ASRS Recap

Anti-VEGF Therapies Continue to Impress

At the 2012 ASRS conference, several presentations illustrated how effective aflibercept can be in patients with recalcitrant disease.

By Michelle Dalton, ELS

Anti-VEGF drugs have rapidly become the first-line treatment for patients with wet AMD, yet some patients remain non-responders while others have improved vision even though retinal fluid remains.

During the 2012 American Society of Retinal Specialists’ meeting in Las Vegas, several presentations highlighted findings on aflibercept (Eylea, Regeneron), the newest of the anti-VEGF treatments for the treatment of AMD. The study results presented at the meeting suggested that aflibercept could improve outcomes in patients who are recalcitrant to ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech) and may improve anatomic outcomes after a single injection based on OCT, regardless of previous treatment regimens.

Presenters said the move to aflibercept was an attempt to dry the retina in the hopes of improving visual acuity down the road. Since long-term damage occurs with persistent retinal fluid, aflibercept may surpass ranibizumab as a first-line treatment of choice, especially if the ability to dry the retina can be maintained over the long term, some of the clinicians suggested.

Recalcitrant Patients

Vincent S. Hau, MD, PhD, of the Retina Institute of California, doseloaded 41 eyes (35 patients) that had previously undergone a mean of 17.2 anti-VEGF injections (7.1 injections of ranibizumab and 10.1 injections of bevacizumab), with three monthly injections of 2.0 mg aflibercept, then moved patients to as-needed therapy, which averaged 4.5 injections over 6 months. Central foveal thickness went from 350 μm before the aflibercept treatment to 275-280 μm at month 6, which was statistically significant. Visual acuity improved as well, but didn’t reach statistical significance, he said.

“Some of these patients saw immediate improvement with just one injection,” said Dr. Hau.

In one of the larger retrospective chart reviews, Chirag P. Shah, MD, MPH, and colleagues at Ophthalmic Consultants of Boston analyzed the effects of one intravitreal aflibercept injection in 155 patients who had been classified as suboptimal responders to other anti-VEGF regimens; 123 patients (79%) showed an anatomic response after one aflibercept injection. Central subfoveal thickness went from 311 μm to 284 μm (P<0.001). Of the 123 patients who responded anatomically, 67% had improved subretinal fluid, 40% had improved intraretinal fluid, 12% had improved pigment epithelial detachment (PED), and 23% were dry.

Several additional presentations highlighted improved anatomic responses after a single injection.

In eyes receiving multiple previous anti-VEGF injections with no response, PED height was reduced by about 17% in 79 eyes, with a majority showing improvement in as little as 1 week after the aflibercept injection in one such study. “The number of anti-VEGF injections before switching to aflibercept was significantly but weakly correlated to the response,” said James C. Major Jr., MD, PhD, FACS, Retina Consultants of Houston.

In 54 eyes, the mean foveal thickness (FT) decreased from 351 μm to 300 μm. Of the 44 patients with macular volume data, the mean improvement was from 7.72 mm³ to 7.25 mm³, both of which were statistically significant changes, said Patrick Dewey Williams, MD, Texas Retina Associates.

“One injection of aflibercept may reduce persistent fluid on OCT,” he said. “Whether or not improved OCT data reduces the risk of future vision loss in these patients is still unclear.”

Another study showed that by 1 month after an initial aflibercept injection in eyes with chronic neovascular AMD that had previously been treated with either ranibizumab or bevacizumab, 38/93 eyes (41%) showed resolution of subretinal fluid, 12/93 (13%) had partial resolution, 29/93 (31%) had improvement, and 14/93 (15%) had no change, said Ashish G. Sharma, MD, FACS, Retina Consultants of Southwest Florida.

“In our patients, there was some improvement in visual acuity as well, with 7% gaining three or more lines in that first month,” he said. Central foveal thickness decreased from 368 μm to 275 μm at month 1, but slowly increased to 294 μm in an extended follow-up subgroup.

“All of these patients had previously undergone anti-VEGF therapy, with a range of 6-34 injections per eye before we switched them to aflibercept,” Dr. Sharma said.

Irene Barbazetto, MD, with Vitreous Retina Macular Consultants in New York, reported on 61 eyes of 50 patients who had received an average of 18 prior injections (ranging from 1-56 previous treatments); treatment failure was the primary reason for switching to aflibercept. In a short-term evaluation (4 months), visual acuity (VA) improved, but did not reach statistical significance. Central retinal thickness, however, improved from 279.2 μm to 252.9 μm (P<0.01). On OCT, the number of patients with subretinal fluid dropped by more than half, and cystic changes improved similarly.

“Further studies are needed to determine if patients stabilized with other anti-VEGF agents require three monthly loading doses for optimal response,” she said. In a subgroup analysis of 45 eyes that underwent three monthly doses, central thickness decreased from 298.8 μm to 254.6 μm (P<0.001); VA improved but was not statistically significant.

