9/25/2018. New Generation Glaucoma Care. Disclosures. Overview

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1 New Generation Glaucoma Care MARK MARAMAN, O.D. NOA MEETING KEARNEY, NE OCT 4 TH, 2018 Disclosures I have no financial relationships or conflicts of interest with the manufacturers of any commercial products in this presentation. Overview Glaucoma Background Challenges Historical surgical options Recent Surgical Options MIGS Future Surgical Options New Glaucoma Medications Future Glaucoma Delivery Systems 1

2 Glaucoma Treatment Challenges Medications: Patient compliance Cost: generics vs. branded Side effects/irritation Refill issues Surgical: Complications Failure (initial trabeculectomy =10-20%, 5 year = almost 50%) Testing Variability and Reliability Asymptomatic Disease The Majority of Patients with Glaucoma Are Noncompliant Across multiple studies, it has been shown that the majority of patients do not take their glaucoma medications as prescribed by their doctor In a study of over 5,500 managed care patients, 90% were noncompliant and more than 50% of patients failed to refill their initial prescription in the 1st year 1 25% of patients in a US government health plan, with minimal out of pocket costs, failed to fill their second glaucoma prescription 2 In a separate trial, patients, on average, took their glaucoma medications only 7 out of 10 days 3 In a hospital based trial, 41% of patients who are compliant indicated that they experience challenges in paying for their medications 4 Noncompliance is the number one reason for drug therapy failure 5 1 Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005;140: Gurwitz JH, Glynn RJ, Monane M, et al.treatment for glaucoma: adherence by the elderly. Am J PublicHealth. 1993;83: Gurwitz JH,Yeomans SM, Glynn RJ, Lewis BE, Levin R, Avorn J. Patient noncompliance in the managed care setting. The case of medical therapy for glaucoma. MedCare. 1998;36: Sleath B, Robin AL, Covert D, Byrd JE, Tudor G, Svarstad B. Patient-reported behavior and problems in using glaucoma medications. Ophthalmology. 2006;113(3): Surgical Options (Open Angle Glaucoma) Shunt (Molteno, Baerveldt and Ahmed 1990 s) Trabeculectomy (1968) Laser Trabeculoplasty (ALT, 1979 SLT, 2001) ECP: Endoscopic Cyclophotocoagulation (1992) Ex-PRESS shunt (2002) Trabectome (2005) Canaloplasty (2007) MIGS: Micro or Minimally Invasive Glaucoma Surgery (2012) 2

3 Primary Source of Resistance: Diseased Trabecular Meshwork Abnormality of the trabecular meshwork (TM) is the primary source of elevated intraocular pressure (IOP) in open-angle glaucoma % of total resistance to aqueous humor outflow is found in the juxtacanalicular tissue of the TM 2,3 Bypassing the TM allows access to Schlemm s canal and the distal system in order to improve aqueous outflow through the conventional outflow pathways 8 1 Grant WM. Further studies on facility of flow through the trabecular meshwork. Arch Ophthalmol.1958;60(4 )1: Rosenquist R, Epstein D, Melamed S, Johnson M, Grant WM. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res. 1989;(12): Johnson DH, Johnson M. How does non-penetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgery. J Glaucoma.2001;10: Micro-Invasive Glaucoma Surgery (MIGS) 3

4 MIGS: Defined Ab-interno approach -- Clear corneal micro-incision (<2.0mm) -- Conjunctival sparing Minimally traumatic -- Negligible disruption of normal anatomy/physiology -- Excellent biocompatibility Efficacious Extremely high safety profile Rapid recovery H. Saheb, I. Ahmed. Curr Opin Ophthalmol 2012, 23: The istent Trabecular Micro-Bypass Stent System 11 1 st FDA approved MIG therapy (2012) : Improves aqueous outflow through the natural physiologic pathway Bypasses TM into Schlemm s Canal The istent Trabecular Micro-Bypass Stent is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild to moderate open-angle glaucoma currently treated with ocular hypotensive medication istent Specifications 12 istent is the smallest medical device known to be implanted in the human body and weighs just 60 µg Snorkel 0.3 mm Lumen 120 µm Self-Trephining Tip Made of surgical-grade nonferromagnetic titanium Heparin-coated to promote self-priming 4

