innovations in dry eye and primary eye care 2 hours...dry eye relief and daily eyelid hygiene...

Innovations in Dry Eye and Primary Eye Care

November 1, 2019

Greg A. Caldwell, OD, FAAO [email protected] 814-931-2030 cell 1

Innovations in Dry Eye and

Primary Eye Care

Greg Caldwell OD, FAAOOptometric Education Consultants

Music City Fall ClassicNovember 1, 2019

Disclosure Statement(next slide)

1

Disclosures- Greg Caldwell, OD, FAAO

$ Will mention many products, instruments and companies during our discussion¬ I don’t have any financial interest in any of these products, instruments or

companies $ Pennsylvania Optometric Association –President 2010

2 POA Board of Directors 2006-2011

$ American Optometric Association, Trustee 2013-2016 $ I never used or will use my volunteer positions to further my lecturing career$ Lectured for: Aerie, Alcon, Allergan, BioTissue, OptoVue$ Advisory Board: Allergan, Sight Sciences, Sun, Takeda $ Envolve: PA Medical Director, Credential Committee

$ OCT Connect – Facebook page co-administer with Dr. Julie Rodman $ Optometric Education Consultants- Scottsdale, St. Paul, Quebec City, and Nashville,

Owner

2

Financial Obligations

3

Course Description and Learning Objectives

This course will reveal, feature, and spotlight innovations in dry eye and primary eye care that will impact every optometrist. Technologies, pharmaceuticals, products, services, and processes that advance eye care will be discussed in a rapid-fire presentation. This course will keep you "in the know" for delivering advanced patient care.

$Introduce the innovation to the clinician in each of the topic areas$Discuss how the innovation will impact the diagnosis and treatment in eye care

$Reveal the benefit of embracing the innovation $Demonstrate how it will impact patient care$Demonstrate how to integrate the innovation into the clinician’s practice$Enhance the clinician’s knowledge of selected innovations that impact eye care

4

How Many People With

$Diabetes$Thyroid$Glaucoma$Dry Eye

¬ 30 million

5

Experts Gather for Recommendations and Algorithms

$Corneal, External Disease, and Refractive Society¬ Dysfunctional Tear Syndrome (DTS)

$Tear Film & Ocular Surface Society ¬ Dry Eye Workshop II (TFOS DEWS II)

$Delphi Panel International Task Force¬ Delphi Panel

6


November 1, 2019


7 8

9 10

11

Vital Dyes $ Fluorescein

¬ Detects disruption of intercellular junctions

¬ Positive (stain)-pooling

¬ Negative (stain)-high or elevated areas

$ Rose bengal and Lissamine green ¬ Stains devitalized cells and cells that have lost

normal mucin surface

¬ Detects abnormal epithelial cells

12


November 1, 2019


Why are Conjunctival Staining and SPK Often Missed or Under Scored?

Wratten Filter

13 14

Aqueous Deficient vs Evaporative

$What’s the common denominator?¬ Eyes burn/discomfort/pain¬ pH

$What’s the next question?¬ When is it worse?

2 AM/PM

$AM- bacteria/parasite related$PM- aqueous deficient

15

Let’s Focus on Evaporative ---------------------------------------------------------------------------------------

48 year old manOU red, gritty, sandy and dry feeling

Va 20 20 20cc 20

Current CorrectionR -2.00 sphereL -3.00 sphere

EOMS: full, unrestricted PERRL (-)APDCT: ortho D/N CF: full by FC OU

16

$Diagnosis¬ Rosacea

$What findings support your diagnosis?¬ Telangiectasias¬ Erythema of the cheeks,

forehead and nose

¬ Rhinophyma2 Indicates chronic

$Let us get a closer look

17

A Closer Look

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November 1, 2019


Meibomian Gland DysfunctionExacerbated by Rosacea

Evaporative

$Treatment?¬Warm compresses¬Lid hygiene¬Artificial tears¬Omega 3 fatty acid

2 EPA and DHA total 1500 mg (1000 mg minimum) ¬Dermatological consult (Acne Rosacea)¬Oral antibiotics…???

2 Which one and why??

19

Minocycline

Leukotrienes

Arachidonic Acid

Staph Aureus

Staph EpidermidisLipase

Meibomian Gland Secretions(Lipid)

Prostaglandins

Thromboxines

Marginal Foam(Soap)

TurbidInspissated MG

How About Steroids?

Phospholipids

Tetracycline Analog

20

Clinical PearlTreatment Failure

$ If you continue to think of doxycycline and minocycline as antibiotics, treatment failure will be the result

$From this point on consider them a steroid

21

Minocycline / Doxycycline

$Drug of choice for MGD, marginal inflammatory blepharitis (posterior blepharitis)

$AB, anti-inflammatory and anti-collagenase$Inhibits lipase enzyme$No renal adjustment$50-100 mg qd-bid 2-12 weeks (pulse)

¬Lower maintenance dose

$20 mg Periostat (Doxycycline)¬Helpful in those with stomach or GI sensitivity

¬Excellent for those requiring long maintenance dose

22

Hyclate vs Monohydrate

$ I get calls from the pharmacist¬ Doxycycline

2 Doryx

– Enteric coated hyclate pellet)

2 Adoxa

– Monohydrate

23

My Paradigm for Minocycline / Doxycycline

$Status of MG

¬Inspissated

¬Turbid

¬Clear

$ Minocycline / Doxycycline Paradigm

¬Maximum dosage for 2-12 weeks (pulse)2 100 mg BID, QD

¬50-100mg qd while turbid¬20 mg longer treatments

2 Periostat (Doxycycline)

¬20 mg if maintenance dose needed

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November 1, 2019


What is an Inspissated MG?

