Assistant Professor of Ophthalmology University of … 2013 rounds.pdfAssistant Professor of Ophthalmology University of Ottawa Eye Institute Outline: Vision Loss in the Elderly Introduction

Visual Impairment in the Elderly

Bernard R. Hurley, MD, FRCSCAssistant Professor of Ophthalmology

University of Ottawa Eye Institute

Outline: Vision Loss in the Elderly

Introduction

The eye as an optical system»

Relevant anatomy

Disease of the aging eye

Cataract

Retinal vascular disease

Glaucoma

Age related macular degeneration»

Wet and Dry

Emphasize current and future treatments for each

Life is Beautiful to Look At

Life is Beautiful to Look At

My daughter Jenna shows us what it is like to suffer vision loss

Outline

Introduction


Relevant anatomy


Cataract


Glaucoma


Wet and Dry


The Eye –

A Living Camera

The Eye –

A Living Camera

The Eye as an Optical System

Cornea

Lens

Retina

Optic Nerve


Center of retina is macula

Affected in macular degeneration

Cornea

Lens

Retina

Cataract

Optic Nerve

Vascular Disease

Glaucoma

Outline

Introduction


Relevant anatomy


Cataract


Glaucoma


Wet and Dry



Lens

Retina

Cataract

Optic Nerve

Cataract

Aging change of lens

Loss of clarity

Major cause of blindness on global scale

Most common surgery performed in Canada

Replacing the Lens –

Cataract Surgery

Cornea

Focusing elements of eye

Most common surgery in Canada

Lens

http://images.google.ca/imgres?imgurl=www.drboop.com/mature-cataract.jpg&imgrefurl=http://www.drboop.com/cataract.html&h=486&w=736&sz=37&tbnid=BMCLmI3E_7AJ:&tbnh=91&tbnw=137&prev=/images%3Fq%3Dcataract%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8

Cataract Surgery Procedure

1.

Clear corneal incision

Surgeon’s View of Surgery

1.

Clear corneal incision2.

Viscoelastic formation of the anterior chamber


1.



3.

Capsular rhexis and hydro-dissection


1.



3.


4.

Grooving


1.

Clear corneal incision 2.


3.


4.

Grooving5.

Nuclear division6.

Emulsification and extraction


1.



3.


4.

Grooving5.

Nuclear division6.


7.

Lens insertion


1.

Clear corneal incision


1.




1.



3.



1.



3.


4.

Grooving


1.



3.


4.

Grooving

http://www.eyemdlink.com/pop/phaco_tip.htm


1.



3.


4.

Grooving5.

Nuclear division6.


http://www.eyemdlink.com/pop/phaco_tip.htm

Real Life Operation

One More Time

What’s new: Choice of Lens

Previously

Limited to monofocal lens

Now

Technology allows custom lens»

Correct all ocular aberrations»

Multifocal

Distance and near correction

Requires

Bio-Imaging to measure optical aberrations of the eye

»

Correction beyond sphere and cylinder

Lens Selection

Oculus Pentacam

AMO/VISX Wavescan

The Eye as an Optical System –

Distant Objects

Take home message:

The eye is designed to place distance objects in focus on the retina

20mm

50 D

The Eye as an Optical System –

Near Objects

The eye NO LONGER strong enough

Focus is behind retina

Behind the retina

Requires Reading Glasses

The added power can not come from native lens

Must come from reading glasses

Multifocal IOL

Multifocal IOL

Simultaneously focuses near and distance objects»

Light intensity split between two images»

Result is decreased image quality but no need for reading glasses

Both images appear simultaneously on retina

Multifocal IOL

Older patient

Visual confusion in images

Less light intensity»

Lower contrast sensitivity»

Poorer image quality

Result: New IOL’s may not be best for elderly

Also expensive and not covered by OHIP

Outline

Introduction


Relevant anatomy


Cataract


Glaucoma


Wet and Dry


Glaucoma

Cornea

Lens

Retina

Optic Nerve

Glaucoma

Glaucoma

A spectrum of disorders»

