1. Evidence-Based Glaucoma Therapy Paul Palmberg, MD, PhD Bascom Palmer Eye Institute, University of Miami What is the Role of Medical Therapy in Reaching Target Pressures? XIV Jornadas Dr. Benjamin Boyd Sociedad Panameña de Oftalmologia Panama, R.P. 2003

2. Drug Class Proposed Mechanism of Action Cholinergic agonists  2 -Adrenergic agonists  2 -Adrenergic antagonists  2 -Adrenergic agonists Carbonic anhydrase inhibitors Prostaglandin F 2  derivatives Ciliary muscle contraction (facilitating uveoscleral outflow and trabecular outflow) Inhibition of aqueous production by the ciliary epithelium Inhibition of aqueous production by the ciliary epithelium ± increasing uveoscleral outflow Increased uveoscleral outflow Increasing trabecular outflow by a mechanism that is not completely understood Inhibition of aqueous production by the ciliary epithelium IOP-Lowering Agents Adapted from Kaufman P. Presented at: Glaucoma in the 21st Century 2001.

3. Glaucoma Therapy June 2003 nOcular Hypertension (20% IOP reduction used, but lower better) Ocular Hypertension Treatment Study (OHTS) 2002 Ocular Hypertension Treatment Study (OHTS) 2002 nMild, initial POAG (35% IOP reduction in CIGTS worked well) Comparison of Initial Glaucoma Treatments Study (CIGTS) 2001 Early Manifest Glaucoma Treatment Study (EMGTS) 2002 nNormal Tension Glaucoma (30% IOP reduction recommended) Collaborative Normal Tension Glaucoma Study (CNTGS) 1999 nAdvanced POAG (35-50% reduction did best) Advanced Glaucoma Intervention Study (AGIS) 2000 Antimetabolites in Filtering Surgery Study (AFSS) 2000 Major Clinical Trials Demonstrated Better Outcomes at Lower Intraocular Pressures Than Previously Sought

4. Nature’s Experiment-Epidemiology The lower the better? nThere is a “dose-response relationship” between the IOP and the risk of VF damage nIn the general population: Baltimore Eye Study Data nEvery 3 points changes prevalence by about 50% Prevalence of POAG in Relation to Screening IOP Sommer A, et al. Arch Ophthalmol. 1991;109:1090-1095.

5. Meta-Analysis of Multiple Trials (UK, Scandinavia and USA) Percentage of patients reaching a specific target IOP Diurnal IOP atLatanoprostTimolol end of treatment(n=398)(n=318) Odds ratio  15 mm Hg27142.2*  16 mm Hg39261.8*  17 mm Hg56382.0*  18 mm Hg70551.9*  19 mm Hg83721.9*  20 mm Hg89811.9** *P <0.001 (Pearson chi-square test) latanoprost vs timolol **P <0.002 (Pearson chi-square test) latanoprost vs timolol Pharmacia. Data on file.

6. Emmerich KH. Graefes Arch Clin Exp Ophthalmol. 2000;238:19-23. Emmerich KH, et al. AAO, New Orleans, USA, 1998. Diurnal IOP Reduction at 3 Months Change in IOP From Baseline (mm Hg) (Mean ± SEM) Latanoprost (n=85) Timolol + Dorzolamide (n=90) P=0.79 0 -2 -3 -4 -5 -6 Least Square Means (ANCOVA)

7. Latanoprost vs Timolol in CACG % decrease in IOP from baseline 33% 30% 20% 20% 0 -5 -10 -15 -20 -25 -30 -35 Week 6 Week 12 Latanoprost Timolol ( Chew, on behalf of the EXACT Study Group (2001) ITT population

8. 0 10 20 30 40 50 60 70 80  15  16  17  18  19  20  21 >21 Latanoprost Timolol Latanoprost vs Timolol in CACG P<.001 P<.002 IOP (mm Hg) % patients Group Chew, on behalf of the EXACT Study Group (2001) ITT population

9. Latanoprost Efficacy in Pigmentary Glaucoma 0 1 2 3 4 5 6 7 8 Latanoprost (n=18) Timolol (n=18) 6 months 12 months Diurnal IOP reduction Change in IOP From Baseline (mm Hg) (Mean ± SEM) Mastropasqua L, et al. Ophthalmology, 1999;106:550-555. P<0.001

10. Diurnal IOP Range and Disease Progression *The ratio between the incidence of a disease symptom among individuals with a given risk factor to the incidence among those without it. Relative risk* of disease progression within 5 years 1.00 5.76 Diurnal IOP Range 3.1 mm Hg Diurnal IOP Range 5.4 mm Hg Relative Risk Asrani S, et al. J Glaucoma. 2000;9:134-142.

