Volume 4, Number 3
March 2008



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: ONE-YEAR COHORT 1 RESULTS FROM SAILOR TRIAL PRESENTED; CATT TRIAL BEGINS; AND OTHER ITEMS OF INTEREST






WELCOME

Welcome to Review of Ophthalmology’s Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

In this edition:
The latest published research
Noteworthy, items of interest

Table of Contents





THE LATEST PUBLISHED RESEARCH

AMD Linked to Mortality from Cardiovascular Disease or Stroke
Recently published data suggest age-related macular degeneration may independently predict stroke or coronary heart disease. Researchers at the University of Sydney, Australia, prospectively assessed the relationship between AMD and risk of stroke- or cardiovascular-related death in an Australian population.

Of 3,654 baseline participants (1992 to 1994) older than 49 years, 2,335 were re-examined after five years and 1,952 were re-examined after 10 years. Investigators graded retinal photographs using the Wisconsin System and consulted history and relied on physical examination data for possible risk factors. They confirmed deaths and causes of death by data linkage with the Australian National Death Index. Risk ratios (RR) were estimated in Cox models.

Among participants younger than 75 at baseline, early AMD predicted a doubling of cardiovascular mortality over the next decade (RR, 2.32; 95 percent confidence interval (CI), 1.03 to 5.19), after controlling for traditional cardiovascular risk factors. Late AMD predicted a fivefold higher cardiovascular mortality (RR, 5.57; CI, 1.35 to 22.99) and a ten fold higher stroke mortality (RR, 10.21; CI, 2.39 to 43.60) after adjusting for age and gender only. These associations were not present when participants older than 75 were included.

The study results showed that AMD predicted stroke and cardiovascular events over the long term in people aged 49 to 75. The authors believe these findings may have potential implications for new intravitreal anti-VEGF AMD therapies.

Source: Tan JS, Wang JJ, Liew G, et al. Age-related macular degeneration and mortality from cardiovascular disease or stroke. Brit J Ophthalmol 2008; Feb 29 [Epub ahead of print].


Genotypes Associated with Different Responses to Treatment with Intravitreal Bevacizumab
Researchers from the Washington University School of Medicine in St. Louis conducted a retrospective cohort study to determine whether an association exists between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab (Avastin) for neovascular AMD.

The study involved 86 patients under treatment for neovascular AMD with bevacizumab alone. Researchers performed genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms using allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at six-week intervals until choroidal neovascularization (CNV) was no longer active. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography and Snellen visual acuity was measured before and after treatment.

For the CFH Y402H polymorphism, patients with the CFH TT genotype (n=10) had the largest choroidal neovascular lesions. With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype (n=57), but it fell from 20/206 to 20/341 for the CFH CC genotype (n=19). Only 10.5 percent of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7 percent of CFH TT and TC genotypes. For the LOC387715 A69S variant, patients with the TT genotype (n=15) had the largest choroidal neovascular lesions. There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype.

The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. The authors suggest that prospective studies to confirm or refute this observation be considered.

Source: Brantley MA Jr., Fang AM, King JM, et al. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 2007;114:2168-73.


Effect of Triamcinolone on VEGF and Endostatin in CNV
After extracting and staining samples from 55 patients with CNV secondary to AMD, a group of researchers reported that triamcinolone acetonide monotherapy seems to inhibit CNV by enhancing endostatin expression rather than by suppressing VEGF expression.

Four groups of patients were involved in their retrospective review of an interventional series. Eleven were treated with 4 mg of intravitreal triamcinolone (n=5, triamcinolone-treated CNV group) or with PDT and triamcinolone (n=6, PDT-triamcinolone-treated CNV group) three to nine days before surgery. Forty patients who underwent CNV extraction without previous therapy (control CNV group) and four patients who underwent CNV extraction three days after PDT (PDT CNV group) served as controls.