Pressure related damage to the optic nerve

Glaucoma

Glaucoma



↑

PRESSURE

Glaucoma



Glaucoma

Glaucoma



Glaucoma

Acute Angle Closure Glaucoma

Aqueous Outflow Intraocular Pressure 15 mmHg

60 mmHg

Intraocular Pressure

Presenter

Presentation Notes

Maximize effect and enjoyment, Minimize text/work/effort

Acute Angle Closure Glaucoma

Mechanism60 mmHgIntraocular Pressure

Presenter

Presentation Notes


Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure

Mechanism

Presenter

Presentation Notes



Mechanism

Presenter

Presentation Notes



Mechanism

Presenter

Presentation Notes



Mechanism

Presenter

Presentation Notes



Treatment

on

off

Presenter

Presentation Notes



Treatment

Presenter

Presentation Notes


What’s New in Glaucoma

I stent –

micro valved implants to regulate IOP

Will everyone get one during cataract surgery?

Outline

Introduction


Relevant anatomy


Cataract


Glaucoma


Wet and Dry


Vascular Disease

Cornea

Lens

Retina

Optic Nerve

Vascular Disease

Venous Occlusive Disease

Hypertensive changes in arteries

http://webvision.med.utah.edu/imageswv/retina.jpeg



Retinal Vein Occlusion

Risk factors

Identified by the Eye Disease Case-Control Study

»

Age 60-69 most common»

Hypertension»

Cardiovascular disease»

Increased BMI at age 20»

Glaucoma»

Diabetes

http://www.redatlas.com/RAImages/F/F027/F02700/Branch Retinal Vein Occlusion (BRVO), Misc-004.jpg



Visual Loss

Acute»

Macular hemorrhage»

Macular edema»

Capillary occlusion

With time»

Vascular remodeling/collateral formation may

Restore flow

Reduce edema and hemorrhage

Chronic»

Macular ischemia»

CME»

Macular pigmentary changes»

Epiretinal membrane formation»

Subretinal fibrosis




Photocoagulation

Used to treat:»

Macular edema

Requires intact foveal perfusion

Macular edema»

Allow three months for improvement

»

Vision 20/40 or worse»

Light grid pattern of laser spots to involved sector of retina

»

Branch vein occlusion study

Treated eyes 2X more likely to gain 2 lines of vision


http://www.redatlas.com/RAImages/F/F027/F02705/Branch Retinal Vein Occlusion (BRVO), Case 05-006.jpg


Branch Retinal Vein Occlusion

Vascular Remodeling

Collateral vessels

Help to reduce vascular congestion

Reduce edema

What’s New for Retina Vein Occlusion

Ozurdex implant

Biodegradable dexamethasone intravitreal implant

»

Polymer matrix»

Designed to last 6 months

OTHER OPTIONS?

Ozurdex implant

Biodegradable dexamethasone intravitreal implant

»

Polymer matrix»

Designed to last 6 months

Approved to treat macular edema from RVO

Effect does not last 6 months»

Three good months of control

NOT cheap

Ozurdex results

Ozurdex results: RVO (BRVO+CRVO)

Management

Intravitreal injection of Ozurdex OS

Management

Intravitreal injection of Ozurdex OS

Result

Excellent improvement in VA

Pre-Ozurdex: 20/200

One week Post-Ozurdex: 20/25

Surprising results

Surprising resultsOne week Post-Ozurdex: 20/25

Next visit –

implant in AC !

Outline

Introduction


Relevant anatomy


Cataract


Glaucoma


Wet and Dry


Macular Degeneration (AMD)

Center of retina is macula

Affected in macular degeneration

Cornea

Lens

Retina

Optic Nerve

I love retina !

I love retina too!(not as much as pancakes)

AMD

Leading cause of severe central vision loss

i.e. legal blindness»

western world

people over 50 years old

Social/economic impact increasing

aging of population

AMD

Basic lesion is the druse

Thickening of inner aspect of Bruch’s membrane


AMD

Basic lesion is the druse

Thickening of inner aspect of Bruch’s membrane

»

Phospholipid vesicles»

Electron-dense granules


AMD –

Types

Dry

Most common, less severe

10% of population over 55

»

Degenerative changes only

Wet (exudative, neovascular, CNVM)

90% of pts with ≤20/200

10% of dry ARMD turns wet

»

