Bayer (Leverkusen, Germany) announced the big news during its lunch symposium at the 18th EURETINA Congress on September 21: As of July 20, 2018, aflibercept (EYLEA) has been approved in Europe and elsewhere for use with a proactive treat-and-extend (T&E) regimen starting in the first year of treatment in neovascular age-related macular degeneration (nAMD). This new posology allows for an extension of treatment in two- or four-weekly increments in year one at the discretion of the physician.
Currently, a variety of treatment regimens are used in clinical practice for treatment of nAMD. These include the reactive PRN and treat-to-target and the proactive fixed dosing and T&E. During the symposium, Drs. Peter Kaiser (USA), Gemmy Cheung (Singapore) and Paul Mitchell (Australia) discussed aflibercept in terms of a T&E regimen.
In T&E, patients are injected at scheduled visits, regardless of visual acuity (VA) or anatomic status – treatment is initiated with loading doses until the disease is stable. Then, from there, treatment intervals are extended until sub-retinal fluid recurs or visual acuity (VA) declines. Multiple studies have shown that aflibercept is effective in a proactive T&E regimen.
In the VIEW study, the mean number of injections patients received in year one was 7.5 and in year two, this was reduced to 4.2. Not only was there a reduction in injections, 48% of patients who received aflibercept 2q8 in year one maintained VA gains in year two, with injection intervals of 12 weeks – and the VIEW 1 extension shows that those vision gains were maintained for more than four years with continued proactive aflibercept treatment.
The PLANET study produced similar results. Patients with PCV received q8 aflibercept and mean injections from year one to two dropped from 8.1 to 4.6, respectively. Plus, they gained >10 letters and maintained VA gains to week 96 with optional T&E. This data shows that good visual outcomes can be achieved with a proactive aflibercept regimen in real-world clinical practice.
“Other studies have used this idea of starting q8 week fixed dosing after a loading dose and switching to treat and extend after one year,” said Dr. Kaiser. He notes that in the PLANET study, VA results were great and polyp regression rates were also excellent.
“The important thing to note, is that in that second year of the study they switched to treat-and-extend and there was a dramatic reduction in the need for injections while maintaining visual acuity gains – and that’s really what we want for our patients,” he said.
The VIEW and PLANET studies are joined by mounting evidence from additional real-world studies of proactive q8 and T&E aflibercept dosing.
“Studies from all over the world are showing similar visual acuity results between the real-world studies and the randomized clinical studies of VIEW and PLANET,” said Dr. Kaiser, Professor of Ophthalmology, Cleveland Clinic College of Medicine, Cleveland, Ohio, USA. “But we’re also seeing real world studies using treat-and-extend, which is something we’re seeing more and more worldwide. And results in these real-world studies, using treat-and-extend is similar again to the to the studies using fixed dosing in terms of VIEW and ALTAIR.”
In 2016, Epstein et al. published a retrospective study of 85 patients with nAMD who received intravitreal q8 aflibercept to month 12, followed by a proactive T&E regimen to month 18. They found that VA gains achieved with q8 aflibercept in year one (7.7 mean number of injections in months 0-12) were maintained to with proactive T&E to month 18 (2.2 mean injections from months 12-18).
Other studies (Eleftheriadou et al. 2018; Hosokawa et al. 2018) found similar results: VA was maintained and the number of injections was reduced.
Other than less injections and better visual acuity (VA), this treatment method offers additional benefits to both patients and caregivers. In a 2017 study, Hanemoto et al. found that a proactive T&E regimen was associated with a reduced burden on patients and caregivers compared with PRN, reducing the mean number of visits in one year to 7.9 (T&E) from 14.0 (PRN).
The ALTAIR Study
ALTAIR is a Phase IV study designed to evaluate the efficacy of aflibercept with two different T&E dosing regimens in patients with nAMD. The primary objective was to assess the efficacy of aflibercept with two different treatment regimens in nAMD over two years. The secondary objective assessed the safety. This was a multi-center, randomized open-label study in treatment-naïve patients with nAMD (≥50 years old; BCVA of 25-73 ETDRS letters [~20/40 to 20/320] in the study eye). All patients received aflibercept treatment (3 x q4) and were randomized (1:1) at week 16 to either receive a 2-week interval adjustment (n=124) or 4-week (n=123). At week 52 (the primary endpoint) there was a mandatory visit to note changes in best corrected visual acuity (BCVA) from baseline. At week 96, the endpoint was studied.
