Glaucoma Pharmacology A-Z

11/4/2018

1 GLAUCOMA PHARMACOLOGY A-Z

ERIC E. SCHMIDT, O.D., F.A.A.O. OMNI EYE SPECIALISTS WILMINGTON, NC [email protected]

2 Eric E. Schmidt, O.D. Disclosures

Aerie – Advisory Board Allergan‐ Consultant, Advisory Board AMO – Consultant, Advisory Board B & L – Advisory Board/Speaker bureau Glaukos – Consultant Sensimed – Advisory Board Zeiss – Speaker Bureau

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4 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 • Building-block approach to medical therapy • Establish the strongest foundation prior to resorting to adjunctive therapy

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6 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

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7 PGA

• QHS dosing • Long duration of action • Flatten diurnal curve • Effective on trough and peak IOP • No systemic side effects • Little tachyphylaxis

8 PROSTAGLANDINS 2017

• Bimatoprost (Lumigan) 0.01% • Latanoprost (Xalatan) • Travaprost, Travaprost Z (Travatan, Travatan Z) • Zioptan(tafluprost)

• Vyzulta?? • Xelpros??

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9 PROSTAGLANDIN SIDE EFFECTS

• Conjunctival hyperemia: Severe hyperemia • Lumigan 3.5% • Travatan 1.5% • Xalatan <1% • Vyzulta?? • Is this a transient phenomenon? • Is it an allergic conjunctivitis? • Is it worth stopping the drop?

10 CONJUNCTIVAL HYPEREMIA

• 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!!

• Will switching from 1 PGA to another decrease the hyperemia effect?

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11 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

• SO?

12 OTHER PROSTAGLANDIN SIDE EFFECTS

• 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

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14 PROSTAGLANDINS

• Oh sure, we know they are good, but just how good are they? • Average IOP drop of 34% • Improved compliance • Excellent safety profiles

• In general, PGAs are the initial therapy of choice.

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15 BIMATOPROST AND TIMOLOL 12-MONTH STUDY Mean IOP at Month 12 24

16 * * * * Timolol BID (n = 241) 12 Bimatoprost QD (n = 474)

8 *P < .001 vs timolol

Baseline mean IOP comparable between groups 4

Mean (SEM) IOP (mm Hg) Mean (SEM) IOP Timolol: 25.8, 24.1, 23.2, 22.4 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) Bimatoprost: 26.0, 24.7, 23.8, 22.1 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) 0 8 AM 10 AM 12 AM 2 PM 4 PM 6 PM 8 PM Time of Day Higginbotham et al. Arch Ophthalmol. 2002.

16 BIMATOPROST AND TIMOLOL

12-MONTH STUDY * 90 85 Target Pressures at Month 12 * 80 77 * Timolol BID (n = 241) 69 69 70 Bimatoprost QD (n = 474) * 61 60 *P < .010 vs timolol 58 * 50 47 47 , Month 12 , Month 37 AM 40 * 31 30 * 26 21 20 * 16 IOP at 10 at IOP * 12 7 9 10 5 2 0 Percentage of Patients Reaching Target Percentage of Patients Reaching Target ≤ 12≤ 13 ≤ 14 ≤ 15 ≤ 16 ≤ 17 ≤ 18 ≤ 19 ≤ 20 Target IOP (mm Hg) Higginbotham et al. Arch Ophthalmol. 2002.

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17 BIMATOPROST AND TIMOLOL EFFICACY OVER 4 YEARS Mean IOP Across 48 Months

AM 20 * *** 16 * ** * * ** * * * * * * 12 Timolol BID (n = 35)

(mm Hg) Bimatoprost QD (n = 78) 8 *P ≤ .043

Mean (SEM) at IOP 10 4

0 0 6 12 18 24 30 36 42 48 Month Williams et al. AGS. 2005.

