Demographics and POAG: Time to Consider Alternative Care ModelsDavid S. Friedman, MD, MPH, PhDDirector, Dana Center for Preventive OphthalmologyWilmer Eye Institute, Alfred Sommer Professor of OphthalmologyJohns Hopkins University School of MedicineProfessor, Department of International HealthJohns Hopkins Bloomberg School of Public HealthBaltimore, MD

The Times They Are a Changin’

• Populations are aging

• Number of ophthalmologists is not adequate

• Cost of care is high and much of what we do during the care process is ineffective

• Technology is improving

Developed countries are aging and there will be fewer working age individuals.

Who will see all of the glaucoma patients?

German Population by Age – 2025

100+95-9990-9485-8980-8475-7970-7465-6960-6455-5950-5445-4940-4435-3930-3425-2920-2415-1910-14

5-90-4

AgeGroup

0 0.8 1.6 2.4 3.2 40.8 01.62.43.24

Male Female

Population (Millions) Population (Millions)

United States Population by Age – 2025

100+95-9990-9485-8980-8475-7970-7465-6960-6455-5950-5445-4940-4435-3930-3425-2920-2415-1910-14

5-90-4

AgeGroup

0 3 6 9 12 153 0691215

Male Female

Population (Millions) Population (Millions)

No New Ophthalmologists!!!

The number of ophthalmologists in the United States will increase by about 2% and

full time equivalents (FTE) will decrease over the next decade

About 10% of Whites and over 15% of African-derived populations

over 75 years of age

Nearly 100 million globally with glaucoma in 2020

Many More Need Monitoring

Patients Large numbers with angle closure

without glaucoma

Quigley HA, et al. Ophthalmol. 2013;120(11):2249-2257.

Half of glaucoma care costs are for glaucoma visits

Current management is inefficientand often ineffective

2001

2007

Is This Ideal?

Lots of Wasted Time and Effort

•Patient seen every 4 to 6 months

• IOP stable, field stable, nerve imaging stable

•5 years later confirmed field loss

How much of the time spent with the patient was time well spent???

Visual Acuity

Intraocular Pressure

Anterior Chamber Angle

Anterior Chamber Angle

Fundus Photography

Fundus Photography

NFL Imaging

Visual Field Testing

Visual Field Testing

What about counseling?

Adherence in Clinic Patients

0.0 0.5 1.0

10

30

50

Adherence Rate(Electronic Monitoring, %)

Nu

mb

er

of

Pat

ien

ts

Okeke CO, et al. Ophthalmol. 2009;116(2):191-199.

13 of 50 patients admitted to non-adherence in research interview

Physicians detected only 3 of them

Friedman DS, et al. Ophthalmol. 2009;116(12):2277-2285.

Median weighted kappa for 5 clinicians = 0.32

Clinician ADefinitely

StableProbably

StableProbably

ProgressingDefinitely

Progressing

Definitely Stable 5 4 1 0

Probably Stable 4 1 2 1

Probably Progressing 0 3 1 3

Definitely Progressing 0 1 0 1

Clinician B

Viswanathan AC, et al. Br J Ophthalmol. 2003;87:726-730.

Determining Worsening???

Technology can improve performance

Photoscreening for DR

Local Testing at Remote Locations

• Better integration of data

• More resources allocated to interpretation

• Physician with better data and more time to interact with those who need time

• Rapid upgrade to better technology over time

A New Model of Care

• Testing using ancillary personnel for most visits

• Longer physician appointments when major clinical change is recommended

Health delivery systems can be improved in order to provide high quality care

more efficiently and effectively

The Office of Tomorrow

• Data collected remotely

• Physician with multiple screens reviews

• Ancillary staff interact with the patient

• Longer visits with the doctor for change of care or change of status

The Future Is Here

• Populations are aging and growing

• Resources are finite

• Physician supply is not growing, technology is improving

• All that remains is to figure out the logistics

Recent Discoveries in the Pathophysiology of Glaucoma:Novel TreatmentsW. Daniel Stamer, PhDJoseph A. C. Wadsworth Professor of OphthalmologyProfessor of Biomedical EngineeringDuke UniversityDurham, NC

Which Currently Available Glaucoma Medications Secondarily Target the Conventional Outflow Pathway?

