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Today’s Treatment Algorithms Financial Disclosures: Ian Benjamin Gaddie, O.D. • Allergan • Alcon • Aerie • Sensimed • Reichert • Diopsys • Bausch and Lomb • Akorn • Sun • Zeiss • Heidleberg • Shire

Lipid Family • Xalatan (latanoprost 0.005%) – Prostaglandin Analogue • Travatan-Z (travaprost 0.004%) – Prostaglandin Analogue Receptors • Lumigan (bimatoprost 0.03%) – Prostamide (ocular hypotensive lipid) • Zioptan PF (tafluprost 0.015%)- Prostaglandin Analogue Cannabinoids Prostaglandins Prostamides

Latanoprost • Requires free acid of drug via • Acts as a selective F2α agonist (FP receptor agonist) ester • FP receptors have been identified in ciliary muscle, • Activates FP receptors ciliary epithelium and sclera (receptors for prostaglandin F a) • Enhances outflow through the uveoscleral pathway by 2 • Remodels extracellular matrix

– upregulating matrix metalloproteinase expression (Increasesadjacent uveoscleral outflow)to ciliary muscle cells – remodeling of the ciliary muscle's extracellular matrix • Peak effect occurs at least 8 resulting in Increased extracellular remodeling, increased hours following dosing permeability, decreased outflow resistance

Lim KS, Nau CB, O'Byrne MM, et al. Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study. Ophthalmology. 2008;115(5):790-795.e4.

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Xelpros emulsion (latanoprost emulsion) • Xelpros® was recently released by Sun Pharma Latanoprostene Bunod 0.024%(LBN) • XELPROS (latanoprost ophthalmic emulsion) 0.005% is a sterile, isotonic, buffered aqueous emulsion of latanoprost with a pH approximately 7.0 and an osmolality of approximately • First nitric oxide donating compound investigated for topical 375mOsmol/kg ophthalmic use – Does NOT contain BAK, preserved with potassium sorbate • Novel nitric oxide donating prostaglandin F2α receptor agonist – Potassium sorbate 0.47% is added as a preservative. • Received FDA approval in 2017 • Sun Pharma in-licensed XELPROSTM from SPARC in June 2015 • The data has demonstrated significant IOP lowering and a favorable • Developed using SPARC’s Swollen Micelle Microemulsion (SMM) technology safety profile – helps to solubilize drugs that have limited or no solubility • Dual mechanism of action – eliminating the need for benzalkonium chloride (BAK) • Uses a cash pay - $55/month or $110 for 3 months using mail-order Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension [published correction appears in Drugs. 2018;78(8):857]. Drugs. 2018;78(7):773-780. Fingeret M, Gaddie IB, Bloomenstein M. Latanoprostene bunod ophthalmic solution 0.024%: a new treatment option for open-angle glaucoma and ocular hypertension. Clin Exp Optom. 2019;102(6):541-550. pharmacy

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Vyzulta: Latanoprostene Bunod: NO-Donating Latanoprost Nitric Oxide (NO) • Gas that can freely diffuse across plasma membranes • • Signals via second messenger cGMP with NO plays key roles in both health and disease inhibition of 3 key contractile signals (calcium throughout the body, including the eye influx, intracellular calcium stores and Rhokinase activity) • Relaxes vascular smooth muscle cells à Vasodilation • Exerts relaxing effect on highly contractile TM cells causing cytoskeleton relaxation and enhanced outflow via TM/Schlemm canal

Wareham LK, Buys ES, Sappington RM. The nitric oxide-guanylate cyclase pathway and glaucoma. Nitric Oxide. 2018;77:75-87

Latanoprostene-bunod:

