1. P-1 ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee 17 March 2003

2. P-2 ISTA A specialty pharmaceutical company – with a focus on ophthalmology

3. P-3 Vitrase (ovine hyaluronidase) Proposed Package Label Indication: treatment of vitreous hemorrhage To improve visual acuity To improve visual acuity To facilitate the physician’s ability to diagnose the underlying retinal pathology To facilitate the physician’s ability to diagnose the underlying retinal pathology

4. P-4 Vitrase Single intravitreous injection Single intravitreous injection Highly purified ovine hyaluronidase Highly purified ovine hyaluronidase 10 years in development 10 years in development Approximately 1,500 patients treated at over 130 sites in 13 countries Approximately 1,500 patients treated at over 130 sites in 13 countries

5. P-5 Vitrase Development History 1992Preclinical initiated 1996US IND submitted 1998Phase II trials completed 1998Fast-track designation Sept 2001Last patient completed Month 3 efficacy Throughout 2002NDA filed to FDA March 17, 2003Advisory committee

6. P-6 ISTA Presentation Agenda IntroductionVicente Anido, Ph.D. Clinical Background John W. Chandler, M.D. Study Design and EfficacyLisa R. Grillone, Ph.D. SafetyJohn W. Chandler, M.D. Investigators’ PerspectiveBaruch D. Kuppermann, M.D. Edgar Thomas, M.D. Impact on Clinical Practice Kirk Packo, M.D. ConclusionsLisa R. Grillone, Ph.D.

7. Consultants John W. Chandler, M.D. John W. Chandler, M.D. Ophthalmology Consultant Ophthalmology Consultant Baruch D. Kuppermann, M.D. Baruch D. Kuppermann, M.D. Associate Professor of Ophthalmology, UC Irvine Associate Professor of Ophthalmology, UC Irvine Edgar Thomas, M.D. Edgar Thomas, M.D. Vitreo-retinal private practice, Los Angeles Vitreo-retinal private practice, Los Angeles Kirk Packo, M.D. Kirk Packo, M.D. Rush Medical College, Chicago Rush 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 Member Duke University, DSMB Member P-7

8. ISTA Pharmaceuticals Vicente Anido, Ph.D. Vicente Anido, Ph.D. President and CEO President and CEO Lisa R. Grillone, Ph.D. Lisa R. Grillone, Ph.D. VP Clinical Research & Medical Affairs VP Clinical Research & Medical Affairs Marvin Garrett Marvin Garrett VP Regulatory Affairs, Quality and Compliance VP Regulatory Affairs, Quality and Compliance William Craig, Ph.D. William Craig, Ph.D. VP Research & Product Development VP Research & Product Development Kirk McMullin Kirk McMullin VP Operations VP Operations P-8

9. P-9 Clinical Background John W. Chandler, M.D.

10. P-10 Vitreous Hemorrhage 7 new dense spontaneous vitreous hemorrhages per 100,000 population annually (Europe) 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 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

11. P-11 Vitreous Hemorrhage Common causes (most unilateral) Common causes (most unilateral) Proliferative diabetic retinopathy Proliferative diabetic retinopathy Posterior vitreous detachment (± retinal tear/detachment) Posterior vitreous detachment (± retinal tear/detachment) Trauma Trauma Branch or central retinal vein occlusion Branch or central retinal vein occlusion Retinal macroaneurysm Retinal macroaneurysm Age – related macular degeneration Age – related macular degeneration Subarachnoid hemorrhage Subarachnoid hemorrhage

12. P-12 Vitreous Hemorrhage 63% of bilateral vitreous hemorrhages are due to proliferative diabetic retinopathy 63% of bilateral vitreous hemorrhages are due to proliferative diabetic retinopathy Except for trauma and subarachnoid hemorrhages, at-risk eyes have pre-existing pathology Except for trauma and subarachnoid hemorrhages, at-risk eyes have pre-existing pathology

