prolonged effectiveness of bepotastine besilate

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While the roles of many preformed and newly formed me-diators of allergy are continuously being discovered, hista-mine has remained the fulcrum of the immediate ocularallergic reaction.1,2 The ocular allergic reaction is driven byan IgE-activated mast cell degranulation that leads to hista-mine release and binding of histamine to its cognate H1andH2 receptors on conjunctival nerves and blood vessels, re-sulting in the ocular itching, redness, swelling, and watery

eyes that principally define the ocular allergic reaction. Theshort- and long-term effects of histamine release affectsnerves and vasculature, epithelial cells, fibroblasts, and otherconstitutively maintained cells in ocular tissues.3

Antagonism of histaminereceptor interactions is fre-quently used to treat ocular allergies, which leads to im-provement in ocular itching and in redness, decreasedswelling of the eyelids and conjunctiva, as well as reductionin watery eyes due to allergen exposure. These favorableeffects can be provided by antihistamine medications for-mulated for ophthalmic use. The latest-generation ophthal-mic antihistamines are noted for having multiplemechanisms of action4 that may allow for a longer durationof activity than older antihistamines and fewer side effects.

Bepotastine besilate is one of the newer generation anti-histamines, and is a selective H1 receptor antagonist andmast cell stabilizer with demonstrated preclinical and clinicaleffectiveness.57 Bepotastine has been shown to stabilizemast cells,710 inhibit eosinophil migration,5,6 block the syn-thesis and release of newly formed mediators such asleukotrienes7,11 and interleukin-5,12,13 and reduce the in-flammatory effects of exogenously applied mediators such ashistamine and platelet activating factor.8 The clinical effec-tiveness and safety of bepotastine besilate as an oral medi-cation for treating multiple allergic conditions weredemonstrated in multiple clinical trials in Japan.1420 In 2000,an oral formulation of bepotastine besilate was approved inJapan for the treatment of allergic rhinitis, and in 2002 the

indication was expanded to the management of urticaria andpruritus associated with skin diseases.21 Evaluation of theclinical effectiveness and safety of bepotastine besilate as anophthalmic solution using the well-established conjunctivalallergen challenge (CAC) clinical model of allergic conjunc-tivitis subsequently has been conducted.22,23 As a result ofpositive outcomes in CAC trials and a favorable safety pro-file, bepotastine besilate ophthalmic solution 1.5% was re-cently approved in the United States for treating itchingassociated with the signs and symptoms of allergic con-junctivitis when dosed twice daily.

The CAC is a standardized and reproducible clinicalmethod of inducing an ocular allergic reaction and evaluat-ing the effects of ophthalmic antiallergy medications in a

controlled clinical setting. Although the CAC methodologydoes not directly address the action of compounds as a mastcell stabilizer in human conjunctiva, the CAC has been val-idated by use in clinical trials with earlier generation oph-thalmic agents that were subsequently approved by the U.S.Food and Drug Administration (FDA).2428 Positive resultshave been demonstrated in 2 well-controlled CAC clinicaltrials (one single site, one multisite) for the primary end-points of ocular itching and conjunctival redness when as-sessed 15 min and 8 h after instillation of bepotastine besilateophthalmic solutions,22,23 and for the relief of nonocular al-lergic symptoms, including nasal congestion and rhinor-rhea.29 Those clinical trial results led to the approval of

Bepreve (bepotastine besilate ophthalmic solution) 1.5% inSeptember 2009 by the FDA for the treatment of ocularitching associated with the signs and symptoms of allergicconjunctivitis.30

The single-site CAC clinical trial tested the hypothesis thatbepotastine besilate ophthalmic solution 1.0% or 1.5% mayreduce the primary efficacy variables of CAC-induced ocularitching and conjunctival redness with sustained clinical tol-

erability compared with placebo for at least 8 h duration. Anadditional primary aim addressed in this article was to ex-amine any prolonged beneficial effects seen in the single-siteCAC clinical trial 16 h after dosing of bepotastine besilateophthalmic solutions 1.0% and 1.5% compared with placebofor treating ocular allergic responses. It was postulated thatsuccessful demonstration for reduction in CAC-induced oc-ular allergic responses at 16 h postdosing with bepotastinebesilate ophthalmic solution 1.0% or 1.5% might potentiallysupport once daily dosing by allergic conjunctivitis patients.

