Retinal disease in the form of diabetic macular edema (DME), polypoidal choroidal vasculopathy (PCV), and neovascular age-related macular degeneration (nAMD) can ultimately lead to a substantial loss of vision and decreased quality of life. Not only is proper treatment crucial to improvements in prognosis, but optimal timing is a valuable concern as well.
Clinicians should be informed about anti-VEGF treatment, namely aflibercept, which has since become center stage in current treatment advances for retinal disease. Acclaimed doctors and specialists contributed to this topic at a symposium held at the recent 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) which took place in Shanghai, China.
On the importance of early, intensive treatment
Based on a presentation called “Controversies in DME: Importance of Early, Intensive Treatment” by Dr. Gemmy Cheung, associate professor from Singapore National Eye Centre (SNEC).
VEGF and PGF both contribute to the development of retinal vascular leakage and edema in diabetic eye disease. Add to this the vicious cycle of impaired retinal blood flow and vessel occlusion, and it is no wonder that the most effective treatment targets elevated VEGF and PGF in patients with diabetic retinopathy and macular edema.
So what is aflibercept and how is it used? Aflibercept is a recombinant fusion protein that was specifically designed for high-affinity binding to both VEGF and PGF. Compared to other anti-VEGF agents such as ranibizumab and bevacizumab, aflibercept exhibited the highest binding affinity in vitro with VEGF-A.
In assessing the efficacy of aflibercept in patients with visual impairment due to DME, Dr. Cheung discussed two important studies: VIVID and VISTA. In two multicenter, double-masked trials, patients were randomized 1:1:1 to receive aflibercept 2 mg given intravitreally every 4 weeks, aflibercept 2 mg given intravitreally every 8 weeks (after 5 initial monthly doses), or laser photocoagulation.
Looking at the results, patients showed improvements in visual and anatomic outcomes after 5 doses, gaining on average, 8 letters. About 15 to 18% of patients gained an additional 5-letter gain by the end of the first year.
Dr. Cheung emphasized notable clinical significance of these results, saying: “Five-letter gains can impact quality of life for patients in their day to day activities and improve their ability to read the newspaper and drive in difficult conditions.”
Not only did intensiveness of treatment affect results, but delaying aflibercept treatment also led to suboptimal vision gains. For instance, patients in the laser group were eligible to receive aflibercept on an as-needed basis from Week 10 if they met vision loss and OCT criteria.
As a result, almost 50% of this same group in both studies received aflibercept PRN from Week 100 to Week 148. However, they did not receive the maximal benefits they would have received if they had just started treatment with aflibercept. Dr. Cheung stated: “The important lesson to remember, therefore, is not to delay treatment and save aflibercept as second-line therapy because there might be a later price to pay.”
In addition to the VIVID and VISTA studies, another study known as the Protocol T compared the efficacy of three anti-VEGF agents: aflibercept, bevacizumab and ranibizumab. Results found that those treated with aflibercept gained significantly more letters than those treated with either comparator at the 1-year primary endpoint (change in visual acuity from baseline).
At year 1, significantly greater vision gains were achieved with aflibercept than with either comparator in patients with baseline visual acuity less than 69 letters (less than 20/40), Dr. Cheung said. A post hoc analysis further solidified significantly greater visual acuity gains over 2 years with aflibercept than with comparators, she said. Overall, however, after 6 monthly doses of any anti-VEGF treatment, the proportion of eyes with persistent DME decreased, according to the post hoc analysis.
Staying the course with aflibercept provides robust VA gains in patients with a limited early visual response.
The eyes with limited early VA response (18%) after three initial monthly doses showed improvements with continued aflibercept. In Protocol T, 23% of aflibercept-treated eyes had limited early VA gains (<5 letters) at Week 12; 38% of these achieved gains of more than 10 letters at Week 104.
Aflibercept is also associated with disease modification and progression in patients with DME. According to the VIVID EAST study, which assessed the efficacy of aflibercept in Asian and Russian populations, a high proportion of aflibercept-treated patients achieved greater than a 2-step improvement in the Diabetic Retinopathy Severity Score (DRSS) at Week 52. More specifically, around 60% of patients treated with aflibercept achieved noticeable improvements compared to laser treatment.
The role of aflibercept monotherapy in PCV
Based on a presentation called “Aflibercept Monotherapy in PCV” by Dr. Suqin Yu, professor from Jiao Tong University, Shanghai.
Before the advent of anti-VEGF agents, photodynamic therapy (PDT) was the standard of care for the treatment of PCV. Since 2002, research has demonstrated the efficacy of verteporfin PDT with favorable short to mid-term results in improved vision and polyp regression.