18 CLINICAL COMPARISON TRIALS OF THE ONCE-DAILY PGA

• Evaluation of intra-class differences in efficacy and safety • Seven published, prospective, randomized, investigator-masked, parallel-group studies • Trials varied in duration, patient selection and characteristics, and methods of data analysis

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19 BIMATOPROST AND TRAVOPROST

Parrish et Cantor et Noecker et al, al, al, 2003† 2003* 2005 Sponsor Pfizer Allergan Allergan Length 12 weeks 3 months 6 months Bimatopr n = 136 n = 16 n = 76 ost Travopros n = 138 n = 15 n = 81 t (0.004%) Latanopro n = 136 st*Parrish et al also included study arm with bimatoprost (n = 136). †Study population comprised of African-American patients. Parrish et al. Am J Ophthalmol. 2003; Noecker et al. Adv Ther. 2003; Cantor et al. B J Ophthalmol. 2006.

20 BIMATOPROST AND TRAVOPROST: 12-WEEK STUDY Mean IOP at Week 12 24

12 Travoprost (n = 138) 8 Bimatoprost (n = 136) Mean IOP (mm Hg) Mean IOP

4 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) 0 8 AM 12 PM 4 PM 8 PM Time of Day

Parrish et al. Am J Ophthalmol. 2003.

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21 BIMATOPROST AND TRAVOPROST: 6-MONTH STUDY Mean IOP at Month 6 24

16 * P = .038 P = .095 P = .099 12 Travoprost (n = 81) Bimatoprost (n = 76) 8 Mean IOP (mm Hg) Mean IOP

4 Baseline mean IOP comparable between groups Travoprost: 24.4, 22.6, 22.0 (9 AM, 1 PM, 4 PM; mm Hg) Bimatoprost: 24.6, 22.6, 22.2 (9 AM, 1 PM, 4 PM; mm Hg) 0 9 AM 1 PM 4 PM

Time of Day Cantor et al. Br J Ophthalmol. In press.

22 BIMATOPROST AND TRAVOPROST: 6-MONTH STUDY Response Rate at Month 6 P = .058 78 80 AM

63 60

20 ≥ 20% IOP Reduction at 9 9 at Reduction IOP ≥ 20% 0 Percentage of Patients Achieving Achieving Percentage of Patients Bimatoprost Travoprost (n = 71) (n = 70) Cantor et al. Br J Ophthalmol. In press.

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BIMATOPROST AND TRAVOPROST: 23 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

Cantor et al. Br J Ophthalmol. In press.

24 BIMATOPROST AND LATANOPROST: 3 MONTH STUDY Mean IOP at Week 12 24

12 Study population: previously treated patients Bimatoprost (n = 136) (approximately 50% on

Mean IOP (mm Hg) (mm IOP Mean 8 latanoprost at screening) ) Latanoprost (n = 136 Among-group differences not statistically significant; Baseline mean IOP comparable between groups 4 consistently lower mean IOP Latanoprost: 25.7, 23.7, 23.0, 22.3 (8 AM, 12 PM, 4 PM, with8 PM; bimatoprost mm Hg) Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) 0 8 AM 12 PM 4 PM 8 PM Time of Day Parrish et al. Am J Ophthalmol. 2003.

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BIMATOPROST AND LATANOPROST:

25 6-MONTH STUDY

24 Mean IOP at Month 6

16 P < .001 P < .001 P = .008 12 Latanoprost (n = 136) Bimatoprost (n = 133) 8

Baseline mean IOP Mean (SEM) IOP (mm Hg) Mean (SEM) IOP 4 Latanoprost: 24.9, 23.3, 22.5 (8 AM, 12 PM, 4 PM; mm Hg) Bimatoprost: 25.0, 24.0, 22.6 (8 AM, 12 PM, 4 PM; mm Hg) 0 8 AM 12 PM 4 PM Time of Day • Mean IOP consistently lower throughout the day with bimatoprost

Noecker et al. Am J Ophthalmol. 2003.

26 BIMATOPROST AND LATANOPROST: 6-MONTH STUDY Response Rate at Month 6

Bimatoprost (n = 133) 100 Latanoprost (n = 136) P = .003 P < .001 82 79 P = .002 80 69 62 61 60 50

40 ≥20% ≥20% Reduction IOP 20 Percentage Achieving of Patients 0 8 AM 12 PM 4 PM Time of Day Noecker et al. Am J Ophthalmol. 2003.