25

I Can’t Believe It’s Not Butter!® Squeeze

26

27

2016 Treatment Current Precautions and Innovative Changes?

$Warm Compresses$Lid Scrubs$Artificial Tears, Systane Balance$Omega 3 (1500 EPA and DHA)

$Mino 100 mg PO 6 weeks, 50 mg 3 months, 20 mg maintenance (Doxy)

$Steroids, Tobradex qid (5 weeks with taper)¬ Moderately red and thickened lid margins¬ Marginal infiltrates

28

Precautions with Oral Tetracycline Analogs

$Tetracycline analogs¬ Doxycycline

¬ Minocycline

$Enhanced photosensitivity$Avoid in children and pregnancy (Category D)

$Enhances the effects of ¬ Coumadin¬ Digoxin

$ Idiopathic intracranial hypertension¬ Pseudotumor cerebri

$Hyperpigmentation

29

Benign intracranial hypertension“It’s not rare if it’s in your chair”

8-19-2010

8-31-2010(12 days)

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November 1, 2019


9-13-201025 days

10-6-201048 days

8-19-2010

31

Minocycline Optic Nerve Edema

32

Minocycline Optic Nerve Edema

33

OMG!

34

6 Month Later

35

1 Year Later

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November 1, 2019


Innovations

Dry Eye Disease

37

OTC25%

Rx71%

Procedures4%

Procedures Currently Represent 4% of all US Dry Eye Revenue

$Revenue for Dry Eye Products by Segment¬ Procedures AM, plugs, Lipiflow, Miboflo

Market Scope 2017 Dry Eye Products Report

“Newer dry eye procedures offer the most significant potential for market growth.”

– Market Scope

38

Heat to the MG

What has changed?What is new?

Is it better you decide

39

Bruder Moist Heat Eye Compress

40

Bruder Moist Heat Eye Compress

$ Moist heat treatment ¬ Stabilize the tear film, improve oil gland function, slow tear evaporation

$ Ready in seconds, easy to use¬ Patient compliance increases

$ Patented MediBeads¬ Self-hydrating (no need to add water)

¬ Anti-bacterial and non-allergenic

¬ Washable and reusable

$ Safe for frequent use ¬ Microwave for 20-25 seconds

¬ Apply for 10 minutes

$ Unique pod design provides improved fit and performance

41

Dry Eye Relief and Daily Eyelid Hygiene

Micro-fine sheets are designed to cleanse the eyelids

Bruder Cold Therapy Eye Compress

42


November 1, 2019


Mibo Heating Pad

$5 settings$Aromatherapy

¬ Lavender

$USB powered

43

Mibo Thermoflo$ Ultrasound gel, heat, skin

$ Comfortable treatment, no pressure

$ No disposables (ROI for the practice)

$ Technician driven eliminating the need to burn the doctors chair time

$ Dry eye maintenance

$ Pricing for patients is more affordable than other options

making the treatment more easily accepted by patients

44

Personalized Open Eye ExperienceFor those w ho su ffer from dry eye d isease , TearCare® is the m ost personalized procedure that o ffers a savvy approach

Natural-blink design

Ultra-precise meibomian gland clearance

Patented smart system

45

Fo r th e a p p lica tio n o f lo ca lize d h e a t w h e n th e curre n t m e d ica l co m m un ity re co m m e n d s th e a p p lica tio n o f a w a rm co m p re ss to th e e ye lid s. Such a p p lica tio n s w o u ld in c lud e M e ib o m ia n G la n d D ysfun ctio n (M G D ), D ry Eye , o r B le p h a ritis

46

Pharma Update

47

Nuzyra™(omadacycline)

$Tetracycline antibiotic$Approved 2018$Approved for PO/IV treatment of patients

¬ Bacterial skin infections¬ Community-acquired bacterial pneumonia

$ADRs: ¬ Nausea, vomiting, diarrhea, constipation, insomnia¬ Chelation issues JUST like other tetracyclines!

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November 1, 2019


Seysara™ (sarecycline)

$Tetracycline drug$Approved 2018$ Indicated for the treatment of inflammatory acne in non-nodular, moderate

to severe acne vulgaris$Potential for MGD treatment

$Can be taken WITH or WITHOUT food!

$ADRs: nausea

49

Xerava™ (eravacycyline)

$Tetracycline antibiotic$Approved 2018$ Indicated for the treatment of intra-abdominal infections in adults$ IV ONLY

50

Xiidra™ (lifitegrast) 5%

$Company: Shire, Takeda, Novartis ¬ Approved July 2016

¬Specific treatments/indication: dry eye disease2 Signs and symptoms of dry eye

¬Dosage: one drop twice daily in each eye, 12 hours apart

2Dysgeusia, site irritation, blurred vision ¬Relief as soon as 2 weeks with symptoms

2 Eye Dryness Score ¬Signs improve as soon as 12 weeks

2 Inferior cornea staining

51

Xiidra™ (lifitegrast) 5%

$Mechanism of Action¬ Lymphocyte function-associated antigen-1 antagonist

2 LFA-1 is found on the T-cell

2 Blocks ICAM-1/LFA-1 interaction– Intercellular adhesion molecule-1

2 ICAM is overexpressed in dry eye– Cornea, conjunctiva, lacrimal gland

¬ Anti-inflammatory by inhibiting

2 T-cell activation2 T-cell migration2 Cytokine Release

52

Xiidra™ (lifitegrast) 5% $Xiidra™ or Restasis™? Or BOTH?

