Volume 2, Number 5
May 2006



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NEWS FROM THE ARVO MEETING
NOTEWORTHY: NEW PDT LASER AVAILABLE; AAO SUPPORTS REIMBURSEMENT FOR USING BEVACIZUMAB IN 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 information to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

In this edition:
The latest published research
News from the 2006 meeting of the Association for Research in Vision and Ophthalmology (ARVO), April 30 to May 4, Fort Lauderdale, Florida
Noteworthy, items of interest

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THE LATEST PUBLISHED RESEARCH

Photocoagulation After Triamcinolone Injection for Diffuse DME
In a study involving 86 eyes of 74 patients with diffuse diabetic macula edema, macular photocoagulation maintained improved visual acuity following intravitreal injection with 4 mg of triamcinolone acetonide.

The eyes were randomized into two groups. Eyes in the laser group (n=48) underwent macular grid laser photocoagulation three weeks after triamcinolone injection. Eyes in the control group (n=38) received only the triamcinolone injection.

Mean central macular thickness prior to, three weeks after, and three and six months after triamcinolone injection was 538, 250, 295, and 301 µm in the laser group, and 510, 227, 302, and 437 µm in the control group. Visual acuities were not significantly different between the two groups at baseline or three weeks after injection. However, they were significantly better in the laser group at three (p=.02) and six months (p<.001) after triamcinolone injection.

Source: Kang SW, Sa H-S, Yoon H, Kim JI. Macular grid photocoagulation after intravitreal triamcinolone acetonide for diffuse diabetic macular edema. Arch Ophthalmol 2006;124:653-658.



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NEWS FROM THE ARVO MEETING

Two-Year Results from the MARINA Trial
Two-year efficacy data from the MARINA trial of ranibizumab (Lucentis) showed that the overall improvement in visual acuity endpoints among treated patients was maintained at year two, while vision among patients in the sham group continued to decline. See the "One-Year Versus Two-Year MARINA Data" chart, below.

MARINA is a Phase III multicenter, randomized, double-masked, sham-injection controlled study of 716 patients with minimally classic or occult wet age-related macular degeneration. Patients were randomized 1:1:1 to receive sham injections, 0.3-mg doses or 0.5-mg doses of intravitreal ranibizumab once a month for two years.

Two-year safety data indicated no imbalance in deaths between the sham and ranibizumab groups. A low rate of ocular and key non-ocular serious adverse events was observed in all three treatment groups. Similar rates of Antiplatelet Trialists’ Collaboration (APTC) arterial thromboembolic events were observed in the sham (3.8 percent) and ranibizumab treatment groups (4.6 percent in 0.3-mg dose group and 4.6 in 0.5-mg dose group). A low rate of immunoreactivity was observed at year two, and there was no apparent association with safety or efficacy outcomes.

Source: Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration: two-year efficacy results of the MARINA study, Heier JS, et al., ARVO 2006 paper presentation 2659. Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration: two-year safety results of the MARINA study, Miller JW, et al., ARVO 2006 paper presentation 3539.

One-Year Results from the PrONTO Study
One-year results from the PrONTO study showed that five to six intravitreal injections of ranibizumab over one year improved vision in patients with neovascular AMD. PrONTO is a prospective, open-label, uncontrolled, single-site study evaluating the use of optical coherence tomography to follow ranibizumab-treated patients and determine the need for subsequent injections.

Neovascular AMD patients with visual acuities from 20/40 to 20/400 and macular neovascularization with an OCT central thickness of at least 300 µm were enrolled (n=40). Each patient received three consecutive injections of ranibizumab (500 µg) in the study eye, administered at baseline, month one and month two. They were re-treated only if one of the following occurred: increase in central OCT thickness of at least 100 µm, loss of five letters of acuity in conjunction with recurrent fluid on OCT, new onset classic neovascularization, or new macular hemorrhage.

