Retinal Physician Symposium Covers Broad Range of Topics
specialists provide insights on timely issues.
BY THE RETINAL PHYSICIAN EDITORIAL STAFF
Many of the country's leading retina specialists
gathered at the Atlantis resort on Paradise Island in the Bahamas from May 31
to June 3 for the Second Annual Retinal Physician Symposium (RPS). The theme
of this year's meeting was Current Concepts in Retinal Medicine. The meeting generated
considerable excitement as Genentech chose the RPS to release the first results
of the key PIER trial evaluating quarterly dosing for ranibizumab (Lucentis) in
treating wet age-related macular degeneration (AMD).
The following are condensed recaps of key presentations that took
place during the 4 days of the Symposium.
WET AMD TREATMENTS
A key focus of this year's RPS was the ongoing
assessment of ranibizumab (Lucentis, Genentech). Interest was generated by 2 key
events: the release of 1-year data from the PIER trial and the expectation that
ranibizumab would be approved by the Food and Drug Administration shortly after
the Symposium concluded. Indeed, ranibizumab was approved on June 30 as a treatment
for wet AMD.
Peter Kaiser, MD, provided a recap of the key clinical trials
for ranibizumab, including the 2 pivotal phase 3 studies, MARINA and ANCHOR. He
also noted other, more narrowly focused studies of ranibizumab such as SAILOR, FOCUS,
and PrONTO. (Retinal Physician has previously reported on these studies.)
Based on the already completed key studies, Dr. Kaiser concluded
that Lucentis has shown itself to be an efficacious drug with an excellent safety
profile. He noted that the range of adverse events seen in ranibizumab trials "were
really limited to things that we've come to expect with intravitreal injections."
David Brown, MD, provided new information when he announced the
1-year results of the PIER study, which was primarily designed to determine whether
ranibizumab could be injected quarterly rather than monthly (after 3
monthly injections) and maintain its effectiveness.
Dr. Brown reported that the PIER study showed ranibizumab to be
a safe drug. However, while quarterly dosing on average provided a 15- to 16-letter
improvement over sham injections, the visual acuity of patients receiving quarterly
injections of ranibizumab had on average returned to baseline by month 12.
The PIER data have led Genentech to recommend that patients receive
either monthly injections of ranibizumab, or have their retreatment schedules determined
through individualized testing.
The update on bevacizumab (Avastin, Genentech)
was presented by Philip Rosenfeld, MD, PhD, who pioneered the use of bevacizumab
as an off-label therapy for the treatment of wet AMD.
Dr. Rosenfeld described how he had initially recognized the molecular
similarities between ranibizumab and bevacizumab and determined that bevacizumab
might be an effective treatment for wet AMD. He began with intravenous delivery
of bevacizumab to a few wet AMD patients.
Dr. Rosenfeld said he was well aware of systemic side effects
that occurred with some cancer patients treated with bevacizumab, though he did
not see those side effects in his AMD patients. However, he wanted to avoid the
potential risk of systemic side effects and switched to intravitreal injection as
the delivery method for bevacizumab.
Dr. Rosenfeld reported on a patient who did not respond to photodynamic
therapy (PDT), triamcinolone acetonide (Kenalog, Bristol-Myers Squibb), or pegaptanib
sodium (Macugen, OSI), but who demonstrated significant and long-lasting visual
improvement after just 1 injection of 1.25 mg of bevacizumab.
In terms of safety, he noted that short-term data on 7000
bevacizumab injections raised no major safety concerns.
"No apparent safety signals were identified," he reported.
Dr. Rosenfeld concluded his presentation by saying that retina
specialists should not feel guilty about using bevacizumab as a treatment for wet
"It's legal, and it's ethical if you're using good clinical judgment,"
he asserted. "Obviously, we do need prospective clinical trials."
Peter Kaiser, MD, discussed several potential
but lesser-known wet AMD therapies that are currently in clinical trials
vascular endothelial growth factor (VEGF) Trap (Regeneron), RNA interference (being
developed by both Acuity Pharmaceuticals and Sirna Therapeutics), and squalamine
Dr. Kaiser finds VEGF Trap particularly interesting because in
creating a decoy receptor for VEGF, it binds well to all forms of VEGF and remains
effective at low concentrations, possibly offering a longer-lasting duration of
Following a promising 6-week, 21-patient phase 1 trial during
which the median improvement in visual acuity was 13 letters, Regeneron has initiated
a larger phase 2 trial to determine safety and efficacy at doses up to 4 mg.
