Advances in the Management of Dry Age-related Macular Degeneration (AMD)

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Advances in the Management of Dry Age-related
Macular Degeneration (AMD)

• Lawrence J. Singerman, MD, FACS
• Retina Associates of Cleveland
• Clinical Professor of Ophthalmology
• CWRU School of Medicine
• Voluntary Professor of Clinical Ophthalmology
• Bascom Palmer Eye Institute

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Financial Disclosure

• I have the following financial interests or
  relationships to disclose
• Alcon Laboratories, Inc. - S
• Allergan, Inc. - C
• Eli Lilly Company - S
• Eyetech, Inc. - C
• Genentech, Inc. - C,S
• National Eye Institute - S
• Notal Vision, Ltd. - S
• Ophthotech - O,S
• OPKO Health - C,O,S
• Othera Pharmaceuticals Inc - S
• Pfizer Ophthalmics - S
• Sirion Therapeutic - S

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Emerging Treatments for Dry AMD

• Evidence to support treatment strategies comes
  from
• Histopathological studies
• Animal models
• Epidemiologic studies
• Nutritional studies
• Genetic association studies
• Clinical Trials

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Age-Related Eye Disease Study (AREDS) (NEI)

• Results showed that high levels of antioxidants
  and zinc significantly reduce the risk of
  advanced AMD and its associated vision loss
• Formulation
• 500 milligrams of vitamin C
• 400 International Units of vitamin E
• 15 milligrams of beta-carotene (often labeled as
  equivalent to 25,000 International Units of
  vitamin A)
• 80 milligrams of zinc as zinc oxide
• 2 milligrams of copper as cupric oxide

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Age-Related Eye Disease Study 2 (AREDS2) (NEI)

• Study goals
• Evaluate the effects of oral supplementation of
  macular xanthophylls (lutein and zeaxanthin)
  and/or long-chain omega-3 fatty acids
  (docosahexaenoic acid) DHA and eicosapentaenoic
  acid EPA) on the progression to advanced AMD
• Assess the effect of these supplements doses on
  moderate vision loss
• Evaluate the effect of eliminating beta-carotene
  and reducing zinc in the original AREDS
  formulation

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Age-Related Eye Disease Study 2 (AREDS2) (NEI)

• Supplements
• Lutein 10 mg/zeaxanthin 2 mg
• Omega-3 long chain polyunsaturated fatty acids
  (LCPUFA) 1 gm
• 350 mg docosahexaenoic acid (DHA)
• 650 mg eicosapentaenoic acid (EPA)

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Age-Related Eye Disease Study 2 (AREDS2) (NEI)

• Inclusion criteria
• Bilateral large drusen 125 µm
• Large drusen in one eye, advanced AMD in fellow
  eye
• Geographic atrophy (GA)
• Advanced form of dry AMD
• Approximately 973,000 people in the US have GA in
  at least one eye expected to increase by more
  than 50 by 2020
• Currently no therapeutic treatment

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Fenretinide for GA in AMD

• Lipofuscin
• GA is associated with accumulation of lipofuscin
  in the RPE
• RPE provides nutrients and waste processing for
  retinal cells
• Accumulation of lipofuscin in the RPE can lead to
  death of retinal cells and subsequent loss of
  vision
• Fenretinide was shown in pre-clinical studies to
  reduce the amount of lipofuscin in the eye

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Delivery of Vitamin A to the Eye
Retinol within RPE cells
Photoreceptor cells containing visual chromophore
RPE cell layer
RBP-retinol-TTR complex delivered through blood
circulation
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Early AMD Accumulation of Lipofuscin and Vitamin
A Metabolites
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Advanced AMD Loss of RPE Cell Layer and
Photoreceptors
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Fenretinide(Sirion Therapeutics)
Retinol Binding Protein Retinol Transthyretin
Retinol Binding Protein Fenretinide
Normal physiological complex delivers retinol to
the RPE and other target tissues
Fenretinide competes with retinol binding to RBP
and prevents binding of TTR
Metabolic down-regulation of photoreceptors
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Effect of Fenretinide on Retinoid Levels in the
Visual Cycle
Accumulation of Lipofuscin toxic fluorophores

TTR I
I RBP
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Fenretinide for GA in AMD

• Design
• Randomized, double blind, placebo controlled,
  parallel assignment
• Three groups
• Group 1 3 fenretinide capsules ( 300 mg)
• Group 2 3 placebo (no active ingredients)
  capsules
• Group 3 1 fenretinide capsule ( 100 mg) plus 2
  placebo capsules
• Capsules taken once a day, after the evening
  meal, for 24 months
• Plus multivitamin supplement without beta-carotene

