Ophthalmology Update - Cleveland Clinic

Diverse Spectrum of New and Investigational
AMD Therapies Target VEGF
Identification of the activity of vascular endothelial
growth factor (VEGF) as a regulator of
angiogenesis and vascular permeability and
evidence of its role in the pathogenesis of
exudative age-related macular degeneration
(AMD) has led to the development of a number
of pharmacologic approaches targeting
VEGF as a new strategy to treat AMD.
in december 2004, pegaptanib sodium (macugen)
became the first anti-vegF agent approved by the
Fda for the treatment of wet amd. an aptamer that
acts to bind and inactivate vegF, pegaptanib sodium
was an exciting new modality because it received
an indication for use in eyes with any subfoveal choroidal
neovascular lesion, regardless of size, location
or composition. research with that compound is
continuing, and an ongoing study is evaluating its
role in combination therapy with verteporfin photodynamic
therapy (pdt).
now, Fda approval of a second anti-vegF agent,
ranibizumab (lucentis), is here. ranibizumab is an
antibody fragment that binds vegF, and in phase iii
trials of patients with exudative amd, it demonstrated
impressive potential to improve vision rather than
simply slowing its progressive loss.
meanwhile, a host of other pharmacologic agents
that act through diverse mechanisms of action to
inhibit the activity of vegF are in various stages
of clinical investigation for the treatment of amdrelated
choroidal neovascularization.
“there has been little to offer in the way of therapeutic
intervention for patients who are losing their sight
from amd, and so it is very exhilarating to see this
proliferation of clinical research focusing on amd
treatment. considering the number of compounds
now in clinical trials, their innovative mechanisms,
their favorable safety profiles even with repeated
treatments and the exciting responses that have been
achieved with ranibizumab, this is certainly a hopeful
and exciting time for patients affected with amd
and the physicians who treat them,” said peter K.
Kaiser, m.d., of cleveland clinic cole eye institute.
in January 2006, dr. Kaiser had the honor of being
the first to present publicly the results from the phase
iii anti-vegF antibody for the treatment of predominantly
classic chOroidal neovascularization
in amd (anchOr) study that demonstrated ranibizumab
had activity for improving vision. after 1 year
in that study, about 95% of patients treated with ranibizumab
0.3 mg or 0.5 mg had stable or improved
vision (lost less than 15 etdrs letters), and similar
results were achieved after 1 year in the phase iii
minimally classic/occult trial of the anti-vegF antibody
ranibizumab in the treatment of neovasuclar
amd (marina) study. in anchOr, patients in the
ranibizumab 0.3 mg and 0.5 mg groups had average
vision gains of 8.5 letters and 11 letters, respectively,
and almost 40% had a clinically significant improvement
in vision (gain of 15 letters or more). controls
in anchOr received pdt. they experienced an
average vision loss and only about 6% had a clinically
significant improvement.
“the benefits achieved in this study using ranibizumab
also occurred regardless of lesion subtype and translate
into important effects on patient function and
quality of life,” dr. Kaiser says.
the cole eye institute is also distinguished as the
site of the first human treatment using a novel antivegF
approach based on synthetic small interfering
rna (sirna) therapeutics. the compound being
studied, sirna-027 (sirna), prevents expression
of vegF receptor-1 (vegFr-1) by silencing the gene
coding for that protein.
“the vegFr-1 is stimulated by both vegF and placental
growth factor (plgF), which may also play a
role in angiogenesis and potentiate the activity of
vegF. By interfering with the action of all agonists
for vegFr-1, sirna-027 may offer a more powerful
treatment modality than those approaches targeting
only vegF,” notes dr. Kaiser.
another sirna (cand5, acuity pharmaceuticals) is
also under investigation at other centers. that agent
blocks the formation of vegF altogether, rather than
acting to inhibit the activity of protein that has
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