The mechanism of action of RNA interference is to silence VEGF-producing
genes through the injection of a form of double-stranded RNA. Sirna has completed
a promising 26-patient, phase 1 trial that consisted of 1 injection. The Sirna
compound, which acts against the VEGF receptor, demonstrated improved or stabilized
vision in 96% of the study population, with 23% of patients showing a 3 line vision
gain at 8 weeks. Sirna is now forming a phase 2 trial.
Acuity has conducted a 15-patient, 2 injection phase 1 trial with
its Cand5 compound, which attacks VEGF directly. In this study, 80% of patients
demonstrated stable or improved vision. Dr. Kaiser reported that the safety profile
of Cand5 proved to be excellent in this trial. A phase 2 trial is currently nearing
Dr. Kaiser briefly mentioned squalamine, an antiangiogenic that
is given intravenously and that showed some ability to stabilize vision in phase
2 trials. A new, dose-escalating trial of squalamine has now been initiated.
PDT and Intravitreal Steroids
Albert Augustin, MD, reported on an interesting
combination called "triple therapy" in which the patient is treated with an anti-inflammatory
steroid, bevacizumab, and modified PDT with a lower light dose.
Dr. Augustin said that in 1 series of 64 eyes, 7 patients who
received triple therapy all showed significant improvement in visual acuity in just
1 treatment cycle. A second bevacizumab injection was performed in only 7 eyes.
"We believe this is a more finite treatment," said Dr. Augustin.
"It's more a cure vs a suppression of the disease process. Up to now, we haven't
seen any steroid-related or other severe side effects of the treatment."
The PrONTO Study
Dr. Rosenfeld had the idea which led to
the PrONTO study after treating several patients with ranibizumab who did not require
additional retreatment for as long as
31 months. In fact, their vision continued
to improve without retreatment. He determined that patients responded differently
to this therapy and that retreatment could be determined on an individual basis.
Dr. Rosenfeld reasoned that vision loss was gradual as the fluid
accumulated and that optical coherence tomography (OCT) was reliable in detecting
the fluid before it became symptomatic. Initially, all patients in the study received
3 monthly injections. They received additional injections only if the OCT measurements
showed a need for retreatment.
"Our questions were: how quickly does the OCT improve once we
start injecting? How quickly does the visual acuity improve? And can these visual
acuity improvements be maintained 2 years if we use this prn regimen?"
The criteria for retreatment as measured by OCT were essentially
one or more of the following: loss of at least 5 letters of vision, evidence
of fluid, increase in central retinal thickness, new hemorrhage, and/or new evidence
of classic choroidal neovascularization (CNV).
Using these criteria, the mean number of injections per patient
in year 1 of a 2-year 40-patient study was 5.5, though at least 1 patient received
13 injections. Clearly, the need for re-injection is unpredictable and varies from
individual to individual. The PrONTO study offers one way to determine individual
OCT Assessments of Lucentis
Dr. Brown reported on quantitative vs qualitative
OCT assessments of disease progression following treatment with ranibizumab.
He noted that 4 different types of edema routinely return following
treatment with ranibizumab. These are diffuse edema, intraretinal cysts, subretinal
edema, and subretinal pigment epithelium fluid.
"A patient has anti-VEGF therapy and gets a nice response," noted
Dr. Brown. "With time, after treatment, you get diffuse edema. In other words, there's
a thickening but no bubbles. This will only be shown by quantitative OCT if it accurately
measures the retinal boundaries."
Dr. Brown reports that in performing quantitative OCT assessments
following anti-VEGF treatments, the error rate in identifying the need for retreatment
can be as high as 70%. This is because the computer is prone to fixation errors,
has difficulty in finding retinal boundaries, and fails to note the presence of
subretinal pigment epithelium fluid.
With qualitative OCT assessment, the presence of fluid is visible
and easy to detect. When fluid is detected, it is recommended that the retina specialist
"As Phil (Rosenfeld) says, he treats when he sees fluid," noted
High-Resolution SLO/OCT: The Future
Dr. Rosenfeld reported on the anticipated
arrival of "next-generation" OCT technology, which is called spectral domain and
is currently being developed by several competing companies, including Carl Zeiss
Meditec (Dublin, Calif) and Topcon (Paramus, NJ). Dr. Rosenfeld predicts that one
or more of these systems will be commercially available within the next year.