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27 BIMATOPROST AND LATANOPROST: 6-MONTH SAFETY RESULTS

• Most common side effects: • Hyperemia (bimatoprost 44.4%; latanoprost 20.6%) • Similar rates of discontinuation due to AEs • Bimatoprost: 4.5% overall; 2.3% for hyperemia • Latanoprost: 3.7% overall; 0.0% for hyperemia • Uveitis: One patient in latanoprost group; no cystoid macular edema

Noecker et al. Am J Ophthalmol. 2003.

BIMATOPROST AND LATANOPROST+TIMOPTIC-XE®: 286-MONTH STUDY

Mean Diurnal IOP Over 6 Months

30 Latanoprost + Timoptic-XE® (n = 28) 25 Bimatoprost (n = 28)

10 Baseline mean diurnal IOP comparable between groups Bimatoprost 23.5 mm Hg Mean IOP (mm Hg) Mean IOP 5 Latanoprost / timolol gel 24.1 mm Hg 0 0 30 60 90 120 150 180 Day of Treatment

Manni et al. Graefe’s Arch Clin Exp Ophthalmol. 2004.

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29 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 1 work better than the others?

30 IOP REDUCING EFFECT

• According to package inserts: • Latanoprost – 6.7mm • Bimatoprost – 8.1mm • Tr avap rost – 7 .1 m m

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XLT STUDY – PARRISH, PALMBERG, 31 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

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34 ANOTHER WAY TO LOOK AT EFFICACY:

• % of IOP reduction – • Latanoprost – 27% • Unoprostone – 15% • Bimatoprost – 33% • Travaprost – 28%

• FYI: Timolol 24%

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35 WHAT IS THEIR ABILITY TO LOWER IOP <17MM?

• Latanoprost – 49.5% of pxs • Bimatoprost – 64% • Travaprost – 56.3%

36 LOOK AT THEIR FAILURE RATE:

• Percent of pxs who didn’t reach their target IOP • Latanoprost – 14% • Bimatoprost- 6% • Tr avap rost – 8 %

• SO?

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37 WHAT IF:

• A patient failed on Xalatan?

• If switched to Lumigan, 57% achieved target IOP • If switched to Travatan, 45.5% achieved target IOP

• SO?- Are all prostaglandins really created equal?

38 BOURNIAS, ET.AL , JOURNAL OF OCULAR PHARMACOLOGY (2003)

• Replaced Xalatan w/ Lumigan • Results: • IOP <15mm dropped from 11% to 36% • IOP <18mm dropped from 33% to 66% • Mean IOP decrease of 3.4mm

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39 ARE GENERICS REALLY AS GOOD AS BRANDED PRODUCTS?

WHAT ABOUT WHEN IT COMES TO PROSTAGLANDINS?

40 DROP STUDY – MEYER, 2014

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42 WHAT ELSE IS NEW ?

• Zioptan (Trafluprost) – Merck • Unit dose vial • QHS dosing • Unpreserved • Studies show 6-8 mm Hg drop in IOP from baseline of 24-26 • Excellent safety profile

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43 CLINICAL THOUGHTS ON ZIOPTAN

• Definite a kinder, gentler PGA

• Unit dose vials a perceived benefit

• Compliance enhanced?

• IOP decrease not as robust as other PGAs

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45 FINAL PROSTAGLANDIN THOUGHTS

• They are additive to other G drugs but not with each other • Travatan and Lumigan maintain target IOP 36hrs after instillation and significant IOP drop up to 84 hrs after instillation • Does one really work better than the others on African –Americans? • What about BID dosing?

46 A NEW PGA –AVAILABLE…NOW!!

• Latanoprostene bunod 0.024% • Nitric oxide donating prostaglandin • F2-alpha analog • 1 drop QHS • B & L • Vyzulta – available 2018!!!!

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VYZULTA – LATANOPROST BUNOD 0.024%

• Nitric-oxide donating PGA • B & L • QD dosing • Reduces IOP 7.5 – 9.1mm- superior to timolol • How does it compare to the other PGAs?? • How is it different?? • How is it better ??

