The Effect of Bimatoprost 0.03% vs Travoprost 0.004% in Patients on Latanoprost 0.005% Requiring Additional IOP Lowering

1. The Effect of Bimatoprost 0.03% vs Travoprost 0.004% in Patients on Latanoprost 0.005% RequiringAdditional IOP Lowering Jeffrey A. Kammer,1 Barry Katzman,2 Stacey L. Ackerman,3and David Hollander4 1. Vanderbilt Eye Institute, Nashville, TN; 2. West Coast Eye Care Associates,San Diego, CA; 3. Philadelphia Eye Associates, Philadelphia, PA; 4. Allergan, Inc., Irvine, CA Financial Disclosure This study was sponsored by Allergan, Inc. J.A. Kammer, B. Katzman, and S.L. Ackerman have no proprietary interestin any of the prostaglandin analogs or their manufacturers.D. Hollander is an employee of Allergan, Inc.

2. Abstract • Purpose: To evaluate the efficacy/safety of switching latanoprost patients requiring additional intraocular pressure (IOP) lowering to either bimatoprost or travoprost. • Methods: Investigator-masked, prospective, multicentered study (17 sites) of patients on latanoprost requiring additional IOP lowering randomized to bimatoprost or travoprost. • Results: A total of 266 patients on latanoprost were randomized to bimatoprost or travoprost. On latanoprost therapy, the 2 groups had equivalent mean diurnal baseline IOPs (19.1 mm Hg, 18.9 mm Hg; P = .473). At 3 months, the additional mean diurnal reduction from baseline was 2.1 mm Hg for bimatoprost and 1.4 mm Hg for travoprost (P = .024). In patients with baseline IOP < 20 mm Hg (n = 145) on latanoprost, additional IOP lowering for bimatoprost was 1.8 mm Hg vs 0.5 mm Hg for travoprost (P < .001). Physician-documented hyperemia rates (11% for bimatoprost and 17% for travoprost) and corneal staining (4% for bimatoprost and 5% for travoprost) were not statistically different. • Conclusion: At 3 months, bimatoprost provided greater mean diurnal IOP lowering than travoprost in patients on latanoprost who required additional IOP lowering. Additional IOP lowering was observed with bimatoprost, even at relatively low latanoprost baselines. Longer follow-up is needed to further evaluate the effects of switching prostaglandin analogs (PGAs).

3. Introduction • A primary goal of medical therapy in glaucoma is to reduce intraocular pressure (IOP). Monotherapy with a single IOP-lowering medication is preferred to improve compliance and minimize the adverse effects and other costs of treatment. Patients who fail to achieve their target pressure on a particular medication may be able to maintain monotherapy if they are successfully switched to another more effective monotherapy. • Data from randomized clinical trials suggest that among the prostaglandin analogs (PGAs), bimatoprost and possibly travoprost may reduce IOP more effectively than latanoprost.1-3 • Studies have shown that patients uncontrolled on or unresponsive to latanoprost may have substantial additional IOP lowering when they are switched to bimatoprost or travoprost therapy.4-6 Increased efficacy has also been observed on a population level when patients were systematically switched from latanoprost to bimatoprost.7 • The purpose of the present study was to evaluate the efficacy and tolerability of switching patients from latanoprost monotherapy to either bimatoprost or travoprost monotherapy when IOP was not sufficiently reduced by latanoprost alone. References: 1. Netland et al. Am J Ophthalmol. 2001;132:472-484; 2. Simmons et al. Adv Ther. 2004;21:247-262; 3. Maul et al. Clin Ther. 2007;29:1915-1923; 4. Gandolfi and Cimino. Ophthalmology. 2003;110:609-614; 5. Williams. Adv Ther. 2002;19:275-281; 6. Hollo et al. Curr Med Res Opin. 2005;21:1943-1948;7. Law et al. Ophthalmology. 2005;112:2123-2130.

4. Methods: Study Design and Patients • This was a randomized, prospective, multicenter (17 sites), investigator-masked, parallel-group clinical study. • Adult patients diagnosed with glaucoma or ocular hypertension in each eye who had inadequate IOP control after at least 30 days on bilateral latanoprost monotherapy were enrolled. • Inadequate IOP control was determined by failure of the patient to achieve the target pressure set by the investigator. • Primary exclusion criteria included previous inadequate IOP response to bimatoprost or travoprost and known hypersensitivity or contraindication to any component of the study medications. • Patient eligibility was determined at a screening visit following at least 30 days on latanoprost monotherapy, and patients were subsequently run-in for an additional 2 weeks on latanoprost monotherapy before a baseline visit. • Study visits were scheduled at baseline (following 2-week latanoprost run-in), month 1, and month 3. • At baseline, patients discontinued latanoprost therapy and were randomized to1 of 2 treatment groups: • Bimatoprost 0.03% (Lumigan®; Allergan, Inc.; Irvine, CA) • Travoprost 0.004% (Travatan®; Alcon Laboratories Inc.; Fort Worth, TX) • Study drugs were administered once daily in the evening for 3 months.

5. Methods: Outcome Measures and Analysis • IOP was measured at 9 AM and 4 PM (± 1 hour) at each study visit. • The primary efficacy outcome measures were mean diurnal IOP and mean IOP at each timepoint. • Diurnal IOP for a patient was defined as the mean of the 9 AM and 4 PM measurements taken at a particular visit. • Safety outcome measures included ocular signs (biomicroscopy) and symptoms. • All adverse events were recorded, and their severity and potential relationship to study treatment were documented. • An adverse event was defined as any new condition, worsening of a preexisting condition, or recurrence of a condition that had resolved after the baseline visit. • Biomicroscopic findings were graded on a 4-grade scale of none-to-trace (0 to 0.5), mild (1), moderate (2), and severe (3). • Analyses of IOP were based on the worse eye (the eye with the higher IOP at 9 AM on baseline) for the intent-to-treat patient population with no imputation for missing values. • 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.