• Prostaglandins (direct, but secondary to changes in uveoscleral outflow pathway)

• Pilocarpine (indirect, via ciliary muscle contraction)

IOP= (F - U)/C + EVPSimplified Goldman Equation

C = 1/R

IOP, intraocular pressure;

F, rate of aqueous formation;

U, uveoscleral outflow;

C, facility of aqueous outflow;

EVP, episcleral venous pressure

Aqueous Humor Dynamics: IOP Regulation

The AGIS Investigators. Am J Ophthalmol. 2000,Oct;130(4):429-440.

20.2 mmHg

16.9 mmHg

14.7 mmHg

12.3 mmHg

Vis

ion

Lo

ss(M

ean

Ch

ange

in V

isu

al F

ield

Def

ect

Sco

re)

Follow-up Time (Months)

The lower the pressure…

The better the outcome

Lowering Eye Pressure Is Neuroprotective

-2

0

2

-3

1

-1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

3

IOP = (F - U)/C + EVPSimplified Goldman Equation

Increase conventional outflowNone currently available in US

Decrease inflowß-adrenergic blockers

Carbonic anhydrase inhibitorsa2-adrenergic receptor agonists

Increase uveoscleral outflowProstaglandin F2a receptor agonists

How Do We Medically Lower Eye Pressure?

Li T, et al. Ophthalmol. 2016;123(1):129-140.

Analysis of 114 Randomized Controlled TrialsEfficacy

Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Rank 15

Rank 14

Rank 13

Rank 12

Rank 11

Rank 10

Rank 9

Rank 8

Rank 7

Rank 6

Rank 5

Rank 4

Rank 3

Rank 2

Rank 1

0 0 0 0 0 0 0 0 0 00.042

0.002 0.001 0.0010.353

0 .05 .10 .15 .20 .25 .30 .35 .40 .45

80

70

60

50

40

30

20

10

0

Facility of Outflow, cu mm/min/mmHg

Higher Resistance to Conventional Outflow Causes Ocular Hypertension in Glaucoma

Grant WM. Trans Am Acad Ophthalmol Otolaryngol. 1951;55:774-781.

Lower ResistanceHigher

Resistance

Pre

ssu

re, m

mH

g

Untreated Glaucoma

Normal

Why Do We Need a Conventional Outflow Drug?

• Majority of outflow (70%-90%) via conventional route, offering greater eye-pressure-lowering ability than PGAs

• Avoid interventional treatments (e.g. surgery, laser)

• Additive with current eye-pressure-lowering drugs: Current medical treatments do not lower eye pressure enough in most

• Restore function to conventional pathway

– Diseased tissue

– Better perfusion of tissues/cells

– Possible stimulation of cell division and repopulation/remodeling of tissue

– Dampen eye pressure fluctuations

Conventional Outflow Drugs/Current Status

• Rho kinase inhibitors

– Netarsudil (Awaiting FDA approval in US)

– Netarsudil/latanoprost (Phase III)

– Ripasudil (Approved in Japan)

• Nitric oxide donors

– Latanoprostene bunod (Recently approved in US)

– Nipradilol (Approved in Japan)

Latanoprostene Bunod: Mechanism of Action

corneal esterases

Increase uveoscleral outflow

Kawase K, et al. Adv Ther. 2016;33(9):1612-1627.

Nitric Oxide Lowers IOP by Increasing Outflow Facility

Wizemann AJ, et al. Am J Ophthalmol. 1980;90(1):106-109. Chang JY, et al. Am J Physiol Cell Physiol. 2015;15:309(4)C205-C214.

Infusion

IOP,

%

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

97 μg/min Nitroglycerin

Open-Angle Glaucoma(n = 5)

Narrow-Angle Glaucoma(n = 9)

0 30 60 90 120

Minutes

1.0

0.8

0.6

0.4

0.2

0.0

1.0

1.4SNAP (n = 6)

NAP (n = 5)

Y = 0.051x – 0.309R2 = 0.956

0 10 20 30

IOP, mmHg

Flo

w R

ate

, μ

L/m

in

*

*

**

**

Y = 0.031x – 0.198R2 = 0.965

Rho Kinase Inhibitors: Mechanism of Action

Ren, et al. Invest Ophthalmol Vis Sci. 2016;57(14):6197-6209.

Relaxation

Human Eyes

-10%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Pe

rce

nt

Ch

ange

in O

utf

low

Fac

ility

**

30 min 2 h 3 h

GPBS AR-13324m

MLC, myosin light chain.