VYZULTA

• Adding NO donor increases outflow through Schlemm’s Canal and t.m. • 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

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VYZULTA –MEDEIROS ET AL AJO, 2016

• Additional 1.2mm lowering of nocturnal IOP • Hyperemia rate-9% • Eye irritation – 7.2%

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 2016

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51 LATANOPROSTENE BUNOD (LBN)

• Phase 2 study • Head to head study vs Xalatan • 413 patients • LBN consistently lowered IOP in a dose-dependent manner • Significantly lower IOP than Xalatan at day 28 (also at day 7 and 14) • .98mm Hg lower at all time points • Slightly higher hyperemia rate

ONE MORE NEW PGA!!

• 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?

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54 BETA-BLOCKERS

• 30 year history of successfully lowering IOP

• Reduces aqueous humor formation

• Adrenergic agonists

• Lowers IOP 22-28%

• Ocularly well tolerated

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55 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?

56 BETA-BLOCKER SIDE EFFECTS

• Respiratory- • Fatigue, bronchospasm, SOB! • Cardiac – • Lethargy, bradycardia, lower pulse rate • CNS depression- • Impotence, confusion • But how common are they?

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57 LAMA STUDY (AJO 11/02)

• Conclusions: • ...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?

58 BETA-BLOCKER SIDE EFFECTS

• Cardiac problems • Respiratory problems • Bradycardia • Bronchospasm • Hypotension • Status asthmaticus • Exercise intolerance • Heart block

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59 BETA-BLOCKER SIDE EFFECTS

• CNS • Diabetic problems • Often overlooked • Decreased sense of • ACID caloric need due to • Anxiety depressed adrenergic • Confusion surge • Impotence • Depression • General decreased affect

60 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)

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THE BIGGEST PROBLEM WITH TOPICAL BETA- BLOCKERS?

• Decreased Perfusion To The Optic Nerve Head!! • Especially At Night!!

62 BETA-BLOCKER DEBATE

• Are they still useful? • As initial therapy? • QD or BID? • 0.25% or 0.5%? • Gel or drop? • Monocular therapy? • How bad are the side effects really? • Do systemic beta-blockers affect the efficacy of the drops?

• Tell me something good about beta-blockers!

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63 ADRENERGIC AGONISTS

• Dual mechanism of action 1. Reduce aqueous production 2. Enhance outflow mechanisms • 22-28% IOP reduction • Short duration of action • TID dosage • Avoid in kids

BRIMONIDINE: 64 DUAL MECHANISM OF IOP LOWERING

• Enhances uveoscleral outflow • Suppresses aqueous humor production (inflow)

Toris et al. 1995 and 1999.

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MECHANISM OF ACTION OF 65 BRIMONIDINE-PURITE®

• Complements PGAs because it decreases aqueous production • Complements timolol because it increases uveoscleral outflow

BRIMONIDINE FORMULATION 66 COMPARISON

ALPHAGAN® PALPHAGAN® Concentration of 0.1% 0.15% 0.2% Brimonidine pH 7.7 7.2 6.3-6.5

Preservative PURITE® BAK Viscosity Carboxymethylcellulo Polyvinyl alcohol agent se Potassium chloride, calcium chloride Electrolytes dihydrate, – magnesium chloride hexahydrate

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67 BENZALKONIUM CHLORIDE (BAK)

• 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, 2000; Gasset et al, 1974; Noecker, 2004)

DeSaint et al. Curr Eye Res. 2000; Gasset et al. Am J Ophthalmol. 1974; Noecker et al. Cornea. 2004.

PURITE® IS A GENTLE PRESERVATIVE 68

SEM of rabbit corneal epithelium (800X)

Untreated PURITE® QID 7 days BAK QID 7 days

The clinical significance of these data is unknown. Way et al. Invest Ophthalmol Vis Sci. 2001.

