Point CounterPoint
Two physicians were asked to comment on their
use of 2 AMD drugs: Lucentis and Macugen. While only the latter is FDA approved,
the former has been used extensively in clinical trials and has attracted a lot
of attention. The doctors will discuss how the mechanisms in the medicines work;
how they use the drugs in their practices; and how patients respond to therapy.
Success With Lucentis
A clinician's insights.
DAVID BOYER, MD
I have been in practice for over 25 years and
have been able to observe the shift in the paradigm for the treatment of wet AMD.
During the last 5 years alone, there has been a change from only being able to treat
a small number of extrafoveal classic choroidal neovascularization (CNV) lesions
to the treatment of all CNV lesion subtypes.
With the approval of photodynamic therapy (PDT) using
Visudyne (verteporfin, QLT/Novartis) 5 years ago, we were able to reduce visual
loss in a number of patients with classic CNV, small occult, and minimal classic
lesions who would otherwise have lost vision. With the approval of Macugen, all
subtypes and size CNV lesions were able to be treated, allowing a greater number
of patients to benefit. These treatments gave us the tools needed to reduce the
progression of this dreaded disease. In spite of the advancements, the visual gain
with these treatments was minimal, and most patients continued to lose some vision.
CLINICAL TRIALS
Our retinal practice has participated in many of the trials for
the treatment of wet AMD. We have participated in PDT trials using Visudyne and
SnET2-PDT, and anti-VEGF trials using Macugen (pegaptanib sodium, Pfizer/OSI Pharmaceuticals),
and Lucentis (ranibizumab, Genentech). Most of these studies were masked, and we
did not know who received the drug being tested. Therefore, my experience with Lucentis
is limited to those trials where I knew which patients received Lucentis.
ACTING MECHANISMS, CLINICAL PERFORMANCE
Lucentis is the most potent treatment of wet AMD
I have ever
seen. Lucentis is a recombinant antibody fragment, originally derived from the full-length
anti-VEGF monoclonal antibody bevacizumab. The molecular weight of Lucentis has
been reduced to 48 KD and the molecule has been modified to have a 120-140 higher
affinity to bind all VEGF isoforms than the original molecule.
This drug has the extraordinary ability to stop leakage, reduce
CNV progression, and has resulted in the improvement of vision in a large number
of patients. The first year results of the FOCUS (RhuFab V2 Ocular Treatment Combining
the Use of Visudyne to Evaluate Safety), ANCHOR (ANti-VEGF Antibody for the Treatment
of Predominantly Classic CHORoidal Neovascularization in AMD), and MARINA (Minimally
classic/occult trial of the Anti-VEGF antibody Ranibizumab [formerly, RhuFab]) In
the treatment of Neovascular AMD) studies all showed over 90% stabilization of vision
with an improvement of vision in most cases.
In the MARINA study, in which minimally classic and occult CNV
were treated, nearly 95% of patients treated were stabilized (15 or less letters
of visual loss).
Twenty-five percent of patients treated with the 0.3 mg dose and
34% of patients treated with 0.5 mg dose actually increased vision 15 letters or
more. This was not a subset analysis, but involved 140/478 patients treated. In
addition, 40% of patients treated with Lucentis achieved 20/40 or better, compared
to 11% of control. Lucentis' treated patients gained an average of 7 letters compared
to 10.5
letters lost in the control group. Seventy four percent of
0.3 mg
and 71% of 0.5 mg experienced 0 or more letter improvement compared to 28.6% of
the control.
When the results of the MARINA study were released, many critics
said that this was the less severe type of CNV. The Anchor study, on the other hand,
involved the treatment of classic CNV. This is the subcategory of CNV usually associated
with the worst prognosis. This trial studied Lucentis vs. PDT using Visudyne.
Ninety-four percent of patients treated with 0.3 mg and 96% of
0.5 mg treated patients maintained or gained vision, compared to 64% of the Visudyne-treated
patients. On average, patients treated with Lucentis had an improvement of vision
compared to the Visudyne-treated control arm.
This was an overwhelming improvement compared to the previously
published TAP and VIP data from the PDT trials using Visudyne or the VISION trial
using Macugen. (TAP stands for Treatment of Age–related macular degeneration
with Photodynamic Therapy and VIP for Verteporfin in Photodynamic Therapy).
