Glaucoma Therapy: The “Art” of Medical Management J. James Thimons,O.D.,FAAO Medical Director, Ophthalmic Consultants of CT                                                                                                                                       

The Role of IOP Management in Glaucoma

PEAK Effect with Evening Dose Once daily drug: Peak effect (8 mm Hg) at 12-14 hrs post dose Trough effect (2 mm Hg) at 22-24 hrs post dose Office hours Trough 2:00 am 4:00 am 6:00 am 12:00 pm 8:00 am 10:00 am 2:00 pm 4:00 pm 6:00 pm 8:00 pm 12:00 am 10:00 pm Time of Day (hr) Dose Courtesy of David B. Yan, M.D., F.R.C.S.(C) 3

IOP Variability Highest (peak) IOP may commonly occur outside of usual clinic office hours1,2 In spite of achieving target IOP during office hours patients may experience: “damaging”/above target IOPs at other times of the day disease progression Are we missing IOP spikes, peak, damaging IOP, IOPs at other times of day3? 1. Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. 2. Mosaed S, et al. Am J Ophthalmol. 2005; 139(2): 320–324. 3. Hughes E, et al. J of Glaucoma 2003; 12: 232-236. 4

Peak IOP Outside Office Hours PURPOSE: To determine the relationship between office IOP and peak IOP METHODS (Study One)1: 42 patients with OAG Treated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with Goldmann applanation tomography at 3 hr intervals METHODS (Study Two)2: 103 patients with OAG (including 35 untreated) 24 hr IOP values obtained at 2 hr intervals using a pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position during the nocturnal/sleep period Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324. 5

Peak IOP Outside Office Hours Study 1 Study 2 Times at which maximum and minimum IOP occurred in a 24-hr period1: Time of maximum IOP in 24-hour Time of minimum IOP in 24-hour 8 Number of eyes 28 19 10 40 30 20 3am- 6am 9am- 12pm 3pm- 6pm 9pm- 12am 12 23 67% of peak IOP occurs outside office hours2 Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324. 6

IOP is Higher at Night Higher nocturnal supine IOP than diurnal sitting IOP (healthy and OAG) Supine IOP higher than sitting IOP, regardless of time of day Habitual IOP of healthy eyes Habitual IOP of glaucomatous eyes Diurnal Sitting Nocturnal Supine Diurnal Sitting Diurnal Sitting Nocturnal Supine Diurnal Sitting 26 26 n=24 25 n=24 25 24 24 23 23 22 22 IOP (mm Hg) 21 IOP (mm Hg) 21 20 20 19 19 18 18 17 17 16 16 15 15 *Error bars = SEM 14 14 3:30 PM 5:30 PM 7:30 PM 9:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 3:30 PM 5:30 PM 7:30 PM 9:30 PM 3:30 AM 5:30 AM 7:30 AM 11:30 PM 11:30 AM 9:30 AM 1:30 PM 11:30 PM 1:30 AM 11:30 AM 1:30 PM Clock Time Clock Time Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590. 7 7

Diurnal Fluctuations in IOP: Independent Risk Factor? PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG METHODS: 64 patients with OAG and IOP below 25 mm Hg (over 5 year follow-up) Patients successfully performed tonometry with a self-tonometer 5 times a day for 5 days Baseline status and time to progression of visual field loss identified from clinical charts Level and variability of diurnal IOP characterized and risk of progression analyzed using a nonparametric time-to-event model Asrani S, et al. J Glaucoma 2000; 9: 134-142. 8

Diurnal Fluctuations Correlate with Visual Field Progression 1.0 5.76 Relative risk of disease progression within 5 years Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7 Asrani S, et al. J Glaucoma 2000; 9: 134-142. 9

Patients on More Than One IOP-Lowering Medication 2 Medications 3 Medications 4 Medications Monotherapy does not adequately control IOP in many patients. Market data has shown that of patients who are taking IOP-lowering medication, approximately 30% are taking 2 or more medications. Therefore, there is frequently a need to choose second-line and third-line medication, and there are many drug classes available from which to choose. Note to speaker: This slide shows results from market data on the frequency with which physicians reported giving instructions to patients for use of 1, 2, 3, or 4 IOP-lowering medications. For this analysis, fixed-combination Cosopt® was counted as 1 IOP-lowering medication. Reference Verispan’s PDDA, MAT Nov 2006. 1 Medication Source: Verispan’s PDDA, MAT Nov 2006.

Pathways to lower Intraocular Pressure Inflow Alpha 2- agonists B1 blockers CAI Outflow Alpha 2–agonists Cholinergics Prostaglandins/ Prostamindes

Beta-blockers 30 year history of successfully lowering IOP Reduces aqueous humor formation Adrenergic agonists Lowers IOP 22-28% Ocularly well tolerated

Beta Blockers Beta receptor in the ciliary body epithelium Beta 1 receptors >> Beta 2 receptors in the eye Beta receptors stimulate productions of aqueous. Beta blockers suppress aqueous production

Beta-blockers Timolol maleate – Timoptic, Timoptic XE (1/2, 1/4 %) Carteolol – Ocupress 1% (Intrinsic sympathomimetic activity) Levobunolol – Betagan ½% Timolol hemihydrate – Betimol ¼, ½% Istalol ¼,1/2% - QD dosing indication Betaxolol ¼% - cardioselective, safer?