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OCULAR BIOAVAILABILITY OF BRIMONIDINE IN 69 DIFFERENT FORMULATIONS

Aqueous Humor Concentration in Rabbits

® • Brimonidine-PURITE 0.15% * formulation shows bioavailability g/mL)  in the aqueous humor ( max

comparable to brimonidine C 0.2% BAK ALPHAGAN® P Brimonidine ALPHAGAN® 0.15% 0.15% BAK

*P = .04 vs brimonidine 0.15% BAK The clinical significance of these data is unknown.

Dong et al. J Ocul Pharmacol Ther. 2004.

MEAN IOP AT PEAK (10 AM)

Brimonidine-PURITE® 0.15% (N = 372) Brimonidine 0.2%* (N = 376) Mean IOP (mm Hg)

*Original ALPHAGAN®

Katz. J Glaucoma. 2002.

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MEAN IOP AT TROUGH (8 AM)

Brimonidine-PURITE® 0.15% (N = 372) Brimonidine 0.2%* (N = 376) Mean IOP (mm Hg)

*Original ALPHAGAN®

Katz. J Glaucoma. 2002.

MEAN CHANGE FROM BASELINE AT MONTH 12

8 AM 10 AM 4 PM

Brimonidine 0.2% (n = 218) Brimonidine-PURITE® 0.1% (n = 215)

*P = .043 vs brimonidine 0.2%

Mean IOP Mean reductionIOP (mm Hg) Baseline IOP 8 AM: ALPHAGAN® 24.7 mm Hg; ALPHAGAN® P 0.1% 24.7 mm Hg, P = .946 10 AM: ALPHAGAN® 23.3 mm Hg; ALPHAGAN® P 0.1% 23.4 mm Hg, P = .636 4 PM: ALPHAGAN® 22.1 mm Hg; ALPHAGAN® P 0.1% 22.6 mm Hg, P = .206

ALPHAGAN® P 0.1% demonstrates IOP-lowering efficacy equivalent to ALPHAGAN® 0.2% over 12 months

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ADVERSE EVENTS TYPICALLY ASSOCIATED WITH 73 BRIMONIDINE 0.2%* ARE LOWER WITH BRIMONIDINE- PURITE® 0.15%

Brimonidine-PURITE® 0.15% (n = 381) Brimonidine 0.2%* (n = 383) †P < .025 †

† † Percentage of patients of Percentage †

*Original ALPHAGAN®

Katz. J Glaucoma. 2002.

BRIMONIDINE-PURITE® 0.15% HAS 74 SIGNIFICANTLY LOWER INCIDENCE OF OCULAR ALLERGY

18 †P = .007 vs brimonidine 0.2% 16 14 41% less allergy 12 † 10 8 6 4 2 Percentage patients of Percentage 0 Brimonidine-PURITE® 0.15% Brimonidine 0.2%* (n = 381) (n = 383)

*Original ALPHAGAN®

Katz. J Glaucoma. 2002.

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EFFECT OF BRIMONIDINE-PURITE® 0.1%

75 FORMULATION ON SAFETY

• Ocular surface exposed to 50% less drug with new formulation • Less allergy, redness, irritation • Lower concentration also means fewer systemic effects as less drug enters nasolacrimal duct

Katz. J Glaucoma. 2002.

76 BRIMONIDINE SIDE EFFECTS

• 10-20% • Do these worsen with • Hyperemia time? • Allergic conjunctivitis • Ocular pruritis • 5-9% • How do you know if the • burning sensation, drops are the culprit? • conjunctival folliculosis, • ocular allergic reaction, • oral dryness, • visual disturbance

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77 ALPHAGAN SYSTEMIC SIDE EFFECTS

• Dry mouth (~20%) • Fatigue (1-2%) • Drowsiness • Decreased BP

• This drug can cross blood-brain barrier, esp in older and younger pxs

78 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 0.2% Brimonidine Occurs?

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79 NEUROPROTECTION???

• Does it really exist?

• Does Alphagan promote neuroprotection?

