218
5.6 TG101095 - Wet AMD
Topical
It is a topical tyrosine kinase inhibitor that specifi-
cally targets VEGFR, only tested in animal models.
JAK2 is a signalling kinase that acts downstream from
erythropoietin, a glycoprotein hormone, which, along
with VEGF, is involved in the pathogenesis of diabetic
retinopathy. The VEGF receptor and JAK2 inhibitor
TG101095 dosed topically bid for two weeks sig-
nificantly reduced CNV area in a laser-induced CNV
mouse model
(23)
.
5.7 Multi-targeted kinase inhibitors
Multi-targeted kinase inhibitors have been shown to
be effective in oncology. Newly developed small mol-
ecule kinase inhibitors (including TG100572 and the
prodrug TG100801), which inhibits VEGF, PDGF,
and FGF receptors in addition to Src family of kinases
(sarcoma proto-oncogenic tyrosine kinases family).
They act in intracellular environment
(24)
.
5.8 TG100801 - Wet AMD
Topical
TG100801 a prodrug version of TG100572, is admin-
istered noninvasively as an eye drop and is designed to
suppress VEGF mediated leakage and additionally the
kinase targets associated with inflammation, edema,
and angiogenesis which are the pathological hallmarks
of AMD and of other back of the eye diseases includ-
ing diabetic macular oedema and proliferative diabetic
retinopathy
(25)
.
It is synthesized at TargeGen (TargeGen inc San
Diego). Topical administration of TG100801 sup-
pressed CNV in mice and reduced the retinal oedema
induced by retinal vein occlusion in rats, without
observable safety issues. Data have suggested that the
delivery of these agents occur by local penetration
through sclera rather than by systemic absorption as
neither compound was detectable in the plasma
(24)
.
Therefore, TG100801 may offer equal efficacy to
injectable agents, while offering the convenience and
potential safety advantages due to a non-invasive
route of delivery and eye penetration. Currently a
multicentric, open-label, randomized, phase II study
is evaluating the effects of 30 days of dosing with
two dose levels of TG100801, instilled twice a day,
on central retinal/lesion thickness, as measured by
optical coherence tomography (OCT). The safety of
TG100801 in patients with AMD will also be evalu-
ated in this trial
(26)
.
5.9 Pazopanib (GW786034) - Wet AMD
Topical
Pazopanib (GW786034), by GlaxoSmithKline, is a
second-generation multi-targeted tyrosine kinase inhibi-
tor against all VEGF receptors (VEGFR-1, VEGFR-2,
VEGFR-3) PDGFR-a, PDGFR
β
, and c-kit that blocks
tumour growth & inhibits angiogenesis.
An early phase trial is evaluating the safety, and pharma-
cokinetics of Pazopanib eye drops in patients with neovas-
cular AMD
(27)
.
5.10 AG013958: Wet AMD
Subtenon
AGO013958 (Pfizer Inc.) is a subtenon injectableTyrosine
kinase inhibitor. A phase I/II, randomised, masked, single
and multiple dose, sequential dose-escalation study of the
safety and efficacy of AG-013958 in subjects with sub-
foveal choroidal neovascularization associated with age-
related macular degeneration has been completed
(28)
.
6. mTOR inhibitor
6.1 Sirolimus - Wet AMD
Subconjunctival and intravitreal
Sirolimus (MacuSight inc.), also known as rapamycin, is
an immunosuppressant drug used to prevent rejection in
organ transplantation. It was originally developed as an
antifungal agent and has potent immunosuppressive and
antiproliferative properties.
Sirolimus inhibits the mammalian target of rapamycin
(mTOR). The mammalian target of rapamycin is a pro-
tein kinase that regulates cell growth and metabolism in
response to changes in the environment.
Sirolimus administered via subconjunctival injections
was as effective as sirolimus administered via intravitreal
injection.
A phase II, randomized, multicentric study in wet AMD
is now taking place; (EMERALD) is currently recruiting
patients with wet AMD for a phase II study of an ocu-
lar sirolimus formulation in combination with Lucentis®.
This is a randomized, multicentric study and is taking
place throughout the United States
(29)
.