Netarsudil vs Latanoprost vs Netarsudil/Latanoprost(N = 292)

0.02% AR-13324 Netarsudil (n = 78)

0.01% PG324 Netarsudil/Latanoprost (n = 73)

Lewis RA, et al. Br J Ophthalmol. 2016;100(3):339-344.

Start Tx

mm

Hg

±SE

M

15

28

27

26

25

24

23

22

21

16

20

17

18

19

Pre-Study

8 AM

Qual 18 AM 10 AM 4 PM

Baseline

0.005% Latanoprost (n = 73)

0.02% PG324 Netarsudil/Latanoprost (n = 72)

8 AM 10 AM 4 PM

Day 88 AM 10 AM 4 PM

Day 158 AM 10 AM 4 PM

Day 298 AM

Day 30

Mean Diurnal IOP Reduction

Lewis RA, et al. Br J Ophthalmol. 2016;100(3):339-344.

25.426.0

25.1 25.1

18.6 18.8

16.616.0

18.8 18.7

17.0

15.9

19.118.4

17.316.5

13141516171819202122232425262728

BaselineDay 8Day 15Day 29

IOP,

mm

Hg

±SE

M

0.02% AR-13324 Netarsudil(n = 78)

0.01% PG324 Netarsudil/Latanoprost

(n = 73)

0.005% Latanoprost (n = 73)

0.02% PG324 Netarsudil/Latanoprost

(n = 72)

+2 mmHg

MERCURY 1, 12-Month Netarsudil/Latanoprostvs Individual Components (n = 718)

Source: http://investors.aeriepharma.com/events-and-presentations.

Netarsudil (n = 238)

Latanoprost (n = 236)

Netarsudil/Latanoprost (n = 244)

Start Tx

Pre-Study

8 AM

Qual1

8 AM 10 AM 4 PM

Baseline

mm

Hg

±SE

M

15

26

25

24

23

22

21

16

20

17

18

19

148 AM 10 AM 4 PM

Week 2

8 AM 10 AM 4 PM

Week 6

8 AM 10 AM 4 PM

Month 3

8 AM 10 AM 4 PM

Month 6

8 AM 10 AM 4 PM

Month 9

8 AM 10 AM 4 PM

Month 12

22%

34%

48%

69%

80%

20%

36%

55%

70%

83%

39%

55%

76%

85%

92%

0%

20%

40%

60%

80%

100%

Source: http://investors.aeriepharma.com/events-and-presentations.

At Month 12: Percentage of Patients with IOP Reduced to 18 mmHg or Lower

Pat

ien

ts, %

*P<.05, **P<.01.

≤14 mmHg

IOP on Treatment

≤15 mmHg ≤16 mmHg ≤17 mmHg ≤18 mmHg

***

**

*

Netarsudil (n = 85)

Netarsudil/Latanoprost (n = 87)

Latanoprost (n = 106)

Grade Image Description

0 None/Normal

1 Mild

2 Moderate

3 Severe

Adverse Events(≥5.0% in any group)

Netarsudil/Latanoprost

N = 238

Netarsudiln = 243

LatanoprostN = 237

Eye Related

Conjunctival Hyperemia 150 (63.0%) 125 (51.4%) 52 (21.9%)

Conjunctival Hemorrhage 31 (13.0%) 44 (18.1%) 3 (1.3%)

Cornea Verticillata 42 (17.6%) 33 (13.6%) 0

Eye Pruritus 27 (11.3%) 22 (9.1%) 3 (1.3%)

Punctate Keratitis 12 (5.0%) 18 (7.4%) 10 (4.2%)

Lacrimation Increased 17 (7.1%) 20 (8.2%) 1 (0.4%)

Visual Acuity Reduced 13 (5.5%) 13 (5.3%) 6 (2.5%)

Vision Blurred 11 (4.6%) 15 (6.2%) 3 (1.3%)

Blepharitis 14 (5.9%) 8 (3.3%) 5 (2.1%)

Administration Site Conditions

Instillation Site Pain 55 (23.1%) 60 (24.7%) 18 (7.6%)

12 Month Phase III Safety Profile of Netarsudil vs Latanoprost vs Netarsudil/Latanoprost

Source: http://investors.aeriepharma.com/events-and-presentations.

*70% scored as mild by biomicroscopy

*

*Reported as adverse events.

