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Updates on Corneal Disclosures • Dr. Fuller – provides statistical Cross‐Linking & support for a non‐funded, independent clinical evaluation Control of a CXL device • Educational consultant to • Alcon, • Allergan, Daniel G. Fuller, OD, FAAO Dipl, FSLS • B+L, Chief, Contact Service • Cooper Vision and Supervisor, Cornea Contact Lens Refractive Surgery Residency • JJV The Eye Center, Southern College of Optometry Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Part 1: Objectives What is CXL? • To clarify the underlying principles • fibrils branch and • To critically review the scientific literature extend limbus to limbus • To provide an update on these technologies • Cross‐linking occurs • To guide selection of the appropriate between fibrils in the same candidates lamellar layer • To assist in identifying and managing potential • Provides biomechanical adverse events or loss of efficacy stability • To guide the integration of these technologies into practice

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Man‐made Natural

• Polymer chemistry uses – • Advanced glycation end • Enzymatic CXL –lysyl this is responsible for some products (AGE’s)– age & DM oxidase; a deficiency can of the differences in (prevent or decrease lead to Ehlers‐Danlos; modulus in SiHy lenses severity of KCN) maybe a gene defect in KCN • Reduction in • Photo‐oxidative CXL –UV & • Non‐enzymatic CXL – biodegradation – collagen‐ ionizing radiation glutaraldehyde; based bioprosthesis formaldehyde; diphenylphosphoryl; nitroalcohole; genipin https://www.medtronic.com/us‐en/healthcare‐professionals/products/cardiovascular/heart‐valves‐ surgical/hancock‐ii‐hancock‐ii‐ultra‐bioprostheses.html

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Initial Candidates Potential Candidates

• Primary corneal ectasias • Off‐label • Combined procedures – with • LASIK, INTACS, and • Pellucid marginal procedures degeneration • PiXL – treat low amounts of • Must demonstrate myopia without LASIK progression • Microbial – sterilize the wound • Age cut‐off is arguable • – to strengthen grafts • Secondary corneal ectasias or melts • LASIK/PRK • Corneal dystrophies – Fuch’s

Fuller, 2019 (COPE# 61275‐AS) and other Fuller, 2019 (COPE# 61275‐AS)

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Physical Properties Absorption of UVA/Emittance

CXL Process UV Spectrum • Riboflavin has two peak absorption maxima • Photochemical process • Ultraviolet spectrum • 375nm • Non‐thermal • UVA – 320‐400 nm • 445nm • Comparison to photocoagulation • UVB – 280‐320 nm • Photocoagulation – 630 • W/cm2 • UVC – 180‐280 nm Emits fluorescence at • Photochemical – 3 mW/cm2 534nm • M◦aximum temp. increase of2‐ 3C Lombardo, M et al. Interaction of ultraviolet light with the cornea: Clinical implications for corneal crosslinking. J Cataract Ref Surg. 2015; 41(2):446‐459. Mencucci R1, Mazzotta C, Rossi F, Ponchietti C, Pini R, Baiocchi S, Caporossi A, Menchini U. Riboflavin and ultraviolet A collagen crosslinking: in vivo thermographic analysis of the corneal surface. J Cataract Refract Surg. 2007 Jun;33(6):1005‐8. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Absorption of UVA Tissue Changes

• RF 0.1% sol. • Increase in modulus and firmness by a factor of 1.7x • Selected for an average KCN pach of 400 microns • Increase in shrinkage temp. from 63◦C • Biomechanical effect is independent of concentration over to 70◦C a large area • Decrease in swelling percentage • Higher conc. actually reduce CXL effect • Increase in collagen fibril thickness by • Produces a large absorption coefficient of 90% in the 4.5% stroma protecting the endothelium, lens and . • Increased resistance to collagenase • Creation of molecular aggregates with • 65% absorbed in the first 200 microns higher molecular weights • Decrease in permeability Wollensak G1, Spoerl E, Seiler T. Stress‐strain measurements of human and porcine after riboflavin‐ultraviolet‐A‐induced cross‐linking. J Cataract RefractSurg. Fuller, 2019 (COPE# 61275‐AS) 2003 Sep;29(9):1780‐5. Fuller, 2019 (COPE# 61275‐AS)

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Histological changes in human cornea after cross‐linkingwith Cellular Changes riboflavin and ultraviolet A

