Por Steven Ferrucci, OD, Editorial Review
Board Miembro 15.05.2013
If your interests lie in macular and
vitreoretinal disease, then this year’s ARVO meeting surely did not disappoint.
For the first time, a full-day retina subspecialty symposium was held just
before ARVO—giving retinal specialists and general eye care practitioners an
additional opportunity to hear about the latest and greatest in retina from a
roster of world-renowned experts.
It was the perfect way to gear up for the many
sessions at ARVO that reviewed the constantly evolving landscape of treatments
and imaging technology and introduced new avenues of retinal research.
Attendees were eager to hear the long-awaited results of the Age-Related Eye
Disease Study 2 (See “ The Latest on AREDS2
at ARVO 2013."). Other hot topics this year included
the role of Eylea in age-related macular degeneration (AMD), the genetics of
AMD and several novel treatment approaches to AMD. Presentations also
highlighted a new retinal prosthesis that may offer help to patients with
retinitis pigmentosa (RP), as well as new ways to treat macula edema.
Retinal Prosthesis
It was a milestone
moment for retinal technology in February when the FDA approved the first
implanted device to treat adults with advanced RP. The Argus II Electronic
Retinal Prosthesis System (Second Sight Medical Products)—which has been
cleared in Europe since 2011—should be commercially available in the US later
this year. For now, it’s been granted “humanitarian use,” an approval pathway
limited to devices that treat or diagnose fewer than 4,000 people in the US
each year.
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The Argus II Implant (left) attaches to the retinal surface with a tack. The cable that both powers the chip and conducts the image signal from the episcleral housing is seen temporally. An early frame of a fluorescein angiogram (right) in a patient with the Argus II Implant demonstrates some persistent macular perfusion. Images: Elaine Leibenbaum, Julia Haller, MD, and Carl Regillo, MD.
A few studies evaluated this prosthesis, hopefully paving the way for its more widespread use. One study looked at the safety profile of 16 patients in Europe who had received the implant.1040/C0017 The patients were followed on average for 6.2 months, and reported no surgical or serious, device-related adverse effects. Ten patients experienced no surgery or device-related adverse events at all, whereas the other six reported minor adverse effects, such as IOP elevation, nausea, fainting, conjunctival irritation and a retinal tear.
A second study found that the Argus II implant has good long-term reliability, with only one failure in 30 subjects (each with an average of 4.2 years of use, representing more than 125 cumulative patient years).1037/C0014 Further, accelerated lifetime testing demonstrated that finished implants have more than a 10-year lifetime in accelerated testing. Another study confirmed these results, echoing previous tests that demonstrated the ability of the prosthesis to provide visual function over several years.349
Diabetic Retinopathy
Researchers evaluated 759 patients from
the RISE/RIDE Phase III trials to see if Lucentis (intravitreal ranibizumab,
Genentech) had an effect on the severity of a patient’s diabetic
retinopathy.4028 Results showed that a greater proportion of patients in the
ranibizumab arm had a two- or three-step regression of diabetic retinopathy on
the ETDRS scale vs. those in the sham group. A three-step improvement was
achieved at 36 months in 3.3% of the sham group, compared to 15.0% and 13.2% in
the 0.3mg and 0.5mg treated eyes, respectively. Over the course of 36 months,
33.9% of the sham-treated eyes developed proliferative diabetic retinopathy, as
opposed to only 12.8% and 15.1% of the ranibizumab-treated eyes.
Another study evaluated the safety and
efficacy of Macugen (intravitreal pegaptanib, OSI Pharmaceuticals Inc.)
combined with panretinal photocoagulation (PRP) vs. PRP alone in the regression
of retinal neovascularization in eyes with high-risk proliferative
disease.2439/C0140 At six months, the combination of pegaptanib with PRP showed
better preservation of best-corrected vision, greater decrease in retinal
thickness and maintained visual field better than PRP alone, but showed no
major difference in neovascular regression.
A second study of 30 patients compared
combination therapy of ranibizumab with PRP vs. PRP alone in treatment-naïve
proliferative diabetic retinopathy (PDR).5761/D0008 This study uncovered a
greater change in best-corrected vision, a larger decrease in central retinal
thickness and a lower incidence of vitreous hemorrhage in the combination
treated group––again suggesting that anti-VEGF agents in conjunction with PRP
may be preferred to PRP alone.