Latanoprostene Bunod (LBN), Phase III Apollo Study

N=387

Weinreb RN, et al. Ophthalmol. 2016;123(5):965-973.

18.6

18.0 18.1

18.6

17.8 17.8

18.7

17.9 17.8

19.8

19.419.2

19.6

19.1 19.1

19.7

19.2 19.2

16

17

18

19

20

LBN 0.024% Timolol 0.5%

8 AM 12 PM 4 PM

Week 28 AM 12 PM 4 PM

Week 68 AM 12 PM 4 PM

Month 3

*

**

*

* *

*

* *

Me

an IO

P, m

mH

g

*P≤0.002 versus timolol at the same assessment point.

-7.81-8.3

-9 -8.93

-7.77

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

*P=.005 vs latanoprost. †P =.009 vs latanoprost.

Weinreb RN, et al. Br J Ophthalmol. 2015;99:738-745.

+1.3

3-Month Latanoprostene Bunod, Voyager Phase III Trial (N = 396)

Re

du

ctio

n in

Me

an

Diu

rnal

IOP,

mm

Hg

†*Latanoprost

0.005%

Treatment Group

LBN0.040%

LBN0.024%

LBN0.012%

LBN0.006%

Safety: 12-Month Latanoprostene Bunod Treatment in Japanese Subjects: The Jupiter Study

Kawase K, et al. Adv Ther. 2016;33(9):1612-1627.

Adverse EventsStudy Eye

(N = 130) n (%)Treated Fellow Eye

(N = 126) n (%)≥1 Ocular AE 76 (58.5) 78 (61.9)

≥1 Treatment-Related Ocular AE 62 (47.7) 61 (48.4)

Eye Disorders

Conjunctival Hyperemia* 23 (17.7) 21 (16.7)

Growth of Eyelashes 21 (16.2) 21 (16.7)

Eye Irritation 15 (11.5) 15 (11.9)

Eye Pain 13 (10.0) 13 (10.3)

Iris Hyperpigmentation 5 (3.8) 5 (4.0)

Blepharal Pigmentation 4 (3.1) 4 (3.2)

Blepharitis 3 (2.3) 3 (2.4)

Eye Pruritus 3 (2.3) 3 (2.4)

Asthenopia 3 (2.3) 2 (1.6)

Conjunctival Hemorrhage 2 (1.5) 3 (2.4)

Incidence of Ocular Treatment-Emergent Adverse Events Occurring in at Least 1% of Subjects in the Study Eye or the Treated Fellow Eye (Safety Population)

*Reported as adverse events.

Disease Modification: Addressing the Major Contributors to Elevated IOP and Vision Loss

Progressive Degeneration of the Trabecular Meshwork Drives Elevated IOP and Vision Loss in Glaucoma

Fibrosis, StiffnessContraction

Healthy TM

Less Nutrients, Antioxidants

Cellular StressReduced Aqueous

Perfusion Area

Elevated IOP Vision Loss

Cellular Stress

• Aging

• Oxidation

Wang SK, et al. Clin Ophthalmol. 2014;9;8:883-890. He Y, et al. Clin Ophtalmol. 2008;58(11):3366-3376. Li G, et al. Eur J Pharmacol. 2016; Sept 15;787:2031.

Outflow Drugs Have the Potential to Improve Health of TM in Patients With Glaucoma

Wang SK, et al. Clin Ophthalmol. 2014;9;8:883-890. He Y, et al. Clin Ophtalmol. 2008;58(11):3366-3376. Li G, et al. Eur J Pharmacol. 2016; Sept 15;787:2031.

Healthy TM

More Nutrients, Antioxidants

Less Cellular Stress

ReducedFibrosis, Stiffness

Contraction

Increased Aqueous Perfusion Area

Reduced IOP

+ drugs that decrease contractility

Preserve Vision

Cellular Stress

• Aging

• Oxidation

Reducing Fibrosis, Increasing Trabecular Outflow Could Stop Degeneration of Outflow Tissues in POAG

Summary: Take Home Messages

• Conventional outflow dysfunction causes ocular hypertension

• Effectively lowering IOP preserves vision

• No medication currently available primarily targets the conventional outflow pathway

• One drug that relaxes the trabecular meshwork and increases conventional outflow may soon be available, and another was recently approved for patients

– Safe

– Efficacious (additive with current medications)

– Therapeutic potential Increase functionality of trabecular meshwork (i.e. ability to dampen IOP fluctuations)

Increase blood flow to optic nerve head (evidence of vascular dysfunction in some forms of glaucoma)

Mechanisms of Pressure Relief in Glaucoma: Pharmacologic & Surgical Advances for Refractory POAG or Non-AdherenceSteven J. Gedde, MDJohn G. Clarkson Chair in OphthalmologyProfessor of OphthalmologyBascom Palmer Eye InstituteUniversity of Miami Health SystemMiami, FL

Treatment Algorithm

*Up to 2-3 different drugs. Do not add a drug to a non-effective one; consider switching.