¬Yes, based on Mechanism of Action (MOA)¬Need more longitudinal data from post-marketing surveillance to

determine:2 Efficacy and toxicity as an individual drug2As well as efficacy and toxicity as compared to Restasis

53

Xiidra™ - What I Have Learned

$ Only pharmaceutical indicated for signs and symptoms of dry eye disease$ Works within:

¬ 2 weeks for moderate DED

¬ 6 weeks for mild

¬ Cornea staining takes 12 weeks

$ Use it as a diagnostic $ 30 million USA adults with DED$ BID means 12 hours apart$ Get in front of the dysgeusia $ Works great for GPC and SAC. Look for post IOL patient

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November 1, 2019


CequaTM (cyclosporine ophthalmic solution) 0.09%

$Sun Pharmaceuticals, Approved August 2018 clinically approved¬ September 20, 2019 final

$Dosed BID$Single-use vials$ “New Nanomicellar Ophthalmic Solution for Treatment of

Keratoconjunctivitis Sicca”¬ Formulation technology uses micelles

$ Gelatinous aggregates of amphipathic molecules¬ Hydrophobic and hydrophilic molecules

¬ Ease of entry into conjunctiva and cornea2 High delivery of cyclosporine A (CsA)

55

Cequa™ (cyclosporine ophthalmic solution) 0.09%Indication and Important Safety Information

Indication:

A calcineurin inhibitor immunosuppressant indicated to increase tear production in patients with keratoconjunctivitis sicca

Warnings and Precautions:

Potential for Eye Injury and Contamination: To avoid the potential for eye injury and contamination, advise patients not to touch the vial tip to the eye or other surfaces.

Use with Contact Lenses: CEQUA should not be administered while wearing contact lenses. If contact lenses are worn, they should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of CEQUA ophthalmic solution

Adverse Reactions:The most common adverse reactions reported in greater than 5% of patients were pain on instillation of drops (22%) and conjunctival hyperemia (6%)

Other adverse reactions reported in 1% to 5% of patients were blepharitis, eye irritation, headache, and urinary tract infection

56

56

Cequa™ Formulation$Novel, aqueous, nanomicellar formulation of cyclosporine A 0.09%1–4

$Unpreserved, isotonic, neutral pH fluid that is supplied in unit dose vials

$Well tolerated in a 12-week phase 2b/3 study5

57

1. Cholkar K et al. Recent Pat Nanomed. 2012;2:82-95 2. Mandal A et al. J Control Release. 2017;248:96-116. 3. Vaishya RD et al. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6:422-437. 4. Cholkar K et al. Transl Vis Sci Technol. 2015;4:1-16 5. Tauber J, et al. ASCRS 2017 Paper presentation.

57

Primary Endpoints ,

58

Note: Data shown for the intent-to-treat population (subjects randomized, excluding 1 subject who was assigned to OTX-101 but not treated); missing data on day 84 were imputed by baseline values carried forward.

p <0.0001

LS, least squares; SE, standard error.OTX-101-2016-001 study report; data on file.

Schirmer's test Total conjunctival staining score Central corneal staining score

58

Systane Complete$ The core SYSTANE® technology includes HP-Guar (hydroxypropyl-

guar)¬ Polymer that becomes a gel on instillation with lubricant propylene glycol as the

active ingredient¬ Inactive ingredients phospholipid DMPG and mineral oil to help deliver the active

ingredient

$ Lipid nanodroplet technology that results in better coverage of the ocular surface vs. SYSTANE® BALANCE Lubricant Eye Drops

$ Designed to minimize blur upon instillation due to its nanodroplet formulation

$ Completely free of benzalkonium chloride

$ Contains 3 times the concentration of HP-Guar per unit volume¬ Compared to SYSTANE® BALANCE Lubricant Eye Drops¬ Permits greater cross-linking and persistence of the protective elastic matrix¬ Resulting in better retention of the propylene glycol lubricant and protection against

tear evaporation

$ Nanodroplet technology provides ¬ Better coverage of the ocular surface¬ Fast-acting hydration,¬ Long-lasting relief compared to SYSTANE® BALANCE Lubricant Eye Drops

$ Supports all layers of the tear film and helps protect against tear film

evaporation

59

Hygiene Solutions



60


November 1, 2019


Hypochlorous Acid$ Natural antibacterial agent

¬ Found in white blood cells

¬ Different mechanism of action of antibiotics

2 Oxidant; bactericidal

$ Skin microbiome contributes to infection, blepharitis, and MGD¬ Staphylococcus aureus, Staphylococcus

epidermidis, Corynebacterium, and Propionibacterium acnes

61

(hypochlorous acid .01%)HyClear™ is PureHyClear is a non-cytotoxic, non-irritating solution recommended for daily use

HyClear™ is StableHyClear provides up to an 18 month shelf life after openingHyClear™ is EffectiveHyClear kills the majority of ocular pathogens in seconds

62

63

Nutraceutical Therapies



64

Nutraceutical Therapies in Dry Eye

$Looking for anti-inflammatory fatty acids¬ Dry eye efficacy

$”Fish oil” will provide nice hair, nails, and skin$Gamma-Linolenic Acid GLA

¬ Specific action that ”fish oil” omegas lack¬ 7 randomized controlled trials for dry eye

2 Aqueous-deficient (Barabino S et al. Cornea 22: 97–101, 2003.)2 PRK (Macri A et al. Graefes Arch Clin Exp Ophthalmol 241:561-6, 2003.)2 Sjögren's (Aragona P, et al. Ophthalmol Vis Sci 46:4474-9, 2005.)2 Contact lens (Kokke KH et al. Contact Lens Ant. Eye 31:141-6, 2008.) 2 MGD (Pinna et al. Cornea 26:260-264, 2007.)2 Mild-moderate DE (Brignole-Baudouin et al. Acta Ophthalmologica 89:e591-7, 2007.)

