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AMD Future Perspectives: New promising drugs
9.2 ATG003: nAChR antagonist - Wet AMD
Topical
ATG003 (Mecamylamine) topical delivery in animal
models significantly inhibits laser induced CNV in a
mouse model of AMD.
Currently a phase IIa study and phase IIb study is termi-
nated, 330 subjects are enrolled with dose ranging: 0.3%
and 1% topical solutions and the data is not published
(37)
.
Phase IIb study, with 60 subjects, was design to study
the safety of 1% topical mecamylamine bid for 48 weeks
in patients receiving maintenance injections of Lucentis®
or Avastin®; this study is a double-masked, randomized,
placebo-controlled study. The study is ongoing, but
not recruiting participants
(38)
. In this phase the patients
receive either a dose of ATG003 or a placebo, while con-
tinuing the Lucentis® or Avastin® treatment. All patients
will be treated for up to 48 weeks, during which time
they will be monitored to assess the drug’s safety, toler-
ability and efficacy.
10. Gene therapy
10.1 AdPEDF - Wet AMD
Intravitreal
Pigment epithelium-derived factor (PEDF) is one of the
most potent antiangiogenic proteins. It inhibits VEGF-
induced proliferation, migration of endothelial cells,
reduces VEGF-induced hypermeability and causes vessel
regression in established neovascularization
(39, 40)
. PEDF
is also a neurotrophic factor
(41)
and also inhibits/antago-
nizes other angiogenic factors such as platelet-derived
growth factor and fibroblastic growth factor. GenVec
(GenVec inc, Gaithersburg, Maryland) delivers AdPEDF
utilizing a modified adenoviral vector delivery system.
In phase I studies testing the safety and feasibility of
intravitreal injection AdPEDF was safe and generally
well-tolerated at all dose levels tested in 28 patients
(42,43).
Other phase I studies
(44,45)
in 22 patients with less severe
wet AMD find similar results; there were no dose-lim-
iting toxicities or drug-related severe adverse events.
Further studies for AdPEDF in patients with wet AMD
are under way.
10.2 Lentivirus: Wet and Dry AMD
The LentiVector (Oxford BioMedica plc, Oxford, England)
has been shown to efficiently and effectively deliver genes to
the specialized, nondividing cells of the retina.
The system is based on the lentivirus equine infectious ane-
mia virus (EIAV). Applications for the gene vector system
include gene therapy, trangenesis, stem cell manipulation,
somatic disease models, target validation and gene discovery.
For AMD, RetinoStat aims to preserve and improve the
vision of patients with wet AMD through antiangiogenesis
by delivering endostatin and angiostatin genes directly to the
retina
(46, 47)
.
11. Anti-complement inhibitors
Complement activation has been implicated in a number
of acute and chronic conditions. There is strong evidence
that AMD is an inflammatory disease; Aberrant activation
of the complement system is implicated in the wet and dry
forms of AMD
(48-49)
. Patients with AMD demonstrate ele-
vated systemic inflammatory biomarkers of inflammation
(CRP, IL-6 and homocysteine). Histopathologic analyses
of human AMD neovascular complex specimens demon-
strate inflammatory infiltrates. Recent studies implicated
local inflammation and activation of the complement
cascade in the formation of drusen
(50)
. Complement-
mediated inflammation in AMD is also reinforced by mul-
tiple genetic linkage and association studies published in
Science
(48-51)
and in New England Journal of Medicine
(52)
.
All this, strong support for the complement-mediated dis-
ease in wet and dry forms of AMD.
11.1 POT- 4 inhibits C3 - Dry AMD
Intravitreal
POT-4 developed by Potentia Pharmaceutical (Potencia
Pharmaceutical, inc., Louiseville) affects the body’s “com-
plement” system.
Inflammation plays a role in developing macular degen-
eration. Eight complement proteins are associated with
AMD and POT-4 affects C3. The problem is that inflam-
mation is useful in fighting infections. If the complement
system is completely shut down, there is an increase risk
for the development of bacterial infection.
Potentia has completed a phase I trial for POT-4 (called
ASap) in patients with wet AMD. The trial was designed to
determine the safety and tolerability of an intravitreal injec-
tion of POT-4, as well as its stability and depot-forming
properties. In the study investigators observed only
minimal and mild local adverse events related to the
injection with no serious adverse events related to the
drug itself
(53, 54)
.