13. P-13 Vitreous Hemorrhage Mechanisms Tear of normal retinal blood vessel Tear of normal retinal blood vessel Bleed from site of neovascularization or diseased blood vessel Bleed from site of neovascularization or diseased blood vessel Bleed from other sites such as choroid Bleed from other sites such as choroid

14. P-14 Vitreous Hemorrhage Sequelae Decreases visual acuity Decreases visual acuity Obstructs visualization of posterior pole Obstructs visualization of posterior pole Prevents therapy of sight-threatening pathology Prevents therapy of sight-threatening pathology Retinal and choroidal neovascularization Retinal and choroidal neovascularization Causes retinal pathologic changes and electroretinograph abnormalities Causes retinal pathologic changes and electroretinograph abnormalities Large hemorrhages (non-human primates) Large hemorrhages (non-human primates) Reference: Gaefes Arch Clin Exp Ophthalmol 197:255-267, 1975

15. P-15 Vitreous Hemorrhage Characteristics Rapidly bleeds and disperses Rapidly bleeds and disperses Clears slowly Clears slowly Rate of clearance 1% per day (est.) Rate of clearance 1% per day (est.) Clearance of large hemorrhage slower Clearance of large hemorrhage slower Reference: Surv Ophthalmol 42:2-39, 1997

16. P-16 Natural History Studies Three Studies Three Studies United States United States Spain Spain Diabetic Retinopathy Vitrectomy Study (DRVS) Diabetic Retinopathy Vitrectomy Study (DRVS)

17. P-17 Natural History Study United States Patients with diabetic retinopathy 85 eyes with untreated large vitreous hemorrhage 85 eyes with untreated large vitreous hemorrhage Visual acuity worse or no better in 70% of eyes than 5/200 at 3-10 years follow-up Visual acuity worse or no better in 70% of eyes than 5/200 at 3-10 years follow-up Reference: Ophthalmology 87: 306-312, 1980

18. P-18 Natural History Study Spain Compared to baseline visual acuity At 3 months post massive vitreous hemorrhage with no treatment At 3 months post massive vitreous hemorrhage with no treatment 26% improved 26% improved 63% unchanged 63% unchanged 11% worsened 11% worsened At 2 years with no treatment At 2 years with no treatment 49% worse than HM 49% worse than HM 21% better than HM 21% better than HM Reference: Retina 8:96-101, 1988

19. P-19 Natural History Study DRVS Eyes with severe vitreous hemorrhages (312 eyes) Eligibility Eligibility Onset within 6 months of randomization Onset within 6 months of randomization Vitrectomy delayed one year Vitrectomy delayed one year Visual acuity at entry 5/200 to LP Visual acuity at entry 5/200 to LP Outcome (delayed treatment) Outcome (delayed treatment) 22% of patients had hemorrhage clearance at one year and vitrectomy was not required 22% of patients had hemorrhage clearance at one year and vitrectomy was not required 11% vitrectomy for traction retinal detachment 11% vitrectomy for traction retinal detachment 5% inoperable (retinal detachment, neovascular glaucoma) 5% inoperable (retinal detachment, neovascular glaucoma) Reference: Arch Ophthalmol 103:1644-1652, 1985

20. P-20 Control Arms Delayed vitrectomy arm in DRVS Delayed vitrectomy arm in DRVS Natural history severity analogous for Vitrase studies Natural history severity analogous for Vitrase studies Saline placebo for Vitrase trial Saline placebo for Vitrase trial Involved intravitreous injection Involved intravitreous injection Controlled for efficacy assessment bias Controlled for efficacy assessment bias Caused intraocular inflammation Caused intraocular inflammation

21. P-21 Alternative Therapies Watchful Waiting Watchful Waiting Poor clearance, inability to diagnose and treat Poor clearance, inability to diagnose and treat Progression of underlying pathology Progression of underlying pathology Poor visual function outcome Poor visual function outcome There is no pharmaceutical treatment for vitreous hemorrhage There is no pharmaceutical treatment for vitreous hemorrhage