11. Latanoprost qd vs Dorzolamide tid and Timolol bid Over 24 Hours Orzalesi N, et al. Invest Ophthalmol Vis Sci. 2000;41:2566-2573. Circadian control of IOP IOP (mm Hg) Baselin e Dorzolamide tid Timolol bid Latanoprost qd 3 PM 6 PM 9 PM Midnight3 AM 6 AM 9 AM Noon Time (Hours) 13 15 17 19 21 23 25 0

12. Richard Parrish, II, MD, Paul Palmberg, MD, PhD, Wang-Pui Sheu, PhD, and the XLT Investigators American Journal of Ophthalmology 2003; 135:688-703 Xalatan® (latanoprost ophthalmic solution) Lumigan®† (bimatoprost ophthalmic solution) Travatan®† (travoprost ophthalmic solution)

13. OH OH OH COOCH(CH 3 ) 2 PGF 2  OH OH OH COOH LATANOPROST CH 3 Esterification Phenylsubstitution Double bond saturation 10 years Stjernschantz, IOVS, 2001

14. Latanoprost: hypothesized mechanism of action Latanoprost Latanoprost acid + ester Latanoprost acid Cornea Aqueous humour c-fos Collagen  collagen fragments  Uveoscleral flow Ciliary muscle FP receptor MMP Courtesy of Weinreb

15. Latanoprost Bimatoprost Amide group

16. Latanoprost Travoprost Flouride group

17. Study Design Recruit subjects with POAG, PXE, PG or OAOHRecruit subjects with POAG, PXE, PG or OAOH Perform washoutPerform washout Determine eligibilityDetermine eligibility Baseline diurnal curveBaseline diurnal curve Randomize to the three treatment groupsRandomize to the three treatment groups latanoprost 0.005%latanoprost 0.005% Bimatoprost 0.03%Bimatoprost 0.03% Travoprost 0.004%Travoprost 0.004%  Medication instilled daily at 8 PM 1. Parrish RK et al. Am J Ophthalmol. In press.

18. Unadjusted 8 AM Mean IOP Levels by Treatment and Visit Intent-to-Treat Population Baseline Mean IOP ± SEM (mm Hg) Week 2 Week 6 Week 12 Visits LatanoprostBimatoprostTravoprost 15 16 17 18 19 20 21 22 23 24 25 26

19. Unadjusted Mean IOP Levels by Treatment and Measurement Time at Baseline and Week 12 Intent-to-Treat Population 8:00 AM Mean IOP ± SEM (mm Hg) 12 Noon 4:00 PM 8:00 PM Measurement Times LatanoprostBimatoprostTravoprost15 16 17 18 19 20 21 22 23 24 25 26 Week 12 Baseline

20. IOP & IOP Change (mm Hg) IOP & IOP Change (mm Hg) Unadjusted Means LatanoprostBimatoprostTravoprostLatanoprostBimatoprostTravoprost (n=136) (n=138)(n=136) (n=138) 8 AM 17.0917.0317.59-8.65-8.70-7.92 Noon16.4916.1916.84-7.17-7.60-6.78 4 PM 16.7215.9816.44-6.23-6.84-6.30 8 PM 16.3015.8016.10-5.91-6.52-5.72 Diurnal16.7116.3516.81-7.00-7.33-6.72 Week 12 IOP IOP Change: Baseline to Week 12 Adapted from Parrish RK et al. Am J Ophthalmol., 2003:135:688-703 -0.05 -0.33

21. Distributions of Reductions From Baseline to Week 12 in 8 AM and Diurnal Mean IOP Levels by Treatment Intent-to-Treat Population LatanoprostBimatoprostTravoprostLatanoprostBimatoprostTravoprost 8 AM Diurnal Mean IOP Change (mm Hg) -30 -25 -20 -15 -10 -5 0 5 10 * * * * * ** * * * * * * * * * * * * * * * * * * * *