80 FEKE ET AL, AJO 2014

• Effect of brimonidine on retinal vascular autoregulation and short-term visual function in NTG

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81 FEKE STUDY

• Identified NTG pxs who had retinal blood flow changes upon postural change • Those pxs were placed on Alphagan P 0.15% x 8 weeks then retested • 14/17 demonstrated an improvement in postural induced retinal blood flow • This did not show improvement in visual function

82 BRIMONIDINE MAY NOT WORK AT NIGHT

• Fan et al, J Glaucoma 2014; 23(5) • 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

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83 ALPHAGAN ALSO HAS A SHORT DURATION OF ACTION

• So what does this mean clinically??

84 CARBONIC ANHYDRASE INHIBITORS

• Lower IOP by reducing aqueous production

• Reduce IOP by 16-22%

• Sulfa drugs!!

• Dosage question – BID or TID?

• Are they useful as stand alone drugs?

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85 CAI DIRECTORY

• Trusopt – Dorzolamide 2%

• Azopt - Brinzolamide 1%

• Oral CAI • Acetazolamide – Diamox 250, 500mg • Methazolamide – 25, 50mg

86 CAI SIDE EFFECTS

• ***Stinging*** • **Dryness** • HA • Bad taste • Sulfa drug so: • Aplastic anemia? • Renal stones? • What about Cosopt?

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87 CAI 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

88 COMPANION STUDY #2

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

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89 COMPANION STUDY #3

• Stewart et al, 2006 • Compared to timolol 0.5% as additive to travaprost • No difference at all between the 2 drugs • CAI is effective at controlling night IOP spikes (TID?)

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

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ROCK -INHIBITORS

• 2 drugs in the works –Aerie • Rhopressa – Novel molecule • Works on different receptor sites so.. • Effective IOP reduction with fewer side effects • No lash growth or skin darkening • Targets trabecular meshwork • Roclatan – combo drug • Rhopressa and latanoprost • Availability 2017-2018

RHOPRESSA (NETARSUDIL) – AERIE PHARMACEUTICALS

• New class of drugs – Rho-kinase inhibitor • MOA – “Triple Action” • - 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 • 4th Quarter 2017??

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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 -50% (80% mild and transient) • Conj hemorrhages – 10% • Reduced level of BAK

ROCLATAN – AERIE

• Fixed Combination drug – Rhopressa + latanoprost • QD dosing • “Quadruple acting” MOA – (adds increased uveoscleral outflow) • IOP lowering better than either of its components • Potential to be very effective – lowered IOP an additional 2-3 mm compared to Rhopressa (and other PGAs)

• Currently in Phase 3 • Anticipating Late 2018 release

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ROCLATAN

• What do we think?

• Side effects- same as Rhopressa • Place in therapy? • Clinical impressions

• Cost concerns

96 COMBINATION DRUGS

• 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 timolol and dorzolamide • Same side effects as beta-blockers and CAIs • Capice? Kapeesh?

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COMBIGAN™ 97 (BRIMONIDINE TARTRATE/TIMOLOL MALEATE OPHTHALMIC SOLUTION) 0.2%/0.5%

• Fixed combination of brimonidine and timolol • Alpha-agonist brimonidine • Beta-blocker timolol • Preserved with 0.005% benzalkonium chloride (BAK) • Generic timolol is preserved with 0.01% • Complementary mechanisms of action

BRIMONIDINE/TIMOLOL COMBINATION 98 HAS DUAL MECHANISM OF ACTION

No Outflow Effect Timolol  Aqueous Production

Inflow and  Aqueous Production Outflow Brimonidine  Uveoscleral Outflow Effect

1Neufeld et al. Surv Ophthalmol. 1983; 2Toris et al. Arch Ophthalmol. 1995; 3Toris et al. Am J Ophthalmol. 1999; 4ALPHAGAN® P Prescribing Information.

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MEAN IOP–10 AM

99 • Brimonidine/timolol fixed combination

* * * * * *

*P < .001 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. 1Sherwood et al. Arch Ophthalmol. 2006; 2Data on file, Allergan, Inc.

DIURNAL MEAN IOP AT MONTH 12

100

Dose all treatments Dose brimonidine

* ** * * * ** ** Mean IOP (mm Hg) Mean IOP

*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.