The advantages of spectral domain include increased speed, no
moving parts, and 2000 detector elements that generate 29000 lines per second compared
to 400 lines per second for today's OCT-3. The result is better sensitivity, higher
resolution, and 3-D imaging.
"So, we are going to have higher resolution. It's going to be
faster and you are going to be able to reconstruct images. You're going to be able
to precisely place where the pathology is in the different layers of the retina
based on the vascular landmarks of the fundus image. You are going to be able to
do a lot of neat things because you will have this huge database that can be manipulated
any way you want," concluded Dr. Rosenfeld.
Surgery for AMD: Is It Dead?
Paul Tornambe, MD, says he never felt that
surgery was alive for AMD. Dr. Tornambe says, "Any disease where you treat the effect
of the stimulus rather than treating the stimulus is not going to be successful."
He says "that until we are able to do something directly with the up-regulation
of a VEGF gene, that as long as VEGF keeps getting produced, we're going to have
to keep retreating these people." Dr. Tornambe believes that something has to occur
further upstream to be effective.
He also believes choroidal neovascular membrane (CNVM) removal
is "dead" and that the Submacular Surgery Trials (SST) showed really no visual benefit.
Dr. Tornambe is disappointed with the results in dealing with large clots. He thinks
that the intravitreal injection of dexamethasone and bevacizumab or ranibizumab
is exciting and that drugs will minimize the damage that is ultimately done.
"Ninety-five percent of the macula operations we perform now will
not be performed in 5 years, but I think we're very innovative, and we certainly
try everything once," says Dr. Tornambe.
PREVENTION OF AMD
AMD: Genetics and Nutrition
Darius Moshfeghi, MD, stated in his Nutrition,
AREDS, AREDS II presentation that the AREDS trial, "has demonstrated the feasibility
and efficacy of antioxidant plus zinc supplementation in preventing progression
to advanced forms of AMD in patients with intermediate and advanced forms of AMD."
In addition, Dr. Moshfeghi said the AREDS formulation resulted
in positive visual acuity outcomes relative to placebo. Lastly, the AREDS II trial
is enrolling patients to determine the additional benefit, if any, of xanthophyll
and/or omega-3 long-chain polyunsaturated fatty acid supplementation in prevention
of progression of AMD.
Cataract Surgery and Development of Advanced
Susan Bressler, MD, gave a presentation
on the effect of cataract surgery on the development of neovascular AMD. Dr. Bressler
stated that multiple analytic approaches on a large, well-categorized cohort (AREDS)
provides no clear evidence of an adverse association between cataract surgery and
development of neovascular AMD and that AMD patients in need of cataract surgery
can probably be reassured of little to no increased risk of CNV due to surgery.
Prevention of Advanced AMD
During his talk on risk factors for choroidal
neovascularization and AMD prevention trials, Allen C. Ho, MD, spoke about the exciting
opportunities and developments with ranibizumab for patients with wet AMD. Dr. Ho
covered prevention trials and the status of trials outside of AREDS laser
to drusen, rheopheresis, and the anecortave acetate trial. He said that lutein and
zeoxanthine are going to be explored in the AREDS II trial. In addition, Dr. Ho
is interested in docosahexaenoic acid (DHA) and elco-
sapentanoic acid and said
that omega-3 fatty acids are thought to be protective. He believes that the positive
effects of DHA are very suggestive and compelling.
Dr. Ho is interested in laser to drusen. He likes the notion of
trying to modify the thickened Bruch's membrane that might be a stimulus for choroidal
neovascularization or atrophic AMD, however, preliminary studies did not support
laser to drusen outside the confines of a clinical trial. He thinks that rheotherapy
is a very interesting concept but noted that the MIRA-1 phase 3 trial of rheopheresis
did not meet the primary efficacy outcome; another phase 3 trial is in planning
stages because the initial study may have had significant and real confounder variables.
He highlighted the anecortave acetate study, which is a pharmacologic prevention
trial. He believes the drug to be most apt for prevention of choroidal neovascularization
and may be a useful adjunct to Lucentis in the treatment of existing CNV.
Timothy Murray, MD, reported some promising
results in animal studies for microvascular targeting, which combines pharmacological
therapies for the treatment of retinoblastoma. "Combining anecortave acetate (Retaane,
Alcon) and carboplatin essentially reduces tumor size and has the potential to eradicate
tumor," explained Dr. Murray. He noted the potential of such a therapy depends on
its dosage and delivery schedule.