Methods

Clinical trial design and medications

This was a single-center, double-masked, randomized,placebo-controlled clinical trial. The first 2 clinical trial visitswere screening visits to identify subjects with a reproducibleand consistent response to an ocular test allergen. Efficacywas then determined by inhibition of the allergic reactioninduced by a CAC test 16 h, 8 h, and 15 min after test agentinstillation at successive trial visits.

The test agents were placebo (vehicle), bepotastine besi-late ophthalmic solution 1.0%, and bepotastine besilateophthalmic solution 1.5%. Both bepotastine besilate formu-lations and placebo were identically supplied and labeledand were double-masked as to bottle content from subjectsand investigators.

Clinical trial requirements/guidelines

The clinical trial protocol and informed consent form wereapproved by an independent institutional review board(IntegReview, Austin, TX) before initiation of the clinicaltrial. The clinical trial was registered on the clinicaltrials.govWeb site (NCT00424398). All trial visits for enrolled subjectswere performed in a single outpatient ophthalmic clinicsetting (Andover Eye Associates, Andover, MA) betweenMarch 1, 2007, and April 4, 2007. Before any clinical trialprocedures, a signed informed consent (and assent if thesubject was < 18 years of age), and a signed Health InsurancePortability and Accountability Act form were obtained fromall subjects. The clinical trial was conducted in accordance

with International Conference on Harmonisation GoodClinical Practice guidelines, the World Medical AssociationDeclaration of Helsinki (1996 version), and applicable reg-ulatory requirements. This was a prospective, placebo-controlled CAC clinical trial. All ophthalmic examinationsand trial-related procedures were performed by clinicallytrained researchers with experience with CAC methodology.

Criteria for clinical trial participation

Subjects had to meet the following inclusion criteria to beeligible for participation in the clinical trial: (1) be at least 10years of age and of either sex and any race; (2) have provided

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written informed consent (and assent if applicable); (3) havenegative pregnancy test from all women of childbearingpotential, as well as a medically acceptable form of birthcontrol for the designated period; (4) have a positive historyof ocular allergies and a positive skin test reaction to cat hair,cat dander, grasses, ragweed, and/or trees within the past 24months; (5) have best-corrected visual acuity of 0.7 logMARor better using an Early Treatment Diabetic Retinopathy

Study (ETDRS) chart; (6) have positive bilateral CAC reac-tion within 10min of allergen instillation at visits 1 and 2;and (7) avoid disallowed medication and contact lens wearfor the designated period.

The presence of any of the following conditions prohibitedentry into the trial: (1) known contraindications to trialmedication(s) or their components; (2) any systemic or ocularcondition that could have affected a subjects safety or trialparameters; (3) ocular surgery within 3 months of visit 1 orrefractive surgery within the past 6 months; (4) signs of ac-tive allergic conjunctivitis at the start of any visit; (5) use ofdisallowed topical or systemic medications during the des-ignated period; (6) use of an investigational drug or devicewithin 30 days of the trial or concurrently enrolled in another

trial; and (7) being a woman who was pregnant, planning apregnancy, lactating, or not using a medically acceptableform of birth control for the designated period.

Subjects who met these initial entry criteria and did notmeet any exclusion criterion at visit 1 then underwent trialscreening procedures.

Clinical trial visits

Visit 1 (day - 21 3): allergen titration CAC. Eligible sub-jects underwent a titration CAC with 1 drop of allergen (e.g.,Timothy grass or cat dander) instilled bilaterally in theconjunctival cul de sac at the weakest dilution. If the subjectfailed to react within 10 min, increasingly concentrated doses

of the allergen were instilled bilaterally at 10-min intervalsuntil a positive reaction was elicited (score of 2 for ocularitching and 2 for redness in the conjunctival vessel bed ineach eye). Subjects who did not meet this qualification werediscontinued from screening. Upon completion of the CAC,an ocular examination was performed on each subject thatincluded distance visual acuity using an ETDRS vision chart,slit lamp biomicroscopy, intraocular pressure, and fundu-scopy through dilated pupils.

