Glaucoma Pharmacology A-Z

Transcription

1 GLAUCOMA PHARMACOLOGY A-Z ERIC E. SCHMIDT, O.D., F.A.A.O. Building-block approach to medical therapy Establish the strongest foundation prior to resorting to adjunctive therapy OMNI EYE SPECIALISTS WILMINGTON, NC SELECTING THERAPY Goals of primary therapy Achieve lowest IOP on monotherapy High response rate few to no nonresponders Maintain consistent IOP lowering Obtain patient compliance and adherence by meeting their goals and expectations 2 Eric E. Schmidt, O.D. Wilmington, Disclosures NC Aerie Advisory Board Allergan Consultant, Advisory Board Sun Pharmaceuticals Advisory Board AMO Consultant, Advisory Board Optovue Consultant/Speaker bureau B & L Advisory Board/Speaker bureau Glaukos Consultant Sensimed Advisory Board PROSTAGLANDIN ANALOGS Lower IOP by enhancing uveoscleral outflow They also reduce episcleral venous pressure PGAs work by causing up to a 26% reduction in resistance to outflow Breaks down collagen in the uveoscleral meshwork Create new channels for outflow

2 7 PGA CONJUNCTIVAL HYPEREMIA QHS dosing Long duration of action Flatten diurnal curve PGAs have an effect on EP receptors which are vasodilators The stronger the drug binds to that receptor the more pronounced the vasodilation effect will be Oh Really!! Effective on trough and peak IOP No systemic side effects Little tachyphylaxis Glaucoma Pharmacology hyperemia effect? A-Z Will switching from PGA to another decrease the PROSTAGLANDINS 27 Bimatoprost (Lumigan).% Iris pigmentation Is it reversible? Latanoprost (Xalatan) Is it pre-cancerous? Travaprost, Travaprost Z (Travatan, Travatan Z) Zioptan(tafluprost) PROSTAGLANDIN SIDE EFFECTS Xalatan 6mths 2mths Travatan 2 mths 2mths Vyzulta?? Xelpros?? SO? 9 PROSTAGLANDIN SIDE EFFECTS 2 OTHER PROSTAGLANDIN SIDE EFFECTS Conjunctival hyperemia: Severe hyperemia Lumigan 3.5% Travatan.5% Xalatan <% Rescula % Is this a transient phenomenon? Is it an allergic conjunctivitis? Is it worth stopping the drop? CME Uveitis Reactivation of HSK Hypertrichosis Periorbital skin darkening Periorbital fat atrophy One must take into consideration the benefits of low IOP with the risks of the side effects

3 Glaucoma Pharmacology 2 6 A-Z 2 PROSTAGLANDINS Oh sure, we know they are good, but just how good are they? 2 Average IOP drop of 3% Improved compliance Excellent safety profiles In general, PGAs are the initial therapy of choice. 6 Percentage of Patients Reaching Target IOP at AM, Month 2 7 Mean (SEM) IOP at AM (mm Hg) BIMATOPROST AND TIMOLOL 2-MONTH STUDY 7 2 Target Pressures at Month 2 Timolol BID (n = 2) Bimatoprost QD (n = 7) P <. vs timolol Target IOP (mm Hg) Higginbotham et al. Arch Ophthalmol. 22. BIMATOPROST AND TIMOLOL EFFICACY OVER YEARS Mean IOP Across Months Month Williams et al. AGS Timolol BID (n = 35) Bimatoprost QD (n = 7) P Mean (SEM) IOP (mm Hg) 5 BIMATOPROST AND TIMOLOL 2-MONTH STUDY Mean IOP at Month Timolol BID (n = 2) 2 Bimatoprost QD (n = 7) P <. vs timolol Baseline mean IOP comparable between groups Timolol: 25., 2., 23.2, 22. ( AM, 2 PM, PM, PM; mm Hg) Bimatoprost: 26., 2.7, 23., 22. ( AM, 2 PM, PM, PM; mm Hg) AM AM 2 AM 2 PM PM 6 PM PM Time of Day Higginbotham et al. Arch Ophthalmol. 22. CLINICAL COMPARISON TRIALS OF THE ONCE-DAILY LIPIDS Evaluation of intra-class differences in efficacy and safety Seven published, prospective, randomized, investigatormasked, parallel-group studies Trials varied in duration, patient selection and characteristics, and methods of data analysis