LBN Mechanism of Action • LBN is hydrolyzed by • Latanoprostene = latanoprost endogenous corneal – Increases uveoscleral outflow esterases to • Bunod modification donates nitric – Latanoprost acid: the oxide active compound of – Exerts its effect in trabecular latanoprost smooth muscle – Butanediol mononitrate: – Activating cGMP signaling pathway a NO donating moiety – Resulting in trabecular relaxation and increased conventional outflow Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension [published correction appears in Drugs. 2018;78(8):857]. Drugs. 2018;78(7):773-780. Fingeret M, Gaddie IB, Bloomenstein M. Latanoprostene bunod ophthalmic solution 0.024%: a new treatment option for open-angle glaucoma and ocular hypertension. Clin Exp Optom. 2019;102(6):541-550. • Mechanisms would be expected to additive

Cavet ME, Vittitow JL, Impagnatiello F, et al. Invest Ophthalmol Vis Sci. 2014;55:5005-5015; Ellis DZ, Dismuke WM, Chokshi BM. Invest Ophthalmol Vis Sci 2009; 50: 1808–1813.

Once metabolized, VYZULTA increases outflow through both the uveoscleral pathway and the trabecular meshwork LBN • NO enters cells of TM and inner wall of Schlemm canal via cGMP • May also act downstream by relaxing smooth muscle of collector channels and ê distal outflow resistance • Nitric Oxide IOP lowering effects are distinct from latanoprost

Garcia GA, et al. Clinical Ophthalmol 2016: 10 2035-2050.

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LBN Trials KRONUS Trial • KRONUS Phase 1 trial in healthy Japanese

• Only Phase 1 trial of LBN • VOYAGER Phase 2 Dosing study with • 24 healthy Japanese, open label, single arm, single center latanoprost comparator • LBN 0.024% dosed at 8 PM for 14 days in young adult Japanese males aged 26.8years ± 6.3 • APOLLO/LUNAR Pivotal Phase 3 FDA approval trials • Mean baseline IOP 13.6mmHg ± 1.3 • Significant reduction in IOP in eyes without elevated IOP ( P< .001) • JUPITER Phase 3 – 1-year long trial • 27% mean decrease in IOP (3.6 mm HG ± 0.8 mm Hg) over 24 hours with peak reduction at 12 hours after dosing • Pointed to possible implications for future use in NTG • CONSTELLATION Phase 2 diurnal comparison to timolol Weinreb RN, et al. Br J Ophthalmol. 2015;99:738–45; Weinreb RN, et al. Ophthalmology. 2016;123:965–73; Medeiros FA, et al. Am J Ophthalmol. 2016;168:250–9; Liu JH, et al. Am J Ophthalmol. 2016;169:249– 57; Kawase K, et al. Adv Ther. 2016;33:1612–27; Liu JH, et al. Am J Ophthalmol,. 2016;169:249–57.

Araie M, et al. Adv Ther. 2015;32:1128–39.

LBN Demonstrated Superior IOP Reduction versus Timolol 0.5% at Most Common Ocular Adverse Reactions in Month 31 APOLLO and LUNAR*1,2

Mean IOP Reduction at Month 3 LBN TIMOLOL 0.05% Adverse Reactions (n=811) (n=271)

Conjunctival 5.9% 1.1% At Month 3, mean Hyperemia Mean baseline IOP 26.7mmHg IOP reduction was Eye Irritation 4.6% 2.6% & 26.5 mm Hg 32% Eye Pain 3.6% 2.2%

Ocular Hyperemia 2.0% 0.7%

Instillation 2.0% 1.8% Site Pain

Latanoprostene bunod *Pooled data from all tested time points in the APOLLO and LUNAR studies: Mean Baseline ocular adverse reactions occurring in ≥2% of study eyes IOP 26.6mmHg & 26.4 mm Hg

* Pooled data from all tested time points in the APOLLO and LUNAR studies. Less than 1% discontinuation due to ocular adverse reactions1 • Approximately 0.6% of patients discontinued therapy due to ocular adverse reactions Apollo ( 417 pts ) and Lunar ( 414 pts) 1. Weinreb RN, et al. J Glaucoma. 2018;27(1):7-15. • These included ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, vision blurred, 2. Kaufman PL. Expert Opin Pharmacother. 2017;18(4):433-444. punctate keratitis, and foreign body sensation

1. VYZULTA Prescribing Information. Bausch & Lomb Incorporated. 2018. 2. Weinreb RN, Liebmann JM, Martin KR, et al. J Glaucom a. January 2018;27(1):7- 15.

