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Innovations in Ocular Surface Disease

COPE#55203-AS

Walter O. Whitley, OD, MBA, FAAO

Director of Optometric Services

Virginia Eye Consultants

Residency Program Supervisor

PCO at Salus University

Disclosures - Walter O. Whitley, OD, MBA, FAAO has received consulting fees, honorarium or research funding from:

• Alcon

• Allergan

• Bausch and Lomb

• Biotissue

• Beaver-Visitec

• Carl Zeiss Meditec

• Glaukos

• Collaborative Eye – Co-Chief Medical Editor

• Review of Optometry – Contributing Editor

• Optometry Times – Editorial Advisory Board

• J&J Vision

• Ocusoft

• Science Based Health

• Shire

• Sun Pharmaceuticals

• TearLab Corporation

• Tearscience

Virginia Eye Consultants Tertiary Referral Eye Care Since 1963

• John D. Sheppard, MD, MMSc

• Stephen V. Scoper, MD

• David Salib, MD

• Elizabeth Yeu, MD

• Thomas J. Joly, MD, PhD

• Dayna M. Lago, MD

• Constance Okeke, MD, MSCE

• Jay Starling, MD

• Samantha Dewundara, MD

• Rohit Adyanthaya, MD

• Albert Cheung, MD

• Walter O. Whitley, OD, MBA, FAAO

• Cecelia Koetting, OD, FAAO

• Christopher Kruthoff, OD, FAAO

• Jessica Schiffbauer, OD

• Kelsey Butler, OD

• Mark Enochs, OD

2016-2017 An Exciting Year for FDA Approvals

• Raindrop Near Vision Inlay – Revision Optics

• Tecnis Symfony – J&J

• Cypass Microstent – Alcon

• Angiovue Imaging – Optovue

• Triggerfish – Sensimed

• KXL System – Avedro

• Acrysof IQ Restor Activefocus - Alcon

• Light Adjustable IOL - RxSight

• SMILE – Carl Zeiss

• Xen Glaucoma Stent – Allergan

• Vyzulta – Bausch

• True Tear – Allergan

• Icare HOME Tonometer – Icare USA

• 3D OCT-1 Maestro – Topcon

• GYC-500/GYC-500 Vixi Green Scan Laser Photocoagulater – Nidek

• MP-3 Microperimeter

• Plex Elite 9000 Swept Source OCT – Carl Zeiss

• Zerviate – Nicox

• Bromsite - Sun

• Humira – Abbvie

• Photrexa Viscous and Photrexa - Avedro

• Lucentis - Genentech

• Xiidra – Shire

• Restasis Multidose - Allergan

• Insight 100 – Acrscan

Today’s Optometrists

“To be on the cutting edge of optometry, you need to be on the cutting edge of

science and technology.”

TFOS DEWS II Definition

“Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and

accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage,

and neurosensory abnormalities play etiological roles.”

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Fig. 5

The Ocular Surface 2017 15, 539-574DOI: (10.1016/j.jtos.2017.05.001)

Copyright © 2017 Elsevier Inc. Terms and Conditions

Point of Care Testing

Dynamic Meibomian Imaging Osmolarity

MMP-9 Corneal Topography AS-OCT

LIPCOF

Biomarkers vs. Conventional Diagnostics

Test

Sensitivity

Specificity

Positive Predictive Value

(PPV)

Schirmer I <10mm1 83% 68% 31%

TBUT <10sec1 72% 62% 25%

Staining, rose bengal1 25% 90% 31%

Osmolarity >308 mOsms/L2,3 75-95% 88% 87%

MMP-9 ≥40 ng/ml4 85% 94% 97%

Lactoferrin <0.9 mg/ml 83% 98% Not available

Conv’l Sjögren’s biomarkers5 40-60% 40-60% Not available

New Sjögren’s markers7 95% 95% Not available

1.DEWS Report, 2007. Ocul Surf 2007;5(2):108-52. 2. Sullivan BD, Whitmer D, Nichols KK, et al. Invest Ophthalmol Vis Sci 2010;51(12):6125-30. 3. TearLab Osmolarity Test, Package Insert. 4.