Additionally, a retrospective study of
78 patients seemed to indicate that metformin may reduce the rate of PDR in
type 2 diabetes patients.2249/C0150 In the non-metformin group, 15 patients
(45.5%) developed PDR as compared to just 12 patients (27.3%) in the
metformin-treated group, indicating a trend of less PDR in the
metformin-treated group. A larger study is recommended.
Macular Edema
Several studies are investigating
alternative approaches to treat macular edema––either secondary to diabetes or
vein occlusion. The MOZART study evaluated the safety and efficacy of an
intravitreal dexamethasone implant (Ozurdex, Allergan) in 59 patients with
visual impairment from diabetic macula edema (DME).2387/C0088 Investigators
noted that, over the six months, central retinal thickness was reduced and
acuity improved—28% of patients had 20/40 or better acuity vs. just 6% at
baseline. They observed IOP greater than 25mm in 7% of patients, with 4% of
patients developing cataracts. No endophthalmitis was reported.
A second study showed positive results
using a different intravitreal dexamethasone implant injection (DEX-I), with a
gain of more than 10 letters in 27% of cases at two months and 24% at four
months.2382/C0084 However, this study showed that recurrence of edema was
observed in 76% of cases at four months, leading to re-treatment in more than one-third of cases.
Diabetic macular edema, as confirmed by optical coherence tomography.
Another study
evaluated Ozurdex in patients with macular edema from vein occlusions. Forty
eyes were treated with Ozurdex and were followed for six to 24 months.254/D0099 Overall, 94% showed initial regression
on OCT, lasting an average of 4.2 months, with two lines of improvement.
Overall, 59% improved 14.2 letters on average, while 10% worsened and 31%
remained the same. Approximately 19% had elevated IOP and were treated with
drops. In eyes that were not previously treated, the results were even
better—86% showed improvement. Half of the patients required retreatment, with
an average of 1.6 treatments per year. The results seem to indicate that
Ozurdex may be an effective treatment in such patients––even those who did not
respond well to anti-VEGF agents.
Other research looked at the role of laser, as well as
anti-VEGF in combination with laser, in the treatment of macular edema. The
LLOMD study evaluated 15 eyes of 13 patients with reduced visual acuity
secondary to diabetic macular edema who had a mean VA of 20/100.2396/C0097 At six months, the mean VA gain was
12.6 ETDRS letters, with the central retinal thickness decreasing an average of
76.7µm in patients who received laser in combination with ranibizumab.
Additionally, 37.5% of patients required a second injection at six months.
However, with the addition of laser, the study showed that the number of
injections needed over the first year was greatly reduced compared to previous
studies of injections alone. In total, the researchers determined that
approximately 10 injections are needed during the first year. Further, they
concluded that adding macula grid laser to ranibizumab injection may reduce the
economic burden of treatment.
Two additional studies revealed that reduced-energy
focal macular photocoagulation could have advantages over traditional focal
macular laser. 2375/C0076,2416/C0117 Both seemed to indicate that, by
reducing the laser exposure when performing the procedure, there were decreases
in CRT and increases in vision––with potentially less collateral damage and
inflammation to surrounding viable tissue. More research is needed to
investigate whether reduced-energy focal macular photocoagulation could replace
more traditional laser therapy as the standard.
Eye
on Eylea
Several reports evaluated Eylea (aflibercept, Regeneron Pharmaceuticals), the
latest FDA-approved anti-VEGF agent for the treatment of wet AMD. A number of
these looked at the role of Eylea in patients whose choroidal
neovascularization did not respond to other agents, namely Lucentis
(ranibizumab, Genentech) and Avastin (bevacizumab, Genentech/Roche).
One study evaluated 41 eyes of 34 such patients—77% of
these patients had a good response to Eylea after one month, demonstrating
decrease in central retinal thickness and absorption of subretinal fluid.4176/A0094 Best-corrected visual acuity improved
in these patients to 20/74, from 20/122.5 at baseline.
A second study evaluated 60 eyes of 52 patients that
did not respond after five consecutive injections of the other agents.3806/B0116 After three Eylea injections, 28 eyes
(46.7%) displayed improved acuity, while 18 eyes (30%) showed decreased acuity,
and 14 (23.3%) had no change in acuity at three months.
