Impact of intravitreal aflibercept dosing regimens in treatment-naïve patients with neovascular age-related macular degeneration: 2-year results of RAINBOW

There are two forms of age-related macular degeneration (AMD), the neovascular and the dry forms [1]. Anti-vascular endothelial growth factor (anti-VEGF) agents, such as intravitreal aflibercept (IVT-AFL) and ranibizumab, are available for the treatment of neovascular age-related macular degeneration (nAMD), and the goal of disease management beyond the first year is to maintain or improve functional and anatomical gains while minimizing the burden on patients of clinic visits and injections [2]. Although rapid visual and anatomic improvements can be achieved in the first year of anti-VEGF treatment, regression to baseline after initial gains is not uncommon [2]. Findings from the VEGF Trap-Eye Investigation of Efficacy and Safety in Wet AMD (VIEW) studies showed that, in the second year of treatment, the dosing interval for IVT-AFL can be adjusted according to the patient’s response to treatment, without clinically meaningful loss of visual gains [3, 4].

Before IVT-AFL was authorized in Europe in 2012, anti-VEGF treatments for nAMD in France were administered as needed (pro re nata) [5]. The introduction of IVT-AFL led to changes in standard clinical practice from reactive to proactive treatment protocols/regimens. As clinicians became proficient with newly available anti-VEGF treatments for nAMD, injection intervals varied substantially, as did adherence to the indicated initiation of IVT-AFL with three initial monthly doses [6]. In the Real Life of intravitreal Aflibercept In FraNce: oBservatiOnal study in Wet AMD (RAINBOW) study, patients treated with IVT-AFL for nAMD were expected to receive three initial monthly injections followed by injections every 2 months for the first 12 months, with extensions based on visual and anatomic outcomes thereafter [4]. The purpose of this study was not to identify differences in clinical practices before and after any changes in approved dosing for IVT-AFL, but rather to describe clinically led variations in treatment practices in France and understand any impact of those on patient outcomes.

Currently, there is limited real-world evidence demonstrating how nAMD is managed in daily clinical practice in France. Real-world evidence can complement clinical trial data by providing information on the effectiveness of a treatment under real-world conditions that can support clinical management decisions and improve patient outcomes [7, 8]. Here, we report results from the second year of the RAINBOW, an ongoing study collecting effectiveness and safety data from patients with nAMD treated with IVT-AFL in clinical practice in France.

RAINBOW is an ongoing study investigating the effectiveness and safety of IVT-AFL for the management of treatment-naïve patients with nAMD in real-life clinical practice in France. In the present analysis, visual improvements were observed at Month 24 in patients with nAMD following IVT-AFL treatment, with an increase from baseline in BCVA of + 3.0 letters in the overall population. Notably, patients who received three initial monthly doses and regular IVT-AFL treatment experienced better visual outcomes over 24 months than patients with irregular treatment without initial doses. Visual gains observed with regular versus irregular IVT-AFL treatment with initial doses were not statistically different. A significant mean change from baseline in BCVA was observed in the regular and irregular treatment interval cohorts receiving initial doses, + 4.9 and + 4.0 letters, respectively, while the irregular treatment interval cohort without initial doses of IVT-AFL experienced a change of − 2.5 letters at 24 months. The findings from this analysis at 24 months are consistent with results from the initial 12-month analysis [6] and highlight the importance of three initial monthly IVT-AFL treatments to stabilize the disease and maintain visual outcomes. The change from baseline in BCVA in this analysis was not as large as in the VIEW clinical trials at Week 96 (+ 7.6 letters) [3]. In VIEW the percentage of patients gaining ≥15 letters was 33.4%, and the percentage of patients maintaining visual acuity (losing < 15 letters) was 92.4% at Week 96 in the IVT-AFL 2 mg group. It is important to note that in the VIEW studies, in Year 1 patients received three initial doses and bimonthly injections, while in Year 2 patients received an as-needed injection regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks [3]. In the VIEW study, patients received a mean of 11.2 IVT-AFL injections over the 96-week period, with fewer injections in the second year (4.2 injections from Week 52 to 96) [3]. In comparison, over the analysis period in the present study, the mean number of IVT-AFL injections was 8.8 and, similar to the VIEW studies, there were fewer injections in the second year. However, in the VIEW studies patients exhibited a more severe disease (mean visual acuity at baseline = 53.6 [13.5] letters in the patients treated with IVT-AFL 2 mg bimonthly) [3] than in the RAINBOW study.

Real-world evidence from the use of IVT-AFL for the treatment of nAMD is also being collected in other countries. PERSEUS (Prospective Non-intERventional Study to asSEss the Effectiveness of Aflibercept in roUtine Clinical Practice in patientS With Wet Age-related Macular Degeneration) is a 24-month prospective observational cohort study conducted in hospitals and medical centers in Germany among treatment-naïve or previously treated patients with nAMD. Following IVT-AFL, there was a significant mean visual acuity gain at 1 year of + 6.1 letters in the population with regular treatment intervals for IVT-AFL compared with + 1.5 letters in those with irregularities in their treatment regimen [9]. An observational database study in treatment-naïve patients with nAMD from centers in Australia, New Zealand, and Switzerland was conducted by the Fight Retinal Blindness (FRB) group. Patients completed 2 years of proactive IVT-AFL treatment according to a treat-and-extend regimen. Over 2 years of treatment, a significant increase in mean visual acuity was reported (+ 6.0 letters). In the FRB study, from the first to the second year of treatment there was a decrease in the mean number of injections (7.8 vs 5.7) and visits (8.7 vs 6.5) for eyes completing 2 years of treatment [10]. In the present study, the poor visual acuity in the irregular treatment interval cohort without initial doses appears to be more likely related to few patients (10%) achieving gains ≥15 letters, patients losing > 15 letters (12.5%) and fewer treatment injections and visits over the 24 months than other treatment groups. The findings from the present study add to the real-world evidence supporting the continued use of IVT-AFL through 24 months.

Safety findings from the RAINBOW study at 24 months were consistent with the known safety profile of IVT-AFL in patients with nAMD [3, 11]. Five deaths were recorded during the study; none were considered related to treatment. The incidence of ocular AEs was lower in the present study than in VIEW studies, which may be due to possible underreporting in an observational study compared with a randomized study.

Due to the observational design of the RAINBOW study there are a number of inherent limitations that must be recognized when interpreting these findings. The use of a variety of charts to assess visual acuity may have introduced bias, especially when evaluating the number of letters gained or lost after treatment. Furthermore, the limitations of analysing the evolution of visual acuity in relation to the number of injections only must be recognized. Disease-related evolution of nAMD can occur that may not be directly influenced by treatment, even if treatment is optimal. In addition, these findings reflect real-life clinical practice in France and may not be generalisable across countries.

Findings from the RAINBOW study at 24 months were consistent with results from the primary endpoint at 12 months and highlight the importance of three initial monthly IVT-AFL injections on visual outcomes. Notably, treatment-naïve patients who received three initial monthly IVT-AFL doses followed by regular treatment over the first 12 months experienced better visual outcomes at 24 months compared with irregular treatment without initial doses. The overall safety profile was consistent with previous studies of IVT-AFL. The results of this 24-month analysis of the 4-year RAINBOW study were only slightly lower than those of randomized studies, such as VIEW, and demonstrate that IVT-AFL (with initial doses) offers treatment effectiveness in real-world practice.