Epithelium • Epithelial cells

• Epi‐off – cells grow back in 3‐4 days 250 microns • Normal thickness at 3 to 6 months • Intact epithelium protects limbal stem cells • Keratocytes • Increases apoptosis in first 250‐300 microns • New cells migrate from periphery • Alterations occur up to 36 mos. Endo. Acta Ophthalmologica Volume 88, Issue 2, pages e17‐e18, 23 APR 2009 DOI: Wollensak G1, Spoerl E, Reber F, Seiler T Keratocyte cytotoxicity of riboflavin/UVA‐treatment in vitro. Eye (Lond). 2004 10.1111/j.1755‐3768.2008.01474.x Jul;18(7):718‐22. http://onlinelibrary.wiley.com/doi/10.1111/j.1755‐3768.2008.01474.x/full#f1 Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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From: Collagen Cross-Linking Using Rose Bengal and Green Light to Increase Corneal Stiffness Invest. Ophthalmol. Vis. Sci.. 2013;54(5):3426-3433. doi:10.1167/iovs.12-11509 Cellular Changes

•Endothelial cells • Statistically non‐significant reduction • Density and morphology unchanged at 1 year • Threshold for damage is 0.35 mW/cm2 ; exposure levels are 0.18 mW/cm2 • Assuming a 400 micron thick or greater cornea

Figure Legend: Keratocytes in cornea after photo-cross-linking. (A, B) RB was applied to cornea and exposed to 100 or 200 J/cm2 green light (A) or kept in dark (B). (C, D) Riboflavin/dextran was applied to cornea and exposed to 8.7 J/cm2 UVA (C) or kept in dark (D). Corneas were cultured for 24 hours then fixed, paraffin-embedded, and H&E-stained. (E) Cells in stroma of corneas treated with RB, then with 100 or 200 J/cm2 green light or kept in dark. Only cells in most anterior stroma (200 μm) on section were counted. (F) Cells in Wollensak G1, Spörl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. corneas treated with riboflavin, then with 8.7 J/cm2 UVA or kept in dark. Cells to a depth of 500 μm on the sections were counted. n Ophthalmic Res. 2003 Nov‐Dec;35(6):324‐8. = 3 to 4 cornea for each treatmentcondition. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) The Association for Research in Vision and Copyright © 2015. All rights reserved. Date of download: 6/10/2015 15 16 6/2/2019

Cellular Changes Cellular Changes

•Nerves • Deeper structures • Subepithelial • Lens – protected by the absorption of UVA by RF and nerve plexus cornea disappears • Retina – also protected by absorption and lack of • Regenerates after irradiation being focused in its plane 7 days and is normal by 6 mos.

Xia Y1, Chai X, Zhou C, Ren Q. Corneal nerve morphology and sensitivity changes after ultravioletA/riboflavin treatment. Exp Eye Res. 2011 Oct;93(4):541‐7. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Riboflavin Overseas

Riboflavin Used in the US Trials Riboflavin Formula Use Epithelum Cross‐linking for MedioCROSS 0.25% Riboflavin, 1.2% keratoconus and corneal On • Riboflavin (vitamin B2) 0.1% sol. – m.w. 376 TE HPMC, 0.01% BAC ectasia gm/mol (Photrexa 0.12% / Photrexa Viscous Cross‐linking for 0.1% Riboflavin, 1.1% MedioCROSS M keratoconus and corneal Off 0.12% with Dextran 20% from Avedro) HPMC ectasia • Non‐toxic 0.22% Riboflavin, Saline, Stromal VibeX Xtra LASIK • Absorbs UVA light Isotonic Bed

• Used to create free radicals which cross‐link the 0.1% Riboflavin, Saline, VibeX Rapid Accelerated CXL Off carbonyl groups within and between collagen fibrils HPMC in the same lamellae not between lamellae 0.25% Riboflavin, HPMC, ParaCel Accelerated CXL On • There may be some inter‐fibrillar bonds between BAC

proteoglycans Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Procedures: Dresden v. Athens Comparison of outcomes Bunsen‐Roscoe Law (Intensity x Time= Exposure)

• Dresden protocol • Athens protocol • Outcomes of treatment efficacy • Demarcation line depth is the 2 • Accelerated CXL – shallower measure of treatment efficacy. • Intensity is 3 mW/cm • Maximum intensity up to • Conventional CXL – deeper • Treatment time 30 mins. 43 mW/cm2; Treatment • Regression > with A‐CXL at 2 to 5 min. intervals time 2 min. • Problem epi‐off 3 mW/cm2 epi‐off 10 mW/cm2 • Typical protocols (Kymionis et al.) • Less available oxygen in • Applied over an 8 mm accelerated CXL with epi‐on. • 9mW/cm2 for 14min diameter area to protect • Solution 2 limbus, sclera and goblet • 18mW/cm for 7min • 30mW Pulsed therapy at 1s epi‐on Ionto. 10 mW/cm2 epi‐on 3 mW/cm2 cells • May pulse doses intervals of 3‐ 8min; allows O 2 more time to penetrate

