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Optimizing Anti-VEGF Agents in Neovascular Age-Related Macular Degeneration

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Annual Meeting of the American Academy of Ophthalmology (AAO)

New Orleans, Louisiana / November 16-19, 2013

New Orleans - Vascular Endothelial Growth Factor (VEGF) stimulates vascular endothelial cell growth and proliferation along with hyperpermeability of vessels. Anti-VEGF agents preserve and improve visual acuity by arresting choroidal neovascular growth and reducing vascular permeability. Currently, two anti-VEGF agents are approved for the treatment of neovascular (wet) age-related macular degeneration (AMD) in Canada while a third is used off-label. A series of studies presented here in both wet AMD and pigment epithelial detachments better define which patients groups may optimally benefit from specific anti-VEGF therapy and specific treatment regimens.  

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

In Canada today, ophthalmologists have two approved intravitreal anti-vascular endothelial growth factor (VEGF) agents from which to chose to treat neovascular (wet) age-related macular degeneration (AMD)—ranibizumab and most recently, aflibercept. Bevacizumab is also used but it is not approved for the treatment of wet AMD and its use is therefore off-label.

VIEW 1 and 2 Extension Analysis

Results from the two pivotal phase III trials, VIEW 1 and VIEW 2, showed that aflibercept, given at a dose of 0.5 mg every 4 weeks; at 2 mg every 4 weeks, or at 2 mg every two months after three initial loading doses, was non-inferior to ranibizumab, 0.5 mg every 4 weeks (Ophthalmology 2014:121(1):193-201). At this year's meeting there were a number of abstracts discussing, yet to be published, extension analyses of these trials. Comparing the treatment effect of aflibercept to that of ranibizumab on retinal pigment epithelial elevation (RPEE)/PED), Dr. Chirag Shah, Retina & General Ophthalmology, Calgary, Alberta, found that aflibercept, 2 mg, was superior to ranibizumab for flattening of RPEE/PED whether it was a single or a sustained event (Abstract PA088). “When we looked at the quality of reduction, we again found that aflibercept, 2 mg monthly, was better able to shrink the RPEE/PED by at least 50% compared to ranibizumab or the 2 mg bimonthly dose of aflibercept,” Dr. Shah added.

The effect of the dosing schedules of aflibercept vs that of monthly ranibizumab on early persistent macular fluid and visual acuity was also analyzed by Dr. Peter Kaiser, Cole Eye Institute, Cleveland Clinic, Ohio (Abstract PA087). “The vast majority of patients in the VIEW study on either drug or either dosing regimen had non-persistent leakage at 4 months,” Dr. Kaiser emphasized.

In a comparison of the cumulative incidence of sustained dryness through week 52, patients with persistent leakage who received aflibercept 2 mg every 4 or 8 weeks, were more likely to have sustained dryness compared to those receiving ranibizumab (Relative risk 1.52, 1.10 and 1 respectively). However, the difference between the aflibercept and ranibizumab arm was only statistically significant (P<0.01) in the less frequent dosing arm, as Dr. Kaiser noted. In the same treatment group with persistent leakage, visual acuity was significantly better (P<0.05) in the 4-week aflibercept arm compared to the other 2 treatment arms. This suggests that patients with persistent fluid following 3 monthly loading doses of aflibercept, may benefit from the more frequent dosing regimen, as Dr. Kaiser concluded.

Early vs Delayed Gainers

In the pivotal HARBOR study, both 0.5 fixed monthly and as-needed (PRN) ranibizumab groups achieved clinically meaningful visual improvements of between 8 and 10 letters at 12 months as well as improved anatomic outcomes (Ophthalmology 2013:120:1046-56). At this year’s meeting, HARBOR investigator Dr. Greg Kokame, Retinal Consultants of Hawaii, examined patterns of visual and anatomic response over time to ranibizumab 0.5 or 2.0 mg, given monthly or on a as-needed basis after patients had received 3 monthly loading doses (Abstract PA084). Patients were characterized as “early” gainers if they had achieved ≥10 letters in visual acuity at month 3 and “delayed” gainers if they had not achieved significant gains in visual acuity at the same time point. “The question was: Do early gainers maintain this gain over time?” Dr. Kokame asked.

At 12 months, the answer was that early 10-letter gainers have a more rapid increase in visual acuity than delayed gainers but improvement in their visual acuity  plateaued from month 3 to month 12. In contrast, visual acuity continued to improve steadily from month 3 through to month 12 in the delayed gainers such that at month 12, improvement in visual acuity approached that of the early gainers. Dr. Kokame also noted that PRN dosing was effective in maintaining visual acuity gains in 82% of early 10-letter gainers at month 12.

