1. Vitrase (Hyaluronidase for Injection) Advisory Committee Meeting March 17, 2003 Jennifer D. Harris, MD Medical Officer Division of Anti-inflammatory, Analgesic, and Ophthalmic Drug Products Food and Drug Administration

2. Overview Choice of Endpoints Issues surrounding their validity p-value Correction for Multiple Endpoints Efficacy Results Safety Considerations Conclusions

3. Choice of Endpoints Proposed Composite Clearance of Vitreous Hemorrhage Best Corrected Visual Acuity (BCVA)

4. Proposed Composite Patients were classified as a ‘success’ if the hemorrhage cleared sufficiently to facilitate the diagnosis of the underlying retinal pathology and to provide treatment, if necessary, of the underlying condition

5. Proposed Composite Laser treatment completed or Visualization of the retina revealed that surgery was required and was performed to correct the underlying pathology (e.g., vitrectomy for macular traction detachment, cryo-retinopexy for retinal tear, scleral buckle for peripheral detachment, etc.), or Visualization of the macula and a minimum of 180 degrees of the vitreous base allowed for a diagnosis that the underlying cause of the hemorrhage had been resolved without the need for further therapy and with documentation by a fundus photograph.

6. Laser Treatment Completed Ill-defined Variable between ophthalmologists Many causes of VH not amenable to laser treatment

7. Visualization of Retina Potentially clinically meaningful: if it allows for earlier diagnosis of pathology if the earlier diagnosis translates into better patient outcomes Patient is now exposed to additional invasive procedure

8. Visualization of Macula Potentially clinically meaningful macula clear - patient’s vision should be improved What about the other 180° ?

9. Proposed Composite Potentially useful as a surrogate endpoint if it can be validated as clinically meaningful Interpretation may be difficult based on variability (Style of Practice) Underlying pathology may be missed Patients may be exposed to two invasive procedures

10. Surrogate Endpoints and Validation Surrogate Endpoints - do not directly measure how a patient feels, functions, or survives substitute for a clinically meaningful endpoint Must Validate - adequate and well controlled trials to show that the intervention on the surrogate endpoint translates into the desired clinical outcome

11. Proposed Composite Potential surrogate Not validated Validation plan not completed Therefore, endpoint not accepted by the Agency

12. Vitreous Hemorrhage Density Grading Scale Grade 0 - view of the retina/easily treatable Grade 1 - retinal detail visible, some hemorrhage present but laser photocoagulation would still be possible Grade 2 - large retinal vessels visible, central retinal detail is not visible enough to adequately place panretinal photocoagulation posterior to the equator Grade 3 - red reflex is visible but no central retinal detail is seen posterior to the equator Grade 4 - no red reflex

13. Vitreous Hemorrhage Density Success Criteria Proliferative diabetic retinopathy (PDR) - at least 6 clock hours with density grades of 0 or 1 Branch retinal vein occlusion (BRVO) - at least 3 clock hours with density grades of 0 or 1

14. Vitreous Hemorrhage Density Clinical meaning not validated Impact on trial design Only addresses vitreous hemorrhage associated with PDR or BRVO Does not address retinal tears, detachments, trauma, etc.

15. Improvement in BCVA Doubling of the Visual Angle 3 step change on ETDRS (Early Treatment Diabetic Retinopathy Study) Vision Chart (e.g. 20/80  20/40, etc)

16. Improvement in BCVA Universally Accepted Clinically Meaningful “Gold Standard” for Clinical Trials

17. Multiple Endpoints 3 Doses with 3 Possible Endpoints at 3 Different Timepoints 7.5 IU VitraseProposed CompositeMonth 1 55 IU VitraseClearance of VHMonth 2 75 IU VitraseBCVAMonth 3

18. p-value ? Dose 1 Dose 2 Dose 3 timepoint 1 timepoint 2 timepoint 3 ? p = 0.05 0.0459 3 endpoints + 3 doses + 3 timepoints  p = 0.0051 (0.0459/9) 1 endpoint + 1 dose + 3 timepoints  p = 0.0153 (0.0459/3)

19. Cumulative Percentages of Patients Achieving a 3-Line Improvement in BCVA Study VIT-02 Saline Control 7.5 IU Vitrase55 IU Vitrase75 IU Vitrase n=193n=181n=179n=197 Month 134 (17.6)54 (29.8%)50 (27.9%)62 (31.5%) p=0.008p=0.024p=0.002 Month 251 (26.4%)61 (33.7%)70 (39.1%)79 (40.1%) p=0.155p=0.012p=0.006 Month 370 (36.3%)67 (37.0%)78 (43.6%)89 (45.2%) p=0.966p=0.183p=0.092

20. Cumulative Percentages of Patients Achieving a 3-Line Improvement in BCVA Study VIT-03 Saline Control55 IU Vitrase75 IU Vitrase n=190n=186n=180 Month 143 (22.6%)62 (33.3%)43 (23.9%) p=0.028p=0.870 Month 254 (28.4%)80 (43.0%)65 (36.1%) p=0.004p=0.141 Month 362 (32.6%)86 (46.2%)75 (41.7%) p=0.009p=0.091