Spadea L, et al. Corneal stromal demarcation line after 4 protocols of corneal crosslinking in keratoconus determined with anterior segment optical coherence tomography. J Cataract Kymionis GD, et al. Accelerated versus conventional corneal Ref Surg. 2018; 44(5)596‐602. Fuller, 2019 (COPE# 61275‐AS) crosslinking for refractive instability: an update. Curr Opin Fuller, 2019 (COPE# 61275‐AS) Ophthalmol. 2017;28:343‐347 21 22

Epithelium‐on (Transepithelial) Delivery of Epithelium‐off Delivery of Riboflavin Riboflavin • RF 0.1% every 1 to 5 • Improving penetration • Increase contact time (viscous mins. for 30 mins. sol. or ring application) • Eliminates the barrier to • Change permeability (pilocarpine with either BAK and EDTA; diffusion presented by tetracaine; hypo‐osmotic the epithelium riboflavin sol.) • Dextran inhibits conductance • Diffusion achieves a when added, whereas 0.01% BAC maximum in the anterior and 0.44% NaCl increase stroma at 20 to 30 mins., permeability. • Using a Daya disrupter you can protecting the pock‐mark the epithelium endothelium/lens/retina improving permeability

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Direct Application of Riboflavin Iontophoresis Delivery of Riboflavin

http://www.eyegatepharma.com/technology/iontophoresis‐delivery‐system/ • Create a pocket as in Intacs • Riboflavin in negatively charged • Current is delivered for 5 mins. • Inject riboflavin into the across the intact epithelium pocket or after flap creation • CONCLUSION: I‐CXL using 0.1% riboflavin halts keratoconus in LASIK progression within 24mo, resulting in a significant improvement in visual and topographic parameters. Moreover, the depth of the demarcation line is similar to that previously reported in standard epithelium‐off CXL procedures.

Int J Ophthalmol. 2017; 10(5): 717–722. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Devices Devices

• Overseas • United States FDA Trials • Avedro (Waltham, MA) KXL was • CBM VEGA X‐linker the submission device but UVX (Constuzione Strumenti, used in trials Oftalmici, FL, IT) • 30 min. induction every 2 mins. with Photrexa Viscous • CCL‐365 (PESCHKE or until flare is observed in the Meditrade GmbH, AC continues throughout tx. Huenberg, SW) • 3 mW/cm2 for 30 mins. • UV‐X (IROC GmbH, • 5.5 J/cm2 maximum energy density Zurich, SW) acquired by Avedro Fuller, 2019 (COPE# 61275‐ Fuller, 2019 (COPE# 61275‐AS) AS) 27 28 6/2/2019

Devices Case #1 • United States FDA Trials • 17 y.o. w/m with decreasing vision and contact lens • Selectable apertures deliver beams 7.5 intolerance mm, 9.5 mm & 11.5 mm • Dx with KCN Oct. 2012 • Subjective alignment by fluorescence • Cornea OD: Inf. Temp. scarring; Vogt’s striae; Fleischer’s ring • Touchscreen interface • Cornea OS: clear • Internal battery • Rapid progression to PK OD Mar. 2015 • Delivered through a gantry, upright or • Referred for trans‐epithelial CXL OS July 2015 supine MRE 10/8/12 MRE 9/29/14 MRE 6/11/15 ‐8.00‐5.25 x140 (20/200) ‐6.00‐12.00 x025 (20/30) ‐7.00‐6.00 x025 (20/30) • Software lockout ensures operators stay ‐‐3.25‐325 x095 (20/20) ‐2.75‐2.75 x095 (20/20) ‐1.75‐3.00 x095 (20/20) within allowable parameters 54.4/61.5 37.6/39.4 42.7/48.8 42.1/45.3 46.2/48.7 44.0/49.4 Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Case #1 54.4/61.5 Kmax 57.9

OD Lens History Date BCVA Comments Rose K 1/11/13 20/30 Synergeyes Clear Kone 1/18/13 20/30 Office visit 6/12/13 Corneal abrasion FTK Essilor Jupiter 6/19/13 20/30 Surgery OD 5/14 20/30 PK 42.1/45.3 Kmax 43.7 Synergeyes PS 9/14 20/15 Episode of rejection 3/15 20/20 PF 1% Maintenance Switch to UltraHealth 6/15 20/20 Not tolerating PS/UH Valley Contax Cust. Stable Elite 7/15 20/20

