Author: Sebastian Wolf (Switzerland)
Co-authors: Varun Chaudhary, Frank G. Holz, Philip Hykin, Edoardo Midena, Eric Souied, Tobias Machewitz
Purpose
Understanding the impact of the different fluid compartments is critical in developing anti-vascular endothelial growth factor treatment paradigms that optimize patients’ vision and reduce treatment burden. Therefore, the aim of this analysis was to explore the relationship between intraretinal fluid (IRF) and/or subretinal fluid (SRF) and best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) to guide treatment extension decisions.
Setting/Venue
ARIES (NCT02581891) was a multicenter, randomized, open-label, active-controlled, parallel-group, Phase 3b/4 study that compared the efficacy of IVT-AFL administered in two different proactive, individualized treat-and-extend (T&E) dosing regimens over 2 years in treatment-naïve patients with nAMD.
Methods
): All patients received three initial monthly doses of 2 mg IVT-AFL (Weeks [W] 0, 4, and 8), followed by an injection after an 8-week treatment interval (W16). At W16, patients were randomized 1:1 to an early-start T&E arm (IVT-AFL T&E regimen adjusted in 2-week steps) or a late-start T&E arm (IVT-AFL every 8 weeks in Year 1, followed by a T&E regimen starting from W48, adjusted in 2-week steps). The maximum treatment interval was 16 weeks. The primary endpoint was change in BCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from randomization (W16) to W104. Fluid compartment status (presence/absence of SRF and IRF) was assessed by the central reading center at baseline (BL), W16 and at every treatment visit based on optical coherence tomography images. Treatment intervals were extended if IRF was absent, there was no new neovascularization, and SRF did not exceed 50 µm in thickness. This post hoc analysis explored the relationship between presence of fluid (SRF and IRF) and BCVA by describing absolute BCVA by fluid subgroups at BL and by fluid status at fixed visits (W4, W8, W16, W52, and W104) in the per-protocol set (two treatment arms combined).
Results
The per-protocol set comprised 210 patients. Absence of SRF at BL was associated with lower BCVA (5–10 less letters) than if SRF was present; a similar association was observed at every subsequent timepoint (no SRF vs SRF: 64.5 vs 67.2 [W4]; 66.3 vs 68.5 [W8]; 66.4 vs 70.7 [W16]; 68.3 vs 73.6 [W52]; 65.4 vs 72.9 [W104]). Presence of IRF at BL was associated with lower BCVA (7–9 less letters) than if IRF was absent; a similar association was observed at most subsequent timepoints (IRF vs no IRF: 61.2 vs 65.9 [W4]; 66.6 vs 66.8 [W8]; 59.0 vs 69.3 [W16]; 66.2 vs 70.0 [W52]; 70.1 vs 67.4 [W104]). The presence of both SRF and IRF at BL was associated with lower BCVA (6–8 less letters) than if only SRF was present, but was associated with a higher BCVA (3–9 more letters) than if only IRF was present. Absence of SRF and IRF was not associated with higher BCVA (letters) at any timepoint (no fluid vs fluid: 64.7 vs 66.8 [W4]; 66.5 vs 67.7 [W8]; 67.3 vs 69.2 [W16]; 68.5 vs 72.6 [W52]; 65.3 vs 71.9 [W104]).
Conlusions
In ARIES, proactive, individualized IVT-AFL T&E was effective at reducing fluid and improving vision in treatment-naïve nAMD eyes regardless of fluid type. Post hoc analyses showed that good functional outcomes were achieved in the presence of SRF, whereas IRF was consistently associated with poorer functional outcomes. These findings indicate the need to differentiate SRF and IRF as surrogate markers for BCVA, in order to guide treatment extension decisions and optimize patient outcomes.
Financial Disclosure
Sebastian Wolf: Steering Committee for Bayer; Consultant for Allergan, Bayer, Boehringer-Ingelheim, Chengdu Kanghong Biotech, Heidelberg Engineering, Novartis, Oxurion, Zeiss, and Roche Varun Chaudhary: Grant support from Allergan Inc., Bayer Healthcare, and Novartis ; Scientific advisor for Alcon Laboratories, Bayer Healthcare, and Novartis Frank G. Holz: Steering Committee for Bayer; Consultant for Acucela, Apellis Pharmaceuticals, Bayer, Boehringer-Ingelheim, Bioeq/Formycon AG, Roche/Genentech, Geuder AG, Graybug Vision, Heidelberg Engineering, Chengdu Kanghong Pharmaceuticals, Lin Bioscience, Novartis, Pixium Vision, Oxurion, and Stealth BioTherapeutics; Research support from Acucela, Apellis Pharmaceuticals, Bayer, Bioeq/Formycon AG, CenterVue, Roche/Genentech, Heidelberg Engineering, Chengdu Kanghong Pharmaceuticals, NightstaRx, Novartis, Optos, Pixium Vision, and Zeiss Pharma; Philip Hykin: Consultant fees from Bayer HealthCare, Novartis, and Allergan; Travel support to participate in review activities for meetings from Bayer; Support for provision of writing assistance, medicines, equipment, or administrative support from Bayer; Payment for lectures and support for conference attendance from Allergan and Novartis; ARIES Steering Committee member for Bayer Edoardo Midena: Steering Committee member for Bayer Eric Souied: Steering Committee member for Bayer Tobias Machewitz is an employee of Bayer George Lambrou is an employee of Bayer Paul Mitchell: Steering Committee member for Bayer; Consulting fees from Bayer, Novartis, and Allergan
Comments
Important add below co-authors: 7. George Lambrou: Bayer Consumer Care AG, Basel, Switzerland 8. Paul Mitchell: University of Sydney (Westmead Institute for Medical Research), Sydney, NSW, Australia