Lastly, a study evaluated 19 eyes of 17 patients receiving
Eylea as primary therapy, with dosing as needed.3817/B0127 Over a 20-week period, patients
received on average 1.84 injections, with an interval between injections of
approximately 11 weeks. Five of these patients were determined to be
non-responders to other anti-VEGF agents. Of these five, four responded
positively to Eylea, indicating again that Eylea may be an effective
alternative for patients who do not respond to other agents. Also, this study
seems to indicate that the interval to repeat injections may be longer with
Eylea than the other agents.
However, a separate study looked at the costs
associated with Eylea.3838/B0148 The
researchers hypothesized that, despite fewer injections, the cost of treatment
per patient would actually increase. The study reviewed the records of 30
patients treated for wet AMD from 2011 to 2012 at the Cincinnati Eye Institute.
The average duration between Avastin or Lucentis injections was 29 days, as
opposed to 34 days with Eylea injections. No complications were noted in any
groups. Total cost over the six months was $3,700 for Avastin, $96,000 for
Lucentis and $366,300 for Eylea. This study suggests that while Eylea may
reduce the frequency of injections, office visits and possibly complications,
it appears to add considerable health care costs per patient.
New AMD Treatments
Several studies evaluated novel treatments for AMD. One study investigated the
safety and feasibility of an episcleral brachytherapy device (SMD-1) for wet
AMD.3787/B0097 Six
patients received radiation for five and a half minutes to the macular CNV
using a brachytherapy probe adjacent to the macular sclera via a subtenon
retrobulbar approach. Patients also received concomitant anti-VEGF injections,
as needed. The procedure was readily performed and well tolerated, with no
adverse effects. At three months, all patients experienced improved
best-corrected vision, with a mean gain of 19 ETDRS letters. At 12 months,
three patients continued to demonstrate improved vision of seven letters on
average, and two of those patients did not require any additional injections.
All patients had reduced macular thickness compared to baseline, but two
patients did demonstrate a reduction in vision.
Another study evaluated the
safety of 1% CLT-005 topical eye drops, designed to inhibit Stat3, which has
been associated with neovascular and inflammatory processes in animal studies.1716 The researchers determined that the
drug was able to deliver the active ingredient to the RPE/choroid in animal
eyes, without adverse effects—paving the way for additional studies regarding
its role in the treatment of AMD or geographic atrophy (GA).
Australian researchers looked
at the progression of early AMD after treatment with nanosecond pulse laser
compared to patients with a natural history of AMD.4146/A0064 They treated 48 patients with
bilateral high-risk AMD with ultra-low energy laser in 12 spots around the
macula of one eye. At 12 months, three of the 48 treated participants
progressed to GA, while seven of the 70 control group progressed. At 24 months,
four in the treated group and nine in the control groups progressed to GA,
suggesting that a single course of nanosecond laser intervention may
potentially reduce the odds of progression to advanced AMD. A larger randomized
controlled study is now underway.
Another study evaluated the
safety and tolerability of an extrafoveal subretinal injection called
rAAV.sFlt-1, an anti-VEGF gene therapy for AMD, in elderly patients.4504 Twelve patients underwent the
procedure with minor adverse effects and no evidence of local or systemic
toxicity. The researchers noted that this injection should be further evaluated
as a potential strategy for long-term anti-VEGF therapy.
Research continues on Emixustat HCL, a novel orally
administered agent in development for the treatment of GA associated with dry
AMD.4506 Emixustat HCL
is a rod visual cycle modulator that inhibits isomerase activity and reduces
retinal toxins, such as A2E, which damages the RPE and overlying
photoreceptors. Four dose levels and two dose regimens were examined in 72
patients who were followed for 90 days. No adverse systemic effects of concern
were noted, with just two patients experiencing treatment-related events. All
ocular adverse effects resolved upon drug cessation, and were mild with no
severe events observed. Results were encouraging, and a long-term Phase II
study in now underway to evaluate its role in GA patients.
Other studies looked at using existing therapy more
effectively. A team of researchers in Italy evaluated whether ketorolac eye
drops combined with ranibizumab intravitreal injections would provide
additional efficacy over ranibizumab alone in wet AMD.4175/A0093 Sixty eyes were divided into two
groups: one received ranibizumab alone, and one was treated with ranibizumab
plus ketorolac BID for six months. At the end of six months, there was no
statistically significant difference in best-corrected vision or number of
injections required. However, the mean six-month change in central macular
thickness was 146.53µm in the combination group, while the change was 106.88µm
in the ranibizumab-only group. This is the first study to identify an
additional effect of ketorolac eye drops combined with ranibizumab. More
studies would be needed before a change in current protocol would be
appropriate.
