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AMD Future Perspectives: New promising drugs
3. Vascular endothelial growth factor
(VEGF) blockers:
3.1 Monoclonal antibodies
3.1.1 Lucentis® and Avastin® - Wet AMD
Intravitreal
These two drugs emerged from the promising techno-
logical platforms of monoclonal antibodies. Technology
platforms of monoclonal antibodies are promising and
allow the development of many new drugs, given the
ease to develop drugs for mediators or receptors that
were previously identified.
Current conditions for these drugs are exposed in the
corresponding chapter. Future prospects about their use
in AMD are essentially made by process innovation, with
adoption of optimized therapeutic schemes of combined
therapy and improvement of intra-eye drug delivery.
3.2 Aptamers
3.2.1 Macugen®- Wet AMD
Intravitreal
Aptamers are oligonucleotide ligands that are selected for
their high-affinity to bind molecular targets. Pegaptanib
sodium (Macugen®; Eyetech Pharmaceuticals/Pfizer) is
an RNA Aptamer directed against vascular endothelial
growth factor (VEGF)-165, the VEGF isoform prima-
rily responsible for pathological ocular neovasculariza-
tion and vascular permeability.
“
Pegaptanib therefore has the notable distinction of being
the first aptamer therapeutic approved for use in humans,
paving the way for future aptamer applications.
”
(1)
Like the use of Lucentis® and Avastin® future prospects
with the use of Macugen® are essentially made by proc-
ess innovation, with adoption of optimized therapeutic
schemes of combined therapy.
3.3 Fusion proteins
3.3.1 VEGF Trap-Eye - Wet AMD
Intravitreal
The aflibercept, VEGF-Trap, results of a process of bio-
engineering where extramembrane fragments of recep-
tors 1 and 2 of VEGF are merged to IgG1 FC frag-
ment. This recombinant fusion protein is a composite
decoy receptor based on VEGF receptors VEGFR1 and
VEGFR2. The VEGF Trap (Regeneron Pharmaceuticals,
Tarrytown, NY, USA) is an 110kDa soluble recombinant
protein with the binding portions of VEGF receptor 1
and 2 fused to the Fc region of human IgG that binds
all VEGF isoforms with a very high affinity (about 140
times that one of ranibizumab). Aflibercept is a fully
human soluble fusion protein that binds all forms of
VEGF-A along with the related Placental Growth Factor
(PlGF)
(2)
.
This high affinity fusion protein is used to block the bio-
logical activities of VEGF by preventing it to bind to
its receptors. VEGF-Trap effectively suppresses tumor
growth and vascularization
in vivo
(3)
.
In phase I, randomized, placebo-controlled trial of
VEGF Trap administered intravenously for treatment of
choroidal neovascularization, the Clinical Evaluation of
Antiangiogenesis in the Retina (CLEAR)-AMD 1 group
found a dose-dependent increase in systemic blood pres-
sure with a maximum tolerated dose of 1mg/kg. This
dose resulted in the elimination of about 60% of excess
retinal thickness after either single or multiple adminis-
trations. CLEAR IT-1 was a phase I dose escalation study
of a single intravitreal injection of various doses of VEGF
Trap (0.05, 0.15, 0.5, 1, 2, and 4mg)
(4)
. At 6 weeks, mean
visual acuity gain was 4.8 letters and mean OCT central
retinal thickness decreased from 298μm to 208μm across
all groups. Higher doses resulted in gaining more letters.
The potential benefit of VEGF Trap is its longer dura-
tion of action compared with single injections of other
anti-VEGF agents because of its higher affinity and lon-
ger intravitreal half-life. It seems that VEGF Trap would
offer less frequent dosing resulting in fewer injections,
lower cost and reduced risk of complications
(5)
.
From August 2007 it’s initiated a phase III global devel-
opment program for VEGF Trap-Eye in wet AMD.
During the first year of the two phase III trials, the
companies (Regeneron Pharmaceuticals, Inc. and Bayer
HealthCare AG ) are evaluating VEGF Trap-Eye dosed
0.5 mg every 4 weeks, 2 mg every 4 weeks, or 2 mg every
8 weeks (following three monthly doses) in direct com-
parison with ranibizumab (Lucentis® Genentech, Inc.)
administered 0.5 mg every 4 weeks according to its U.S.
label. PRN dosing will be evaluated during the second
year of each study .
Currently phase III clinical trials, VIEW 1 and 2 study
will assess its efficacy and safety in patients with neovas-
cular AMD. The VIEW1 study (in the United States and
Canada) and the VIEW2 study (in Europe, Asia Pacific,
Japan, and Latin America)
(6,7)
enrolled 1200 patients.