2 Post-menopausal women (HydroEye) (Sheppard JD, Pflugfelder SC, et al. Cornea 32 :1297-1304, 2013.)

65

$Prostaglandins¬ Myth buster- they are not all bad

$Prostaglandin E1 (PGE 1) -good¬ Shown to stimulate lacrimal production (Phalpramool, 1980, 1983)

¬ Supports mucin production 2 Conjunctiva, other membranes (Viau, 2009, Willemsen, 2003, Nygren, 1984)

¬ Experimental deprivation of vitamin C a required cofactor for PGE 1 2 Stops lacrimal production, produces Sjögren's-like signs & symptoms Wood, 1970

¬ Precursor GLA

$Prostaglandin E2 (PGE 2) – bad¬ Precursor AA

$Prostaglandin E3 (PGE 3)- good¬ Precursor Omega-3 “fish oil”


66


November 1, 2019


Gamma-Linolenic Acid GLA$Consistently shown improvement in markers of inflammation /

inflammatory mediators in dry eye$Shown promise in other inflammatory diseases, like rheumatoid

arthritis, IBD, dermatitis, and diabetic retinopathy$In Sjögren's increases tear production, raises PGE1 in tears (Aragona, 2005)

$Supports meibomian glands ((Pinna, 2007)

¬ Probably through anti-inflammatory action

$2,000-3,000 mg omega-3s usually required to have significant effect¬ In contrast 235 mg of GLA significantly reduced 2 different inflammatory

markers (HLA-DR, CD11c) in the HydroEye trial (Sheppard, Pflugfelder, Whitley et al. Cornea, 2013)

67

Is GLA offered in the triglyceride (TG) form? aka “re-esterified”

$These forms of omegas triglyceride (TG) vs ethyl ester (EE) mainly apply only to fish oils

$ Fish oil when it’s purified is transformed from the natural TG form in fish to the EE form¬ Which allows the omegas to be concentrated & purified

$ Fish oil companies have heavily marketed re-esterified or TG fish oils as vastly more absorbable and bioavailable

$ GLA only comes as TG form¬ No other form¬ TG vs EE discussion is purely about different fish oils

68

$Pick the right nutraceutical not “fish oil” ad get:¬ Improvement in irritation symptoms ¬ Better cornea smoothness

¬ Significantly lower levels of inflammatory markers


69

Regenerative Healing

Amniotic MembraneProkera

70

Amniotic Membrane

$To help reset the eye from a stage 3-4 back to something manageable$Failure on multiple therapies$Sjogren’s and the rheumatological patient

71

Dry Eye and Amniotic Membrane

72


November 1, 2019


Neurostimulation



73

Ocular Surface Disease/Dry Eye

$ Aqueous production¬ True Tear-Allergan

2 FDA approved (April 25, 2017)

2 New development for treatment of ocular surface disease2 Intranasal Tear Neurostimulator

2 Uses mild electric pulse to stimulate branch of trigeminal V1

2 Research showing stimulates all 3 layers of the tear film

2 Disposable end caps need to be replaced daily

2 Sold by docs and/or Allergan and tips prescribed by optometrist

74

In-Office Lab Testing



75

In-Office Lab Testing

$Helps with:¬ Switching patient to dailies¬ Starting nutraceuticals

¬ Starting pharmaceuticals¬ Following patients over time

76

TearLab Osmolarity TestTearLab Osmolarity Test

77

TearLab Osmolarity Test

$300 and above¬ Helps confirm dry eye

$Asymmetry ¬ Helps confirm unstable tear film

78


November 1, 2019


TearLab Discovery™ Assay Platform

$Panel Testing of Tear Fluid Biomarkers¬ Tear Osmolarity plus inflammatory marker¬ Capable of quantitative measurement

¬ Single 100 nanoliter tear collection.

$Fluorescent Immunoassay$Rapid < 2 minutes from collection to result$Study Panel: DED + Inflammation

¬ Osmolarity¬ MMP-9

79

TearLab Discovery™ Assay Platform

Control Spots Intensity Calibration

Protein SpotsSignal Detection

80

Traditional Lateral Flow Tests Highly Volume Dependent

Traditional lateral flow tests need to collect upwards of 10 µL of sample which is not generally feasible to sample in clinical practice. In DED patients, much less than 1 µL is readily available without reflex tearing.

1 µL 2 µL 10 µL

≈ 40ng/mL

500ng/mL

TearLab Discovery™ requires about 100 nL, 1/100th of the

volume required by traditional tests

*TearLab data on file

81

TearLab Discovery™ Compares Well to InflammaDry®

Despite using 1/100th the volume of tear fluid, TearLab Discovery shows

good agreement with the InflammaDry® method

TearLab = 0.1 µLInflammaDry = 10.0 µL

*TearLab data on file

82

TearLab Discovery™ Platform Timing

$ 510(k) submission in January 2017

$ Expected approval à 2019

83

InflammaDry®

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November 1, 2019


InflammaDry®For inflammatory dry eye detection

Normal levels of MMP-9 in human tears ranges from 3-41 ng/ml

NEGATIVE TEST RESULT

MMP-9 < 40 ng/ml

POSITIVE TEST RESULTMMP-9 ≥ 40 ng/ml

85

InflammaDry

86

Sjö Diagnostic Test

$Uses proprietary biomarkers to create an advanced diagnostic panel

$ Early detection of Sjögren’s syndrome in your patients

87

Innovations Outside of Dry Eye

Pharma UpdateGlaucoma

88

Xelpros™(latanoprost ophthalmic solution 0.005%)