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Fenretinide for GA in AMD

• Efficacy and safety results (Roger Vogel, MD AAO
  meeting 2009)
• At 18 months, 78 of lesions in the 300-mg group
  grew less than the median of the placebo
• 100-mg dose appeared most protective against
  growth in small lesions (lt 3 DA)
• Conversion to wet AMD occurred less in the 100-mg
  (6) and 300-mg groups (7) than in the placebo
  group (13.4)

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Fenretinide for GA in AMD

• Efficacy and safety results (Roger Vogel, MD AAO
  meeting 2009)
• Conclusions
• There was a strong trend for efficacy regardless
  of baseline lesion size in the 300-mg group and
  for smaller lesions in the 100-mg group
• Dose-related dark-adaptation delay was as expected

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ACU-4429 (Acucela Inc.) Inhibits conversion of
all-trans retinol to 11-cis retinal
RPE
Photoreceptor
By inhibiting RPE65, ACU-4429 reduces the levels
11-cis retinal and suppresses rod photoreceptor
function
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Brimonidine Sustained Release Implant

• Brimonidine formulated in the Allergan Novadur
  delivery system
• Phase II clinical trial underway
• Bilateral GA
• 200µg or 400µg in study eye q6 mos
• Fellow eye serves as control
• Primary outcome is the comparison of treated and
  untreated eyes

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Intravenous RN6G (PF-4382923, Pfizer)

• Phase I completed
• Safe and well tolerated
• Phase II
• Double-masked, placebo-controlled
• Four cohorts
• 5, 15, 25 and 35 mg/kg monthly X 6 mos
• 32 subjects with advanced dry AMD
• Start date December 2009

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Glucocorticoids in Dry AMD

• Iluvien Non-bioerodible polyimide tube
  containing 180µg of the corticosteroid
  fluocinolone acetonide (Alimera Sciences)
• Insertion via 25G intravitreal injector results
  in self-sealing wound

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Phase 2 Iluvien Dry AMD Trial Design

• 40 patients with bilateral GA
• Study eye randomized to high (0.5µg/day) or low
  (0.2µg/day) dose Iluvien
• Fellow eye serves as control
• Primary outcome Difference in enlargement rate
  between treated and untreated eyes

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Complement Inhibition in AMD

• Inhibition of complement C3
• POT-4
• Potentia Pharmaceuticals
• Intravitreal injection
• Phase I

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POT-4 Potent Inhibitor of C3
Classical Pathway
Lectin Pathway
Alternative Pathway
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POT-4 Potent Inhibitor of C3
Classical Pathway
Lectin Pathway
Alternative Pathway
POT-4
STOP
STOP
STOP
STOP
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POT-4 Study in AMD Phase I

• Appears safe and well tolerated
• Sustained release deposits persist for as long as
  6 months
• Complement C3 inhibition decreases VEGF activity
• Potentia has now partnered with Alcon
• Phase II in 2010

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Complement Inhibition in AMD

• Inhibition of complement C5
• Eculizumab (SOLIRIS) Phase II
• Alexion Pharmaceuticals
• ARC1905 Phase I
• Ophthotech Corp.

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The OMEGA Study use of eye drops to treat
geographic atrophy associated with AMD (Othera)

• The purpose of this trial is to compare the
  ability of two doses of OT-551 ophthalmic
  solution and drug-free solution to safely and
  effectively treat geographic atrophy associated
  with AMD

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Natural History of Geographic Atrophy Progression
(GAP) (Alcon)

• Prospective, observational study to evaluate
  natural hx
• 1000 pts, age 55 yrs, GA without CNV
• Visits q 6 months, 18-month follow-up
• Primary outcome measure GA progression rate as
  assessed with fundus autofluorescence
• Secondary outcome measure GA progression rate as
  assessed with fundus photography

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Geographic Atrophy Treatment Evaluation (GATE)
(Alcon)

• Eye drop given 2x/day
• Pharmacology
• Oxidative stress and inflammation are thought to
  play pivotal roles in the etiology of AMD
• In vivo model, drug used in GATE
• provided dose-dependent protection of retinal
  function (ERG) and structure
• decreased accumulation of by-products of
  oxidative stress to levels not different from
  those observed in controls

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GATE

• Overview
• Objective to evaluate safety and efficacy
  compared with placebo for tx of geographic
  atrophy due to AMD
• Primary efficacy variable mean lesion
  enlargement btw. baseline and month 24 as
  assessed with fundus autofluorescence imaging
• Secondary efficacy variables mean change in
  BCVA, mean change in VFQ-25 QOL scores, btw.
  baseline and month 24