22. P-22 Alternative Therapies Vitrectomy Vitrectomy Major ocular procedure Major ocular procedure Some eyes/patients poor risks Some eyes/patients poor risks Costs Costs Serious complications (DRVS 30-40%) Serious complications (DRVS 30-40%)

23. P-23 Goals of New Therapy Management of Vitreous Hemorrhage Safe with low risk to treated eyes Safe with low risk to treated eyes Speeds hemorrhage clearance Speeds hemorrhage clearance Restores visual function Restores visual function Allows early therapy of underlying pathology Allows early therapy of underlying pathology Does not preclude future vitrectomy Does not preclude future vitrectomy Office procedure Office procedure

24. P-24 If Vitrase Meets These Goals, What Will it Mean to Patients? Early diagnosis and treatment of underlying condition Early diagnosis and treatment of underlying condition Early return of visual function Early return of visual function Unilateral hemorrhage causes significant visual impairment Unilateral hemorrhage causes significant visual impairment Many patients have decreased vision in the other eye and become bilaterally impaired Many patients have decreased vision in the other eye and become bilaterally impaired

25. P-25 Vitrase Lyophilized preparation of highly purified ovine testicular hyaluronidase Lyophilized preparation of highly purified ovine testicular hyaluronidase Preservative-free Preservative-free Reconstituted with Sodium Chloride Injection USP Reconstituted with Sodium Chloride Injection USP

26. P-26 Vitrase: Pharmacokinetics Intravitreous administration Intravitreous administration Animal studies Animal studies Half-life (plasma): 49 hours Half-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

27. P-27 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 proinflammatory chemotactic factors Facilitates diffusion of molecules including proinflammatory chemotactic factors Promotes ingress of phagocytic cells and egress of red blood cells and proteins Promotes ingress of phagocytic cells and egress of red blood cells and proteins

28. P-28 Vitreous Hemorrhage Clearing

29. P-29 Phase III Trials: Study Design & Efficacy Results Lisa R. Grillone, Ph.D.

30. P-30 Vitrase Phase III Studies Two Phase III studies Two Phase III studies Double masked, placebo controlled Double masked, placebo controlled 131 sites contributed patients to the ITT population 131 sites contributed patients to the ITT population 12 countries 12 countries 7.5* IU:181 patients 7.5* IU:181 patients 55 IU:365 patients 55 IU:365 patients 75 IU:377 patients 75 IU:377 patients Saline:383 patients Saline:383 patients TOTAL Intent to Treat = 1306 patients * North American Study

31. P-31 Vit 03 – Ex North America Intent to treat population: 55 IU: 186 75 IU: 180 Saline: 190 Total: 556 Australia (6) Brazil (6) Hungary (6) Italy (3) Netherlands (3) Poland (9) Spain (4) South Africa (9) United Kingdom (12) Centers:

32. P-32 Vit 02 - North America Centers: United States (61) Canada(9) Mexico(3) 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

33. P-33 Efficacy Presentation Study design Study design Efficacy measures Efficacy measures Patient demographics and baseline characteristics Patient demographics and baseline characteristics Efficacy results Efficacy results

34. P-34 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

35. P-35 Study Design Eligibility Criteria Vitreous hemorrhage for at least 1 month Vitreous hemorrhage for at least 1 month Severe hemorrhage at entry that obscured visualization of fundus Severe hemorrhage at entry that obscured visualization of fundus BCVA worse than 20/200 in study eye BCVA worse than 20/200 in study eye

36. P-36 Study Design Eligibility Criteria Hemorrhage density of Grade 3 or 4 in 12 clock hours posterior to the equator 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) 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) No red reflex (Grade 4)

37. P-37 Non-Qualifying Hemorrhage Grade 2 – Some blood vessels visible posterior of the equator

38. P-38 “Headlight in the fog” Grade 3 Vitreous Hemorrhage

39. P-39 Grade 4 Vitreous Hemorrhage “No red reflex”

40. P-40 Study Design Exclusion Criteria Presence or history of retinal detachment, tears or breaks Presence or history of retinal detachment, tears or breaks Ocular trauma Ocular trauma Previous vitrectomy Previous vitrectomy Organized hemorrhage Organized hemorrhage No light perception in either eye No light perception in either eye