4 9 BIMATOPROST AND TRAVOPROST Parrish et al, 23 Noecker et al, 23 Cantor et al, 25 Sponsor Pfizer Allergan Allergan Length 2 weeks 3 months 6 months n = 36 n = 6 n = 76 Glaucoma n = 3 n = 5 n Pharmacology = A-Z 2 Bimatopr ost Travopros t (.%) Latanopro st n = 36 Parrish et al also included study arm with bimatoprost (n = 36). Study population comprised of African-American patients. Parrish et al. Am J Ophthalmol. 23; Noecker et al. Adv Ther. 23; Cantor et al. B J Ophthalmol. 26. Mean IOP (mm Hg) BIMATOPROST AND TRAVOPROST: 2-WEEK STUDY Mean IOP at Week 2 2 travoprost group (P =.326) Travoprost (n = 3) Bimatoprost (n = 36) Baseline mean IOP comparable between groups Travoprost: 25.5, 23., 22., 22. ( AM, 2 PM, PM, PM; mm Hg) Bimatoprost: 25.7, 23., 22., 22.3 ( AM, 2 PM, PM, PM; mm Hg) AM 2 PM PM PM Time of Day 22 BIMATOPROST AND TRAVOPROST: 6-MONTH STUDY Percentage of Patients Achieving 2% IOP Reduction at 9 AM 6 Response Rate at Month 6 P =.5 7 Bimatoprost (n = 7) BIMATOPROST AND TRAVOPROST: 6-MONTH 23 SAFETY RESULTS 63 Travoprost (n = 7) Cantor et al. Br J Ophthalmol. In press. Both medications were well tolerated Most common adverse event: ocular redness 6 patients (2.%) in the bimatoprost group and 2 patients (.%) in the Ocular itching reported for 7.% of travoprost patients and 2.3% of bimatoprost patients (P =.27) Treatment-related adverse events leading to patient discontinuations patients in the travoprost group exited early: for lack of efficacy, 2 for ocular redness and lid erythema, for ocular dryness and itching, and for allergic symptoms 2 patients in the bimatoprost group exited early: for blurry vision and for ocular redness and lid erythema Parrish et al. Am J Ophthalmol. 23. Cantor et al. Br J Ophthalmol. In press. 2 BIMATOPROST AND TRAVOPROST: 6-MONTH STUDY Mean IOP at Month BIMATOPROST AND LATANOPROST: 3 MONTH STUDY Mean IOP at Week Mean IOP (mm Hg) 6 2 P =.3 P =.95 P =.99 Travoprost (n = ) Bimatoprost (n = 76) Baseline mean IOP comparable between groups Travoprost: 2., 22.6, 22. (9 AM, PM, PM; mm Hg) Bimatoprost: 2.6, 22.6, 22.2 (9 AM, PM, PM; mm Hg) 9 AM PM PM Time of Day Cantor et al. Br J Ophthalmol. In press. Mean IOP (mm Hg) 6 2 Study population: previously treated patients Bimatoprost (n = 36) (approximately 5% on latanoprost at screening) Latanoprost (n = 36) Among-group differences not Baseline mean IOP comparable between groups statistically significant; consistently lower mean IOP Latanoprost: 25.7, 23.7, 23., 22.3 ( AM, 2 PM, PM, with PM; bimatoprost mm Hg) Bimatoprost: 25.7, 23., 22., 22.3 ( AM, 2 PM, PM, PM; mm Hg) AM 2 PM PM PM Time of Day Parrish et al. Am J Ophthalmol. 23.

5 BIMATOPROST AND LATANOPROST: 6-MONTH 25 STUDY Bimatoprost and Latanoprost+Timoptic-XE : 2 6-Month Study Mean (SEM) IOP (mm Hg) Mean IOP at Month 6 P <. P <. P =. Latanoprost (n = 36) Bimatoprost (n = 33) 5 Baseline mean IOP Baseline mean diurnal IOP comparable between groups Latanoprost: 2.9, 23.3, 22.5 ( AM, 2 PM, PM; mm Hg) Bimatoprost 23.5 mm Hg Glaucoma Bimatoprost: 25., 2., 22.6 ( AM, 2 PM, PM; mm Hg) Pharmacology 5 A-Z Latanoprost / timolol gel 2. mm Hg AM 2 PM PM Time of Day Mean IOP consistently lower throughout the day with bimatoprost Mean IOP (mm Hg) Mean Diurnal IOP Over 6 Months Latanoprost + Timoptic-XE (n = 2) Bimatoprost (n = 2) Day of Treatment Noecker et al. Am J Ophthalmol. 23. Manni et al. Graefe s Arch Clin Exp Ophthalmol. 2. Percentage of Patients Achieving 2% IOP Reduction BIMATOPROST AND LATANOPROST: 6-MONTH STUDY Response Rate at Month 6 Bimatoprost (n = 33) Latanoprost (n = 36) P =.3 P < P =.2 69 AM 2 PM PM Time of Day Noecker et al. Am J Ophthalmol PROSTAGLANDINS All decrease IOP by increasing uveoscleral outflow All are effective at squashing the diurnal curve They have either no effect or a positive effect on retinal perfusion But does work better than the others? 27 BIMATOPROST AND LATANOPROST: 6-MONTH SAFETY RESULTS 3 IOP REDUCING EFFECT Most common side effects: According to package inserts: Hyperemia (bimatoprost.%; latanoprost 2.6%) Latanoprost 6.7mm Similar rates of discontinuation due to AEs Bimatoprost:.5% overall; 2.3% for hyperemia Bimatoprost.mm Travaprost 7.mm Latanoprost: 3.7% overall;.% for hyperemia Uveitis: One patient in latanoprost group; no cystoid macular edema Noecker et al. Am J Ophthalmol. 23.