Intraretinal Cysts

In an exploration of clinically relevant parameters in optical coherence tomography (OCT) in wet AMD eyes treated with 1 of 2 anti-VEGF agents over 96 weeks (Abstract PA086), Dr. Ursula Schmidt-Erfurth, Professor and Chair, Department of Ophthalmology, University Eye Hospital, Vienna, Austria, found that intraretinal cysts at baseline had a “strong negative impact” on visual acuity regardless of the anti-VEGF agent used.

She also found that exudative cysts responded well to anti-VEGF treatment, whereas eyes with degenerative cysts at baseline had worse visual acuity outcomes. Degenerative cysts also had a high risk of recurrence. Pigment epithelial detachment (PED) had a similarly negative impact on gains in visual acuity over a 96-week-treatment interval, she added. At 96 weeks, investigators also noted that eyes with subretinal fluid only at baseline achieved the best outcomes with gains in visual acuity of 12 letters or more.  In contrast, eyes with both intraretinal cysts and PED at baseline performed the worst with a gain in visual acuity of only 6 letters or more.

“Intraretinal cysts are the most important parameter for vision loss in patients with wet AMD—especially in PRN regimens--and may reflect irreversible retinal degeneration,” Dr. Schmidt-Erfurth concluded.

Long-term Anti-VEGF Safety and Efficacy

The long-term safety profile of anti-VEGF agents was in turn explored in several separate presentations. In a comprehensive patient-level meta-analysis, Dr. Baruch Kuppermann, Professor of Ophthalmology and Biomedical Engineering and Chief, Retina Service, University of California, Irvin, and colleagues performed a meta-analysis of 14 phase II and IIIb ranibizumab clinical trials involving 6504 patients followed for a total of 7544 patient-years (Abstract P0214). Pairwise comparisons were made for 0.5 mg or 0.3 mg vs controls as well as 0.5 mg vs 0.3 mg doses of ranibizumab.

Results showed that in patients with either wet AMD or retinal vein occlusion, no imbalances were observed between the 2 pairwise comparisons. In diabetic macular edema, investigators did note small numerical imbalances for wound healing complications as well as for stroke and death in the second year of monthly treatment compared with controls. However, as Dr. Kuppermann concluded, event rates were low for all groups and results are “consistent” with the established safety profile of ranibizumab.

In a separate analysis of data out to week 192 among patients entering the VIEW 1 extension study (Abstract P0435), Dr. Lloyd Clark, Assistant Clinical Professor of Ophthalmology,  University of South Caroline School of Medicine, West Columbia and colleagues found that visual acuity was “well maintained” out to 4 years across all treatment arms. At week 192, very similar percentages of patients (13%) in all treatment groups had lost 10 or more letters. No new safety signals were observed between year two and year four.

Switch Data

This observation appears to be corroborated by switch data. In a poster presented by Dr. Clement Chan, Associate Clinical Professor of Ophthalmology, Loma Linda University, San Diego, California. (Abstract P0445), 161 patients with partial or suboptimal responses to bevacizumab, ranibizumab or both were switched to aflibercept, initiated as a standard loading dose for 3 months, then PRN after that. The average number of injections over the 6-month follow-up was 5 (including the 3 loading doses). “At 6 months, vision was either maintained or improved by 4.1 letters,” Dr. Chan said, “and the percentage change in all OCT measures was also significantly improved for all parameters tested.”

Similarly positive findings in non-naïve wet AMD eyes with PED were reported by Dr. James Mason, Associate Professor of Ophthalmology, University of Alabama. In a retrospective review of 65 eyes (Abstract P0190) with persistent PEDs despite a mean number of 24 prior anti-VEGF injections, mean PED height was reduced by 22% at 12 months while mean logMAR visual acuity remained stable following a switch to aflibercept, 2 mg. Aflibercept was given every other month or as a treat-and-extend protocol as investigator determined. “This PED improvement was evident 1 month after the initial switch to aflibercept and persisted through 1 year,” Dr. Mason added, “and as PEDs contribute to vision loss and scarring in neovascular AMD, a timely and more complete resolution of PED should minimize residual pathology.”

Summary

AMD is the leading cause of irreversible blindness among elderly patients in developed countries. Intravitreal anti-VEGF agents have revolutionized the treatment of the neovascular form of the disease. Today, with newly approved anti-VEGF therapies that offer different dosing schedules, the disease can be safely, effectively and conveniently controlled for the long foreseeable future.   

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