Compared with the control CNV samples, VEGF expression was stronger in the PDT CNV samples (p<.001), triamcinolone CNV samples (p=.01) and PDT-triamcinolone CNV samples (p=.007). No statistically significant differences in VEGF expression were seen among the PDT CNV samples, triamcinolone CNV samples and PDT-triamcinolone CNV samples. Endostatin expression was weaker in the PDT CNV samples than it was in the control CNV samples (p=.008). Endostatin expression was stronger in the triamcinolone CNV samples and the PDT-triamcinolone CNV samples compared with the control CNV samples (p=.001 and p<.001, respectively) and the PDT CNV samples (p<.001 for both).

Sources: Tatar O, Shinoda K, Kaiserling E, et al. Early effects of triamcinolone on vascular endothelial growth factor and endostatin in human choroidal neovascularization. Arch Ophthalmol 2008;126:193-199.


OCT Measurement Repeatability in Wet AMD
According to a recent study, optical coherence tomography (OCT)-derived retinal thickness measurements are subject to considerable measurement variability in patients with neovascular AMD. Therefore, the authors of the study paper concluded, changes in central macular thickness of more than 50 µm may more accurately reflect true clinical change in scan sets without significant segmentation error.

To test measurement repeatability, an operator certified for clinical trial work used the Stratus OCT instrument to acquire two fast macular thickness map protocol scans sets from 51 eyes of 51 consecutive patients. Coefficients of repeatability for nine Early Treatment of Diabetic Retinopathy Study-like regions, foveolar center-point retinal thickness and total macular volume were calculated. Two observers analyzed the scans for errors in retinal boundary placement, and revised coefficients of repeatability were calculated after exclusion of any scan sets with significant segmentation error.

The coefficient of repeatability for the central 1-mm macular subfield was 67 µm (23 percent) and was less than 75 µm for all macular subfields. There was much larger variability in the center-point thickness measure, with a coefficient of repeatability of 88 µm (32 percent) for the automated center-point thickness. After excluding nine scan set pairs with significant segmentation error, the coefficient of repeatability for the central 1-mm macular subfield was reduced to 50 µm (19 percent).

Source: Patel PJ, Chen FK, Ikeji F, et al. Repeatability of stratus optical Coherence tomography measures in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49:1084-1088.


SD-OCT Provides New View of Vitreomacular Traction and Idiopathic ERM
An analysis of vitreomacular interface abnormalities utilizing spectral domain OCT with 3-D image reconstruction resulted in unprecedented views of vitreomacular traction (VMT) and idiopathic epiretinal membrane (ERM). It also showed significant overlap between the two conditions. Forty-eight eyes of 35 patients with VMT or idiopathic ERM were investigated.

Focal VMT (diameter of vitreous attachment 1,500 µm or less) was observed in five eyes, and broad VMT (diameter of vitreous attachment more than 1,500 µm) was observed in seven eyes. Of these 12 eyes, concurrent ERMs under the detached vitreous were seen in 10 eyes, and zones of hyperreflectivity affecting the adjacent detached posterior hyaloid face were seen in 11 eyes.

Eyes with focal VMT showed a foveal cavitation, whereas eyes with broad VMT had more widespread cystoid macular edema. Idiopathic ERM was seen in 36 eyes. Thirty had complete posterior vitreous detachment; five had partial PVD associated with attached posterior hyaloid at some peripheral portion of the ERM; and one had no PVD.

Source: Koizumi H, Spaide RF, Fisher YL, et al. Three-dimensional evaluation of vitreomacular traction and epiretinal membrane using spectral-domain optical coherence tomography. Am J Ophthalmol 2008;145:509-517.

ICG with ILM for Macular Hole Appears to Adversely Affect Outcomes
A meta-analysis of the literature indicated that functional outcomes were worse when intravitreal indocyanine green was used with peeling of the internal limiting membrane in the treatment of macular hole.