5 Microstenting Schlemm s Canal Advantages: Enhancement of natural physiological outflow Lowers IOP and may reduce or eliminate medication burden Decrease risk of IOP fluctuations Physiologic floor minimizes risk of hypotony (Natural episcleral venous pressure typically 8-11mm Hg) Lack of bleb or conjunctival manipulation Does not preclude further glaucoma surgery if needed Minimal disruption of angle anatomy Minimize risk related to cell damage, inflammation, fibrosis, PAS 13 Concomitant Cataract & Glaucoma Patients - US 3.5M US Cataract Procedures One in Five Eyes with Cataract on OHT Medication 20.5% Cataract + Minimum of 1 OHT Med 718K % Cataract Only Centers for Medicare and Medicaid Services Medicare Standard Analytical File. Baltimore, MD istent Efficacy 5

6 Effect of Cataract Surgery on IOP Reduction Baseline IOP (mm Hg) n=19 n=62 n=86 n=223 n= IOP (mm Hg) Chart review of 588 normotensive and OHT subjects 1 53% had a mean reduction of 1.6 to 2.5 mm Hg Poley BJ, Lindstrom RL, et al. Long-term effects of phacoemulsification with intraocular lens implantation in normotensive and ocular hypertensive eyes. J Cataract Refract Surg.2008;34(5): istent Pivotal US IDE Trial Prospective, randomized, multi centered study of POAG patients who underwent istent + cataract surgery vs. cataract surgery (CE) alone. 290 subjects at 29 sites 240 randomized subjects with cataract and mild to moderate OAG (1:1 randomization) 50 additional non randomized subjects for safety Patient population Mild to moderate POAG (also PXE and PDS) IOP 24 mm Hg on 1 3 medications Post medication washout IOP mm Hg Efficacy endpoints Primary: IOP 21 mm Hg without medications at month 12 Secondary: IOP reduction 20% without medications at month 12 Follow up through 2 years postoperative Samuelson TW. Prospective randomized trial of cataract surgery with istent implantation and cataract surgery alone in mild moderate open angle glaucoma. Paper presented at: American Academy of Ophthalmology Annual Meeting; October 2009; San Francisco, CA. istent Pivotal US IDE Trial Primary Efficacy Outcomes (12 months) 80 Primary Endpoint 21 mm Hg IOP with no medications p =.004 % eyes % 50% istent + Cataract Cataract Months 18% more patients with CE plus istent achieved target pressures of 21 mm Hg with no medications 6

7 istent Pivotal US IDE Trial Secondary Efficacy Outcomes (12 months) Secondary Endpoint 20% IOP reduction with no medications p = % eyes % 47% istent + Cataract Cataract Months 17% more patients with CE plus istent achieved 20% reduction in IOP with no medications At M36: 7.8 mmhg (33.6 %) reduction from baseline Figure 2. Mean intra ocular pressure over time stratified by prior glaucoma surgery status, consistent cohort with follow up through 36 months (M) (n = 39). (n = 39) Preop: (74% on 2+ meds) M36: (74% on 0 meds) Mean Medication reduction = 1.6 (84% reduction) Neuhann, T. Trabecular micro-bypass stent implantation during small-incision cataract surgery for open-angle glaucoma or ocular hypertension: Long-term results. J Cataract Refract Surg 2015; 41: (At 48 Months) (n = 10) (n = 14) Medication reduction in istent/cataract group = 1.4 Cataract alone group = mmhg difference in mean IOP 4 years post-op between Cataract/iStent group vs. Cataract alone group following medication washout Fea, AM. Micro-Bypass Implantation for Primary Open-Angle Glaucoma Combined with Phacoemulsification: 4-Year Follow-Up. Journal of Ophthalmology. Vol. 2015,