Visit 2 (day - 14 3): allergen confirmation CAC. A con-firmatory CAC was performed bilaterally with the same al-lergen and concentration that elicited the adequate allergicresponse at visit 1. Subjects who reacted positively in both

eyes as defined for visit 1 for at least 2 out of 3 time pointswithin this 20 min interval continued in the clinical trial; allother subjects were discontinued from the clinical trial.Ocular itching was graded by subjects at 3, 5, and 7 min post-CAC, and conjunctival redness was graded by the investi-gator at 7, 15, and 20 min post-CAC.

Visit 3A (day 0): 16h duration of action dosing. Afterupdating a subjects medical and medication history, thedistance visual acuity using ETDRS and slit lamp biomicro-scopic examinations were performed. Baseline ocular aller-gic symptomatology also was assessed. Eligible subjectswere enrolled into 1 of 3 treatment groups according to a

computer-generated randomization code to receive placebo,bepotastine besilate ophthalmic solution 1.0%, or bepotastinebesilate ophthalmic solution 1.5%. No attempt was made tostratify the randomization process. A trained technician in-stilled 1 drop from the subjects double-masked test agentbottle onto each eye. After 15 min, a safety (visual acuity andbiomicroscopy) examination was performed in subjects < 18years of age. All subjects were told to return *15.5 h after

drug instillation for the visit 3B CAC.

Visit 3B (day 1): 16 h duration of action CAC. Sixteen hours( 30 min) after drug or placebo instillation, subjects at visit3B received 1 drop of the allergen solution bilaterally. Ocularitching was graded by the subjects at 3, 5, and 7 min post-challenge and conjunctival redness was graded by the in-vestigator at 7, 15, and 20 min postchallenge. Grades forsecondary ocular efficacy variables (tearing, ciliary andepiscleral redness, eyelid swelling, chemosis, and mucousdischarge) were also determined.

Details of visit 4 and visit 5 procedures and effectivenessoutcomes, including study exit procedures, have been pre-viously described.22,23,29 In brief, subjects received 1 drop of

assigned test agent in each eye at visit 4 (day 14

3), and thena CAC test was performed 8 h after the test agent instillation.At visit 5 (day 28), enrolled female subjects capable of be-coming pregnant received a second urine pregnancy test. Allsubjects then received a third and final drop of assigned testagent in each eye. Fifteen minutes after test agent instillationat visit 5, a CAC test was performed and subjects were exitedfrom the clinical trial. Grading of ocular itching, conjunctivalredness, and all secondary efficacy variables was conductedfor visit 4 and visit 5 as at visit 3B.

Efficacy and safety assessments

Primary ocular efficacy variables were subject-assessed

ocular itching and physician-assessed conjunctival redness.Severity scales for both variables were based on a 5-point (04 U) standardized scale, with half-unit increments allowed.25

Tearing and ocular mucous discharge as ocular secondaryefficacy variables were graded as present or absent.

Safety assessments included distance visual acuity usingan ETDRS chart and slit lamp biomicroscopy performed atthe beginning of each visit. For enrolled subjects under theage of 18, these assessments were also performed 15 minpostdrug instillation at visit 3A. The intraocular pressure andfunduscopy through dilated pupils examinations were con-ducted after efficacy assessments at visit 1 and at the last trialvisit. Treatment emergent adverse events (AEs; reported,elicited, or observed) were recorded at visit 3A and 3B as

well as at later study visits.

Data analysis and statistical methods

Demographic and baseline medical history data weresummarized descriptively. For quantitative baseline demo-graphic variables, summaries included the mean, median,and standard deviation, and were analyzed using a 2-sidedt-test. Qualitative demographic variables were summarizedusing counts and percentages, and were analyzed usingFishers exact test.

The prospectively defined primary analysis populationwas the per protocol (PP) population. Subjects had to attend