22. Percent of Patients Receiving IOP-Reducing Medication at Screening Intent-to-Treat Population Patients (%) Patients (%) Prostaglandin analogs (n=205) Carbonic anhydrase inhibitors (n=142)  -adrenergic receptor antagonists (  -blockers) (n=116) Adrenergic receptor agonists (n=55) Combination (n=14) Masked investigational medication (n=10) Cholinergic agonists (n=4) Ocular Hypotensive Medications at Screening Before randomization to:

23. Mean IOP at Screening by IOP-Reducing Medication Intent-to-Treat Population Mean IOP (mm Hg) Prostaglandin analogs (n=205) Carbonic anhydrase inhibitors (n=142)  -adrenergic receptor antagonists (  -blockers) (n=116) Adrenergic receptor agonists (n=55) Combination (n=14) Masked investigational medication (n=10) Cholinergic agonists (n=4) Ocular Hypotensive Medications at Screening

24. Distributions of Reductions From Baseline to Week 12 in 8 AM Mean IOP Levels by Treatment and Prostaglandin Therapy at Screening Intent-to-Treat Population; Post Hoc Analysis 10 No prostaglandin analog -30 -25 -20 -15 -10 -5 5 Mean IOP Change (mm Hg) 0 * * * * ** * * * * * * LatanoprostBimatoprostTravoprost Prostaglandin analog No prostaglandin analog Prostaglandin analog No prostaglandin analog Prostaglandin analog

25. Hyperemia Grading Scale 1 Based on standard photographs providedBased on standard photographs provided Four-point scaleFour-point scale  0 = none  1 = mild  2 = moderate  3 = severe Valid scores: 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0Valid scores: 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0

26. Hyperemia Grading Scale Doctor’s Assessment Adapted from Parrish RK et al. Am J Ophthalmol. 2003;145:

27. Patient’s Assessment of Hyperemia “Have you or anyone else noticed any redness in your eyes since the last visit?”“Have you or anyone else noticed any redness in your eyes since the last visit?” If yes:If yes: “To what extent does the redness bother you?” “To what extent does the redness bother you?” –not at all –small amount –moderate amount –a great deal

28. Mean Hyperemia Score by Treatment and Visit Investigators’ Assessments Baseline Mean Hyperemia Score ± SEM Week 2 Week 6 Week 12 Visits 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0LatanoprostBimatoprostTravoprost‡ ‡ ‡ P=.001, Latanoprost vs Bimatoprost.

29. Distributions of Reductions From Baseline to Week 12 in 8 AM Mean IOP Levels by Treatment and Occurrence of Hyperemia Intent-to-Treat Population; Post Hoc Analysis -30 -25 -20 -15 -10 -5 510 Mean IOP Change (mm Hg) 0 * * * * * * * * * * * * * * * * * Hyperemia No Hyperemia Hyperemia Hyperemia LatanoprostBimatoprostTravoprost

30. Patients’ Assessments of Hyperemia All Randomized Patients LatanoprostBimatoprostTravoprost Percent Reporting Any Redness in Eye(s) Visits § P<.01, Latanoprost vs Bimatoprost. 1 § P<.01, Latanoprost vs Bimatoprost. 1 || P<.03, Latanoprost vs Travoprost. 1 § Adapted from Parrish RK et al. Am J Ophthalmol. 2003;145 1. Data on file. Pharmacia & Upjohn Company, Kalamazoo, MI. §, ||

31. Summary of Efficacy Results 1 Mean IOP levels at baseline were not significantly differentMean IOP levels at baseline were not significantly different Mean IOP levels at 8 AM at week 12 were not significantly differentMean IOP levels at 8 AM at week 12 were not significantly different Mean IOP levels at week 12 were not significantly different at any time pointMean IOP levels at week 12 were not significantly different at any time point Mean diurnal IOP levels at week 12 were not significantly differentMean diurnal IOP levels at week 12 were not significantly different No racial differences in response to treatments were observed (exploratory analysis)No racial differences in response to treatments were observed (exploratory analysis) 1. Parrish RK et al. Am J Ophthalmol. 2003;135:411-417.

