Doh Lee, M.D., Ph.D. Hyung Seok Cho, M.D., Jin Hyoung Kim, M.D., Ph.D.,

1. Effect of Bevacizumab andRanibizumab Injection on Corneal Neovascularization Doh Lee, M.D., Ph.D. Hyung Seok Cho, M.D., Jin Hyoung Kim, M.D., Ph.D., Department of Ophthalmology, Ilsan Paik Hospital, Inje University College of Medicine, Gyeonggi, Korea • Authors have no relevant financial interests pertaining to this research

2. Anti VEGF therapy of NV in ocular surface disease What’s the difference? • Anti VEGF therapy is also effective on corneal neovascularization : widely accepted • most studies, using Bevacizumab • Increase its affinity • for binding and inhibiting • the growth factor • Higher and faster • retinal penetration ability • (smaller molecular size) • Longer duration of action • (larger molecular size)

3. PURPOSE To evaluate and compare the short term effect of subconjunctival and/or intrastromal Bevacizumab and Ranibizumab injection on corneal neovascularization(CNV) in various ocular surface disorders in terms of regression

4. METHODS Pateint selection • Longstanding CNV more than 6months without other corneal disease • Prospective randomized study Injection method • Subconjunctival or intrastromal adjacent corneal NV Group I Bevacizumab (Avastin): 1.25 mg/0.05cc 0.1ml injection Group II Ranibizumab (Lucentis): 0.5 mg/0.05cc 0.1ml injection • Patients were followed up at 1, 7, 30 days after treatment. Analysis of NV regression Photographs taken at 1:1.8 magnification using digital camera (x 4.0 zoom up, x10 magnification) under slit lamp examination Image J software (image processing and analysis in Java, NIH) used to analyze the vascularized corneal area

5. Results Demographics of patients No effective regression after 1month : additional Avastin injection after 2months Group I : 8 eyes of 7 patients+8 eyes of 6 patients =16 eyes of 13 patients Group II : 9 eyes of 7 patients S : subconjunctival injection I : Intrastromal injection S/A : Same as above

6. Results Bevacizumab Case No. 1 Lipid keratopathy POD # 7D Pre injection

7. Results Ranibizumab Case No. 9Post herpetic CNV with corneal opacity POD # 7D Pre injection

8. Results Comparison of % of NV area reduction Number of Available case for analysis using Image J software Group I: 5 eyes, Group II: 5 eyes P=0.016 (Mann-Whithney test)

9. Results Comparison of NV area at pre& postinjection * P=0.043, Wilcoxon signed ranks test * P=0.043, Wilcoxon signed ranks test P=0.4, Friedman test * P=0.022, Friedman test

10. VEGF Discussion Bevacizumab injection showed more effective to reduce CNV than Ranibizumab injection. Why? hypothesis - Ranibizumab : because of low MW, higher clearance rate than Bevacizumab ( half life: 4.32 days Vs 2.88days in animal study via intravitreal injection) - Subconjunctival space :abundant subconjunctival vessel and lymphatics much faster clearance than intravitreal cavity - Fc portion of Bevacizumab: active transport to NV of Bevacizumab ?? mediated by NK cell, Neutrophils ,Macrophage, or mast cells - Higher effective dosage than in intravitreal use : especially in case of low MW Ranibizumab • Limitation of this study • The improvement of NV measurement technique is needed • Too small cases & short term F/U

11. Conclusion • Subconjunctival and intrastromal Bevacizumab injection is effective to regress CNV induced by various causes during short term follow-up, whereas there is no significant effect for reduction of CNV after Ranibizumab injection. • Evaluation of potential duration time, side effects and minimal effective dose of Bevacizumab including larger volume of cases in Corneal NV treatment will be needed. • Further research for the delivery mechanism of subconjunctival Bevacizumab and Ranibizumab will be needed.