InflammaDry Package Insert-English, Canada, Rapid Pathogen Screening, Inc. 5.Huang Y, Cheng Q, Jiang C, et al. Clin Dev Immunol 2013. 6. Finis D, Pischel N, Schrader S, Geerling G. Cornea 2013;32(12):1549-53. 7. Data on file, Nicox

POC Diagnostics Guide Treatments

• Evaluate structure and function of MG • Lipiflow?? Miboflo? IPL??

• Presence of inflammation??? • Rx drops?? Punctal Plugs?? TCN??

• Is the tear film stable? • Are additional therapies needed??

Copyright © 2017 Elsevier Inc. Terms and Conditions

The Ocular Surface 2017 15, 575-628DOI: (10.1016/j.jtos.2017.05.006)

Leading the Future of Diagnostics

• TearLab DISCOVERY™ Platform: • Quantitative

• Rapid testing (< 2 minutes)

• Multiplexed biomarkers

• EHR Integration

• First test card to include: • Osmolarity

• Two Inflammation markers:

• MMP-9

• IL1-Ra

Osmolarity in Diagnosis & Grading of Dry Eye

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I-PEN® by I-MED Pharma Inc.

• Quantitative measurement

• Rapid results in <5 seconds

• Handheld, light & simple to use

• Affordable point-of-care testing

Tear Film Analyzer - Visiometrics

High Resolution Meibography Imaging

Cloud-based Computing

Easy to Use

Increased clinic efficiency

Regular Software Updates

Small Footprint

Very Portable

Customized and printable patient reports

Central Unit Available

LipiScan™

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REACTIVE CARE PROACTIVE CARE

Duct dilation, atrophy and dropout

Severe atrophy and dropout

Epi-Mapping - Optovue

• Quantitative measurements of the epithelial and stromal layers of the cornea

• Indications • Refractive surgery

• Keratoconus

• Dry eye disease

• Commercially available on the iVue and iFusion OCT systems

Rocha KM, Straziota CP, Stutling RD, et. Al. Spectral-Domain OCT Analysis of Regional Epithelial Thickness Profiles in Keratoconus, Postoperative Corneal Ectasia, and Normal Eyes. J Refract Surg. 2013 Mar; 29(3): 173-179. Li Y, Tan O, and Huang D. Corneal epithelial thickness mapping in Normal and keratoconic eyes with fourier-domain optical coherence tomography. Investigative Ophthalmology & Visual Science. April 2010, Vol.51, 5819.

Fig. 1

The Ocular Surface 2017 15, 575-628DOI: (10.1016/j.jtos.2017.05.006)

Copyright © 2017 Elsevier Inc. Terms and Conditions

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RestasisTM (cyclosporine 0..05% ophthalmic emulsion)

Works on All Three Layers and Underlying Inflammation

XiidraTM (lifitegrast ophthalmic solution 5%)

• Lifitegrast is a small molecule integrin antagonist that interferes with binding of ICAM-1 to the integrin LFA-1 on the T cell surface, inhibiting T cell recruitment and activation associated with dry eye disease (DED)

• Lifitegrast ophthalmic solution 5.0% has been investigated in 3 (one Phase 2 and three Phase 3) randomized controlled trials for treatment of DED1–3

1. Semba CP, et al. Am J Ophthalmol. 2012;153(6):1050-60. 2. Sheppard JD, et al. Ophthalmology. 2014;121(2):475–83. 3. Tauber J, et al. Ophthalmology. 2015;122(12):2423-31.

Lotemax gel (loteprednol etabonate ophthalmic gel 0.5%)

• Ester based steroid

• Vehicle: Polycarbophil (mucoadhesive polymer matrix)

• A component of the vehicle DuraSite that adheres to mucous membrane-like tissues

• This increases retention time and drug penetration

• Added moisturizing agents

• glycerin and propylene glycol

• Preservative: BAK

The Asclepius Panel Recommended Treatment Model for Dry Eye Inflammation

Adapted from Holland EJ. Ophthalmol Times. 2007;32:3-11.

