Corneal Effects of 1.5% Levofloxacin Ophthalmic Solution (IQUIX

®

) in Humans

Mark B. Abelson, MD 1,2 Gail Torkildsen, MD 2 ; Aron Shapiro 2 ; Ingrid Lapsa 2 1 Harvard Medical School, Schepens Eye Research Institute, Boston, MA 2 Ophthalmic 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 cultures 1  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 1 Bezwada P et al. Curr Med Res Opin 24:419-24, 2008 2 Clark 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 Days 1-3 (27 doses/day) Days 4-14 (13 doses/day) 1 drop OD every 30 min 8 AM – 8 PM 1 drop OD at 12 AM & 2 AM 1 drop OD every hr 8 AM – 8 PM  Assessments: Baseline, Day 8, Day 15, Day 21 (7-days post-dosing)  Safety analysis: Baseline vs 7-days post-dosing

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

Intensive IQUIX ® Dosing

Corneal Endothelial Cell Density

3500 3000 2500 2000 1500 1000 500 0

2767 ± 317 2786 ± 295 Baseline Post-dosing

Intensive IQUIX ® Dosing

Endothelial Cell Size: Coefficient of Variation

20 10 0 50 40 30

31.4

± 5.2

31.8

± 5.9

Baseline Post-dosing

Intensive IQUIX ® Dosing

Percent Hexagonal Cells in Corneal Endothelium

100 80 60 40 20 0

59.8

± 10.8 61.9

± 11.3

Baseline Post-dosing

Intensive IQUIX ® Dosing

Corneal Thickness

700 600 500 400 300 200 100 0

560 ± 36 568 ± 46 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