A randomized, double masked, active controlled, phase 3 study of the efficacy, safety, and tolerability of repeated doses of intravitrial VEGF Trap-Eye in subjects with neovascular age-related macular degeneration (AMD)

Vascular Endothelial Growth Factor (VEGF), a protein growth factor that both
stimulates angiogenesis and increases vascular permeability, is a major
pathogenic factor in AMD. AMD is a leading cause of adult blindness in the
developed world. VEGF Trap-Eye is a potent, specific inhibitor of VEGF. VEGF
Trap-Eye has a high affinity for VEGF. The phase 3 studies for VEGF Trap-Eye
will assess whether this agent may be able to offer non-inferior efficacy to
existing therapy, and whether there may be potential advantages, such as
greater improvement in visual function or ability to be dosed less frequently
than other agents while still maintaining clinical benefit.

Primary objective
To assess the efficacy of intravitreally (ITV) administered VEGF Trap-Eye
compared to ranibizumab (in a non-inferiority paradigm) in preventing moderate
vision loss in subjects with all subtypes of neovascular AMD
Secondary objective
To assess the safety and tolerability of repeated ITV administration of VEGF
Trap-Eye in subjects with all subtypes of neovascular AMD for up to 2 years

To assess the effect of repeated ITV administration of VEGF Trap-Eye in
vision-related quality of Life (QOL) in subjects with all subtypes of
neovascular AMD, as assessed using the NEI VFQ-25

To describe systemic exposure to study drug in subgroup of subjects from
selected PK centers

This is a multicenter, double-masked, randomized, phase 3 study. Subjects will
be randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) 0.5 mg
VEGF Trap-Eye administered every 4 weeks (0.5Q4), 2) 2 mg VEGF Trap-Eye
administered every 4 weeks (2Q4), 3) 2 mg VEGF Trap-Eye administered every 8
weeks (2Q8), and 4) 0.5 mg ranibizumab administered every 4 weeks (RQ4).
Approximately 200 centers in the European Union (EU) and centers in other
regions such as Asia Pacific and Latin America will participate. Approximately
1.200 subjects will be randomized with a target of 300 subjects per treatment
arm.

1) 0.5 mg VEGF Trap-Eye administered every 4 weeks (0.5Q4)
2) 2 mg VEGF Trap-Eye administered every 4 weeks (2Q4)
3) 2 mg VEGF Trap-Eye administered every 8 weeks (2Q8)
4) 0.5 mg ranibizumab administered every 4 weeks (RQ4)

Intravitreal injection of VEGF Trap-Eye in this study of subjects with
neovascular AMD seems to be justified and supported by the drug`s safety and
tolerability profile. ITV injection permit direct targeting of the drug to the
areas of abnormal neovascularization in the retina. Proteinuria and
hypertension are potential systemic effects from IV or SC administration of
this class of drug; however the low systemic blood levels observed in previous
ITV studies suggest that direct ITV injection, at the dose levels proposed for
this study, will not have significant systemic effects. The risks attendant
upon ITV administration of VEGF Trap-Eye are thought to be similar to those of
ITV administration of pegaptanib and ranibuzumab.

Given its higher affinity for VEGF as compared with ranibizumab and its ability
to be administered at higher doses, VEGF Trap-Eye may provide a clinical
benefit, with the potential for a longer dosing interval, that is equivalent to
and potentially greater than that of ranibizumab. Given that the subjects to be
enrolled in this study generally have advanced blinding disease with a poor
prognosis, and given the potential for VEGF Trap-Eye to provide as good or
potentially better therapy than ranibizumab without known increased risk, it is
reasonable to assume that the potential benefit of VEGF Trap-Eye outweighs any
attendant short-term risks for subjects participating in this study.