Lotemax® QID (loteprednol etabonate ophthalmic suspension 0.5%)

Artificial Tears

Lotemax® BID (loteprednol etabonate ophthalmic suspension 0.5%)

Lotemax®…up to QID for flare-ups (loteprednol etabonate ophthalmic suspension 0.5%)

Restasis® BID (cyclosporine ophthalmic emulsion) 0.05%)

Thereafter

Cornea/External Disease Advisory Group Treatment Consensus

TRUETEAR™: PRODUCT INNOVATION

• First-ever neurostimulation device in eye care

• An easy-to-use and drug-free option to temporarily increase tear production during neurostimulation in adult patients

• Provides small electrical pulses to stimulate production of your own natural tears

• First “smart” device in eye care with Bluetooth® enabled and connected application

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LFU REGULATES TEAR PRODUCTION1-4

• Lacrimal Functional Unit (LFU) maintains a healthy environment for the eye by regulating tear production

• Neurostimulation in the nasal cavity targets the trigeminal nerve to trigger the nasolacrimal reflex to emulate the normal neural signals to create a natural tear

BY COMMUNICATING WITH CENTRAL NERVOUS SYSTEM (CNS)

1. Kossler et al. Ophthal Plast Reconstr Surg. 2015; 2. Beuerman et al. In: Pflugfelder et al, eds. Dry Eye and Ocular Surface Disorders. 2004; 3. Dartt. Ocul Surf. 2004. 4. Freidman et al. A nonrandomized, open-label study to evaluatethe effects of nasal stimulation on tear production in subjects with dry eye disease. 2016

CLINICAL DATA • In Study 1, patients saw an approximate 2.5x greater increase in tear production with

intranasal stimulation on study day compared to sham or external stimulation1

1. Data on file, Allergan; OCUN-009

CLINICAL DATA (CONTINUED)

• In Study 2, clinically and statistically significant increase in tear production was seen at 180 days1

1. Data on file, Allergan; OCUN-010

GOBLET CELL DEGRANULATION WITH THE INTRANASAL NEUROSTIMULATOR

Impression Cytology After Neurostimulator Application

Extranasal Intranasal

K Gumus, Shcuetzle K, Pflugfelder S. Randomized Controlled Cross Over Trial Comparing the Impact of Sham or Intranasal Tear Neurostimulation on Conjunctival Goblet Cell Degranulation. Am J Ophthalmol 2017: 177; 159-168.

Total Protein Total Lipid

Mea

n T

ota

l Lip

id (

µg/

µL)

± S

EM

Mea

n T

ota

l Pro

tein

(µ

g/µ

L) ±

SEM

Tear Biochemistry

• Conclusion: Tears stimulated by use of TrueTear contained equivalent concentrations of total protein and total lipid compared to the subjects normal (basal or unstimulated) tears

Ousler et al 2016; Argueso and Woodward 2016; Basso et al 2016

Tear Biochemistry

• Total protein data results: amount of lysozyme and lactoferrin in post-stimulation tears are equivalent to basal tears

Lysozyme Lactoferrin

Mea

n R

elat

ive

Lyso

zym

e Le

vel

± SE

M

Mea

n R

elat

ive

Lact

ofe

rrin

Lev

el ±

SEM

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OTX-101 – Sun Pharmaceuticals

• A nanomicellar formulation of cyclosporine 0.09%

• In this 12 week, multicenter, randomized, double-masked, vehicle controlled Phase 3 confirmatory study, 744 dry eye patients were treated either with OTX-101 or its vehicle. • Met primary endpoint of Schrimer’s Score (p<0.0001)

• The demonstration of efficacy at 12 weeks is earlier than other drugs approved for dry eye in the same class.

NovaTears / EvoTears – Novaliq Inc.

• Non-preserved tx for evaporative dry eye

• Innovative mode of action due to the patented EyeSol®-Technology – Made in Germany

• Forms a protective layer over the tear film

• Long-lasting effect for greater patient satisfaction – clinically proven¹

• Extremely well tolerated as free from preservatives, phosphates and emulsifiers

Neuropathic Dry Eye Pain

• Role of cannabis

• EyeSol – a novel semi-fluorinated alkane drug delivery technology • Low surface tension

• No water

• Metabolically inert

• Refractive index similar to H20

Steven, P. Realm of dry eye therapy expanding. Ophthalmology Times. November 15, 2017

Amniotic Membranes

• Used to manage ocular surface healing for a variety of indications including: • Corneal epithelial defects

• High-risk corneal transplants

• Recurrent Corneal Erosion

• Infectious Diseases (Herpes/Keratitis)**

• Stevens-Johnson Syndrome & Chemical Burns

Key Amniotic Membrane Components

• Regenerative • Heavy chain hyaluronic acid

• Proteoglycans

• Biological scaffolding • Growth factors

• Collagens (types I, III, IV, V and VI)

• Fibronectin

• Laminin

• Glycosaminoglycans

1. Rinastiti M, et al. Int J Oral Maxillofac Surg. 2006;35:247-251. 2. Jin CZ, et al. Tissue Eng. 2007;13:693-702. 3. Niknejad H, et al. Eur Cell Mater. 2008;15:88-99. 4. He H, et al. J Biol Chem. 2009;284:20136-20146. 5. Data on file, Bio-Tissue, Inc., 2012. 6. Hopkinson A, et al. Invest Ophthalmol Vis Sci. 2006;47:4316-4322.