Mean visual acuity in treated eyes improved nearly two lines (9.3 letters) at one year. Additionally, 95 percent of patients lost fewer than three lines of visual acuity with 82 percent of patients having the same or better visual acuity after one year, and 35 percent of patients gaining three lines of acuity. The median number of re-treatments was five, and the mean number was 5.5 over one year. Improvements in vision were associated with a decrease in fluid leakage from the abnormal blood vessels in these eyes.

Aside from mild post-injection discomfort, no treatment-related or drug-related serious ocular or systemic adverse events occurred. The study is ongoing through two years.

Sources: Visual acuity outcomes following a variable-dosing regimen for ranibizumab (Lucentis) in neovascular AMD: the PrONTO study, Rosenfeld PJ, 2006 ARVO paper presentation 2958.

VEGF Trap Meets Endpoints in Phase I Trial
The Vascular Endothelial Growth Factor (VEGF) Trap met the primary safety and tolerability endpoints and demonstrated positive preliminary efficacy results as treatment for neovascular AMD in a Phase I clinical trial. Twenty-one patients received a single intravitreal injection of 0.05, 0.15, 0.5, 1, 2, or 4 mg of VEGF Trap and were followed for six weeks.

Single doses were generally well-tolerated at all dose levels tested, and no systemic or serious adverse events occurred. Dose escalation to the highest planned dose was achieved without reaching a maximum tolerated dose. Of the 20 patients evaluable for efficacy, 95 percent had stabilization or improvement in ETDRS visual acuity. Best-corrected visual acuity increased by a mean of 4.8 letters at six weeks. In the two highest dose groups, the mean improvement in BCVA was 13.5 letters, with three of six patients gaining 15 or more letters. The median excess retinal thickness, as measured by OCT, was 194 µm at baseline and 60 µm at six weeks. As assessed by the Fast Macular Scan protocol, the median excess retinal thickness was 119 µm at baseline and 27 µm at six weeks.

Based on the Phase 1 results, a 12-week, 150-patient, Phase II trial is under way.

Source: Results of a Phase I, dose-escalation, safety, tolerability, and bioactivity study of intravitreous VEGF Trap in patients with neovascular age-related macular degeneration, Nguyen QD, 2006 ARVO poster presentation 2144/B723.

Drug Candidate Reduces Cytokines Associated with Diabetic Retinopathy
In a preclinical model designed to develop diabetes, the drug candidate VP025 significantly reduced (p<0.05) expression in the retina of several pro-inflammatory cytokines including IL-1, IL-6, and MCP-1, which are associated with the initiation stages of diabetic retinopathy. Concurrently, the intramuscular administration of VP025 resulted in the increased expression of both IL-10 and TGF-beta, two potent anti-inflammatory cytokines. This effect is believed to be mediated through the regulation of microglial cell activation. Microglial cells are inflammatory cells found in the central nervous system and in the retina.

VP025 is based on synthetic lipid technology. It is composed of bilayered phospholipid microparticles and interacts with macrophages and other cells of the immune system to elicit an anti-inflammatory response.

Source: The role of microglial reactivity in diabetic retinopathy, Krady JK, 2006 ARVO poster presentation 1721/B808.

Predictor of Success of Ovine Hyaluronidase for Vitreous Hemorrhage Associated With Diabetes
According to a pooled subset analysis of data from patients with diabetes in the Phase III clinical trials of ovine hyaluronidase (Vitrase), a relatively simple measurement for the density of vitreous hemorrhage (Total Hemorrhage Point Score or THPS) allowed prediction of treatment success following a single intravitreous injection of 55 IU or 75 IU.

THPS at one month was a predictor of treatment success with ovine hyaluronidase as measured by change in BCVA of three or more lines at three months when compared to a single injection of saline solution (p<.0001 for 55 IU, p<.0003 for 75 IU). THPS at one month was also a predictor of treatment success with ovine hyaluronidase as measured by completion of panretinal laser photocoagulation by three months without vitrectomy when compared to a single injection of saline solution (p<.0001 for 55 IU, p<.0003 for 75 IU).

