1. Bimatoprost 0.03% vs Bimatoprost 0.03% Plus Fixed Combination Brimonidine 0.2%/Timolol 0.5% in Glaucoma or Ocular Hypertension Patients Previously on Latanoprost: Randomized 12-Week Trial Steven D. Vold, MD 1 ; Fiaz Zaman, MD 2 ; Steven H. Rauchman, MD 3 ; Julia M. Williams, MA 4 ; David A. Hollander, MD, MBA 4 1 BoozmanHof, Rogers, AZ; 2 Houston Eye Associates, Houston, TX; 3 North Valley Eye Medical Group, Mission Hills, CA; 4 Allergan, Inc., Irvine, CA Study funded by Allergan, Inc. Steven D. Vold has received research support and lecture fees from Allergan. Fiaz Zaman has received research support, lecture fees, and travel reimbursement from Allergan. Steven H. Rauchman has received research support and travel reimbursement from Allergan. Julia M. Williams and David A. Hollander are employees of Allergan, Inc.

2. Introduction The prostaglandin analogs (PGAs) latanoprost, bimatoprost, and travoprost are commonly used first-line therapy for treatment of glaucoma and ocular hypertension (OHT). –Patients on latanoprost requiring additional IOP lowering may benefit from switching within the PGA class. 1,2 –Evidence from clinical trials suggests that bimatoprost 0.03% may provide greater IOP lowering in glaucoma and OHT patients. 3 Patients, even those who start on a PGA, frequently need multiple medications to reach their target IOP. 4 –When multiple medications are needed, the number of bottles and drops used should be minimized to promote adherence to treatment. 5,6 Use of a once-daily PGA and a twice-daily fixed combination of 2 other classes of medications may represent maximum tolerated medical therapy for many patients. –The fixed combination of brimonidine 0.2%/timolol 0.5% has been shown to be well-tolerated and to effectively reduce IOP when added to a PGA. 7 The purpose of this study was to evaluate the IOP-lowering efficacy and safety of bimatoprost monotherapy compared to bimatoprost plus fixed-combination brimonidine/timolol in patients on latanoprost monotherapy who required additional IOP lowering.

3. Methods This was a prospective, randomized, multicenter, investigator-masked, parallel-group study. Eligible patients were diagnosed with glaucoma or OHT and had a baseline IOP of ≥ 20 mm Hg and < 34 mm Hg in at least 1 eye at 8 AM after ≥ 30 days of latanoprost 0.005% monotherapy. Following baseline evaluations, patients discontinued latanoprost and were randomized to either bimatoprost 0.03% QD (with an artificial tear BID to maintain masking) or bimatoprost 0.03% QD plus fixed-combination brimonidine 0.2%/timolol 0.5% BID for 12 weeks. IOP was measured at 8 AM (immediately before dosing), 10 AM, and 4 PM at baseline, week 4, and week 12. The primary efficacy endpoint was the mean diurnal IOP at week 12. Safety measures included adverse events (AEs) and biomicroscopy. –Biomicroscopy findings were graded on a scale of 0 = none, 0.5 = trace, 1 = mild, 2 = moderate, 3 = severe. Efficacy was evaluated in the worse eye (the eligible eye with the higher baseline IOP) in the intent-to-treat population of all randomized patients with last-observation-carried-forward for missing values. IOP and change from baseline IOP at weeks 4 and 12 were analyzed by analysis of covariance (ANCOVA) with baseline IOP as the covariate.

