Bepotastine Besilate Ophthalmic Solution 1.5% and Degree of Reduced Ocular Itching in a Conjunctival Allergen Challenge Test JI Williams 1, G Torkildsen 2, JA Gow 1, P Gomes 2, TR McNamara 1 for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group 1 ISTA Pharmaceuticals®, Inc., Irvine, CA; 2 Ora, Inc., Andover, MA Financial support: ISTA Pharmaceuticals ®, Inc., Irvine, CA, USA Financial disclosures: JI Williams, ISTA Pharmaceuticals ®, Inc., employee; G Torkildsen, principal investigator; JA Gow, ISTA Pharmaceuticals ®, Inc., employee; P Gomes, Ora, Inc., employee; TR McNamara, ISTA Pharmaceuticals ®, Inc., employee.

ABSTRACT  Purpose: Bepotastine besilate ophthalmic solution 1.5% is an antihistamine indicated for the treatment of itching associated with allergic conjunctivitis. The extent of decreased ocular itching with bepotastine besilate 1.5% at 15 minutes and 8 hours after dosing was assessed using the Conjunctival Allergen Challenge (CAC) clinical model.

ABSTRACT  Methods: This was a single center, double-masked, randomized, placebo-controlled clinical trial. Subjects were enrolled in the clinical trial after 2 screening visits that determined subjects had an adequate and reproducible allergic response to a test allergen. Eligible subjects were assigned randomly to bepotastine besilate ophthalmic solution 1.5% (n=35) or placebo (n=36). The subjects instilled a test allergen into the conjunctival sac and ocular itching was assessed in a CAC test using a 0-4 unit quantitative grading scale at study visits spaced 2 weeks apart.

ABSTRACT  Results: The percent improvement in ocular itching by ≥1.0 unit compared to baseline values for subject eyes with bepotastine besilate ophthalmic solution 1.5% was substantial at 15 minutes and 8 hours post-dosing. More than 95% of eyes treated with bepotastine besilate ophthalmic solution 1.5% 15 minutes prior to a CAC test improved by ≥1.0 unit relative to baseline, and 90% of eyes dosed 8 hours prior to a CAC test showed ≥1.0 unit improvement. Neither treatment-emergent serious nor severe ocular adverse events were reported for bepotastine besilate ophthalmic solution 1.5%. Additional follow-up visits were not needed for any enrolled subjects.

ABSTRACT  Conclusion: Bepotastine besilate ophthalmic solution 1.5% is very effective at reducing ocular itching for at least 8 hours when assessed with the CAC clinical model of allergic conjunctivitis. These clinical results, combined with minimal adverse events, demonstrate a very favorable benefit/risk profile for bepotastine besilate ophthalmic solution 1.5%.

CAC STUDY PROCEDURES 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 ocular itching was 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 ocular itching was quantitatively graded A 1.0 unit difference in mean ocular itching scores (Placebo – Bepotastine Besilate Ophthalmic Solution 1.5%) was prospectively defined as a clinically significant difference at either CAC Test Visit. 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

EFFICACY RESULTS = Placebo = Bepotastine Besilate Ophthalmic Solution 1.5% 3 Min 5 Min 7 Min Time of Assessment Post-CAC Figure 2. The mean ocular itching grades as a function of time of assessment at screening Visit 2. The range of statistical differences between treatment groups at Visit 2 was (2-sample T-test). Statistical differences by the Wilcoxon rank sum test (applicable for non-normally distributed data) between treatment groups were Similarity in the results by the two statistical tests implies the data distributions for both treatment groups approached a Normal distribution. CONCLUSION: The two treatment groups (Placebo and Bepotastine Besilate Ophthalmic Solution 1.5%) were well balanced at Screening Visit 2 for the degree of ocular itching. 3 Min 5 Min 7 Min

EFFICACY RESULTS = Placebo = Bepotastine Besilate Ophthalmic Solution 1.5% Onset of Action CAC Test 8-Hr Duration of Action CAC Test Figure 3. Improvement in ocular itching grades relative to baseline – aggregate results on a subject-by-subject (eye-by-eye) basis. What About Reduced Ocular Itching on a Subject-by-Subject Basis? Reduced itching on a subject basis is as important as comparing treatment group means since it reflects the personal impressions of relief experienced by subjects. Bepotastine Besilate Ophthalmic Solution 1.5% produced at least a 1.0 unit reduction in ocular itching in 95% of eyes at the onset of action CAC test and at least a 2.0 unit reduction in 73% of eyes at an 8-hour duration of action CAC test. Bepotastine Besilate Ophthalmic Solution 1.5% was statistically superior to placebo (P ≤ 0.001) in all comparisons for the percent of eyes demonstrating at least a 1.0 unit or 2.0 unit reduction in itching compared to baseline. CONCLUSION: Bepotastine Besilate Ophthalmic Solution 1.5% was statistically superior to placebo in producing at least 1.0 unit and 2.0 unit improvements for reduced itching relative to baseline values. ≥ 1.0 Unit ≥ 2.0 Unit

ADVERSE EVENTS There were no serious or severe adverse events in this clinical trial; all adverse events listed in Table 1 were judged to be mild or moderate by the investigator. There were 3 subjects in the bepotastine besilate ophthalmic solution 1.5% treatment group withdrawn from the clinical trial (2 for non-compliance and 1 due to unacceptable baseline redness at Visit 5) and 1 subject in the placebo treatment group (for non-compliance). Adverse Events (by System/Organ/Class) Number of Subjects Reporting Adverse Event Related to Treatment Placebo Treatment Group Bepotastine Besilate 1.5% Treatment Group Eye Disorders 32 Nervous System Disorders 03 Respiratory, Thoracic, and Mediastinal Disorders 13 Gastrointestinal Disorders 12 Psychiatric Disorders 01 Table. Adverse Events Reported that were Related to Treatment

CONCLUSIONS This single site, randomized, placebo-controlled, parallel group clinical trial was well controlled for the degree of ocular itching, a primary endpoint for this clinical trial, at subject entry into the trial Bepotastine besilate ophthalmic solution 1.5% is very effective at reducing ocular itching for at least 8 hours when assessed on a subject-by-subject basis when using the CAC clinical model of allergic conjunctivitis There was very little difference in the degree of benefit for reduced ocular itching conferred by bepotastine besilate ophthalmic solution 1.5% when assessing immediate relief (onset of action) and relief 8 hours after dosing (duration of action) in CAC tests These clinical results, combined with minimal adverse events, demonstrate a favorable benefit/risk profile for bepotastine besilate ophthalmic solution 1.5% 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: Williams JI, Torkildsen G, Gow JA, Gomes P, McNamara TR for the Bepotastine Besilate Ophthalmic Solutions Clinical Study Group. Bepotastine besilate ophthalmic solution 1.5% and degree of reduced ocular itching in a conjunctival allergen challenge test. 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