181
Anti-VEGF in the treatment of AMD
In clinical trials, the benefits of ranibizumab regard-
ing visual acuity were independent of the type of CNV
lesion. Additionally, these benefits were associated with
a low rate (< 0.1%) of severe adverse events (endo-
phthalmitis, retinal detachment, traumatic cataract).
Less severe ocular adverse events occurred in less than
2% of patients, including intraocular inflammation
and increase in intraocular pressure. In all clinical tri-
als, Lucentis® revealed to be a well-tolerated drug, with
no statistically significant differences observed in ocular
adverse events between treatment arms. The results of the
SAILOR
study suggest a possible increase in the risk of
de novo cardio vascular adverse events (CVA) in patients
treated with ranibizumab with previous history of CVA
or its risk factors (e.g., cardiac arrhythmias), although
the differences observed were not statistically significant.
Safety monitoring during the post-marketing period has
confirmed the good ocular and systemic safety profile
of ranibizumab, whose risk management plan has been
strictly implemented.
Other clinical trials are in course for other therapeutic
indications, namely Diabetic Macular Oedema, Central
Retinal Vein Occlusion and other ocular pathologies
involving choroidal neovascularization, whose prelimi-
nary results have revealed to be promising.
4. Pegaptanib ( Macugen®)
4.1 Introduction
Pegaptanib sodium (Macugen
®
, OSI-Eyetech Pharma
ceuticals, Pfizer), was the first anti-VEGF inhibitor avail-
able for the treatment of choroidal neovascularization
(60)
.
This medicine is part of a new drug set called aptamers.
The aptamers are synthetic oligonucleotides which acquire
a specific tridimensional shape and allow high specificity
and affinity to a great extent of therapeutic agents. These
compounds are chemically synthetised with the use of
nucleotide bases and the use of reverse transcription and
PCR - polymerase chain reaction technology
(61)
.
Pegaptanib sodium is a 28-base ribonucleic acid (RNA)
oligonucleotide with two branched 20KDa polyethyl-
ene glycol (PEG) moieties attached in order to increase
the half-life of the drug in the vitreous cavity. The RNA
sugar background is modified to prevent its degradation
by endogenous endo and exo-nucleases
(62)
. Pegaptanib
sodium specifically targets the VEGF165 isoform
(63)
.
The pharmacokinetics of pegaptanib following intravit-
reous injection were profiled in a study of 147 subjects
with exsudative AMD (Apte RS, 2007). Either 1 or 3
mg of pegaptanib sodium per study eye was administered
every 6 weeks for 54 weeks. For the 1 mg dose, mean
maximal plasma concentrations were 20 – 24 ng/ml, and
pegaptanib was measurable (> 8 ng/ml) in the plasma for
up to 1 week after injection. The mean apparent termi-
nal plasma half-life, determined from the 3 mg group,
was 10 days. There was no plasma accumulation with
administration of repeated doses. In addition, no serum
antibodies against pegaptanib were detected
(64, 65)
.
In monkeys’ eyes, biologically active pegaptanib could
be detected in the vitreous humor for at least 28 days,
following a single 0.5 mg intravitreous injection dose
(66)
.
4.2 Clinical trials with pegaptanib
4.2.1 Phases I and II studies
A phase IA safety study with 15 patients with exudative
AMD
(67)
, as well as a phase II study with 21 patients
treated with pegaptanib associated or not to photo-
dynamic treatment (PDT)
(68)
, with a follow up of 3
months, have shown that the intravitreous administra-
tion of pegaptanib with 6 week intervals was well toler-
ated and had anatomic and visual benefits
(69)
.
4.2.2 Phase III study
The study
VISION
(VEGF Inhibition Study in Ocular
Neovascularization) consists of two multicentric, ran-
domized, prospective, controlled, dose-ranging and
double-blinded phase III clinical trials, used for testing
the safety and efficiency of pegaptanib sodium in the
treatment of choroidal neovascularization secondary to
AMD
(70)
.
There were 1208 patients in this study, distributed by
117 centers and the main criteria for inclusion were:
50-year old or above with any kind of angiographic
subtype of subfoveal choroidal neovascularization in
the study eye secondary to AMD, with a lesion of 12
or below disc areas (including blood, scarring, atrophy
and neovascularization). The best-corrected visual acuity
varied between 20/320 and 20/40.
Patients were randomized in four branches of the study:
a group for simulation of pegaptanib intravitreous injec-
tions and one of three groups for administration of pegap-
tanib sodium intravitreous injections (with doses of 0,3
mg, 1mg or 3 mg). The injections (or simulations) were
performed with 6-week intervals for 48 weeks, in a maxi-
mum of 8 injections per patient. All patients underwent
