1. Fixed-Combination Brimonidine-Timolol vs Latanoprost in Glaucoma and Ocular Hypertension Patients: A 12-Week, Randomized, Comparison Study L. Jay Katz, MD 1 ; Steven H. Rauchman, MD 2 ; Andrew J. Cottingham, MD 3 ; Steven T. Simmons, MD 4 ; Julia Williams, MA 5 ; Rhett M. Schiffman, MD 5 ; David A. Hollander, MD, MBA 5 1 Wills Eye Hospital, Philadelphia, PA; 2 North Valley Eye Medical Group, Mission Hills, CA; 3 South Texas Eye Institute, San Antonio, TX; 4 Glaucoma Consultants of the Capital Region, Slingerlands, NY; 5 Allergan, Inc., Irvine, CA Study funded by Allergan, Inc. Dr. L. Jay Katz received research support and travel reimbursement from Allergan, Inc. Drs. Steven H. Rauchman, Andrew J. Cottingham, and Steven T. Simmons received research support from Allergan, Inc. Ms. Julia Williams, Dr. Rhett M. Schiffman, and Dr. David A. Hollander are employees of Allergan, Inc.

2. Introduction Reducing intraocular pressure (IOP) to a low target pressure minimizes the risk of progression in glaucoma. 1 Prostaglandin analogs (PGAs), including latanoprost, bimatoprost, and travoprost, are commonly used as first-line therapy in glaucoma and ocular hypertension (OHT). Treatment decisions must be individualized. While IOP lowering is ideally controlled with monotherapy, over 20% of PGA patients, for example, may be required to add another IOP-lowering medication to their treatment regimen within a year of initiating treatment. 2 The fixed combination of brimonidine 0.2% and the beta-blocker timolol 0.5% (Combigan ® ; Allergan, Inc.) acts by a dual mechanism of action: increasing uveoscleral outflow and decreasing aqueous production. 3 Fixed-combination brimonidine-timolol has been shown to be well tolerated and to reduce IOP more effectively than either brimonidine or timolol used as monotherapy. 4 The purpose of this study was to evaluate the IOP-lowering efficacy of fixed-combination brimonidine-timolol compared with latanoprost in patients with glaucoma or OHT.

3. Methods This was a prospective, randomized, multicenter, investigator-masked, parallel-group study. Eligible patients were adults at least 18 years of age with a diagnosis of glaucoma or OHT requiring treatment with IOP-lowering medication. Any IOP-lowering medication used previously was washed out prior to the baseline visit.  Washout periods ranged from 4 days for parasympathomimetics and carbonic anhydrase inhibitors to 4 weeks for beta-blockers and PGAs. At the baseline visit, patients with IOP ≥ 24 mm Hg and < 34 mm Hg in at least 1 eye at 8 AM were randomized to treatment with twice-daily fixed brimonidine-timolol (n = 73) or once-daily latanoprost (n = 75, dosed in the evening with a vehicle control in the morning to maintain masking) for 12 weeks. IOP was measured at 8 AM (immediately prior to dosing), 10 AM, and 3 PM at baseline, week 6, and week 12. The primary efficacy endpoint was the mean diurnal IOP at week 12. Safety measures included biomicroscopy, with findings graded on a scale of 0 = none, +0.5 = trace, +1 = mild, +2 = moderate, and +3 = severe. Efficacy was evaluated in the worse eye (the eye with higher mean diurnal IOP at baseline) based on the intent-to-treat population of all randomized patients with last observation carried forward for missing values. Mean diurnal IOP was compared between treatment groups with 2-sample t-tests; proportions of patients were compared between treatment groups with Fisher exact tests.

4. Patient Demographics Fixed Brimonidine-Timolol (n = 73) Latanoprost (n = 75) Mean (SD) age, years63.3 (12.7)63.6 (12.0) Female, n (%)42 (57.5%)44 (58.7%) Race/ethnicity, n (%) Black 5 (6.8%) 6 (8.0%) Caucasian48 (65.8%)48 (64.0%) Hispanic17 (23.3%)17 (22.7%) Asian 1 (1.4%) 2 (2.7%) Other 2 (2.7%) Most of the patients enrolled in the study were Caucasian and female.

