216
3.4 siRNA
3.4.1 Bevasiranib (Cand5) - Wet AMD
Discontinued
Despite Bevasiranib has been discontinued it’s worth men-
tioning because it was the first therapy based on the Nobel
Prize-winning RNA interference (RNAi) technology to
advance to phase III clinical trials. Bevasiranib was a first-
in-class small interfering RNA (siRNA) drug designed to
silence the genes that produce vascular endothelial growth
factor (VEGF).
“
The decision to conclude the clinical program follows
a review of preliminary trial data by the Independent
Data Monitoring Committee, which found that although
Bevasiranib showed activity when used in conjunction with
Lucentis® (ranibizumab, Genentech), the trial was unlikely to
meet its primary endpoint.
”
(8)
The trial was COBALT for “Combination of Bevasiranib
and Lucentis® Therapies” for AMD. It was a phase III,
randomized, double-blinded, parallel-assignment study of
the RNAi drug administered either every 8 or 12 weeks
as a maintenance therapy following three injections of
Lucentis®
(9).
3.4.2 PF-04523655 -Wet AMD
Intravitreal
It is a siRNA, 19 nucleotides in length, that inhibits the
expression of the hypoxia-inductible gene RTP801. This
stress-response gene mediates the mammalian target of rapa-
mycin (mTOR) pathway. PF-04523655 has been shown
to reduce the volume of choroidal neovascularization in a
mousemodel. PF-04523655 has been shown to cause regres-
sion of CNV in experimental studies of mice and primates.
Intravitreal small-interfering RNA (siRNA) PF-04523655
(Quark; licensed to Pfizer) used to treat choroidal neovas-
cularization (CNV) secondary to age-related macular degen-
eration (AMD) seems to be safe and well tolerated in an
interim phase I analysis. “No adverse events were observed
up to the 3,000-µg dose”
(10)
.
3.4.3 AGN-745 (Sirna-027) -Wet AMD
Development was halted
Allergan has halted development of its siRNA-based wet age-
related macular degeneration, Sirna-027 is the first chemi-
cally modified short interfering RNA (siRNA) targeting
Vascular Endothelial Growth Factor Receptor-1 (VEGFR-
1). VEGFR-1 is found primarily on vascular endothelial cells
and is stimulated by both VEGF and placental growth
factor (PlGF), resulting in the growth of new blood ves-
sels
(11)
. By targeting VEGFR-1, Sirna-027 is designed to
reduce pathologic angiogenesis mediated by both VEGF
and PlGF. Development was halted for AGN-745 after
the drug failed to meet a key efficacy endpoint in a phase
II study.
The trial compared the effect of three different monthly
doses of AGN-745 with Genentech’s antibody drug
Lucentis®, the standard of care for AMD, in treating the
subfoveal choroidal neovascularization associated with
the disease. Both drugs were administered via intravit-
real injection
(12)
.
Apparently no safety issues were associated with AGN-
745, a chemically modified siRNA. But since the drug
did “not meet its efficacy hurdle” — improvement in vis-
ual acuity — Allergan opted to halt its development
(13)
.
4. Anti-platelet derived growth factor
4.1 E10030 (Aptamer) - Wet AMD
Intravitreal
One of them is E10030 (Ophthotech), an anti-platelet-
derived growth factor (anti-PDGF-B) aptamer. E10030
strongly binds to PDGF-B. PDGF-B plays a key role in
recruiting the pericytes that envelop the new vessels and
make them more resistant to the anti-VEGF attack. In
combination with anti-VEGF, this new agent could rep-
resent a breakthrough therapy.
A phase I study
(14)
with an intravitreal anti-platelet-
derived growth factor (PDGF) aptamer that targets
pericytes, was evaluated in combination therapy with
ranibizumab (Lucentis®, Genentech) in patients with
neovascular age-related macular degeneration (AMD)
with promising results regarding safety and efficacy
(15)
.
5. Anti tyrosine kinase
Approximately 2000 kinases are known, and more than
90 Protein Tyrosine Kinases (PTKs) have been found in
the human genome. They are divided into two classes,
receptor and non-receptor PTKs.
5.1 Anti receptor kinase (suffix ~nib):
“
At present, 58 receptor tyrosine kinases (RTKs) are known,
grouped into 20 subfamilies. They play pivotal roles in diverse