DIABETIC MACULAR EDEMA
Pegaptanib Sodium (Macugen)
Christine Gonzales, MD, spoke about the
phase 2 trial evaluating pegaptanib sodium for diabetic macular edema (DME). This
study was designed to explore the safety and efficacy of the drug through week 36
for patients given pegaptanib every 6 weeks for up to 36 weeks.
Patients were randomized 1:1:1 into 3 different doses of pegaptanib
or sham injection. Physicians had to feel comfortable deferring focal laser treatment
for up to 16 weeks.
Dr. Gonzales reported a treatment effect as early as 6 weeks and
a significant difference between the sham group and the pegaptanib group at
weeks. "Subjects that were assigned to Macugen in the phase 2 trial had better visual
acuities," reported Dr. Gonzales. "They were more likely to show a reduction
in the center thickness, and less likely to need focal laser when compared to the
Quan Dong Nguyen, MD, presented the 1-year
interim results of the Ranibizumab for Edema of the MAcula in Diabetes (READ) study.
In this READ phase 1 trial, intravitreal ranibizumab was safe and tolerable at
multiple injections for patients who have DME that has been refractory to laser
photocoagulation or intravitreal injections of triamcinolone. No ocular or systemic
side effects and no inflammation had been observed with repeated dosages of 0.5
mg of ranibizumab.
"The primary outcome of the READ study, beyond safety, was change
in foveal thickness between baseline and 7 months and the secondary outcome
measures were changes from baseline in visual acuity and macular volume," explained
Dr. Nguyen. Dr. Nguyen reported that at 7 months, (1 month after the fifth injection),
the mean foveal thickness was 257 μm, a reduction of 246 μm (85% of the
excess foveal thickness present at baseline; P=.005). The macular volume
was 7.47 mm3, a reduction
of 1.75 mm3, (77% of the
excess macular volume at baseline; P=.009). "In addition," said Dr. Nguyen,
"at month 7, we observed a mean visual acuity of 40.4 letters (20/40), an improvement
of 12.3 letters (P=.005)."
Dr. Kaiser presented results from the Diabetic
Retinopathy Studies (DRS)-1 and 2 for this drug. He reported that protein kinase
C beta inhibitor (Ruboxistaurin, Eli Lilly) showed it could reduce the risk of sustained,
moderate vision loss over a 3-year time period in patients with moderate, severe,
to very severe non-proliferative DR disease.
"In addition, the drug was able to improve the number of patients
with visual gain, specifically 3-line gainers with less decrease from baseline visual
acuity in those patients receiving the drug," explained Dr. Kaiser. He concluded
by saying the drug was being reviewed by the FDA.
Dr. Kuppermann discussed studies on these
2 drugs as agents for pharmacologic vitreolysis. Vitrase (purified ovine lyophilized
hyaluronidase, ISTA Pharmaceuticals) completed 2 large phase 3 studies assessing
its safety and efficacy for clearance of vitreous hemorrhage, but the 2 pivotal
studies did not result in the drug being approved for that indication. "While Vitrase
showed a clinical benefit in clearing vitreous hemorrhage in some eyes, the data
did not show statistical significance in its 2 individual trials for a variety of
complex reasons," explained Dr. Kuppermann.
Vitrase is currently approved as a spreading agent for retrobulbar
use, and is available as an off-label agent for intravitreal use. Dr. Kuppermann
also discussed the use of Vitrase to induce a posterior vitreous detachment in patients
with moderately severe non-proliferative diabetic retinopathy (PDR) in order to
decrease the risk of progression to proliferative diabetic retinopathy. However,
to date, only a pilot trial for this indication has been conducted with Vitrase.
Dr. Kuppermann also discussed the potential role of another agent
for enzymatic vitreolysis, plasmin. He reported that 3 types of plasmin were in
various stages of development autologous plasmin, pooled plasmin, and microplasmin.
Autologous plasmin is difficult to develop as a commercial product because it entails
using an affinity cartridge to extract the plasmin from the patients' blood. Dr.
Kuppermann saw either pooled plasmin (Bausch & Lomb) or microplasmin (ThromboGenics)
as the more likely plasmin-based future of therapeutic agents. Dr. Kuppermann explained
that pooled plasmin and microplasmin are being studied as surgical adjuvants for
vitrectomy surgery in ongoing trials, and other indications are being explored as
He also pointed out some other possible indications for both drugs.