8 Pre-operative Indications 22 Concomitant cataract & glaucoma Mild to moderate open angle glaucoma Visually significant cataract is present on examination Need to reduce medication burden Need for reduction of IOP fluctuations/better IOP control Need for preservation of future surgical options Pre-operative Considerations 23 Glaucoma workup Visual field Determination of severity of the glaucoma Optic nerve head imaging/assessment Pachymetry IOPs Gonioscopy evaluating for synechia, iris processes, narrow anatomical angles, angle recession or any other abnormalities of the angle structure that may interfere with placement of the istent Anterior segment and Dilated fundus examination rule out significant other ocular pathology Contraindications: Closed/narrow angle Neovascular Angle recession Uveitic Anatomical variability lack of TM pigment making placement difficult PAS, severe iris processes 8

9 Surgery Mechanism of Action: Anatomic Placement & Rationale 26 Placed in inferonasal locations with high presence of collector channel congregations Designed to improve continuous, physiological outflow in the lower nasal quadrants 9

10 Complications: Microhyphema Tube positioning/stent obstruction (4%) Iris blocking snorkel Debri blocking stent IOP spike Treatment failure Postop Management 30 Same as with cataract surgery alone Normal postop schedule (1 day, 1 week, 1 month) Same post op medications Hyphema blurry vision IOP spike/steroid responder treated the same Assessment of stent position 1 week gonioscopy Final effect on IOP not until 2-3 months postop When do you consider discontinuing one or more glaucoma medications? Not until post-op medications are finished 1-3 months 10

11 Suprachoroidal MIGS CyPass micro-stent (Alcon)- 6mm polyimide device, multiple fenestrations distal end istent Supra (Glaukos)- 4mm device Good for pts with angle anomalies, easy to implant? Miriam Karmel. Cataract + Glaucoma: New Options May Change the Equation. EyeNet Magazine. April 2012 CyPass Micro-Stent (Alcon) Approved by FDA in August st Suprachoroidal MIG Stent passed between the iris and scleral spur into the supraciliary space Advantages of stent in suprachoroidal space: Large surface area = greater fluid absorption Negative oncotic pressure = easier outflow from AC CyPass Demensions/Features 6.35 mm in length 510 µm in diameter Distal two-thirds fenestrated 11

12 COMPASS Study Number of U.S. sites: 24 Patients: 505 enrolled, 480 completed CyPass + cataract: 355 Cataract only: 125 Follow-up: 2 years Primary endpoint: Proportion of eyes with >20% reduction in IOP without medication at 2 years COMPASS Study Results: Number of Participants Analyzed CyPass Micro-Stent + Cataract Cataract Surgery Only Surgery Proportion of Eyes With 20% Decrease in Intraocular Pressure (IOP) From Baseline to the Hypotensive Medication-free 24- month Postoperative Examination COMPASS Study Results: CyPass Micro-Stent + Cataract Surgery Cataract Surgery Only Number of Participants Analyzed Mean Change in IOP Between Baseline and Hypotensive Medication-free 24-month Postoperative Examination [units: mmhg] Mean (Standard Deviation) -7.0 (4.53) -5.3 (3.95) 12

13 COMPASS Study Results: CyPass Micro-Stent + Cataract Surgery Cataract Surgery Only Number of Participants Analyzed Proportion of Eyes With Postoperative IOP 6 and 18 mmhg, as Measured by Goldmann Tonometry, at the Hypotensive Medication-free 24-month Postoperative Examination CyCLE study (Europe) 136 Patients 15 sites 2 year follow-up data Two groups: >21 mm Hg and on medication (uncontrolled) with CyPass + CE (51) <21 mm Hg and on medication (controlled) with Cypass + CE (85) No Control group of CE alone 21% had prior surgical intervention (including 6% Trabeculectomy) CyCLE study results: (24 months) Cohort 1 (>21 mm Hg, uncontrolled) Mean IOP reduction from 25.5 (baseline) to 16.4 Medication reduced from 2.2 meds to 1.0 meds Cohort 2 (<21 mm Hg, controlled) Mean IOP reduction from 16.4 (baseline) to 16.1 Medication reduced from 2.0 meds to 1.1 meds 13