5. Results: Mean Diurnal IOP There was no statistically significant difference between treatment groups in mean diurnal IOP at baseline or week 12 (primary study endpoint). The mean percent reduction in diurnal IOP from baseline at week 12 was 28% in the fixed brimonidine-timolol group and 30% in the latanoprost group (P =.347). Error bars, SEM. P =.118 P =.794

6. Results: Percentage of Patients Achieving a ≥ 20% Reduction From Baseline Mean Diurnal IOP at Week 12 There was no statistically significant difference between treatment groups in responder rates. At Week 12, 87.7% of patients treated with fixed brimonidine-timolol and 77.3% of patients treated with latanoprost achieved at least a 20% reduction in mean diurnal IOP from baseline (P =.131). P =.131 vs latanoprost. Latanoprost (n = 75) Fixed Brimonidine-Timolol (n = 73)

7. Results: Percentage of Patients Achieving a Mean Diurnal IOP of < 18 mm Hg at Week 12 There was no statistically significant difference between treatment groups in the achievement of diurnal IOP < 18 mm Hg. At Week 12, 60.3% of patients treated with fixed brimonidine-timolol and 52.0% of patients treated with latanoprost achieved a mean diurnal IOP of < 18 mm Hg (P =.325). P =.325 vs latanoprost. Latanoprost (n = 75) Fixed Brimonidine-Timolol (n = 73)

8. Mean Scores on Biomicroscopy Mean scores on all biomicroscopic parameters remained in the none (0) to trace (+0.5) range in both treatment groups. Hyperemia (Conjunctiva) Follicles (Conjunctiva) Erythema (Lids/Lashes) Corneal Staining

9. Discussion Primary considerations in choosing antiglaucoma medication for use in individual patients include IOP-lowering efficacy and tolerability. In this study, fixed brimonidine-timolol and latanoprost demonstrated similar efficacy in lowering IOP in patients with glaucoma or OHT.  Fixed brimonidine-timolol and latanoprost provided equivalent mean diurnal IOP after 12 weeks of treatment.  Patients treated with fixed brimonidine-timolol were at least as likely as patients treated with latanoprost to achieve a mean diurnal IOP < 18 mm Hg and 20% or larger reductions in mean diurnal IOP from baseline at week 12. Biomicroscopic examinations showed a favorable ocular surface tolerability profile of both fixed brimonidine-timolol and latanoprost. These results suggest that fixed brimonidine-timolol may be an acceptable alternative to latanoprost for treatment of patients with glaucoma or OHT. Currently, the primary aim of glaucoma treatment is to reduce IOP to a low target pressure. In the future, treatment strategies also may strive to improve the health and viability of retinal ganglion cells.  At the present time, preclinical studies have suggested that brimonidine can reduce retinal ganglion cell loss and vision loss independently of IOP. 5 Further investigations are required to replicate these in vitro findings in a clinical setting.

10. Conclusions Fixed-combination brimonidine-timolol was as effective as latanoprost in reducing IOP in patients with glaucoma or OHT. Both treatments demonstrated favorable ocular surface tolerability.

11. References 1.The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429-440. 2.Covert D, Robin AL. Adjunctive glaucoma therapy use associated with travoprost, bimatoprost, and latanoprost. Curr Med Res Opin. 2006;22(5):971-976. 3.Cantor LB. Brimonidine in the treatment of glaucoma and ocular hypertension. Ther Clin Risk Manag. 2006;2(4):337-346. 4.Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed- combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230-1238. 5.Gandolfi SA, Sangermani C, Cimino L, et al. Is there a non IOP-related effect of brimonidine on visual field progression in human glaucoma? Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 2298.

12. Author Bio and Photo L. Jay Katz, MD, FACS, is a Professor of Ophthalmology at Jefferson Medical College and Director of the Glaucoma Service at Wills Eye Institute, Philadelphia. He received his MD degree from Yale University Medical School and completed an internship in Internal Medicine at the University of Virginia, a residency in Ophthalmology at Yale, and a Fellowship in Glaucoma at Wills Eye Hospital. He received the 2002 AAO Senior Achievement Award. His research interests include glaucoma.