Systemic Bradycardia Congestive heart failure Exacerbation of heart block Bronchospasm Mood change Impotence Lipid profile

Contraindications Asthma Severs COPD CHF Heart block Myasthenia gravis Diabetes

Lama study (AJO 11/02) Conclusions: So? ...identifies no scientific studies supporting the development of worsening claudication, depression, hypoglycemia,sexual dysfunction or impaired neuromuscular transmission Recommends careful medical history and checking pulse rate and rhythm So?

Timolol Equally effective in AA’s and Whites IOP decrease 30-60 min Long term drift 47% decrease at 1 wk 25% at 1 yr

Carteolol (ocupress) Intrinsic sympathomimetic activity Less likely to increase systemic lipid profile

Ocular Side Effects Punctate keratopathy Corneal anesthesia ( Watch for DESx) Blepharoconjunctititis

Brimonidine 0.1% Alphagan alpha-2 Decrease aqueous production Also increase uveoscleral outflow (small amount) Not as effective as timolol but close May be neuroprotective More effective than or dorzolamide? Can cause mild mydriasis Comes in 0.1%, 0.15%, 0.2%

Brimonidine: Dual Mechanism of IOP Lowering Enhances uveoscleral outflow Suppresses aqueous humor production (inflow) Brimonidine Has a Dual Mechanism of IOP Lowering Brimonidine lowers IOP by decreasing inflow of aqueous humor at the ciliary body AND increasing its outflow through the uveoscleral pathway (Toris et al, 1995; Toris et al, 1999). This dual mechanism of action means that brimonidine can be effectively used as an adjunct with either aqueous suppressants or outflow enhancers for additional IOP lowering. References Toris CB, Camras CB, Yablonski ME. Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients. Am J Ophthalmol. 1999;128:8-14. Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol. 1995;113:1514-1517. Toris et al. 1995 and 1999. 22

Brimonidine Formulation Comparison ALPHAGAN® P ALPHAGAN® Concentration of Brimonidine 0.1% 0.15% 0.2% pH 7.7 7.2 6.3-6.5 Preservative PURITE® BAK Viscosity agent Carboxymethylcellulose Polyvinyl alcohol Electrolytes Potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate – The differences in formulation between brimonidine 0.2% and brimonidine PURITE® (brimonidine tartrate ophthalmic solution) 0.15% and 0.1% have been summarized here. 23

Side effects 10-30% dry mouth 10% allergy rate Avoid with MAO inhibitors Alphagan P 0.1% Better tolerated

Mean IOP at Peak (10 am) Brimonidine-PURITE® 0.15% (N = 372) Brimonidine 0.2%* (N = 376) Mean IOP (mm Hg) IOP at the 10 AM time point was measured at all visits. At baseline, mean IOP at 10 AM was similar between the groups (approximately 23.6 mm Hg). At the 10 AM time point, both brimonidine-PURITE® 0.15% and brimonidine 0.2% were effective in IOP lowering, and the between-group difference in mean IOP was less than or equal to 0.4 mm Hg at all visits. There was no statistically significant difference in the mean change from baseline IOP at peak effect between the two groups. Note to presenter The results presented here are based on the per-protocol (PP) patient population. There was no significant difference in the IOP results between the intent-to-treat (ITT) population with last observation carried forward (LOCF) for missing values and the PP population, and the efficacy conclusions drawn from the 2 populations were the same. brimonidine = brimonidine tartrate ophthalmic solution Reference Katz LJ. Twelve-month evaluation of brimonidine-PURITE® versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma. 2002;11:119-126. *Original ALPHAGAN® Katz. J Glaucoma. 2002. 25

Mean IOP at Trough (8 am) Brimonidine-PURITE® 0.15% (N = 372) Brimonidine 0.2%* (N = 376) Mean IOP (mm Hg) IOP was measured at 8 AM at all visits, and the results over the 12-month treatment period are shown in this graph. At baseline, mean IOP at 8 AM was similar between the groups (approximately 24.9 mm Hg). Both the treatments showed comparable IOP lowering, and the difference in mean IOP at morning trough between brimonidine-PURITE® 0.15% and brimonidine 0.2% was less than or equal to 0.4 mm Hg at all visits. There was no statistically significant difference in the mean change from baseline IOP at trough effect between the 2 groups. Note to presenter The results presented here are based on the per-protocol population. There was no significant difference in the IOP results between the ITT (LOCF) and PP populations, and the efficacy conclusions drawn from the 2 populations were the same. Results at 10 AM, 3 PM and 5 PM also showed comparable efficacy of the study medications. There were no statistically significant between-group differences in diurnal mean IOP at any time point in the study except at 5 PM at month 3 when the mean IOP difference was 0.5 mm Hg in favor of brimonidine 0.2% (P = .046). Brimonidine-Purite 0.15% was determined to be noninferior to brimonidine 0.2% because 40/40 of the upper limits of the 95% confidence intervals of the between-group difference in mean IOP (brimonidine-PURITE® 0.15% minus brimonidine 0.2%) were less than or equal to 1.5 mm Hg, with 36/40 less than or equal to 1.0 mm Hg. brimonidine = brimonidine tartrate ophthalmic solution Reference Katz LJ. Twelve-month evaluation of brimonidine-PURITE® versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma. 2002;11:119-126. *Original ALPHAGAN® Katz. J Glaucoma. 2002. 26

Alpha Agonists-side effects Ocular- dermatitis, lid retraction, conjunctival blanching, allergic reactions Systemic dry mouth, dry eye lethargy, apnea in children, hypotension

