Review of Ophthalmology's Retina Online

Volume 2, Number 11

November 2006

Contents:

		WELCOME

		THE LATEST PUBLISHED RESEARCH

		NOTEWORTHY: RESEARCHERS LOCATE ADDITIONAL GENE THAT INCREASES AMD SUSCEPTIBILITY; RUBOXISTAURIN REDUCED VISION LOSS IN PATIENTS WITH NON-PROLIFERATIVE DIABETIC RETINOPATHY; AND MORE 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

THE LATEST PUBLISHED RESEARCH

Bevacizumab for CNV Due to Pathological Myopia
The results of two studies published online prior to print suggest that intravitreal bevacizumab (Avastin) may be a safe and effective treatment for choroidal neovascularization (CNV) secondary to pathologic myopia.

In one of the studies, researchers reviewed a consecutive series of 11 eyes of nine pathologic myopia patients treated with 1.25 mg of bevacizumab at the New England Eye Center in Boston between August 2005 and January 2006. Three eyes received two injections, and eight eyes received one injection. Five of the 11 eyes had been treated previously with photodynamic therapy (PDT). Baseline visual acuity was 20/50 to 20/100 in six eyes and 20/200 or worse in five eyes. Mean follow-up was 153 days (35 to 224 days).

After treatment, visual acuity improved an average of 3.5 lines (1 to 8 lines), was 20/20 to 20/40 in seven eyes, 20/50 to 20/100 in one eye, and 20/200 or worse in three eyes. Mean central foveal thickness improved from 340 µm to 234 µm.

No endophthalmitis, cataract, retinal detachment, glaucoma or uveitis occurred.

In another study, a nonrandomized, interventional case series, a single 1-mg injection of bevacizumab was evaluated in eight eyes of eight patients. Three patients received a second injection up to two months after the first because CNV was still active. Two patients had received sub-Tenon’s injections of triamcinolone prior to the study.

Mean follow-up time was 4.4 months (three to seven months). The mean pre-treatment best-corrected visual acuity (BCVA) of 0.26 improved to 0.51 (p=0.009) at the last visit. BCVA improved by two or more lines in six eyes (75 percent) and remained the same in two eyes (25 percent).

Mean foveal thickness decreased from 198.4 +/-66.5 µm to 155.1 +/-74.6 µm (p=0.027). Mean CNV size decreased from 0.72 +/-0.78 disc areas to 0.64 +/-0.73 disc areas (p=0.049). In five eyes (62.5 percent) CNV size decreased. In three eyes (37.5 percent) it remained the same. CNV size decreased in four of the five eyes (80 percent) with areas of CNV smaller than 0.5 disc areas and in one of the three eyes (33.3 percent) with a larger area of CNV.

No infectious endophthalmitis, vitreous hemorrhage or retinal detachment occurred.

Source: Yamamoto I, Rogers AH, Reichel E, et al. Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularization secondary to pathologic myopia. Br. J. Ophthalmol published online 26 Jul 2006; doi:10.1136/bjo.2006.096776. Sakaguchi H, Ikuno Y, Gomi F, Kamei M, et al. Intravitreal injection of bevacizumab for choroidal neovascularization caused by pathological myopia. Br. J. Ophthalmol published online 16 Aug 2006; doi:10.1136/bjo.2006.099887.

Final CAPT Results Published
Final results from the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) showed that low-intensity green laser treatment does not prevent visual acuity loss in patients with bilateral large drusen. The randomized, 22-center trial involved 1,052 patients with 10 or more large (>125 µm) drusen and 20/40 or better visual acuity in each eye. One eye of each patient was assigned to laser treatment, and the contralateral eye was assigned to observation.

As initial treatment, patients received 60 barely visible burns in a grid pattern within an annulus between 1,500 and 2,500 µm from the center of the macula. Fifteen burns were applied in each quadrant. Additional treatment was performed at 12 months if 10 or more large drusen within 1,500 µm of the foveal center remained. Retreatment consisted of 30 burns in the 1,000 to 2,000 µm annulus centered on the fovea, and drusen were treated directly. If all drusen within the annulus could be treated with fewer than 30 burns, the remainder of the burns was applied evenly within the treatment annulus, avoiding retinal vessels and previous burns.