JUPITER Trial JUPITER

• Single arm, multicenter open label, Phase 3 trial in Japan • 1-year dosing in 130 Japanese OAG or OHT • Baseline IOP: 19.6 + 2.9 mm Hg, (Range 15-30 mm Hg) • Majority had IOP ≤21.0 mm Hg • IOP measured monthly at 10 AM x 1 year • At 1-year, mean IOP was decreased by 5.3 mm Hg • Demonstrated long-term safety and efficacy

Kawase K, et al. Adv Ther. 2016;33:1612–27.

Kawase K, et al. Adv Ther. 2016;33:1612–27.

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Nitric Oxide Released by VYZULTA Inhibits Rho Kinase and Calcium Signaling

Nitric oxide inhibits Rho kinase and calcium signaling—key causes of trabecular meshwork contraction—by activating the soluble guanylate cyclase–cGMP cascade

Activation of soluble guanylate cyclase–cGMP cascade produces relaxation of the trabecular meshwork and increased permeability

1. Cavet ME, Vittitow JL, Impagnatiello F, et al. Invest Ophthalmol Vis Sci. 2014;55:5005-5015. 2. Buys ES, Potter LR, Pasquale LR, Ksander BR. Front Mol Neurosci. 2014;7:38. 3. Schneemann A, Dijkstra BG, van den Berg TJ, et al. Graefes Arch Clin Exp Ophthalmol. 2002;240:936-941.4. Wiederholt M, Sturm A, Lepple-Wienhues A. Invest Ophthalmol Vis Sci. 1994;35:2515-2520. 5. Tamm ER, Braunger BM, Fuchshofer R. IntProg Mol Biol Transl Sci. 2015;134:301-314. 6. Braunger BM, Fuchshofer R, Tamm ER. Eur J Pharm Biopharm. 2015;95(Pt B):173-181.

FDA Indication on PI

CASE : VYZULTA is the only • 63-year-old man nitric oxide–releasing agent • Works in the Middle East for an oil company; only home in the indicated for the reduction of IOP in United States 1-2x per year • First seen in June of 2017 patients with open-angle glaucoma – IOP: 20 mm Hg OD; 30 mm Hg OS – Gonio open to Ciliary Body with 2+ PTM or ocular hypertension. – Pachymetry: 531 micron OD and 567 OS – Corneal Hysteresis: 9.1 OD and 5.0 OS – No family history of glaucoma

CASE: Imaging

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CASE: Treatment CASE: Follow-up visits | 2018

• Started on benzalkonium chloride-free travoprost QHS OU • April 2018: patient decides due to the nature and riskiness of his job, he – Pressure checked - August 2017 would rather not be on drops – IOP dropped from 20 mm Hg OD and 30 mm HG OS to 10 mm • Performed SLT OD followed by OS a month later; PGA discontinued Hg OD and 13 mm Hg OS • June 2018 • Pressure checked - February 2018 – IOP: 12 mm Hg OD; 15 mm Hg OS S/P SLT OU • 14 mm Hg OD and 16 mm Hg OS

CASE: Follow-up visits | 2019 Case: Follow-up visits | 2020

• August 2019 No drops S/P SLT OU • January 2020 Vyzulta HS OS only – IOP: 16 mm Hg OD; 25 mm Hg OS – IOP 15 mm Hg OD and 15 mm Hg OS – Restart PGA OS only (Lumigan)

• May 2020 Vyzulta HS OS only • October 2019 No drops OD S/P SLT and Lumigan HS OS – IOP 14 mm Hg OD and 15 mm Hg OS – IOP: 14 mm Hg OD; 21 mm Hg OS • Switch OS from Lumigan to Vyzulta

Rho Kinase Inhibitors CASE: Follow-up visits Netarsudil ophthalmic solution 0.02%

• -When additional IOP lowering is needed beyond a PGA, latanoprostene bunod could be a good option to avoid multiple • Rho kinase drug discovery program initiated in 2006 medications • Goal to identify an effective and well-tolerated ROCK inhibitor with a durable IOP lowering effect. • -Consider treatment options that minimize the number of bottles • Most effective compounds were ROCK/NET inhibitors (norepinephrine of medication used, simplifies dosing and avoid side effect and transporter) drug interactions • In addition to trabecular outflow, animal and donor eye studies showed a decrease in aqueous humor production and episcleral venous pressure • The decrease in EVP is felt to be related to NET inhibition.