Contraindication Children MAO inhibitors

Nocturnal Efficacy: Brimonidine Monotherapy PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period DESIGN: Prospective, open-label study METHODS: Baseline data of 24 hr IOP in untreated patients collected in a sleep laboratory Measurements of IOP taken using a pneumatonometer every 2 hrs in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions Liu JH, et al. Ophthalmology 2010; 117: 2075–2079. 29

Brimonidine Efficacy During Nocturnal Period DIURNAL/WAKE NOCTURNAL/SLEEP DIURNAL/WAKE brimonidine brimonidine brimonidine Habitual IOP (mmHg) Error bars = SEM N = 15 Clock Time Liu JH, et al. Ophthalmology 2010; 117: 2075–2079. 30

Glaucoma & Pregnancy BJO 2009; JD Ho: 244 pregnant women treated for glaucoma analyzed for birth weight 1,952 age matched controls No significant difference between women on BB’s vs: no Tx Herndon, L: D/C Brimonodine several weeks before d/t risk of apnea

COMBIGAN™ (Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution) 0

Diurnal Mean IOP at Month 12 Dose all treatments Dose brimonidine * ** * * * ** ** Mean IOP (mm Hg) This slide shows the mean IOP results at month 12 at each time point during the day. Brimonidine and timolol monotherapies are approved for first line therapy. Note to presenter: There were no statistically significant between-group differences in baseline mean IOP at the 8 AM, 10 AM, or 3 PM measurements. Mean baseline IOP in the 3 treatment groups ranged from 24.7 to 25.0 mm Hg at 8 AM, from 23.3 to 23.5 mm Hg at 10 AM, and from 22.1 to 22.5 mm Hg at 3 PM. At 5 PM, baseline mean IOP was slightly lower in the fixed brimonidine-timolol group (21.8 mm Hg) than in the timolol group (22.4 mm Hg; P = .01) or the brimonidine group (22.2 mm Hg; P = .06) but was within 0.6 mm Hg of both groups. Analyses of IOP used ANCOVA with baseline IOP as the covariate to adjust for any baseline differences in IOP. Reference Sherwood MB, Craven ER, Chou C, et al; for COMBIGANTM Study Groups I and II. 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. *P < .001 vs timolol **P < .001 vs brimonidine 8 AM 10 AM 3 PM 5 PM ***Brimonidine and timolol monotherapies are approved for first line therapy. Statistical significance does not necessarily correlate to clinical significance. Sherwood et al. Arch Ophthalmol. 2006.

Treatment-Related Adverse Events * P ≤ .03 vs brimonidine 0.2% TID ** P ≤ .02 vs timolol 0.5% BID Percentage of patients This graph shows all treatment-related adverse events with an incidence of 5% or greater over 12 months in any group and a statistically significant between-group difference in incidence. Adverse events were determined by the investigator to be treatment-related if they were possibly, probably, or definitely related to treatment. The incidence of treatment-related adverse events associated with conjunctival allergy or inflammation (including any combination of conjunctival hyperemia, eye pruritus, follicular conjunctivitis, conjunctival folliculosis, allergic conjunctivitis, conjunctivitis, chemical conjunctivitis, conjunctival edema, and blepharoconjunctivitis) was lower in the fixed-combination group (26.0%) than in the brimonidine group (39.8%; P < .001). The incidence of allergic conjunctivitis (ocular allergy) was 45% lower in the fixed-combination group than in the brimonidine group (P = .020). The incidence of treatment-related oral dryness was lower in the fixed-combination group (2.1%) than in the brimonidine group (9.2%; P < .001). Brimonidine and timolol monotherapies are approved for first line therapy. Reference Sherwood MB, Craven ER, Chou C, et al; for COMBIGANTM Study Groups I and II. 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. Conjunctival hyperemia Ocular stinging Eye pruritus Allergic conjunctivitis Conjunctival follicles Oral dryness ***Brimonidine and timolol monotherapies are approved for first line therapy. Sherwood et al. Arch Ophthalmol. 2006.

COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOP Added to a PGA baseline -6.9 mm Hg (29%) Mean IOP (mm Hg) * * COMBIGAN™(brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% + PGA (n = 37) When used as an adjunct to prostaglandin analogue (PGA) therapy, COMBIGAN™ ophthalmic solution significantly reduced IOP from the PGA-treated baseline at both month 1 and month 3 (P < .0001). At month 3, adjunctive COMBIGAN™ therapy provided an additional mean change from baseline IOP of 6.9 mm Hg (29%). Mean IOP was 21.9 mm Hg in the COMBIGAN™ group at PGA-treated baseline and 15.3 mm Hg after 3 months of adjunctive COMBIGAN™ therapy. Note to presenter: Results presented represent observed values in the worse eye. Baseline data were available for all 37 patients in the COMBIGAN™ group who used the fixed combination as adjunctive therapy with a PGA. Data were missing for 5 patients in the COMBIGAN™ group at month 1 and for 6 patients in the COMBIGAN™ group at month 3. References 1. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN™ vs. Cosopt® fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA. 2. Data on file, Allergan, Inc. *P < .0001 vs baseline Month 1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.