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TREATMENT-RELATED ADVERSE EVENTS

101

* P ≤ .03 vs brimonidine 0.2% TID ** P ≤ .02 vs timolol 0.5% BID Percentage of patients

Conjunctival Ocular Eye Allergic Conjunctival Oral hyperemia stinging pruritus conjunctivitis follicles dryness ***Brimonidine and timolol monotherapies are approved for first line therapy. Sherwood et al. Arch Ophthalmol. 2006.

FIXED COMBINATION VS CONCOMITANT 102 THERAPY: EQUIVALENT MEAN IOP

Fixed Brimonidine/Timolol BID (n = 188) Concomitant Brimonidine BID + Timolol BID (n = 183) Hour 0 Hour 2 Mean IOP (mm Hg) (mm IOP Mean

Weeks after initiating study Weeks after initiating study medication from run-in medication from run-in monotherapy monotherapy Goni et al. Eur J Ophthalmol. 2005.

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NEXT STEP FROM A BETA-BLOCKER 103

• Additional IOP lowering achieved with fixed combination after beta-blocker run-in

Week 2 Week 6 Week 12 Hour 0 Hour 2 Hour 0 Hour 2 Hour 0 Hour 2 treated baseline (mm IOP Hg) Mean change from beta-blocker– Fixed-combination brimonidine/timolol BID (n = 121)

Baseline mean IOP = 25.0 mm Hg (hour 0); 22.7 mm Hg (hour 2)

Goni et al. Eur J Ophthalmol. 2005.

COMBIGAN™ AND COSOPT®

104

• 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

PGA = prostaglandin analogue 1Nixon and Hollander. AAO. 2007; 2Data on file, Allergan, Inc.

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COMBIGAN™ AND COSOPT® AS

105 MONOTHERAPY: MEAN IOP

*P = 0.04 (mean change from baseline) Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) Mean IOP (mm Hg) Mean IOP

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™ IN ADJUNCTIVE THERAPY WITH A 106 PGA: MEAN IOP

Added to a PGA baseline

-6.9 mm Hg (29%)

* *

Mean IOP (mm Hg) Mean IOP COMBIGAN™(brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% + PGA (n = 37)

*P < .0001 vs baseline

Month 1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.

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® 107 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

Stinging Burning Unusual taste P = .0001 P = .0149 P = .0047

1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.

OCULAR COMFORT: COMBIGAN™ (BRIMONIDINE TARTRATE/TIMOLOL MALEATE ® 108OPHTHALMIC SOLUTION) 0.2%/0.5% AND COSOPT (DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION)

30–40 Seconds After Drop Instillation * 80% *P < .0001 vs Cosopt®

n = 30 Percentage of subjects rating treatment as most comfortable 10% 10%

COMBIGAN™ Cosopt® Treatments equally comfortable

Chan et al. J Ocul Pharmacol Ther. 2007.

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109OCULAR DISCOMFORT: COMBIGAN™ (BRIMONIDINE TARTRATE/TIMOLOL MALEATE OPHTHALMIC SOLUTION) 0.2%/0.5% AND COSOPT® (DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION)

30–40 Seconds After Drop Instillation

1.97 *P < .0001 vs Cosopt®

n = 30 * 0.43 Mean ocular discomfort score

COMBIGAN™ Cosopt®

Chan et al. J Ocul Pharmacol Ther. 2007.

TREATMENT-RELATED ADVERSE EVENTS

110

*P ≤ .03 vs brimonidine 0.2% TID **P ≤ .02 vs timolol 0.5% BID 5.2% Percentage of patients

Conjunctival Ocular Eye Allergic Conjunctival Oral hyperemia stinging pruritusconjunctivitisfollicles dryness

• 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. 2006.

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111 COMBINATION DRUG #3

• Cosopt PF

• Preservative free • Unit dosage vial • Able to lower IOP as good as preserved, branded Cosopt • BID • So???

112 COMBINATION DRUG #4

• Simbrinza (Alcon) • Brinzolamide 1.0%/Brimonidine 0.2%

• TID Dosing

• Approved for adjunctive therapy

• Adjunctive to what??

