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Abstract Background To investigate the relationship between intraretinal hyperreflective foci (HRF) and visual function in intermediate age-related macular degeneration (iAMD). Methods Retrospective, cross-sectional study. iAMD patients underwent spectral domain optical coherence tomography (SD-OCT) imaging and vision function testing: normal luminance best corrected visual acuity (VA), low luminance VA (LLVA), quantitative contrast sensitivity function (qCSF), low luminance qCSF (LLqCSF), and mesopic microperimetry. Each OCT volume was graded for the presence and number of HRF. Each HRF was graded for: separation from the retinal pigment epithelium (RPE), above drusen, and shadowing. Central drusen volume was calculated by the built-in functionality of the commercial OCT software after manual segmentation of the RPE and Bruch’s membrane. Results HRF group: 11 eyes; 9 patients; mean age 75.7 years. No-HRF group: 11 eyes; 10 patients; mean age 74.8 years. In linear mixed effect model adjusting for cube-root transformed drusen volume, HRF group showed statistically significant worse VA, LLVA, LLqCSF, and microperimetry. HRF group showed worse cone function, as measured by our pre-defined multicomponent endpoint, incorporating LLVA, LLqCSF and microperimetry (p = 0.018). For eyes with HRF, # of HRF did not correlate with any functional measures; however, % of HRF separated from RPE and # of HRF that created shadowing were statistically associated with low luminance deficit (LLD). Conclusions The association between the presence of HRF and worse cone visual function supports the hypothesis that eyes with HRF have more advanced disease.

Purpose: Faricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.