1. The Additive IOP-Lowering Effect of Brimonidine 0.1% vs Brinzolamide 1.0% Adjunctive to Latanoprost 0.005% Douglas Day 1 and David Hollander 2 1. Omni Eye Services, Atlanta, GA; 2. Allergan, Inc., Irvine, CA Financial Disclosure This study was sponsored by Allergan, Inc. D. Day has no proprietary interest in any of the study drugs or their manufacturers. D. Hollander is an employee of Allergan, Inc.

2. Abstract  Purpose: Evaluate efficacy/safety of brimonidine 0.1% vs brinzolamide adjunctive to latanoprost.  Methods: Investigator-masked, randomized, parallel-group study of 40 patients randomized to brimonidine 0.1% or brinzolamide 1.0% TID adjunctive to latanoprost. Subjects administered latanoprost once daily in the evening and the study medication 3 times daily for 3 months. Mean diurnal intraocular pressure (IOP) was calculated based on IOP measurements at 8 AM, 10 AM, and 4 PM at each study visit (baseline, 1 month, and 3 months).  Results: Equivalent mean diurnal baseline IOPs on latanoprost (19.6, 19.8 mm Hg; P =.846). At 3 months, the additional mean reduction from latanoprost baseline for brimonidine and brinzolamide, respectively, was 3.3 and 2.1 mm Hg (P =.028). Blurred vision (P =.011) at 1 month and unusual taste at 1 and 3 months were more common with brinzolamide (P =.002, P =.031, respectively).  Conclusion: Brimonidine 0.1% provided greater or equivalent IOP lowering compared with brinzolamide adjunctive to latanoprost.

3. Introduction  The once-daily prostaglandin analogs (PGAs) (bimatoprost, latanoprost, and travoprost) effectively reduce intraocular pressure (IOP) and are often used as monotherapy to treat glaucoma and ocular hypertension (OHT). Many patients, however, do not achieve sufficiently low IOP with a single medication. 1 Over 20% of patients who are initiated on monotherapy with a once-daily PGA may be expected to require adjunctive therapy within the next year. 2  A primary consideration in choosing adjunctive medication is IOP-lowering efficacy. An adjunctive therapy ideally provides at least an additional 15% reduction in IOP from baseline on the initial therapy. 3 Several classes of IOP-lowering medications have been evaluated as adjunctive therapies to PGAs. Brinzolamide is an ophthalmic suspension of a carbonic anhydrase inhibitor (CAI). When used as adjunctive therapy to latanoprost, brinzolamide has been demonstrated to reduce IOP as effectively as dorzolamide, the first topical CAI introduced for IOP lowering, and to be associated with less ocular discomfort. 4 Brimonidine, a highly selective alpha-adrenergic agonist, has similarly been shown to effectively reduce IOP when used in combination with PGAs including latanoprost. 5-7  The purpose of the present study was to evaluate the IOP-lowering efficacy and tolerability of brimonidine Purite ® 0.1% compared with brinzolamide 1% when used as adjunctive therapy to latanoprost in patients with glaucoma or OHT. References: 1. Kass et al. Arch Ophthalmol. 2002;120:701-713; 2. Covert and Robin. Curr Med Res Opin. 2006;22:971-976; 3. Glaucoma Disease Management Guide. PDR 2004; 4. Tsukamoto et al. J Ocul Pharmacol Ther. 2005;21:395-399; 5. Lee and Gornbein. J Glaucoma. 2001;10:220-226; 6. Konstas et al. Ophthalmology. 2005;112:603-608; 7. Netland et al. Adv Ther. 2003;20:20-30.