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113 SIMBRINZA

• 5-9 mm Hg IOP reduction

• Baseline IOP – 22 -36mm Hg

• 21- 35% IOP reduction

• TID dosing

114 SIMBRINZA

• Compared to Azopt head-to –head • Compared to Brimonidine 0.2% head- to –head

• Statistically superior to either of the components in lowering IOP 2 3 mths • At all time points

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115 SIMBRINZA – SAFETY DATA

• Side effects are similar to each of the component drugs • D/C rate – 11% • 3-5% incidence rate of: • Blurred vision • Ocular irritation • Bad taste • Dry mouth • Ocular allergy

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

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BIMATOPROST SR

• 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 • Lowers IOP over a 4-6 month period

BIMATOPROST SR

• Phase 1 data • Proved safety and good tolerance • Phase 2 data • 2 weeks • IOP 23.8 in Bimatoprost group • 24.1 in timolol group

• At 6 months • 20.1 in implant group • 19.0 in timolol group

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BIMATOPROST SR

• Second study showed IOP decrease of 7.2 -9.5 mm Hg • At month 6, 70% of subjects did not require topical IOP gtt • Biggest side effect is transient hyperemia and FB sensation

• Implications for ODs

NOVEL DRUG DELIVERY SYSTEMS- THE NEXT FRONTIER

• Drug Eluting Punctal Plugs • QLT – latanoprost • 75% -80% retention rate • Results- 3-4mm drop in IOP

• Ocular Therapeutix – Intracanalicular latanoprost • Good sustained release of drug but doesn’t lower IOP as good as topical Xalatan

• SOOOO????

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BRIMONIDINE DRUG-ELUTING PLUGS

• Similar technique to inserting collagen lacrimal plugs • Early studies show better and more sustained IOP release than latanoprost plugs • Good safety profile • SOOOO>>>???

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123 ERIC’S 7 SIMPLE RULES FOR TREATMENT

1. Choose 30% IOP decrease as initial target 2. Squash the diurnal curve (Keep IOP peak <18mm) 3. Assess risk factors for progression and rate of progression (CT<555, IOP >26,C/D 0.5)

ERIC’S RULES CONT.

4. If you are going to treat; treat aggressively

5. KISS

6. Be mindful of perfusion issues

7. Above all, do no harm

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IOP LOWERING WITH 125MONOTHERAPY IS IDEAL

• Initial therapy with PGA can provide > 30% 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

126PATIENTS ON MORE THAN ONE IOP-LOWERING MEDICATION

2 Medications 3 Medications

4 Medications

1 Medication

Source: Verispan’s PDDA, MAT Nov 2006.

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HOWEVER, PATIENTS ON MONOTHERAPY MAY 127NOT ACHIEVE TARGET IOP

• In a study of ocular hypertension patients (OHTS)1 • At month 60, 40% required 2 or more medications to reach 20% IOP reduction • In patients treated with PGAs2 • Adjunctive medication use was 30.2% with latanoprost, 23.2% with bimatoprost, and 22.5% with travoprost

1Kass et al. Arch Ophthalmol. 2002; 2Covert and Robin. Curr Med Res Opin. 2006.

128 REGARDING PROSTAGLANDINS:

• Generally the 1st 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 1st?

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129 TREATMENT PARADIGM – STEP 2

• Prostaglandins 1st • If not successful – try another agent by itself: Brimonidine bid or timolol • If neither of these get IOP to desired level then add

MANY PATIENTS REQUIRE ADJUNCTIVE 130 THERAPY

• Ocular Hypertension Treatment Study (OHTS)1 • 817 patients with OHT; target pressure reduction = 20% • At month-60 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 • 307 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 therapy3

1. Kass et al. Arch Ophthalmol. 2002; 2. Lichter et al. Ophthalmology. 2001. 3. Robin et al. AGS. 2003.

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CONSIDER MECHANISM OF ACTION (MOA) 131 WHEN ADDING MEDICATIONS

• 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

132 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

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133 TREATMENT PARADIGM, PART IV

• If on 2 meds and target IOP not met…

• What is maximum medical therapy nowadays? • SLT and trabeculectomy should not be considered weapons of last choice or last chance