Researchers conducted a PubMed search spanning January 1999 to June 2004, and resulting manuscripts included 837 eyes and all types of macular hole. The statistical analysis included studies that defined anatomic outcomes as closure of the hole and disappearance of the fluid cuff and functional outcomes as improvement of two or more lines of Snellen visual acuity. The incidence of retinal pigment epithelium alterations with and without ICG staining was also analyzed.

The same anatomic success, but worse functional outcomes, occurred when ICG was part of the procedure (p=0.0008; odds ratio 0.587, 95 percent CI 0.427-0.808). Also, the incidence of RPE alterations was found to be 1.98 percent, while RPE changes were noted in 13.83 percent of 201 patients with ICG application (odds ratio 7.998).

Source: Rodrigues EB, Meyera CH. Meta-analysis of chromovitrectomy with indocyanine green in macular hole surgery. Ophthalmologica 2008;222:123-129.

Daclizumab for the Treatment of Birdshot Chorioretinopathy
In a retrospective review of the medical records of eight patients with birdshot chorioretinopathy (BSCR) refractory to traditional immunomodulatory therapy (IMT), daclizumab effectively stabilized vision and decreased inflammation. Daclizumab is a humanized monoclonal antibody to the IL-2Rα of T cells.

All of the patients received daclizumab intravenously at two-week intervals initially at one referral uveitis practice. During a mean follow-up time of 25.6 months, seven patients had either stabilization or improvement of visual acuity in both eyes and complete resolution of vitreous inflammation. Six patients had resolution of vasculitis on fluorescein angiography. Four patients were able to discontinue all other IMT and remain inflammation-free while receiving daclizumab. Two patients developed adverse effects that led to discontinuation of daclizumab treatment.

The authors of the study paper noted that electroretinogram parameters continued to decline in some patients despite adequate control of inflammation. They also pointed out that regular serologic monitoring is crucial for detecting adverse events.

Source: Sobrin L, Huang JJ, Christen W, et al. Daclizumab for treatment of birdshot chorioretinopathy. Arch Ophthalmol 2008;126:186-191.

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NOTEWORTHY: ONE-YEAR COHORT 1 RESULTS FROM SAILOR TRIAL PRESENTED; CATT TRIAL BEGINS; AND OTHER ITEMS OF INTEREST

One-Year Cohort 1 Results from SAILOR Trial Presented
At Bascom Palmer Eye Institute’s Angiogenesis 2008 meeting, David S. Boyer, MD, presented the one-year Cohort 1 results from the Phase IIIb SAILOR clinical trial. SAILOR is a one-year study designed to evaluate the safety of two different doses of ranibizumab (Lucentis, 0.3 mg and 0.5 mg) for the treatment of all subtypes of new or recurrent active neovascular AMD. Treatment was administered once a month for three months and thereafter as needed based on specific criteria. SAILOR is the largest randomized clinical trial ever conducted in wet AMD, involving approximately 4,300 patients. (Cohort 1 included 2,378 patients.)

The one-year Cohort 1 results support the long-term safety of ranibizumab. The FDA-approved dose (0.5 mg) was not associated with the higher rate of stroke observed during the planned interim analysis at six months. The interim analysis was preliminary and based on a limited number of patients and follow-up data.

The latest data suggested a trend toward a higher incidence of stroke in the 0.5-mg dose group (1.2 percent vs. 0.7 percent in the 0.3-mg group), but the results were not statistically significant (p=0.21). At one year, patients with a prior history of stroke had a higher rate of stroke in the 0.5 group (9.6 percent) compared to the 0.3 group (2.7 percent). However, this trend was inconclusive because the number of events was small. The data are consistent with epidemiologic data showing that prior history of stroke predisposes patients to subsequent stroke. Rates of ocular and nonocular serious adverse events at one year were similar in patients receiving either dose and consistent with previous studies.

Final efficacy results from Cohort 1 of the SAILOR trial were as follows:

The one-year efficacy data suggested that treating patients with ranibizumab on an as-needed basis may be less effective than monthly dosing. Results from Cohort 2 are expected later this year.

Source: Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, February 2008.