21. 55IU Vitrase vs. Saline at 2 months VIT-02

22. 55 IU Vitrase vs. Saline at 2 months VIT-03

23. Cumulative Percentages with Reduction in Vitreous Hemorrhage Density VIT-02 Saline Control7.5 IU Vitrase55 IU Vitrase75 IU Vitrase n=193n=181n=179n=197 month 122 (11.4%)45 (24.9%)37 (20.7%)48 (24.4%) p=0.001p=0.021p=0.001 month 245 (23.3%)60 (33.1%)63 (35.2%)71 (36.0%) p=0.046p=0.016p=0.008 month 361 (31.6%)65 (35.9%)73 (40.8%)84 (42.6%) p=0.441p=0.083p=0.032

24. Cumulative Percentages with Reduction in Vitreous Hemorrhage Density VIT-03 Saline Control55 IU Vitrase75 IU Vitrase n=190n=186n=180 Month 120 (10.5%)37 (19.9%)24 (13.3%) p=0.017p=0.501 Month 237 (19.5%)57 (30.6%)43 (23.9%) p=0.017p=0.366 Month 348 (25.3%)68 (36.6%)60 (33.3%) p=0.024p=0.111

25. Cumulative Incidence of Patients Achieving Proposed Composite VIT-02 Saline Control7.5 IU Vitrase55 IU Vitrase75 IU Vitrase n=193n=181n=179n=197 month 112 (6.2%)23 (12.7%)27 (15.1%)28 (14.2%) p=0.048p=0.009p=0.015 month 233 (17.1%)46 (25.4%)56 (31.3%)55 (27.9%) p=0.065p=0.002p=0.015 month 357 (29.5%)57 (31.5%)68 (38.0%)70 (35.5%) p=0.765p=0.106p=0.248

26. Cumulative Incidence of Patients Achieving Proposed Composite VIT-03 Saline Control55 IU Vitrase75 IU Vitrase n=190n=186n=180 Month 19 (4.7%)21 (11.3%)12 (6.7%) p=0.031p=0.564 Month 229 (15.3%)37 (19.9%)25 (13.9%) p=0.296p=0.820 Month 341 (21.6%)52 (28.0%)45 (25.0%) p=0.189p=0.512

27. Cumulative Incidence of Vitrectomy at Each Post-treatment Visit VIT-02 Saline Control7.5 IU Vitrase55 IU Vitrase75 IU Vitrase n=193n=181n=179n=197 on or prior to3 (1.6%)7 (3.9%)1 (0.6%)2 (1.0%) month 1 on or prior to9 (4.7%)12 (6.6%)11 (6.1%)7 (3.6%) month 2 on or prior to48 (24.9%)50 (27.6%)36 (20.1%)46 (23.4%) month 3 on or prior to83 (43%)90 (49.7%)77 (43.0%)89 (45.2%) month 12

28. Cumulative Incidence of Vitrectomy at Each Post-treatment Visit VIT-03 Saline Control55 IU Vitrase75 IU Vitrase n=190n=186n=180 on or prior to4 (2.1%)3 (1.6%)1 (0.6%) month 1 on or prior to8 (4.2%)5 (2.7%)4 (2.2%) month 2 on or prior to29 (15.3%)21 (11.3%)25 (13.9%) month 3 on or prior to62 (32.6%)51 (27.4%)58 (32.2%) month 12

29. Discontinued Patients VIT-02 Saline Control7.5 IU Vitrase55 IU Vitrase75 IU Vitrase n=193n=181n=179n=197 month 19 (4.7%)8 (4.4%)10 (5.6%)14 (7.1%) month 24 (2.1%)6 (3.3%)4 (2.2%)6 (3.0%) month 36 (3.1%)6 (3.3%)4 (2.2%)6 (3.0%) cumulative19 (9.9%)20 (11.0%)18 (10%)26 (13.2%)

30. Discontinued Patients VIT-03 Saline Control55 IU Vitrase75 IU Vitrase n=190n=186n=180 Month 17 (3.7%)5 (2.7%)2 (1.1%) Month 20 3 (1.6%)3 (1.7%) Month 37 (3.7%)1 (0.54%)3 (1.7%) cumulative14 (7.4%)9 (4.8%)8 (4.4%)

31. Death Rate Study% (# deaths) VIT-025.4% (40/740) VIT-035.1% (28/551) Majority of Causes: Cardiovascular (MI, Embolus, Stroke, etc) Other Causes: Renal Failure, Sepsis, Malignancy

32. Safety Similar events seen in all treatment groups Most are likely to be related to intraocular injection versus Vitrase

33. Safety (continued) Increased risk of dose dependent sterile hypopyon Increased risk of dose dependent iritis All sterile hypopyon appeared to clear with topical steroids and cycloplegics

34. Conclusions Replicative efficacy demonstrated in BCVA at 2 months for 55 IU Vitrase dose Approximately 50% of patients have non-functional vision (i.e. Count fingers, hand motion or light perception) Replicative efficacy demonstrated in clearance of vitreous hemorrhage at 2 months for 55 IU Vitrase dose Efficacy no longer present at month 3

35. Questions Has sufficient evidence been submitted to support the efficacy of Vitrase for the treatment of vitreous hemorrhage? If not, then what additional studies are needed to establish the efficacy of this product? Are additional analyses of the current data needed to understand the efficacy or safety of Vitrase for the treatment of vitreous hemorrhage?

36. Questions (continued) Should the potential interaction (positive and/or negative) of Vitrase with current treatments for vitreous hemorrhage be evaluated? Are there adverse experiences that are of particular concern for this product? Is there a concern about the death rate observed in these studies? Do the benefits of using Vitrase outweigh the risks in the treatment of vitreous hemorrhage?