Two separate studies evaluated photodynamic therapy in
combination with anti-VEGF injections.4509,3790/B0100Both indicated
that this therapeutic combination might be an effective way of improving acuity
in patients with wet AMD, while perhaps reducing the overall number of
treatments needed. In one of the studies, 96.2% of eyes lost fewer than 15
letters, and 27.3% gained 15 or more letters.
Genetics
in AMD
Genetics in eye care have been garnering a lot of attention lately,
specifically the role of genetics in AMD.
One study evaluated data from the 100 Genomes Project
to confirm the contribution of known genetic risk factors for AMD.6166/C0051 This investigation revealed that, in
the population of European descent, CFH has the largest attributable risk
(25.6%), followed by ARMS 2 (22.5%), then C3 (9.1%) and CST3 (5.8%). In other
populations, the risk allele in ARMS2 is the major contributor to risk,
followed by CFH. In Asian and African populations, CST3 takes precedent over C3
as the third strongest contributor to AMD risk.
This patient is at high risk for AMD due to multiple confluent drusen in both eyes. Perhaps genetic testing could one day identify patients like this earlier.
In Spanish patients,
a study found that CFH and CB genes, combined with environmental risk factors
such as smoking and body mass index, were associated with an increased risk of
GA.6183/C0068 A second
abstract confirmed the role of CFH gene in AMD risk in a cohort of Brazilian
AMD patients.6175/C0060
In another study evaluating the genetic contribution
of AMD in 38 Armenian patients, researchers found no genetic differences in the
risk alleles compared to a Caucasian population.6196/C0081 All of this research indicates the
genetic factors that could influence the development or AMD may be very similar
across different groups.
Interestingly, some of these same studies seem to
suggest that the HDL-related CETP gene may be associated with AMD in African
Americans, pointing to a potential risk modifier in lipid pathways.6168/C0053
An abstract submitted by Johanna Seddon, MD, ScM,
identified three new genes that may add to the predictive power of risk models
for progression to advanced AMD.6178/C0063 They are the R1210c mutation in CFH,
and variants to the genes COL8A1 and RAD51B. She suggested that these new genes
will be useful for AMD surveillance in the future, along with genes that have
already been identified and established factors such as drusen size, baseline
AMD status, demographics and environmental factors (including smoking, age and
body mass index).
Additional studies attempted to see if there was a
link between genetic profile and response to treatment. One study evaluated the
genetic profile of 835 patients from the CATT (Comparison of AMD Treatment
Trial) trial to determine if certain genotypes responded better to treatment
than others.6187/C0072 Results
revealed there were no strong associations between the studied genotypes and response
to anti-VEGF treatment.
A second study evaluated the IVAN study and also was
unable to find any associations between genetic profiles and response to
anti-VEGF treatment.6185/C0070 However,
another study of 43 patients seemed to indicate that patients with high-risk
alleles for AMD responded more poorly to treatments than those with low-risk
alleles.6186/C0071
This link of genetic profiles to treatment response
may continue to be investigated, as this could bring us closer to personalized
treatment of AMD––based on genetic factors and other components.
| The Latest on AREDS2 at ARVO 2013 |
The Age-Related Eye Disease Study 2 (AREDS2) Research Team presented the results of the multi-center randomized, controlled clinical trial of oral supplementation with lutein/zeaxanthin (10mg/2mg) and/or omega-3 long-chain polyunsaturated fatty acids (1,000mg) for the treatment of AMD and cataract at the ARVO meeting.
Conducted at 82 clinical sites across the US from 2006 to 2012, the trial included 4,203 participants, ages 50 to 85. The AREDS2 subjects consented to either take the original AREDS formulation or a randomly assigned variation of the AREDS formulation.
The main outcome measurement was progression to advanced AMD, neovascular or central geographic atrophy. Progression to cataract surgery and progression of lens opacity was a secondary outcome.The addition of lutein and zeaxanthin, DHA and EPA, or both to the AREDS formulation in primary analysis did not further reduce the risk of progression to advanced AMD. However, because of increased incidence of lung cancer in former smokers, lutein with zeaxanthin may be an appropriate carotenoid substitute of beta-carotene in the original AREDS formulation.
The comparison of low-dose vs. high-dose zinc showed no evidence of a statistically significant effect, so a clinical recommendation cannot be reached. Lastly, daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss. It will take some time to digest these results and see how they should be implemented in practice.
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