6. Results: Patient Characteristics and Disposition • Patient demographics were generally similar between treatment groups, but there were more male patients in the travoprost group. • Most patients were diagnosed with chronic open-angle glaucoma. • Study completion rates were high in each group, with 97.4% of patients completing the study as planned. Dark eye color = brown; light = all other colors.

7. Mean Diurnal IOP • Mean diurnal baseline IOPs on latanoprost were similar in the 2 treatment groups. • After switching from latanoprost, the mean diurnal IOP was significantly lower with bimatoprost than with travoprost at both month 1 and month 3. • At month 3, the additional mean reduction from baseline diurnal IOP was2.1 mm Hg with bimatoprost and 1.4 mm Hg with travoprost (P = .024). Mean (± SEM) Diurnal IOP (mm Hg) * * *P ≤ .024 vs travoprost Baseline onLatanoprost Month After Switch

8. Mean IOP at Each Hour and Visit 9 AM 4 PM • Baseline mean IOPs on latanoprost were similar in the 2 treatments at each hour. • After switching from latanoprost, the mean IOP was significantly lower with bimatoprost than with travoprost at the 9 AM timepoint at month 1 (P = .004) and the 4 PM timepoint at month 3 (P = .047). Mean IOP (mm Hg) * * *P = .004 vs travoprost *P = .047 vs travoprost Baseline onLatanoprost Baseline onLatanoprost Month After Switch Month After Switch

9. Subgroup Analysis: Patients With Baseline IOP < 20 mm Hg Mean Diurnal IOP • For patients whose baseline IOP on latanoprost was < 20 mm Hg (n = 145), mean diurnal IOPs were significantly lower with bimatoprost than with travoprost at both 1 and 3 months. • At month 3, the mean reduction from latanoprost-treated baseline diurnal IOP was 1.8 mm Hg with bimatoprost vs 0.5 mm Hg with travoprost (P < .001). Mean (± SEM) Diurnal IOP (mm Hg) * * *P ≤ .007 vs travoprost Baseline onLatanoprost Month After Switch

10. Safety Results • On biomicroscopy, conjunctival hyperemia and punctate keratitis were the only findings with ≥ 1-grade increases in severity reported in ≥ 4% of patients in either treatment group. • Rates of increased conjunctival hyperemia and corneal staining were low in each group with no significant difference between groups. • Treatment-related adverse events were reported for only 8.4% of patients in the bimatoprost group and 6.0% in the travoprost group. • The incidence of treatment-related ocular or conjunctival hyperemia was 3.1% in the bimatoprost group and 1.5% in the travoprost group. Biomicroscopy Findings Percentage of patients withat least a 1-grade increasefrom baseline severity score Month 1 Month 3

11. Discussion • A primary goal of glaucoma treatment is to reduce IOP to the target pressure using a minimal number of medications.1 If the target pressure is not met on initial therapy, switching to another monotherapy rather than adding a second medication is often advisable.1 Previous studies have demonstrated that patients uncontrolled on latanoprost may benefit from switching within the PGA class to bimatoprost or travoprost.2-5 • In this study, baseline mean diurnal IOPs on latanoprost were fairly well controlled at approximately 19 mm Hg, yet patients achieved mean diurnal IOP reductions of 2.1 mm Hg with bimatoprost and 1.4 mm Hg with travoprost (P = .024, bimatoprost vs travoprost). • The decision of whether to switch or add medication may be difficult when the IOP of the patient is < 20 mm Hg. For patients whose baseline IOP on latanoprost was < 20 mm Hg, bimatoprost and travoprost provided 1.8 mm Hg and 0.5 mm Hg of mean additional diurnal IOP lowering, respectively (P < .001). These results suggest that switching to bimatoprost may be a preferred treatment option for patients on latanoprost who have IOP < 20 mm Hg yet have not met their target pressure. • Both study medications were well tolerated. Adverse event reports and biomicroscopic evaluations showed a low incidence of increased conjunctival hyperemia with each PGA. • The incidence of hyperemia for patients switched directly from latanoprost to another PGA is lower than that expected when treatment-naïve patients or patients washed out of previous medications are initiated on bimatoprost or travoprost therapy. This might be explained by the development of tolerance during latanoprost treatment. References: 1. European Glaucoma Society. 2003; 2. Gandolfi and Cimino. Ophthalmology. 2003;110:609-614; 3. Williams. Adv Ther. 2002;19:275-281;4. Hollo et al. Curr Med Res Opin. 2005;21:1943-1948; 5. Kaback et al. Curr Med Res Opin. 2004;20:1341-1345.

12. Conclusions • Switching therapy within the PGA class may allow patients to reach their target pressure while maintaining monotherapy. • The results of this study suggest that for patients on latanoprost who need lower IOP, switching to bimatoprost provides greater additional mean diurnal IOP lowering than switching to travoprost. • Additional IOP lowering was observed after the switch to bimatoprost, even at relatively low latanoprost baselines. • The rate of increased hyperemia is low in patients switched directly from latanoprost to either bimatoprost or travoprost.