New blood vessel formation

AMD –

Causes of severe vision loss

Neovascular (CNV)Neovascular (CNV)90%90%

DryDry10%10%

AMD -

Dry

Drusen

Phospholipid deposits

Geographic Atrophy

Loss of retinal cells

Responsible for vision loss

AMD -

Wet

Lipid (fat) deposits

Blood and fluid

AMD –

Wet End Stage

Scar tissue formation

“Diskaform scar”

Sub-retinal fibrosis

Treatment Options for Dry AMD

There is not cure

Life style modifications important

Quite smoking

Eat fresh fruits and vegetables

Maintain a healthy weight»

Exercise, Blood pressure control

? Reduce blue light/UV light exposure

Role of Nutrients in Dry AMD

therapy and prevention

Treatment of AMD -

DRY

AREDS

Age-Related Eye Disease Study

Multicenter, randomized trial

Up to 10 years follow-up

Assessed risk of:

Progression to wet AMD

Visual loss

AREDS -

Results

Vitamins reduce progression(CNV/visual loss)

25% at 5 years

Vitamins used

Vitamin C

Vitamin E

Beta-carotene

Zinc

Copper

Centrum Silver in addition is ok

What’s New for Dry AMD

AREDS II

Lower concentration of Zinc

Addition of new components

»

Lutein»

Zeaxanthin

»

Omega 3 fatty acids (fish oil)

Not available at the time of AREDS

Why Would These Vitamins Help?

The retina

One of the most metabolically activetissues in the body

This metabolism leads to the generation of “free radicals”

Highly reactive oxygen intermediates (ROIs)

ROIs:

Negatively charged molecules

Interfere with cellular function & damage retina layers

ROIs and antioxidants are balanced:

Antioxidants protect cells from potentially damaging effects of ROIs

What Is Oxidative Stress?

Disturbance in the ROI/antioxidant balance occurring because:

ROI production is increased, and/or

Availability of antioxidants is decreased

Believed to play major role in development of AMD

Presenter

Presentation Notes

Disturbance in the ROI/antioxidant balance = potential cell damage

Factors Contributing To Oxidative Stress

Age

Low intake of antioxidants and minerals

Excessive exposure to blue light

Smoking

Pollution

Presenter

Presentation Notes

The retina is particularly vulnerable to oxidative stress for a number of reasons: Age Low intake of antioxidants and minerals Excessive exposure to blue light Smoking Pollution

Oxidative Stress & Cell Damage

ROIs damage Retinal Pigment Epithelium (RPE) & photoreceptors in two ways by:

Reacting with cell membranes & impairing normal cell function

Contributing to cellular waste products

Cells do not regenerate

Accumulating damage results in characteristic visual changes of AMD

Presenter

Presentation Notes

ROIs produced as a result of oxidative stress damage the RPE and photoreceptors in two ways: 1. by reacting with cell membranes & impairing normal cell function 2. by contributing to cellular waste products: creates debris and build up in the RPE leads to death of cells of the RPE and photoreceptors

Protection Against Oxidative Stress

1.

Blocking the formation of excess ROIs:

Lutein and zeaxanthin:»

Absorb harmful blue light

2.

Preventing the build-up of excess ROIs:

Antioxidants:»

Bind to and neutralize ROIs»

Renders ROIs harmless to cells in the RPE»

Prevents cell damage

Presenter

Presentation Notes

The best course of action to preserve sight is to prevent oxidative stress. There are two ways to protect against oxidative stress and in order to maximize protection you need to address both the formation & build-up of excess ROIs 1. block the formation of excess ROIs Lutein and zeaxanthin absorb harmful blue light, thereby stopping the production of excess ROIs. As a result, ensuring adequate daily intake of lutein is key. Clinical studies have demonstrated protective benefits with supplementation of 10 mg of lutein/day. 2. prevent the build-up of excess ROIs ROIs are generated as part of normal metabolic processes, therefore, they exist in the eye under normal conditions. In order to avoid oxidative stress from occurring, a balance must exist between the ROIs and antioxidants. As a result, a sufficient level of daily antioxidant intake is required in order to maintain the balance and avoid oxidative stress & the resulting damage.

