Corneal Effects of 1.5% Levofloxacin Ophthalmic Solution (IQUIX®) in Humans Mark B. Abelson, MD1,2 Gail Torkildsen, MD2; Aron Shapiro2; Ingrid Lapsa2 1Harvard Medical School, Schepens Eye Research Institute, Boston, MA 2Ophthalmic Research Associates, Inc., North Andover, MA Financial Disclosure: MB Abelson, A Shapiro, I Lapsa are full-time employees of Ophthalmic Research Associates, Inc.

Study Background IQUIX® approved for treating bacterial keratitis In vitro: Levofloxacin least cytotoxic fluoroquinolone in human corneal keratocyte and endothelial cell cultures1 In vivo: Wound healing in rabbits and primates (2 drops QID x 4 days)2 No adverse effect on cornea, re-epithelialization, keratocyte structure / organization, or wound healing 1Bezwada P et al. Curr Med Res Opin 24:419-24, 2008 2Clark L et al. Cutaneous Ocular Toxicology 23:1-18, 2004

Purpose To evaluate corneal endothelial integrity and morphology in humans after 2-wk intensive dosing regimen with 1.5% levofloxacin ophthalmic solution (IQUIX®).

Methods: Prospective Single-Center, Investigator-Masked Study Healthy human volunteers (n=48) 224 IQUIX® doses OD over 14 days Assessments: Baseline, Day 8, Day 15, Day 21 (7-days post-dosing) Safety analysis: Baseline vs 7-days post-dosing Days 1-3 (27 doses/day) 1 drop OD every 30 min 8 AM – 8 PM 1 drop OD at 12 AM & 2 AM Days 4-14 (13 doses/day) 1 drop OD every hr 8 AM – 8 PM

Key Safety Assessments Intensive IQUIX® Dosing Key Safety Assessments Specular microscopy Endothelial cell density Endothelial cell morphology (cell size variability, % hexagonal cells) Pachymetry: central corneal thickness Slit-lamp biomicroscopy Visual acuity

Corneal Endothelial Cell Density Intensive IQUIX® Dosing Corneal Endothelial Cell Density 2767 ± 317 2786 ± 295 Density, cells / µm2, mean Baseline Post-dosing

Endothelial Cell Size: Coefficient of Variation Intensive IQUIX® Dosing Endothelial Cell Size: Coefficient of Variation Coefficient of Variation, mean 31.4 ± 5.2 31.8 ± 5.9 Baseline Post-dosing

Percent Hexagonal Cells in Corneal Endothelium Intensive IQUIX® Dosing Percent Hexagonal Cells in Corneal Endothelium Percent, mean 59.8 ± 10.8 61.9 ± 11.3 Baseline Post-dosing

Corneal Thickness Intensive IQUIX® Dosing Thickness, µm, mean 560 568 ± 36 568 ± 46 Thickness, µm, mean Baseline Post-dosing

Intensive IQUIX® Dosing: Summary of Findings No clinically significant negative changes in any measured safety parameter Endothelial cell density Endothelial cell morphology Central corneal thickness Visual acuity* Slit-lamp biomicroscopy* Intraocular pressure* Dilated fundoscopy* Treatment-related adverse events: dysgeusia (30%); eye irritation (7%); eye pruritis (6%) *Data not shown

Intensive IQUIX® Dosing: Conclusion Intensive dosing with IQUIX® (levofloxacin 1.5%) does not adversely affect corneal endothelium