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Case #2

37.6/39.4 [9/14] 46.2/48.7 [9/14] 42.7/48.8 [6/15] 44.0/49.4 [6/15] • 21 y.o w/m; applying to the US Navy • Dx: KCN in 2010 • Sx: CXL and Intacs Feb 2015 • Successfully fit with Custom Stable Elite (Valley Contax) scleral lenses MRE BCVA Sim K’s ‐5.50‐2.75 x070 20/25 46.6/52.0 ‐6.00‐5.00 x170 20/100 31.60/37.50 CS Elite 7.85/15.8 ‐3.50 20/20‐3 CS Elite 7.85/15.8 pl‐2.00 x022 20/25+

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Approval granted for the treatment of Case #2 progressive keratoconus in April 2016 • The KXL system and the two • 12 months results photoenhancers, • Reduction in mean Kmax of 1 D in study 1 and 0.5 D in study 3 • Photrexa 0.146% (riboflavin compared with increase of 1 D in study 1 and 0.5 D in study 3 5’‐phosphate ophthalmic in sham-controlled eyes. solution) • Adverse events included corneal • Photrexa Viscous 0.146% opacity, corneal epithelium defect, (riboflavin 5’‐phosphate in corneal striae, dry eye, eye pain, punctate keratitis, , 20% dextran ophthalmic reduced visual acuity and blurred solution) vision.

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Overseas Experience Overseas Experience

Primary Keratoconus Author Follow‐up (mos.) Kmax dec. (D) BCVA’s Inc. lines Wollensak et al. 2003 3‐47 2.01D in 70% 1.26 lines in 65% Secondary Ectasia Author Follow‐up (mos.) Kmax dec. (D) BCVA’s Inc. lines Raiskup‐Wolf et al.2008 6‐72 2.68D in 62% >1 in 53% Kohlhaas et al. 2005 18 Stable Not recorded Wittig‐Silva et al. 2008 3‐12 1.45D 0.12 LogMAR Hafezi et al. 2007 12‐25 Dec. in all Improved in 90% Vinciguerra et al. 2009 12 1.35D 0.15 LogMAR Hersh et al. 2011 48‐60 2.0D >2 in 21.1% Vinciguerra et al. 2010 12 2.02D 0.1 LogMAR Asri et al. 2011 12 >2.0D in 21.3% 40% improved Kissner et al. 2011 96 Stable in 60% Stable in 60% Poli et al. 2012 12‐36 No significant trend Significant Improvement Salgado et al. 2011 12 Not statistically significant Not statistically significant Hersh et al. 2011 12 1.0D Significantly improved

1998 – First CXL in C.G. CarusFUullneri,v2e01r9si(CtyOPHE#o6s1p27i5ta‐AlS,) Dresden, GE. Fuller, 2019 (COPE# 61275‐AS)

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Final Data Included Meta‐Analysis

• Review of efficacy epi‐off KCN or surgical ectasia • 39 of 49 papers graded as very low quality evidence

Analysis of epithelium‐off CXL • Only 46 of 49 papers included efficacy & AE data Number (%) papers by study type • Data included for analysis from 40 studies out of these Randomized controlled trial 8 (16%) 46 papers Prospective case series 25 (51%) Prospective comparative case series 4 (8%) Retrospective case series 7 (14%) Case series 5 (10%) 46 papers TOTAL N= 49 49 papers 40 studies Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, Mandava L, Powell J, Figueiredo F. Epithelium‐Off Photochemical Corneal Collagen Cross‐Linkage Using efficacy + AE Riboflavin and Ultraviolet A for Keratoconus and Keratectasia: A Systematic Review and Meta‐Analysis. The Ocular Surface 2014;12:202‐214 .

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Outcomes Assessed Results

• Time points 6, 12 and 24 months Topography Visual Acuity Results • Topography– Mean, Max and Min K • Changing up to 12 mo. • Statistically significant • Visual acuity – corrected and uncorrected • Mean and Max K’s – improvement at all time • Refraction Reduction of 1.00D periods • Central corneal thickness (CCT) • Min K – reduction of 0.75 D • UCVA improved more than BCVA Maintained over time

Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, Mandava L, Powell J, Figueiredo F. Epithelium‐Off Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, Mandava L, Powell J, Figueiredo F. Epithelium‐Off Photochemical Corneal Collagen Cross‐LinkageFuUllesri,n2g01R9ib(oCfOlaPvEin# 6a1n2d75U‐lAtrSa)violet A for Keratoconus and Keratectasia: A Photochemical Corneal Collagen Cross‐LinkageFuUllesri,n2g01R9ib(oCfOlaPvEin# 6a1n2d75U‐lAtrSa)violet A for Keratoconus and Keratectasia: A Systematic Review and Meta‐Analysis. The Ocular Surface 2014;12:202‐214 . Systematic Review and Meta‐Analysis. The Ocular Surface 2014;12:202‐214 . 41 42