6 3 XLT STUDY PARRISH, PALMBERG, ET. AL. (AJO, MAY 23, VOL. 35, 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. ANOTHER WAY TO LOOK AT EFFICACY: % of IOP reduction Latanoprost 27% Unoprostone 5% Bimatoprost 33% Travaprost 2% Latanoprost exhibited greater ocular tolerability FYI: Timolol 2% 3 Bimatoprost 6% WHAT IS THEIR ABILITY TO LOWER IOP <7MM? Latanoprost 9.5% of pxs Travaprost 56.3% LOOK AT THEIR FAILURE RATE: Percent of pxs who didn t reach their target IOP Latanoprost % Bimatoprost- 6% Travaprost % SO?

7 37 WHAT IF: DROP STUDY MEYER, 2 A patient failed on Xalatan? If switched to Lumigan, 57% achieved target IOP If switched to Travatan, 5.5% achieved target IOP SO?- Are all prostaglandins really created equal? BOURNIAS, ET.AL, JOURNAL OF OCULAR PHARMACOLOGY (23) Replaced Xalatan w/ Lumigan Results: 3 IOP <5mm dropped from % to 36% IOP <mm dropped from 33% to 66% Mean IOP decrease of 3.mm 39 ARE GENERICS REALLY AS GOOD AS BRANDED PRODUCTS? 2 WHAT ELSE IS NEW? Zioptan (Trafluprost) Merck WHAT ABOUT WHEN IT COMES TO PROSTAGLANDINS? Unit dose vial QHS dosing Unpreserved Studies show 6- mm Hg drop in IOP from baseline of 2-26 Excellent safety profile

8 3 CLINICAL THOUGHTS ON ZIOPTAN Definite a kinder, gentler PGA Unit dose vials a perceived benefit How does it compare to the other PGAs?? Compliance enhanced? How is it different?? Glaucoma Pharmacology How is it better?? A-Z IOP decrease not as robust as other PGAs VYZULTA LATANOPROST BUNOD.2% Nitric-oxide donating PGA B & L QD dosing Reduces IOP mm- superior to timolol FINAL PROSTAGLANDIN VYZULTA THOUGHTS They are additive to other G drugs but not with each other Travatan and Lumigan maintain target IOP 36hrs after Canal and t.m. instillation and significant IOP drop up to hrs after instillation Does one really work better than the others on African Americans? What about BID dosing? Adding NO donor increases outflow through Schlemm s Increases relaxation of these tissues Non-inferior to timolol (LUNAR Study) However nearly twice as many eyes had IOP lowered >25% as compared to timolol 5 A new PGA coming SOON!!! Latanoprostene bunod.2% Nitric oxide donating prostaglandin F2-alpha analog drop QHS Nicox (marketed by B&L) Vyzulta available 2?? VYZULTA MEDEIROS ET AL AJO, 26 Additional.2mm lowering of nocturnal IOP Hyperemia rate-9% Eye irritation 7.2%

9 LBN AND OPP LBN exhibited better ocular perfusion pressure than timolol, especially at night!!! Better IOP reduction at night as well Liu et al, AJO 26 LATANOPROSTENE BUNOD (LBN) Phase 2 study Head to head study vs Xalatan 5 3 patients LBN consistently lowered IOP in a dose-dependent manner Significantly lower IOP than Xalatan at day 2 (also at day 7 and ).9mm Hg lower at all time points Slightly higher hyperemia rate 53 BETA-BLOCKERS 3 year history of successfully lowering IOP Reduces aqueous humor formation Adrenergic agonists Lowers IOP 22-2% Ocularly well tolerated ONE MORE NEW PGA!! 5 BETA-BLOCKERS Xelpros (Sun Pharmaceuticals) Latanoprost BAK-free drops New delivery option Multi dose bottle Similar in efficacy to latanoprost Has not been compared to Xalatan What about side effect profile? What about cost? Timolol maleate Timoptic, Timoptic XE (/2, / %) Carteolol Ocupress % (Intrinsic sympathomimetic activity) Levobunolol Betagan ½% Timolol hemihydrate Betimol ¼, ½% Istalol ¼,/2% - QD dosing indication Betaxolol ¼% - cardioselective, safer?