Early Experiences

“Having some fluid on OCT while on anti-VEGF therapy is fairly common,” said Kirk H. Packo, MD, professor and chairman, Rush University Medical Center, Chicago, noting that well over half his patients have persistent fluid after 2 years, regardless of monthly or PRN dosing with ranibizumab or bevacizumab (although PRN dosing resulted in a higher percentage of patients with persistent fluid). In a retrospective review of all patients who were being treated “on demand” with ranibizumab therapy, Dr. Packo identified 20 with chronic recalcitrant fluid, defined here as “persistent intraretinal fluid, subretinal fluid, and/or subretinal pigment epithelium (RPE) fluid in at least six consecutive visits,” he said. Any patient who had skipped visits or had at least one fluid-free visit in the same time period was excluded. The mean total ranibizumab injections was 25, with a range of 6 to 45 injections, and the mean consecutive injections was 18, with a range of 6 to 43 injections. Mean central macular thickness on OCT was 257 μm (ranging from 151 μm to 357 μm).

Each of the 20 patients was given a single injection of aflibercept, with additional injections given if fluid remained after one month. If the retina was dry, some patients received additional injections and others were observed. After one injection, 65% of patients (13/20) were completely dry; 3/20 (15%) were significantly better, but not dry — although for two patients a second injection rendered complete dryness; 2/20 (10%) had no change in fluid — one went totally dry with a second aflibercept injection and one did not; and 2/20 (10%) had slightly worse fluid and a second injection “didn’t help,” Dr. Packo said. The mean central macular thickness decreased to 228 μm (P=0.05).

Five of the 13 patients who were completely dry were observed and 80% (4/5) had recurrent fluid on the subsequent visit. Of the remaining eight patients who were also dry and re-injected, three developed recurrent fluid.

“In our patients, aflibercept may have a rapid drying effect (within a week) that needs to be considered when looking at overall response,” Dr. Packo said. “Aflibercept showed a release of effect, and some patients subsequently showed fluid, but less than seen with ranibizumab.” He added that subretinal fluid and intraretinal fluid seemed to respond better to aflibercept than sub-RPE fluid, although the reasons remain unclear.

Philip Ferrone, MD, and colleagues from Long Island Retina retrospectively analyzed 250 patients’ response to aflibercept, (29 were treatment naive; 145 had been on ranibizumab; 76 had been on bevacizumab). The previously treated group averaged injections every 6 weeks. The treatment-naive group was injected with aflibercept on a 4 week/4 week/7 week induction schedule, while the previously treated group immediately went to an every-7-week aflibercept injection regimen.

Visual acuity improved substantially for the treatment-naïve with baseline vision of 20/200 or worse (P=0.0023). Although vision improved in the previously treated (regardless of baseline VA) and treatment-naïve groups with baseline vision better than 20/200, none of those groups reached a statistically significant improvement.

“There was some decrease in VA on average in the treatment-naïve group when the treatment interval increased from 4 to 8 weeks,” Dr. Ferrone said.

OCT improved also over time, reaching statistical significance in the treatment-naïve group, regardless of baseline vision.

“There was a small improvement overall with respect to PED, subretinal fluid and macular edema findings on OCT after switching from bevacizumab or ranibizumab to aflibercept in most patients,” he said.

Aflibercept Use in the Presence of Active Disease

In eyes that are being actively treated with anti-VEGF therapy, but have active choroidal neovascularization (CNV) secondary to AMD, can a single injection of aflibercept be useful? H. Matthew Wheatley, MD, and colleagues at the Retina Vitreous Center, PA, and Robert Wood Johnson University Hospital, New Brunswick, NJ, addressed this question by analyzing chart data from 43 eyes of 43 patients who had persistent CNV despite being actively managed with anti-VEGF injections. The eyes had received 22 injections on average.

“On average, these patients were last injected between 5 and 6 weeks before the aflibercept injection,” Dr. Wheatley said.

Mean VA improved from 20/71.5 to 20/62.6 (P=0.043); mean spectral domain-OCT measurements improved from 278.3 μm to 252.8 μm (P=0.032); and macular volume decreased from 9.58 mm³ to 9.27 mm³ (P=0.0003).

“There was significant qualitative improvement,” Dr. Wheatley said. “Fifty-four percent had significantly improved or normalized anatomy after one injection.”

Conclusions

Aflibercept is capable of drying the retina in as little as one dose in some patients, but it is not yet known whether drying will translate into improved vision. That said, the presentations at ASRS demonstrated that aflibercept is equally effective in its ability to dry the retina in treatment-naïve patients and in patients previously treated with ranibizumab or bevacizumab. ✦