COMBIGAN™ and Cosopt® Randomized, investigator-masked, 3-month, parallel comparison Pooled data from 2 studies at 10 sites with identical protocols (Canada) Patients with OAG/OHT requiring additional IOP lowering Two subgroups Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54) and Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) Adjunctive: COMBIGAN™ added to PGA (n = 37) and Cosopt® added to PGA (n = 42) IOP 2 hours after morning dose Visits at baseline, 1 month, and 3 months COMBIGAN™ ophthalmic solution and Cosopt® have been compared head-to-head in randomized, investigator-masked, 3-month, parallel-group clinical trials carried out at 10 sites in Canada. Because the trials had identical protocols, the results were pooled for analysis. Notes on study design: Enrolled patients had IOP that was insufficiently controlled. If patients were using a prostaglandin analogue (PGA) as 1 of their medications, they continued on that PGA throughout the study. All other glaucoma medications were washed out before the baseline study visit. At the baseline visit, patients were randomly assigned to treatment with either brimonidine/timolol or dorzolamide/timolol twice daily for 3 months. Study visits were at baseline, month 1, and month 3. IOP was measured approximately 2 hours after the morning dose of study medication (peak effect for both treatments). Patients completed a comfort and tolerability questionnaire at month 1 study visit. Efficacy analyses were based on the IOP in the worse eye of the patient (eye with the higher IOP at baseline, or the mean of both eyes if IOP was equal between eyes). Mean IOP and change from baseline IOP were evaluated for 2 subgroups of patients: those who used the fixed combination as monotherapy and those who used the fixed combination as an adjunct to a PGA. References 1. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN™ vs. Cosopt® fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA. 2. Data on file, Allergan, Inc. PGA = prostaglandin analogue 1Nixon and Hollander. AAO. 2007; 2Data on file, Allergan, Inc.

COMBIGAN™ and Cosopt® as Monotherapy: Mean IOP * Mean IOP (mm Hg) *P = 0.04 (mean change from baseline) Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) When used as monotherapy, both COMBIGAN™ and Cosopt® significantly reduced IOP from baseline at month 1 and month 3 (P < .001). At month 3, mean change from baseline IOP was 7.7 mm Hg in the COMBIGAN™ group vs 6.7 mm Hg in the Cosopt® group (P = .040). Mean baseline IOP was comparable between groups (23.0 mm Hg in the COMBIGAN™ group and 23.6 mm Hg in the Cosopt® group, P = .522). Note to presenter: Results presented represent observed values in the worse eye. Baseline data were available for all 54 patients in the COMBIGAN™ group and 47 patients in the Cosopt® group who used the fixed combination as monotherapy. At month 1, data were missing for 2 patients in the COMBIGAN™ group and 1 patient in the Cosopt® group. At month 3, data were missing for 5 patients in the COMBIGAN™ group and 4 patients in the Cosopt® group. References 1. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN™ vs. Cosopt® fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA. 2. Data on file, Allergan, Inc. COMBIGAN™ (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54) Month Mean IOP reductions from baseline at month 3 were 7.7 mm Hg with COMBIGAN™ and 6.7 mm Hg with Cosopt® (P = .040) 1Nixon and Hollander. AAO. 2007; 2Data on file, Allergan, Inc.

COMBIGAN™ and Cosopt ® Tolerability and Comfort COMBIGAN™(brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 85) Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 86) Percentage of patients with rating of moderate or severe Patients reported low stinging, burning, and bad taste with COMBIGAN™ ophthalmic solution (P < .0001; Wilcoxon tests). These side effects were rated on a 5-point scale with 0 = none, 1 = very minimal, 2 = mild, 3 = moderate, and 4 = severe. This slide shows that the percentage of patients responding to the questionnaire who rated stinging, burning, and unusual taste as moderate or severe. Moderate to severe stinging, burning, and unusual taste: The percentage of Cosopt® patients responding to the questionnaire who reported moderate to severe stinging, burning, and unusual taste was 31.4%, 19.8%, and 18.6%, respectively. The percentage of COMBIGAN™ patients responding to the questionnaire who reported moderate to severe stinging, burning, and unusual taste was 8.2%, 7.1%, and 4.7%, respectively. Mean overall comfort scores were 0.32 with COMBIGAN™ ophthalmic solution and 0.10 with Cosopt® on a 3-point scale with –1 = uncomfortable, 0 = comfortable, and 1 = very comfortable. References 1. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN™ vs. Cosopt® fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA. 2. Data on file, Allergan, Inc. Stinging Burning Unusual taste P = .0001 P = .0149 P = .0047 1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.

Carbonic Anhydrase Inhibitors 4 types of isoenzymes I erythrocytes and corneal epithelium II non pigmented ciliary body epithelium , iris retinas lens III skeletal muscle IV kidney

Carbonic Anhydrase Inhibitors Aqueous humor formation depends on secretion of bicarbonate from the ciliary processes when bicarbonate is formed, it tied with sodium and water follows Similar process in CSF production and in kidney

CAI Dorzolamide 2% Brinzolamide 1% Acetazolamide 125, 250, 500mg sequels Methazolamide 25, 50 mg

Systemic Side Effects Oral Use Malaise and fatigue Weight loss Anorexia Loss of libido Depression Sulfa allergies Sickle cell Marked kidney/liver Low potassium Low sodium level Transient myopia Swelling of CB Pregnancy Category C Paresthesia Tinitus Nausea Taste alterations Metabolic acidosis

Contraindications to Oral Therapy Sulfa allergies Sickle cell Marked kidney/liver Low potassium Low sodium level Pregnancy Category C Metabolic acidosis