POAG, primary open-angle-glaucoma; XFG, exfoliative/pseudoexfoliative glaucoma; PDG, pigment dispersion glaucoma.

©European Glaucoma Society 2014.

Goniotomy or Trabeculotomy

Medical treatment is recommended during the

waiting time prior to surgery

No treatment

Consider:• Medical therapy options

on the basis of IOP values• Risk factors profileDiscuss with the patient

Congenital Glaucoma

Juvenile Glaucoma

POAG / XFG / PDGOcular

Hypertension

Surgery

Laser Trabeculoplasty

Medical Therapy*

If the above procedures not successful or feasible, consider repeat filtration surgery with anti-metabolites or long-tube drainage implant/cyclodestructive procedure

• Traditional glaucoma surgery

– Trabeculectomy

– Aqueous shunts

– EX-PRESS® implant

• Nonpenetrating glaucoma surgery

– Deep sclerectomy

– Viscocanalostomy

– Canaloplasty

• Endoscopic cyclophotocoagulation(ECP)

• Minimally invasive glaucoma surgery (MIGS)

– Ab interno trabeculectomy (Trabectome®)

– Trabecular microbypass stent (iStent®)

– Gonioscopy-assisted transluminal trabeculotomy (GATT)

– Kahook Dual Blade

– CyPass® Micro-Stent

– XEN® Gel Stent

– Trab™360

Incisional Glaucoma Surgery

Trabeculectomy

• Scleral fistula allows drainage of aqueous humor into subconjunctival space creating a filtering bleb

• Only titratable glaucoma procedure

• Success enhanced with use of antifibrotic agents (MMC, 5-FU)

• Growing concern about bleb-related complications (leaks, infection, dysesthesia)

Surgical Trends

0

2000

4000

6000

8000

10000

12000

14000

0

10000

20000

30000

40000

50000

60000

70000

80000

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Trabeculectomy

Tube Shunt

Arora KS, et al. Ophthalmol. 2015;122:1615-1624.

Nu

mb

er

of

Pro

ced

ure

s

Year

Aqueous Shunts

• Silicone tube shunts aqueous humor to end plate located in equatorial region of globe

• Design

– Valved: Ahmed, Krupin

– Nonvalved: Baerveldt, Molteno

• Traditionally used in eyes at high risk for filtration failure, but indications are expanding

ABC/AVB Studies

Christakis PG, et al. Am J Ophthalmol. 2017;176:118-126.

Follow-up (Months)

Cu

mu

lati

ve P

rop

ort

ion

Fai

ling

1.0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0.8

0.9

0 6 12 18 24 30 36 42 48 54 60

P=.03

AhmedBaerveldt

Follow-up (Months)

Me

an IO

P, m

mH

g

40

30

25

20

15

10

5

35

0 6 12 18 24 36 48 60

Ahmed (n)

Baerveldt (n)

267 222 221 189 193 174 147 133

247 212 205 179 178 161 137 133

TVT Study

P=.002

46.9%

29.8%

Gedde SJ, et al. Am J Ophthalmol. 2012;153:789-803.

0.4

0.2

0.0

0.6C

um

ula

tive

Pro

po

rtio

n F

ailin

g

0 12 24 36 48 60

Follow-up (Months)

Trabeculectomy Group

Tube Group

PTVT Study

P=.013

17.3%

7.9%

0.2

0.1

0.0

0.3C

um

ula

tive

Pro

po

rtio

n F

ailin

g

0 3 6 9 12

Follow-up (Months)

Trabeculectomy Group

Tube Group

EX-PRESS® Implant

• Nonvalved, stainless steel tube

• No sclerostomy or iridectomy required

• High rate of hypotony and extrusion prompted placement under a scleral flap

• Similar long-term safety and efficacy compared with trabeculectomy

Courtesy of Marlene Moster.