14 Potential complications: Hyphema Hypotony (6%) Myopic shift IOP spike (both initially and post 30 days) Iritis (greater than 30 days post-op) COMPASS study: CyPass + CE = 8.6%, CE only = 3.8% Tube obstruction 2 to PAS Endothelial Cell loss Company pulled it from the market in August. Subconjunctival MIGS Xen gel implant (AqueSys) 6mm gelatin tube, lumen size- 45 µm, Tested 63 µm, 140 µm Bypasses natural drainage pathway by shunting fluid from AC to subconjunctival space. Ab interno approach Potential for lower IOPs like trabs/tube shunts while minimizing hypotony and post op wound leaks 14

15 Subconjunctival MIGS Indications: Refractory primary open angle glaucoma in which the patient has failed previous glaucoma surgeries or is on maximum tolerated medical therapy. Medicare requires an IOP of >20 Subconjunctival MIGS Xen gel Stent Efficacy summary: 30-41% reduction from pre-surgical medicated IOP. Approximately % of patients needed fewer topical medications post-operatively at 1 year. Efficacy varied based on stand alone vs. with CE, and with or without MMC Stand alone Xen45 vs. Trabeculectomy both with MMC 354 (n =185 Xen, 169 Trab) eyes with no prior filtering surgery Efficacy, failure rate and safety was equilvalent between groups. Schlenker MB, Gulamhusein H, Conrad-Hengerer I, et al. Efficacy, safety, and risk factors for failure of standalone Ab interno gelatin microstent implantation versus standalone trabeculectomy. Ophthalmology. 2017;124(11): [PubMed] Subconjunctival MIGS Xen gel complications Tube erosions Hypotony Choriodal effusion Conjunctival scarring Up to 30% will need 5FU injections and/or bleb needling Use of MMC at time of implant reduces this rate. Aqueous misdirection Endophthalmitis 15

16 What s Next? Trabecular Bypass MIGS istent Inject- 2 nd generation Easier to insert Multiple stents (2) in one injector to improve IOP lowering istent SA(Stand alone) same as istent inject without CE Istent Infintie 3 stents and also stand alone procedure. istent Inject Efficacy IDE pivotal study: 505 eyes (n=387 istent, n=118 CE alone) for 2 years 75.8% vs. 61.9% (difference of 13.9%) had 20% or greater reduction in unmedicated IOP 64% vs 47% (difference of 17%) for original istent Medication free mean IOP reduction was 7 mmhg vs 5.4 (difference 1.6) 63.2% were on no medications Mean reduction in medications from 1.6 to year data: 37% reduction in mean IOP from medicated pre-operative IOP. Medications reduced from 2.5 to

17 istent Inject SA Efficacy Research by Jay Katz, et al. One, two or three stents 119 eyes (n = 38, 41,40) 37 month endpoint showed mean IOP (unmedicated): 17.4 vs 15.8 vs 14.2 mm Hg (baseline was 25.0 for all three groups) Katz LJ, Erb C, Carceller Guillamet A, et al., Long-term titrated IOP control with one, two, or three trabecular micro-bypass stents in open-angle glaucoma subjects on topical hypotensive medication: 42-month outcomes, Clin Ophthalmol, 2018;12: Trabecular Bypass MIGS Hydrus Microstent (Ivantis) 8 mm long nitinol alloy Placed through trabecular meshwork into Schlemm s canal Acts as a scaffold for 3 clock hours of Schlemm s canal with end extending into the A/C Recently approved Aug For Mild to Moderate Glaucoma Hydrus Microstent Results: (Horizon Trial) 331 patients (556 globally), for 2 years Comparing Hydrus with CE vs. CE alone 20 % or greater reduction in IOP: 79% vs 55% (24% difference) Mean IOP reduction (after medication washout): 7.9 mm Hg vs 5.2 mm Hg (2.7 mm Hg difference) Medication free: 79% vs 39% 17