CAIs make wonderful partners Feldman, et al 2006 – 1.5-1.8 mm lower IOP as compared to brimonidine 0.15% when added to travaprost This significance was present at all time points BID dosing

Companion study #2 When compared to brimonidine 2% adding them to Travaprost... IOP lowered by 13% w/ brimonidine IOP lowered by 23% w/ brinzolamide

Brinzolamide as an Adjunct to Latanoprost PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension METHODS: 14 patients with open-angle glaucoma or ocular hypertension who had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy) Incidence of adverse events examined Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507. 46

Brinzolamide as an Adjunct to Latanoprost Adjunctive therapy lowered IOP by an additional 5.2 mm Hg after 3 months ** Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507. 47

Brinzolamide or Timolol: Adjunct to Latanoprost in an Open-Label Study DIURNAL/WAKE NOCTURNAL/SLEEP DIURNAL/WAKE Habitual IOP (mm Hg) N=26 Error bars = SEM Clock Time Liu JH, et al. Ophthalmology 2009; 116(3): 449-54. 48

This slide shows the packaging for COSOPT PF. Packaging for COSOPT® PF (dorzolamide HCl-timolol maleate ophthalmic solution). Key Point: This slide shows the packaging for COSOPT PF. 49

50

COSOPT® PF (dorzolamide HCl-timolol maleate ophthalmic solution) Has Been Proven to Provide the Same Powerful Efficacy as Original COSOPT® (dorzolamide HCl-timolol maleate ophthalmic solution) In an active-treatment controlled, parallel, double-masked study in 261 patients with elevated IOP 22 mmHg in 1 or both eyes, COSOPT PF had an IOP-lowering effect equivalent to that of COSOPT. 51

COSOPT® PF (dorzolamide HCl-timolol maleate ophthalmic solution) Is the First Preservative-Free, Fixed-Dose Combination Therapy for Lowering IOP The IOP-lowering effect of COSOPT® (dorzolamide HCl-timolol maleate ophthalmic solution) twice daily was greater (1–3 mmHg) than that of monotherapy with either 2.0% dorzolamide 3 times daily or 0.5% timolol twice daily. The IOP-lowering effect of COSOPT twice daily was approximately 1 mmHg less than that of concomitant therapy with 2.0% dorzolamide 3 times daily and 0.5% timolol twice daily. Open-label extensions of 2 studies were conducted for up to 12 months. During this period, the IOP-lowering effect of COSOPT twice daily was consistent during the 12-month follow-up period. 52

Prostaglandins /Prostamides Uveal seleral outflow Affects many properties with the 1955-Ambache described irin which medicated ocular response to inflammation Naturally synthesized by trabecular endothelial cells/ciliary muscle cells May have only minor inflammatory Regulatory effects

Prostaglandins /Prostamides Different receptor sites DP,EP,IP Prostaglandins E and F most effective in lowering IOP They seem to facilitate aqueous outflow via the uvealscleral pathway

Brimatoprost 0.03% Lumigan Latanoprost 0.005% Xalatan Prostaglandin F 2a analogue Prodrug Travoprost 0.004% Travatan Brimatoprost 0.03% Lumigan Synthetic prostamide analog Not a prodrug Tafluprost Zioptan - Non-preserved unit dose

XLT Study – Parrish, Palmberg, et al. (AJO, May 2003, Vol. 135, No.5) Multicenter study to compare IOP lowering efficacy of Bimatoprost vs Latanoprost vs Travaprost Also compared safety profiles of the 3 drugs Conclusions: All 3 drugs were comparable in their ability to lower IOP at all time periods. Latanoprost exhibited greater ocular tolerability

PGAs: IOP-Lowering Effects PURPOSE: To compare the IOP-lowering effect and safety of latanoprost, bimatoprost, and travoprost METHODS: 12-week, randomized, parallel-group study conducted at 45 US sites Previously treated patients with OAG or OH and an IOP ≥ 23 mm Hg in one or both eyes after washout Received either latanoprost (0.005%), bimatoprost (0.03%), or travoprost (0.004%) once daily in the evening At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, noon, 4:00 PM, and 8:00 PM. The primary efficacy outcome measure was change between baseline and week 12 in the 8:00 AM IOP Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 57

Primary Outcome 8 A.M. IOP reduction (mm Hg) from baseline to week 12: Latanoprost: 8.6 ± 3.7 Travoprost: 7.9 ± 3.4 Bimatoprost: 8.7 ± 3.8 Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 58

Adverse Effects Latanoprost (n=136) Bimatoprost (n=137) Travoprost (n=138) n No. events hyperemia 64 71 94 110 80 90 Eye irritation 9 10 15 16 6 Vision blurred 5 2 Eye pain 1 4 Growth of lashes Skin discoloration Dry eye 3 Visual acuity reduced Pruritus Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 59

Look at their failure rate: Percent of pxs who didn’t reach their target IOP Latanoprost – 14% Bimatoprost- 6% Travaprost – 8%

Adverse Effects Changes to pigmented tissues Iris pigmentation starts at pupil and spreads concentrically Long thick lashes Periobital pigment changes Caution with macular edema, iris/uveitis, keratitis Caution with renal/hepatic dysfunction Pregnancy category C

Prostaglandin Side Effects Iris pigmentation Is it reversible? Is it pre-cancerous? Xalatan – 6.7% @ 6mths 16% @ 12mths Travatan – 3% @ 12 mths Lumigan – 1.9% @ 12mths