Adjustment of T&E treatment intervals was guided by specific criteria. Intervals were extended if there was no sub-retinal fluid and no loss of ≥5 ETDRS letters, no increase of CRT of ≥100 µm, no new neovascularization and no new macular hemorrhage. Intervals were shortened if new fluid was present, or there was persistent unchanged or increased fluid, along with any of the following: loss of ≥5 ETDRS letters, increase in CRT of ≥100 µm, new neovascularization or new macular hemorrhage. Intervals were maintained if there was residual but decreased sub-retinal fluid, along with the same criteria of the extended treatment regimen. From weeks 16 to 96, the minimum interval was 8 weeks, while the maximum interval was 16 weeks.
“We have experienced that there is a proportion of eyes that just cannot dry up completely, but their vision is stable, they don’t have new fluid, or new hemorrhage,” said Dr. Gemmy Cheung, Senior Consultant Ophthalmologist at the Singapore National Eye Centre (SNEC) and a Clinician Investigator at the Singapore Eye Research Institute (SERI). “There might be a bit of residual fluid, but this is actually decreasing and vision is stable, there are no other signs of activity.”
At the primary endpoint (52 weeks) rapid vision gains were achieved in both treatment groups, and mean injections were similar (7.2 in 2-week group and 6.9 in 4-week group). These vision gains were maintained until week 96, while the number of injections continued to drop (3.6 in 2-week group and 3.7 in 4-week group). Around 30% of patients gained ≥15 ETDRS (3 lines of vision) in both treatment groups at week 52 and week 96. Fifty-seven to 60% of patients were maintained with injection intervals of 12 weeks or beyond at week 96.
“Over 40% percent of patients, those who do very, very well reach the maximum retreatment level of 16 weeks,” said Dr. Cheung. “Data from ALTAIR underlines the efficacy of proactive T&E with aflibercept over two years of treatment in patients with nAMD. It has demonstrated considerable visual gains at the end of the first year, which is well maintained at the end of the second year, at the same time with a significant reduction in the number of injections, particularly seen in the second year.”
In addition, the safety profile of intravitreal aflibercept in ALTAIR is consistent with results in previous studies.
The ARIES Study
ARIES is a Phase IIIb/IV study designed to investigate the efficacy of aflibercept with early (initiated after the first 8-week treatment interval) versus late initiation (at year one) of a T&E dosing regimen in patients with nAMD.
This was a multi-center, open-label, active-controlled, parallel group, Phase V study in treatment-naïve patients with nAMD. Patients were randomized at week 16 into either “early start” aflibercept 2mg with a two-week interval extension, or “late start” aflibercept 2mg q8 regimen. At 52 weeks, a mandatory visit was required and the late start group began a two-week interval extension.
The study found that rapid vision gains were maintained to week 52 and were similar in both groups. The mean change in BCVA from baseline to week 52 was +6.8 letters in the early start group and +8.4 in the late start group. These results were parallel and the difference in BCVA was attributed to baseline characteristics rather than the treatment regimen. Professor Paul Mitchell, University of Sydney, Australia, notes that any changes in CRT were also due to differences in baseline characteristics. Additionally, around 98% of patients maintained vision from baseline in ARIES, which is consistent with aflibercept-treated patients in the VIEW trials.
“In summary, preliminary data from ARIES corroborates existing evidence supporting the suitability of aflibercept for early proactive treat and extend regimen, with 52-week analysis the visual and anatomic outcomes were similar in patients in both early start and late start,” concluded Prof. Mitchell. Overall, the dual mechanism of action and high binding affinity of aflibercept, and its sustained suppression of intraocular VEGF, make it suitable for a proactive T&E dosing regimen in nAMD. In addition, in clinical practice, proactive T&E dosing with aflibercept starting in year one is associated with rapid vision gains that are maintained thereafter with a reduced treatment burden.
Editor’s Note: A version of this article first appeared in PIE Post Day 2 issue published at EURETINA 2018 Congress in Vienna, Austria (page 6-7, 10). PIE Post is PIE Magazine’s Daily Congress News on the Posterior Segment.