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visit 3A and 3B or visit 4 and also had to attend visit 5 to beconsidered for the PP population. An alternative analysispopulation evaluated for significant changes in efficacyoutcomes was the intent-to-treat (ITT) population with lastobservation carried forward (LOCF) for imputation ofmissing data. The Wilcoxon rank sum test was used tocompare outcomes for the primary efficacy variables of oc-ular itching and conjunctival redness between each active

treatment group and the placebo group in the primaryanalysis population at each observation time point for visit3B, the CAC test occurring 16h after instillation of testagents. The significance levels used to assess the P values forthe primary efficacy variables were adjusted for multiplecomparisons using conservative Bonferroni corrections torecognize multiple bepotastine besilate concentrations and2 potential duration of actions, efficacy at 16h assessed atvisit 3B or efficacy at 8 h assessed at visit 4. As a predefinedresult, treatment differences for either primary efficacyvariable therefore were considered statistically significantat a (2-sided) 0.0125 when observed at a majority of ob-servation time points. Since secondary efficacy variableswere considered nonvalidated surrogates for possible clinical

activity,P values determined for all secondary efficacy var-iables other than allergen-induced tearing and ocular mu-cous discharge were calculated by the Wilcoxon rank sumtest and were adjusted by the false discovery rate method.31

Statistical significance for allergen-induced tearing and ocu-lar mucous discharge was evaluated using generalized linearmodels, treating each subject as a cluster. Statistical signifi-cance for all secondary efficacy variables required a(2-sided) 0.05 at all observation time points.

A treatment group response considered clinically mean-ingful required achievement of clinical significance at a ma-jority of observation time points, as well as statisticalsignificance. Clinical significance at each time point was de-fined as a 1.0-U difference between bepotastine besilate

ophthalmic solution (1.0% or 1.5%)treated eyes and placebo-treated eyes, applicable for all primary and secondary efficacyvariables except tearing and mucous discharge. For allergen-induced tearing and mucous discharge, clinical significancewas equated to statistical significance.

Additional analyses were performed to examine the clin-ical and statistical significance for the coprimary endpoints ofocular itching and conjunctival redness for the subset ofsubjects who experienced grade 3 or greater itching atscreening visit 2 in 1 or both eyes, or received a total rednessscore of 4.5 or greater summed for both eyes. Fishers exacttest was used to compare the proportion of subjects fromeach treatment group who achieved a mean itching grade of0 to 0.5-U, etc at all post-CAC time points within the PP

study population. This analysis was also performed for thesubjects who were more severely affected by a CAC, havingan itching grade of 3 or greater in 1 or both eyes at any timepoint at visit 2.

Assuming the standard deviation of the mean scores forocular itching and conjunctival redness were each 1.0-U forall 3 treatment groups (based on the results of previous CACstudies with ophthalmic antihistamines), a sample size of 23subjects per group was anticipated to have > 85% power at apost-CAC time point to detect a true mean score difference of1.0-U between any 2 groups using a 2 sample t-test. Giventhe nonparametric nature of measures for primary and sec-ondary efficacy endpoints, and with the anticipation of an

approximate 10% drop-out rate, 30 subjects per treatmentgroup was used as a target enrollment guide.

Results

Subject sample characteristics

A total of 179 subjects were screened and 107 were en-rolled and randomly assigned a masked test agent: 36 sub-

jects to each of placebo and bepotastine besilate ophthalmicsolution 1.0% and 35 subjects to bepotastine besilate oph-thalmic solution 1.5%. Of those enrolled, 102 completed theclinical trial including attendance at visit 3A and 3B, ofwhom 3 subjects committed protocol violations that re-moved them from consideration for the PP population. Thisleft 34 subjects in the placebo group, 35 subjects in the be-potastine besilate ophthalmic solution 1.0% group, and 30subjects in the bepotastine besilate ophthalmic solution 1.5%group comprising the PP population with data for the 16 hduration of action (i.e., visit 3A and 3B). The subject demo-graphics among all subjects were well balanced for bepo-tastine besilate ophthalmic solution 1.0% and 1.5% comparedwith placebo for age, gender, race, and iris color (Table 1).

Efficacy variable outcomes

Ocular itching. For reduction in CAC-induced ocularitching, both bepotastine besilate ophthalmic solutions 1.0%and 1.5% achieved statistical significance in comparison toplacebo at all time points 16 h after dosing in both the PPpopulation (P< 0.001) and the ITT population with LOCF(P 0.001) with LOCF (Table 2). Bepotastine besilate oph-thalmic solution 1.5%, but not bepotastine besilate ophthal-mic solution 1.0%, also achieved clinical significance incomparison to placebo in the PP population for the reductionof ocular itching at all time points 16 h after dosing.