Other Prostaglandin side effects CME Uveitis Reactivation of HSK Hypertrichosis Periorbital skin darkening One must take into consideration the benefits of low IOP with the risks of the side effects

Travatan (Travoprost 0.004%) Lowers IOP 30-33% Contraindicated in pregnant woman Excellent responder rated in black pts No CME

Responder rates in all patients 56.3% for IOP 17 mm Hg for travatan 49% for xalatan 39% for timolol

PGAs: Effects on Circadian IOP PURPOSE: To compare 24 hr reduction in IOP with latanoprost, travoprost and bimatoprost in patients with OAG and ocular hypertension (OH) DESIGN: Randomized, double-masked, crossover study PARTICIPANTS: 24 OAG and 20 OH patients METHODS: Patients treated with randomized cross-over sequence of latanoprost, travoprost and bimatoprost for 1 month each, with 30 day washout in between 24 hr tonometric curves were recorded at baseline (prior to each treatment) and after each treatment period in seated and supine positions Baseline and post-treatment IOP measured at 3:00, 6:00, 9:00 AM and noon and 3:00, 6:00, 9:00 PM and midnight Orzalesi N, et al. Ophthalmology 2006; 113: 239-246. 66

Bimatoprost and Travoprost: 12-Week Study Baseline mean IOP comparable between groups Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) 8 AM 12 PM 4 PM 8 PM Time of Day Mean IOP (mm Hg) 4 8 12 16 20 24 Travoprost (n = 138) Bimatoprost (n = 136) Mean IOP at Week 12 Pfizer sponsored the XLT lipid-comparison trial. This multicenter, randomized, investigator-masked, 12-week study involved 410 patients with glaucoma or ocular hypertension. Only patients who had been previously treated with ocular hypertension medication were eligible for the trial, and approximately 50% of the enrolled patients were using latanoprost at the screening visit. Enrolled patients were randomized to treatment with once-daily bimatoprost (n = 136), latanoprost (n = 136), or travoprost (n = 138) for 12 weeks. Baseline IOP was comparable among treatment groups. This slide shows mean IOP at week 12 in the intent-to-treat population. Mean IOP at week 12 ranged from 15.8 to 17.0 mm Hg in the bimatoprost group and 16.1 to 17.6 mm Hg in the travoprost group. Between groups difference in IOP ranged from 0.5 to 0.8 mm Hg for bimatoprost versus travoprost. Reference Parrish RK, Palmberg P, Sheu W, for the XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135(5):688-703. Parrish et al. Am J Ophthalmol. 2003. 67

Travoprost Appears Consistent Peak to Trough 100% 95% Peak-to-trough loss: Bimatoprost = 38% Latanoprost = 26% Travoprost = 14% 90% 85% % of peak IOP reduction (@ 12 hr) 80% 75% Travoprost Latanoprost Bimatoprost 70% 65% 60% 9:00 am 3:00 pm 9:00 pm Time 12 hours post dose = peak IOP reduction 24 hours post dose = trough IOP reduction Orzalesi N, et al. Ophthalmology 2006; 113: 239-246. 68

Effect of Travoprost on Diurnal and Nocturnal IOP PURPOSE: To assess the diurnal and nocturnal persistence of IOP reduction after omission of up to two doses of once-daily topical travoprost in patients with OAG or OH DESIGN AND METHODS: Prospective, open-label study 20 patients underwent 24 hr IOP monitoring at baseline prior to treatment and after 4 weeks or more of travoprost treatment Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133. 69

Effect of Travoprost on Diurnal and Nocturnal IOP NOCTURNAL/SLEEP DIURNAL/WAKE 28 26 24 22 20 18 16 14 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 11:30 AM 1:30 PM Habitual IOP (mmHg) Clock Time Baseline “On Treatment” Measured in the usual “habitual position” of the patients during those time periods Diurnal period – sitting Nocturnal period – supine Error bars = SEM Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133. 70

Bimatoprost and Travoprost: 6-Month Safety Results Both medications were well tolerated Most common adverse event: ocular redness 16 patients (20.8%) in the bimatoprost group and 12 patients (14.8%) in the travoprost group (P = .326) Ocular itching reported for 7.4% of travoprost patients and 2.3% of bimatoprost patients (P = .278) Treatment-related adverse events leading to patient discontinuations 8 patients in the travoprost group exited early: 4 for lack of efficacy, 2 for ocular redness and lid erythema, 1 for ocular dryness and itching, and 1 for allergic symptoms 2 patients in the bimatoprost group exited early: 1 for blurry vision and 1 for ocular redness and lid erythema Both study medications were well tolerated. Ocular redness was the most commonly reported adverse event in each treatment group. Note for presenter This was a randomized, investigator-masked, parallel-group clinical trial. After washout of previous glaucoma medications, patients were randomized to receive once-daily bimatoprost or travoprost for 6 months. Study visits were at baseline, week 1, and months 1, 3, and 6. IOP was measured at 9 AM at each visit and also at 1 PM and 4 PM at baseline and months 3 and 6. Mean baseline IOP at 9 AM was 24.6 mm Hg in the bimatoprost group and 24.4 mm Hg in the travoprost group. Both study medications were well tolerated and ocular redness was the most commonly reported adverse event in both treatment groups. Reference Cantor LB, Hoop J, Morgan L and all Bimatoprost-Travoprost Study Group. IOP-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in patients with glaucoma or ocular hypertension. Br J Ophthalmol. In press. Cantor et al. Br J Ophthalmol. In press. 71

