The Effect of Bimatoprost 0.03% vs The Effect of Bimatoprost 0.03% vs Travoprost 0.004% in Patients on Travoprost 0.004% in Patients on

Latanoprost 0.005% RequiringLatanoprost 0.005% RequiringAdditional IOP Lowering Additional IOP Lowering

Jeffrey A. Kammer,Jeffrey A. Kammer,11 Barry Katzman, Barry Katzman,22 Stacey L. Ackerman, Stacey L. Ackerman,33

and David Hollanderand David Hollander44

1. Vanderbilt Eye Institute, Nashville, TN; 2. West Coast Eye Care Associates,1. Vanderbilt Eye Institute, Nashville, TN; 2. West Coast Eye Care Associates,San Diego, CA; 3. Philadelphia Eye Associates, Philadelphia, PA; San Diego, CA; 3. Philadelphia Eye Associates, Philadelphia, PA;

4. Allergan, Inc., Irvine, CA 4. Allergan, Inc., Irvine, CA

Financial Disclosure Financial Disclosure

This study was sponsored by Allergan, Inc. This study was sponsored by Allergan, Inc. J.A. Kammer, B. Katzman, and S.L. Ackerman have no proprietary interestJ.A. Kammer, B. Katzman, and S.L. Ackerman have no proprietary interest

in any of the prostaglandin analogs or their manufacturers.in any of the prostaglandin analogs or their manufacturers.D. Hollander is an employee of Allergan, Inc.D. Hollander is an employee of Allergan, Inc.

AbstractAbstract

Purpose:Purpose: To evaluate the efficacy/safety of switching latanoprost patients requiring To evaluate the efficacy/safety of switching latanoprost patients requiring additional intraocular pressure (IOP) lowering to either bimatoprost or travoprost.additional intraocular pressure (IOP) lowering to either bimatoprost or travoprost.

Methods:Methods: Investigator-masked, prospective, multicentered study (17 sites) of patients Investigator-masked, prospective, multicentered study (17 sites) of patients on latanoprost requiring additional IOP lowering randomized to bimatoprost or on latanoprost requiring additional IOP lowering randomized to bimatoprost or travoprost. travoprost.

Results:Results: A total of 266 patients on latanoprost were randomized to bimatoprost or A total of 266 patients on latanoprost were randomized to bimatoprost or travoprost. On latanoprost therapy, the 2 groups had equivalent mean diurnal baseline travoprost. On latanoprost therapy, the 2 groups had equivalent mean diurnal baseline IOPs (19.1 mm Hg, 18.9 mm Hg; IOPs (19.1 mm Hg, 18.9 mm Hg; PP = .473). At 3 months, the additional mean diurnal = .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 reduction from baseline was 2.1 mm Hg for bimatoprost and 1.4 mm Hg for travoprost ((PP = .024). In patients with baseline IOP < 20 mm Hg (n = 145) on latanoprost, = .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 (additional IOP lowering for bimatoprost was 1.8 mm Hg vs 0.5 mm Hg for travoprost (PP < .001). Physician-documented hyperemia rates (11% for bimatoprost and 17% for < .001). Physician-documented hyperemia rates (11% for bimatoprost and 17% for travoprost) and corneal staining (4% for bimatoprost and 5% for travoprost) were not travoprost) and corneal staining (4% for bimatoprost and 5% for travoprost) were not statistically different.statistically different.

Conclusion:Conclusion: At 3 months, bimatoprost provided greater mean diurnal IOP lowering At 3 months, bimatoprost provided greater mean diurnal IOP lowering than travoprost in patients on latanoprost who required additional IOP lowering. than travoprost in patients on latanoprost who required additional IOP lowering. Additional IOP lowering was observed with bimatoprost, even at relatively low Additional IOP lowering was observed with bimatoprost, even at relatively low latanoprost baselines. Longer follow-up is needed to further evaluate the effects of latanoprost baselines. Longer follow-up is needed to further evaluate the effects of switching prostaglandin analogs (PGAs). switching prostaglandin analogs (PGAs).

IntroductionIntroduction

A primary goal of medical therapy in glaucoma is to reduce intraocular pressure 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 (IOP). Monotherapy with a single IOP-lowering medication is preferred to improve compliance and minimize the adverse effects and other costs of treatment. Patients 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 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 maintain monotherapy if they are successfully switched to another more effective monotherapy. monotherapy.