32. Conclusions At week 12 IOP reduction from baseline was not significantly different in patients treated with latanoprost, bimatoprost, or travoprostIOP reduction from baseline was not significantly different in patients treated with latanoprost, bimatoprost, or travoprost All 3 agents were generally well tolerated systemicallyAll 3 agents were generally well tolerated systemically Significantly fewer patients reported symptoms of ocular hyperemia with latanoprost treatmentSignificantly fewer patients reported symptoms of ocular hyperemia with latanoprost treatment Investigators reported ocular hyperemia in significantly fewer patients treated with latanoprost than with bimatoprostInvestigators reported ocular hyperemia in significantly fewer patients treated with latanoprost than with bimatoprost

33. IOP Reduction as Demonstrated in Head-to-Head Trials of PG Analogs 1 Parrish RK et al. Am J Ophthalmol. 2003;135:411-417. XLT Study: (XALATAN ® [latanoprost ophthalmic solution], Lumigan, and Travatan)—a multicenter, randomized, parallel-group, masked- evaluator trial in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) and a baseline IOP of  23 mm Hg; study drugs dosed once daily at 8 PM.

34. IOP Reduction as Demonstrated in Head-to-Head Trials of PG Analogs 1 Parrish RK et al. Am J Ophthalmol. In press. 2 Netland PA et al. Am J Ophthalmol. 2001;132:472-484. A phase III, 4-arm, randomized trial in patients with OAG or OHT; travoprost and latanoprost dosed once daily.

35. IOP Reduction as Demonstrated in Head-to-Head Trials of PG Analogs 1 Parrish RK et al. Am J Ophthalmol. 2003; 135;411-417. 2 Netland PA et al. Am J Ophthalmol. 2001;132:472-484. 3 Gandolfi S et al. Advances in Therapy. 2001;18:110-121. A multicenter, randomized, investigator-masked, parallel- group study in patients with glaucoma or OHT and a mean baseline IOP of 25.7 mm Hg; study drugs dosed once daily in the evening.

36. IOP Reduction as Demonstrated in Head-to-Head Trials of PG Analogs 1 Parrish RK et al. Am J Ophthalmol. 2003;135:411-417.. 2 Netland PA et al. Am J Ophthalmol. 2001;132:472-484. 3 Gandolfi S et al. Advances in Therapy. 2001;18:110-121. 4 Noecker RS et al. Am J Ophthalmol. 2003;135:55-63. A multicenter, randomized, investigator- masked study in patients with OHT or POAG; study drugs dosed once daily. † P<.001.

37. Mean Diurnal IOP Reductions Latanoprost Phase III vs Noecker et al UK (6 mos) n=179 Scandinavia (6 mos) n=183 IOP Reduction (mm Hg) Mean ± SEM USA (6 mos) n=128 Reduction of Diurnal IOP Japan (3 mos) n=89 Philippines (3 mos) n=30 Mexico (3 mos) n=57 Korea (3 mos) n=38 China (3 mos) n=63 Noecker (6 mos) n=136

38. Responder Rates Noecker Parrish Noecker Parrish Xal Lum Xal Tra Lum Xal Lum Xal Tra Lum > 15% 72% 89% 91.9% 91.3% 91.9% > 15% 72% 89% 91.9% 91.3% 91.9% >20% 62% 79% 86.8% 84.8% 87.5% >20% 62% 79% 86.8% 84.8% 87.5% at 8 AM at end study at 8 AM at end study

39. Achieving Target Pressures Xalatan Travatan Lumigan Xalatan Travatan Lumigan 13 mm Hg 11% 12% 10% AGIS13 mm Hg 11% 12% 10% AGIS 14 mm Hg 19% 19% 18%14 mm Hg 19% 19% 18% 15 mm Hg 27% 26% 29%15 mm Hg 27% 26% 29% 16 mm Hg 40% 33% 43%16 mm Hg 40% 33% 43% 17 mm Hg 52% 46% 59% CIGTS 18 mm Hg 65% 60% 68%18 mm Hg 65% 60% 68% 19 mm Hg 77% 72% 77%19 mm Hg 77% 72% 77% 20 mm Hg 84% 80% 82%20 mm Hg 84% 80% 82% 21 mm Hg 90% 83% 90%21 mm Hg 90% 83% 90%

40. More Aggressive Medical Therapy nAdvanced Glaucoma Intervention Study (AGIS) supports a 35-50% IOP reduction nCollaborative Normal-Tension Glaucoma Study (CNTGS) supports a 30% IOP reduction nComparison of Initial Glaucoma Treatment Study (CIGTS) supports a 35% IOP reduction and EMGT would seem to support more aggressive control. nOcular Hypertension Treatment Study (OHTS) supports a 20-30% IOP reduction

41. IOP vs 5 Yr Risk of Progression