An analysis was performed to determine the proportion of

subjects in each group that evidenced a 2.0-U, etc reductionin itching scores compared with their screening visit scoreswithin the PP population, as well as for the subgroup ofsubjects in the PP population with the most severe itching(defined as an ocular itch score of 3 or more in each eye at ascreening visit 2 time point). Within the PP population,40.0% of subjects in the bepotastine besilate ophthalmic so-lution 1.5% group experienced a 2.0-U reduction for at least 1post-CAC time point at visit 3B compared with 34.3% ofthose in the bepotastine besilate ophthalmic solution 1.0%group and 5.9% in the placebo group, demonstrating a dose-dependent reduction in itch. Of those in the severe itchingsubpopulation, a 2.0-U reduction in eye itching scores for atleast 1 post-CAC time point was measured in 8.7% of the

placebo group compared with 37.5% and 43.5% of the be-potastine besilate ophthalmic solution 1.0% and 1.5% groupsubjects, respectively (Fig. 1). In both the PP population andsevere itching subpopulation, the greater number of subjectsthat experienced 2.0-U reductions in itching scores with ei-ther bepotastine besilate ophthalmic solution (1.0% or 1.5%)treatment compared with placebo was statistically significant(P= 0.001 andP = 0.008, respectively).

Given that subject enrollment required an ocular itchingscore of 2.0-U or greater at visit 1 and visit 2, a 2.0-Ureduction in itching would be expected to produce nearcomplete elimination of ocular itching. Figure 2 illustratesthe proportion of subjects that achieved complete or near

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complete elimination of ocular itch (score of 0 or 0.5-U) 16 hafter dosing at a post-CAC time point. A greater number ofsubjects receiving either bepotastine besilate ophthalmic so-lution achieved complete or nearly complete elimination ofitch following a CAC compared with placebo in both the PPpopulation (P< 0.001) and the baseline severe itching sub-population (P= 0.005). For both study populations, the de-

gree of reduction or elimination of ocular itching was greaterin the bepotastine besilate ophthalmic solution 1.5% grouprelative to results for the bepotastine besilate ophthalmicsolution 1.0% group, although the differences were not sta-tistically significant (P> 0.05).

Conjunctival redness. Bepotastine besilate ophthalmic so-lution 1.0% was statistically superior (P 0.012) to placebofor reducing mean conjunctival redness only at the 7 min

time point 16 h after dosing in both the PP population andthe ITT population with LOCF. However, there were noclinically significant (i.e., 1.0-U) differences in conjunctivalredness between bepotastine besilate ophthalmic solutions(1.0% or 1.5%) and placebo at any time point 16h afterdosing.

Tearing (lacrimation). Shown in Table 3 is the proportionof subjects eyes with allergen-induced tearing absent at allpost-CAC time points exclusively for those subjects thathad tearing eyes observed during screening visit 2. A doserelationship was found for the relative reduction in allergen-induced tearing measured between screening and 16hpostdosing. The placebo group had a 27.5% reduction in eyeswith tearing present at baseline, compared with a 51.2% re-duction in the bepotastine besilate ophthalmic solution 1.0%

Table1. Demographic Information of Enrolled Patients (Intent-to-Treat Population)

PlaceboBepotastine besilate

ophthalmic solution 1.0%Bepotastine besilate

ophthalmic solution 1.5%

No. of subjects randomized 36 36 35Mean age ( SD) (years) 40.9 ( 11.4) 39.9 ( 15.2) 44.3 ( 16.0)Range of ages (years) 13.065.0 12.064.0 11.073.0

> 18 years of age, N(%) 34 (94.4) 33 (91.7) 33 (94.3)

18 years of age, N(%) 2 (5.6) 3 (8.3) 2 (5.7)Pvaluea 0.75 0.31Gender,N(%)

Female 17 (47.2) 14 (38.9) 18 (51.4)Male 19 (52.8) 22 (61.1) 17 (48.6)Pvalue 0.63 0.81

Race, N(%)Caucasian 33 (91.7) 35 (97.2) 31 (88.6)African-American 1 (2.8) 0 (0.0) 1 (2.9)Asian 2 (5.6) 0 (0.0) 0 (0.0)Other 0 (0.0) 1 (2.8) 3 (8.6)Pvalue 0.36 0.15

Iris color, N(%)Blue 12 (33.3) 11 (30.6) 11 (31.4)Brown 19 (52.8) 15 (41.7) 17 (48.6)Green 2 (5.6) 3 (8.3) 1 (2.9)Hazel 3 (8.3) 7 (19.4) 6 (17.1)Pvalue 0.51 0.72

aPvalue for age as a continuous variable was calculated by 2 sample t-test. All other P values were calculated using Fishers exact test.SD, standard deviation.