Moshirfar M, Parker L, Birdsong OC, et al. Use of Rho kinase Inhibitors in Ophthalmology: A Review of the Literature. Med Hypothesis Discov Innov Ophthalmol. 2018;7(3):101-111.

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Netarsudil Netarsudil

v Netarsudil is a ROCK/NET inhibitor • Netarsudil v In the trabecular meshwork ROCK activation leads to: – Disrupts actin stress fibers and focal adhesions in TM qActomyosin contraction qExtracellular matrix production cells qIncrease in cell stiffness – Blocks TGF- beta 2 v Inhibitors of ROCK in cultured TM and Schlemm canal cells – Increases EVP qReduce cell contraction qDecrease expression of fibrosis-related proteins qReduce cell stiffness

Tanna AP, Johnson M. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension Ophthalmology 2018;125:1741-1756

Tanna AP, Johnson M. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension Ophthalmology 2018;125:1741-1756

Rho-kinase Increases TM Contraction Disease at the TM is Responsible for and Elevates IOP Elevated IOP in Glaucoma1,2 Healthy TM POAG TM Stiffness Normal IOP Elevated IOP

↑ Actin-Myosin Stress Fibers

Cellular Damage (eg, Oxidative Stress)

Increased TM Cell ↑ Focal Cell Adhesions Contraction

Extracellular Matrix Elevated IOP ↑ 1. Rao et al. Exp Eye Res. 2017;158:23.

Scanning electron microscopy (2000x) was used to examine human TM under physiological conditions and in patients with POAG.2 POAG, primary open-angle glaucoma; TM, trabecular meshwork. 1. He et al. Invest Ophthalmol Vis Sci. 2008;49:1447. 2. Saccà et al. J Cell Physiol. 2015;230:510.

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Rho-kinase Inhibitors Relax TM Cells Healthy Donor Eyes Perfused for 3 Hours With and Reduce Fibrosis1,2 Netarsudil Active Metabolite or Control Vehicle

↓ Actin-Myosin Stress Fibers Rho-kinase CONTROL Inhibitor

Decreased TM Cell ↓ Focal Cell Adhesions Contraction Light microscopy, 20× +NETARSUDIL objective along the inner wall of the Schlemm Canal. Reduced IOP Ren et al. Invest Ophthalmol ↓ Extracellular Matrix Vis Sci. 2016;57:6197.

1. Rao et al. Exp Eye Res. 2017;158:23.

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Netarsudil Decreased EVP in Healthy and Glaucomatous Eyes Netarsudil

Once Daily dosing NetarsudiNo contraindications l No significant systemic side effects Healthy Eyes: Up to 6.1 mm Hg IOP lowering 10% vs baseline (p=0.01) (MERCURY Trials) POAG/OHT: ≈10%˜ 9.5% vs baseline (p=0.0113) 12.6% vs vehicle (p=0.0003)

Asrani S, Bacharach J, Holland E, et al. Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2. Adv Ther. 2020;37(4):1620-1631.

Kazemi et al. J Ocul Pharmacol Ther. 2018;34:380.