18 Hydrus Microstent Hydrus vs. 2 istents 152 patients for 12 months Stand alone procedure 73% (Hydrus) vs 47% (istent) had a 20% or greater reduction in IOP 47% (Hydrus) vs. 24% (istent) were medication free Medication reduced by: 61% (Hydrus) vs. 37% (istent) Rhee D, Ahmed I, Fea A, et al. Prospective, multicenter, randomized comparison of stand-alone Hydrus versus two istents for reduction of IOP in open-angle glaucoma. Paper presented at: the 28th Annual AGS Meeting; March 1, 2018; New York, NY. Hydrus Microstent Complications: 3.8% PAS causing obstruction 2.7% IOP elevated significantly 1.1% transient hyphema No cases of hypotony Subconjuctival MIGS MicroShunt (InnFocus soon to be Santen) Ab Interno Tube shunt Poly(Styrene-b-IsoButylene-b-Styrene) ("SIBS") Implanted in over 250 patients worldwide 3 year data (22 patients): Mean IOP reduction from 23.8 to 10.7 (55% reduction) 80% achieved an IOP of <14 mm Hg 85% on 0.3 meds or less (64% on no medications) 2 patients had hypotony (<6mm Hg) and 2 with choroidal effusion (resolved within 3 months) 18

19 Where do MIGS fit in? Review of Ophthalmology/ April 2015 New Glacoma Medications Vyzulta ( Latanoprostene bunod) Metabolized into Latanoprost acid and Butanediol mononitrate Butanediol releases nitric oxide which relaxes the TM Mechanism of action: Trabecular meshwork outflow Uveoslceral outflow 19

20 Vyzulta Efficacy 20-25% IOP reduction VOYAGER (Vyzulta vs latanoprost) Mean IOP reduction greater with Vyzulta compared to latanoprost group CONSTELLATION, APOLLO, JUPITER Vyzulta vs timolol In all three studies Vyzulta lowered mean IOP greater than timolol Improved diurnal ocular perfusion pressure with Vyzulta Use in normotensive patients? Small study in Japan showed a 27% reduction in IOP in normotensive patients Vyzulta side effects Same as prostaglandins alone Hyperemia Eyelash growth Burning Periorbital pigment changes? maybe Orbital fat loss? maybe Rhopressa (netarsudil) Inhibits Rho kinase (ROCK) and Norepinephrine transporter (NET) Mechanism of action: Increases aqueous outflow by increasing perfusion through TM other mechanisms as well? Lowers episcleral venous pressure (ROCK inhibition) decreases aqueous production (NET inhibition) Synergistic with prostaglandin Future combo product with netarsudil and latanoprost 20

21 Rhopressa Efficacy ROCKET 2 Study: Similar efficacy as timolol,about 20% (5mm Hg) reduction in IOP 1 mm Hg worse than latanoprost Baseline IOP > 25 mm Hg: timolol had greater effect BID dosing showed slightly greater effect, but with increased side effects Roclatan: Phase 2b study showed: 34% reduction in IOP 2 mm Hg more than latanprost group alone Rhopressa side effects Hyperemia 50% Vortex keratopathy (Verticillata) 20% Future Glaucoma Delivery Systems Sustained Release Intraocular Implants Intracameral Intravitreal Sub-conjunctival or Sub-Tenon s Punctal plug implants Contact lens like polymer Goal: 3-12 months of continuous effect with minimal complications and ease of insertion/removal 21

22 Questions? Caywood, R. and Omidghaemi, S. MIGS Madness: An Atlas of Options. Review of Optometry, July Richter, G. and Coleman, A. Minimally invasive glaucoma surgery: current status and future prospects. Clin Ophthalmol. 2016; 10: