222
11.2 JPE1375 inhibits C5 - Dry AMD
Intravitreal
JPE-1375 (Jerini AG, Berlin Germany) is a small mol-
ecule peptidomimetic antagonist targeting the comple-
ment pathway, a highly validated target for dry AMD. It
targets C5aR, the receptor for complement factor C5a,
which is a key component involved in the activation of
inflammatory cells
(55)
. JPE-1375 has shown significant
efficacy in multiple preclinical models.
11.3 ARC1905 inhibits C5 - Dry/Wet AMD
Intravitreal
ARC 1905 (Ophthotech Corp. Princeton, NJ) is a
PEGylated, stabilized aptamer targeting complement
factor C5. ARC1905 inhibits activation of the down-
stream proinflammatory complement cascade (including
generation of C5a and the membrane attack complex).
“Ophthotech’s anti-C5 aptamer, ARC1905, is a potent
and selective inhibitor of factor C5 of the complement
cascade. Inhibition of the complement cascade at the
level of C5 prevents the formation of the key terminal
fragments responsible for tissue pathology, C5a and the
membrane attack complex (MAC: C5b-9). The C5a frag-
ment is pro-inflammatory, while the membrane attack
complex initiates cell lysis and releases proangiogenic
molecules (eg. PDGF and VEGF). Histopathologic
specimens of human dry AMD lesions strongly stain for
C5 and MAC at the key sites of pathology. ARC1905
spares the formation of upstream complement compo-
nents such as C3b, which are important in host defense
mechanisms. By inhibiting C5-mediated inflammatory
and MAC activities, therapeutic benefit may be achieved
in both dry and wet AMD while sparing the immuno-
protective functions of the complement system.
A phase I open-label, multicenter study of ARC1905, in
combination with an anti-VEGF agent (Lucentis®), in
patients with wet AMD is ongoing. In addition, a study
investigating ARC1905 in patients with dry AMD will
be initiated in Q2 2009.”
(56)
11.4 Eculizumab: Inhibits C5 - Dry AMD
Intravitreal
Eculizumab (Soliris, Alexion Pharmaceuticals) is a
humanized monoclonal antibody derived from a murine
antihuman C5 antibody. Eculizumab specifically inhib-
its the terminal complement protein C5, thereby pre-
venting its cleavage to C5a and C5b during complement
activation. The strategic blockade of the complement cas-
cade at C5 prevents the release of the downstream ana-
phylatoxin C5a and prevents the formation of the cyto-
lytic membrane attack complex (MAC). Eculizumab is
FDA-approved for the intravenous treatment of another
complement-mediated disease known as paroxysmal
nocturnal hemoglobinuria.
Currently a phase II study with eculizumab for the
treatment of patients with dry AMD, known as the
Complement Inhibition with Eculizumab for the
Treatment of Non-Exudative Age-related Macular
Degeneration (COMPLETE) Study.
(57)
Patients with
GA or high-risk drusen are being randomized 2:1 to
receive intravenous infusions of eculizumab or placebo.
12. Radiation
12.1 Strontium-90 beta radiation -Wet AMD
CABERNET is a multicenter, randomized, controlled
phase III study that enrolls 450 subjects at 45 clini-
cal centers worldwide. In this research, patients receive
either the standard injection of Lucentis® (ranibizumab)
or the radiation plus Lucentis®
(58)
.
A tiny source of radiation is placed inside the eye near
the macula, held there for about 4 minutes and then
removed. The radiation destroys the abnormal blood
vessels and prevents the growth of blood vessels to stop
the progression of wet macular degeneration vision loss.
The system treats neovascularization of retinal tissue by
means of a focal, directional delivery of radiation to the
target tissues in the retina. Using standard vitreoretinal
surgical techniques, the sealed radiation source is placed
temporarily over the retinal lesion by means of a hand-
held medical device. If epiretinal brachytherapy proves
successful, it can reduce the number of injections needed
to just two injections over a period of 12 months.
12.2 TheraSightTM ocular brachytherapy System:
Wet AMD
A trial sponsored byTheragenics Corporation® will inves-
tigate the safety and ability of using the TheraSightTM
Ocular Brachytherapy System to treat wet AMD. A
radioactive button mounted on an applicator wand is
positioned behind the eye and held in place touching the
outer surface of the eye for 5 to 20 minutes. A study will
take place at 6 clinical sites and will compare 3 different
dosages or amounts of radiation, so all participants will