41. P-41 Data Safety Monitoring Board Reviewed throughout the conduct of the study Reviewed throughout the conduct of the study Conducted four unmasked interim evaluations for safety and efficacy Conducted four unmasked interim evaluations for safety and efficacy Made recommendations to continue Made recommendations to continue

42. P-42 Study Design Randomization Patients randomly assigned to receive Single intravitreous injection (50 µL) in one eye Single intravitreous injection (50 µL) in one eye Three or four treatment groups Three or four treatment groups 7.5 IU* Vitrase 7.5 IU* Vitrase 55 IU Vitrase 55 IU Vitrase 75 IU Vitrase 75 IU Vitrase Saline Control Saline Control *North American study only

43. P-43 Efficacy Measures 1. Reduction in vitreous hemorrhage density 2. Improvement in BCVA 3. Outcome determined by investigator (clearance, diagnosis +/- treatment) 4. Surrogate success evaluation (clearance, diagnosis +/- treatment, confirmation)

44. P-44 Surrogate Success Evaluation Efficacy assessment on or prior to Month 3 Efficacy assessment on or prior to Month 3 Hemorrhage clearance sufficient to allow: Hemorrhage clearance sufficient to allow: Diagnosis of underlying condition that caused baseline hemorrhage Diagnosis of underlying condition that caused baseline hemorrhageAnd Confirmatory documentation that treatment was completed (e.g. adequate laser therapy), if required for underlying condition Confirmatory documentation that treatment was completed (e.g. adequate laser therapy), if required for underlying conditionOr Confirmatory documentation (fundus photo) that no further treatment required Confirmatory documentation (fundus photo) that no further treatment required

45. P-45 Outcome Determined by Investigator As recorded on the CRF at Months 1, 2 and 3: Same as surrogate success evaluation Same as surrogate success evaluation Without confirmatory documentation that treatment was completed or not required

46. P-46 Reduction in Hemorrhage Density Definition of Grade 0 and 1 Grade 0: Grade 0: Anatomical details of the retina are visible and pathology is easily treatable Anatomical details of the retina are visible and pathology is easily treatable Grade 1: Grade 1: Retinal detail is visible, some hemorrhage may be present but laser photocoagulation would still be possible Retinal detail is visible, some hemorrhage may be present but laser photocoagulation would still be possible

47. P-47 Grade 0 and Grade 1 Vitreous Hemorrhage Grade 0 Grade 1

48. P-48 Reduction in Hemorrhage Density Success = hemorrhage density reduced from Grades 3-4 to Grades: 0 or 1 in at least 6 clock hours 0 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)

49. P-49 Improvement in BCVA Success = Three line improvement measured in LogMAR units Success = Three line improvement measured in LogMAR units Three lines = 0.3 LogMAR units Three lines = 0.3 LogMAR units Each letter = 0.02 LogMAR units Each letter = 0.02 LogMAR units LP to HM = 1 Line Improvement LP 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 resulting from the hemorrhage density reduction?” Reference: J Ref Surg 13:388-391, 1997

50. P-50 Efficacy Presentation Roadmap Study Sequence Study Sequence Vit 03 Ex North America Vit 03 Ex North America Vit 02 North America Vit 02 North America Integrated Phase III Integrated Phase III

51. P-51 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

52. P-52 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% Macroaneurysm0.7%0.0%0.4% Hemorrhagic PVD 2.3%2.0%2.2% Other4.0%0.7%2.4% *does not include 7.5 IU Vitrase

53. P-53 Duration of Baseline Vitreous Hemorrhage Duration (Days) at Entry Ex-North America (N = 556) North America (N = 750) Integrated* (N = 1125) Mean125.3116.9120.4 SD113.0104.6110.0 *does not include 7.5 IU Vitrase