Results Summary Adverse Events

Refraction Central Pachs A Matter of Record from the Advisory Panel Report • Statistically significant • Statistically significant decrease (301) 890‐4188 improvement in cylinder in central corneal thickness of ….“the most common adverse events for either indication (approx. 0.50 D) approx. 0.14 microns (keratoconus or surgical ectasia) at greater than or equal to 10 • Stable by 12 mo. and stable percent are corneal epithelial defect, corneal opacity, corneal thereafter striae, eye pain, and punctate keratitis. Most of these events • Statistically significant appear to represent sequelae following corneal epithelial improvement in spherical debridement.” equivalent

Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, Mandava L, Powell J, Figueiredo F. Epithelium‐Off Photochemical Corneal Collagen Cross‐LinkageFuUllesri,n2g01R9ib(oCfOlaPvEin# 6a1n2d75U‐lAtrSa)violet A for Keratoconus and Keratectasia: A Fuller, 2019 (COPE# 61275‐AS) Systematic Review and Meta‐Analysis. The Ocular Surface 2014;12:202‐214 . 43 44 6/2/2019

Integration into Practice • Understand criteria Part 2 • Look for progressing cones and surgical ectasias Myopia Control • Younger patients without scarring are prime candidates • Results are clinically and statistically significant • Results are long lasting • The safety profile based on the evidence is great • Work with your state boards, this may be in your scope of Daniel G. Fuller, OD, FAAO, FSLS practice already. Chief, Cornea Contact Lens Service Supervisor, Cornea Contact Lens Refractive Surgery Residency • Reimbursement varies The Eye Center, Southern College of Optometry Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Part 2: Objectives Epidemic of Myopia Progression •To understand the scope of the epidemic of • Worldwide prevalence – 22% or 1.5 B people1 myopia progression • United States2 (ages 12‐54 years) •To appreciate the impact on public health • 1971‐1972 – 25% • 1999‐2004 – 41.6% •To provide an evidenced‐based summary • Myopes >8.00D increased 8x •To review contact lens applications • Varies with ethnicity1 •To guide practice implementation • East Asia – 70‐80% • Western countries – 25‐40%

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Global Prevalence of Myopia and High Myopia from 2000 through 2050 7 Graph showing the distribution of people estimated to have myopia across age groups in 2000 and 2050. 6 B 70%

I 5 60% Myopia Prevalence 2050 L 50% L 4 40% I 3 O 30% N 2 20% S Myopia Prevalence 2000 1 10%

0% 0 0 2550 75 100 2000 2010 2020 2030 2040 2050 AGE

Holden, BH et al. Ophthalmology 2016 123, 1036-1042. DOI: (10.1016/j.ophtha.2016.01.006) Ophthalmology 2016 123, 1036-1042 DOI: (10.1016/j.ophtha.2016.01.006) Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Increased Prevalence of Myopia in the United States Increased Prevalence of Myopia in the United States Between 1971‐1972 and 1999‐2004 Between 1971‐1972 and 1999‐2004

SEX & AGE 1971‐1972 (%) 1999‐2004 (%) P‐VALUE AGE 1971‐1972 (%) 1999‐2004 (%) P‐VALUE Female 18‐24 31.4 42.6 0.004 Total 27.1 45.8 <0.001 25‐34 32.3 51.6 <0.001 Male 35‐44 39.3 49.4 0.02 45‐54 22.8 37.4 <0.001 45‐54 39.5 51.8 0.01

Arch Ophthalmol. 2009;127(12):1632-1639. doi:10.1001/archophthalmol.2009.303

Arch Ophthalmol. 2009;127(12):1632-1639. doi:10.1001/archophthalmol.2009.303

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Ocular Changes Associated with Myopia

Retinal/Posterior Complications3‐11 • Chorioretinal atrophy • Myopic macular • Lattice degeneration degeneration (leading • Pigmentary degeneration cause of vision loss across • Lacquer cracks the world) • Posterior staphyloma • Rhegematogenous defects • Fuch’s spot • Posterior vitreal SRNVM detachment

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High Myopia with rhegmatogenous detachment Rhegmatogenous Detachment

Eye BCVA OD ‐17.00‐6.00x045 20/50 OS ‐16.00‐1.50x090 20/400

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Rhegmatogenous Detachment Other Potential Complications •Glaucoma12‐14 – odd ratio of 1.5 to 3.3x greater risk •Cataracts15 – nuclear and subcapsular • anomalies3,16 •Crescents •Tilted discs •Larger disc areas