10 55 BETA-BLOCKER SIDE EFFECTS 5 BETA-BLOCKER SIDE EFFECTS Respiratory- Fatigue, bronchospasm, SOB! Cardiac Lethargy, bradycardia, lower pulse rate Confusion CNS depression- Impotence Impotence, confusion Depression But how common are they? Glaucoma Pharmacology General decreased affect A-Z CNS Often overlooked ACID Anxiety Diabetic problems Decreased sense of caloric need due to depressed adrenergic surge LAMA STUDY (AJO /2) Conclusions:...identifies no scientific studies supporting the development of worsening claudication, depression, hypoglycemia,sexual dysfunction 56 or impaired neuromuscular transmission Recommends careful medical history and checking pulse rate and rhythm So? 59 BETA-BLOCKER SIDE EFFECTS 22% of pxs have contraindication to or significant side effect from beta-blocker Question, query and query some more! Be specific Remember the dose relationship so: ¼% rather than ½% QD rather than BID They are real (may be anecdotal) 57 BETA-BLOCKER SIDE EFFECTS Cardiac problems Respiratory problems Bradycardia Bronchospasm Hypotension Status asthmaticus Exercise intolerance Heart block THE BIGGEST PROBLEM WITH TOPICAL BETA-BLOCKERS? Decreased Perfusion To The Optic Nerve Head!! Especially At Night!!

11 6 BETA-BLOCKER DEBATE Mechanism of Action of Brimonidine- 6 PURITE Are they still useful? As initial therapy? QD or BID?.25% or.5%? Gel or drop? Monocular therapy? How bad are the side effects really? Do systemic beta-blockers affect the efficacy of the drops? Complements PGAs because it decreases aqueous production Complements timolol because it increases uveoscleral outflow Tell me something good about beta-blockers! ADRENERGIC AGONISTS COMPARISON Dual mechanism of action. Reduce aqueous production Concentration Enhance outflow mechanisms 22-2% IOP reduction Short duration of action TID dosage Avoid in kids BRIMONIDINE FORMULATION 65 of Brimonidine ALPHAGAN P ALPHAGAN.%.5%.2% ph Preservative PURITE BAK Viscosity agent Electrolytes Carboxymethylcellulo se Potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate Polyvinyl alcohol BRIMONIDINE: DUAL 63 MECHANISM OF IOP LOWERING 66 BENZALKONIUM CHLORIDE (BAK) Enhances uveoscleral outflow Suppresses aqueous humor production (inflow) Most commonly used preservative in glaucoma products BAK can accumulate and remain in ocular tissue Has been shown to cause cytotoxic effects on the ocular surface in numerous studies (DeSaint, 2; Gasset et al, 97; Noecker, 2) Toris et al. 995 and 999. DeSaint et al. Curr Eye Res. 2; Gasset et al. Am J Ophthalmol. 97; Noecker et al. Cornea. 2.

12 PURITE IS A GENTLE PRESERVATIVE 67 MEAN IOP AT TROUGH ( AM) 7 SEM of rabbit corneal epithelium (X) 2 Glaucoma Pharmacology 6 A-Z Untreated PURITE QID 7 days BAK QID 7 days The clinical significance of these data is unknown. Way et al. Invest Ophthalmol Vis Sci. 2. Aqueous Humor Concentration in Rabbits - -2 OCULAR BIOAVAILABILITY OF BRIMONIDINE IN 6 DIFFERENT FORMULATIONS Brimonidine-PURITE.5% formulation shows bioavailability in the aqueous humor comparable to brimonidine.2% BAK C max (μg/ml).5 ALPHAGAN P.5% Brimonidine.5% BAK ALPHAGAN P =. vs brimonidine.5% BAK The clinical significance of these data is unknown. Mean IOP (mm Hg) Brimonidine-PURITE.5% (N = 372) Brimonidine.2% (N = 376) Months of treatment Original ALPHAGAN MEAN CHANGE FROM BASELINE AT MONTH 2 7 Mean IOP reduction (mm Hg) AM AM PM Brimonidine.2% (n = 2) Brimonidine-PURITE.% (n = 25) Katz. J Glaucoma. 22. P =.3 vs brimonidine.2% Baseline IOP AM: ALPHAGAN 2.7 mm Hg; ALPHAGAN P.% 2.7 mm Hg, P =.96 AM: ALPHAGAN 23.3 mm Hg; ALPHAGAN P.% 23. mm Hg, P =.636 PM: ALPHAGAN 22. mm Hg; ALPHAGAN P.% 22.6 mm Hg, P =.26 ALPHAGAN P.% demonstrates IOP-lowering efficacy equivalent to ALPHAGAN.2% over 2 months Dong et al. J Ocul Pharmacol Ther. 2. MEAN IOP AT PEAK ( AM) 69 Mean IOP (mm Hg) Brimonidine-PURITE.5% (N = 372) Brimonidine.2% (N = 376) Months of treatment Original ALPHAGAN Katz. J Glaucoma. 22. ADVERSE EVENTS TYPICALLY ASSOCIATED WITH BRIMONIDINE 72.2% ARE LOWER WITH BRIMONIDINE- PURITE.5% Percentage of patients Brimonidine-PURITE.5% (n = 3) Brimonidine.2% (n = 33) Allergic Conjunctivitis Oral Dryness Conjunctival Hyperemia Eye Discharge P <.25 Somnolence Original ALPHAGAN Katz. J Glaucoma. 22.

