196
Trap-Eye in wet AMD was initiated in August 2007. Two
phase III trials conducted by two pharmaceutical compa-
nies (Regeneron Pharmaceuticals, Inc. and Bayer Health-
Care AG) are evaluating treatment with VEGF Trap-Eye,
at doses of 0.5mg every 4 weeks, 2mg every 4 weeks, or
2mg every 8 weeks (following three monthly doses), com-
pared with treatment with 0.5mg of ranibizumab (Lucen-
tis
®
, a registered trademark of Genentech, Inc.), adminis-
tered every 4 weeks, according to its U.S. label, during
the first year of the studies. PRN dosing will be evaluated
during the second year of each study. The VIEW1 study
is currently enrolling patients in the United States and
Canada; the VIEW2 study is currently enrolling patients
in Europe, Asia-Pacific, Japan, and Latin America
(33)
.
5.2 FGF-2 inhibition
RPE from CNV patients expresses angiogenic growth fac-
tors whose action is partly independent from VEGF.
In a study, Sthal concluded that anti-VEGF treatment
(bevacizumab) inactivated all RPE-derived VEGF in a
3D collagen matrix culture of RPE isolated from surgi-
cally excised CNV-membranes (CNV-RPE) used to
stimulate sprouting of endothelial cell (EC) spheroids,
but was unable to fully inhibit EC sprouting induced by
CNV-RPE. Combined anti-VEGF/anti-FGF treatment
inactivated both growth factors and reduced EC sprouting
significantly. In a comparison between the antiangiogenic
effect of solitary anti-VEGF antibodies and combination
treatment with anti-VEGF and anti-FGF-2 antibodies,
greater inhibition was achieved for the latter. Targeted
combined therapy can be superior to solitary anti-VEGF
therapy. One possible candidate for combined therapy is
FGF-2
(34)
.
5.3 The balancing effect of PEDF and its delivery
In AMD, PEDF is significantly lower in RPE cells, the
RPE basal lamina, Bruch’s membrane and choroidal
stroma. These data suggest the existence of a critical bal-
ance between PEDF and VEGF and the hypothesis that
PEDF may be able to counteract the angiogenic poten-
tial of VEGF. A decrease in PEDF may disrupt this bal-
ance and induce choroidal neovascularization (CNV) in
AMD
(35)
.
Results from a phase I clinical trial of intravitreal admin-
istration of an IE4-deleted adenoviral vector expressing
human pigment epithelium-derived factor (AdPEDF.11)
suggest that antiangiogenic activity may be sustained
for several months after single intravitreal injection of
This is not yet clear and will need to be demonstrated by
evidence from the ongoing studies already mentioned.
As already known, although PIER
(28)
and PRONTO
(29)
study results reveal that the number of injections
required to stabilize vision corresponds to an average
of 6 injections/year, it is also true that the visual out-
comes observed in these studies were not as good as those
observed in the MARINA and ANCHOR studies.
However, as already referred, if the number of treatment
sessions and anti-VEGF vials required decreases and if
patients make fewer visits to the hospital, we have a sig-
nificant gain in efficiency, even in the absence of com-
parative gains in visual acuity (i.e., the same efficacy),
as well as better use of resources – a larger number of
patients treated with the same budget.
4.4 PDT combined with vitrectomy and dexametha-
sone
A combined pharmacosurgical intravitreal procedure
was performed 24 to 36 hours after PDT, consisting
of 23-gauge core vitrectomy and intravitreal substitu-
tion with BSS, dexamethasone and bevacizumab. The
intravitreal retreatment rate was low (13/52) for this safe
pharmaco-surgical regimen, corresponding to 25%
(30)
.
5. Other promising forms of combined
therapy
5.1 VEGF Trap – aflibercept – VIEW 1 and 2 studies
Aflibercept, a VEGF Trap, is the product of a bioengi-
neering process where extramembranous VEGFR-1 and
2 receptor fragments are fused with the IgG1 Fc frag-
ment. This recombinant protein is a composite decoy
receptor based on VEGF receptors VEGFR-1 and
VEGFR-2.
This fully soluble human VEGF-receptor fusion pro-
tein binds to all forms of VEGF-A, as well as the related
placental growth factor (PlGF), constituting a specific,
highly potent, long-acting blocker of these growth fac-
tors
(31)
.
High-affinity fusion proteins may be used to block the
biological activities of VEGF by preventing its bind-
ing to receptors. This VEGF Trap effectively suppresses
tumor growth and vascularization
in vivo
, resulting in
stunted and almost completely avascular tumours
(32)
.
The VEGF Trap may be used to treat choroidal neovascu-
larization, alone or in combined treatment.
A global development phase III programme for VEGF