Netarsudil Maintained Consistent and Stable IOP Reduction Across all Baseline IOPs

Pooled ROCKET Studies: Change in Mean Diurnal IOP Between Baseline and Month 3

Once-daily Netarsudil 0.02% Twice-daily timolol 0.5%

Maximum Baseline IOP, mmHg: <22 <23 <25 <27 <22 <23 <25 <27 0.0 n=7 n=194 n=378 n=538 n=6 n=206 n=438 n=632 5 3 -1.0

-2.0 SEM

- -3.0

- -4.0 mmHg mmHg 3.5 -3.9 - - - - 4.0 4.0 -4.3 -5.0 4.1 4. 1 - Change in mean diurnal IOP, IOP, diurnal mean in Change 4.6

-6.0 78% of patients with glaucoma have IOP <25 mm Hg at diagnosis

FDA Briefing Document. Oct 2017. Netarsudil ophthalmic solution 0.02% [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf. Accessed January 3, 2020.

Serle JB, et al. Am J Ophthalmol. 2018;186:116-27. Open Access.

Cornea Verticillata Cornea verticillata (lipid micro-deposits in the corneal epithelial layer) • RocklatanTM: ~5% • RhopressaTM: ~4% • ~5-9% reported in Rocket 1 and Rocket 2 • Asymptomatic • Only visible via biomicroscopy evaluation • Benign corneal deposits (phospholipidosis) are a familiar outcome with other drugs such as amiodarone

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M.O.S.T. Study Results: Adjunctive Therapy

Percentage of Patients on Adjunctive Therapy achieving ≤18 mm Hg or Lower

A Phase 4, multicenter open-label study that evaluated the IOP-lowering efficacy of netarsudil in a real-world clinical setting in patients with OHTN or OAG Ba se line ( n=15 1) Week 1 2 (n=143) (n=261)a Nearly 2/3 72.7 65 Netarsudil Ophthalmic Solution 0.02% Netarsudil Ophthalmic Solution 0.02% of patients using netarsudil as monotherapy, once daily as adjunctive therapy2, once daily as adjunctive therapy 50.3 40.6 12 Weeks achieved a mean IOP of 34.4 30.1

Patients,% 25.2 Primary outcome measure: IOP percent change from baseline ≤17 mm Hg at Week 12 19.9 15.9 11.3

≤14 mm Hg ≤15 mm Hg ≤16 mm Hg ≤17 mm Hg ≤18 mm Hg IOP

a261 patients were enrolled, with only 260 treated. One patient signed informed consent but changed his mind and was not treated. Ophthalmology Management. Accessed July 22, 2020. https://www.ophthalmologymanagement.com/videos/real-world-experience-with-rhopressa. 1. ClinicalTrials.gov. Accessed July 22, 2020. https://clinicaltrials.gov/ct2/show/NCT03808688 2. Ophthalmology Management. Accessed July 22, 2020. https://www.ophthalmologymanagement.com/videos/real-world-experience-with-rhopressa.

Netarsudil Provided Consistent IOP Reductions Netarsudil Was Well Tolerated as Whether Added to Prior PGA Monotherapy or Prior Combination Therapy (≥2 Meds) Adjunctive Therapy in M.O.S.T. Study

Adverse Events in the M.O.S.T. Safety Population Adjunctive Therapy Baseline Week 6 Week 12 Treatment Group Conjunctival hemorrhage (Discontinued… 5.00% Netarsudil + PGA (n=55) Mean IOP (mm Hg) 21.1 17.0 16.9 Instillation site pain (Di scontinued rate:… 5.00% Mean Change from Baseline (mm Hg) - -4.1 (-19%) -4.3 (-20.2%) Vision blurred (Discontinued rate: 1.9%) 6.20% Netarsudil + ≥2 Meds (n=64) Conjunctival hyperemia (Discontinued… 19.90% Mean IOP (mm Hg) 20.6 16.9 16.2 Mean Change from Baseline (mm Hg) - -3.7 (-17.5%) -4.5 (-20.9%) 0% 5% 10% 15% 20% 25%

Note: Excludes patients for whom a prior medication was switched out for netarsudil. Treatment emergent adverse events reported in ≥5% of patients using netarsudil as adjunctive therapy

Ophthalmology Management. Accessed July 22, 2020. https://www.ophthalmologymanagement.com/videos/real-world-experience-with-rhopressa. PGA = prostaglandin analogues. Ophthalmology Management. Accessed July 22, 2020. https://www.ophthalmologymanagement.com/videos/real-world-experience-with-rhopressa.