"Future potential uses include the possibility of using vitreolytic agents such
as Vitrase and plasmin for floaters, as well as modifying or enhancing the efficacy
of other ophthalmic drugs," said Dr. Kuppermann.
Robert Avery, MD, discussed his off-label
use of bevacizumab for patients with PDR. He found the therapy to be useful in an
adjunctive role because of its ability to treat patients who cannot be fully treated
with panretinal photocoagulation or patients with DME and severe PDR. Dr. Avery
explained that bevacizumab was helpful for DME and PDR patients in preventing exacerbation
of their edema. He pointed out that the drug's efficacy and safety profile were
promising as well.
"It works at very low doses, and that may be in part because it
doesn't have to penetrate the retina to get where the disease is," stated Dr. Avery.
"The vessels in diabetes are on the surface of the retina, and are on the iris,
so there's no retinal penetration concern." He concluded by saying prospective trials
were needed, but he was "excited" to have another PDR treatment tool.
FEVR and ROP
Michael Trese, MD, presented on the pharmacologic
management if pediatric retinal vascular disease, specifically on the use of pegaptinib
sodium for blocking VEGF in familial exudative vitreoretinopathy (FEVR) and retinopathy
of prematurity (ROP). Dr. Trese reported that in his experience, pegaptanib sodium
reduces subretinal exudates in FEVR with repeat injection infrequently required.
However, there is evidence showing that preretinal neovascularization is less responsive
to therapy. In the treatment of ROP, pegaptanib sodium appears not to be as effective
for rescue therapy as originally thought, However, Dr. Trese said that anti-VEGF
therapy may be relative to the involution of tractional detachment cells and the
hyaloid and tunica vasculosa lentis, so earlier therapy with pegaptanib sodium may
have a favorable effect for ROP as an alternative to laser therapy, which destructs
two-thirds of the retina.
"We do think that further study is needed to look at both
maybe selective, but also non-selective blockage of VEGF-A, to see if that's something
which will improve our outcomes," said Dr. Trese.
RETINAL VASCULAR DISEASE
RVO and SCORE
In her discussion on the NEI-sponsored SCORE
study, Sharon Fekrat, MD, FACS, reviewed the 2005 Preferences and Trends (PAT) survey
results on how retinal specialists treat retinal venous occlusive diseases (RVO),
with the results being widely spread between grid pattern laser photocoagulation,
intravitreal triamcinolone injection, and a combination of both approaches, among
others. The SCORE study's goal is to assess the risks and the benefits of these
2 widely used therapies for RVO. Dr. Fekrat discussed several cases where triamcinolone
has shown promise and outlined the SCORE protocol and its entry criteria. The SCORE
study may indeed answer many unanswered questions about the use of intravitreal
triamcinolone in eyes with RVO, she concluded.
Bevacizumab for Retinal Vascular Disease
Dr. Rosenfeld reported several cases where
bevacizumab was used to treat retinal vascular disease with positive outcomes. Many
of the cases presented were patients who had undergone previous therapy with intravitreal
triamcinolone. Some of the patients responded well to triamcinolone but, because
of IOP rises, required alternative therapy. Not all the patients did well on bevacizumab
due to fluid persistence, and not all patients experienced visual acuity improvement
that correlated with the anatomic improvement after bevacizumab injections. Of the
treatment option for retinal vascular disease, Dr. Rosenfeld said, " We have limited
data available. The duration of effect is quite unpredictable, and usually, multiple
injections are necessary."
He added that he would still consider triamcinolone therapy better
for patients with risks associated with glaucoma and cataracts, as well as those
for whom frequent injections present a problem or for those who show fluid persistence
despite monthly injections with bevacizumab.
Editor's Note: Expanded coverage of the presentations
from the Second Annual RPS will be published in a special edition of Retinal
Physician, coming this November.
join us next year for Retinal Physician Symposium 2007, April 12-15, 2007 at Sanibel
Harbour Resort in Fort Myers, Fla. The Resort boasts all-new luxurious accommodations
embodying the essence of seaside grandeur. Please contact Heather Seasholtz, director
of the Conference Group at 215-643-8073 with any questions about the meeting.
Retinal Physician, Issue: September 2006