XVT Study

Netland PA, et al. Am J Ophthalmol. 2014;157:433-440.

Pe

rce

nt

Succ

ess

Time (Months)

100

80

60

40

20

00 8 2412 184 20

P=.563

NE =NT =

59 59 5761 60 57

Trabeculectomy EX-PRESS®

0.0

0.4

0.6

0.8

0.2

0 6 12 18 24

Vis

ion

, lo

gMA

RTime (Months)

20

10

0

30

0 6 12 18 24

Me

an IO

P, m

mH

g

*

Time (Months)

Nonpenetrating Glaucoma Surgery

• Excision of corneoscleral tissue under scleral flap leaves thin window of trabecular meshwork (TM) and Descemet’s membrane to provide resistance to aqueous outflow

• Reduces risk of hypotony

• Technically difficult

• Types:

– Deep sclerectomy

– Viscocanalostomy

– Canaloplasty

Nonpenetrating Glaucoma Surgery

Chiselita D. Eye (Lond). 2001;15:197-201.

Follow-up (Months)

Cu

mu

lati

ve P

rop

ort

ion

of

Succ

ess 1.0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0.8

0.9

Follow-up (Months)

Intr

aocu

lar

Pre

ssu

re

Preoperative 1 2 3 12 180 2 4 6 8 10 12 14 16 20 2218

Trabeculectomy

Nonpenetratingdeep sclerectomy

30

26

22

20

18

14

12

28

24

16

6

Nonpenetratingdeep sclerectomy

Trabeculectomy

Endoscopic Cyclophotocoagulation (ECP)

• Treatment of ciliary processes under direct visualization with endoscopic camera and laser

• Frequently combined with phaco

• Provides moderate long-term IOP reduction

• CME is most common cause of vision loss

Minimally Invasive Glaucoma Surgery (MIGS)

• Newer group of glaucoma procedures characterized by:

– Ab interno approach

– Minimal trauma to tissue

– Modest efficacy

– Excellent safety profile

– Rapid postoperative recovery

• Frequently performed in combination with phaco

• Growing in popularity

Saheb H, et al. Curr Opin Ophthalmol. 2012;23:96-104.

Ab Interno Trabeculectomy (Trabectome®)

• Electrocautery removes a strip of TM and Schlemm’s canal

• Meta-analysis

– 31% reduction in IOP

– 66% success rate at 2 years

• Prior laser trabeculoplasty and trabeculectomy does not appear to influence results

Kaplowitz K, et al. Br J Ophthalmol. 2016;100:594-600.Courtesy of Brian Francis.

Ab Interno Trabeculectomy (Trabectome®)

Jea SY, et al. Ophthalmol. 2012;119:36-42.

P<.001

76.1%

22.4%

0.4

0.2

0.0

1.0C

um

ula

tive

Pro

bab

ility

of

Succ

ess

Follow-up (Months)

0.8

0.6

0 6 24 36 42 5448 603012 18

Trabeculectomy Group

Study Group

Trabecular Micro-Bypass Stent (iStent®)

• Snorkel-shaped device made of heparin-coated titanium is inserted into Schlemm’s canal

• FDA-approved for use with CE in patients with mild-moderate glaucoma

• RCTs show greater reduction in IOP and medical therapy than phaco alone

• Multiple stents may provide greater IOP reduction than single stent

Postoperative (6 month)

Courtesy of Ike Ahmed.

Samuelson TW, et al. Ophthalmol. 2011;118:459-467.

IOP ≤21 mmHg Without Meds

IOP Reduced ≥20% Without Meds

Trabecular Micro-Bypass Stent (iStent®)

% o

f P

atie

nts

100%

80%

60%

40%

20%

0%

Stent + Cataract Cataract Only

P=.003

Month1 3 6 12 LOCF

P<.001

% o

f P

atie

nts

100%

80%

60%

40%

20%

0%

Month1 3 6 12 LOCF

CyPass® Micro-Stent

• Flexible 6.35 mm fenestrated micro-stent with internal lumen of 300 micron

• Inserted with a guidewire

• Shunts aqueous humor from the AC to the suprachoroidal space

• Pressure gradient drives flow through device

Courtesy of Ike Ahmed.

**

CyPass® Micro-Stent

Vold S, et al. Ophthalmol. 2016;123:2103-2112.