Data from randomized clinical trials suggest that among the prostaglandin analogs Data from randomized clinical trials suggest that among the prostaglandin analogs (PGAs), bimatoprost and possibly travoprost may reduce IOP more effectively than (PGAs), bimatoprost and possibly travoprost may reduce IOP more effectively than latanoprost.latanoprost.1-31-3

Studies have shown that patients uncontrolled on or unresponsive to latanoprost may Studies have shown that patients uncontrolled on or unresponsive to latanoprost may have substantial additional IOP lowering when they are switched to bimatoprost or have substantial additional IOP lowering when they are switched to bimatoprost or travoprost therapy.travoprost therapy.4-64-6 Increased efficacy has also been observed on a population level Increased efficacy has also been observed on a population level when patients were systematically switched from latanoprost to bimatoprost.when patients were systematically switched from latanoprost to bimatoprost.77

The purpose of the present study was to evaluate the efficacy and tolerability of The purpose of the present study was to evaluate the efficacy and tolerability of switching patients from latanoprost monotherapy to either bimatoprost or travoprost switching patients from latanoprost monotherapy to either bimatoprost or travoprost monotherapy when IOP was not sufficiently reduced by latanoprost alone.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.

Methods: Study Design and PatientsMethods: Study Design and Patients This was a randomized, prospective, multicenter (17 sites), investigator-masked, parallel-group This was a randomized, prospective, multicenter (17 sites), investigator-masked, parallel-group

clinical study.clinical study. Adult patients diagnosed with glaucoma or ocular hypertension in each eye who had inadequate 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. 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 Inadequate IOP control was determined by failure of the patient to achieve the target pressure set by the

investigator. investigator.

Primary exclusion criteria included previous inadequate IOP response to bimatoprost or Primary exclusion criteria included previous inadequate IOP response to bimatoprost or travoprost and known hypersensitivity or contraindication to any component of the study travoprost and known hypersensitivity or contraindication to any component of the study medications.medications.

Patient eligibility was determined at a screening visit following at least 30 days on latanoprost 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, and patients were subsequently run-in for an additional 2 weeks on latanoprost monotherapy before a baseline visit.monotherapy before a baseline visit.

Study visits were scheduled at baseline (following 2-week latanoprost run-in), month 1, and Study visits were scheduled at baseline (following 2-week latanoprost run-in), month 1, and month 3. month 3.

At baseline, patients discontinued latanoprost therapy and were randomized toAt baseline, patients discontinued latanoprost therapy and were randomized to1 of 2 treatment groups:1 of 2 treatment groups:

– Bimatoprost 0.03% (LumiganBimatoprost 0.03% (Lumigan®®; Allergan, Inc.; Irvine, CA); Allergan, Inc.; Irvine, CA)– Travoprost 0.004% (TravatanTravoprost 0.004% (Travatan®®; Alcon Laboratories Inc.; Fort Worth, TX) ; Alcon Laboratories Inc.; Fort Worth, TX)

Study drugs were administered once daily in the evening for 3 months. Study drugs were administered once daily in the evening for 3 months.

Methods: Outcome Measures and Methods: Outcome Measures and AnalysisAnalysis

IOP was measured at 9 IOP was measured at 9 AMAM and 4 and 4 PMPM (± 1 hour) at each study visit. (± 1 hour) at each study visit. The primary efficacy outcome measures were mean diurnal IOP and mean IOP at each The primary efficacy outcome measures were mean diurnal IOP and mean IOP at each

timepoint.timepoint.– Diurnal IOP for a patient was defined as the mean of the 9 Diurnal IOP for a patient was defined as the mean of the 9 AMAM and 4 and 4 PMPM measurements taken at a measurements taken at a

particular visit. particular visit.

Safety outcome measures included ocular signs (biomicroscopy) and symptoms.Safety outcome measures included ocular signs (biomicroscopy) and symptoms. All adverse events were recorded, and their severity and potential relationship to study All adverse events were recorded, and their severity and potential relationship to study

treatment were documented.treatment were documented.– An adverse event was defined as any new condition, worsening of a preexisting condition, or recurrence 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. 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 Biomicroscopic findings were graded on a 4-grade scale of none-to-trace (0 to 0.5), mild (1), moderate (2), and severe (3). (1), moderate (2), and severe (3).

