received known isoforms of VEGF-A. This molecule lacks a

received a mean of 4.6 and 6.9 injections of bevacizumab
and ranibizumab over 12 months, respectively. A meta-analysis
of anti-VEGF-A treatment regimens for nAMD suggests
that there is a positive linear correlation with VA gains and
number of injections over 12 months, although there was a
ceiling effect, in which over 9 injections annually did not
result in further gains 8. There are many barriers that pose
a challenge to patient compliance with frequent anti-VEGF-A
injection, such as patient anxiety/discomfort, financial burden,
time constraints, and lack of transportation 9. Due to
these barriers, there is great interest in development of
long-acting anti-VEGF formulations.
Although anti-VEGF-A therapies initially improve vision by
reducing leakage from neovascularization during the first
months of treatment, they have limited ability to cause regression
of this pathologic submacular neovascularization.
Ultimately, the formation of submacular scar limits further
visual benefit despite treatment; a recent large randomized
controlled study showed that submacular scar develops in
nearly 50% of subjects despite 2 years of anti-VEGF-A treatment
10. For those patients with incomplete response to
anti-VEGF-A therapy, there is great interest in targeting other
pathways involved in angiogenesis.
3. Existing treatment
3.1. Previous nAMD treatments
Prior to the advent of anti-VEGF-A therapy, nAMD was treated
with focal laser therapy, intravitreal steroids, photodynamic
therapy with verterporfin, and surgical excision of choroidal
neovascular membranes. These treatments did not significantly
improve vision and thus are not used frequently today
9. The four currently available anti-VEGF agents are described
below and summarized in Table 1.
3.2. Pegaptanib
In 2004, pegaptanib sodium (Macugen®, Bausch and Lomb), an
aptamer designed to target the 165 isoform of VEGF-A, was the
first of its class agent approved for the treatment of nAMD.
Registration studies (VISION-1) showed that subjects receiving
intravitreal 0.3 mg pegaptanib every 6 weeks for 1 year experienced
approximately half the vision loss as those subjects who
received sham 11. Pegaptanib use has fallen out of favor since
more effective anti-VEGF-A agents have become available.
3.3. Ranibizumab
Ranibizumab (Lucentis®, Roche/Genentech), a smaller recombinant
humanized monoclonal antibody fragment targeting
VEGF-A, was specifically manufactured for use in the eye,
and inhibits all known isoforms of VEGF-A. This molecule
lacks a fragment crystallizable (Fc) region, which allows for
faster systemic clearance 12. In the MARINA and ANCHOR
registration trials involving monthly ranibizumab, nAMD subjects
experienced a mean improvement in vision acuity of 7.2
and 11.3 ETDRS letters respectively at 1 year, compared to a
mean loss of 10.4 and 9.5 ETDRS letters in the sham and
Verteporfin control groups, respectively4,13. Ranibizumab
0.5 mg was approved for the treatment of nAMD in 2006.
3.4. Bevacizumab
Bevacizumab (Avastin®, Roche/Genentech) is a full-length recombinant
humanized monoclonal anti-VEGF that binds all isoforms of
VEGF-A 14. It was originally approved for the treatment of metastatic
colorectal cancer, but was used off-label in 2005 for the
treatment of exudative AMD. It is the least costly anti-VEGF-A
option 15 and hence the first option considered for many
patients. Off-label bevacizumab 1.25 mg was found to be noninferior
to ranibizumab in the Comparison of AMD Treatments
Trials (CATT, a National Institutes of Health sponsored study) 13
and the analogous IVAN Study performed in the United
Kingdom 16.
3.5. Aflibercept and ziv-aflibercept
Aflibercept (Eylea®, Regeneron) is a recombinant fusion protein
that is composed of human VEGF Receptor-1 and VEGF
Receptor-2 fused to the Fc domain of human immunoglobulin
G1 domain. It inhibits VEGF-A, VEGF-B, and placental growth


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