At five years, 188 (20.5 percent) treated eyes and 188 (20.5 percent) observed eyes lost at least three lines of visual acuity from baseline (p=1.00). The rate of CNV was the same (13.3 percent) among treated and observed eyes (p=0.95). The rate of geographic atrophy was 7.4 percent among treated eyes and 7.8 percent among observed eyes (p=0.64). Contrast threshold doubled in 23.9 percent of treated eyes and in 20.5 percent of observed eyes (p=0.40). Critical print size doubled in 29.6 percent of treated eyes and in 28.4 percent of observed eyes (p=0.70). Seven treated eyes and 14 observed eyes lost six or more lines of visual acuity in the absence of late age-related macular degeneration (AMD) or cataract.

Sources: Complications of Age-Related Macular Degeneration Prevention Trial Research Group. Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial. Ophthalmology 2006;113:1974-1986.

One-Year Results from FOCUS Study Published
According to results from the FOCUS study, at one year, ranibizumab (Lucentis) plus PDT was more effective than PDT alone for treating predominantly classic CNV associated with AMD. In the Phase I/II, multicenter, randomized, single-masked, controlled study, patients received monthly 0.5-mg injections of ranibizumab (n=106) or sham (n=56) injections. PDT was performed seven days prior to the initial injection and then quarterly as needed.

At one year, 90.5 percent of patients treated with ranibizumab lost fewer than 15 letters of visual acuity compared with 67.9 percent of patients treated with PDT alone (p<.001). Intraocular inflammation was the most frequent serious ocular adverse event associated with ranibizumab, occurring in 11.4 percent of patients. (The proportion of patients experiencing inflammation decreased after a protocol change.) On average, patients with serious inflammation had better visual acuity outcomes at one year than did controls. Endophthalmitis occurred in 1.9 percent of patients treated with ranibizumab (4.8 percent including presumed cases). Serious nonocular adverse events included myocardial infarctions in the PDT-alone group (3.6 percent) and cerebrovascular accidents in the ranibizumab-treated group (3.8 percent). FOCUS is a two-year study.

Source: Heier JS, Boyer DS, Ciulla TA, et al. for the FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration year 1 results of the FOCUS study. Arch Ophthalmol 2006;124:1532-1542.

One-Year Results with an Implantable Telescope for End-Stage AMD
The results of a prospective, open-label, multicenter clinical trial showed that an implantable telescope can improve visual acuity and quality of life in patients with moderate to profound visual impairment caused by bilateral, end-stage AMD (untreatable geographic atrophy, disciform scars or both). A total of 217 patients with 20/80 to 20/800 visual acuity were enrolled in the study. The telescope was implanted in one eye, and the fellow eye served as the control.

At one year, mean best-corrected distance visual acuity (BCDVA) improved by 3.5 lines in implanted eyes compared with 0.8 lines in control eyes (p<0.0001). Mean best-corrected near visual acuity (BCNVA) improved by 3.2 lines in implanted eyes compared with 1.8 lines in fellow eyes (p<0.0001). An improvement of three or more lines in BCDVA was seen in 67 percent of implanted eyes compared with 13 percent of controls (p<0.0001). An improvement of three or more lines in both BCDVA and BCNVA was seen in 53 percent of implanted eyes compared with 10 percent of fellow eyes (p<0.0001). Mean NEI VFQ-25 scores improved by more than seven points from baseline (p<0.01) on seven of eight relevant subscales.

The implantation procedure was aborted in 11 eyes. Reduction in endothelial cell density (ECD) was 25 percent at one year, which exceeded the 17 percent defined end point. However, beyond three months after implantation, the rate of ECD change decreased and was similar to changes in pseudophakic fellow eyes.

Source: Hudson HL, Lane SS, Heier JS, et al. Implantable miniature telescope for the treatment of visual acuity loss resulting from end-stage age-related macular degeneration: 1-year results. Ophthalmology 2006;113:1987-2001.

Intravitreal Triamcinolone for Macular Edema Due to CRVO
The authors of two different papers on intravitreal triamcinolone acetonide for macular edema secondary to central retinal vein occlusion (CRVO) reached a similar conclusion: Visual acuity gains following the treatment appear to be transient. Both studies were retrospective reviews.

