Integrated Trial Results of Bepotastine Besilate Ophthalmic Solution 1.5% on Eyelid Swelling in a Clinical Model of Allergic Conjunctivitis TR McNamara 1, MT Bergmann 2, EB McLaurin 3, JI Williams 1, JA Gow 1 for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group 1 ISTA Pharmaceuticals®, Inc., Irvine, CA; 2 Eye Care Associates of Greater Cincinnati, Inc., Cincinnati, OH; 3 Total Eye Care, Memphis, TN Financial support: ISTA Pharmaceuticals®, Inc., Irvine, CA, USA Financial disclosures: TR McNamara, ISTA Pharmaceuticals ®, Inc., employee; MT Bergmann, ISTA Pharmaceuticals ®, Inc., principal investigator; EB McLaurin, ISTA Pharmaceuticals ®, Inc., principal investigator; JI Williams, ISTA Pharmaceuticals ®, Inc., employee; JA Gow, ISTA Pharmaceuticals ®, Inc., employee.

ABSTRACT  Purpose: To establish the efficacy of bepotastine besilate ophthalmic solution 1.5%, a dual acting histamine H1 receptor antagonist approved by the FDA, compared to placebo in reducing allergen-induced eyelid swelling at 15 minutes and 8 hours after ophthalmic dosing using the Conjunctival Allergen Challenge (CAC) model of allergic conjunctivitis.

ABSTRACT  Methods: Two CAC clinical trials (1 single center, 1 multi- center) were each masked, randomized, placebo- controlled studies conducted under an identical protocol. Eligible subjects were assigned randomly to either bepotastine besilate ophthalmic solution 1.5% (n=78) or placebo (n=79). Eyelid swelling efficacy was self-assessed by subjects during the enrollment period following a CAC test conducted 15 minutes and 8 hours after ophthalmic dosing of test agent. The subjects instilled a test allergen into the conjunctival sac and eyelid swelling was assessed 7, 15, and 20 minutes after allergen instillation using a 0-3 unit quantitative grading scale at study visits spaced 2 weeks apart.

ABSTRACT  Results: Bepotastine besilate ophthalmic solution 1.5% was statistically superior in the intent-to-treat population to placebo (P ≤ 0.007) by t-test and the orthogonal Wilcoxon rank sum test at all observational time points 15 minutes and 8 hours after dosing for reducing CAC-induced eyelid swelling. Discontinued subjects included 8 subjects in both the bepotastine besilate ophthalmic solution 1.5% and placebo treatment groups, principally for subject non- compliance. Neither severe nor serious treatment- emergent ocular adverse events were reported for bepotastine besilate ophthalmic solution 1.5%, and no additional study visits were needed for any enrolled subjects.

ABSTRACT  Conclusion: Bepotastine besilate ophthalmic solution 1.5% is superior to placebo for producing reduction in allergen-induced eyelid swelling for at least 8 hours in the CAC model. The integrated trial results, combined with minimal adverse events, demonstrate a favorable benefit/risk profile for bepotastine besilate ophthalmic solution 1.5%.

CAC STUDY PROCEDURES Visit 1 and Visit 2:: Allergen Titration; Screening and Confirmation CAC Tests Screening and confirmation CAC tests performed with allergen titration to induce bilateral ocular itching and conjunctival redness grades ≥2 using a standardized 0-4 scale Figure 1. Algorithm of the CAC clinical trial procedures. BID Duration of Action CAC Test Visit: 8 Hours Post-Instillation of Investigational Product One drop of bepotastine besilate ophthalmic solution 1.5% or placebo OU CAC OU of the challenge allergen subsequently was performed on each subject 15 minutes after investigational product instillation, and eyelid swelling was graded Onset of Action CAC Test Visit: 15 Minutes Post-Instillation of Investigational Product One drop of bepotastine besilate ophthalmic solution 1.5% or placebo OU CAC OU of the challenge allergen subsequently was performed on each subject 15 minutes after investigational product instillation, and eyelid swelling was graded

EFFICACY RESULTS Figure 2. Mean eyelid swelling grades at screening Visit 2. Placebo Treatment Group Bepotastine Besilate Ophthalmic Solution 1.5% Treatment Group N.S. N.S. = Not Significantly Different From Placebo Mean Eyelid Swelling Grade as a function of Time Post-CAC

EFFICACY RESULTS Placebo Bepotastine Besilate Ophthalmic Solution 1.5% Placebo Bepotastine Besilate Ophthalmic Solution 1.5% Figure 3. Mean eyelid swelling grades post-dosing with investigational product. Onset of Action CAC Test8-Hour Duration of Action CAC Test * P ≤ * * * * * * Mean Eyelid Swelling Grades as a Function of Time Post-CAC

EFFICACY RESULTS Figure 4. Unit improvement in eyelid swelling (all time points combined). Onset of Action CAC Test8-Hour Duration of Action CAC Test 62% Improvement Over Baseline 105% Improvement Over Baseline

ADVERSE EVENTS  No subject experienced a serious adverse event during the study  There were 14/79 [17.7%] reports of adverse events in the placebo treatment group (5 ocular, 9 non-ocular) and 24/78 [30.8%] reports in the bepotastine besilate ophthalmic solution 1.5% treatment group (5 ocular, 19 non-ocular)  The majority of non-ocular adverse events were a transient, mild taste to the investigational product upon instillation  All adverse events were rated as mild or moderate  Subjects withdrawn included: – placebo group: 8 subjects because of non-compliance – bepotastine besilate ophthalmic solution 1.5%: 8 subjects  5 subjects because of non-compliance  3 subject with an unacceptable baseline levels of ocular itching or redness at Visit 4 or Visit 5  Additional follow-up visits were not needed for any of the enrolled subjects

CONCLUSIONS  Although eyelid swelling upon undergoing a CAC test was not a requirement for enrollment in the two Phase 3 CAC trials, the eyelid swelling scores at Screening Visit 2 were well balanced between the pooled data for the two treatment groups  Eyelid swelling was only a modest response to a CAC at all observation time points at all study visits, including at Screening Visit 2  Eyelid swelling peaked at or after the 15 minute observation time point  Mean eyelid swelling scores decreased at the onset of action and 8-hour duration of action CAC tests compared to those values seen at Screening Visit 2  There was high statistical significance (P ≤ ) for improvement in eyelid swelling following a CAC test for bepotastine besilate ophthalmic solution 1.5% compared to placebo, although the improvement with bepotastine besilate ophthalmic solution 1.5% was not clinically significant  A substantial placebo effect compared to baseline was seen. However, the improvement compared to baseline for bepotastine besilate ophthalmic solution 1.5% was much greater than seen with placebo, approaching a doubling of the placebo effect  BEPREVE™ (bepotastine besilate ophthalmic solution) 1.5% was approved by the FDA in September 2009 for the treatment of ocular itching associated with the signs and symptoms of allergic conjunctivitis, and is not indicated for treatment of eyelid swelling associated with allergic conjunctivitis Reference: McNamara TR, Bergmann MT, McLaurin EB, Williams JI, Gow JA for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group. Integrated trial results of bepotastine besilate ophthalmic solution 1.5% on eyelid swelling in clinical model of allergic conjunctivitis. Poster presented at: 36th Symposium on Cataract, IOL, and Refractive Surgery of the American Society of Cataract and Refractive Surgery; April 9-14, 2010; Boston, MA. Abstract