$Sun Pharmaceuticals$Approved September 2018$Dosage: QD$Reduce IOP in open-angle glaucoma and ocular hypertension$Xelpros is the first latanoprost product not formulated with the preservative

benzalkonium chloride¬ Potassium sorbate 0.47% - preservative

$Mechanism of delivery with castor oil $Reduces IOP in patients with open-angle glaucoma and ocular hypertension

¬ Up to a mean of 6 mm Hg to 8 mm Hg in randomized clinical trials

89

Xelpros™(latanoprost ophthalmic solution 0.005%)

$Not available in pharmacies$A direct pay between patient and partnering pharmacies

¬ Capstan Pharmacy ¬ Transition Pharmacy

$Xelpros Xpress offers:¬ No prior authorizations¬ No coupon activation¬ No callbacks

¬ Prompt fulfillment and refills¬ $55 for 30 days, $110 for 90 days

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November 1, 2019


Rhopressa™ 0.02%(netarsudil ophthalmic solution)

$Aerie Pharmaceuticals¬ Approved December 2017¬ Treatment of glaucoma or ocular hypertension

¬ Rho kinase inhibitor2 ROCK-NET Inhibitor

¬ Once daily in the evening2 Twice a day dosing is not well tolerated and is not recommended

¬ Side Effects2 Conjunctival hyperemia

2 Corneal verticillata

2 Conjunctival hemorrhage

9192

Rhopressa (ROCK-NET Inhibitor) Triple-Action

Ciliary Processes

Cornea

Uveoscleral Outflow

+ Outflow

+ Outflow

AR-13324

RKI

NETRKI- Inflow

NETRKI

Trabecular Meshwork

Episcleral Veins

Schlemm’s Canal

1. Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthal 2014;8:883-890.2. Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous

humor dynamics in normotensive monkey eyes. J Glaucoma2015. 24(1):51-4. 3. Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. ARVO2014. Abstract 2900

3 Identified IOP-Lowering Mechanisms � ROCK inhibition relaxes TM1,

increases outflow1,2

� NET inhibition reduces fluid production2

� ROCK inhibition lowers Episcleral VenousPressure (EVP)3

92

Rhopressa™ 0.02% (netarsudil)Causes Expansion of TM in Donor Eyes

Increases TM Outflow Facility in Clinic

TM: Trabecular Meshwork; SC: Schlemm’s Canal; Control: buffered saline solution; ESV: Episcleral Vein1. Ren R et al. Invest Ophthalmol Vis Sci. 2016;57(14):6197-6209. 2. Sit AJ et al. Presented at AGS 2017.

+Netarsudil

FLOW

Trabecular Meshwork (Donor Eyes)1

Chan

ge(%

)

*p<0.05

Control

200 um

FLOW

1922

-10-10

-15

-5

0

5

10

15

20

25

vs. Baseline vs. Placebo

**

TM Outflow Facility(Healthy Volunteers)2

Netarsudil Placebo

93

Netarsudil is Similarly Effective at Baseline IOPs<25 mmHg and ≥25 mmHg

Pooled Analysis Rocket 1, Rocket 2, Rocket 4

Day 90: Change from Baseline IOP by Baseline Subgroup (Pooled)

Netarsudil Timolol

Cha

nge

in M

ean

Diu

rnal

IOP

(mm

Hg)

Baseline IOP >20 to <25 ≥25 to 30N=428 N=266

>20 to <25 ≥25 to 30N=453 N=269

Median

Mean

Max

-4.0

-3.7

-12.3

-5.3

-5.3

-12.0

Netarsudil QD Timolol BID

Median -4.2 -4.3

Mean -4.1 -4.3

Max -10.7 -10.8

Baseline IOP >20 to <25 mmHg

Baseline IOP ≥25 to <30 mmHg

Netarsudil QD Timolol BID

94

Rhopressa™ 0.02%

$No labeled contraindications for Rhopressa™$No clinically relevant effects on vital signs

¬ Blood Pressure2 Changes were generally small and not clinically relevant in both groups

¬ Heart Rate2 Timolol caused statistically significant reduction in the phase 3 studies by an average of 2-3 beats

per month

95

81

Adverse Events

Netarsudil 0.02% QD(N=839)

n (%)

Timolol 0.5% BID(N=839)

n (%)

TEAE Conjunctival Hemorrhage 144 (17.2) 15 (1.8)

AE Resulting in Discontinuation 8 (1.0) 0

Conjunctival Hemorrhage was Sporadic and Severity did not Increase with Continued Dosing

Majority 92.4% (133/144) of the conjunctival hemorrhage in netarsudilQD group was mild, 6.3% (9/144) was moderate and 1.4% (2/144) was severe

Self-resolving with continued dosing

Images were taken from netarsudil subjectsSource: Courtesy of study investigators AR-13324-CS301, -CS302

Conjunctival hemorrhage

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November 1, 2019


Cornea Verticillata Observed in Phase 3 Studies

Images were taken from netarsudil subjectsSource: Courtesy of study investigators AR-13324-CS302

AR-13324-CS302netarsudil BIDsubject

AR-13324-CS302netarsudil QDsubject

Cornea verticillata

$ Cornea verticillata refers to a whorl-like pattern of deposits typically

localized to the basal corneal epithelium

$ Subjects are asymptomatic

$ The onset was ~6 to 13 weeks (netarsudil QD)

97

83

Cornea Verticillata Due to Phospholipidosis

Due to phospholipidosis where the parent drug is complexed with phospholipids in the lysosomes

Literature review suggested it is an adaptive response by the bodyrather than an adverse pathology*

Data on File Based on AR-13324-IPH07* Raizman MB et al. Surv. Ophthalmol. 2017;62:286-301

