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Baudouin C, et al. European Ophthalmic Review. 2015;9(2):121-127. Open Access.

TFOS DEWS II Management and Therapy Report

Aim of DED management is to restore homeostasis

– “Algorithm is not a rigid stepwise approach”

– “Heterogeneity that exists in the DED patient population precludes an overly formulaic approach”

▪ Considers both disease etiology and severity

▪ Risk/benefit and cost considerations contribute to treatment choices

• “In summary, the management of DED remains something of an art, not easily lending itself to a rigid, evidence-based algorithm that accommodates all patients….”

DED = dry eye disease; DEWS = Dry Eye Workshop; IPL = intense pulsed light; MGD = meibomian

gland dysfunction; TFOS = Tear Film and Ocular Surface Society.

Jones L, et al. Ocul Surf. 2017;15(3):575-628.

Step 1:• Modify local environment• Recommend to potentially modify diet, including oral

essential fatty acids and supplementation• Identify and potentially modify offending systemic and

topical medications• Recommend oral lubricants of various types (consider

lipid-containing supplements if MGD is present)• Recommend warm compresses and lid hygiene

Step 2 if above options are inadequate:• Nonpreserved ocular lubricants• Tea tree oil if Demodex is present• Tear conservation approaches• Overnight treatments• In-office physical heating and expression of meibomian

glands; IPL for MGD• Prescription drugs to manage DED

Step 3 if above options are inadequate:• Oral secretagogues• Autologous/allogeneic serum eye drops• Therapeutic contact lens options

Step 4 if above options are inadequate:• Topical corticosteroid for longer duration• Amniotic membrane grafts• Surgical punctal occlusion• Other surgical approaches

Staged Management and Treatment Recommendations for DED

Treatment Strategies

• Less common to be purely aqueous deficiency (<10%)

• Meibomian gland dysfunction involved in >80% of DED

• Targeted strategies

– Based on disease severity

– Etiology

– Treat signs and symptoms

Akpek EK, et al. Ophthalmology. 2019;126(1):P286-P334.

Dry Eye Treatment BEFORE Drops

• Exacerbating medications should be eliminated when possible.

• Cigarette smoking is associated with dry eye.

– Adverse effects on the lipid layer and tear proteins

• Humidifying ambient air and avoiding air drafts by using shields and by changing the characteristics of airflow at work, at home, and in the car may be helpful.

• Lowering computer screens below eye level to decrease lid aperture, scheduling regular breaks, and increasing blink frequency may decrease the discomfort associated with computer and reading activities.


Dry Eye Treatment BEFORE Drops

• Dry eye symptoms may have many contributory factors.

• Tear replacement is frequently unsuccessful when used as the sole treatment if additional causative factors are not concomitantly addressed.

• It is imperative to treat any causative factors that are amenable to treatment.

– Lid malposition – entropion/ectropion, lagophthalmos

– Trichiasis

– Blepharitis, meibomianitis/MGD

– Medications



Lubricants

• Tears (emulsions, solutions), gels, ointments, sustained-release formulation

• Ingredients

– Hyaluronic acid

– Methylcellulose

– Lipid based

Nutrition

• Oral essential fatty acids

– DREAM study

• Vitamin A ointment



Anti-inflammatory agents:

• Topical cyclosporine A emulsion (CSA), 0.05%, 0.09%

• Topical corticosteroids

• Oral doxycycline

• Topical azithromycin

• Combination topical antibiotic and steroid

• Topical lifitegrast, 5%

Serum tears

Amniotic membrane therapy1

• Self-retaining

• Drops/gels (eg, ACE)

Surgical treatment - tarsorrhaphy

ACE = amniotic cytokine extract.