Antioxidants

Two types of antioxidants:

Antioxidant nutrients:

Carotenoids –

lutein, zeaxanthin and beta-carotene

Vitamin C

Vitamin E

Antioxidant enzymes:

Zinc

Glutathione peroxidase

Catalase

Presenter

Presentation Notes

ANTIOXIDANT NUTRIENTS Most antioxidant nutrients cannot be synthesized by the body and therefore have to be supplied in the diet. Increased dietary intake of fruit and vegetables can increase the levels of antioxidants nutrients in the retina however, nutritional studies have shown that the more sedentary lifestyle of the elderly, together with their lower food consumption predisposes them to insufficient dietary intake. This reinforces the need for appropriate supplementation. ANTIOXIDANT ENZYMES Antioxidant enzymes are produced in the body but require specific minerals for their chemical reaction to take place. The activity of these antioxidant enzymes can be restricted if there is insufficient intake of minerals. Increasing the intake of such minerals would be expected to increase the activity of the antioxidant enzymes, but, as with antioxidant nutrients, it is probably impractical to achieve a sufficient increase by a change in diet alone.

Carotenoids

A subclass of xanthophylls

Yellow, oxygen-containing pigments found in plants

Dietary sources:

Spinach, collard greens, broccoli, carrots, corn, citrus fruit

Two major eye nutrients:

Lutein

Zeaxanthin

Lutein Supplementation

Lutein Supplementation

Increases macular pigment optical density (MPOD)

Filtersblue light

Provides protective effect

Presenter

Presentation Notes

Lutein Supplementation has been clinically shown to have many benefits to eye health: increases macular pigment optical density filters blue light provides protective effect against oxidative stress and resulting damage

Clinical Studies on Beneficial Effects of Supplements

Dietary Intake Of Antioxidants & Risk Of Age- Related Macular Degeneration

•

van Leeuwen et al •

JAMA, December 28, 2005 –

Vol 294, No 24:

3101-3107

Study Overview

Objective:

To investigate whether regular dietary intake of antioxidants is associated with a lower risk of incident AMD

Design:

Dietary intake assessed»

Rotterdam Study (1990-1993) »

Divided into 3 intake groups

Study Population:

4170 adults >55 years of age

Mean follow-up of 8.0 years

van Leeuwen R et al, Dietary Intake of Antioxidants and Risk of Age-related Macular Degeneration. JAMA. 2005; 294: 3101-3107

Presenter

Presentation Notes

OBJECTIVE: objective of the study was to investigate whether regular dietary intake of antioxidants is associated with a lower risk of incident AMD incident AMD defined as the presence of any of the following: Soft distinct drusen with pigment alterations (early stage) Indistinct or reticular drusen (early stage) Geographic atrophy (late stage) or Choroidal Neovascularization (late stage) DESIGN: study was designed as a prospective, population-based cohort observational study assessed patients dietary intake at baseline based on what was used in the Rotterdam study in 1990 to 1993, which used a food frequency questionnaire divided the study population into 3 groups: High intake group – those with an above-median intake of each of the 4 nutrients (beta carotene, vitamin C, vitamin E, and zinc) Low Intake group – had a below-median intake of each of the 4 nutrients Median Intake group - used as the cutoff value; levels at or above the RDA, meaning that the majority of the study population presumably consumed a healthy diet. incident AMD was determined by grading fundus colour transparencies. STUDY POPULATION: patient population = 4170 adults over the age of 55 followed for approximately 8 years cohort group were considered to be at-risk patients with no AMD in either eye at baseline

Study Overview

Primary Outcome:Incident AMD

»

People who had no AMD at baseline»

Progression to incident AMD in at least one eye


Presenter

Presentation Notes

PRIMARY OUTCOME: primary outcome measure was to assess incidence of AMD in people who had no AMD at baseline & progressed to incident AMD in at least one eye. incident AMD defined as the presence of any of the following: Soft distinct drusen with pigment alterations (early stage) Indistinct or reticular drusen (early stage) Geographic atrophy (late stage) or Choroidal Neovascularization (late stage) DATA ANALYSIS: investigators adjusted out the risk factors in the study population in order to determine the pure nutrition effect this provided a controlled approach to determining the role of nutrition alone in reducing the incidence of AMD. Risk factors adjusted for included: age, sex, body mass index, smoking status, pack-years smoking, systolic blood pressure, serum total cholesterol, composite atherosclerosis score, and alcohol intake. Also adjusted for intake of polyunsaturated fat in the analysis of the fat soluble vitamin E because of reported association between this fat and AMD.