All types of choroidal neovascular membranes respond to Lucentis.
In the patients treated with Lucentis, therapy is immediate. The Optic Coherence
Tomography (OCT) reductions were noted as early as 1 day in some patients. Many
lesions are totally dry as viewed on OCT in
1 month. This response was rarely
seen in Macugen-treated patients. For those lesions not totally dry at 1 month with
Lucentis, an additional injection or 2 almost always dries the lesion. Only a few
patients using Macugen have shown a similar response.
PATIENT RESULTS
Visual improvement in patients treated with Lucentis occurs as
early as 1–2 weeks out, with most patients showing an improvement over a 3-month
period. My patients receiving Macugen rarely show this visual improvement although
their vision tends to remain stable during the period of treatment.
I have not observed any untoward local inflammatory reactions
associated with the injection of Lucentis since the lyophilized form of ranibizumab
was discontinued. No significant inflammation, visual disturbance, cataract, or
glaucoma was observed in any of the patients that I have treated.
I have not encountered any problematic systemic side effects such
as significant increases in blood pressure, myocardial infarction, or stroke. My
observations may be due in part to the small number of patients I have studied.
The current SAILOR trial (Safety Assessment of Intravitreal Lucentis for AMD) will
hopefully give us a definitive answer to this question and others concerning the
potential systemic effects of this treatment.
The total pan-suppression of all forms of VEGF has been thought
to be detrimental to the choroid, and pigment epithelium. I have not observed any
significant changes in patients who have received 24 months of continuous suppression.
I have some patients who had minimal drop off of vision after 24 months of continuous
treatment with Lucentis but it is impossible to know if this was due to pan-VEGF
suppression or the natural progression of the disease. In the future, I don't think
this will be a problem clinically because we will dose our patients intermittently
and not use continuous treatment.
Based on the Horizon study, I can say that the long-term effects
of the drug on the CNV complex are variable. I have a few patients who have needed
to have treatments repeated 2 months after their last Lucentis injection but I have
also had many patients who received their last injection 4–6 months ago with
their lesions still remaining inactive. Interestingly enough, even some patients
with active CNV lesions who did not respond to Macugen or Visudyne therapy in the
SAILOR trial had vision improvement and showed a reduction in OCT thickness.
TODAY'S TREATMENT, TOMORROW'S HOPE
This is an exciting time to be a retinal specialist treating patients
with wet AMD. I look forward to Lucentis being available for use by all retinal
surgeons. The "treatment bar" has been lifted and this is not only wonderful for
our patients, but for those of us who treat them.
David Boyer, MD
is in private practice in Beverly Hills, Calif. He is an associate clinical professor
at the USC Keck School of Medicine. He is a consultant for OSI, Genentech, Novartis,
and Alcon. Dr. Boyer can be reached at Vitdoc@aol.com.
Treating AMD Here and Now
A physician's experience with Macugen.
VICTOR GONZALEZ, MD
In recent years, our keen understanding of
the pathogenesis of neovascular AMD has paved the way for new and exciting treatment
options that aim to improve patient outcomes. In particular, the identification
of VEGF in promoting the blood vessel growth and leakage associated with neovascular
AMD has led to the rapid exploration and development of anti-VEGF therapies. In
the last year, we have been able to reap the benefits offered by Macugen, the first
and only FDA-approved VEGF inhibitor for ophthalmic use, which has proven to stabilize
vision in as many as 70% of patients.
I have been using Macugen since February 2004, and have
administered more than 1,100 injections to date. Its strong safety and efficacy
profiles, as well as its ability to work in a broad range of patients with neovascular
AMD, make it an invaluable treatment option in my practice.
MACUGEN: MORE SELECTIVE, LESS DESTRUCTIVE
The first antiangiogenic drug available for ophthalmic use, Macugen
selectively targets the VEGF isoform, VEGF165, which is believed to play an important
role in pathologic ocular neovascularization. It is believed that once Macugen selectively
binds to VEGF165, it blocks the blood vessel growth and permeability associated
with wet AMD.
This selective blockade of VEGF165 spares some VEGF for normal
physiological functions, and appears to be responsible for Macugen's strong safety
profile.
