Volume 3, Number 3
March 2007



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: FEASIBILITY STUDIES EVALUATE RADIATION DEVICE FOR AMD; NEW DATA ON EYE DROP FOR AMD; 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

Table of Contents










THE LATEST PUBLISHED RESEARCH

Triple Therapy for AMD Produces Favorable Results
In a prospective, noncomparative, interventional case series, triple therapy with verteporfin (Visudyne) photodynamic therapy (PDT), dexamethasone and bevacizumab (Avastin) resulted in significant and sustained visual acuity improvement in patients with choroidal neovascularization secondary to age-related macular degeneration.

All 104 patients in the study initially received one triple therapy cycle, which included reduced light dose PDT followed approximately 16 hours later by intravitreal injections of bevacizumab and dexamethasone. Five patients received a second triple therapy cycle for persistent CNV activity, and 18 patients received an additional bevacizumab injection. Patients were examined every six weeks, and mean follow-up time was 40 weeks (22-60).

Mean visual acuity increased by 1.8 lines (p<0.01), and mean retinal thickness decreased by 182 µm (p<0.01). No serious adverse events occurred.

Source: Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007;27:133-140.

Bevacizumab for Macular Edema Due to Ischemic Vein Occlusion
A prospective, open-label study evaluated intravitreal injection of bevacizumab (2.0 mg/0.08 mL) at 12-week intervals for the treatment of macular edema associated with ischemic central or hemicentral retinal vein occlusion. The study involved seven eyes of seven patients. Patients were examined at weeks one, six and 12 after each injection. Six patients completed 25-week follow-up.

At the last follow-up visit, compared with baseline, mean logMAR best-corrected visual acuity in the affected eye improved from 1.21 to 0.68. No patient experienced a decrease in BCVA. Mean central macular thickness improved from 730.1 µm to 260.3 µm, and mean total macular volume improved from 17.1 mm3 to 9.0 mm3. Based on optical coherence tomography imaging, macular edema tended to recur between six and 12 weeks after injection. The authors of the study also reported that the most common adverse events were injection-site conjunctival hyperemia and subconjunctival hemorrhage.

Sources: Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab (Avastin) for central and hemicentral retinal vein occlusions: IBeVO Study. Retina 2007;27:141-149.

Bevacizumab for Refractory Idiopathic CNV
In a noncomparative, interventional case series, treatment with intravitreal bevacizumab improved BCVA in eyes with idiopathic CNV that had not resolved after more than one triamcinolone injection over at least three months.

BCVA was measured before and one and three months after a single injection of bevacizumab (1 mg). Improvement in BCVA achieved among the 10 eyes at one month (p=.029) after bevacizumab treatment was maintained at three months (p=.003). Mean visual acuity improved from 0.46 to 0.69. Five of the 10 eyes had improved vision. Also at three months, central retinal thickness decreased significantly (p<.001), and CNV leakage stopped in seven eyes and decreased in two eyes.

Follow-up ranged from five to 12 months. A second bevacizumab injection was given in eyes with remaining leakage. Six eyes received only one injection during the follow-up period. One patient experienced conjunctival swelling after one injection, which did not recur following the next injection.

Source: Gomi F, Nishida K, Oshima Y, et al. Intravitreal bevacizumab for idiopathic choroidal neovascularization after previous injection with posterior subtenon triamcinolone. Am J Ophthalmol 2007;143:507-509.

OCT Correlation with Visual Acuity in DME
To compare OCT-measured retinal thickness and visual acuity in eyes with diabetic macular edema, the Diabetic Retinopathy Clinical Research Network enrolled 251 eyes of 210 patients in a randomized, cross-sectional, longitudinal study. Researchers measured retinal thickness on OCT and visual acuity using the electronic Early Treatment of Diabetic Retinopathy procedure both before and after macular laser photocoagulation.

They reported the following correlation coefficients: 0.52 at baseline; 0.49 at 3.5 months after laser treatment; 0.36 at eight months post-laser; and 0.38 at 12 months post-laser. The correlation between change in visual acuity and change in OCT center point thickening 3.5 months after laser treatment was 0.44, with no important difference at the other follow-up times. Some eyes showed paradoxical improvement in visual acuity with increased center point thickening or vice versa.

Based on the results, the researchers concluded that OCT-measured center point thickness and visual acuity modestly correlate, as do changes in retinal thickening and visual acuity after focal laser treatment for DME. However, a wide range of visual acuity can be noted for a given degree of edema. Therefore, OCT retinal thickness measurements are an important tool for clinical evaluation, but cannot reliably be used as a surrogate for visual acuity at a given time point.

Source: Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology 2007;114:525-536.

Exploring PEDF for Prevention of Diabetic Retinopathy
Results of a study in eyes of streptozotocin-induced diabetic rats indicated that pigment epithelium derived factor (PEDF) may protect against diabetic retinopathy by diminishing the harmful effects of advanced glycation end products (AGEs). Researchers observed that PEDF suppressed gene expression of the AGE receptor (RAGE) in the rat eyes. In addition, intravenously injecting AGEs into normal rats increased RAGE expression, which PEDF also blocked.