1.20

1.00

0.65

0.00

0.20

0.40

0.60

0.80

1.00

1.20

Hazzard Ratio (Fully Adjusted)

Low Median HighCategory of Dietary Intake

Risk of AMD by Intake Group

Results

An above median intake of all 4 nutrients

beta carotene, vitamin C, vitamin E, and zinc

associated with a 35% reduced risk of AMD

35% risk reduction

Presenter

Presentation Notes

It is important to note that it was those taking above average intake of all 4 nutrients that showed the 35% reduced risk of developing AMD The same benefit was not seen if above average intake was achieved for individual nutrients or for other nutrient combinations. Only 434 patients out of a total of 4170 (10.4%) actually achieved the high daily intake, which highlights how difficult it can be to reach these dietary intake levels.

Van Leeuwen*

Vitamin C 114 mg

Vitamin E 20 IU

Beta carotene 6,000 IU

Zinc 10 mg

minimum dose to be considered above-

median intake

Antioxidants Demonstrated Risk Reduction Of AMD

*total daily dose


Presenter

Presentation Notes

Chart shows dietary intake cutoff points in van Leeuwen study (JAMA. 2005; 294: 3101-3107) Levels stated are the minimum intake dose required in order to be considered above-median intake Important to note that intake could be at levels higher than this, however, if they were below these cut-off values in one or more of the nutrients, they would not be considered in the above-average intake group Study patients taking daily amounts at or above these levels were those that demonstrated the 35% reduction in risk of developing AMD.

Conclusions

1.

A larger risk reduction (35%) was observed for dietary intake for all 4 nutrients than for individual nutrients alone

2.

Dietary antioxidants may delay the development of early AMD and, possibly, of AMD in general

3.

Information may be useful to persons with signs of early AMD or to those with a family history of AMD


Presenter

Presentation Notes

The investigators concluded that: 1. A larger risk reduction (35%) was observed for dietary intake of all 4 nutrients than for individual nutrients alone. 2. Dietary antioxidants may delay the development of early AMD and possibly, of AMD in general. 3. Lastly, this information may be useful to persons with signs of early AMD or to those with a family history of AMD.

Antioxidants -

The Challenge

Antioxidant nutrients:

Cannot

be synthesized by the body

Must be supplied from dietary sources

Difficult and often impractical to obtain a sufficient amount of antioxidants from the diet alone

Treatments for Wet AMD

Established treatment

Laser therapy

Photodynamic therapy»

PDT

Modern Era

Intra-ocular injection»

The anti-VEGF revolution

Older treatments reduced the rate of visual loss but did not improve vision

Unequalled success

Now a treatable disease

Vision restored and protected

Life changing therapy

Wet AMD Therapy: Anti-VEFG Revolution

Before (20/400) After (20/40)

Profound impact

Driving

Reading

Independence

Life expectancy

Vascular Endothelial Growth Factor

What is VEGF?

Presenter

Presentation Notes

VEGF (or VEGF-A), the most potent direct-acting angiogenic protein known, �is an EC-specific mitogen and inducer of vascular permeability.11,12 Essential for early development of vasculature A basic, heparin-binding homodimeric glycoprotein, with monomers�assembled in antiparallel fashion Available to EC either as a freely diffusible intact protein, or following�protease activation and cleavage Mitogenic activity requires the heparin-binding domain of the larger isoforms The VEGF family consists of 6 known members11,12: VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor� (PlGF) All contain a “cysteine knot” motif (characteristic regular spacing of �8 cysteine residues) They belong to a structural superfamily of growth factors that includes�PDGF-BB and TGF-beta 2 The structure of VEGF as determined by x-ray crystallography is illustrated.12-14 Individual polypeptides are shown in different colors Receptor-binding domains on the end of each polypeptide chain enable�VEGF to cross-link 2 VEGF receptors together on the cell surface, �a dimerization that is key to the initiation of signaling