1. Akpek EK, et al. Ophthalmology. 2019;126(1):P286-P334.

Lid Margin Disease Management

• Warm compresses and lid massage– Difficult to maintain adequate temperature; poor compliance

• Lid scrubs

– Commercial soap scrubs (eg, hypochlorous acid)– Tea tree oil for Demodex mite infestation

• In-office lid margin cleansing and meibomian gland expression for anterior

blepharitis and posterior blepharitis

– Motorized/mechanical devices– Thermal pressure and thermal pulsation– Intraductal probing– IPL


Lid Margin Disease Management

• Thermal pulsation

– Heats posterior lid and then compression of lid

• IPL, with meibomian gland expression

– Series of monthly treatments

• Microblepharoexfoliation

– Removal of bacterial biofilm obstructions are key to successful MGD management

– Exfoliation of the eyelid margin unroofs the meibomian glands


New Dry Eye Therapy

FDA = US Food and Drug Administration.

FDA accepts NDA for OTX-101 to treat dry eye disease. December 27, 2017. Accessed July 22, 2021. https://eyewire.news/articles/fda-accepts-sun-pharmas-nda-for-otx-101-

to-treat-dry-eye-disease/

Cyclosporine

• FDA approval in August 2018 for treatment of dry eye

• Utilizes nanomicellar technology

• Allows cyclosporine to overcome solubility challenges

• Better penetration of the aqueous layer and prevents release of the active lipophilic molecule prior to penetration

0.09% cyclosporine A

Novel Cyclosporine Formulations

Agarwal P, et al. Drug Discov Today. 2016;21(6):977-988.

Chemical modification of the drug Prodrug

Novel application of excipientsCyclodextrins

Semifluorinated alkanes

Positively charged vectors

Novel ophthalmic dosage forms

In situ gelling systems

Hydrogels

Lysosomes

Micelles

NanoparticlesNanomicellar cyclosporine

0.09%

Nanomicellar Cyclosporine 0.09% (OTX-101):Pooled Analysis of Phase 2b/3 and Phase 3 Studies

OTX-101: N= 523; vehicle: N=525

ITT = intention-to-treat; SANDE = Symptom Assessment iN Dry Eye.Sheppard J, et al. Eye Contact Lens. 2020;46 Suppl 1:S14-S19.

SANDE scoreGreater % of patients with an increase in Schirmer test scores of ≥10 mm at week 12

relative to baseline for OTX-101 versus vehicle

aP value from the Cochran–Mantel–Haenszel test for general association with day 84/early discontinuation increase at least 10 mm or any lesser increase or decrease versus the treatment group.

aP value from the Wilcoxon rank-sum test for differences between treatment groups (2-sided normal approximation).

Population, % OTX-101 Vehicle P Value

ITT population 16.6 9.0 P<.0001

Score <10 mm at baseline

18.7 10.2 P=.0001a

Population, % OTX-101 Vehicle P Value

ITT population −29.0 −30.4 P<.3539a

Score <10 mm at baseline

−27.3 −31.4 P=.1343a

Primary Endpoint: Lissamine Green Staining (Study Eye)

ANCOVA = analysis of covariance; mITT = modified intention-to-treat.

Tauber J, et al. Clin Ophthalmol. 2018;12:1921-1929. Open Access.

Loteprednol Etabonate 0.25% Mucus-Penetrating Particles (MPP)

• Only FDA-approved steroid for short-term treatment of signs and symptoms of dry eye disease

• Innovation in drug delivery

• Proprietary mucous-membrane particle coating that helps to increase diffusion and penetration of the steroid on the ocular surface

Perez VL, et al. Exp Eye Res. 2020;201:108294. Open Access.

Loteprednol Etabonate 0.25%

• Episodic inflammatory flares occur in most patients with chronic DED

• Flares result from complex inflammatory cascades

• Example: asthma

• Increased understanding of flares may guide management and improve outcomes

Perez VL, et al. Exp Eye Res. 2020;201:108294. Open Access.