13 BRIMONIDINE-PURITE.5% HAS 73 SIGNIFICANTLY LOWER INCIDENCE OF OCULAR ALLERGY 76 ALPHAGAN SYSTEMIC SIDE EFFECTS Percentage of patients 6 2 P =.7 vs brimonidine.2% Dry mouth (~2%) Fatigue (-2%) % less allergy Drowsiness Decreased BP 6 2 This drug can cross blood-brain barrier, esp in older and younger pxs Brimonidine-PURITE.5% Brimonidine.2% (n = 3) (n = 33) Original ALPHAGAN Katz. J Glaucoma. 22. Ocular surface exposed to 5% less drug with new formulation EFFECT OF BRIMONIDINE-PURITE.% FORMULATION 7 ON SAFETY Less allergy, redness, irritation Lower concentration also means fewer systemic effects as less drug enters nasolacrimal duct 77 BRIMONIDINE QUESTIONS What is the correct dosage? Which of the 3 products should be prescribed? Can it be used as stand alone therapy? Effect on diurnal curve? What Happens If Hypersensitivity To.2% Brimonidine Occurs? Katz. J Glaucoma BRIMONIDINE SIDE EFFECTS 7 NEUROPROTECTION??? -2% Hyperemia Allergic conjunctivitis Ocular pruritis 5-9% burning sensation, conjunctival folliculosis, ocular allergic reaction, oral dryness, visual disturbance Do these worsen with time? How do you know if the drops are the culprit? Does it really exist? Does Alphagan promote neuroprotection?

14 79 FEKE ET AL, AJO 2 2 ALPHAGAN ALSO HAS A SHORT DURATION OF ACTION Effect of brimonidine on retinal vascular autoregulation and short-term visual function in NTG So what does this mean clinically?? FEKE STUDY Identified NTG pxs who had retinal blood flow changes upon postural change Those pxs were placed on Alphagan P.5% x weeks then retested /7 demonstrated an improvement in postural induced retinal blood flow This did not show improvement in visual function 3 CARBONIC ANHYDRASE INHIBITORS Lower IOP by reducing aqueous production Reduce IOP by 6-22% Sulfa drugs!! Dosage question BID or TID? Are they useful as stand alone drugs? BRIMONIDINE MAY NOT WORK AT NIGHT CAI DIRECTORY Fan et al, J Glaucoma 2; 23(5) Trusopt Dorzolamide 2% Increased uveoscleral meshwork outflow during day with corresponding IOP reduction Drug has no effect on aqueous outflow, episcleral venous pessure or outflow facility There is a dramatic reduction in uveoscleral outflow at night Azopt - Brinzolamide % Oral CAI Acetazolamide Diamox 25, 5mg Methazolamide 25, 5mg

15 5 CAI SIDE EFFECTS COMPANION STUDY #2 Stinging Dryness HA Bad taste When compared to brimonidine 2% adding them to Travaprost... IOP lowered by 3% w/ brimonidine IOP lowered by 23% w/ brinzolamide Sulfa drug so: Aplastic anemia? Renal stones? What about Cosopt? ORAL CAI SIDE EFFECTS Paresthesia Stewart et al, 26 Depression 6 Kidney stones Metallic taste Diarrhea Aplastic anemia 9 COMPANION STUDY #3 Compared to timolol.5% as additive to travaprost No difference at all between the 2 drugs CAI is effective at controlling night IOP spikes (TID?) These are virtually non-existent with drops 7 CAI MAKE WONDERFUL PARTNERS 9 ORAL CAI Feldman, et al 26 Is there still a place for them?.5-. mm lower IOP as compared to brimonidine.5% when added to travaprost This significance was present at all time points What is the correct dosage? BID dosing Are there precautions we need to take?