Analyses of IOP were based on the worse eye (the eye with the higher IOP at 9 Analyses of IOP were based on the worse eye (the eye with the higher IOP at 9 AMAM on on baseline) for the intent-to-treat patient population with no imputation for missing values.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 Baseline differences in IOP between treatment groups were evaluated using analysis of variance (ANOVA).variance (ANOVA).

An analysis of covariance (ANCOVA) model with baseline IOP as the covariate was used An analysis of covariance (ANCOVA) model with baseline IOP as the covariate was used to evaluate differences between treatment groups at follow-up.to evaluate differences between treatment groups at follow-up.

Results: Patient Characteristics and Results: Patient Characteristics and DispositionDisposition

Patient demographics were generally similar between treatment groups, but there were more male Patient demographics were generally similar between treatment groups, but there were more male patients in the travoprost group. patients in the travoprost group.

Most patients were diagnosed with chronic open-angle glaucoma.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.Study completion rates were high in each group, with 97.4% of patients completing the study as planned.

Bimatoprost (n = 131)Bimatoprost (n = 131) Travoprost (n = 135)Travoprost (n = 135)

Mean age (years)Mean age (years) 63.463.4 62.762.7

Sex (male/female)Sex (male/female) 38%/62%38%/62% 51%/49%51%/49%

RaceRace

BlackBlack 28%28% 24%24%

WhiteWhite 57%57% 59%59%

Hispanic or LatinoHispanic or Latino 12%12% 11%11%

OtherOther 3%3% 5%5%

Eye color (dark/light)Eye color (dark/light) 63%/37%63%/37% 62%/38%62%/38%

DiagnosisDiagnosis

Ocular hypertensionOcular hypertension 21%21% 22%22%

Chronic open-angle glaucomaChronic open-angle glaucoma 77%77% 73%73%

OtherOther 2%2% 5%5%

Dark eye color = brown; light = all other colors.

Mean Diurnal IOPMean Diurnal IOP

Mean diurnal baseline IOPs on latanoprost were similar in the 2 treatment groups.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 After switching from latanoprost, the mean diurnal IOP was significantly lower with

bimatoprost than with travoprost at both month 1 and month 3.bimatoprost than with travoprost at both month 1 and month 3. At month 3, the additional mean reduction from baseline diurnal IOP wasAt month 3, the additional mean reduction from baseline diurnal IOP was

2.1 mm Hg with bimatoprost and 1.4 mm Hg with travoprost (2.1 mm Hg with bimatoprost and 1.4 mm Hg with travoprost (PP = .024). = .024).

Month After SwitchBaseline onLatanoprost

Mea

n (±

SEM

) Diu

rnal

IOP

(mm

Hg)

*P ≤ .024 vs travoprost

14

16

18

20

0 1 2 3

Travoprost (N = 135)

Bimatoprost (N = 131)

* *

Mean IOP at Each Hour and VisitMean IOP at Each Hour and Visit

Baseline mean IOPs on latanoprost were similar in the 2 treatments at each hour.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 After switching from latanoprost, the mean IOP was significantly lower with

bimatoprost than with travoprost at the 9 bimatoprost than with travoprost at the 9 AMAM timepoint at month 1 ( timepoint at month 1 (PP = .004) and = .004) and the 4 the 4 PMPM timepoint at month 3 ( timepoint at month 3 (PP = .047). = .047).

9 AM 4 PM

Month After SwitchBaseline onLatanoprost Month After Switch

Baseline onLatanoprost

Mea

n IO

P (m

m H

g)

*P = .004 vs travoprost *P = .047 vs travoprost

*

*

Subgroup Analysis: Subgroup Analysis: Patients With Baseline IOP < 20 mm HgPatients With Baseline IOP < 20 mm Hg

For patients whose baseline IOP on latanoprost was < 20 mm Hg (n = 145), For patients whose baseline IOP on latanoprost was < 20 mm Hg (n = 145), mean diurnal IOPs were significantly lower with bimatoprost than with travoprost mean diurnal IOPs were significantly lower with bimatoprost than with travoprost at both 1 and 3 months.at both 1 and 3 months.

At month 3, the mean reduction from latanoprost-treated baseline diurnal IOP 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 (was 1.8 mm Hg with bimatoprost vs 0.5 mm Hg with travoprost (PP < .001). < .001).