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Nature Nature

• Genetics17‐33 • Genetics17‐33 • Biometric components of • If two parents myopic risk is 5x myopic eye to 6x greater compared to no or • Axial length (AL)– longer; one parent heritability 40‐94% • • Anterior chamber depth Myopic children shown to (ACD) – deeper spend more time indoors and • Keratometry – flatter reading than those of • Lens thickness – thinner emmetropic parents • If of east Asian ethnicity 8x risk

Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Nurture Nurture •Environmental34‐40 • Environmental34‐40 •Time outdoors seems to be protective • Increased near work regardless of race – BUT only prior to onset of increases risk of myopia myopia • Duration reading at close •Urban populations at higher risk distances have significant associations rather than •Myopia shown to progress during winter total time on all near months activities

•Sunlight exposure inversely related to myopia http://inventorspot.com/articles/antimyopia_school_desks_bar_chinese_students_nearsightedness

independent of aFculletr, i20v19 i(CtOPyE# 61l27e5‐AvS) el Fuller, 2019 (COPE# 61275‐AS)

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Proposed mechanisms of action 41–57 (MOA) MOA Takeaways •Animal models from past 30 years – chickens, •Form deprivation – plus lens and minus lens mice, monkeys, tree shrews AL •Emmetropization process – matches AL to optical •Peripheral focus – hyperopic and myopic AL power •Animal studies suggest association not causation •Structural protein control defective – retina, RPE, •CLEERE Study – excessive does and/or sclera not cause myopia

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MOA Takeaways41–57 MOA Limitations

• (Kang et al, 2010; Sng et al, 2011) Hyperopia • (Mutti et al, 2007,2011) – Collaborative Longitudinal • Emmetropes & hyperopes Evaluation of Ethnicity and Refractive Error (CLEERE) exhibit peripheral myopia Emmetropia • “A more negative refractive error, longer axial length, and relative to central refraction more hyperopic relative peripheral refractive error in and an oblate ocular shape Low Myopia addition to faster rates of change in these variables may • Myopes exhibit more hyperopic be useful for predicting the onset of myopia, but only within a span of 2 to 4 years before onset.” peripheral defocus relative to • The inconsistent link between retinal peripheral central refraction and less Mod. To High Myopia hyperopia and axial elongation suggests other oblate ocular shapes T Central N mechanisms are in play

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Comparative Overview of Treatments Comparative Overview of Treatments Favors Control Favors Treatment Under‐minus CL’s Decrease in Myopia (D) Decrease in Axial Length (mm)

PAL SVSL/Placebo SVSL/Placebo USVL USVL SCL SCL Timolol GPCL Bifocals GPCL BSL BSL PDMSL PDMSL PAL PAL Pirenzepine MOA PDMFCL PDMFCL PBSL PBSL Pir Pir Atropine OK Cyc AtL AtL AtM AtM AtH AtH

‐0.2 ‐0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 ‐0.25 ‐0.2 ‐0.15 ‐0.1 ‐0.05 0 0.05 Leo SW, Young TL. An evidenced‐based update on myopia and interventions to retard its progression. JAAPOS. 2011;15(2):181‐189. Huang J, et al. Efficacy Comparison of 16 Interventions for Myopia Control in Children A Network Meta‐analysis. Ophthalmology 2016;123:697‐708 Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Treatment Options Treatment Options • Pharmacological • Optical • Atropine65–96 (ATOM Study) •Undercorrection85,86,92,94,96,103–107 • statistically and clinically significant decrease in • Seems to promote progression in humans but not progression over two years (77% reduction in animals myopia and no change in AL) • Human studies– more myopia in group treated with • SE are significant 0.75D under correction (Chung et al, 2002); no significant • Rebound effect is concerning affect (Alder & Millodot, 2006) • Counter both with low dose (0.01%) • Bifocals84,85,88,92,96,108–123 – (US, Finland andDenmark) • Pirenzipine 2% gel bid82–85,88,89,92–102 no significant slowing • M1 selective antagonist (accommodation and •PAL (COMET Study) 47,85,93,96,101,104,113,124–142 – ) statistically but not clinically significant

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Treatment Options Soft Multifocals

•Contact lenses56,84–86,88–96,102,103,105,138,143–186 •Bifocals/Dual focus85,86,91,92,94,163,165,173,180 • GP lenses – Differing results but they do not slow • Average reduction in myopic progression of 46% versus 43% for progression in children92 OK lenses • Soft lenses – “myopic creep” not found in • Only center distance lenses investigated Single Vision Author Bifocal Design Add Power Study Bifocal (D) randomized studies and SCL do not prevent Control (D) progression Anstice Concentric +2.00 Contralateral ‐0.44+0.33 ‐0.69+0.38 • Comparing GP to SCL –lower amounts of myopia Lam Concentric +2.50 Randomized ‐0.59+0.49 ‐0.79+0.56 Prospective, ‐0.84+0.47 Sankaridurg Progressive +2.00 ‐0.28+0.28 in GP wearers but no difference based on AL. historical control Prospective, Walline Progressive +2.00 ‐0.51+0.06 ‐1.03+0.06 Corneal flattening accounts for the difference historical control