16 9 COMBINATION DRUGS Mean IOP AM 9 Brimonidine/timolol fixed combination Cosopt timolol-dorzolamide Timolol ½%, Dorzolamide 2% This drop works better than either timolol or dorzolamide does on their own Cosopt is not as effective as if you were using both 2 Brimonidine TID (n = 32) timolol and dorzolamide Same side effects as beta-blockers and CAIs Glaucoma Pharmacology A-Z Capice? Kapeesh? 2 COMBIGAN 92 (Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution).2%/.5% Fixed combination of brimonidine and timolol Alpha-agonist brimonidine Beta-blocker timolol Preserved with.5% benzalkonium chloride (BAK) Generic timolol is preserved with.% Complementary mechanisms of action Timolol BID (n = 392) Brimonidine/timolol BID (n = 35) P <. vs brimonidine or timolol Months of treatment Brimonidine and timolol monotherapies are approved for first line therapy. Statistical significance does not necessarily correlate to clinical significance. Sherwood et al. Arch Ophthalmol. 26; 2 Data on file, Allergan, Inc. DIURNAL MEAN IOP AT MONTH 2 Mean IOP (mm Hg) Dose all treatments Brimonidine (n = 32) Timolol (n = 392) Fixed brimonidine/timolol (n = 35) Dose brimonidine P <. vs timolol P <. vs brimonidine AM 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. 26. BRIMONIDINE/TIMOLOL COMBINATION 93 HAS DUAL MECHANISM OF ACTION TREATMENT-RELATED ADVERSE EVENTS 96 No Outflow Effect Inflow and Outflow Effect Timolol Brimonidine Aqueous Production Aqueous Production Uveoscleral Outflow Percentage of patients Fixed Brimonidine/Timolol BID (n = 35) Brimonidine.2% TID (n = 32) Timolol.5% BID (n = 392) P.3 vs brimonidine.2% TID P.2 vs timolol.5% BID Neufeld et al. Surv Ophthalmol. 93; 2 Toris et al. Arch Ophthalmol. 995; 3 Toris et al. Am J Ophthalmol. 999; ALPHAGAN P Prescribing Information. Conjunctival hyperemia Ocular stinging Eye pruritus Allergic Conjunctival conjunctivitis follicles Oral dryness Brimonidine and timolol monotherapies are approved for first line therapy. Sherwood et al. Arch Ophthalmol. 26.

17 FIXED COMBINATION VS CONCOMITANT 97 THERAPY: EQUIVALENT MEAN IOP COMBIGAN AND COSOPT AS MONOTHERAPY: MEAN IOP Mean IOP (mm Hg) Mean change from beta-blocker treated baseline IOP (mm Hg) 2 2 Fixed Brimonidine/Timolol BID (n = ) Concomitant Brimonidine BID + Timolol BID (n = 3) Hour Hour Weeks after initiating study medication from run-in monotherapy Weeks after initiating study medication from run-in monotherapy Goni et al. Eur J Ophthalmol Week 2 Week 6 Week 2 2 Hour Hour 2 Hour Hour 2 Hour Hour 2 NEXT STEP FROM A BETA-BLOCKER 9 Additional IOP lowering achieved with fixed combination after beta-blocker run-in Fixed-combination brimonidine/timolol BID (n = 2) Baseline mean IOP = 25. mm Hg (hour ); 22.7 mm Hg (hour 2) Goni et al. Eur J Ophthalmol. 25. Mean IOP (mm Hg) Mean IOP reductions from baseline at month 3 were 7.7 mm Hg with COMBIGAN and 6.7 mm Hg with Cosopt (P =.) P =. (mean change from baseline) Cosopt (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 7) COMBIGAN (brimonidine tartrate/timolol maleate ophthalmic solution).2%/.5% (n = 5) 2 3 Month Nixon and Hollander. AAO. 27; 2 Data on file, Allergan, Inc. COMBIGAN IN ADJUNCTIVE THERAPY WITH A PGA: MEAN IOP Mean IOP (mm Hg) Added to a PGA baseline Month Nixon and Hollander. 2 AAO, 27. Data on file, Allergan, Inc mm Hg (29%) COMBIGAN (brimonidine tartrate/timolol maleate ophthalmic solution).2%/.5% + PGA (n = 37) P <. vs baseline COMBIGAN and Cosopt 99 COMBIGAN and Cosopt 2 Tolerability and Comfort Randomized, investigator-masked, 3-month, parallel comparison Pooled data from 2 studies at sites with identical protocols (Canada) Patients with OAG/OHT requiring additional IOP lowering Two subgroups Monotherapy: COMBIGAN (brimonidine tartrate/timolol maleate ophthalmic solution).2%/.5% (n = 5) and Cosopt (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 7) Adjunctive: COMBIGAN added to PGA (n = 37) and Cosopt added to PGA (n = 2) IOP 2 hours after morning dose Visits at baseline, month, and 3 months Percentage of patients with rating of moderate or severe % 3% 2% % COMBIGAN (brimonidine tartrate/timolol maleate ophthalmic solution).2%/.5% (n = 5) Cosopt (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 6) % Stinging Burning Unusual taste P =. P =.9 P =.7 PGA = prostaglandin analogue Nixon and Hollander. AAO. 27; 2 Data on file, Allergan, Inc. Nixon and Hollander. 2 AAO, 27. Data on file, Allergan, Inc.

