Ocular Comfort Assessment of Bepotastine Besilate Ophthalmic Solution 1.5% in Multicenter Conjunctival Allergen Challenge Clinical Trial JA Gow 1, TT Macejko 2, EJ Meier 2, JI Williams 1, TR McNamara 1 for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group 1 ISTA Pharmaceuticals®, Inc., Irvine, CA; 2 Eye Care Associates of Greater Cincinnati, Inc., Fairfield, OH; 3 Eye Care Associates of Greater Cincinnati, Inc., Mason, OH Financial support: ISTA Pharmaceuticals®, Inc., Irvine, CA, USA Financial disclosures: JA Gow, ISTA Pharmaceuticals®, Inc., employee; TT Macejko, ISTA Pharmaceuticals®, Inc., principal investigator; EJ Meier, ISTA Pharmaceuticals®, Inc., principal investigator; JI Williams, ISTA Pharmaceuticals®, Inc., employee;. TR McNamara, ISTA Pharmaceuticals®, Inc., employee.

ABSTRACT  Purpose: To quantitatively establish the ocular comfort of bepotastine besilate ophthalmic solution 1.5%, a dual acting histamine H1 receptor antagonist approved by the FDA, compared to placebo using the Conjunctival Allergen Challenge (CAC) clinical model of allergic conjunctivitis

ABSTRACT  Methods: This was a multi-center (5 sites), double-masked, randomized, placebo-controlled clinical trial using the CAC model. Eligible subjects were assigned according to a computer-generated randomization list to either bepotastine besilate ophthalmic solution 1.5% (n=44) or placebo (n=43). Ocular comfort examination of test agent was subject-assessed during the 3 separate study visits, immediately upon instillation into the conjunctival sac and at 5 minutes post-instillation using a 0-3 grading scale (0=comfortable or discomfort absent; 3=severely uncomfortable or intolerable). A difference in mean comfort grades ≥1.0 unit was considered clinically significant. Comfort results were compared to the adverse event profiles of test agents.

ABSTRACT  Results: There were no clinically or statistically significant differences in ocular comfort or tolerability between bepotastine besilate ophthalmic solution 1.5% compared to placebo at any study visit during the enrollment period. The mean comfort scores (all eyes) for the bepotastine groups ranged from 0.05 to 0.14 units, while the mean comfort score for the placebo group ranged from 0.03 to 0.14 units, a difference (active – placebo) not above the clinical or statistical significance thresholds. Neither treatment- emergent serious adverse events nor severe adverse events were reported for bepotastine besilate ophthalmic solution 1.5%, and follow-up visits were not needed for any enrolled subjects.

ABSTRACT  Conclusion: Based upon the ocular comfort scale results, bepotastine besilate ophthalmic solution 1.5% is comfortable after ophthalmic dosing when assessed during a CAC efficacy clinical trial. The multi- center clinical results, combined with minimal adverse events, demonstrate a favorable safety profile for bepotastine besilate ophthalmic solution 1.5%.

CAC TRIAL 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 test article instillation, and efficacy parameters as well as ocular comfort were quantitatively graded BID Duration of Action CAC Test Visit: 16 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 test article instillation, and efficacy parameters as well as ocular comfort were quantitatively 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 test article instillation, and efficacy parameters as well as ocular comfort were quantitatively graded

Ocular Comfort Grading Scale ● 0 Comfortable; discomfort absent 1 Generally comfortable; mild discomfort 2 Some discomfort, but tolerable; moderate comfort 3 Severely uncomfortable or intolerable NCOOH O N H C l SO 3 H NCOOH O N H C l Figure 2. Chemical structure of bepotastine besilate. ● NCOOH O N H C l SO 3 H Figure 2. Chemical structure of bepotastine besilate. ●

EFFICACY RESULTS = Right Eye = Left Eye Figure 2. Comfort immediately upon instillation of test article Clinically Significant Evidence of Discomfort = Maximum Discomfort Enlargement of Graph Figure 3A. Comfort upon instillation of test article Onset of Action 8-Hr Duration 16-Hr Duration CAC of Action CAC of Action CAC Onset of Action 8-Hr Duration 16-Hr Duration CAC of Action CAC of Action CAC Placebo Treatment Group Bepotastine Besilate Ophthalmic Solution 1.5% Treatment Group Onset of Action 8-Hr Duration 16-Hr Duration CAC of Action CAC of Action CAC Onset of Action 8 Hr Duration 16 Hr Duration CAC of Action CAC of Action CAC Onset of Action 8 Hr Duration 16 Hr Duration CAC of Action CAC of Action CAC Placebo Treatment Group Bepotastine Besilate Ophthalmic Solution 1.5% Treatment Group [Enlargement of Graph]

EFFICACY RESULTS = Maximum Discomfort Enlargement of Graph Figure 3A. Comfort upon instillation of test article Figure 3. Comfort 5 minutes after instillation of test article = Right Eye = Left Eye Onset of Action 8 Hr Duration 16 Hr Duration CAC of Action CAC of Action CAC Onset of Action 8 Hr Duration 16 Hr Duration CAC of Action CAC of Action CAC Placebo Treatment Group Bepotastine Besilate Ophthalmic Solution 1.5% Treatment Group Clinically Significant Evidence of Discomfort [Enlargement of Graph]

ADVERSE EVENTS Table 1. Number of Subjects Reporting Adverse Events Considered Possibly, Probably, or Definitely Related to Treatment, by Category There were no serious or severe adverse events in this study No subjects were discontinued from the study due to an adverse event All adverse events were rated as mild or moderate No follow-up visits were needed for any enrolled subject Adverse Event (All Mild or Moderate) Number of Subjects Reporting Adverse Event Related to Treatment Related to Treatment Placebo Treatment Group Bepotastine Besilate 1.5% Treatment Group Eye Irritation 12 Eye Pain 10 Taste Related Issue 02

CONCLUSIONS  The mean comfort scores assessed by enrolled subjects were very similar in both treatment groups  The comfort of bepotastine besilate ophthalmic solution 1.5% eyedrops was not different from placebo eye drops as judged by clinical or statistical significance (P > 0.05 in all comparisons)  There was neither immediate nor delayed discomfort noted with instillation of either placebo eye drops or bepotastine besilate ophthalmic solution 1.5% eye drops  There was a generally high correlation in mean comfort scores for both eyes of all subjects  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 Reference: Gow, JA, Macejko TT, Meier EJ, Williams JI, McNamara TR for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group. Ocular comfort assessment of bepotastine besilate ophthalmic solution 1.5% in multicenter conjunctival allergen challenge clinical trial. 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