54. P-54 Baseline Diabetic Status Ex-North America (N = 556) North America (N = 750) Integrated* (N = 1125) Non-Diabetic28.6%17.3%23.7% Diabetic71.4%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

55. P-55 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

56. P-56 Surrogate Success Evaluation Efficacy assessment on or prior to Month 3 Efficacy assessment on or prior to Month 3 Hemorrhage clearance sufficient to allow: Hemorrhage clearance sufficient to allow: Diagnosis of underlying condition that caused study hemorrhage Diagnosis of underlying condition that caused study hemorrhageAnd Confirmatory documentation that treatment was completed (e.g. adequate laser therapy), if required for underlying condition Confirmatory documentation that treatment was completed (e.g. adequate laser therapy), if required for underlying conditionOr Confirmatory documentation (fundus photo) that no further treatment required Confirmatory documentation (fundus photo) that no further treatment required

57. P-57 Surrogate Success Evaluation Ex-North America *P < 0.05 **P < 0.005

58. P-58 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

59. P-59 Surrogate Success Evaluation North America *P < 0.05 **P < 0.005

60. P-60 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

61. P-61 Surrogate Success Evaluation Integrated Phase III *P < 0.05 **P < 0.005

62. P-62 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

63. P-63 Outcome Determined by Investigator As recorded on the CRF at Months 1, 2 and 3: Same as surrogate success evaluation Same as surrogate success evaluation Without confirmatory documentation that treatment was completed or not required

64. P-64 Outcome Determined by Investigator Ex-North America *P < 0.05 **P < 0.005

65. P-65 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

66. P-66 Outcome Determined by Investigator North America *P < 0.05 **P < 0.005

67. P-67 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

68. P-68 Outcome Determined by Investigator Integrated Phase III *P < 0.05 **P < 0.005

69. P-69 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

70. P-70 Reduction in Hemorrhage Density Success = hemorrhage density reduced from Grades 3-4 to Grades: 0 or 1 in at least 6 clock hours 0 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)

71. P-71 Reduction in Hemorrhage Density Ex-North America *P < 0.05 **P < 0.005

72. P-72 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

73. P-73 Reduction in Hemorrhage Density North America *P < 0.05 **P < 0.005

74. P-74 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

75. P-75 Reduction in Hemorrhage Density Integrated Phase III *P < 0.05 **P < 0.005

76. P-76 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

77. P-77 Improvement in BCVA Success = Three line improvement measured in LogMAR units Success = Three line improvement measured in LogMAR units Three lines = 0.3 LogMAR units Three lines = 0.3 LogMAR units Each letter = 0.02 LogMAR units Each letter = 0.02 LogMAR units LP to HM = 1 Line Improvement LP 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 resulting from the hemorrhage density reduction?” Reference: J Ref Surg 13:388-391, 1997

78. P-78 Improvement in BCVA Ex-North America *P < 0.05 **P < 0.005

79. P-79 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

80. P-80 Improvement in BCVA North America *P < 0.05 **P < 0.005

81. P-81 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

82. P-82 Improvement in BCVA Integrated Phase III *P < 0.05 **P < 0.005

83. P-83 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

84. P-84 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

85. P-85 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 

86. P-86 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 

87. P-87 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

88. P-88 Vitrase Safety North America & Ex-North America John W. Chandler, M.D.

89. P-89 Safety Population All patients who received a single intravitreous injection in Phase III Studies All patients who received a single intravitreous injection in Phase III Studies Ex-North America = 551 Ex-North America = 551 North America = 740 North America = 740 Original Watchful Waiting Study = 53 Original Watchful Waiting Study = 53 Total Safety Populations = 1344 Total Safety Populations = 1344

90. P-90 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%)

91. P-91 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%)

92. P-92 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 (94.1%) Month 12 Follow-up Data 7 (38.9%) 14 (77.8%) 15 (83.3%) 11 (64.7%)