Netarsudil-Latanoprost Fixed Tolerability of Netarsudil Combination

Superior efficacy compared to latanoprost: 1.5-nd2.4 mm Hg additional IOP lowering 89% Once daily Dosing of patients reported that netarsudil was tolerated “well,” Excellent safety profile “mostly well,” or “very well” The only fixed dose combination of two true QD dosing glaucoma solutions

73.2% of physicians rated patient acceptance as “good” or “excellent”

Uveoscleral Outflow. Brubaker et al. Annual Meeting of the American Glaucoma Society 2018 Poster Presentation.

Ophthalmology Management. Accessed July 22, 2020. https://www.ophthalmologymanagement.com/videos/real-world-experience-with-rhopressa.

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Fixed Combination Netarsudil/Latanoprost Achieved Statistical Pooled MERCURY Studies: Proportion Of Patients By Month 3 With Mean Diurnal Superiority vs Individual Components at All Time Points at 12 months IOP ≤18 mm Hg

100 Mean IOP over 12 months (ITT population) Netarsudil 0.02%/Latanoprost 0.005% FDC 90 * (n=421) 26 Netarsudil/Latanoprost FDC (n=238) 79 Latanoprost 0.005% (n=458) 80 * * 25 Netarsudil (n=244) 68 70 24 70 * Latanoprost (n=236) 23 58 60 53 SEM 22 * ± 21 50 43 20 * 40 37 mmHg mmHg 19 % Patients, 32 18 30 21 17 20 16 12 15 10 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 14 Baseline Week 2 Week 6 Month 3 Month 6 Month 9 Month 12 0 ≤18 mmHg ≤17 mmHg ≤16 mmHg ≤15 mmHg ≤14 mmHg On-treatment IOP

aStatistical superiority = Reduction in IOP 1-3mmHg greater with netarsudil/latanoprost FDC than with either netarsudil or latanoprost at all time points. *P<0.0001; **P<0.05 SEM, standard error of the mean Asrani S, et al. Presented at: 13th Biennial Meeting of the European Glaucoma Society; May 19-22, 2018; Florence, Italy. 1. Brubaker et al. Annual Meeting of the American Glaucoma Society 2018 Poster Presentation.

Over 60% of Rocklatan® Patients Rocklatan® Achieved the Primary Endpoint of Superiority vs Both Individual Components Over 3 Months Achieved ≥30% Mean IOP Reduction at

• Primary efficacy endpoint for both trials was mean IOP at 8 AM, 10 AM, and 4 PM at Week 2, Week 6, and Month 3, 3 Months respectively. Primary safety endpoint was ocular and systemic AEs over the treatment period2,3 Pooled MERCURY Studies: Proportion of Patients Achieving Prespecified Percentage of Mean Diurnal IOP Reduction at Month 3 (ITT Population) 100 Rocklatan® (netarsudil and latanoprost ophthalmic 87* solution) 0.02%/0.005% (n=421) 90 Rhopressa® (netarsudil ophthalmic solution) 0.02% 75 75* (n=426) 80 Latanoprost 0.005% (n=458)

70 62* PRIMARY SAFETY PRIMARY EFFICACY 56 n EFFICACY ANALYSIS ANALYSIS POPULATION 60 53 50 43* ® n=238 (Rocklatan QD) >20 mmHg @ 08:00 AM, 37 2 >17 mmHg @ 10:00 AM and 40 33 MERCURY-1 ® 3 months 12 months 31* n=244 (Rhopressa QD) 16:00 PM, and <36 mmHg any time prior to randomization PATIENTS,30 % 24 n=236 (latanoprost QD) 17 20 14 ® 9 n=245 (Rocklatan QD) >20 mmHg @ 08:00 AM, 6 >17 mmHg @10:00 AM and 10 MERCURY-23 ® 3 months 3 months n=255 (Rhopressa QD) 16:00 PM, and <36 mmHg any time prior to randomization 0 n=250 (latanoprost QD) ≥20% ≥25% ≥30% ≥35% ≥40% AE, adverse event; FDC, fixed-dose combination; QD = once a day. IOP REDUCTION FROM BASELINE, % 1. Asrani S et al. 13th Biennial Meeting of the European Glaucoma Society. Poster #2210. 2. Brubaker et al. Annual Meeting of the American Glaucoma Society 2018. Poster #074. 3. Walters et al. Annual Meeting of the American Glaucoma Society 2018, Poster #073.