Mean Diurnal IOP

Month After SwitchBaseline onLatanoprost

*P ≤ .007 vs travoprost

Mea

n (±

SEM

) Diu

rnal

IOP

(mm

Hg)

14

16

18

20

0 1 2 3

Travoprost (N = 75)

Bimatoprost (N = 70)

* *

On biomicroscopy, conjunctival hyperemia and punctate keratitis were the only findings with ≥ 1-grade 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.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 Rates of increased conjunctival hyperemia and corneal staining were low in each group with no significant difference between groups.significant difference between groups.

Treatment-related adverse events were reported for only 8.4% of patients in the bimatoprost group and Treatment-related adverse events were reported for only 8.4% of patients in the bimatoprost group and 6.0% in the travoprost group. 6.0% in the travoprost group.

– The incidence of treatment-related ocular or conjunctival hyperemia was 3.1% in the bimatoprost group and The incidence of treatment-related ocular or conjunctival hyperemia was 3.1% in the bimatoprost group and 1.5% in the travoprost group.1.5% in the travoprost group.

4%

11%

4%

10%

5%

17%

5%

10%

0

10

20

30

40

Conjunctivalhyperemia

Corneal punctatekeratitis

Conjunctivalhyperemia

Corneal punctatekeratitis

Bimatoprost

Travoprost

Safety ResultsSafety ResultsPe

rcen

tage

of p

atie

nts

with

at le

ast a

1-g

rade

incr

ease

from

bas

elin

e se

verit

y sc

ore Biomicroscopy Findings

Month 1 Month 3

DiscussionDiscussion A primary goal of glaucoma treatment is to reduce IOP to the target pressure using a A primary goal of glaucoma treatment is to reduce IOP to the target pressure using a

minimal number of medications.minimal number of medications.11 If the target pressure is not met on initial therapy, If the target pressure is not met on initial therapy, switching to another monotherapy rather than adding a second medication is often switching to another monotherapy rather than adding a second medication is often advisable.advisable.11 Previous studies have demonstrated that patients uncontrolled on latanoprost Previous studies have demonstrated that patients uncontrolled on latanoprost may benefit from switching within the PGA class to bimatoprost or travoprost.may benefit from switching within the PGA class to bimatoprost or travoprost.2-52-5

In this study, baseline mean diurnal IOPs on latanoprost were fairly well controlled at 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 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 (with bimatoprost and 1.4 mm Hg with travoprost (PP = .024, bimatoprost vs travoprost). = .024, bimatoprost vs travoprost).

The decision of whether to switch or add medication may be difficult when the IOP of the 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, 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 bimatoprost and travoprost provided 1.8 mm Hg and 0.5 mm Hg of mean additional diurnal IOP lowering, respectively (IOP lowering, respectively (PP < .001). These results suggest that switching to bimatoprost < .001). These results suggest that switching to bimatoprost may be a preferred treatment option for patients on latanoprost who have IOP < 20 mm Hg may be a preferred treatment option for patients on latanoprost who have IOP < 20 mm Hg yet have not met their target pressure.yet have not met their target pressure.

Both study medications were well tolerated. Adverse event reports and biomicroscopic Both study medications were well tolerated. Adverse event reports and biomicroscopic evaluations showed a low incidence of increased conjunctival hyperemia with each PGA.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 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 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 previous medications are initiated on bimatoprost or travoprost therapy. This might be explained by the development of tolerance during latanoprost treatment.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.

ConclusionsConclusions

Switching therapy within the PGA class may allow Switching therapy within the PGA class may allow patients to reach their target pressure while maintaining patients to reach their target pressure while maintaining monotherapy. monotherapy.

The results of this study suggest that for patients on The results of this study suggest that for patients on latanoprost who need lower IOP, switching to bimatoprost latanoprost who need lower IOP, switching to bimatoprost provides greater additional mean diurnal IOP lowering provides greater additional mean diurnal IOP lowering than switching to travoprost.than switching to travoprost.

Additional IOP lowering was observed after the switch to Additional IOP lowering was observed after the switch to bimatoprost, even at relatively low latanoprost baselines.bimatoprost, even at relatively low latanoprost baselines.

The rate of increased hyperemia is low in patients The rate of increased hyperemia is low in patients switched directly from latanoprost to either bimatoprost or switched directly from latanoprost to either bimatoprost or travoprost.travoprost.