93. P-93 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%)

94. P-94 Incidence of Deaths WW Control Saline Control 7.5 IU Vitrase 55 IU Vitrase 75 IU Vitrase Ex-North America NA5.3%NA3.8%6.1% North America (Saline) NA3.1%3.9%5.7%5.2% North America (WW) 33.3%NA5.6%0%0% Integrated33.3%4.2%4.0%4.5%5.4%

95. P-95 Safety Analysis No Light Perception WW Control Saline Control 7.5 IU Vitrase 55 IU Vitrase 75 IU Vitrase P-value Ex-North America NA0.5%NA0.5%1.7%p=0.459 North America (Saline) NA1.6%2.8%2.3%1.5%p=0.818 North America (WW) 5.6%NA22.2%5.6%17.6%NA Integrated5.6%1.1%4.5%1.6%2.3%NA

96. P-96 Safety Analysis Systemic Adverse Events Ex-North America No systemic body systems with  10% incidence in combined Vitrase groups No systemic body systems with  10% incidence in combined Vitrase groups North America Systemic body systems with  10% incidence in combined Vitrase groups: Systemic body systems with  10% incidence in 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)

97. P-97 Discontinued Due to Serious Adverse Events Event Saline Control 7.5 IU Vitrase 55 IU Vitrase 75 IU Vitrase Systemic AE 0103 Death1001 Retinal Detachment 0103 Vitreous Hemorrhage 0021 Cataract0000 Increased IOP 0100

98. P-98 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%

99. P-99 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%

100. P-100 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%

101. P-101 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 Iritis19.3%40.2%43.3% Hyperemia24.6%37.0%39.4% Pain12.3%22.3%28.3% Overall Generalized Fisher Exact Test

102. P-102 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 Iritis19.3%40.2%43.3% Hyperemia24.6%37.0%39.4% Pain12.3%22.3%28.3% Overall Generalized Fisher Exact Test

103. P-103 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% 47.1%61.1%76.6%78.4% Hyperemia49.2%56.1%70.9%67.5% Irritation43.5%52.8%62.9%61.3% Pain31.9%35.0%50.3%50.5% Inc. Lacrimation 34.6%31.1%46.3%48.5% Photophobia21.5%28.9%31.4%34.5% Photopsia7.9%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

104. P-104 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% 47.1%61.1%76.6%78.4% Hyperemia49.2%56.1%70.9%67.5% Irritation43.5%52.8%62.9%61.3% Pain31.9%35.0%50.3%50.5% Inc. Lacrimation 34.6%31.1% 46.3% 46.3%48.5% Photophobia21.5%28.9%31.4%34.5% Photopsia7.9%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

105. P-105 Vitrase: Safety Findings Vitrase administration is associated with inflammation Vitrase administration is associated with inflammation Iritis was frequent, with dose response, but not severe Iritis was frequent, with dose response, but not severe Frequently self-limited or managed with topical medications Frequently self-limited or managed with topical medications Also seen in the saline treated eyes but to lesser extent Also seen in the saline treated eyes but to lesser extent Not a cause of SAEs Not a cause of SAEs Inflammation may help clear vitreous hemorrhage Inflammation may help clear vitreous hemorrhage

106. P-106 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) AE47.1%61.1%76.6%78.4% Mild38.7%41.7%32.0%29.9% Moderate6.8%15.0%32.0%30.9% Severe1.6%4.4%12.6%17.5% SAE0.5%0.6%01.0% 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%

107. P-107 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*00.6%1.7%7.2% SAE001.1%1.5% * P = <0.00001

108. P-108 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% SAE4.2%7.2%6.9%8.2% (DRVS 11%) * P = 0.172

109. P-109 Safety Conclusions Iritis accounted for majority of AE’s Iritis accounted for majority of AE’s Higher incidence in Vitrase treated eyes Higher incidence in Vitrase treated eyes Associated with other most common AE’s Associated with other most common AE’s Self-limited or treated with topical drugs Self-limited or treated with topical drugs Not a cause of SAE’s Not a cause of SAE’s Sterile hypopyon infrequent and medically treated Sterile hypopyon infrequent and medically treated NLP not Vitrase related NLP not Vitrase related