Walline J . Myopia Control: A Review. Eye & Contact Lens: Science & Clinical Practice. 42(1):3‐8, January 2016. DOI: 10.1097/ICL.0000000000000207 Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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How they work How they work

• MOA • Challenges • Aspheric designs with center distance increase • Power profiles for adds vary across spherical peripheral retinal SA in a positive direction power ranges even in the same lens design (de la (Atchison et al, 2006; Kang et al, 2013; Ticak et al, 2013) Jara et al, 2014) • (Walline et al, 2013) Compared aspheric dist. • Effects on accommodation were not considered Center to spherical soft lens over 2 years • (Bickle and Walline, 2013) Add powers above • 50% reduction in progression +2.50 in center distance design may not be • 29% reduction in AL tolerated by myopic children

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Dual‐focus Soft Multifocals Dual‐focus Soft Multifocals • Dual‐Focus design (MiSight, Cooper Vision) • Dual‐Focus design (MiSight, Cooper Vision) • Proclear material • (Anstice and Phillips, 2011) Cross‐over design • +2.00 add; 3.36 mm OZ • MiSight v. Spherical control • MOA – center drives • 10 month duration; N=34 accommodation, treatment • zones create myopic 30% reduction in myopia in MiSight eye peripheral defocus • No significant loss of CSF in this study, but……

Anstice NS, Phillips JR. Ophthalmology 2011; 118(6):1152–1161

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Dual‐focus Soft Multifocals Aspheric Concentric Soft Multifocals

• Limitations • Unnamed Myopia Control Lens (Alcon) • No significant loss of CSF in this study, but…… • Air Optix (Lotrafilcon B) • (Kollbaum et al, 2013) compared dual‐focus & near centered designs against spectacle correction finding more ghosting for • 8.6/14.2 both and loss of one line of LogMAR VA in dual focus • +0.25 in central 1.5mm progresses to +1.00 at 2.0 mm and • Small sample size +2.00 at edge of the 9.0 mm zone • Short duration • Peripheral plus powered aspheric design • Paired‐eye is not binocular as will be used • At cross‐over the fellow eye has progressed and is not matched • Not commercially available unlike the MiSight which is to the treated eye available overseas and Canada • Duration of effect and rebound issues are unknown

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Aspheric Concentric Soft Multifocals Aspheric Concentric Soft Multifocals • Alcon myopia control lens • Alcon myopia control lens • Results: • Methods: • Progression in SER at 12 months was 34% less • Chinese children (n = 45) aged 7 to 14 years, (−0.57 D) with the novel contact lenses (95% • −0.75 to −3.50 D and cylinder ≤1.00 D) confidence interval [CI], −0.45 −0.69 D) than • Followed up for 12 months (−0.86 D) SRx (95% CI, −0.74 to −0.99 D). • Control group (n = 40) matched for age, sex, refractive error, axial length, and parental myopia • Estimated increase in axial length (AL) was 33% wearing single‐vision spectacles. less for CL group [0.27 mm (95% CI, 0.22–0.32 mm)] than SRx group [0.40 mm (95% CI, 0.35– 0.45 mm Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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EODF Soft Multifocals EODF Soft Multifocals • EDOF (Novel design, BHVI; NaturalVue, VTI) • Tilia et al, 2016 • Tilia et al., 2016 • BHVI design compared against Air Optix MF (Hi, • BHVI against Acuvue Oasys for ; N=41; Med, Lo adds); N=52; prospective, randomized, prospective, cross‐over, randomized, single masked trial cross‐over design • Results: EODF lenses provided better intermediate and • Results: near vision without compromising the distance. • No difference at 6m • EODF better in all other distances, better stereopsis, fewer complaints of glare and ghosting, preferred 5x more often

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EODF Soft Multifocals EODF Soft Multifocals

• Sha et al., 2018 • EODF for Myopia Control • BHVI design compared to 1‐Day Acuvue Moist MF; • Cooper et al N=57, double‐masked, prospective, randomized, cross‐ • VTI lens, retrospective, case series from 10 practices over design. • Results: Reduction in annualized myopia progression by • Results: No difference in HCVA at dist or stereopsis. 95.4%‐96.25%; 98.4% of children showed reduced EODF better at intermediate and near with fewer progression, 81.25% showed complete halting; 6.25% photic complaints showed regression of progression • Limitations: Numerous