IOP

↓ ≥

20

% v

s B

ase

line

(% o

f G

rou

p)

100

80

60

40

20

0

Time (Months)

2412

IOP

Re

du

ctio

n,

mm

Hg

***

Control Stent

66%

82%

60%

77%

Time (Months)

2412

*** ***

-6.2

-7.9

-5.4

-7.4

0

-1

-3

-6

-5

-9

-2

-4

-7

-8

**P<.01, ***P<.001.

XEN® Gel Stent

• 6 mm tubular collagen implant placed translimbally

• 27-gauge needle inserter

• Drains aqueous into subconjunctival space

• High needling rate (32%-47%)

Courtesy of Joseph Panarelli.

XEN® Gel Stent

Schlenker MB, et al. Ophthalmol. 2017;124(11):1579-1588.

Pro

po

rtio

n S

ucc

ess

ful

1.0

0.6

0.4

0.2

0.0

0.8

Months0 5 10 15 20 25 30

1.0

0.6

0.4

0.2

0.0

0.8

Months0 5 10 15 20 25 30

1.0

0.6

0.4

0.2

0.0

0.8

Months0 5 10 15 20 25 30

Qualified Success at IOP 6-14 Qualified Success at IOP 6-17 Qualified Success at IOP 6-21

Microstent

Trab

185 168 122 85 41 20 10

169 153 135 100 60 40 23

Trabeculectomy Microstent

185 168 123 86 41 20 10

169 153 137 101 62 41 24

185 168 125 87 42 20 10

169 154 137 102 62 41 26

Gonioscopy-Assisted Transluminal Trabeculotomy (GATT)

• Microcatheter or suture used to perform 360° trabeculotomy

• Hyphema is most common complication

Courtesy of Davinder Grover.

GATT, gonioscopy-assisted transluminal trabeculotomy.

Kahook Dual Blade

• Removal of TM using dual blade

• Single use ophthalmic blade

• Blade composition

– Pointed tip easily pierces TM

– Ramp elevates and stretches TM

– Dual blade excises strip of TM

– Foot plate prevents damage to collateral tissue

Courtesy of Malik Kahook.

TRAB™360

• Cannula used to incise TM and introduce flexible trabeculotome 180°

• Filament is retracted back into device and procedure is repeated in other direction

• 360° goniotomy performed

Investigational

• Translimbal implant

– InnFocus MicroShunt®

• Schlemm’s canal implants

– Hydrus™ Microstent

– iStent inject®

• Suprachoroidal shunts

– Gold Micro Shunt

– iStent Supra®

Courtesy of Len Pinchuk

Courtesy of Reay Brown.

Courtesy of Ike Ahmed.

Courtesy of Steven Vold.

Courtesy of Ike Ahmed.

In Summary

•Surgical options for managing glaucoma are rapidly expanding

•Traditional glaucoma surgery (tubes and trabs) provide excellent IOP reduction, but surgical complications are common (generally transient and self-limited)

•MIGS are newer procedures that offer an improved safety profile, but reduced efficacy

In the Pipeline: New Approaches to Drug Delivery for GlaucomaDavid S. Friedman, MD, MPH, PhDDirector, Dana Center for Preventive OphthalmologyWilmer Eye Institute, Alfred Sommer Professor of OphthalmologyJohns Hopkins University School of MedicineProfessor, Department of International HealthJohns Hopkins Bloomberg School of Public HealthBaltimore, MD

Modest Advances in Medical Therapy: Largely Stagnant Over Last 20 Years

• Combination therapies

• Preservative free

Adherence in Clinic Patients Monitored Electronically

Okeke CO, et al. Ophthalmol. 2009;116(2):191-199.

0.0 0.5 1.0

10

30

50

Adherence Rate(Percent of Drops Taken)

Nu

mb

er

of

Pat

ien

ts

Drops Are Not Ideal

• Half of new scripts are not filled after 6 months, low adherence

• Administrative errors

• Local and systemic side effects

Ideal Glaucoma Medical Treatment

• Patient-proof

• Few symptoms

• Can achieve the IOPs we need

• Cost effective

Drug Delivery Through a Scleral Ring

• Ability to incorporate drugs into polymer

• Phase 2 trials completed

Consistent Performance in Clinical Trials: Four Phase 1 (N = 73) and Four Phase 2 (N = 251)

• Uneventful safety profile• Regulatory pathway: NDA in 2019

• Topical, comfortable (90%), well-retained (90% at 6 months)

• One ring provides clinically significant IOP reduction for 6 months

• 85% of patient recommend insert• 80% of doctors prefer insert to drops

• Validated platform for fixed combination glaucoma, allergy, dry eye, other pipeline

Patient Acceptance

Durable Efficacy

Safety and Benefits

Market Value

Future

Goldberg I, et al. Poster presented at: World Glaucoma Congress; 2015 (Hong Kong).