Medications known to cause verticillata: amiodarone, chloroquine, naproxen, phenothiazine, ocular gentamicin and tobramycin*

Phospholipids accumulation

Control Amiodarone Netarsudil

83

Cornea Verticillata Due to Phospholipidosis

Due to phospholipidosis where the parent drug is complexed with phospholipids in the lysosomes

Literature review suggested it is an adaptive response by the bodyrather than an adverse pathology*

Data on File Based on AR-13324-IPH07* Raizman MB et al. Surv. Ophthalmol. 2017;62:286-301

Medications known to cause verticillata: amiodarone, chloroquine, naproxen, phenothiazine, ocular gentamicin and tobramycin*

Phospholipids accumulation

Control Amiodarone Netarsudil

98

Rocklatan™(netarsudil/latanoprost ophthalmic solution)

0.02%/0.005%

Approved March 14, 2019$Aerie pharmaceuticals

$Once-daily eye drop

$First PGA combination in USA¬ Passes superiority testing

99

Bimatoprost SR Sustained Release

$Allergan$Phase 3 Clinical Trial Update

¬ 20 month efficacy and safety study¬ 528 people with POAG or Ocular HTN

2 30% reduced IOP over 12 week primary efficacy period – Met predefined criteria for noninferiority to the comparator

Ø Timolol 2 These results similar to topical PGA

$Designed to lower IOP for 4 months$Well tolerated to this point

$New drug application most likely second half of 2019

100

Innovation

Neurotrophic Keratitis

101

Oxervate™ (cenegermin-bkbj)$ Approved 2018$ Dompé farmaceutici SpA$ Ophthalmic solution indicated for the treatment of neurotrophic keratitis

$ Dosing: Instill 1 drop in affected eye 6 times per day (at 2 hour intervals) for 8 weeks

$ Storage issues: in the freezer at the pharmacy; patient keeps the individual vials in the fridge – once “actively ready” for use, then it is only stable for 12 hours

$ ADRs: eye pain, inflammation, corneal deposits

102


November 1, 2019


Endogenous NGF maintains corneal integrity by three mechanisms

1. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017 Apr;232(4):717-724. 2. Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003 May;76(5):521-42. 3. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-9. 4. Muzi S, Colafrancesco V, Sornelli F, et al. Nerve Growth Factor in the Developing and Adult Lacrimal Glands of Rat With and Without Inherited Retinitis Pigmentosa. Cornea. 2010;29:1163–1168

SHOWN IN PRECLINICAL MODELS1

TEAR SECRETION

CELL PROLIFERATION AND DIFFERENTIATION

NGF plays a role in nerve function and stimulates the regeneration and survival of

the sensory nerves2,3

NGF binds receptors on lacrimal glands and

promotes sensory-mediated reflex tearing secretion1,4

NGF stimulates proliferation, differentiation, and survival of

corneal epithelial cells1

Endogenous Nerve growth factor acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e. p75NTR)

nerve growth factor receptors in the anterior segment of the eye to support corneal innervation and integrity.1

CORNEAL INNERVATION

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Active ingredient structurally identical to human nerve growth factor produced in ocular tissues

• Naturally occurring neurotrophin is responsible for differentiation, growth, and maintenance of neurons1

• The regenerative potential of nerve growth factor (NGF) was discovered by Nobel-prize winning scientists in the early 1950s1

• Cenegermin-bkbj, a novel recombinant human nerve growth factor (rhNGF), is STRUCTURALLY IDENTICAL to the NGF protein2

1. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med 1998;338:1174-80. 2. Voelker R. New Drug Treats Rare, Debilitating Neurotrophic Keratitis. JAMA.2018;320(13):1309.

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OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% Weekly Device Kit

• OXERVATE™ is supplied in a weekly carton containing 7 multiple-dose vials*• A separate weekly Delivery System Kit contains the supplies needed to administer treatment

OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/ml) [US package insert]. Boston, MA: Dompe U.S. Inc.; 2018.

The Delivery System Kit Contains:

• 7 vial adapters• 42 pipettes

• 42 sterile disinfectant wipes• 1 dose recording card

• 1 extra adapter, 3 extra pipettes, 3 extra wipes are included asspares

*Extra drug is available in each vial to take into consideration for loss or spillage during treatment administration

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OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% Dosing and Administration

Every 2 hours Apply 6 times daily

2 6 8Continue for 8 weeks

Instill 1 drop of OXERVATE™(cenegermin-bkbj) ophthalmic solution 0.002%

in the affected eye(s)

OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/ml) [US package insert]. Boston, MA: Dompe U.S. Inc.; 2018.

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Innovation

loteprednol etabonateLotemax

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SteroidsKetones versus Esters

$Prednisolone acetate molecule modified to undergo predictable degradation to inactive metabolites by local esterases

$Corticosteroids, C-20 ketone replaced with a C-20 ester$C-20 ester steroids are associated with a lower incidence of IOP elevations vs.