18 OCULAR COMFORT: COMBIGAN (BRIMONIDINE TARTRATE/TIMOLOL MALEATE OPHTHALMIC 3 SOLUTION).2%/.5% AND COSOPT (DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION) 6 COMBINATION DRUG #3 Percentage of subjects rating treatment as most comfortable % 6% Able to lower IOP as good as preserved, branded Cosopt n = 3 % BID So??? Glaucoma 2% Pharmacology A-Z % 3 Seconds After Drop Instillation % P <. vs Cosopt % % COMBIGAN Cosopt Treatments equally comfortable Chan et al. J Ocul Pharmacol Ther. 27. Cosopt PF Preservative free Unit dosage vial Mean ocular discomfort score 3 Seconds After Drop Instillation Simbrinza (Alcon) OCULAR DISCOMFORT: COMBIGAN (BRIMONIDINE TARTRATE/TIMOLOL MALEATE OPHTHALMIC SOLUTION).2%/.5% AND COSOPT (DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION) COMBIGAN Cosopt P <. vs Cosopt n = 3 7 COMBINATION DRUG # Brinzolamide.%/Brimonidine.2% TID Dosing Approved for adjunctive therapy Adjunctive to what?? Chan et al. J Ocul Pharmacol Ther. 27. TREATMENT-RELATED ADVERSE EVENTS 5 SIMBRINZA Percentage of patients Fixed Brimonidine/Timolol BID (n = 35) Brimonidine.2% TID (n = 32) Timolol.5% BID (n = 392) 5.2% P.3 vs brimonidine.2% TID P.2 vs timolol.5% BID 5-9 mm Hg IOP reduction Baseline IOP 22-36mm Hg 2-35% IOP reduction Conjunctival Ocular Eye Allergic Conjunctival Oral hyperemia stinging pruritusconjunctivitisfollicles dryness TID dosing Oral dryness and adverse events related to conjunctival allergy/inflammation significantly less common with fixed brimonidine/timolol than with brimonidine Sherwood et al. Arch Ophthalmol. 26.

19 9 SIMBRINZA ROCK -INHIBITORS 2 drugs in the works Aerie Compared to Azopt head-to head Rhopressa Novel molecule Compared to Brimonidine.2% head- to head Works on different receptor sites so.. Effective IOP reduction with fewer side effects Statistically superior to either of the components in No lash growth or skin darkening lowering IOP 2 3 mths Targets trabecular meshwork At all time points Roclatan combo drug Glaucoma Pharmacology Rhopressa and latanoprost A-Z Availability 27-2 SIMBRINZA SAFETY DATA Side effects are similar to each of the component drugs D/C rate % MOA Triple Action 3-5% incidence rate of: Blurred vision Ocular irritation Bad taste Dry mouth Ocular allergy RHOPRESSA (NETARSUDIL) AERIE PHARMACEUTICALS New class of drugs Rho-kinase inhibitor - relaxes trabecular meshwork similar to pilocarpine (enhances outflow) - lowers episcleral venous pressure - blocks fibrotic response at t.m.(increases perfusion) QD dosing Looks especially effective at IOP 25 mmhg or less th Quarter 27?? NEW GLAUCOMA DRUGS TAPPING THAT PIPELINE!!! Nothing New For The Past 5 Years All Of A Sudden BOOOM! Rhopressa Roclatan Vyzolta Trabodenoson Xelpros Bimatoprost -SR WHAT S TO LIKE ABOUT RHOPRESSA? New MOA so it is absolutely different It should be additive Definitely works better at lower IOP What about side effects? High rate of hyperemia -5% (% mild and transient) Conj hemorrhages % Reduced level of BAK