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Summary comparison of selected designs Orthokeratology lenses Subjects Reduction in Reduction in Duration Study Design Completing Study Myopia Axial Length (%) (n=) Progression (%) (mos.) • Many players in this space (Paragon CRT, B+L Specialty Proclear® Multifocal Center-distance, aspheric, 5512924 (CoopperVision, concentric Vision Products; Emerald, Euclid, etc.) Pleasanton, CA)83 Novel design Alcon Center-distance, aspheric, • MOA (Duluth, GA).84 concentric 43 34 32 12 40 54 80 20 MiSight (CooperVision, Center-distance, • Myopic peripheral retinal defocus (Kang et al, Pleasanton, CA)62,85 concentriczones (144) (59) (52) (36) 2011) Defocus IncorporatedSoft Contact (DISC) [Centre Center-distance, for Myopia Research,the • Increase in spherical aberration (Gifford et al, concentriczones 65 25 31 24 Hong Kong Polytechnic University]86 2013) Acuvue Bifocal (JJV, Distance-center zonular 87 78 72 79 12 Jacksonville, FL) • Increase in amplitude of accommodation (Zhu et Novel designs (Brien EODF low and (high) 6 Holden Vision PtLtd., al, 2014) adds 508 in 5 groups 27 to (33) 38 to (56) Sydney, NSW, AU)88 (12) NaturalVue Multifocal1 Day® (VTI, Alpharetta, EODF 32 95 to 96 No data 6 to 25 GA)57 Fuller, 2019 (CO PE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Orthokeratology lenses Orthokeratology lenses

•Orthokeratology lenses27,86,88,91–94,96,116,147,149,160,166–172,181,182,184,187–193 •Rebound effect found (Swarbrick, 2015) • Average reduction in myopic progression of • Design – Cross‐over OK in one eye GP sphere in the 43% other after 6 mos. • AL 0.36+0.24 mm OK v. 0.09+0.09 mm sph GP • OK eye had less of an inc. in AL (Swarbrick et al, 2015) • Switching the GP lens to the OK eye caused AL growth • ROMIO study – effective in children already rate to double until it caught up with >5.00 DS myopia(Cho and Cheung, 2012) • Similar results seen in atropine v. placebo studies • AL for OK group 0.19+0.1 mm v. spectacles only • Conclusion – slows progression up to 3 years but not 0.51+0.32 mm (P=0.005) clear how long treatment should be continued to maintain the effect. Rebound may be an issue.

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Environmental options Summary

•Environmental33,194–198,86,92,95,96,103,107,115,116,142,167,199–206 • Take‐aways • Low dose atropine provides best effect • Outdoor time (Jones et al, 2007) • OK, Soft Dual Focus/BF contacts are second best effect but • Possibly reduces onset but not progression more practical • Recommendations for 8‐15 hours a week • Center distance designs are preferred in DF/BF contact • Supported by human and animal studies as being lenses or EDOF protective • Multiple profiles in lens designs are indicated (Cooper, Alcon and Essilor are players) • Combining low dose atropine with OK/DF/BF CL’s is likely additive From: Parental History of Myopia, Sports and Outdoor Activities, and Future Myopia Invest. Ophthalmol. Vis. Sci.. 2007;48(8):3524‐3532. doi:10.1167/iovs.06‐1118

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Implementation into Practice Implementation into Practice

• FDA • FDA • There are no FDA approved treatments for myopia control or prevention – all are • If a lens was submitted off‐label in the United States • Public Workshop ‐ Controlling the today it would likely take Progression of Myopia: Contact Lenses 7 years to approve (2017) and Future Medical Devices, September 30, 2016 • A 33% decrease in myopia • Purpose was to discuss increasing progression could reduce prevalence and reach a consensus on best study designs for devices IOVS 2019;60:M184‐2013 myopia >‐5.00D by 73% https://wayback.archive‐ according to the Brien it.org/7993/20170404181842/https://www .fda.gov/MedicalDevices/NewsEvents/Work Holden Institute shopsConferences/ucm500404.htm

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Doctrine of Informed Consent Applies Fee Agreements

• Risks‐Benefits‐Alternatives • Vary widely • Must tread lightly • Global fee • Must inform parents/patient this is an off‐label treatment • Fee per visit • The science of underlying cause is not definitively • Should disclose approach clearly established • Parents/Patients must be committed to the long haul • The MOA of various devices is not completely understood • Study the evidence, attend major meetings (e.g. AAO,

AOA, GSLS, IAO, AAOMC)Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS)

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Equipment

• Topographers, Tomographers and Swiss Army knives • Axial length biometry • Cycloplegic refractions

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