Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration Beyond One Year of Treatment: AZURE, a Randomized Trial of Treat-and-Extend vs. Fixed Dosing.

INTRODUCTION: AZURE was a 76-week, randomized, open-label, parallel-group, phase IIIb noninferiority study comparing the efficacy and safety of intravitreal aflibercept (IVT-AFL) in a treat-and-extend (T&E) regimen with fixed dosing in patients with neovascular age-related macular degeneration (nAMD) previously receiving IVT-AFL for ≥ 1 year. METHODS: Patients were aged ≥ 51 years and had completed ≥ 1 year of IVT-AFL treatment prior to enrollment (IVT-AFL once per month [- 1 or + 2 weeks] for 3 months followed by IVT-AFL every 2 months [6-12 weeks]). Patients were randomly assigned (1:1) to receive IVT-AFL 2 mg in either a T&E (minimum treatment interval of 8 weeks with no upper limit, adjusted according to functional and anatomic outcomes, as assessed by the investigator; n = 168), or a fixed dosing regimen (treatment every 8 weeks [± 3 days]; n = 168). The primary endpoint was best-corrected visual acuity (BCVA) change from baseline to week (W) 52. The key secondary endpoint was the proportion of patients maintaining vision (< 15-letter loss) at W52. RESULTS: The full analysis set comprised 332 patients (T&E: n = 165; fixed dosing: n = 167). Mean BCVA change (baseline to W52) was - 0.3 ± 7.5 vs. - 0.5 ± 8.4 letters (T&E vs. fixed dosing; least-squares mean difference [95% CI]: 0.22 [- 1.51 to 1.96] letters; P < 0.0001 for noninferiority test [5-letter margin]). From baseline to W52, 95.2% (T&E) and 94.0% (fixed dosing) of patients maintained vision. Mean central subfield thickness change from baseline to W52 was - 24 ± 55 (T&E) and - 33 ± 47 (fixed dosing) µm. Last treatment interval to W76 was ≥ 12 weeks for 37.0% of T&E patients. No new safety signals were identified. CONCLUSION: IVT-AFL T&E can achieve similar functional and anatomic outcomes to fixed dosing every 8 weeks over 52 weeks in patients with nAMD who have completed ≥ 1 year of treatment, while reducing treatment burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02540954.

Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial.

INTRODUCTION: The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. METHODS: Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. RESULTS: Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. CONCLUSION: The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818998.

Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study.

PURPOSE: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). DESIGN: AQUA was a multicenter, open-label, single-arm, phase 4 study. PARTICIPANTS: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. METHODS: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. MAIN OUTCOME MEASURES: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. RESULTS: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 µm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 µm (SD, 132.62 µm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. CONCLUSIONS: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.