One of the studies, at Bascom Palmer Eye Institute, involved 40 eyes of 40 patients with a three-month median duration of symptoms. At baseline, median visual acuity was 20/400. It improved to 20/300 at one month and three months. At one year it was 8/200 (p=0.569; n=17). Acuity improved by three or more lines in 21 percent of eyes at one month, 27 percent at three months, 14 percent at six months, and 12 percent at one year. Visual acuity was unchanged from baseline in 71 percent of eyes at one year. The mean number of injections given was 1.6, with half of the eyes receiving more than one.

Overall, intraocular pressure increased by 10 mmHg or more in 24 percent of eyes at one year. Trabeculectomy was performed for two of 12 eyes, which had pre-existing open-angle glaucoma.

Another study involved 29 eyes of 29 patients and had a mean follow-up time of 348 days. Median visual acuity was 20/250 at baseline and 20/125 three months after injection. Final median acuity, not statistically significant, was 20/250. Five of 22 patients experienced elevated intraocular pressure (excluding that related to neovascularization). The authors characterized the risk of glaucoma as significant, and noted that a subgroup analysis indicated that patients who received multiple injections had better outcomes.

Source: Gregori NZ, Rosenfeld PJ, Puliafito CA, et al. One-year safety and efficacy of intravitreal triamcinolone acetonide for the management of macular edema secondary to central retinal vein occlusion. Retina 2006;26(8):889-895. Goff MJ, Jumper JM, Yang SS, et al. Intravitreal triamcinolone acetonide treatment of macular edema associated with central retinal vein occlusion. Retina 2006;26(8):896-901.

Anecortave Acetate Monotherapy Ineffective Against RAP
In a pilot study of anecortave acetate for the treatment of RAP, the therapy reduced capillary permeability, but neovascularization progressed and vision declined significantly. Thirty-four patients with RAP and any stage of neovascularization were randomized 1:1:1 to treatment with three different doses of anecortave: 30 mg, 15 mg and 3 mg. Treatments were administered juxtasclerally. A six-month retreatment interval was established with a follow-up of 12 months.

In all eyes, detachment of the neurosensory retina and retinal pigment epithelium improved, but lesion size increased. Vision loss occurred in 22 of the 34 eyes (64.7 percent) independent of the drug concentration administered. The investigators wrote that, like other monotherapies used to treat RAP, anecortave acetate alone does not appear to be beneficial, and future studies should evaluate combination therapies.

Source: Klais CM, Eandi CM, Chiara M, et al. Anecortave acetate treatment for retinal angiomatous proliferation: a pilot study. Retina 2006;26(7):773-779.

NOTEWORTHY: RESEARCHERS LOCATE ADDITIONAL GENE THAT INCREASES AMD SUSCEPTIBILITY; RUBOXISTAURIN REDUCED VISION LOSS IN PATIENTS WITH NON-PROLIFERATIVE DIABETIC RETINOPATHY; AND MORE ITEMS OF INTEREST

Researchers Locate Additional Gene that Increases AMD Susceptibility
Researchers have identified a potential new pathway in the pathogenesis of AMD. Genotyping 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah, they discovered that a single-nucleotide polymorphism (rs11200638) in the promoter region of HTRA1 is the most likely causal variant for AMD at chromosome 10q26. They estimated that the variant confers a population attributable risk of 49.3 percent.

The researchers reported that a preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients showed that the risk allele was associated with elevated expression of HTRA1 mRNA and protein. In addition, drusen in eyes with AMD were strongly immunolabeled with HTRA1 antibody.

The HTRA1 gene encodes a secreted serine protease and appears to regulate the degradation of extracellular matrix proteoglycans. This activity is thought to facilitate access of other degradative matrix enzymes to their substrates. Therefore, overexpression of HTRA1 may alter the integrity of Bruch’s membrane. HTRA1 also binds and inhibits transforming growth factor-b (TGF-b), a regulator of extracellular matrix deposition and angiogenesis.

Source: Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992. DOI: 10.1126/science.1133811.