Table2. Conjunctival Allergen Challenge at16 H Postdosing

Difference in mean itching scores

(placeboactive)Analysispopulation

Time of itchingassessment after a CAC

Bepotastine besilateophthalmic solution 1.0%

Bepotastine besilateophthalmic solution 1.5%

PP 3 min 0.7a 1.0a

5 min 0.9a 1.1a

7 min 0.9a 1.1a

ITT with LOCF 3 min 0.7a 0.8a

5 min 0.8a 0.9a

7 min 0.9a 0.8a

Difference in mean itching scores in the PP and the ITT with LOCF populations.aP 0.001.CAC, conjunctival allergen challenge; ITT, intent-to-treat; LOCF, last observation carried forward; PP, per protocol.



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group (P 0.05 relative to placebo) and an 85.7% reduction inthe bepotastine besilate ophthalmic solution 1.5% group(P< 0.0001 relative to placebo). There was also a significantlygreater reduction of tearing in the bepotastine besilate oph-thalmic solution 1.5% group as compared with the bepotas-tine besilate ophthalmic solution 1.0% group (P= 0.0046).

In general, regardless of whether or not subjects experi-enced allergen-induced tearing at visit 2, there was lesstearing in both bepotastine besilate ophthalmic solutiongroups as compared with placebo at all 3 post-CAC timepoints at visit 3B, in both the PP population and the ITTpopulation with LOCF. In the PP population in particular,there were between 3.1% and 9.4% tearing eyes in the be-potastine besilate ophthalmic solution 1.5% group as com-pared with between 36.8% and 47.1% tearing eyes in theplacebo group, and the differences were statistically signifi-cant at each time point (P< 0.001). Tearing in the bepotastinebesilate ophthalmic solution 1.0% group ranged between20.0% and 24.3%, and also was significantly less than theplacebo group 7 and 15 min post-CAC (P 0.030).

Safety

The safety population (n = 107) was defined as subjectswho received at least 1 dose of test agent. A total of 5 ocularAEs were reported, 2 originating from the bepotastine besi-late ophthalmic solution 1.5% group (eye irritation andconjunctival cyst) and 3 from the placebo group (eye irrita-tion and foreign body sensation). Eighteen subjects reported29 nonocular AEs (Table 4). Fourteen of these nonocular AEswere classified as related to treatment, reported by 9 subjects.Unpleasant or bitter drug taste was reported upon eyedropinstillation by 6 subjects in the bepotastine besilate ophthal-

mic solution 1.0% group and by 3 subjects in the bepotastinebesilate ophthalmic solution 1.5% group. All 9 subjects re-ported this event as mild or moderate.

Discussion

Bepotastine besilate ophthalmic solutions 1.0% and 1.5%were both previously reported to be effective for the reduc-tion of ocular itching in this double-masked, single-site trialfor at least 8 h using the CAC model of allergic conjunctivi-tis.22,23 The data analyses presented here for bepotastinebesilate ophthalmic solution 1.5% also show clinical success( 1.0-U improvement relative to placebo; P< 0.001) in re-ducing ocular itching when challenged 16 h after drug de-livery, suggesting the possibility of a once daily dosingregimen. It appears that the higher bepotastine besilate

FIG. 1. Percent of subjects with 2-U improvement in ocularitching scores (placeboactive) at 1 or more observation timepoints relative to visit 2 screening values. Changes in ocularitching scores were pair-matched for each subject by eye andobservation time point at 16 h after dosing with maskedmedication. Results for left and right eyes were averaged. PP,per protocol population.

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Placebo 1.0%

Bepo

1.5%

Bepo

Placebo 1.0%

Bepo

1.5%

Bepo

%WithCompleteorNe

arlyCompleteClearance

ofItchingPost-CAC(ave

rageeyescorecombined)

BaselineSevere Itch PP

*

*

*

*

P 0.05 relative to Placebo

PP

FIG. 2. Percent of subjects with complete or nearly com-plete clearance of itching post-CAC at 1 or more observationtime points 16 h after dosing. Results for left and right eyeswere averaged. PP, per protocol population.