CATT Trial Begins
The National Eye Institute announced the start of the multicenter clinical trial comparing the relative safety and effectiveness of ranibizumab and bevacizumab for the treatment of wet AMD. The trial, called Comparison of AMD Treatments Trials (CATT), involves 1,200 patients at 47 clinical centers across the country.

Patients will be treated with either:
• ranibizumab once every four weeks for one year, with random assignment in the second year to either an injection of ranibizumab every four weeks or on a variable schedule depending on response to treatment
• injection of bevacizumab once every four weeks for one year, with random assignment in the second year to either an injection of bevacizumab every four weeks or on a variable schedule depending on response to treatment
• injection of ranibizumab on a variable schedule
• injection of bevacizumab on a variable schedule.

The primary outcome measure will be change in visual acuity. Secondary outcome measures will include number of treatments, anatomical changes in the retina, adverse events and cost.

Source: National Institutes of Health, National Eye Institute, February 2008.


Enrollment Complete for Phase I Study of Retinal Prosthesis
Second Sight Medical Products has completed enrollment for the first phase of a U.S. FDA-approved clinical study of the Argus II Retinal Prosthesis System. The Argus II is the second generation of an electronic retinal implant designed for the treatment of blindness due to retinitis pigmentosa. The implant consists of an array of 60 electrodes that are attached to the retina. The electrodes conduct information acquired from an external camera to the retina to provide a rudimentary form of sight.

Ten subjects have been recruited for the Phase I trial at four leading U.S. ophthalmic centers. According to Second Sight, this three-year Investigational Device Exemption trial is the only long-term study of a retinal prosthesis currently being conducted anywhere in the world.

Source: Second Sight Medical Products Inc., February 2008.


Stem Cell-Laser Treatment for AMD to be Studied
Stemedica Cell Technologies, a manufacturer of adult stem cells, has entered into a collaboration agreement with Lumenis to implement a first-of-its-kind, comprehensive clinical study for the treatment of AMD using Stemedica’s MCT (Multiple Cell Technology) adult stem cells and the Lumenis SRT (selective retina therapy) Laser. The clinical study will be conducted at the Fyodorov Eye Institute in Moscow, which is regarded as a global leader in treating ocular diseases. A parallel study will occur at Hospital Angeles in Tijuana.

Source: Stemedica Cell Technologies, January 2008.


Antibody Fragment Reaches Retina, Choroid with Topical Delivery
ESBATech AG, a Switzerland-based, privately held drug discovery and development company, announced that several independent preclinical in vivo tests showed its antibody fragment, ESBA105, to be capable of reaching high concentrations in all segments of the eye with topical delivery via eyedrops. Anticipated therapeutic concentrations were observed in the anterior chamber and posterior segment, including the vitreous, retina and choroid. ESBA105 is a TNFa antagonist scheduled to enter clinical development later this year.

For more information, visit esbatech.com.

Source: ESBATech AG, February 2008.


Topical NSAID Tested in Combination with Ranibizumab for AMD
ISTA Pharmaceuticals released results from a retrospective case control series evaluating bromfenac ophthalmic solution 0.09% (Xibrom) therapy in combination with ranibizumab injection in patients with neovascular AMD.

The study results were gathered from 60 patients receiving ranibizumab therapy for wet AMD. Thirty of the patients received bromfenac twice daily in addition to their ranibizumab injections, and their results were compared to those of 30 patients who received only ranibizumab. Patients who received bromfenac required 1.6 +/-0.69 injections of ranibizumab during the six-month study period, while patients who received only ranibizumab received 4.5 +/-0.41 injections. Patients receiving ranibizumab alone received significantly more (2.83 times) injections (p=0.0002) than those receiving the combination. There was a numerical trend in favor of the combination treatment group on improvement in visual acuity, but this difference did not achieve statistical significance. No adverse events were associated with the extended topical administration of bromfenac. Calvin A. Grant, MD, conducted the study.

Source: ISTA Pharmaceuticals, February 2008.

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