C-20 ketone steroids ¬ IOP and cataracts

$Retrometabolic drug design of loteprednol aims to improve safety while maintaining efficacy

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November 1, 2019


Loteprednol Etabonate ProductsEster Steroids

$Lotemax suspension 0.5%$Alrex suspension 0.2%$Lotemax gel 0.5%

$Lotemax SM gel 0.38%$ Inveltys suspension 1.0%$KPI-121 loteprednol etabonate suspension 0.25%

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Lotemax SM (loteprednol etabonate) 0.38%

$ Indicated for the treatment of post-operative inflammation and pain following ocular surgery

$SubMicron - Particle size reduced to facilitate ocular penetration¬ Allowing for a decrease in drug concentration and dosing frequency (TID)¬ Increase intraocular penetration¬ Median particle diameter size reduced 5 to 12.5-fold:

2 LE gel 0.38% = 0.4-0.6 µm

2 Lotemax gel 0.5% = 3-5 µm

¬ Potential for a ~10-fold increase in rate of drug dissolution2 Based on a 10-fold increase in relative surface area with smaller particles

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$ Increased concentrations demonstrated in ocular tissues ¬ Cornea and aqueous humor ¬ Following single topical ocular instillation of Lotemax SM 0.38% vs Lotemax gel 0.5% in

rabbits

$ Compared to Lotemax Gel 0.5%¬ Single topical instillation of Lotemax SM 0.38% were greater in the aqueous humor and

cornea¬ Concentrations in the conjunctiva remain the highest out of the ocular tissues, with ample

drug to mediate anti-inflammatory effects at the ocular surface

$ Formulation advancement while maintaining a low BAK¬ Lowest concentration of BAK, 0.003% among the commercially available corticosteroid

ocular drops2 Inveltys is 0.01%


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$Submicron formulation is designed to reduce the Lotemax Gel drug concentration 0.38% vs. 0.5%)

$ Dosing frequency TID vs. QID$Formulation builds on the heritage and advantages of Lotemax gel 0.5%:

$ Retrometabolically designed corticosteroid¬ Retains potent anti-inflammatory activity

¬ Minimal potential for class Aes

$Mucoadhesive, non-settling, shear-thinning gel¬ A gel in the bottle; transitions to a liquid upon instillation

¬ Becomes mucoadhesive liquid on dilution with tears¬ No need to shake - uniform dosing¬ Non-blurring


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Inveltys ™ - loteprednol etabonate suspension 1.0%

$ Kala (ka-la) Pharmaceuticals $ August 2018$ Now in distribution centers and pharmacies $ Nanoparticle-based Mucus Penetrating Particles (MPP)

¬ “Amplified Technology”

¬ MOD

¬ Allows drug to penetrate through tear mucins

2 Increased penetration into tissues, 3-fold to other loteprednol

$ 1.0% post-operative inflammation and pain after ocular surgery¬ Dosage BID

2 First ocular corticosteroid to be BID

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KPI-121 loteprednol etabonate suspension 0.25%

Stay Tuned$ Kala (ka-la) Pharmaceuticals $ First product indicated for the temporary relief of signs and symptoms of dry eye disease $ Phase 2 and Phase 3 efficacy and safety trials

¬ STRIDE- Short Term Relief in Dry Eye

2 Over 2000 patients with dry eye disease

$ PDUFA date: August 15, 2019¬ Recruiting more people¬ Strict inclusion and exclusion criteria

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November 1, 2019


Innovations

GlaucomaMinimally Invasive Glaucoma Surgery

MIGS

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The iStent inject Trabecular Micro-bypass

$ For patients with cataracts and glaucoma, iStent inject is:

$ FDA approved therapy for the treatment of elevated IOP in adult patients with mild-to-moderate primary open-angle glaucoma in conjunction with cataract surgery

$ The first available ab interno, micro-bypass system designed to restore natural physiological outflow through two openings through the trabecular meshwork

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iStent

iStent inject creates two patent bypass pathways through the trabecular meshworkResulting in multi-directional flow through Schlemm’s canal

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MIGS Technologies

Glaukos

iSte

nt

iSte

nt in

ject

Supr

a Xen

CyPa

ss Hydr

us

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Innovations

Instruments

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OCT Angiography A New Approach to Protecting Vision

} Non-invasive visualization of individual layers of retinal vasculature} Pathology not obscured by fluorescein staining or pooling} Image acquisition requires less time than a dye-based procedure} Reduced patient burden allows more frequent imaging to better follow disease

progression and treatment response

OCTA of CNVFA of CNV

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November 1, 2019


Enface OCT-A SlabsBased on Retinal Anatomy

Deep Plexus (INL – OPL)

Superficial Plexus (ILM – IPL) Outer Retinal Zone (ONL – BM)

Choroid Capillaris

En Face Visualization of Layers Based on Retinal Anatomy

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OCT-A (Angiography)Normal Retinal Vasculature

Superficial Capillary Plexus

3µm Below ILM → 15 µm Below IPL

Deep Capillary Plexus

15µm Below ILM → 70 µm Below IPL

Outer Retina

70µm Below IPL → 30 µm Below RPE Reference

Choriocapillaris

30 µm Below RPE Reference → 60 µm Below RPE Reference

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What Does Glaucoma Look Like? Normal Moderate Glaucoma Advanced Glaucoma

Disc

Retina

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Diabetes 12-19-2018 OD

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Diabetes 12-19-18 OS

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Diabetes 12-19-2018

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November 1, 2019


Diabetes 12-19-2018

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Diabetes 12-19-2018

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Diabetes 12-19-2018

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Humphrey Field Humphrey Field Analyzer 3 Continuous Innovation

2017SITA Faster

Mixed SITA GPA

With the best of over 45 years of Standard-setting Technologies:-STATPAC-SITA-Gaze tracking-GPA-VFI

201824-2C

Synchronize & Review

With the best of over 45 years of Standard-setting Technologies:-STATPAC-SITA-Gaze tracking-GPA-VFI

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Sita Faster$Turns off False Negatives$Turns off Blind Spot monitor$Leaves on False Positives$Leaves on Gaze Tracking

$Faster test with same reliability

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November 1, 2019


Sita Faster

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Sita Faster

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$Glaucomatous damage of the macula is common and can occur early in the disease

$Can be missed or underestimated or both, with standard 24-2 VF tests that use a 6°grid

Opportunities for Improvement in Central 10 Degrees

24-2 and 10-2 VF Examples

Blue cross region on the 24-2 VF = central 10-2 VF (A) Both are abnormal. (B) 24-2 VF normal; 10-2 VF abnormal(C) 24-2 VF abnormal; 10-2 VF normal

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Highest Importance Locations Chosen from 10-2 Pattern

$ The expert group selected specific 10-2 test point locations

$ Prevalence and depth of glaucomatous macular defects were systematically evaluated to select optimum test points

$ Pattern covers areas known to be susceptible to glaucomatous defects both from structural and functional studies

The expert group: Donald C. Hood, Stuart K. Gardiner, Allison M. McKendrick and William H. Swanson.