Efficacy of Loteprednol 0.25% MPP (KPI-121)

CRL = complete response letter; NDA = New Drug Application; SD = study day.Holland E, et al. Efficacy and safety of KPI- 121 0.25% for short-term relief in dry eye (STRIDE). Poster presented at: American Society of Cataract and Refractive Surgery Virtual Annual Meeting; May 16-17, 2020.Loteprednol etabonate ophthalmic suspension. Prescribing information. Accessed July 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210933s000lbl.pdf Healio.com. Accessed May 1, 2021. https://www.healio.com/news/ophthalmology/20200310/kalas-dry-eye-treatment-meets-primary-secondary-endpoints-in-phase-3-trial

KPI-121N=459

Vehicle

N=456

• NDA w/ STRIDE 1 and STRIDE 2 data received CRL from the FDA in August 2019; additional efficacy data requested.

• Resubmission with STRIDE 3 data was approved by the FDA in October 2020 for short-term treatment of DED (up to 2 weeks)

STRIDE 1, 2, and 3 showed significant

improvements in ocular discomfort

for KPI-121 versus vehicle on

Day 8

Tear Secretion Is Regulated by the Lacrimal Functional Unit

Sheppard JD, et al. Ocul Surf. 2019;17(1):142-150. Open Access.

Intranasal Neurostimulation

• Handheld device

• Transmits small electrical pulses to the disposable tip

• Inserted into the nostrils

• Stimulation of trigeminal afferent nerve in the nasal mucosa triggers the nasolacrimal reflex pathway

– Contributes to both basal and stimulated tear production

Sheppard JD, et al. Ocul Surf. 2019;17(1):142-150. Open Access.

Intranasal Neurostimulation:Schirmer Test Score Increases

*P<.0001, active versus controls; error bars represent standard error of the mean.Sheppard JD, et al. Ocul Surf. 2019;17(1):142-150. Open Access.

Significantly greater tear production with intranasal stimulation

than with control extranasal or sham stimulation

Study eye (n=48) Fellow eye (n=35)

Tear Neurostimulation: OC-01 (Varenicline)

• OC-01 (varenicline) is a novel compound delivered via nasal spray.

• It is a highly selective nicotinic acetylcholine receptor agonist that activates the trigeminal parasympathetic pathway that stimulates the lacrimal functional unit to reestablish the natural tear film

Karpecki PM. June 15, 2019. Accessed July 22, 2021. https://www.reviewofoptometry.com/article/dry-eye-therapy-getting-nosySheppard JD, et al. Ocul Surf. 2019;17(1):142-150. Open Access.

Tear Neurostimulation: OC-01 (Varenicline)

• OC-01 nasal spray demonstrated statistically significant improvement in signs (Schirmer score) by day 28 compared with placebo

• OC-01 nasal spray demonstrated nominally statistically significant improvement in symptoms (EDS) as early as day 14 and by day 28 compared with placebo

• No significant changes were seen in mean change from baseline in EDS in the CAE chamber at day 28

CAE = controlled adverse environment; EDS = eye dryness score.Vollmer PM, et al. Varenicline nasal spray (OC-01) for the treatment of dry eye disease: the ONSET-2 study. Presented at: New Technologies and Treatments in Eye Care Conference; March 19-20, 2021.

New dry eye drop provides balance of compliance, cost. June 11, 2018. Accessed July 22, 2021. http://www.ophthalmologytimes.com/dry-eye/new-dry-eye-drop-provides-

balance-compliance-cost

New Dry Eye Therapy: Preservative-Free 0.1% Cyclosporine A

Cyclosporine

▪ Semifluorinated alkane vehicle

– Nonaqueous

– Low viscosity and surface tension allows drug dissipation in minutes

– Does not impair vision like emulsions, oils, and gels do

▪ Amphiphilic nature

– Increases solubility, stability, and tissue penetration of poorly soluble small molecules like cyclosporin A does

• Phase 2 trial showed efficacy equal to cyclosporine 0.05% but with a quicker onset – as early as 14 days

• Currently in clinical development, with anticipated new drug filings in the United States, Japan, and Europe

Preservative-free 0.1% cyclosporine A

New Dry Eye Therapy: OCU310 (Brimonidine 0.2% + Loteprednol 0.2%)