Table3. Percent of Eyes with Tearing Presentat Screening and Percent Cleared Relative

to Baseline at16 H After Dosing with Medication

Baseline, visit

2 (tearing eyes/total eyes)

16 h duration ofaction, visit 3B

(nontearing eyes/visit 2 tearing eyes)

Placebo 58.8% (40/68) 27.5% (11/40)Bepotastine

besilate ophthalmicsolution 1.0%

61.4% (43/70) 51.2% (22/43)a

Bepotastinebesilate ophthalmicsolution 1.5%

46.7% (28/60) 85.7% (24/28)b,c

aP 0.05 relative to placebo.bP 0.0001 relative to placebo.cP 0.005 relative to bepotastine besilate ophthalmic solution 1.0%.P values calculated using Fishers exact test.

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concentration provided the potency required to achieve thisclinically significant effect for up to 16 h. Subgroup analysesfor the present clinical trial revealed a dose-dependent im-provement in ocular itching that was statistically significantamong subjects with more severe ocular itching scores atscreening as well as for all subjects when treated with eitherconcentration of bepotastine besilate ophthalmic solution.This finding has important implications since increased se-verity of allergic conjunctivitis symptoms can lead to a morerefractory therapeutic response. Bepotastine besilate oph-thalmic solutions therefore appear to offer an efficacious andrapid therapy for the severely allergic patient, which may

allow such severe patients to avoid or reduce steroid use andthereby minimize the detrimental effects associated withthose drugs.32 Based on the analysis of AEs from this trial,both concentrations of bepotastine besilate ophthalmic so-lution also were safe and well tolerated. Ocular AEs in thisclinical trial were minimal and did not include any instancesof dry eye.

Results of this clinical trial are comparable to previousclinical trials of bepotastine besilate as a systemic medicationin treating itching associated with other allergic condi-tions.13,16,3337 Statistical significance for reduced itching wasseen in the multicenter CAC trial for both bepotastine besi-late ophthalmic solutions (1.0% and 1.5%) compared withplacebo for the 16-h CAC test (P< 0.0055 at all time points),

but a 1.0-U improvement in ocular itching compared withplacebo was not demonstrable for either bepotastine besilateformulation and clinical benefit was not seen for reducingconjunctival redness.

Lacrimation is a major problem in patients with allergicrhinoconjunctivitis. A cross-sectional survey of patients(n = 447) with allergic rhinitis and their physicians showedthat at the time of their consultation, 44.0% of patients weresuffering from both nasal and ocular symptoms.38 Further-more, 13.6% of patients reported itchy, red eyes, or wateryeyes as their most troublesome symptom.38 An ocular allergytreatment for tearing or watery eyes that did not induce dryeye side effects would address the needs of such patients.

The data presented here therefore demonstrate that bothbepotastine besilate ophthalmic solutions (1.0% and 1.5%)have possible clinical value by virtue of showing significantactivity for reducing allergen-induced excessive tearing orwatery eyes in the CAC model.

Sisler et al.39 reported in 1982 that the lacrimal drainagesystem included valves assuring the progression of tears in 1direction; secretions pumped from the lacrimal gland are

distributed over the ocular conjunctiva and drain from theocular surface through the punctum; the punctum carriessecretions to the common canaliculus, moving then to thelacrimal sac and nasolacrimal duct, where secretions draininto the nose. This one-way drainage hypothesis is sup-ported by a conjunctival and nasal allergen challenge studysuggesting that lacrimal secretions gained access to the nosethrough the nasolacrimal duct but nasal secretions could notreach the eye.40 Therefore, it is likely that CAC-induced in-flammation causing nasal congestion might block thedrainage of tears through the nasolacrimal duct and lead toexcessive watery eyes. It is notable that in the present study,the dose-dependent reduction in watery eyes observed 16 hafter treatment in subjects receiving bepotastine ophthalmic

solution 1.0% and 1.5% correlates with previously publishedresults demonstrating statistically significant reductions(P 0.01) in nasal congestion and rhinorrhea with bepotas-tine besilate ophthalmic solution 1.5% 16 h after subjectdosing.29 Further studies appear warranted to better under-stand the relationship between CAC-induced tear produc-tion and the actions of H1 receptor antagonists such asbepotastine besilate ophthalmic solutions.