Source: A simple predictor of Vitrase efficacy for BCVA improvement in diabetic patients with severe vitreous hemorrhage, Bhavsar AR, 2006 ARVO poster presentation 973/B906. A simple predictor of Vitrase efficacy for successful laser treatment in diabetic patients with severe vitreous hemorrhage, Landers MB, 2006 ARVO poster presentation 998/B931.



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NOTEWORTHY: NEW PDT LASER AVAILABLE; AAO SUPPORTS REIMBURSEMENT FOR USING BEVACIZUMAB IN AMD; AND MORE ITEMS OF INTEREST

The Quantel Activis has been approved by the FDA for use in ocular photodynamic therapy.
New PDT Laser Available
The Food and Drug Administration approved Quantel Medical’s Activis laser and ZSL30, ZSL120, and HSBMBQ ACT slit-lamp adapters for photoactivation of verteporfin for injection (Visudyne). The red, diode, 689-nm system guides the user through preparation and treatment of the patient with step-by-step surveillance of the procedure. Its motorized slit-lamp adapter is driven and controlled from the laser console to ensure precise laser spot settings. Users can customize their contact lens magnification factors and also memorize bilateral treatment parameters.

Source: Quantel Medical, April 2006.

AAO Supports Reimbursement for Using Bevacizumab in AMD
A letter from the American Academy of Ophthalmology to the Centers for Medicare & Medicaid Services stated that the AAO supports physician reimbursement for using intravitreal bevacizumab to treat neovascular AMD in patients as determined by the physician. The letter stated that bevacizumab is being used by a large number of retinal specialists who believe it is reasonable and medically necessary for some patients with neovascular AMD. The Academy cautioned that while the scientific studies related to the use of intravitreal injections of bevacizumab for the treatment of neovascular AMD are supportive, they are "not conclusive of its safety and efficacy." AAO Executive Vice President H. Dunbar Hoskins, MD, said the letter is not an endorsement of intravitreal bevacizumab, but a recommendation that physicians who choose to use it should be reimbursed as they are with other off-label therapies.

Source: American Academy of Ophthalmology, April 2006.

Professional Societies Update ROP Recommendations
The AAO, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Pediatrics have updated their recommendations for the effective detection and treatment of retinopathy of prematurity (ROP). The update includes a table designed to help practitioners better determine the timing of the first eye examination, based on gestational age at time of birth rather than chronological age. "Determining the infant’s gestational age gives us a much more accurate assessment of when the child should be examined, as the youngest infants at birth take the longest time to develop serious ROP," said Michael X. Repka, MD, president of the American Association for Pediatric Ophthalmology and Strabismus and a member of the statement review subcommittee. "The table provides a schedule for detecting ROP before it becomes severe enough to miss the optimum time for ablative therapy, while at the same time minimizing the number of potentially traumatic examinations."

According to the joint statement, the overall goal of a screening program should be to identify the premature infants who require treatment for ROP from among the larger population of at-risk infants, while limiting exams as much as possible.

Source: American Academy of Ophthalmology, April 2006.

Pegaptanib Safety Labeling Revised
The FDA and Pfizer Pharmaceuticals have notified health-care professionals of revisions to the safety labeling for pegaptanib sodium injection. The revisions address rare postmarketing reports of anaphylaxis/anaphylactoid reactions, including angioedema, in patients receiving the drug along with various medications administered as part of the injection procedure, according to an alert sent from MedWatch, the FDA’s safety information and adverse event reporting program. According to the FDA, it is not possible to reliably estimate the frequency of the adverse events or to establish a direct relationship to pegaptanib or other concurrently administered medications because these reactions are reported voluntarily from a population of uncertain size. Eye-care practitioners are advised to evaluate a patient’s medical history for hypersensitivity reactions. Use of pegaptanib is contraindicated in patients with known hypersensitivity to the active ingredient or any product excipients.

Health-care professionals are encouraged to report pegaptanib-related adverse events to Pfizer at (800) 438-1985 or MedWatch at (800) FDA-1088 or www.fda.gov/medwatch.

Source: U.S. Food and Drug Administration, April 2006.

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