Vascular Endothelial Growth Factor

Primary angiogenic factor

Endothelial cell»

Proliferation»

Migration»

Survival

Vascular permeability factor

78,000 times as potent as histamine

Four main isoforms of VEGF

VEGF165 most common isoform

Upregulated in angiogenesis

VEGF Isoforms: VEGF A

Dimer

165 121 110

165121110 189

189206

206

VEGFVEGF

VEGFVEGF86 -

89

Presenter

Presentation Notes

VEGF binds to its receptor at amino acids 86 to 89 and binds all isoforms (VEGF189, VEGF165, VEGF121, and VEGF110 have been tested). Plasmin cleaves VEGF at amino acid 110 to produce the biologically active form VEGF110. Macugen binds at amino acid 137.

VEGF Isoforms

Dimer

165 121 110

165121110 189

189206

206

VEGFVEGF

VEGFVEGF86 -

89

VEGF189

is sequestered in extracellular matrix

VEGF165

is most abundant and physiologically important isoform for normal angiogenesis

VEGF121

is highly diffusible

VEGF110

is a soluble and bioactive form that lacks the heparin binding domain; activated by plasmin

Presenter

Presentation Notes


Endothelial Cell

VEGF receptor

Capillary formation (angiogenesis)

VEGF

VEGF


Anti VEGF Therapy

VEGF

Endothelial Cell

VEGF receptor

Lucentis binds VEGF in extracellular space

Endothelial cell Endothelial cell apoptosisapoptosis

H+H+

VEGF with Lucentis

Endothelial Cell

VEGF receptor

Prevents binding to endothelial cell

Anti-VEGF Treatment

Endothelial Cell

VEGF receptor

Antibodies against VEGF block

Embryonic development

Bone morphogenesis

Female reproductive cycling

Retinal and corneal angiogenesis

Growth of several tumor types in animal models

VEGF is required for embryonic development

Blocking VEGF is lethal

Even a 50% reduction of VEGF is lethal

Presenter

Presentation Notes

Animal studies using antibodies or soluble receptors to bind VEGF reveal that VEGF is required for angiogenesis in normal development and in models of tumor growth. Postnatal suppression of VEGF in normal newborn mice resulted in growth arrest and mortality within 4–6 days when the treatment was initiated on either day 1 or day 8 postnatally.17 Suppression of tumor angiogenesis in animal models using an anti-VEGF antibody resulted in reductions in tumor vascularity. This was accompanied by marked changes in vessel morphology and reductions in diameter and tortuosity.17,18 Loss of a single VEGF allele in mice resulted in embryonic lethality between days 11 and 12. The VEGF+/- embryos were growth-retarded and exhibited a number of developmental abnormalities. In situ hybridization confirmed expression of VEGF mRNA. Therefore, the VEGF+/- lethal phenotype is due to gene dose and not maternal imprinting.17

VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1

Anti-VEGF(Avastin, Lucentis)

VEGF Receptor

Aptamer (Macugen)

Kinase Inhibitors

VEGF Trap

siRNA

Squalamine

Extracellular and CellularTargeting the VEGF Pathway

(Small interferening RNA)

Presenter

Presentation Notes

There are many ways to block VEGF, including apatmers like Macugen, antibodies and antibody fragments like Avastin and Lucentis, antibodies to the VEGF receptor itself, small molecules that work inside cells to block the enzymatic activity of the VEGF receptor, and, not shown on this slide, siRNAs. The VEGF Trap is unique in that it takes key elements of the VEGF Receptor (blue), and combines them with tha backbone of an antibody (lavender). This gives the VEGF trap the high binding affinity of an receptor, combined with te long circulating half life of an antibody.

What about other Anti-VEGF medications?

Macugen (Pegaptanib)

First FDA-approved anti-angiogenic agent for CNVM, Dec. 2004

Now clinically dead

Minimally Classic Occult (no classic)Predominantly Classic

Neovascularization

VEGF Macugen

Permeability

All CNVAll CNV

VEGF Isoforms

Dimer

165 121 110

165121110 189

189206

206

VEGFVEGF

VEGFVEGF86 -

89

Presenter

Presentation Notes


Lucentis/Avastin Binds All VEGF Isoforms

*VEGF-189, -165, -121, and -110 have been tested.

