Outline course proposal
Macugen , A new therapy for Wet Macular Degeneration
Vascular Endothelial Growth Factor
(VEGF)
Disclosures
The presenters have no financial interests
This presentation describes an FDA-Approved indication for the medication discussed
This presentation does not include any off-label uses
There are no alternative medications approved for this indication
The Fight Against Blindness
In the developed world:
AMD is the leading cause of blindness in people >50
Diabetic Retinopathy is the leading cause of blindness in people < 50
Major cause of blindness is invasion of new blood vessels in choroid / retina & leakage
VEGF is implicated in this pathologic neovascularization
Properties of VEGF
Stimulates angiogenesis
Potent inducer of vascular permeability
Pro-inflammatory
VEGF Induces Vascular Permeability
Potent vascular permeability inducer
(50,000x >histamine)
Induces vessel leakage via multiple mechanisms
Leukocyte-mediated endothelial cell injury
Formation of fenestrae
Dissolution of tight junctions & transcellular bulk flow
Vascular permeability may be an antecedent & necessary step for neovascularization
VEGF in Normal Physiology
Essential for normal embryonic development
Inactivation of single VEGF allele in mice resulted in embryonic death
Role
in female reproductive cycle
Follicular growth & development of corpus luteum dependent on new capillary vessels
Expressed
in non-angiogenic tissues in the brain, kidney & GI mucosa
VEGF in Normal Healing Processes
Corrective role in wound healing and bone repair
needed
for directional bone growth and blood vessel invasion of cartilage
Promotes new vessel growth following myocardial ischemia
VEGF in the Normal Eye
VEGF and VEGF receptors expressed in normal eye
Receptors present in neural elements of inner retina
High VEGF expression in RPE
Role of normal VEGF expression in the eye is unknown
VEGF in the Diseased Eye
VEGF is implicated in:
Choroidal Neovascularization/ AMD
Diabetic Retinopathy
Retinal Vein Occlusion
Retinopathy of Prematurity
Corneal Neovascularization
Iris Neovascularization
VEGF in the Diseased Eye:
Increased VEGF in normal tissue induces pathological neovascularization
VEGF alone can produce pathological neovascularization
VEGF and neovascularization are linked in experimental models (cornea, iris, retina,
choroid)
Selective VEGF inhibition suppresses vessel growth in these models
VEGF in Neovascular AMD
High mRNA level & increased VEGF receptor level observed in areas of choroidal
neovascularization in primates
VEGF
elevated in choroidal neovascular membranes of AMD patients
VEGF
expressed in choroidal neovascular membranes of autopsy eyes with AMD
VEGF
accumulates in vascular endothelial cells of AMD patients
VEGF in Diabetic Retinopathy

Retinal VEGF levels elevated in experimental diabetes

VEGF injected in primates induces vascular leakage

VEGF levels elevated in patients with diabetic macular edema

Increased VEGF levels found in vitreous of eyes with proliferative diabetic retinopathy
Diabetic retinopathy patients have higher VEGF levels in the aqueous
VEGF in Macular Edema
VEGF induced permeability linked to development of macular edema
Elevated VEGF levels found in patients with diabetic macular edema
Increased retinal VEGF levels in patients with macular edema secondary to uveitis
VEGF isoforms
In a mouse ROP model, VEGF 164* is preferentially elevated during pathology
In mice, selective blockade of VEGF 164* inhibits pathologic vessels and spares
normal vessels
Blockage of VEGF 164 is as effective as non-selective VEGF blockade at
preventing pathologic neovascularization
VEGF Summary
Necessary for pathologic neovascularization
Sufficient to trigger neovascularization
Preferential role for VEGF 165 suggested in pathologic neovascularization
Blocking VEGF 165 inhibits abnormal vessel growth & spares normal vessels
Target protein affinity & selectivity of aptamers make them clinically relevant
Pegaptanib Sodium Injection (Macugen®) and Neovascular AMD
Macugen
The first aptamer therapeutic in man
The first Anti-VEGF therapy for the eye
The first pharmacological therapy for neovascular AMD
The first FDA approved therapy for all subtypes of neovascular AMD
VEGF – Common Denominator in AMD
2004 – Anti-VEGF Therapy—Macugen
Pharmacological treatment targets the protein responsible for the hallmarks of all CNV
V.I.S.I.O.N. Study Design
Key Ocular Inclusion Criteria
Baseline VA: 20/40 - 20/320
Angiographic criteria
All subfoveal angiographic subtypes
Lesion size ≤12 total disc areas
≥50% of total lesion size must be active CNV
Subretinal hemorrhage and/or lipid and/or ≥3 line loss in VA in previous 12 weeks for
minimally classic and occult with no classic lesions
Study Sites and Patients
EOP1003 – Europe, Israel, Australia, South America, USA, and Canada
EOP1004 – USA and Canada
117 sites
Approximately 1200 patients
High Patient Compliance – 1st year
Macugen Met Primary Efficacy Endpoint
% of Patients Losing <15 letters
Macugen Treatment Benefit Over Time
Early and Sustained Treatment Effect
Prevention of Severe Vision Loss
Maintain and/or Gain Visual Acuity
Distribution of VA at Baseline
Distribution of VA at Baseline and Wk 54
Multiple Logistic Regression
Macugen 0.3 mg vs. Usual Care
PDT Use – Low
Prior to the study
At baseline visit
Post-baseline
Prior/Baseline PDT Use Similar Across All Treatment Arms
No Evidence of PDT Use Contributing to Macugen Efficacy
Was there increased PDT use in Macugen patients relative to usual care?
(could suggest that some of Macugen efficacy was derived from PDT)
Answer: NO
No Evidence of Increased IOP Over Time
Macugen – First Year
Achieved statistical significance for a clinically meaningful, pre-specified primary
endpoint in replicate trials
Supportive data in secondary clinical and anatomical endpoints
No subgroup driving the results
Usual care as control group
Favorable safety profile
Macugen Safety and Efficacy at Two Years
Re-randomization at End of Year 1
Macugen Safety and Efficacy at Two Years
High Compliance Over Two Years
1053 patients
Mean # of injections: 15.7 (of 17 max)
Distribution of VA Over Time
Benefit of Continuing Macugen During 2nd Year
Two Year Safety
No change in systemic or ocular safety profile compared to Year 1
No systemic safety concerns were identified
No new ocular safety concerns were noted
Endophthalmitis
Injection protocol amendment implemented by May ’03 to reinforce aseptic technique
Sterile lid speculum
Drape & Gloves
Endophthalmitis (# cases / total injections)
Before amendment: 16/8679 = 0.18%
After amendment:
3/7659 = 0.04%
Macugen – Summary
First Anti-VEGF Therapy for Neovascular AMD
Achieved statistical significance for a clinically meaningful, pre-specified primary
endpoint in replicate trials
Early and sustained treatment benefit through two years compared with usual care
Data suggests second year of therapy is warranted to maximize treatment benefit
Favorable safety profile through two years