Mean Diurnal IOP with Bimatoprost Insert: Phase I Efficacy Results (N = 27)

• Mean IOP reduction: 4.7 to 6.5 mmHg from washout

Goldberg I, et al. Poster presented at: World Glaucoma Congress; 2015 (Hong Kong).

16.3

23.9

17.418.2

18.8 18.7 19.218.8

14

16

18

20

22

24

26

Screening Wash-out Week 2 Week 6 Week 12 Week 16 Month 5 Month 6

Diurnal Average

mm

Hg

(S.E

.)

5.1mmHg

Scleral Ring Pros and Cons

• Comfort???

• Cosmesis???

• Medication can be placed by the patient (no physician involvement needed)

• Possible compliance issues

• Local side effects???

Drug Delivery Into Suprachoroidal Space

Ongoing Research

• Currently focused on macular edema and neovascular age-related macular degeneration

• One Phase I/II study completed

• Phase II and III studies on macular edema ongoing

• Injections every 12 weeks

• Planned research on delivery of glaucoma medicines using this technology

Suprachoroidal Delivery Pros and Cons

• Likely to eliminate many local side effects

• Low drug requirement

• Harm to retina and choroid unknown???

• Dosing frequency may exceed visit frequency

• Patient acceptance of “injection” unknown

Intracameral Injection of Printed Particles

Intracameral Injection of Printed Particles: Early Development

• Current product includes printed travoprost

• Ongoing Phase II study

• Novel design: enrolling patients scheduled for phaco within 60 days

• Evidence of efficacy >6 months in dogs

Months

IOP,

mm

Hg

0

25

1 2 3 4 5 6 7 8

Baseline

Placebo

ENV51520

15

10

30% change from baseline

Intracameral Delivery Pros and Cons

• Likely to eliminate many local side effects

• Evidence of long duration of action

• Possibility of infection, harm to cornea, other?

• Difficulty removing implant if side effects occur

• Patient acceptance of “injection” unknown

Bioerodible Subconjunctival Implant

Two views and their delivery system

Bioerodible Subconjunctival Implant

• Ongoing Phase I/II study

• Retinal products: duration of action as long as three years

Bioerodible Subconjunctival Implant: Pros and Cons

• Potentially long duration of action

• Avoids intraocular injection

• Possibility of removing implant if side effects occur

• May still have normal drug side effects

• Patient acceptance of “injection” unknown

• Possible adverse effect on later glaucoma surgeries

Bioerodible Tear Duct Plug

Bioerodible Tear Duct Plug

• Phase III trial completed for dexamethasone implant after cataract extraction

• Completed Phase I study comparing travoprost plug vs timolol

• IOP lowering noted for 3 months with minimal side effects

Bioerodible Tear Duct Plug: Pros and Cons

• Easy to insert

• Likely to be accepted by patients

• No possibility of removing implant if side effects occur

• May still have normal drug side effects, could fall out

• Dosing frequency may be > visit frequency

Biodegradable Nanoparticles

Subconjunctival Dorzolamide Particles LoweredIOP for 30 Days in Normotensive Rabbits

0 10 70

-4

0

4

Days Post-Treatment

IOP

Re

du

ctio

n, m

mH

g

20 30 40 50 60-6

2

2

* ** * * *

*

** *

* *

*

*Outliers more than 1.5x the interquartile range from the median.

Welsbie DS, et al. Proc Natl Acad Sci USA. 2013;110(10):4045-4050.

Particles Potentially Useful for Delivering Neuroprotective Agents as Well

25

75

125

0

100

50

0 10 20 30 40 50 60 70 80 90

Dru

g R

ele

ase

, μg

Time (Days)

Tozasertib

150

0

100

50

*

*

LaserVehicle

Tozasertib

‒

‒

+

+

+

‒

+

‒

Axo

n C

ou

nts

, x1

00

0

Medical Therapy Likely to Be a Rapidly Evolving Field

• Multiple new drug delivery platforms emerging

• Doctor and patient acceptance as well as business models will influence uptake