Amniotic Membranes

Cryopreserved Prokera

Dry Membrane BioD

Dry Membrane Ambiodisc

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Amniotic Cytokine Extract Drop • Genesis - Amniotic cytokine extract (ACE) for

the treatment of ocular surface disease. • Cryopreserved amniotic eye drops contain more

than 120 cytokines, growth factors and anti-inflammatory molecules to modulate and restore balance to the tear film

• Regener-Eyes • Sterile, acellular biologic made from 771 anti-

inflammatory cytokines, and growth factors

Imprimis Pharmaceutical

Klarity-C Drops (Chondroitin Sulfate/Cyclosporine 0.1%) Preservative-

Free

5.5mL

First 3-month

supply $99.99

Autologous Serum Tears Preservative-Free (20-100%)

3mL bottles

$350**

Commonly Requested Formulations*

Unit Size Price

Omega-3 AR 500mg

360 capsules

$156 (a typical 3-month supply)

Doxycycline 10mg/Omega-3 AR

180 capsules

$109 (a typical 3-month supply)

CMHA-S Crosslinked Hyaluronic Acid • HA occurs naturally in the human body with qualities ideal for the

ocular surface • Promotion of wound healing and lubrication

• Native HA has a relatively short half-life

• Crosslinking HA creates a 3D structure that stabilized the molecule • Adheres longer to the ocular surface (up to 90 min)

• Higher viscosity that thins with blinking and is non blurring

• Matrix protects the ocular surface

CMHA-s: Animal studies Commercially available as a veterinary device;

Manufactured by SentrX Animal Care

Sold in the U.S. by Bayer Animal Health as Remend® Corneal Repair1

Sold world wide with 5 years experience in thousands of dogs, cats and horses, with an excellent safety profile

Efficacy has been demonstrated in masked, randomized clinical studies of corneal defects in dogs and cats

1. EyeGate (NASDAQ: EYEG) has human ophthalmic rights only. Visit http://www.bayerdvm.com/show.aspx/remend-cross-linking-video

M O L L Y A 1 2 Y E A R O L D

C A T W I T H A N O N -

H E A L I N G C O R N E A L

D E F E C T A T 4 2 D A Y S

( A )

H E A L I N G U L C E R A F T E R 1 2

D A Y S W I T H 0 . 7 5 % C M H A - S

G E L D R O P S

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C M H A - s : O c u l a r B a n d a g e G e l

A clear hydrogel (or liquid-gel) eye drop with a 0.75% concentration of CMHA-S

Crosslinked to provide reduced degradation on the eye

Exhibits significant shear thinning properties

Enables better residence time with no optical blur

Forms a thin layer over the ocular surface, protecting the eye

May accelerate re-epithelialization of corneal epithelial defects

PRK, superficial keratectomy, PKP

Corneal abrasions and ulcers

Neurotrophic keratitis

Severe SPK

Obstructive MGD leads to atrophy and gland dropout

B: Obstruction: hyperkeratinization of epithelium and/or increased viscosity of

meibum-reduced delivery of meibum onto the lid margin

E: Cornification of the whole ductal epithelium: gland dropout

A: Normal

C: Dilation: increasing pressure inside the glands, leading to gradual dilation of the

central duct

D: Atrophy: dilation of the connecting ductules and a pressure atrophy of the acini

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Intense Pulsed Light

• The specific mechanism of action is not well understood but is believed to be partially due to the thermal heating of the meibum coupled with the therapeutic effects of treating superficial telangiectasia

Radiofrequency

• ThermiEyes™: • FDA cleared (K130689) and

indicated for use in dermatological and general surgical procedures for electrocoagulation and hemostasis; creation of lesions in nerve tissue.