4. Methods: Study Design and Patients  This was a randomized, single-center, investigator-masked, parallel-group study.  Patients diagnosed with glaucoma or OHT who were currently on latanoprost monotherapy and in need of additional IOP lowering were enrolled.  Patients were required to have been on latanoprost monotherapy for at least 30 days prior to study enrollment and to have a screening IOP of 18 mm Hg or higher in at least 1 eye.  Eligible patients were randomized to 1 of 2 adjunctive treatment groups: –Brimonidine P 0.1% TID (Alphagan ® P 0.1%; Allergan, Inc.; Irvine, CA) –Brinzolamide 1% TID (Azopt ® ; Alcon Laboratories, Inc.; Fort Worth, TX)  Study drugs were dosed at 8 AM, 4 PM, and 10 PM (± 1 hour) for 3 months.  Marketed bottles of brimonidine P and brinzolamide were provided to patients in identically appearing masked cartons labeled with the patient randomization number.  Latanoprost was provided in its marketed bottle and was dosed in the evening 10 minutes apart from the instillation of study medication.  Study visits were at baseline, month 1, and month 3.

5. Methods: Outcome Measures and Analysis  IOP was measured at each visit at 8 AM (morning trough, just before study drug instillation), 10 AM (peak effect) and 4 PM (before second dose of study drug).  Efficacy outcome measures included mean diurnal IOP at each visit and mean IOP at each timepoint and visit.  Safety measures included comfort/tolerability, ocular signs and symptoms, adverse events, and visual acuity.  A written questionnaire was administered at each follow-up visit to evaluate the comfort and tolerability of study drug instillation.  Analyses of IOP were based on the worse eye (the eye with the higher IOP at 8 AM on baseline) for the intent-to-treat patient population with imputation for missing values using the last observation carried forward.  Diurnal IOP for a patient was defined as the mean of the 8 AM, 10 AM, and 4 PM measurements taken at a particular visit.  Baseline differences in IOP between treatment groups were evaluated using analysis of variance (ANOVA).  An analysis of covariance (ANCOVA) model with baseline IOP as the covariate was used to evaluate differences between treatment groups at follow-up visits.

6. Results: Patient Characteristics and Disposition  There were no significant differences between treatment groups in patient demographics. –Half of the patients were black, and most were diagnosed with chronic open-angle glaucoma.  Thirty-four patients (85%) completed the study as planned. –In the brinzolamide group, 3 patients exited the study early because of adverse events (eye pain, pruritus, and brain tumor) and 1 was lost to follow-up. –In the brimonidine P group, 1 patient discontinued due to an adverse event (hypertension) and 1 due to lack of efficacy. Brimonidine P 0.1% (N = 20) Brinzolamide 1% (N = 20) Mean age (years) 60.057.5 Sex (male/female) 45%/55%65%/35% Race Black Black55%45% White White45%45% Hispanic Hispanic 0% 0% 5% 5% Asian Asian 0% 0% 5% 5% Diagnosis OHT OHT 5% 5%10% Chronic open-angle glaucoma Chronic open-angle glaucoma85%75% Chronic angle-closure glaucoma Chronic angle-closure glaucoma10%10% Mixed Mixed 0% 0% 5% 5% Mixed diagnosis = one eye with OHT and the other with chronic open-angle glaucoma.

7. Results: Mean Diurnal IOP  Baseline mean diurnal IOPs on latanoprost were similar in the 2 treatment groups (bimatoprost: 19.6 mm Hg, travoprost: 19.8 mm Hg; P =.846).  Both brimonidine P 0.1% and brinzolamide reduced diurnal IOP substantially when added to ongoing latanoprost therapy.  Adjunctive brimonidine P provided significantly lower mean diurnal IOP than adjunctive brinzolamide at both follow-up visits (P ≤.028).  At month 3, the additional mean reduction from latanoprost baseline was 3.3 mm Hg with brimonidine P vs 2.1 mm Hg with brinzolamide (P =.028). Mean (± SEM) diurnal IOP (mm Hg) *P ≤.028 vs brinzolamide Month Brinzolamide 1% (N = 20) Brimonidine Purite ® 0.1% (N = 20) * *