However, as explained by Dr. Yu, long-term outcomes of PDT monotherapy may be associated with a high rate of PCV recurrence, deterioration of VA and risk of complications. For example, a pooled analysis of 29 different studies reported a PCV recurrence rate of up to 80% after years 2 and 3 in eyes treated with PDT.
Other concerns regarding overtreatment with initial and repeated use of PDT include efficacy and safety, practicality, and cost, Dr. Yu said. The procedure often results in several side effects over the long term and proves to be quite costly, he said. In addition, the procedure may be more time-consuming compared to intravitreal anti-VEGF injections due to necessary specialist equipment and training, Dr. Yu explained.
Dr. Yu added to the discussion by reviewing two trials to support her case: EVEREST II and PLANET.
The EVEREST II trial is a 24-month multicenter study that compared ranibizumab monotherapy versus combination ranibizumab and PDT combination therapy in Asian participants. In this trial, vision gains were notably greater with ranibizumab and prompt PDT than with ranibizumab alone.
The PLANET study evaluated the use of aflibercept monotherapy versus aflibercept plus PDT combination therapy. The study protocol implemented 3 monthly injections of aflibercept with a follow-up protocol of treat and extend (T&E). Results showed that patients in both study arms gained over 10 letters from baseline at Week 52. What’s remarkable, according to Dr. Yu, is that vision gains were maintained at Week 96 with T&E dosing. In both study arms, over 94% of patients did not experience loss of over 15 letters over 96 weeks.
In comparison, one-third of patients receiving aflibercept monotherapy had complete polyp regression while over 80% of patients had complete polyp inactivation at Week 96. Furthermore, in the second year, T&E with aflibercept was associated with a reduced injection number compared with the first year. In the same fashion, around 40% of patients had injection intervals of 12 weeks or more with the same regimen.
Dr. Yu concluded that aflibercept monotherapy leads to favorable vision gains and high rates of polyp inactivation. She also noted that more than 80% of patients never required rescue PDT over 2 years. Therefore, aflibercept monotherapy may be a promising option for certain patients.
Optimized aflibercept therapy in nAMD
Based on a presentation called “Proactive Treatment in nAMD” by Dr. Paul Mitchell, professor from University of Sydney, Australia.
Treat-and-Extend (T&E) has become a preferred regimen for clinicians who treat patients with nAMD. With this specific plan of dosing, clinical decision-making has become clearer with support from findings in the ALTAIR and ARIES studies.
So what exactly is T&E?
Dr. Mitchell contributed to this particular aspect of aflibercept therapy by defining it as the initiation of treatment with loading doses until the disease is stable. Gradually extending the time between treatments until fluid recurs or VA declines can determine a maximal fluid-free interval. Of course, Dr. Mitchell mentioned that “it’s important to treat more frequently if VA and/or anatomic outcomes deteriorate”.
In contrast with a reactive PRN regimen, it is important to use a proactive T&E regimen, according to Dr. Mitchell. This way, clinicians can minimize the risk of over-treatment and certainly avoid under-treatment. Consequently, proactive T&E regimens can relieve injection burden and improve visual outcomes while maintaining personalization of treatment.
In the ALTAIR study, a multicenter randomized trial, two groups were assigned to receive either aflibercept T&E with 2-week interval adjustments or 4-week interval adjustments. As confirmed by Dr. Mitchell, the study sought to assess the efficacy of two different T&E regiments with aflibercept in nAMD over 2 years.
While adjustment of T&E treatment intervals were guided by specific criteria, rapid vision gains were achieved in both groups and maintained to Week 52 of the study. Moreover, vision gains that were maintained to Week 96 with half the number of injections given in the first year. The study ultimately found that almost 60% of patients both reached treatment intervals of 12 weeks or more after the first year and also maintained these intervals into the second year.
The ARIES study compared the efficacy of early versus late initiation with aflibercept in nAMD over 2 years. The study served to supplement the growing evidence of aflibercept for proactive T&E dosing starting in the first year. Results found that visual and anatomic outcomes were similar in both early and late initiation groups. Plus, T&E patients were also receiving fewer injections as demonstrated in the ALTAIR study.
Implications in real-world practice
So, how does this discussion translate to real-world practice with aflibercept? With relatively low safety concerns, intensive and early treatment with aflibercept has become an emerging option for clinicians to treat patients with retinal disease. Overall, studies about aflibercept demonstrated its superiority and versatility in certain treatment regimens for DME, PCV and nAMD.
Editor’s Note: Reporting for this story took place at the 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) in Shanghai, China.