165 121 110 1

1651211101

LucentisLucentis

LucentisLucentis

189

189206

Plasmin cleavage site

206

VEGFVEGF

VEGFVEGF86 - 89

Plasmin Cleaves VEGF165 to Produce Biologically Active VEGF110

Anti-VEGF Antibody (Lucentis, Avastin)

Presenter

Presentation Notes


-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102

Week

Visu

al A

cuity

(let

ters

)

2 Years Treatment (N=133;0.3 mg)Usual Care (N=107)

Treatment Effect Continues for 2 Years

45% Benefit,

P<0.01

Year One Year Two

Macugen (Aptamer)



VEGF Receptor

Aptamer (Macugen)

Kinase Inhibitors

VEGF Trap

siRNA

Squalamine


Presenter

Presentation Notes


Study 2425: Occult CNV-

Group 1Day 140: 20/63 (+17 letters)Day 0: 20/125

457 µ 166

µ

FluoresceinAngiogram

OCT

Slide courtesy of Dr. P Rosenfeld, BPEI, Miami, FL

Anti-VEGF Antibody (Lucentis)

Lucentis = rhuFab V2 = ranibizumab

recombinantly produced

humanized

monoclonal Ab vs VEGF

Fab fragment

V2

–

Version 2 Affinity Matured

rhuMabMW 150 kD

rhuFabMW 48 kD

rhuFab V2MW 48 kD


Presenter

Presentation Notes

Next slide shows why Genentech explored a fab fragment

Fab Retinal Penetration Following Intravitreal Injection

FabIgG

Fab (e.g. Lucentis)

MW 48 kD

IgG (e.g. Avastin™)MW 150 kD

Fab penetrates through all

retinal layers while IgG only penetrates superficially.

Toxicologic Pathology. 27(5):536-44, 1999 Sep-Oct.

Inner retina

Outer retina


Presenter

Presentation Notes

One of the features of the Fab molecule is its enhanced permeability as compared with the full length antibody. This slide shows a histoautoratiogram of two retinas exposed to radiolabeled IgG (on the left) or to (radiolabeled Fab on the right). Because of its much lower molecular weight, the Fab fragment is able to penetrate all of the retinal layers while the IgG is localized to the surface of the retina.

Lucentis/Avastin Binds All VEGF A Isoforms

*VEGF-189, -165, -121, and -110 have been tested.

165 121 110 1

1651211101

LucentisLucentis

LucentisLucentis

189

189206

Plasmin cleavage site

VEGF-receptor binding site

206

VEGFVEGF

VEGFVEGF86 - 89

Plasmin Cleaves VEGF165 to Produce Biologically Active VEGF110


Presenter

Presentation Notes


Lucentis™: Phase I/II (FVF2128g) Mean Change in VA (3 and 6 Months)Mean change in visual acuity to day 210

12.8

–5.1

8.1

15.012.6

–10

–5

0

5

10

15

20

ETD

RS

lette

rs

Usual care0.3 mg0.5 mg

n = 22

n = 20

n = 19

n = 21

Baseline

N = 11

Day 210Day 98


First therapy to improve vision

Avastin (Bevacizumab)

Recombinant humanized monoclonal IgG1 antibody

Full length antibody

Binds and inhibits human VEGF (all isoforms)

FDA approved for

Metastatic colorectal cancer

Colorectal cancer

Renal cell carcinoma

Glioblastoma

Non-small cell lung cancer

Intravenous avastin for neovascular AMD showed promising results in small series1

Intravitreal avastin for neovascular AMD effective in anecdotal reports2

1Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab therapy for neovascular age-related macular degeneration. Ophthalmology 2005;112:1035-47.2Rosenfeld PJ, Moshfeghi AA, Puliafito CA. OCT findings after an intravitreal injection of bevacizumab for neovascular age-

related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-335.