Preclinical efficacy data of proprietary nanoemulsion technology at ARVO 2018. May 2, 2018. Accessed July 22, 2021. https://www.prnewswire.com/news-releases/ocugen-

presents-preclinical-efficacy-data-of-its-proprietary-nanoemulsion-technology-at-arvo-2018-300639908.html

• Brimonidine 0.2% + loteprednol 0.2% (OCU310)

– Plans to begin phase 3

• Brimonidine (OCU300)

– Nanoemulsion of 0.18% brimonidine

– Treatment for ocular discomfort and redness in patients with graft-versus-host disease

– Phase 2 showed 90% of patients with improved symptoms after 6 months, especially reduction of ocular redness

New Dry Eye Therapy: Reproxalap

• Small-molecule reactive aldehyde species (RASP) inhibitor that covalently binds free aldehydes and diminishes excessive RASP levels

Sheppard JD. Multi-center, randomized, double-masked, parallel-group, vehicle-controlled phase 2b dry eye disease clinical trial to evaluate safety and efficacy of topical ocular

reproxalap, a novel RASP inhibitor. Paper presented at: ARVO 2019; April 28-May 2, 2019; Vancouver, BC. Paper 5206.

Blockade of RASPElevated RASP Level in Tears of

Patients With Dry Eye

Reproxalap Mechanism of Action

Sheppard JD. Multi-center, randomized, double-masked, parallel-group, vehicle-controlled phase 2b dry eye disease clinical trial to evaluate safety and efficacy of topical ocular

reproxalap, a novel RASP inhibitor. Paper presented at: ARVO 2019; April 28-May 2, 2019; Vancouver, BC. Paper 5206.

Reproxalap Phase 2a Clinical Trial Results: Reduction in Tears

MDA = malondialdehyde; SEM = standard error of the mean.Clark D, et al. J Ocular Pharmacol Ther. 2021;37(4):193-199. Open Access.

RGN-259

Sosne G, et al. Clin Ophthalmol. 2015;9:877-884. Open Access.

▪ Thymosin beta-4

• Naturally occurring peptide

• Important in protection, regeneration, and remodeling of damaged tissues

▪ Treatment of moderate to severe dry eye and neurotrophic keratitis

▪ Currently in repeat phase 3

RGN-259

New Dry Eye Therapy: TOP1630

• p38α, Syk, Lck, and Src are significantly upregulated in the ocular surface of persons with

DED1

– This upregulation is associated with increase in the inflammatory cytokines IL-1β, IL-8, MCP-1, and in the inflammatory mediator MMP-9

• Nonsystemic kinase inhibitors are a novel class of agents that selectively target p38α,

Syk, Lck, and Src1

– They produce broad, potent anti-inflammatory effects in vitro and in vivo, exhibiting potent inhibition of cytokine release in cellular assays and mimicking both innate and adaptive immune systems, as well as in vivo models2

– They are small molecules designed for topical administration and demonstrate an exemplary safety profile in preclinical and clinical studies, with very low systemic exposure2

IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; Lck = lymphocyte-specific protein tyrosine kinase; MMP = matrix metalloproteinase; Syk = spleen tyrosine kinase; Src = proto-oncogene c-Src.1. Hagan S, et al. Invest Ophthalmol Vis Sci. 2018;59(3):1443-1453. 2. Bianchieri P, et al. Inflamm Bowel Dis. 2016;22(6):1306-1315.

TOP1630 Phase 2 Results

CAE = controlled adverse environment; SE = standard error; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.Taylor M, et al. Clin Opthalmol. 2019;13:261-275. Open Access.

Safety and tolerability• 12/61 participants reported TEAEs

• 7 reported in 6 patients in the TOP1630 group• 9 in 6 patients in the placebo group• All were mild to moderate in severity

• No SAEs reported• Drop comfort was similar between treatment groups

Activity presentations are

considered intellectual property

These slides may not be published or posted online

without permission from Vindico Medical Education

([email protected]).

Please be respectful of this request so we may

continue to provide you with presentation materials.

activity presentations are considered intellectual property

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