Aqueous Humor Biomarkers, Efficacy, and Safety in Patients with Naïve Diabetic Macular Edema Treated with Faricimab: The ALTIMETER Study

Objective: To explore associations between clinical endpoints, multimodal imaging, and aqueous humor (AH) biomarker patterns in patients with diabetic macular edema (DME) treated with faricimab. Design: A phase IIb, multicenter, open-label, single-arm, 24-week exploratory study. Participants: Adults with treatment-na & iuml;ve DME, best-corrected visual acuity (BCVA) of 20-75 ETDRS letters, and central subfield thickness (CST) >= 325 mu m were eligible to participate. Methods: Patients received six 4-weekly intravitreal doses of faricimab 6.0 mg. Functional and multimodal imaging assessments were conducted through week 24. Aqueous humor samples were collected at baseline and week 16 for targeted proteomic analysis. Patients were monitored for safety. Main Outcome Measures: Prespecified exploratory endpoints included changes from baseline over time in BCVA, CST, the proportion of patients with >= 2-step ETDRS Diabetic Retinopathy Severity Scale (DRSS) improvement, intraretinal/subretinal fluid and macular leakage on multimodal imaging, and AH biomarker patterns. Results: Ninety-nine patients were enrolled. At week 24, treatment with faricimab resulted in clinical and anatomical improvements consistent with phase III trials in DME (YOSEMITE/RHINE); the adjusted mean (95% confidence interval) change from baseline was +9.2 (7.5-10.9) letters for BCVA and -200.2 mu m (-214.1 to -186.2) for CST, and 50.0% (37.2-62.8) of patients achieved >= 2-step DRSS improvement. Macular leakage area reduced from a median (interquartile range) of 28.6 mm(2) (16.9-36.5) at baseline to 2.8 mm(2) (0.9-15.3) at week 20. Total AH protein concentration decreased significantly from baseline to week 16 (P < 0.0001), with reductions across plasma-derived, inflammatory, and hypoxia response proteins. Notably, faricimab treatment significantly reduced the levels of key proteins associated with worse baseline DRSS scores (including angiopoietin-2, placental growth factor, and erythropoietin) and high baseline macular leakage, suggesting normalization of the AH proteomic profile. Safety was consistent with the known safety profile of faricimab. Conclusions: In patients with treatment-na & iuml;ve DME, faricimab treatment resulted in meaningful improvements in functional and anatomical outcomes. These clinical gains were accompanied by a significant reduction in the levels of key AH proteins associated with disease severity, which underscores their potential as biomarkers for assessing disease activity and therapeutic response.