20 ROCLATAN AERIE BIMATOPROST SR Fixed Combination drug Rhopressa + latanoprost QD dosing Quadruple acting MOA (adds increased uveoscleral outflow) IOP lowering better than either of its components Lowers IOP over a -6 month period Potential to be very effective lowered IOP an additional 2-3 mm compared to Rhopressa (and other PGAs) Currently in Phase 3 Anticipating Late 2 release Biodegradable sustained release implant Injected intracamerally using single use applicator Implant is visible in irido corneal angle Could make a big impact on non-compliance issues ROCLATAN Phase data Proved safety and good tolerance What do we think? BIMATOPROST SR Phase 2 data Side effects- same as Rhopressa 2 weeks Place in therapy? IOP 23. in Bimatoprost group Clinical impressions 2. in timolol group Cost concerns At 6 months 2. in implant group 9. in timolol group ONE FINAL WORD ABOUT GLAUCOMA DRUGS A lot of money is being spent on delivery systems These may be cheaper alternatives Optometry cannot sleep on this BIMATOPROST SR Second study showed IOP decrease of mm Hg At month 6, 7% of subjects did not require topical IOP gtt Biggest side effect is transient hyperemia and FB sensation Implications for ODs

21 NOVEL DRUG DELIVERY SYSTEMS- THE NEXT FRONTIER 2 ERIC S 7 SIMPLE RULES FOR TREATMENT Drug Eluting Punctal Plugs. Choose 3% IOP decrease as initial target QLT latanoprost 75% -% retention rate 2. Squash the diurnal curve (Keep IOP peak <mm) Results- 3-mm drop in IOP 3. Assess risk factors for progression and rate of progression (CT<555, IOP >26,C/D.5) Ocular Therapeutix Intracanalicular latanoprost Good sustained release of drug but doesn t lower IOP as good as topical Xalatan SOOOO???? BRIMONIDINE DRUG-ELUTING PLUGS Similar technique to inserting collagen lacrimal plugs Early studies show better and more sustained IOP release ERIC S RULES CONT.. If you are going to treat; treat aggressively than latanoprost plugs 5. KISS Good safety profile SOOOO>>>??? 6. Be mindful of perfusion issues 7. Above all, do no harm IOP LOWERING WITH 26 MONOTHERAPY IS IDEAL Initial therapy with PGA can provide > 3% IOP lowering Monotherapy may reduce the risk of adverse events, drug interactions, and exposure to preservatives Monotherapy is convenient, may help patient compliance, and may have lower acquisition cost IOP = intraocular pressure PGA = prostaglandin analogue

22 PATIENTS ON MORE THAN 27 ONE IOP-LOWERING MEDICATION 3 TREATMENT PARADIGM STEP 2 Medications 69.% Medication 2 Medications 2.% 3 Medications 5.6%.2% Prostaglandins st If not successful try another agent by itself: Brimonidine bid or timolol If neither of these get IOP to desired level then add Source: Verispan s PDDA, MAT Nov 26. THERAPY In a study of ocular hypertension patients (OHTS) At month 6, % required 2 or more medications to HOWEVER, PATIENTS ON MONOTHERAPY MAY 2 NOT ACHIEVE TARGET IOP reach 2% IOP reduction In patients treated with PGAs 2 Adjunctive medication use was 3.2% with latanoprost, 23.2% with bimatoprost, and 22.5% with travoprost MANY PATIENTS REQUIRE ADJUNCTIVE 3 Ocular Hypertension Treatment Study (OHTS) 7 patients with OHT; target pressure reduction = 2% At month-6 visit, 39.7% of patients in the medical treatment group required 2 or more medications to reach the target IOP Collaborative Initial Glaucoma Treatment Study (CIGTS) 2 37 newly diagnosed patients with mild to advanced glaucoma; aggressive target pressures set per formula After first 2 years, >75% of patients required 2 or more medications to reach target IOP Even patients on the most powerful IOP-lowering medications often require adjunctive therapy 3 Kass et al. Arch Ophthalmol. 22; 2 Covert and Robin. Curr Med Res Opin Kass et al. Arch Ophthalmol. 22; 2. Lichter et al. Ophthalmology Robin et al. AGS REGARDING PROSTAGLANDINS: CONSIDER MECHANISM OF ACTION (MOA) 32 WHEN ADDING MEDICATIONS Generally the st line of treatment There are interindividual differences in efficacy Are there racial differences? If at first one fails; try, try, try again (with another prostaglandin) Why wouldn t you use a prostaglandin st? Best chance of additivity by combining medications with different mechanisms Hypotensive lipids lower IOP by increasing aqueous outflow (uveoscleral/trabecular) Complement a hypotensive lipid by adding a drug that inhibits aqueous production Brimonidine CAI Beta-blocker

23 33 TREATMENT PARADIGM, PART III The Paradigm Is Changing Be Creative Understand your options Understand what you are trying to Achieve VF Preservation and Neuroretinal Rim Preservation Be aware of side effects TREATMENT PARADIGM, PART IV If 2 meds and target IOP not met 3 What is maximum medical therapy nowadays? SLT and trabeculectomy should not be considered weapons of last choice or last chance