Bepotastine Besilate Ophthalmic Solution 1.5% and Degree of Bepotastine Besilate Ophthalmic Solution 1.5% and Degree of Reduced Ocular Itching Reduced Ocular Itching

in a Conjunctival Allergen Challenge Testin a Conjunctival Allergen Challenge Test

JI WilliamsJI Williams11, G Torkildsen, G Torkildsen22, JA Gow, JA Gow11, P Gomes, P Gomes22, TR McNamara, TR McNamara11 for the Bepotastine for the Bepotastine Besilate Ophthalmic Solutions Clinical Study GroupBesilate Ophthalmic Solutions Clinical Study Group

11ISTA Pharmaceuticals®, Inc., Irvine, CA; ISTA Pharmaceuticals®, Inc., Irvine, CA; 22Ora, Inc., Andover, MAOra, 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.

ABSTRACTABSTRACT

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

ABSTRACTABSTRACT

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

ABSTRACTABSTRACT

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

ABSTRACTABSTRACT

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

CAC STUDY PROCEDURESCAC 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 RESULTSEFFICACY RESULTS

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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 0.12-0.94 (2-sample T-test). Statistical differences by the Wilcoxon rank sum test (applicable for non-normally distributed data) between treatment groups were 0.18-0.96.

• 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 RESULTSEFFICACY RESULTS

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= 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≥ 1.0 Unit ≥ 2.0 Unit

ADVERSE EVENTSADVERSE 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 Adverse Events

(by System/Organ/Class)(by System/Organ/Class)

Number of Subjects Reporting Adverse Event Related to Number of Subjects Reporting Adverse Event Related to TreatmentTreatment

Placebo Treatment GroupPlacebo Treatment Group Bepotastine Besilate 1.5% Bepotastine Besilate 1.5% Treatment GroupTreatment Group

Eye Disorders Eye Disorders 33 22

Nervous System DisordersNervous System Disorders 00 33

Respiratory, Thoracic, and Respiratory, Thoracic, and Mediastinal DisordersMediastinal Disorders 11 33

Gastrointestinal Disorders Gastrointestinal Disorders 11 22

Psychiatric Disorders Psychiatric Disorders 00 11

Table. Adverse Events Reported that were Related to Treatment

CONCLUSIONSCONCLUSIONS

• 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 738030.