Intravitreal Avastin

Advantages

400-fold less drug required compared to intravenous dose

Higher safety margin

Lower cost $50 per dose

Disadvantages

No efficacy or safety data

Systemic side effects: »

hypertension, hemorrhage, GI perforation, arterial thromboembolic events (stroke, MI), proteinuria, CHF

No protocol for dosing or frequency of injection

Limited retinal penetration (in theory)



VEGF Receptor

Kinase Inhibitors

VEGF Trap

siRNA

Squalamine


Presenter

Presentation Notes


Direct acting anti-angiogenic small molecule

Rapid systemic clearance

Long intracellular half-life and effects

Excellent safety profile with intravenous use

Inhibits VEGF and othergrowth factors

O H

NH H

O

OH

NHNH2

S OO

Squalam ineSqualamine

Squalamine lactate (investigational)

Given by intravenous

injection

Growth factors (VEGF, bFGF, etc.)

Endothelial Cell

Growth factor enhanced uptakeof squalamine aborts intracellular signaling

Squalamine

calmodulin

Intracellular Effects of Squalamine: Mechanism Of Action Model

Capillary formation (angiogenesis) F-Actin Filaments

Endothelial cell Endothelial cell apoptosisapoptosis

H+H+

Squalamine chaperonescalmodulin

Blockade of VEGF signaling, Blockade of VEGF signaling, decreased motility &decreased motility &integrin expressionintegrin expression

Squalamine lactate (investigational)



VEGF Receptor

Kinase Inhibitors

VEGF Trap

siRNA

Squalamine


Presenter

Presentation Notes


VEGF Trap (New Kid on the Block)

Soluble “decoy”

receptor

Fusion protein

Smaller than antibody

“Mops-up”

VEFG in extracellular space

Binds VEFG more tightly than native receptors, antibodies (Lucentis, Avastin) or aptamers (Macugen)

Blocks VEGF in mammalian species (VEGF A, VEFG B and Placental Growth Factor)



VEGF Receptor

Kinase Inhibitors

VEGF Trap

siRNA


Presenter

Presentation Notes


Double stranded RNA silences gene expression specifically and potently

siRNA (investigational)

How does siRNA work?Once activated the RISC complex destroys targeted mRNA in

a multiple turnover kinetic fashion.

ActivatedActivatedRISCRISC

V

V

V

V

V

V

RISC RISC SurveillanceSurveillance

ModeMode

No VEGF


What activates the RISC?

Small interfering RNA (siRNA) 21 Nucleotide double stranded RNA

siRNA is the key that activates the RISC



Inhibits VEGF in vitro and in vivo

Intravitreal injection inhibits laser induced CNV in mouse and monkey



VEGF Receptor

Kinase Inhibitors

VEGF Trap

siRNA


Presenter

Presentation Notes


The Big ThreeRanibizumab (Lucentis)Bevacizumab (Avastin)Aflibercept (VEFG Trap, Eylea)

May be differentiated by:Pharmacology EffectivenessSafety profile

Summary of Choices

Avastin

Never designed for the eye »

Label specifically states not for intra-ocular use»

No clinical trial support»

Vast world wide experience (60 million doses)

Cheap: $60/dose

Duration: 6 weeks

? Systemic side effects

Lucentis

Specifically designed and manufactured for the eye

Expensive: $1600/dose

Duration: 1 month

Eylea

New kid on the block

Still expensive

Duration: 2 months

Unequalled success

Practical limitations to achieving this

Physician factors

Patient/family factors

Societal factors

Wet AMD Therapy: Anti-VEFG Revolution

The Future: Long Acting Implants

The Ultimate Perhaps

Topical therapy

Summary

Major disease of the aging eye

Cataract»

Good surgical treatment available

New lenses for “super vision”

May not be good choices in elderly

Retinal vascular disease»

Age, Diabetes, Hypertension»

Long acting steroid implants

Glaucoma»

Medical and Surgical treatments»

Micro-valve implants


Most common cause of age related blindness»

New exciting treatments»

Need longer acting formulations

Thanks for listening to my Dad



Thank-you

Documents

Assistant Professor of Ophthalmology University of … 2013 rounds.pdfAssistant Professor of Ophthalmology University of Ottawa Eye Institute Outline: Vision Loss in the Elderly Introduction