The CAC model has been accepted by the FDA as astandardized and reproducible means of evaluating the ef-ficacy and duration of action of ophthalmic antiallergicagents.41,42 At a CAC visit, the test agent is instilled into theconjunctival cul de sac of subjects with a history of allergicconjunctivitis. At a predetermined time later, an allergen is

instilled to induce an ocular allergic response intended to besimilar across all subjects. Changes in the signs and symp-toms resulting from the allergen challenge are graded ac-cording to standardized severity scales at predeterminedtime points, allowing for relatively precise comparisons ofthe effects of ocular allergy drugs among subjects and thereproducibility of effects for any 1 subject. The scales andgrading procedures also afford the sensitivity needed fordrug onset of action and duration of action clinical studies, incomparison to either placebo or to an active comparator.However, the CAC model does have study limitations. Toavoid interference by seasonal allergens, CAC clinical trialsare often conducted outside the allergy season. Exposure tohigh concentrations of different allergens in the CAC model

and study designs that emphasize prevention rather thantreatment of allergic symptoms may be seen as limitations ofthe model. However, the more numerous drawbacks inher-ent in a seasonal allergic conjunctivitis trial, such as day-to-day variability of allergen exposure and differences inintersubject symptoms, are resolved by the use of this model.

In conclusion, this CAC clinical trial demonstrates thepotential of once daily dosing with bepotastine besilateophthalmic solutions. Since patient treatment, adherence,and quality of life are important issues in allergic diseases,the benefits of once daily dosing are considerable. Studies inother therapeutic areas indicate that a key factor in treatmentadherence is the prescribed dosing schedule for a drug.4345

Table4. Treatment-Emergent NonocularAdverse Events

Placebo

Bepotastinebesilate

ophthalmicsolution 1.0%

Bepotastinebesilate

ophthalmicsolution 1.5%

AE (n = 36) ( n = 36) ( n= 35)

Total nonocularAEs 2 (5.6%) 9 (25.0%) 7 (20.0%)

Dysgeusia 0 6 (16.7%) 3 (8.6%)Respiratory,

thoracic,mediastinaldisorders (all)

1 (2.8%) 1 (2.8%) 3 (8.6%)

Gastrointestinaldisorders (all)

1 (2.8%) 0 2 (5.7%)

Nasopharyngitis 0 2 (5.6%) 0Lymphadenopathy 0 1 (2.8%) 0Anxiety 0 0 1 (2.9%)Cyst removal 0 1 (2.8%) 0

AE, adverse event.



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Suboptimal adherence to treatment regimens results in re-duced clinical benefits and diminished quality of life formany patients, especially those with persistent allergies,contact lens wearers, and children. Interestingly, patientadherence has been shown to double when drug regimensdecrease from twice a day to once a day.46 Bepotastine be-silate ophthalmic solutions 1.0% and 1.5% have been shownin this CAC trial to be safe and effective topical therapies that

provide potent relief of ocular itching in the CAC model ofallergic conjunctivitis for at least 16 h. Further clinical re-search to explore alternative dosing regimens with bepotas-tine besilate ophthalmic solution 1.5%, the approvedophthalmic antihistamine, in patients having allergic con-junctivitis therefore may be warranted.

Acknowledgments

The authors would like to thank Mauricio Munoz andRandi L. Rohlman of ISTA Pharmaceuticals, Inc., for assis-tance in editing the article.

Author Disclosure Statement

This clinical trial was funded by a grant from ISTAPharmaceuticals, Inc. The authors have made the followingfinancial disclosures: J.I.W., J.A.G., and T.R.M. are employeesof ISTA Pharmaceuticals, Inc.; K.S.K. is an employee ofStatistics and Data Corporation; no competing financial in-terests exist. G.L.T. is an employee of Andover Eye Associ-ates, and P.J.G and M.B.A. are employees of Ora, Inc.; theyhave no competing financial interests to disclose.

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Received: January 14, 2011Accepted: April 30, 2011

Address correspondence to:Dr. Jon I. Williams

ISTA Pharmaceuticals, Inc.50 Technology Drive

Irvine, CA 92618-2301

E-mail: [email protected]



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