AAO/SEO 2008: New Dosing Strategies, Agents Demonstrate Efficacy in Neovascular AMD

November 12, 2008

November 12, 2008 (Atlanta, Georgia) — Flexible dosing strategies and novel agents are being evaluated for the treatment of neovascular age-related macular degeneration (AMD) to try to minimize the number of injections delivered while maintaining efficacy.

Researchers presented the findings here at the 2008 Joint Meeting of the American Academy of Ophthalmology and the European Society of Ophthalmology.

Neovascular AMD can be treated with agents that target the vascular endothelial growth-factor (VEGF) pathway and inhibit angiogenesis. Pegaptanib is a pegylated anti-VEGF aptamer that specifically binds to VEGF 165. Ranibizumab is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab. Both agents are approved for use in AMD. Intravitreal bevacizumab is used off-label. Another agent in development, VEGF-Trap-Eye, blocks all forms of VEGF-A.

Injections to the eye for the treatment of neovascular AMD can be painful; thus, a goal of studies has been to find ways to maximize efficacy while reducing the number of injections required.

LEVEL Study

In the LEVEL study, presented by Thomas R. Friberg, MD, from the University of Pittsburgh School of Medicine, in Pennsylvania, pegaptanib given every 6 weeks for 1 year was found to maintain outcomes after initial VEGF inhibition with off-label bevacizumab or ranibizumab.

"Such a strategy might be particularly relevant in patients with a history of stroke or myocardial infarction, so that their systemic exposure to pan-VEGF inhibitors can be limited," Dr. Friberg said.

Pegaptanib 0.3 mg was given every 6 weeks for 1 year after successful treatment with previous therapy, which included off-label bevacizumab in 36% of the study group and ranibizumab in 42%. During the maintenance phase, patients received pegaptanib and additional booster therapy at the discretion of the treating investigator.

Of the 568 patients, 88% completed 1 year of maintenance with pegaptanib. Visual acuity and central retinal thickness were maintained at week 54. Pegaptanib appeared safe, and there were no cases of retinal detachment or traumatic cataract.

SUSTAIN Study

In another presentation at the same session, Frank G. Holz, MD, from the University of Bonn, in Germany, described results from a preplanned interim analysis of the SUSTAIN phase 3b study, designed to assess a flexible dosing schedule for ranibizumab.

A total of 69 ranibizumab-naïve patients received 3 fixed monthly injections of either 0.3 mg or 0.5 mg ranibizumab in the initial phase, and then returned every 4 weeks in the maintenance phase, for a total study period of 12 months. Criteria for retreatment in the maintenance phase included visual deterioration greater than 5 letters or an increase in central retinal thickness of more than 100 µm.

Visual acuity and central retinal thickness was maintained over the course of 12 months using guided individualized as-needed dosing; there was a decrease from 9.2 letters to 6.7 letters from month 3 to month 12, but this difference was not significant, and there was a slight decrease in central retinal thickness of 89.6 µm to 78.7 µm from month 3 to month 12. The average number of injections given during the maintenance phase was low, at 2.3 (range, 0–7). Ocular adverse events occurred in 55.1% of study eyes and were mostly mild in nature.

"These results suggest that flexible dosing based on predefined treatment criteria with monthly monitoring results in fewer injections overall and can maintain efficacy outcomes," Dr. Holz said.

CLEAR-IT 2 Study

One-year results from the CLEAR-IT 2 study evaluating VEGF-Trap-Eye were presented by David S. Boyer, MD, from the Retina-Vitreous Associates Medical Group, in Beverly Hills, California. The phase 2 study was designed to assess responses at 12 weeks to a range of VEGF-Trap-Eye doses administered monthly and quarterly. The durability of as-needed dosing response was also measured out to 1 year.

A total of 159 patients were randomized to 1 of 5 equal groups: 0.5 mg or 2 mg VEGF-Trap-Eye every 4 weeks; or 0.5, 2, or 4 mg every 12 weeks.

A mean improvement in visual acuity of 5.7 letters (P < .0001) and a reduction in central retinal thickness to 119 µm (P < .0001) was noted for all groups combined over the study period.

In addition, groups dosed quarterly (at baseline and at week 12), showed improved visual acuity and retinal thickness, although the effect was not as robust as with monthly dosing. Notably, visual acuity was maintained with a single dose for up to 8 weeks.

Patients received, on average, about 2 additional injections over the 40-week as-needed dosing phase following a 12-week fixed-dosing period. Of the patients, 19% received no additional injections after week 12. Treatment was generally well tolerated, with no serious treatment-related adverse events.

"These findings were very encouraging and exciting because they suggest that VEGF-Trap-Eye produces at least similar results to those of standard care," said study author Quan Dong Nguyen, MD, assistant professor of ophthalmology at the Wilmer Eye Institute at Johns Hopkins University, in Baltimore, Maryland. "We are also very encouraged by the long duration of action of the drug," he told Medscape Ophthalmology.

CATT Study

Speaking at a press conference, George A. Williams, MD, with the Beaumont Eye Institute, in Royal Oak, Michigan, compared ranibizumab and off-label intravitreal bevacizumab for the treatment of neovascular AMD. Although both are offered by Genentech, ranibizumab is more than $2000 per dose, whereas bevacizumab is $50 per dose, and this significantly influences prescribing, Dr. Williams said.

"There is increasing consensus worldwide that intravitreal bevacizumab appears to be safe and effective, yet we don't know the precise safety or efficacy," said Dr. Williams. "The systemic side effects of bevacizumab are concerning, yet whether they apply to intravitreal use remains to be seen," he added.

According to Dr. Williams, the CATT study, sponsored by the National Eye Institute, is designed to answer many of these questions. The trial of 300 patients will directly compare both monthly and as-needed dosing of ranibizumab and bevacizumab.

All studies discussed were funded by the respective manufacturers of each drug evaluated. Dr. Friberg reports receiving research and consulting support from Eyetech, Inc, and Pfizer Inc. Dr. Holz reports a financial relationship with Novartis. Dr. Boyer reports no relevant financial relationships. Dr. Nguyen has disclosed receiving grants for clinical research from Regeneron. Dr. Williams states that he has received research funding from Genentech.

2008 Joint Meeting of the American Academy of Ophthalmology (AAO) and the European Society of Ophthalmology (SOE): Scientific sessions PA078, PA079, and PA80. Presented November 12, 2008.

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