110. P-110 Safety Conclusions Retinal detachment Retinal detachment rates prior to vitrectomy low rates prior to vitrectomy low not Vitrase related not Vitrase related Significant SAE’s tended to occur after 90 days 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 The safety profile of Vitrase supports human intravitreous administration of Vitrase for the treatment of vitreous hemorrhage

111. P-111 Clinical Investigators’ Perspective and Patients’ Response Baruch D. Kuppermann, M.D. Edgar Thomas, M.D.

112. P-112 Physicians Perspective Clinical practice characteristics Clinical practice characteristics Patient population Patient population Teaching hospital Teaching hospital Goal of vitreous hemorrhage treatment Goal of vitreous hemorrhage treatment

113. P-113 Vitrase Impact on a Patient Patient: Patient: 35 years old 35 years old Diagnosis: Diabetic Diagnosis: Diabetic Severe vitreous hemorrhage Severe vitreous hemorrhage Treatment: Vitrase 55 IU, single injection Treatment: Vitrase 55 IU, single injection

114. P-114 Vitreous Hemorrhage Treatment Options Watchful waiting Watchful waiting Natural history Natural history 70% - 80% will never clear 70% - 80% will never clear Patient issues Patient issues Physician issues Physician issues Vitrectomy Vitrectomy Post “watchful waiting” for at least 3 months Post “watchful waiting” for at least 3 months Effective surgery Effective surgery Risk Risk Cost Cost

115. P-115 Vitreous Hemorrhage Treatment Option Vitrase Vitrase More effective than “watchful waiting” More effective than “watchful waiting” Less risk than vitrectomy Less risk than vitrectomy Patient: restores QOL Patient: restores QOL Physician: ability to diagnose and treat Physician: ability to diagnose and treat Summary: a treatment option that will improve our current standard of care Summary: a treatment option that will improve our current standard of care

116. P-116 Impact on Ophthalmology Practice Kirk Packo, M.D.

117. P-117 Conclusions Lisa R. Grillone, Ph.D.

118. P-118 Overall Conclusions A 55 IU dose of Vitrase provides the following benefits: 1. At least a 3-line improvement in BCVA 2. Significant reduction in vitreous hemorrhage density allows the physician to visualize, diagnose, and treat the underlying cause of the hemorrhage allows the physician to visualize, diagnose, and treat the underlying cause of the hemorrhage

119. P-119 Overall Conclusions Evidence: Improvement of at least 3 lines of BCVA Improvement of at least 3 lines of BCVA As early as 1 month following treatment As 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 treatment As early as 1 month following treatment Significance maintained through 3 months Significance maintained through 3 months

120. P-120 Risk Benefit Assessment Vitrase for the Treatment of Vitreous Hemorrhage A single intravitreous injection of 55 IU Vitrase would provide A single intravitreous injection of 55 IU Vitrase would provide The first pharmaceutical treatment with: The first pharmaceutical treatment with: Early reduction in hemorrhage density and Early reduction in hemorrhage density and Significant improvement in BCVA Significant improvement in BCVA Low incidence of adverse events overall, except for inflammation Low incidence of adverse events overall, except for inflammation Iritis, and its associated signs and symptoms, can be managed with topical therapy Iritis, and its associated signs and symptoms, can be managed with topical therapy

121. P-121 Does Vitrase Meet the Goals for New Therapy? Safe with low risk to treated eyes + Safe with low risk to treated eyes + Speeds hemorrhage clearance + Speeds hemorrhage clearance + Restores visual function + Restores visual function + Allows early therapy of underlying pathology + Allows early therapy of underlying pathology + Does not preclude future vitrectomy + Does not preclude future vitrectomy + Office procedure + Office procedure +

122. P-122 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”