179
Anti-VEGF in the treatment of AMD
(Lucentis®) and bevacizumab (Avastin®), of which only
the first two have been approved for this therapeutic
indication.
3. Ranibizumab (Lucentis®)
Ranibizumab is a Fab fragment of a recombinant
humanized monoclonal antibody with high affinity for
VEGF-A (the ranibizumab binding site has an affinity for
binding VEGF-A 140-fold higher than that displayed by
the bevacizumab binding site) specifically studied for the
treatment of AMD
(39,40,41)
. Ranibizumab has a solid clini-
cal development program for this therapeutic indication,
involving over 7,000 patients. Ranibizumab binds to an
amino acid chain common to all VEGF-A isoforms, thus
rendering them inactive, reducing retinal and choroidal
angiogenesis and halting the increase in capillary perme-
ability. It has been shown in animal models that ranibi-
zumab effectively penetrates the retina and the subretinal
space after intravitreal injection. Its systemic half-life is
short (2-3 hours, following intravitreal administration)
and systemic clearance is fast, which makes its adminis-
tration safe. The average vitreous elimination half-life is
approximately10 days
(42,43)
.
Ranibizumab has been approved for all types of exuda-
tive/neovascular AMD lesions: classic, predominantly
classic, minimally classic and occult lesions with no clas-
sic component, up to 12 disc areas (DA), where the neo-
vascular component is ≥ 50% of the entire lesion. The
recommended dose is 0.5 mg. Treatment includes a load-
ing phase, consisting of 3 monthly injections, in the first
3 months, and a maintenance phase, where retreatment
is decided according to disease progression, mostly evalu-
ated in monthly visits through VA and OCT criteria, at
least during the initial stage or recent neovascularization
activity
(44)
.
Phase III clinical trials
MARINA
and
ANCHOR
, which
supported ranibizumab approval for the treatment of
AMD, demonstrated that treatment with monthly intra-
vitreal injections for a 12 months period was associated
with a significant increase in visual acuity, compared to
photodynamic therapy and placebo
(45)
. After 12 months,
25-40% of patients treated with ranibizumab showed
gains of ≥ 15 letters (ETDRS), compared to 5-6% of
the control group patients (p<0.001). Similar results
were confirmed after 2 years. Both these studies have
established ranibizumab as the first therapy not only
capable of preventing loss of vision but also of improv-
ing vision in a substantial percentage of patients: 33% of
the patients treated with ranibizumab in the MARINA
study and 41% in the
ANCHOR
study showed visual
gains of at least 15 letters
(45, 46,47,48, 49)
.
Subsequent studies (
PIER, SUSTAIN, EXCITE
) were
aimed at defining flexible and individual dose regimes
for the maintenance stage of treatment with ranibi-
zumab, allowing an effective approach to maintaining
visual gains, practical in terms of hospital follow-up and
with maximum systemic and ocular safety
(50,51,52)
.
These visual gains translate into real benefits for patients.
This effect was evaluated through 3 VFQ-25 sub-scales
(near vision, distance vision and vision-related depen-
dency); in fact, patients treated with ranibizumab
showed improvements in these 3 sub-scales (
MARINA
and
ANCHOR
endpoints). Specifically regarding
dependency, ranibizumab allowed patients to become
more independent in their daily activities. Overall aver-
age VFQ scores increased by 4.6 points in the Lucentis®
0.5 group, compared to a 4.4-point decrease observed in
the placebo group
(53)
.
The
PIER
study evaluated an alternative therapeutic
regime consisting of monthly injections, in the first 3
months, followed by quarterly injections, correspond-
ing to a total of 6 injections within a year. After an ini-
tial gain of 4.8 letters at month 3, patients treated with
ranibizumab had lost an average of 0.2 letters at month
12, whereas patients in the control group lost 16.3 let-
ters. These results indicate that individual treatment cri-
teria should be adopted during the maintenance stage,
allowing an effective approach to maintaining visual
gains, as well as allowing follow-up in clinical practice,
with maximum systemic and ocular safety.
Vision is expected to be maintained in 90-95% of
patients; a minimum gain of 3 lines should be observed
in 30-40% of patients treated with ranibizumab
(50)
.
In the
EXCITE
study, the quarterly treatment regime
used in the
PIER
study (0.3 mg and 0.5 mg) was directly
compared with a monthly regime (0.3 mg). An average
increase in VA was observed in all treatment groups dur-
ing the 12 months of study duration. At month 12, com-
pared to month 3, VA gains had decreased slightly with
the quarterly regime (by -2.2 and -3.1 letters with ranibi-
zumab 0.3 mg and 0.5 mg, respectively), having slightly
increased (by +0.9 letters) with monthly administration
of 0.3 mg of ranibizumab
(52)
.
PrONTO
, a small prospective, unicentric, open-label,
non-randomized study sponsored by the investigator,
evaluated the efficacy of 3 consecutive monthly injec-
tions, followed by individual retreatment based on OCT
results (at intervals ≥ 1 month). Retreatment criteria