My patients experience few side effects. These typically include
mild foreign body sensation and redness at the injection site — all of which
resolve within a week. Furthermore, none of my patients have experienced a serious
side effect, such as endophthalmitis, as a result of the Macugen injection. Although
some data has shown that nonselective blockade also may be safe and effective, there
are no long-term data yet to support this, as there is with Macugen, which has safety
data near the 3-year mark.
TREATMENT PROTOCOL
I give Macugen to all my patients who have wet AMD, no matter
the angiographic classification subtype. My experience mimics the results of the
landmark VISION (VEGF Inhibition Study In Ocular Neovascularization) trial, in which
the benefits of Macugen were similar in patients with predominantly classic, minimally
classic, and occult neovascular AMD.
I have developed a successful protocol for monitoring patients
who present with wet AMD. Every 6 weeks, I give an intravitreal injection of 0.3
mg of Macugen and monitor them using VA, FA, and OCT. If the OCT is negative for
edema or subretinal fluid and the fluorescein angiogram has lost its hyperfluorescence,
then I withhold treatment.
I retreat if the patient loses more than 5 letters
(1 line) of VA, there is activity on the FA, or the central macular thickness increases
by 100 μm on OCT. Once a patient's vision has stabilized and leakage is controlled,
I continue to monitor the patient every 6 weeks.
Some of my patients have responded better or more quickly than
others, but overall, I have a high success rate with Macugen. Seventy percent to
75% of my patients
stabilize or improve with Macugen therapy.
In addition, my patients have tolerated the intravitreal injection
very well. In my practice, the key to a high compliance rate has been to provide
patients with a detailed explanation of the procedure, as well as administer a local
anesthetic — both of which provide a sense of calm.
EARLY TREATMENT, COMBINATION THERAPY
Patients come to my practice at all stages of their disease, but
when they come at an early stage — when the lesion size is small — they
have even better results with Macugen. My findings have been consistent with those
of the recent analysis of the VISION trial, in which patients with earlier manifestations
of neovascular AMD (eg, lesion size <2 disc areas, baseline VA �54
ETDRS letters, absence of lipid) who were treated with Macugen, achieved better
results than previously seen.
Of course, we all are faced with the challenge of getting our
patients to come to us earlier on in the disease process. This can prove quite difficult
because when patients leak blood under the retina, it is painless and patients do
not realize something is amiss. It is therefore our continual obligation to educate
the public and health providers about the importance of encouraging an eye exam
for those at high risk of wet AMD.
I have also experienced a benefit in combining Macugen with PDT
in a select number of patients. If after 4 injections, a patient's vision does not
improve, or there still is leakage, I will treat with Macugen followed by PDT. Because
these therapies have different effects on neovascularization (PDT destroys the lesion
while Macugen prevents the blood vessel growth and leakage), there is a strong rationale
for combining the 2 to achieve optimal results.
PATIENT EDUCATION AND MANAGEMENT
One of the most important aspects of treating patients with neovascular
AMD is explaining to them the true nature of the disease and what he or she can
realistically expect from treatment. I tell my patients AMD is a chronic progressive
disorder that will not go away and that current treatments do not offer a cure,
but rather a way to stop vision loss and slow leakage. At this time, I cannot promise
100% of my patients will experience a positive outcome, but with Macugen, I can
assure them 70% of them show a treatment benefit.
Patients ask me about other anti-VEGF therapies, and I explain
these drugs are not yet approved by the FDA, and although some studies have shown
promising results, there still is not enough long-term data to substantiate their
safety and efficacy.
A BEGINNING TO A PROMISING FUTURE
Macugen has truly revolutionized the way I treat neovascular AMD.
For the first time, I have a treatment option to offer all my patients with the
disease. This therapy is safe and effective when used alone, and appears to be well
tolerated and effective when used in combination with PDT.
As we look toward
the future of wet AMD treatments, one thing is clear — antiangiogenic therapies
appear to be the most promising. I look forward to the day when we have many treatment
options for wet AMD, but until then, Macugen remains at the core of my treatment
arsenal. RP
Victor Gonzalez,
MD, is the principal of the Valley Retina Institute located in McAllen, Texas. He
can be reached at maculadoc@aol.com.
Retinal Physician, Issue: January 2006