Aflibercept for Macular Degeneration Maintains Improvement

CHICAGO — In patients with neovascular, age-related macular degeneration, improvements in visual acuity as a result of intravitreal injections of aflibercept were maintained out to 96 weeks in the phase 3 VIEW 1 and VIEW 2 trials, according to an update presented at the American Academy of Ophthalmology (AAO) and Asia-Pacific Academy of Ophthalmology 2012 Joint Meeting.

"Visual and anatomic improvements observed at Week 52 were largely maintained through Week 96 with modified quarterly dosing," reported Peter Kaiser, MD, from the Cleveland Clinic, Ohio. "The efficacy of aflibercept 2.0 mg given every 2 months was similar to monthly ranibizumab."

Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF) family members VEGF-A, VEGF-B, and placental growth factor. This prevents these ligands from binding to, and activating, their cognate receptors.

The drug was evaluated in 2 pivotal phase 3 trials: Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW 1 and VIEW 2), which were multicenter, randomized, double-blind trials comparing intravitreal aflibercept with ranibizumab in 1217 and 1240 patients, respectively.

Three doses of aflibercept were evaluated: 0.5 mg injected every 4 weeks, 2 mg every 4 weeks, and 2 mg every 8 weeks. Ranibizumab was dosed at 0.5 mg every 4 weeks. All were given after 3 loading doses, with treatment continued through week 52.

Between years 1 and 2 (week 96), patients were maintained on a modified quarterly dosing schedule and retreated according to the following criteria: 12 weeks since previous injection, new or persistent fluid on optical coherence tomography (OCT), increase in central retinal thickness of ? 100 µm compared to the lowest previous value, loss of ≥ 100 µm 5 ETDRS (Early Treatment Diabetic Retinopathy Study) letters from the best previous score in conjunction with recurrent fluid on OCT, new-onset classic neovascularization, new or persistent leak on fluorescein angiography, or new macular hemorrhage.

Visual Acuity Maintained, With Fewer Injections of Aflibercept

Over a period of 96 weeks in the VIEW studies, patients receiving the recommended regimen of aflibercept during the first year (2 mg every 2 months) followed by modified quarterly treatment during the second year had a similar visual acuity gain to those receiving the recommended regimen of ranibizumab (0.5 mg monthly) during the first year followed by modified quarterly treatment during the second year, but, on average, required 5 fewer injections, Dr. Kaiser reported.

At week 96, visual acuity gains were 7.9 letters (ranibizumab 0.5 mg monthly); 7.6 letters (aflibercept 2 mg monthly); 6.6 letters (aflibercept 0.5 mg monthly); and 7.6 letters (aflibercept 2 mg every 2 months), he reported.

The proportions of patients maintaining vision (loss of < 15 ETDRS letters) at week 52 were 94%, 95%, 96%, and 95%, and at week 96 were 92%, 92%, 91%, and 92%, respectively.

"The visual acuity improvements with aflibercept and ranibizumab at Week 52 were largely maintained through Week 96, and the efficacy of the 2 mg dose every 2 months was similar to monthly ranibizumab," Dr. Kaiser noted.

The outcomes were achieved with fewer active injections of aflibercept through week 96, especially with aflibercept 2.0 mg injected every 2 months, he added. Mean number of injections was 16.5 with ranibizumab, 16.0 with aflibercept 2.0 mg monthly, 16.2 with aflibercept 0.5 mg monthly, and 11.2 with aflibercept 2.0 mg every 2 months.

"From Week 52 to Week 96, there were more patients receiving fewer than 6 injections in the aflibercept arms, and more receiving 6 or more in the ranibizumab arm," he said. "The need for this was primarily driven by the presence of fluid at the end of year 1."

Additionally, more patients were without fluid in both aflibercept 2.0-mg groups, compared with ranibizumab. "This difference appeared early and was maintained through Week 52," he added.

Aflibercept was generally well tolerated in the VIEW studies. The ocular and nonocular adverse event profile of the drug was similar to that of ranibizumab, with the main side effects being conjunctival hemorrhage, eye pain, retinal hemorrhage, and reduced vision.

What Should Be Done in Clinical Practice?

K. Bailey Freund, MD, from Vitreous-Retina-Macula Consultants of New York, a panelist at the session, noted, "The [visual acuity] curve looks pretty flat in the second year, but there is some slight fall off, and it is more than we saw in ANCHOR and MARINA [trials of ranibizumab] when we continued to treat patients monthly. So there seems to be a little difference with [as needed] (PRN) dosing. With aflibercept having been approved for about 1 year, we are getting to the point where we will have to make a decision to maybe follow this regimen for a year, or change. It seems strange to tell a patient who has been coming in every 2 months for an injection, to now come in monthly, or to get an injection at least every third visit." He asked Dr. Kaiser how he is tackling these questions in his clinical practice.

"That is a good and topical question," Dr. Kaiser said. "Do we continue a fixed dosing regimen or switch to an as-needed schedule? We know that with ranibizumab the as-needed dosing is not as good as continuing it monthly. And in the VIEW trials we did not continue monthly injections. Would we have gotten better results if we had? We don't know. My personal opinion is to use a treatment-extend regimen, but that is without clinical evidence to support it."

He treats new patients according to their insurance coverage and their response to the anti-VEGF agents. "For the patient with good insurance coverage, I start with aflibercept," he said. "For patients with poor or no insurance, I start with bevacizumab and see how they do but I have a very low threshold for switching to another medication. For patients currently doing well on an anti-VEGF agent, I keep them on this but I do switch if they are doing poorly, sometimes from aflibercept to ranibizumab, or from ranibizumab or bevacizumab to aflibercept. We have at least short-term data showing some benefit for switching."

Dr. Kaiser has received consulting fees from Alcon Laboratories, ArcticDx, Bayer, Genentech, Novartis, Regeneron, and SKS Ocular. Dr. Freund reported consulting fees and research support from Bayer, Genentech, Regeneron, and Novartis.

American Academy of Ophthalmology (AAO) and Asia-Pacific Academy of Ophthalmology 2012 Joint Meeting. Abstract PA057. Presented November 12, 2012.