Selected test locations are shown in red boxes

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Resulting SITA Faster 24-2C Pattern on HFA3

The 24-2C test pattern combines all 24-2 points + ten selected 10-2 points (shown in OD orientation)

Large Gray 24-2 pattern

Large Orange Ten additional

24-2C points

Small Gray 10-2 pattern

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SITA Faster 24-2C showed enhanced sensitivity to detect visual field loss in Central 10 degrees

$ SITA Faster 24-2C showed an enhanced sensitivity to detect visual field loss in the central 10 degrees

over the SITA Fast 24-2 pattern

$ Increased total and pattern deviation flagging of the ten additional SITA Faster 24-2C points

corresponded to the flagging of the same points tested on the SITA Fast 10-2 testZeiss ARVO Poster 2018

2-3 more flagged points Similar flagged points

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November 1, 2019


Minimize Time and Maximize Information with HFA3

SITA Faster 24-2

• test in 2 minutes or less

• ~50% faster than SITA Standard; ~30%

faster than SITA Fast

SITA Faster 24-2C

• More information in the central field

• ~20% faster than SITA Fast 24-2

Mixed SITA GPA

• Clinical equivalence of tests allows

intermixing SITA Faster, Fast, Standard, 24-2, 30-2, and 24-2C in progression analysis

• Add new tests to patient progression

• Helps immediately adopt SITA Faster

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24-2C SITA FasterFlagged points detected centrally in OD

24-2 SITA Standard 24-2C SITA Faster

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24-2C SITA FasterFlagged points detected centrally in OS

24-2 SITA Standard 24-2C SITA Faster

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What is it?$The Icare® HOME tonometer

¬Handheld ¬Battery operated device¬Without the need for topical

anesthetic

$Intended as an adjunct for monitoring IOP of adult patients (self-use)

$Caregivers in cases where the patient is not able to obtain their own measurements

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TechnologyLight weight (26.5 mg) probe touches the cornea with low speed (0.25-0.30 m/s)

Main Signal Characteristics

-1000-800-600-400-2000

20040060080010001200

0 10 20 30 40 50 60 70 80

time (sample clock)

spee

d (A

DC

uni

ts)

c o n ta c t w i th c o r n e a

p r o b e s p e e d i s z e r o , r e b o u n d s ta r t s

Light weight probe

Low probe speed

Minimal energy

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Icare ® HOME tonometer

$IOP, date, time, eye recognition (right/left) and measurement quality are all stored in the internal memory.

$Data is transferred to a PC for further analysis by the prescribing physician.

$New features: positioning light, automatic eye recognition system, series or single measurements, new user interface panel.

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November 1, 2019


Icare EyeSmart: Automatic Eye Recognition

The tonometer includes an automatic eye recognition system that identifies which eye is being measured.

$ Two infrared LED transmitters below probe (1)$ One infrared LED sensor above probe (2)$ The infrared light is reflected from nose back to the sensor$ The sensor knows from which transmitter the reflected

infrared light came from and thus which eye, right or left, was measured

$ The resulting eye indication is stored into the memory of the tonometer

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Rebound Tonometry is Safe$No significant safety issues reported for the Icare® ic100 & TA01i tonometers with a

large number sold worldwide (40,000) and in the United States (9,000) ¬ In use by health care personnel with varying degrees of tonometer experience and some of

which have little or no ophthalmic training.$No significant safety issues reported for the Icare® HOME tonometer or its

predecessor, Icare ONE; over 2,000 tonometers in use worldwide¬ Majority in Europe after Icare ONE received CE mark in late 2009 and was introduced in 2010.

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Why 24 Hr Monitoring?

24 hour IOP monitoring can reveal higher peaks and wider fluctuations of IOP than those found during routine office visits. Research reports a steady daily increase in IOP in some patients being treated for glaucoma.

ü Barkana Y, Anis S, Liebmann J, et al. Arch Ophthalmol. 2006;124:793-797.

Studies have shown IOP rises when a patient is supine; IOP peaks were measured upon awakening and declined within 30 minutes.

ü Barkana Y, Anis S, Liebmann J, et al. Arch Ophthalmol. 2006;124:793-797.

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Innovations

Instruments Wide Field

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GA-00336 / 1

The only ultra-widefield retinal imaging device with integrated OCT enabling eye care professionals enhance their clinical exams and improve practice economics

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GA-00336 / 1

Monaco can capture color and optomap af images along with posterior pole OCT scans of both eyes in as little as 90 seconds.

This quick, comprehensive look inside the eye has been shown to enhance pathology detection and significantly improve clinic flow.

Monaco…provides more information faster

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November 1, 2019


GA-00336 / 1

Monaco…imaging modalities

Color

AF

Sensory

Choroid Simulated White Light

Widefield OCT

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Clarus-Zeiss

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Clarus-Zeiss

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Clarus-Zeiss

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Thank-Youand

Hope You Enjoyed

Greg Caldwell, OD, [email protected]

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innovations in dry eye and primary eye care 2 hours...dry eye relief and daily eyelid hygiene...

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