In vitro, PEDF or an antioxidant N-acetylcysteine blocked AGE-induced RAGE gene induction in microvascular endothelial cells and inhibited superoxide generation and NF-ß activation in AGE-exposed endothelial cells. The researchers reported that the results suggested that PEDF could inhibit diabetes- or AGE-induced RAGE gene expression by this blocking of superoxide-mediated NF-ß activation.

Source: Yamagishi S, Matsui T, Nakamura K, et al. Pigment-epithelium-derived factor suppresses expression of receptor for advanced glycation end products in the eye of diabetic rats. Ophthalmic Res 2007;39:92-97 (DOI: 10.1159/000099244).

Dye Technique for Visualizing Retinal Breaks
In a series of five patients, the use of 0.15% trypan blue dye proved useful for identifying retinal breaks during vitrectomy for rhegmatogenous retinal detachment. Dye was injected transretinally into the subretinal space using a 41-ga. cannula. After injection of perfluorocarbon heavy liquid into the vitreous cavity, the eyes were rotated so that the dye would vent out of the break, making it visible. Subretinal fluid was then drained through the break or a retinotomy and standard surgery was performed.

In four of the five patients, the technique allowed visualization of a previously unseen break. All of the retinas remained attached, and median visual acuity among the eyes was 6/12.

Trypan blue injected into the subretinal space. (Image courtesy of Timothy L. Jackson PhD, FRCOphth, and William Aylward, FRCOphth)
Trypan blue vented through a previously unseen retinal break. (Image courtesy of Timothy L. Jackson PhD, FRCOphth)

Source: Jackson TL, Kwan ASL, Laidlaw AH, Aylward W. Identification of retinal breaks using subretinal trypan blue injection. Ophthalmology 2007;114:587-590.

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NOTEWORTHY: FEASIBILITY STUDIES EVALUATE RADIATION DEVICE FOR AMD; NEW DATA ON EYE DROP FOR AMD; AND MORE ITEMS OF INTEREST

Feasibility Studies Evaluate Radiation Device for AMD
The NeoVista Strontium-90 Applicator delivers radiation to the choroidal vascular bed. It will be tested in combination with ranibizumab in an upcoming clinical trial.
Two feasibility studies indicated that NeoVista Inc.’s Epi-Rad90 Ophthalmic System is potentially beneficial in the treatment of neovascular AMD. One study tested the delivery of two doses of radiation to the eye (15 Gy and 24 Gy). The other study (n=26) evaluated the 24 Gy dose in combination with bevacizumab, one injection at the time of radiation treatment and one injection 30 days later.

In a company press release, Eugene de Juan, Jr., MD, said the results from the combination trial were extremely encouraging. Visual acuity improved by more than three lines in 50 percent of the patients.

NeoVista plans to begin a pivotal FDA study in the first half of this year. The study will evaluate the combination approach but use ranibizumab (Lucentis) instead of bevacizumab. It will be conducted at approximately 30 sites worldwide and enroll all lesion subtypes.

Source: NeoVista Inc., January 2007.

New Data on Eye Drop for AMD
Recently presented preclinical data indicate that the experimental eye drop OT-551 may act synergistically with ranibizumab or bevacizumab to improve visual acuity outcomes in the treatment of neovascular AMD. The data are from a study that utilized the Chick Chorioallantoic Membrane model of angiogenesis.

OT-551 is delivered to the eye topically and metabolized by enzymes into the compound TP-H. Animal models have shown that it acts against multiple disease pathways in the eye, including angiogenesis. Len Parver, MD, medical director of Othera Pharmaceuticals, commented on the latest results in a press release: "We’re encouraged to enter Phase II testing in wet AMD, as these results demonstrate that OT-551 could potentially improve the outcome of patients already on Lucentis by treating the underlying macular degeneration and decreasing the need for frequent Lucentis injections."

Source: Othera Pharmaceuticals Inc., February 2007.

Top-Line Results from CA4P Trial Announced
OXiGENE Inc., reported positive results from its Phase II study of intravenous Combretastatin A4 Phosphate (CA4P) for the treatment of subfoveal CNV in patients with pathologic myopia. All patients met the study’s primary endpoint, which was maintenance of visual acuity (less than a three-line loss) at three months. The company said safety results were favorable, with no drug-related serious adverse events occurring.

In the double-masked, three-arm study, patients (n=23) received one of three CA4P doses: 27, 36 or 45 mg/m2. They received two doses of CA4P one week apart with up to three additional doses and were followed for three months. Full results of the trial will be presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology in Fort Lauderdale, Fla., in May.

Pre-clinical studies in eye disease have shown that CA4P, a vascular targeting agent, suppresses development and induces regression of aberrant blood vessels. The company has completed a pre-IND meeting with the Food and Drug Administration and plans to proceed with development of two topical formulations (drops and ocular mini-tabs) of CA4P for the treatment of AMD.

Source: OXiGENE Inc., February 2007.

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