8. Mean IOP (SEM) at Each Hour (mm Hg)  Baseline mean IOPs on latanoprost were similar in the 2 treatment groups at each hour.  Brimonidine P provided significantly lower IOP compared with brinzolamide at the 10 AM (peak effect) and 4 PM time points at both 1 and 3 months (P ≤.050).  At 8 AM (trough effect) mean IOP was similar in the 2 treatment groups.  The reduction from baseline IOP on latanoprost at individual time points during follow-up ranged from 2.2 to 4.8 mm Hg with brimonidine P and from 1.4 to 2.9 mm Hg with brinzolamide. Month 1 Month 3 Brim P 0.1% (N = 20) Brinz 1.0% (N = 20) P Value Brim P 0.1% (N = 20) Brinz 1.0% (N = 20) P Value 8 AM (trough) 17.8 (0.68) 18.1 (0.60).896.896 18.2 (0.76) 18.2 (0.71).716.716 10 AM (peak) 15.1 (0.65) 17.6 (0.76).002.002 14.6 (0.63) 17.4 (0.51) <.001 4 PM 16.2 (0.67) 18.1 (0.78).035.035 16.3 (0.61) 17.8 (0.49).050.050

9. Comfort and Tolerability of Eye Drop Instillation: Survey Results  Brinzolamide-treated patients were significantly more likely than brimonidine P-treated patients to report an unusual taste associated with eye drop instillation at both months 1 and 3.  Patients in the brinzolamide group were also more likely than those in the brimonidine P group to report changes in vision (usually described as blurred vision) at month 1.  One patient in the brinzolamide group reported that the bitter taste associated with eye drop instillation caused him to want to discontinue his study medication. Patients were asked whether they experienced an unusual taste, an unusual ocular sensation, ocular discomfort, or any change in vision after instilling their eye drop medications. All patient responses were “yes” or “no”; there were no responses of “not sure.” Number of Patients Responding “Yes” (% of Total Responses) Month 1 Month 3 Brim P 0.1% Brinz 1.0% P Value Brim P 0.1% Brinz 1.0% P Value Unusual taste 1 (5.0%) 9 (50.0%).002 2 (11.1%) 7 (43.8%).031 Unusual sensation in eye 1 (5.0%) 1 (5.6%).939 1 (6.3%).932 Ocular discomfort 3 (15.0%) 5 (29.4%).289 3 (16.7%) 2 (12.5%).732 Change in vision 2 (10.0%) 8 (47.1%).011 1 (5.6%) 2 (12.5%).476

10. Other Safety Parameters  There were no significant differences between treatment groups in biomicroscopic findings or changes from baseline visual acuity.  Treatment-related adverse events were reported for 4 patients (20%) in the brimonidine P group and 3 patients (15%) in the brinzolamide group.  There was no significant between-group difference in the overall incidence of treatment-related adverse events or in the incidence of any individual treatment-related adverse event.

11. Discussion  In patients with inadequate IOP control on latanoprost, mean IOP at 10 AM and 4 PM and mean diurnal IOP were significantly lower with adjunctive brimonidine P than with brinzolamide. Mean IOP at 8 AM was similar in the 2 treatment groups.  The difference between treatment groups in mean diurnal IOP at months 1 and 3 is likely to be clinically significant, because in the Early Manifest Glaucoma Trial, each 1 mm Hg decrease in IOP was associated with a 10% decrease in the risk of glaucoma progression. 1  Although brimonidine P and brinzolamide are often dosed twice daily in clinical practice, they were dosed thrice daily in this study as recommended in their prescribing information.  It is unlikely that the additional afternoon dose of drugs affected the efficacy results, because all of the IOP measurements were taken prior to the second daily dose of medication given in the afternoon.  Transient side effects associated with eye drop instillation may cause patient discomfort and decrease patients’ compliance with treatment.  At month 1, more brinzolamide-treated patients than brimonidine P–treated patients reported blurred vision and bitter taste associated with eye drop instillation.  By month 3, the number of brinzolamide-treated patients who reported blurred vision had decreased, but bitter taste remained more common in patients treated with brinzolamide.  Both brimonidine P and brinzolamide were well tolerated. Reference: 1. Leske et al. Arch Ophthalmol. 2003;121:48-56.

12. Conclusions  Brimonidine P provided significantly lower diurnal IOP than brinzolamide when added to latanoprost therapy.  Bitter taste after eye drop instillation was significantly less common with brimonidine P than with brinzolamide adjunctive therapy.