• Associated with improving skin laxity and wrinkle reduction using a Radio Frequency Thermistor Heating Device

Slide Courtesy of Drs. Christensen and Hauser

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LipiFlow® Thermal Pulsation System

Diagnostic Interferometry Included

Investigational: Not Covered

Professional Fee = $795 OU per patient**

MiBoFlo ThermoFlo® Meibomian Duct Therapy

TearCare System - Procedure

51

Procedure 1. Place iLid Devices on patient’s lower

and upper lids 2. Heat delivered to eyelids while

patient’s eyes remain open and blinking

3. Clear: lower and upper lids

76YOWF – Present for follow up for Glaucoma and dry eye disease • Compliant with drops OU. Vision

has been blurry and eyes irritated more in the past few months • Previous treated with topical

azithromycin

• Current Ocular Meds: Restasis BID OU, latanoprost qhs OU

• Numerous systemic meds including singulair, synthroid

• SPEED Score: 25

• Tear Osmolarity 308 / 315

• SLE: 2+ MGD OD / 3+ MGD OS / 1+ SPK OU • Cloud secretions OU

• MG Structure: See images

• IOP: 14/13

Early to Moderate Structural Changes to Meibomian Glands

Advanced Gland Atrophy / Dropout

Post Treatment

6 Weeks Post Treatment • Post Tx Osmolarity • 300/299

• Post Lipiflow Management • Heat masks qhs OU

• Hydroeye as directed

• Restasis BID OU

• Lipid based tear BID OU

• Latanoprost qhs OU

• F/u 3 months dry eye • Order tear osmolarity

• Order inflammadry

• SPEED Questionnaire

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The Ophthalmic Resources System

Neurolens / SIGHTSYNC

• Proprietary testing techniques and sophisticated eye tracking technology to objectively measure the amount of binocular misalignment a patient is experiencing at distance and near.

• Creates a dynamic customized measurement of misalignment at 6 meters and 50 cm, analyzing all elements of ocular fusion, including: • Heterophoria • Vergence conditioning • Binocular peripheral fusion • Fixation disparity • Accommodative convergence response • Alternating monocular central fixation

HOW IS IT DIFFERENT FROM TRADITIONAL TESTING? • Objective: 100% objective. No patient or

operator interaction. Sophisticated eye-tracking.

• Accurate: Measurements are calculated to the one-hundredth of a prism diopter.

• Efficient: Testing performed in less than three minutes by a technician.

• Standardization: Consistent, reproducible measurement (standard deviation is <0.8 prism diopter).

• DIGITAL VISION SYNDROME (DVS) STUDY • Patient Reported Symptom Relief – 90 Day

• 22 participants – inclusion criteria = Qualified as DVS sufferer by validated questionnaire

• 86% reported DVS symptoms as “Reduced Substantially” or “Basically Gone”

• CHRONIC DAILY HEADACHE STUDY • Patient Reported Symptom Relief – 90 Day

• 179 participants – inclusion criteria = refractory, end-of-line chronic headache & migraine

• 54% reported headache symptoms as “Reduced Substantially” or “Basically Gone”

Get That Red Out

• OTC Products

• Tetrahydrozoline HCl 0.05%

• Naphazoline hydrochloride 0.03%

• Off-label treatments

• Brimonidine <0.1%

• Topical anti-inflammatories

• Introducing B&L LUMIFY™ (brimonidine tartrate ophthalmic solution 0.025%)

• FDA Approved 12/17

DED - Other Investigational Approaches

• Artificial tears: hyaluronic acid and F6H8 based

• Anti-inflammatories: • Novel CSA formulations

• Novel corticosteroid formulations (dexamethasone intracanalicular depot and loteprednol etabonate mucus penetrating particle technology)

• Cis-urocanic acid (inhibits Janus N-terminal kinase signaling)

• EBI-005 (interleukin-1 antagonist)

• MIM-D3 (tropomyosin receptor kinase A receptor agonist/nerve growth factor mimetic)

• SkQ1 (antioxidant reactive oxygen species scavenger)

• RGN-259 (thymosin beta-4 antagonist)

Abelson MB, et al. Review of Ophthalmology. https://www.reviewofophthalmology.com/content/c/57512. Phadatare SP, et al. Advances in Pharmaceutics. http://www.hindawi.com/journals/ap/2015/704946.