Ruboxistaurin Reduced Vision Loss in Patients with Non-Proliferative Diabetic Retinopathy
Eli Lilly announced results from a three-year, Phase III clinical trial of ruboxistaurin mesylate (proposed brand name Arxxant) for the treatment of moderate to severe nonproliferative diabetic retinopathy. Once-daily, oral ruboxistaurin is designed to limit the overactivation of protein kinase C beta.

The multicenter, 36-month, placebo-controlled, double-masked trial randomized patients at 70 sites to placebo (n=340) or 32 mg per day of ruboxistaurin (n=340). Ruboxistaurin reduced the risk of sustained moderate vision loss (SMVL) by 40 percent compared with placebo. SMVL, defined as a three-line loss sustained for at least six months, occurred in 5.5 percent of treated patients and 9.1 percent of patients receiving placebo (p=0.034). Baseline-to-endpoint visual improvement of greater than or equal to 15 letters was more frequent (4.9 percent vs. 2.4 percent), and greater than or equal to 15 letters of decline was less frequent (6.7 percent vs. 9.9 percent) in ruboxistaurin-treated patients compared with placebo (p=0.005). The benefits of ruboxistaurin were not accompanied by a reduction in the progression from nonproliferative to proliferative disease.

Patient discontinuations due to adverse events were not statistically different between groups. There were 36 patient deaths, none of which were related to the study drug. The company plans to appeal a request from the Food and Drug Administration for an additional Phase III clinical trial.

Source: Eli Lilly and Co., November 2006.

OSI to Exit Eye Business
OSI Pharmaceuticals plans to exit its eye disease business--pegaptanib sodium (Macugen) for the treatment of neovascular AMD--via out-licensing, partnering or an outright sale. The company said it believes that the product’s profile, its induction/maintenance treatment strategy and promising data in the diabetic retinopathy area will ultimately result in a meaningful place for pegaptanib in the treatment of retinal disease. OSI and marketing partner Pfizer intend to continue to support the brand commercially. Pfizer plans to evaluate its response to OSI’s announcement based on the needs of patients and physicians on a region-by-region basis.

Source: OSI Pharmaceuticals Inc., November 2006.

Eye Protein Responsible for Stopping Angiogenesis
Jayakrishna Ambati, MD, of the University of Kentucky, and Balamurali Ambati, MD, of the Medical College of Georgia, have discovered that a protein known as SFLT-1 is singularly responsible for warding off blood vessel growth in the cornea, an attribute that could make it the basis for new AMD and cancer treatments. Their research, published in the journal Nature, shows that when SFLT-1 is deactivated, angiogenesis begins and blood vessels spontaneously invade the cornea. The next step, according to the researchers, is to test the protein in other areas of the body, encouraging tissues to produce it on their own. "We want to know what it is in the cornea that produces so much of this protein which inhibits angiogenesis," said Jayakrishna. "With that knowledge we will be closer to fighting the growth of everything from vision-obscuring blood vessels in the eye to cancers."

Source: University of Kentucky News, October 2006.

Trial to Assess Eye Drop for Steroid-Associated IOP Increase
pSivida Limited has initiated a Phase II clinical trial of mifepristone (RU486) as an eye drop treatment for steroid-associated elevated intraocular pressure (IOP). The trial, which will involve up to 45 patients in the United States, will investigate the use of mifepristone as a means to prevent elevation of IOP from intraocular steroid exposure. Mifepristone is an FDA-approved steroid receptor antagonist. This study represents a potential new use of the drug, made possible by a new delivery system.

Source: pSivida Ltd., September 2006.

FDA Approves Spectral Domain OCT Instrument

Arterial occlusion and embolus captured on the new Spectralis HRA+OCT from Heidelberg Engineering, a simultaneous fluorescein angiograph and spectral domain optical coherence tomography instrument.

Heidelberg Engineering has received Food and Drug Administration approval to market the Spectralis HRA+OCT, the world’s first commercial spectral domain optical coherence tomography (OCT) instrument combined with laser angiography. The instrument captures high-resolution cross-sectional images of the retina with any of four imaging modalities: autofluorescence, infrared, fluorescein angiography, or ICG angiography. It scans the retina 100 times faster (40,000 scans per second) than existing time domain OCT instruments and allows the clinician to correlate the outer visible retina structure with the internal structure. The company expects to begin shipping the product in mid-2007.

Source: Heidelberg Engineering, November 2006.

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