4. Baseline Characteristics of Patients Most of the patients in the study were diagnosed with open-angle glaucoma, and almost all were using 1 or more IOP-lowering medications at the screening visit. There were no significant differences between treatment groups in baseline IOP on latanoprost (P ≥.111) Bimatoprost (n = 62) Bimatoprost Plus Fixed Brimonidine/Timolol (n = 59) Mean age, years (range)62.6 (21-83)64.0 (35-86) Male, n (%)26 (41.9%)31 (52.5%) Race/ethnicity, n (%) White Hispanic Black Other 32 (51.6%) 19 (30.6%) 11 (17.7%) 0 (0.0%) 32 (54.2%) 17 (28.8%) 7 (11.9%) 3 (5.1%) Diagnosis in study eye, n (%) Glaucoma Ocular hypertension 51 (82.3%) 11 (17.7%) 51 (86.4%) 8 (13.6%) Mean corneal pachymetry (µm)550553 Using IOP-lowering medication at screening, n (%)58 (93.6%)56 (94.9%) History of latanoprost use at screening, n (%)46 (74.2%)34 (57.6%) Mean IOP at baseline on latanoprost, mm Hg 8 AM 10 AM 4 PM 23.3 21.8 21.4 23.3 20.6 20.4

5. Results : Mean Diurnal IOP There was no significant difference between treatment groups in the baseline mean diurnal IOP on latanoprost (22.1 and 21.4 mm Hg, P =.198). At week 12, the mean diurnal IOP was 19.2 mm Hg with bimatoprost and 15.4 mm Hg with bimatoprost plus fixed brimonidine/timolol (P <.001, primary efficacy endpoint). The within-group changes from baseline diurnal IOP at week 12 were statistically significant in both groups (bimatoprost vs latanoprost baseline, P <.001; bimatoprost plus fixed brimonidine/timolol vs latanoprost baseline, P <.001). The mean percent reduction in diurnal IOP from latanoprost baseline at week 12 was 13.2% with bimatoprost and 27.0% with bimatoprost plus fixed brimonidine/timolol (P <.001). a P <.001 vs latanoprost baseline b P <.001 vs bimatoprost

6. Change From Latanoprost Baseline IOP at Week 12 The mean reduction in IOP from latanoprost baseline was statistically significant at each timepoint at month 12 in both the bimatoprost group (P <.001 for bimatoprost vs latanoprost baseline) and the bimatoprost plus fixed brimonidine/timolol group (P <.001 for bimatoprost plus brimonidine/timolol vs latanoprost baseline). The mean reduction from baseline IOP on latanoprost during follow-up ranged from 2.5 mm Hg to 3.7 mm Hg in patients who replaced latanoprost with bimatoprost alone and 4.8 mm Hg to 7.1 mm Hg in patients who replaced latanoprost with bimatoprost plus fixed brimonidine/timolol. The mean reduction from latanoprost-treated baseline IOP was significantly greater with bimatoprost plus fixed brimonidine/timolol than with bimatoprost alone at each follow-up timepoint (P <.001).

7. Percentage of Patients With a ≥ 15% or ≥ 25% Decrease in Diurnal IOP From Latanoprost Baseline Patients treated with bimatoprost plus fixed brimonidine/timolol were more likely than patients treated with bimatoprost alone to achieve at least a 15% and 25% decrease in diurnal IOP from the latanoprost baseline at both weeks 4 and 12 (P <.001). ≥ 25% Decrease≥ 15% Decrease P <.001

8. Safety Analyses Adverse Events Both bimatoprost and bimatoprost plus fixed brimonidine/timolol were well-tolerated. The incidence of adverse events was 11.3% in the bimatoprost group and 28.8% in the bimatoprost plus fixed brimonidine/timolol group. The rate of discontinuations due to adverse events was 3.2% in the bimatoprost group and 6.8% in the bimatoprost plus fixed brimonidine/timolol group. Biomicroscopy Few patients in either treatment group had a mild (1-unit) or greater increase in the severity of ocular surface findings on biomicroscopy at week 12.

