(N = 181) | 55 IU Vitrase(N = 179) | 75 IU Vitrase(N = 197) |
| --- | --- | --- | --- | --- |
| Month 1 | 11.4% | 24.9%p = 0.001 | 20.7%p = 0.021 | 24.4%p = 0.001 |
| Month 2 | 23.3% | 33.1%p = 0.046 | 35.2%p = 0.016 | 36.0%p = 0.008 |
| Month 3 | 31.6% | 35.9%p = 0.441 | 40.8%p = 0.083 | 42.6%p = 0.032 |

## Reduction in Hemorrhage DensityIntegrated Phase III

***P < 0.05  ******P < 0.005**

## Reduction in Hemorrhage DensityIntegrated Phase III

|  | Saline Control(N = 383) | 55 IU Vitrase(N = 365) | 75 IU Vitrase(N = 377) |
| --- | --- | --- | --- |
| Month 1 | 11.0% | 20.3%p < 0.001 | 19.1%p = 0.002 |
| Month 2 | 21.4% | 32.9%p < 0.001 | 30.2%p = 0.006 |
| Month 3 | 28.5% | 38.6%p = 0.003 | 38.2%p = 0.005 |

## Improvement in BCVA

**Success** = _**Three line**_ improvement measured in LogMAR units
*Three lines = 0.3 LogMAR units*
*Each letter = 0.02 LogMAR units*
*LP to HM = 1 Line Improvement*
- Answers an Important Clinical Question:
- 	“Is there a meaningful improvement in the patient’s vision resulting from the hemorrhage density reduction?”

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

## Improvement in BCVAEx-North America

***P < 0.05  ******P < 0.005**

## Improvement in BCVAEx-North America

|  | Saline Control(N = 190) | 55 IUVitrase(N = 186) | 75 IUVitrase(N = 180) |
| --- | --- | --- | --- |
| Month 1 | 22.6% | 33.3%p = 0.028 | 23.9%p = 0.870 |
| Month 2 | 28.4% | 43.0%p = 0.004 | 36.1%p = 0.141 |
| Month 3 | 32.6% | 46.2%p = 0.009 | 41.7%p = 0.091 |

## Improvement in BCVA North America

***P < 0.05  ******P < 0.005**

## Improvement in BCVANorth America

|  | Saline Control(N = 193) | 7.5 IU Vitrase(N = 181) | 55 IU Vitrase(N = 179) | 75 IU Vitrase(N = 197) |
| --- | --- | --- | --- | --- |
| Month 1 | 17.6% | 29.8%p = 0.008 | 27.9%p = 0.024 | 31.5%p = 0.002 |
| Month 2 | 26.4% | 33.7%p = 0.155 | 39.1%p = 0.012 | 40.1%p = 0.006 |
| Month 3 | 36.3% | 37.0%p = 0.966 | 43.6%p = 0.183 | 45.2%p = 0.092 |

## Improvement in BCVAIntegrated Phase III

***P < 0.05  ******P < 0.005**

## Improvement in BCVAIntegrated Phase III

|  | Saline Control(N = 383) | 55 IUVitrase(N = 365) | 75 IUVitrase(N = 377) |
| --- | --- | --- | --- |
| Month 1 | 20.1% | 30.7%p < 0.001 | 27.9%p = 0.013 |
| Month 2 | 27.4% | 41.1% p < 0.001 | 38.2%p = 0.002 |
| Month 3 | 34.5% | 44.9%p = 0.004 | 43.5%p = 0.011 |

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

|  | Saline Control(N = 383) | 55 IUVitrase(N = 365) | 75 IU Vitrase(N = 377) |
| --- | --- | --- | --- |
| Month 1 | 20.4% | 30.7%p = 0.0013 | 27.9%p = 0.0163 |
| Month 2 | 27.7% | 41.1%p = 0.0001 | 38.2%p = 0.0021 |
| Month 3 | 34.2% | 44.9%p = 0.0027 | 43.5%p = 0.0091 |

## Conclusions: Vitrase Efficacy Ex-North America - 55 IU

| Measurement: | Month 1 | Month 2 | Month 3 |
| --- | --- | --- | --- |
| Reduction in hemorrhage density |  |  |  |
| Improvement in BCVA |  |  |  |
| Outcome by investigator |  |  |  |
| Surrogate success |  |  |  |