Bimatoprost (Lumigan 0.03%) Lowers IOP 30-33% Favorable lowering of IOP with lumigan vs xalatan Side effects 15-45% hyperemia 15% ocular pruritis 45% Eyelash growth CME rare

Bimatoprost and Timolol 12-Month Study Bimatoprost QD (n = 474) Timolol BID (n = 241) *P < .010 vs timolol Target IOP (mm Hg) Percentage of Patients Reaching Target IOP at 10 AM, Month 12 ≤ Target Pressures at Month 12 * 2 5 9 16 26 37 47 61 69 7 12 21 31 58 77 85 10 20 30 40 50 60 70 80 90 13 14 15 17 18 19 This slide shows the percentage of patients that achieved target pressures less than or equal to 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm Hg at 10 AM (peak timolol effect) at month 12 in the pooled phase 3 trials of bimatoprost versus timolol. Percentage of patients achieving low target pressures. 85% of bimatoprost QD patients and 69% of timolol patients (P < .001) achieved target pressures of less than or equal to 20 mm Hg 77% of bimatoprost QD patients and 61% of timolol patients (P < .001) achieved target pressures of less than or equal to 19 mm Hg 69% of bimatoprost QD patients and 47% of timolol patients (P < .001) achieved target pressures of less than or equal to 18 mm Hg 58% of bimatoprost QD patients and 37% of timolol patients (P < .001) achieved target pressures of less than or equal to 17 mm Hg 47% of bimatoprost QD patients and 26% of timolol patients (P < .001) achieved target pressures of less than or equal to 16 mm Hg 31% of bimatoprost QD patients and 16% of timolol patients (P < .001) achieved target pressures of less than or equal to 15 mm Hg 12% of bimatoprost QD patients and 5% of timolol patients (P < .001) achieved target pressures of less than or equal to 14 mm Hg 7% of bimatoprost QD patients and 2% of timolol patients (P < .001) achieved target pressures of less than or equal to 13 mm Hg Reference Higginbotham EJ, Schuman JS, Goldberg I, et al for the Bimatoprost Study Groups 1 and 2. One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension. Arch Ophthalmol. 2002;120(10):1286-1293. Higginbotham et al. Arch Ophthalmol. 2002. 73

Additive IOP-Lowering Effect Additional Intraocular Pressure Lowering (mm Hg) Alpha Agonist Beta-blocker TCAI -0.5 -1 N=23 N=25 -1.5 -2 N=25 -2 -2.5 -2.5 -3 -3.5 -4 -3.9 -4.5 O’Connor DJ, et al. Am J Ophthalmol. 2002; 133(6): 836-7. 74

Nocturnal Efficacy: Timolol vs. Latanoprost PURPOSE: To compare the nocturnal effects of once-daily timolol and latanoprost on IOP DESIGN: Prospective, open-label, crossover study METHODS: 18 patients received topical treatments with timolol (0.5%), latanoprost (0.005%), and no IOP-lowering medication, for at least 4 weeks At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hrs and IOP was measured every 2 hrs using a pneumotonometer Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395. 75

Timolol: Nocturnal IOP Sitting Supine Sitting Habitual IOP (mm Hg) N=18 Error bars = SEM Clock Time Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395. 76

Can There be Too much Prostaglandin? Alverado, J; Oct 2009 UCSF Laboratory Analysis of Effect of SLT on Trabecular Outflow SCE’s were exposed to six different IOP lowering drugs and SLT/TME’s The junction assembly/dissassembly was monitored by confocal flourescent time lapse microscopy Latanaprost, bimatoprost & Travaprost shared a common mechanism of action with SLT Widening of the paracellular pathways Induction of intercellular junction dissassembly Decreased transepithelial flow across SCE’s Clinical impact: TME’s play a critical role in regulating SCE’s Non-Competing IOP agents may improve IOP spot SLT

Packaging for ZIOPTANTM (tafluprost ophthalmic solution) Key Point: This slide shows the packaging for ZIOPTAN (tafluprost ophthalmic solution) 0.0015%. 78

What Is ZIOPTANTM (tafluprost ophthalmic solution) 0.0015%? Key Points: ZIOPTAN is a fluorinated analog of prostaglandin F2α indicated for reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. ZIOPTAN is dosed once daily in the evening. ZIOPTAN does not contain a preservative. 79

12-Week Study Evaluating ZIOPTANTM (tafluprost ophthalmic solution) vs Preservative-Free Timolol: Study Design1 Key Points This study was a randomized, double-masked, active-controlled, parallel-group, multinational, multicenter, phase III study in patients (N=643) with primary open-angle glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, or ocular hypertension. The primary hypothesis of the study was that the efficacy of once-daily tafluprost 0.0015% would be noninferior to that of twice-daily timolol 0.5% up to 12 weeks of treatment. The primary efficacy analysis was mean change from baseline of IOP based on worse eye at all 9 time points during the study (8 AM, 10 AM, and 4 PM at weeks 2, 6, and 12). Patients were randomized to treatment with either ZIOPTAN (n=320) once daily (with preservative-free vehicle to match) or preservative-free timolol maleate 0.5% (n=323) twice daily for 12 weeks. IOP=intraocular pressure. 1. Chabi A et al. Am J Ophthalmol. 2012 Feb: In Press. 80

