Authors: Varun Chaudhary, Frank G. Holz, Edoardo Midena, Eric Souied, Sebastian Wolf, George Lambrou, Tobias Machewitz, Paul Mitchell.

Disclosure Block: V. Chaudhary: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Alcon Laboratories, Bayer Healthcare, Novartis Pharma AG. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Served as a Scientific Advisor, Served as a Scientific Advisor, Served as a Scientific Advisor. Funded grants or clinical trials; Name of for-profit or not-for-profit organization(s); Allergan Inc, Bayer Healthcare, Novartis Pharma AG. Funded grants or clinical trials; Description of relationship(s); Grant. F.G. Holz: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Acucela, Apellis Pharmaceuticals, Bayer, Ellex, Roche/Genentech, Graybug Vision, Heidelberg Engineering, Lin Bioscience, Novartis, Pixium Vision, Oxurion, Stealth BioTherapeutics, Zeiss Pharma. Any direct financial payments including receipt of honoraria; Description of relationship(s); Honoraria or travel reimbursement. Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Steering Committee member. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Name of for-profit or not-for-profit organization(s); 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, Stealth BioTherapeutics, Acucela, Apellis Pharmaceuticals, Bayer, Bioeq/Formycon AG, CenterVue, Roche/Genentech, Heidelberg Engineering, Chengdu Kanghong Pharmaceuticals, NightstaRx, Novartis, Optos, Pixium Vision, Zeiss Pharma. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Description of relationship(s);  Consultant, Research support. E. Midena: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Steering Committee member. E. Souied: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Steering Committee member. S. Wolf: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Steering Committee member. Funded grants or clinical trials; Name of for-profit or not-for-profit organization(s); Heidelberg Engineering. Funded grants or clinical trials; Description of relationship(s); Grant. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Name of for-profit or not-for-profit organization(s); Allergan, Bayer, Boehringer-Ingelheim, Chengdu Kanghong Biotech, Heidelberg Engineering, Novartis, Oxurion, Zeiss, Roche. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Description of relationship(s);  Consultant. G. Lambrou: All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Name of for-profit or not-for-profit organization(s); Bayer. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Description of relationship(s); Employee. T. Machewitz: All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Name of for-profit or not-for-profit organization(s); Bayer. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Description of relationship(s); Employee. P. Mitchell: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Steering Committee member. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Name of for-profit or not-for-profit organization(s); Bayer, Novartis, Allergan. All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity; Description of relationship(s);  Consultant.

Purpose: To explore the relationship between retinal fluid compartment status and functional outcomes in patients with nAMD treated with IVT-AFL to guide treatment extension decisions.
Study Design: ARIES (NCT02581891; ethics approved) was a randomized, open-label, Phase 3b/4 study that compared the efficacy of IVT-AFL administered in two T&E dosing regimens over 2 years in treatment-naïve patients with nAMD.
Methods: Patients received three initial monthly doses of 2mg IVT-AFL (Weeks [Wks] 0, 4, 8), followed by an injection at Wk16. At Wk16, patients were randomized to early start T&E or late-start T&E (IVT-AFL every 8wks in Year 1, followed by T&E starting from Wk48); both adjusted in 2-wk steps (maximum treatment interval 16wks). The primary endpoint was change in best-corrected visual acuity (BCVA, Early Treatment Diabetic Retinopathy Study letters) from randomization to Wk104. Fluid compartment status (presence/absence of subretinal fluid [SRF] and intraretinal fluid [IRF]) was assessed by the central reading center based on optical coherence tomography. Treatment intervals were extended if IRF was absent, there was no new neovascularization, and SRF did not exceed 50µm in thickness. A post-hoc analysis combining the two treatment arms explored relationships between presence of fluid (SRF and IRF) and BCVA at fixed-time visits (Wks 4, 8, 16, 52, and 104).
Results: In the per-protocol set (n=210), the absence of SRF at every timepoint was associated with poorer BCVA (letters) than if SRF was present (no SRF vs SRF: 64.5 vs 67.2 [Wk4]; 66.3 vs 68.5 [Wk8]; 66.4 vs 70.7 [Wk16]; 68.3 vs 73.6 [Wk52]; 65.4 vs 72.9 [Wk104]). The presence of IRF was associated with poorer BCVA (letters) than if IRF was absent at most timepoints (IRF vs no IRF: 61.2 vs 65.9 [Wk4]; 66.6 vs 66.8 [Wk8]; 59.0 vs 69.3 [Wk16]; 66.2 vs 70.0 [Wk52]; 70.1 vs 67.4 [Wk104]). The absence of SRF+IRF was not associated with better BCVA (letters) at any timepoint (no fluid vs fluid: 64.7 vs 66.8 [Wk4]; 66.5 vs 67.7 [Wk8]; 67.3 vs 69.2 [Wk16]; 68.5 vs 72.6 [Wk52]; 65.3 vs 71.9 [Wk104]).
Conclusions: In ARIES, early start or late-start IVT-AFL T&E was effective at reducing retinal fluid and improved vision in treatment-naïve nAMD eyes regardless of fluid type. Post-hoc analyses suggest good functional outcomes can be achieved in the presence of SRF, whereas IRF was consistently associated with poorer functional outcomes. The use of combined SRF+IRF as a surrogate marker for BCVA and its use to guide treatment extension decisions alone should be reconsidered.