## Conclusions: Vitrase Efficacy North America - 55 IU & 75 IU

| Measurement: | Month 1 | Month 2 | Month 3 |
| --- | --- | --- | --- |
| Reduction in hemorrhage density |  |  | 75 IU Only |
| Improvement in BCVA |  |  |  |
| Outcome by investigator |  |  |  |
| Surrogate success |  |  |  |

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

| Measurement: | Month 1 | Month 2 | Month 3 |
| --- | --- | --- | --- |
| Reduction in Hemorrhage Density |  |  |  |
| Improvement in BCVA |  |  |  |
| Outcome by investigator |  |  |  |
| Surrogate success |  | 55 IU Only | 55 IU Only |

## Vitrase Safety North America & Ex-North America

- John W. Chandler, M.D.

## Safety Population

- All patients who received a single intravitreous injection in Phase III Studies
- Ex-North America = 551
- North America = 740
- Original Watchful Waiting Study = 53
- Total Safety Populations = 1344

## Summary of Patient Follow-upEx-North America

|  | Saline Control(N = 187) | 55 IU Vitrase (N = 184) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Mean days (SD) | 296.3 (192.7) | 297.6 (193.9) | 293.1 (186.6) |
| Min – Max | 6 – 755 | 7 – 790 | 8 – 750 |
| Patients with: |  |  |  |
| 	Month 6 Follow-up Data | 133 (71.1%) | 138 (75.0%) | 126 (70.0%) |
| 	Month 12 Follow-up Data | 89 (47.6%) | 90 (48.9%) | 90 (50.0%) |

## Summary of Patient Follow-upNorth America (Saline)

|  | Saline Control(N = 191) | 7.5 IU Vitrase(N = 180) | 55 IU Vitrase (N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| Mean days (SD) | 289.0 (208.1) | 328.4 (227.2) | 293.9 (216.8) | 295.1 (207.7) |
| Min – Max | 5 – 784 | 7 – 784 | 1 – 874 | 6 – 798 |
| Patients with: |  |  |  |  |
| 	Month 6 Follow-up Data | 132 (69.1%) | 133 (73.9%) | 119 (68.0%) | 145 (74.7%) |
| 	Month 12 Follow-up Data | 81 (42.4%) | 91 (50.6%) | 81 (46.3%) | 85 (43.8%) |

## Summary of Patient Follow-upNorth America (WW)

|  | WWControl(N = 18) | 7.5 IU Vitrase(N = 18) | 55 IU Vitrase (N = 18) | 75 IU Vitrase(N = 17) |
| --- | --- | --- | --- | --- |
| Mean days (SD) | 305.6 (284.2) | 547.3 (331.3) | 545.6 (294.9) | 529.3 (319.6) |
| Min – Max | 31 – 966 | 27 – 964 | 110 – 972 | 81 – 965 |
| Patients with: |  |  |  |  |
| 	Month 6 Follow-up Data | 11 (61.1%) | 16 (88.9%) | 16 (88.9%) | 16 (94.1%) |
| 	Month 12 Follow-up Data | 7 (38.9%) | 14 (77.8%) | 15 (83.3%) | 11 (64.7%) |

## Summary of Patient Follow-upIntegrated Phase III

|  | Saline Control(N = 378) | 7.5 IU Vitrase(N = 198) | 55 IU Vitrase (N = 377) | 75 IU Vitrase(N = 391) |
| --- | --- | --- | --- | --- |
| Mean days(SD) | 292.6 (200.4) | 348.3 (245.7) | 307.7 (216.4) | 304.3 (209.3) |
| Min – Max | 5 – 784 | 7 – 964 | 1 – 972 | 6 – 965 |
| Patients with: |  |  |  |  |
| 	Month 6 Follow-up Data | 265 (70.1%) | 149 (75.3%) | 273 (72.4%) | 287 (73.4%) |
| 	Month 12 Follow-up Data | 170 (45.0%) | 105 (53.0%) | 186(49.3%) | 186 (47.6%) |