ZIOPTANTM (tafluprost ophthalmic solution) Delivered Powerful IOP Reductions Up to 12 Weeks1,2 Key Points: A randomized, double-masked, active-controlled, parallel-group, multinational, multicenter, phase III study in patients (N = 643) with POAG, pigmentary glaucoma, pseudoexfoliation glaucoma, or OHT. The per-protocol population included patients who received at least 1 dose of study treatment, had at least 1 efficacy measurement available, and did not commit any protocol violations expected to substantially alter efficacy results. A total of 31 patients were excluded from the per-protocol population used for the primary efficacy analysis, 21 in the PF tafluprost group and 10 in the PF timolol group. Patients taking ZIOPTAN exhibited decreases in IOP at all efficacy time points (measurements below were taken at 8 AM, 10 AM, and 4 PM, respectively): Mean baseline ZIOPTAN: 26.1, 24.8, and 23.8 mmHg Preservative-free timolol: 26.0, 24.6, and 23.5 mmHg Week 2 reductions ZIOPTAN: 7.2, 6.8, and 6.3 mmHg Preservative-free timolol: 6.8, 6.1, and 5.2 mmHg Week 6 reductions ZIOPTAN: 7.3, 7.1, and 6.5 mmHg Preservative-free timolol: 7.4, 6.6, and 5.4 mmHg Week 12 reductions ZIOPTAN: 7.5, 7.1, and 6.4 mmHg Preservative-free timolol: 7.5, 6.6, and 5.6 mmHg ANCOVA analysis showed that the noninferiority criterion of 1.5 mmHg for the upper limit of the 95% CI (for the difference in IOP between ZIOPTAN and preservative-free timolol) was achieved by ZIOPTAN at all 9 time points over 12 weeks of therapy (range of the upper limits was –0.4 to 0.6 mmHg). IOP=intraocular pressure; OHT=ocular hypertension; PF=preservative-free; POAG=primary open-angle glaucoma. 1. Chabi A et al. Am J Ophthalmol. 2012 Feb: In Press. 2. Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package OPHT-1027523-0000. 81

82 Substantial IOP Lowering Was Demonstrated Throughout the Day1,2 Key Points: Patients taking ZIOPTANTM (tafluprost ophthalmic solution) exhibited decreases in IOP at all efficacy time points. Mean baseline IOP: Mean (SD) IOP at baseline was 24.9 (2.8) mmHg in the PF tafluprost group and 24.7 (2.5) mm Hg in the PF timolol group. Percentage reductions for preservative-free timolol at 12, 14, and 20 hours postdose Week 2: 26%, 25%, 22% Week 6: 28%, 27%, 23% Week 12: 29%, 27%, 24% PF tafluprost was noninferior to PF timolol at all timepoints. IOP=intraocular pressure; PF=preservative-free; SD=standard deviation. 1. Chabi A et al. Am J Ophthalmol. 2012 Feb: In Press. 2. Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package OPHT-1027523-0000. 82

Demonstrated Safety Profile Key Points: This slide presents pooled safety data from 905 patients enrolled in 5 trials of both preservative-containing and preservative-free tafluprost of up to 24 months’ duration. The most common adverse reaction observed in patients treated with tafluprost was conjunctival hyperemia, which was reported in 4% to 20% of patients. Other adverse events that occurred at an incidence of ≥2% in these studies included ocular stinging/irritation, ocular pruritus including allergic conjunctivitis, cataract, dry eye, ocular pain, eyelash darkening, growth of eyelashes, and blurred vision. 83

Cholinergics Cholinergics are bound by melanin and may need a high concentration to affect darker irides Anticholinesterases have similar effects to cholinergics These medications facilitate outflow via the trabecular meshwork Echothiophate iodine may prolong the effects of succinylcholine

Cholinergics Generally contraindicated in synechial angle closure, neovascular glaucoma Uveitic glaucoma, retinal detachment of peripheral breaks Pilocarpine pregnancy category C Anticholinesterases contraindicated in pregnant women

Cholingegics Cholinergics Cholinesterase Inhibit Mixed Pilocarpine HCL 0.25%-10% Pilocarpine nitrated 1%, 2%, 4% Pilocarpine ocuserts 20%, 40% Cholinesterase Inhibit Echothiophate 0.03%, 0.06% 0.125% Demecarium 0.125%, 0.25% Mixed Carbachol 0.75%,1.5%, 2.25%, 3.%

Pilocarpine Low concentrations deepen chamber High concentrations may cause pupillary block Increase axial length of the lens, shallows AC Induce myopia Decrease uveosclearl outflow

Pilocarpine Cilary block (malignant) glaucoma is worsened with miotis Increase permeability of blood aqueous barrier Increase post-op inflammation Need higher concentration in pigmented irides Max effect occurs in 2 hours last 8 hours; 12-15 hr still 14-15% reduction in IOP

Pilo toxicity-Wet Salivation Lacrimation Sweating Vomiting/diarrhea Pulmonary edema/death Makes Parkinsons disease worse (more acetylcholine than dopamine) 10 ml 1% pilocarpine, 100mg is dangerous

Ocular Side Effects Conj hyperemia/follicle Miosis Brow aches Epitheliopathy Myopia Shallowing of the AC Iritis Pupillary cysts Lens opacities Retinal detachment Pemphigoid type reaction

Systemic side effects Diarrhea Bradycardia Tearing Salivation Nausea Diaphoresis Cramps