9. Discussion In this study, patients who had inadequate IOP lowering on latanoprost alone achieved substantial additional IOP lowering when they replaced latanoprost with either bimatoprost or bimatoprost plus fixed-combination brimonidine/timolol. –Mean IOP reductions from the latanoprost baseline were significantly larger with bimatoprost plus fixed brimonidine/timolol (up to 7.1 mm Hg) than with bimatoprost alone (up to 3.7 mm Hg, P <.001). Both bimatoprost alone and bimatoprost plus fixed-combination brimonidine/timolol were well-tolerated. Two-bottle therapy with bimatoprost and fixed-combination brimonidine/timolol involves 3 potential mechanisms of action in reducing IOP: increasing trabecular meshwork outflow, increasing uveoscleral aqueous outflow, and decreasing aqueous production. 8-10 –Fixed-combination brimonidine/timolol is effective as adjunctive therapy to bimatoprost. A regimen of bimatoprost plus fixed-combination brimonidine/timolol may represent maximum tolerated medical therapy for many patients requiring the instillation of only 3 drops daily in each eye.

10. Conclusions Both bimatoprost and bimatoprost plus fixed-combination brimonidine/timolol were well-tolerated and reduced IOP in patients who did not achieve their target IOP on latanoprost. The decision to switch medication within the PGA class and/or add combination adjunctive therapy will depend on the amount of IOP lowering needed to achieve target IOP.

11. References 1.Law SK, Song BJ, Fang E, Caprioli J. Feasibility and efficacy of a mass switch from latanoprost to bimatoprost in glaucoma patients in a prepaid Health Maintenance Organization. Ophthalmology. 2005;112(12):2123-2130. 2.Kammer JA, Katzman B, Ackerman SL, Hollander DA. Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre study. Br J Ophthalmol. 2010;94(1):74-79. 3.Aptel F, Cucherat M, Denis P. Efficacy and tolerability of prostaglandin analogs: a meta-analysis of randomized controlled clinical trials. J Glaucoma. 2008;17(8):667-673. 4.Covert D, Robin AL. Adjunctive glaucoma therapy use associated with travoprost, bimatoprost, and latanoprost. Curr Med Res Opin. 2006;22(5):971-976. 5.Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology. 2005;112(5):863-868. 6.Djafari F, Lesk MR, Harasymowycz PJ, Desjardins D, Lachaine J. Determinants of adherence to glaucoma medical therapy in a long-term patient population. J Glaucoma. 2009;18(3):238-243. 7.Nixon DR, Yan DB, Chartrand JP, Piemontesi RL, Simonyi S, Hollander DA. Three-month, randomized, parallel-group comparison of brimonidine-timolol versus dorzolamide-timolol fixed-combination therapy. Curr Med Res Opin. 2009;25(7):1645-1653. 8.Christiansen GA, Nau CB, McLaren JW, Johnson DH. Mechanism of ocular hypotensive action of bimatoprost (Lumigan) in patients with ocular hypertension or glaucoma. Ophthalmology. 2004;111(9):1658-1662. 9.Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol. 1995;113(12):1514-1517. 10.Johnson TV, Fan S, Zhan G, Camras CB, Toris CB. Efficacy and mechanisms of intraocular pressure reduction with latanoprost and timolol in participants with ocular hypertension: a comparison of 1 and 6 weeks of treatment. J Glaucoma. 2010;19(6):356-364.

12. Author Bio and Photo Steven D. Vold, MD Dr. Vold received his medical degree from the University of Minnesota Medical School and did his residency and glaucoma fellowship at Northwestern University Medical School in Chicago. He specializes in the diagnosis and management of glaucoma and in small-incision cataract surgery. At the Scott & White Eye Institute at Texas A&M College of Medicine, Dr. Vold served as vice chairman of the Department of Ophthalmology, director of the Division of Glaucoma, and assistant professor in the Department of Surgery and Ophthalmology. In May 2007, he joined the Boozman-Hof Regional Eye Clinic in Rogers, Arizona. Dr. Vold has published many journal articles, and he lectures frequently on various aspects of the diagnosis and treatment of glaucoma. He has been awarded numerous scholarships and academic awards.