3/31/2019. Role of IOP. Role of IOP. Role of IOP. Role of IOP. Evaluation of glaucoma has changed Why hasn t treatment?

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1 Glaucoma Update ROLE FOR RHOPRESSA Gregory D. Searcy, M.D. 1857: German ophthalmologist Albrecht Van Graefe concluded all glaucomatous optic disc excavation is associated with high IOP based on the only instrument available digital palpation. 1863: Albrecht von Graefe designed the first instrument to attempt to measure intraocular pressure. Professional Education March 31, 2019 Rested on forehead and cheek bone by two brass feet. Pressure on central plunger could be varied by position of the weight on the scale indicator. Sclera indented. No cocaine until : Prominent ophthalmologists such as Snellen and Landolt thought IOP estimation by digital palpation was still the method of choice. 1905: Hjalmar Schiotz produced his indentation tonometer. This made tonometry a simple and routine clinical test. Pamphlet advice enclosed with the Schiotz X Tonometer: Hospitals and eye-specialists should have two Tonometers for cross-checking. If a Tonometer needs adjustment or repair, it should be sent to me. I am the only one able to guarantee an accurate adjustment. Notice that after repair a Tonometer always needs adjustment. Warning is given against imitations, even if they bear the name of Professor Schiotz. The legitimate Professor Schiotz Tonometer is made only by me, and my Tonometer are guaranteed to confirm to the original specifications of Professor Schiotz. With each Tonometer follows a guarantee signed by me, to prove that the Tonometer is accurately adjusted. On top of each Tonometer-case is printed my trademark, <<Schiotz Norway>> 1954: Goldmann applanation tonometer Evaluation of glaucoma has changed Why hasn t treatment? Where is evolution in glaucoma medical management? 1

2 Most treatments lower IOP by decreasing aqueous production or increasing uveoscleral outflow, ignoring the normal outflow pathway through trabecular meshwork Rhopressa Muscarinic agonists TM Ciliary muscle PGAs Beta-blockers Alpha2 agonists CAIs Rhokinases promote actin-myosin contraction Rhokinase inhibitors reduce the actin-myosin contraction in the TM pathway, thereby reducing resistance to aqueous outflow Rhopressa Causes Expansion of TM Tissue, Opening Spaces For Increased Outflow Rhopressa-induced Increase in TM Outflow OCT imaging in mice Expansion of Schlemm s Canal due to increased flow through TM Increased inter-trabecular spaces = increased outflow Rhopressa Potential Anti-Fibrotic Activity in Human TM Cells FIBROSIS MARKERS Smooth muscle actin Neuroprotective Effects Fibroblast-specific protein 1 Collagen 1A 2

3 Unilateral optic nerve crush study on young rats Rhopressa or placebo TID for 14 days Day 14 Retinas, optic nerves collected Neuroprotective Effects Neuroprotective Effects Retinas flat-mounted, stained to quantify RGC survival Optic nerves quantified using fluorescent and confocal microscopy Exp Eye Res 2017 May;158:33-42 Retina flat-mounts Rhopressa vs Eylea In Preclinical AMD Model Topical Rhopressa Provides Added Efficacy to Eylea in Proliferative Diabetic Retinopathy Model Oxygen-induced retinopathy model of PDR (mouse) 0.06% Rhopressa delivered topically from P12 to P17 Supports Rhopressa as a potential adjunct therapy to anti-vegf therapies Saline Rhopressa Rhopressa Rhopressa Eyelea n= ug/ml 0.6 ug/ml 6 ug/ml 800 ug/ml n=28 n=25 n=25 n=20 Vehicle Rhopressa Eyelea Rhopressa (control) n=28 n=26 + Eyelea n=18 NTG Moderate stage Target pressure 15 (30% per CNTGS) NTG Moderate stage Target pressure 15 (30% per CNTGS) 3

4 NTG Moderate stage Target pressure 15 (30% per CNTGS) OD 08/2017 Severe NPDR + CSME OS 08/2017 Active PDR + CSME OD 09/2018 Moderate NPDR Improved CSME s/p Avastin x 3 OS 09/2018 Severe NPDR Improved CSME s/p Avastin x 6, target 15 Different pt: 77 yo male 11/15/2018 Mod POAG, new macular edema OD Cosopt and Travatan 4

5 , target 15 SLT 25 20, target 15 SLT Pre-tx IOP Post-tx IOP American 77 Glaucoma yo male Society 11/15/2018 Annual Meeting, 2014 Lawrence Jindra, MD, Columbia University POAG moderate target 12 SLT primary treatment for one or both eyes Cosopt 31% and reduction, Travatan n= Pre-tx IOP Post-tx IOP American 77 Glaucoma yo male Society 11/15/2018 Annual Meeting, 2014 David Godfrey, MD, Dallas POAG moderate target 12 SLT for MTMT (avg 2.5 meds before SLT) Cosopt 16% and reduction, Travatan n=54, target 15 SLT CAI Rhopressa Add Rhopressa OS BID (one-eye trial) 77 yo male 11/15/2018 POAG moderate target 12 Cosopt and Travatan 5

6 Rhopressa Adverse Events Summary Hyperemia Absent or sporadic for 90% of patients Only 10% of patients had hyperemia at all 6 visits Conjunctival hemorrhage Sporadic subconjunctival petechiae None noted at month 12 visit Corneal deposits (verticillata) Asymptomatic non-toxic lipid deposits, high resolution rate Reduced visual acuity Sporadic, mostly single visit, only one eye Incidence reduced over time Blurred vision Sporadic, significantly reduced over 12 months +Lumify = OTC brimonidine 0.025% US Glaucoma Market Adjunctive therapy represents nearly half the glaucoma market Subconjunctival petechiae seen sporadically in Rhopressa Rocket studies No conjunctival hemorrhages noted at month 12 visit 09/2018: Rhopressa out only 6 months already 2% adjuvant market (larger than Azopt or Simbrinza) Adjunctive Product Safety Comparison Prescriptions for current PGA adjunctive therapies represent nearly half of the entire US glaucoma market Rhopressa qday No systemic absorption and no serous adverse events Beta-blockers BID (timolol) Systemic absorption, less effective with systemic beta-blocker Contraindicated with cardiopulmonary disease (half over 65) Alpha agonists BID to TID (brimonidine) Systemic absorption, clonidine-like somnolence Hyperemia, allergic conjunctivitis, dry mouth CAIs BID to TID (brinzolamide, dorzolamide) Systemic absorption, sulfa reactions, renal failure, dysgeusia Rhopressa equally effective during nocturnal and diurnal periods Current glaucoma meds have no efficacy at night (beta-blockers, alpha agonists) or reduced efficacy at night (PGAs, CAIs) 6

7 Habitual IOP (mm Hg) Circadian Habitual IOP Sitting Supine Sitting :30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 11:30 AM 1:30 PM Clock Time No treatment Timolol gel Latanoprost Roclatan = Rhopressa plus latanoprost Primary efficacy endpoint: Mean diurnal IOP on day 29 Trial design follows FDA requirement for fixed-dose combination Liu, Kripke, Weinreb. Am J Ophthalmol. 2004;138: RHOPRESSA Reduces Potential Roclatan launch 1st half 2019 Reduces Increases More Reduces Visual Preservation Rhopressa: Increases trabecular outflow and reduces the progressive tissue fibrosis of POAG THANK YOU!!! 7