## Incidence of Deaths

|  | WWControl | Saline Control | 7.5 IU Vitrase | 55 IU Vitrase | 75 IU Vitrase  |
| --- | --- | --- | --- | --- | --- |
| Ex-North America | NA | 5.3% | NA | 3.8% | 6.1% |
| North America (Saline) | NA | 3.1% | 3.9% | 5.7% | 5.2% |
| North America (WW) | 33.3% | NA | 5.6% | 0% | 0% |
| Integrated | 33.3% | 4.2% | 4.0% | 4.5% | 5.4% |

## Safety AnalysisNo Light Perception

|  | WWControl | Saline Control | 7.5 IU Vitrase | 55 IU Vitrase | 75 IU Vitrase  | P-value |
| --- | --- | --- | --- | --- | --- | --- |
| Ex-North America | NA | 0.5% | NA | 0.5% | 1.7% | p=0.459 |
| North America (Saline) | NA | 1.6% | 2.8% | 2.3% | 1.5% | p=0.818 |
| North America (WW) | 5.6% | NA | 22.2% | 5.6% | 17.6% | NA |
| Integrated | 5.6% | 1.1% | 4.5% | 1.6% | 2.3% | NA |

## Safety AnalysisSystemic Adverse Events

- Ex-North America
- No systemic body systems with 10% incidence in combined Vitrase groups
- North America
- Systemic body systems with 10% incidence in combined Vitrase groups:
- Infections and infestations (p = 0.680)
- Nervous system disorders (p = 0.575)
- Cardiac disorders (p = 0.265)
- Gastrointestinal disorders (p = 0.364)

## Discontinued Due to Serious Adverse Events

| Event | Saline Control | 7.5 IU Vitrase | 55 IU Vitrase | 75 IU Vitrase |
| --- | --- | --- | --- | --- |
| Systemic AE | 0 | 1 | 0 | 3 |
| Death | 1 | 0 | 0 | 1 |
| Retinal Detachment | 0 | 1 | 0 | 3 |
| Vitreous Hemorrhage | 0 | 0 | 2 | 1 |
| Cataract | 0 | 0 | 0 | 0 |
| Increased IOP | 0 | 1 | 0 | 0 |

## Serious Adverse Events (Incidence 5%)Ex-North America

| Event | Saline Control(N = 187) | 55 IU Vitrase(N = 184) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Vitreous hemorr. (rebleed) | 7.5% | 9.8% | 11.1% |
| Retinal detachment | 6.4% | 7.1% | 6.7% |

## Serious Adverse Events (Incidence 5%)North America

| Event | Saline Control(N = 191) | 7.5 IU Vitrase(N = 180) | 55 IU Vitrase(N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| Vitreous hemorr. (rebleed) | 10.5% | 20.0% | 17.1% | 17.0% |
| Retinal detachment | 4.2% | 7.2% | 6.9% | 8.2% |
| Rubeosis iridis | 5.2% | 5.6% | 4.0% | 3.6% |
| Increased IOP | 2.1% | 12.2% | 5.7% | 8.2% |

## Serious Adverse Events (Incidence 5%)Integrated Phase III

| Event | Saline Control(N = 378) | 7.5 IU Vitrase(N = 198) | 55 IU Vitrase(N = 377) | 75 IU Vitrase(N = 391) |
| --- | --- | --- | --- | --- |
| Vitreous hemorr. (rebleed) | 14.3% | 25.3% | 17.8% | 18.2% |
| Retinal detachment | 6.3% | 8.1% | 8.0% | 8.7% |
| Rubeosis iridis | 4.0% | 6.6% | 3.4% | 3.1% |
| Increased IOP | 3.4% | 11.6% | 4.5% | 5.6% |

## Incidence of Adverse Events 10% Reaching Statistical Significance (p<0.05)Ex - North America

| Adverse Event | Saline Control(N = 187) | 55 IU Vitrase (N = 184) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Pts with 1 Ocular AE | 66.3% | 73.4% | 77.8% |
| Ocular Disorders |  |  |  |
| 	Iritis | 19.3% | 40.2% | 43.3% |
| 	Hyperemia | 24.6% | 37.0% | 39.4% |
| 	Pain | 12.3% | 22.3% | 28.3% |

- Overall Generalized Fisher Exact Test

## Incidence of Adverse Events 10% Reaching Statistical Significance (p<0.05)Ex - North America

| Adverse Event | Saline Control(N = 187) | 55 IU Vitrase (N = 184) | 75 IU Vitrase(N = 180) |
| --- | --- | --- | --- |
| Pts with 1 Ocular AE | 66.3% | 73.4% | 77.8% |
| Ocular Disorders |  |  |  |
| 	Iritis | 19.3% | 40.2% | 43.3% |
| 	Hyperemia | 24.6% | 37.0% | 39.4% |
| 	Pain | 12.3% | 22.3% | 28.3% |

- Overall Generalized Fisher Exact Test

## Incidence of Adverse Events 10% Reaching Statistical Significance (p<0.05)North America

| Adverse Event | Saline Control(N = 191) | 7.5 IU Vitrase(N = 180) | 55 IU Vitrase(N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| Pts with 1 Ocular AE | 91.1% | 97.2% | 97.1% | 99.0% |
| Ocular Disorders |  |  |  |  |
| 	Iritis |  47.1% | 61.1% | 76.6% | 78.4% |
| 	Hyperemia | 49.2% | 56.1% | 70.9% | 67.5% |
| 	Irritation | 43.5% | 52.8% | 62.9% | 61.3% |
| 	Pain | 31.9% | 35.0% | 50.3% | 50.5% |
| 	Inc. Lacrimation | 34.6% | 31.1% | 46.3% | 48.5% |
| 	Photophobia | 21.5% | 28.9% | 31.4% | 34.5% |
| 	Photopsia | 7.9% | 11.7% | 19.4% | 14.4% |
| 	VA reduced | 26.2% | 38.9% | 37.7% | 37.6% |
| 	Vit. Hemorr. (rebleed) | 21.5% | 35.6% | 30.9% | 26.3% |

- Overall Generalized Fisher Exact Test

## Incidence of Adverse Events 10% Reaching Statistical Significance (p<0.05)North America

| Adverse Event | Saline Control(N = 191) | 7.5 IU Vitrase(N = 180) | 55 IU Vitrase(N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| Pts with 1 Ocular AE | 91.1% | 97.2% | 97.1% | 99.0% |
| Ocular Disorders |  |  |  |  |
| 	Iritis |  47.1% | 61.1% | 76.6% | 78.4% |
| 	Hyperemia | 49.2% | 56.1% | 70.9% | 67.5% |
| 	Irritation | 43.5% | 52.8% | 62.9% | 61.3% |
| 	Pain | 31.9% | 35.0% | 50.3% | 50.5% |
| 	Inc. Lacrimation | 34.6% | 31.1% |  46.3% | 48.5% |
| 	Photophobia | 21.5% | 28.9% | 31.4% | 34.5% |
| 	Photopsia | 7.9% | 11.7% | 19.4% | 14.4% |
| 	VA reduced | 26.2% | 38.9% | 37.7% | 37.6% |
| 	Vit. Hemorr. (rebleed) | 21.5% | 35.6% | 30.9% | 26.3% |

- Overall Generalized Fisher Exact Test

## Vitrase: Safety Findings 

- Vitrase administration is associated with  inflammation
- Iritis was frequent, with dose response, but not severe
- Frequently self-limited or managed with topical medications
- Also seen in the saline treated eyes but to lesser extent
- Not a cause of SAEs
- Inflammation may help clear vitreous hemorrhage

## Safety Analysis - IritisNorth America

| Iritis | Saline Control(N = 191) | 7.5 IU Vitrase(N = 180) | 55 IU Vitrase(N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| AE | 47.1% | 61.1% | 76.6% | 78.4% |
| 	Mild | 38.7% | 41.7% | 32.0% | 29.9% |
| 	Moderate | 6.8% | 15.0% | 32.0% | 30.9% |
| 	Severe | 1.6% | 4.4% | 12.6% | 17.5% |
| SAE | 0.5% | 0.6% | 0 | 1.0% |
| Event resolved within: |  |  |  |  |
| 	0-30 Days | 70.7% | 67.1% | 73.4% | 76.7% |
| 	31-60 Days | 10.8% | 9.8% | 13.3% | 14.0% |
| 	61-90 Days | 3.6% | 4.4% | 5.5% | 2.4% |

## Safety Analysis - Hypopyon North America

| Hypopyon | Saline Control(N = 191) | 7.5 IUVitrase(N = 180) | 55 IU Vitrase(N = 175) | 75 IU Vitrase(N = 194) |
| --- | --- | --- | --- | --- |
| AE* | 0  | 0.6% | 1.7% | 7.2% |
| SAE | 0  | 0  | 1.1% | 1.5%  |

- * P = <0.00001

## Safety Analysis – Retinal DetachmentNorth America

| Retinal Detachment | Saline Control(N = 191) | 7.5 IUVitrase(N = 180) | 55 IUVitrase(N = 175) | 75 IUVitrase(N = 194) |
| --- | --- | --- | --- | --- |
| AE* | 5.8%  | 10.6%  | 10.3% | 11.9% |
| SAE | 4.2% | 7.2%  | 6.9% | 8.2% |

- (DRVS 11%)

- * P = 0.172

## Safety Conclusions

- Iritis accounted for majority of AE’s
- Higher incidence in Vitrase treated eyes
- Associated with other most common AE’s
- Self-limited or treated with topical drugs
- Not a cause of SAE’s
- Sterile hypopyon infrequent and medically treated
- NLP not Vitrase related

## Safety Conclusions

- Retinal detachment
- rates prior to vitrectomy low
- not Vitrase related
- Significant SAE’s tended to occur after 90 days
- The safety profile of Vitrase supports human intravitreous administration of Vitrase for the treatment of vitreous hemorrhage

## Clinical Investigators’ Perspective and Patients’ Response

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

## Physicians Perspective

- Clinical practice characteristics
- Patient population
- Teaching hospital
- Goal of vitreous hemorrhage treatment

## Vitrase Impact on a Patient

- Patient:
- 35 years old
- Diagnosis:  Diabetic
- Severe vitreous hemorrhage
- Treatment:  Vitrase 55 IU, single injection

## Vitreous Hemorrhage Treatment Options

- Watchful waiting
- Natural history
- 70% - 80% will never clear
- Patient issues
- Physician issues
- Vitrectomy
- Post “watchful waiting” for at least 3 months
- Effective surgery
- Risk
- Cost

## Vitreous Hemorrhage Treatment Option

- Vitrase
- More effective than “watchful waiting”
- Less risk than vitrectomy
- Patient: restores QOL
- Physician:  ability to diagnose and treat
- Summary:  a treatment option that will improve our current standard of care

## Impact on Ophthalmology Practice

- Kirk Packo, M.D.

## Conclusions

- Lisa R. Grillone, Ph.D.

## Overall Conclusions 

- A 55 IU dose of Vitrase provides the following benefits:
-  	At least a 3-line improvement in BCVA
-  	Significant reduction in vitreous hemorrhage	density
- allows the physician to visualize, diagnose, and treat the underlying cause of the hemorrhage

## Overall Conclusions 

- Evidence:
- Improvement of at least 3 lines of BCVA
- As early as 1 month following treatment
- Significance maintained through 3 months
- Reduction in hemorrhage density
- As early as 1 month following treatment
- Significance maintained through 3 months

## Risk Benefit AssessmentVitrase for the Treatment of Vitreous Hemorrhage

- A single intravitreous injection of 55 IU Vitrase would provide
- The first pharmaceutical treatment with:
- Early reduction in hemorrhage density and
- Significant improvement in BCVA
- Low incidence of adverse events overall, except for inflammation
- Iritis, and its associated signs and symptoms, can be managed with topical therapy

## Does Vitrase Meet the Goals for New Therapy?

- Safe with low risk to treated eyes	 		 **+**
- Speeds hemorrhage clearance				 **+**
- Restores visual function 					 **+**
- Allows early therapy of underlying pathology	 	 **+**
- Does not preclude future vitrectomy			 **+**
- Office procedure	 					 **+**

## Indication and Usage

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