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GATE

• Eligibility criteria
• Age 55 years
• Well-demarcated area of atrophy secondary to AMD
• If lesion is multifocal, 1 focal lesion must be
  1.25 mm2 0.5 Disc Areas (DA) total lesion
  size must be to 20 mm2 8 (DA)
• Presence of hyperautofluorescence adjacent to an
  area of atrophy
• No evidence of CNV
• BCVA 35 letters (20/200 Snellen equivalent) or
  better

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Study Design
Investigator identifies potential subjects
Reading Center Confirms eligibility
Atrophic Lesions Quantified using Fundus
Autofluoresence
Randomization 111
Placebo (n180)
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Single-dose, dose-escalation study of the
safety, tolerability, pharmacokinetics, and
immunogenicity of intravitreal injections of
FCFD4514S in patients with geographic atrophy
(Genentech)
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FCFD4514S in GA

• Phase 1a, first human trials of new human
  monoclonal antibody given one time intravitreally
  for geographic atrophy
• Inclusion criteria
• 50-85 years old
• GA at least 0.75 disc areas in the absence of CNV
• BCVA 20/125 to 20/400 inclusive
• GA resides completely within the color fundus
  photos

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Sirolimus to treat geographic atrophy associated
with AMD (NEI)

• This study will determine if a drug called
  sirolimus is safe to give to people with
  geographic atrophy GA and if it can help preserve
  vision in patients
• Sirolimus helps prevent inflammation and
  therefore may help treat GA

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Sirolimus for Local Delivery

• Versatility
• Intravitreal injection
• Subconjunctival injection
• Extended Release
• Depot Forming
• No dispersion or blocking of visual axis
• Sustained tissue levels with full resorption
• Administration
• Acceptable viscosity
• Through a standard 30g needle
• Low volume
• Ocularly safe with minimal alcohol content

Subconjunctival Sirolimus Depot
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ARC1905 (anti-C5 Aptamer) in subjects with dry
AMD (Ophthotech)

• The objectives of this study are to evaluate the
  safety and tolerability of ARC1905 intravitreous
  injection in subjects with geographic atrophy
  secondary to dry AMD

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Safety and tolerability study of RN6G in patients
with dry AMD (Pfizer)

• The purpose of this study is to determine the
  safety and tolerability of RN6G in patients with
  dry, age-related macular degeneration

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Weekly vaccination with copaxone as a potential
therapy for dry AMD (New York Eye Ear Infirmary)

• The purpose of the project is to investigate, in
  eyes with dry AMD, the efficacy and safety as
  preventive therapy of the immunomodulatory
  substance named copaxone, which had been proven
  as safe and effective agent for a
  neurodegenerative disease, in arresting the
  progression as well as the conversion of dry AMD
  to wet AMD.

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Encapsulated cell technology (ECT) implant for
patients with atrophic macular degeneration
(Neurotech)

• The purpose of this study is to look at the
  safety and effectiveness of CNTF implants on
  vision in participants with atrophic macular
  degeneration
• The implant is a small capsule that contains
  human retinal pigment epithelium cells.

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Emerging Treatments for Dry AMDSummary

• Dry AMD is a uniquely human disease
• Current treatment strategies target
• Preservation of photoreceptors/RPE
• Prevention of oxidative damage
• Suppression of inflammation
• Clinical trials underway

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The Future of Management of Neovascular AMD

• Unlikely one particular approach will completely
  control AMD
• Combination therapy allows multiple targeting
  sites and factors for attacks
• Advances in imaging technology such as SD OCT
  may provide better hope to save vision for
  patients

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Conclusions Current anti-VEGF treatments

• Further research will maximize our options in
  treating AMD to minimize the devastating visual
  consequences of subfoveal CNV and advanced
  geographic atrophy
• However, we have already made dramatic progress
  in understanding and treating AMD, allowing us
  NOW to IMPROVE VISION in many cases that were
  untreatable just several years ago.
• This has made managing AMD much more gratifying
  for ophthalmologists and their patients

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The At Risk Patient

• Over 50 years of age
• Family History of AMD
• Caucasian
• Smoker
• Unhealthy lifestyle
• Nutrition
• Overweight

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Manage The At Risk Patient

• Annual eye exam
• Smoking cessation
• Exercise
• Nutritional modification
• Green leafy vegetables
• Good fats gt Bad fats
• AREDS Supplements
• Enroll in trials!

Thanks