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ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage

ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage. Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee 17 March 2003. ISTA. A specialty pharmaceutical company – with a focus on ophthalmology.

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ISTA Pharmaceuticals Vitrase ® For the treatment of vitreous hemorrhage

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  1. ISTA PharmaceuticalsVitrase®For the treatment of vitreous hemorrhage Food and Drug AdministrationDermatologic and Ophthalmic Drugs Advisory Committee 17 March 2003

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

  3. 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

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

  5. Vitrase Development History 1992 Preclinical initiated 1996 US 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. ISTA Presentation Agenda IntroductionVicente Anido, Ph.D. Clinical BackgroundJohn 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. • 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 P-7

  8. 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-8

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

  10. 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

  11. 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

  12. 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

  13. Vitreous HemorrhageMechanisms • Tear of normal retinal blood vessel • Bleed from site of neovascularization or diseased blood vessel • Bleed from other sites such as choroid

  14. Vitreous HemorrhageSequelae • 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

  15. Natural History Studies • Three Studies • United States • Spain • Diabetic Retinopathy Vitrectomy Study (DRVS)

  16. Natural History StudyUnited 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

  17. Natural History StudySpain 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

  18. 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

  19. 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

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

  21. Goals of New TherapyManagement 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

  22. 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

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

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

  25. 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

  26. Vitreous Hemorrhage Clearing

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

  28. 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

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

  30. Vit 02 - North America Centers: United States (61) Canada (9) Mexico (3) Intent to Treat Population: 7.5 IU: 18 55 IU: 18 75 IU: 17 WW: 18 Total: 71 7.5 IU: 181 55 IU: 179 75 IU: 197 Saline: 193 Total: 750

  31. Efficacy Presentation • Study design • Efficacy measures • Patient demographics and baseline characteristics • Efficacy results

  32. Vitrase EfficacyIntegrated Phase III - 55 IU & 75 IU

  33. Study DesignEligibility 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

  34. Study DesignEligibility 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)

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

  36. Grade 3 Vitreous Hemorrhage “Headlight in the fog”

  37. Grade 4 Vitreous Hemorrhage “No red reflex”

  38. Study DesignExclusion Criteria • Presence or history of retinal detachment, tears or breaks • Ocular trauma • Previous vitrectomy • Organized hemorrhage • No light perception in either eye

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

  40. Study DesignRandomization 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

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

  42. 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

  43. 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

  44. 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

  45. Grade 0 and Grade 1 Vitreous Hemorrhage Grade 0 Grade 1

  46. 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)

  47. 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

  48. Efficacy Presentation Roadmap • Study Sequence • Vit 03 Ex North America • Vit 02 North America • Integrated Phase III

  49. Patient Demographics *does not include 7.5 IU Vitrase

  50. Etiology of Baseline Vitreous Hemorrhage *does not include 7.5 IU Vitrase

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