Rocklatan® Patients Were 2x – 3x More Likely to Achieve IOPs of ≤15 – 14 mmHg Than Latanoprost Patients at 3 Months Xelpros (latanoprost .005%) Sun Pharma Pooled MERCURY Studies: Proportion of Patients by Month 3 With Mean Diurnal IOP ≤18 mmHg (ITT Population) 100 Rocklatan® (netarsudil and latanoprost ophthalmic • solution) 0.02%/0.005% (n=421) Latanoprost preservative free using novel Swollen Micelle Microemulsion (SMM) 90 ** Rhopressa® (netarsudil ophthalmic solution) 0.02% technology * 79 (n=426) 80 Latanoprost 0.005% (n=458) – 70 helps to solubilize drugs that have limited or no solubility, and cuts out the need for 68 70 * a preservative

* 58 60 53 50 • Allows for increased corneal contact and penetration while remaining preseravtive 50 * 43 free 39 40 37

PATIENTS, % 32 28 30 • Expected US launch mid 2017 21 19 20 11 12 • They are also developing a QD dosing formulation of brimonidine 10

0 ≤14 mmHg ≤15 mmHg ≤16 mmHg ≤17 mmHg ≤18 mmHg ON-TREATMENT IOP

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Practical Issues in Glaucoma Glaucoma Medication Coverage Medication Utilization • Why are some glaucoma medications “not • Prior Authorizations and Step Edits covered” or ”not on formulary”? • Compounding pharmacies and glaucoma • How do pharma companies get on a medications formulary? • Cash Pay Models? • How do deductibles and co pays effect patient cost at pharmacy? • Donut holes?

Prior Authorizations • Several ways to do this step – PARx – CoverMyMeds Cash-Pay Model for Glaucoma – Self directed Medications

Xelpros emulsion (latanoprost emulsion) • Xelpros® was recently released by Sun Pharma • XELPROS (latanoprost ophthalmic emulsion) 0.005% is a sterile, isotonic, buffered aqueous emulsion of latanoprost with a pH approximately 7.0 and an osmolality of approximately 375mOsmol/kg – Does NOT contain BAK, preserved with potassium sorbate – Potassium sorbate 0.47% is added as a preservative. • Sun Pharma in-licensed XELPROSTM from SPARC in June 2015 • Developed using SPARC’s Swollen Micelle Microemulsion (SMM) technology – helps to solubilize drugs that have limited or no solubility – eliminating the need for benzalkonium chloride (BAK) • Uses a cash pay - $55/month or $110 for 3 months using mail-order pharmacy

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Compounding Pharmacies in Glaucoma

Does quadruple therapy really work?

How Can These Medication(s) be Quadruple Therapy Prescribed? • Do the medication(s) work? • We don't know anything about the side effect profile of putting 4 medications together in one bottle – Little data to support their efficacy • And what about effectiveness? • – Is there an added benefit (besides compliance) when having 4 Made by compounding pharmacy and medications together compared to 3 .... or even two of them requires a prescription – We have seen that adding timolol to a prostaglandin in the same bottle does not add much to effectiveness of the prostaglandin • Order the medication by calling the Rx to the alone pharmacy • hence the lack of FDA approval of Xalcom, DuoTrav and Ganfort – They call patient, get credit card info and mail • And how would you dose this? – There are two bid-tid medications, and two once a day direct to patient medications in the same bottle • Need to pay for medication at time of order • Adherence should improve

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