The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 μm or more. Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.

To assess prospectively a treat-and-extend (TREX) management strategy compared with monthly dosing of intravitreal ranibizumab in treatment-naïve neovascular age-related macular degeneration (AMD) patients. Phase IIIb, multicenter, randomized, controlled clinical trial. Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX management. Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) from 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or according to a TREX protocol. The TREX patients were treated monthly for at least 3 doses, until resolution of clinical and spectral-domain optical coherence tomography evidence of exudative disease activity; the interval between visits then was individualized according to a strict prospective protocol. Mean ETDRS BCVA change from baseline. At baseline, mean age was 77 years (range, 59-96 years), mean BCVA was 20/60 (Snellen equivalent), and mean central retinal thickness (CRT) was 511 μm. Fifty-seven eyes (95%) completed month 12, at which point mean BCVA improved by 9.2 and 10.5 letters in the monthly and TREX cohorts, respectively (P = 0.60). The mean number of injections administered through month 12 was 13.0 and 10.1 (range, 7-13) in the monthly and TREX cohorts, respectively (P < 0.0001). Among TREX patients, 7 (18%) were maximally extended, 4 (10%) demonstrated fluid at every visit, and at month 12, 18 (45%) had achieved an extension interval of 8 weeks or more; the mean maximum extension interval between injections after the first 3 monthly doses was 8.4 weeks (range, 4-12 weeks). Most TREX patients who demonstrated recurrent exudative disease activity (17/24 [71%]) were unable to extend beyond their initial maximum extension interval. The TREX neovascular AMD management strategy used in this prospective, randomized, controlled trial resulted in visual and anatomic gains comparable with those obtained with monthly dosing.

Diabetic retinopathy (DR) is a leading cause of blindness globally.^1,2 Disease severity ranges from nonproliferative DR (NPDR) to proliferative DR (PDR), with 13 distinct categories on the Diabetic Retinopathy Severity Scale (DRSS) developed in the Early Treatment Diabetic Retinopathy Study (ETDRS).³ The microvascular ischemia associated with DR leads to vision loss, primarily through pathologic neovascularization of the retina and/or anterior segment and diabetic macular edema (DME). Increasing NPDR severity is associated with an increased risk of progression to PDR and vision loss.³

Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden.Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD.Design, Setting, and Participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021.Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 μL) or 2 mg (50 μL) of aflibercept followed by doses at weeks 20 and 32.Main Outcomes and Measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety.Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, –1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, –6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was –159.4 (16.4) vs –137.2 (22.8) μm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, –9.5 [95% CI, –51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, –1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed.Conclusions and Relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema.Trial Registration: ClinicalTrials.gov Identifier: NCT04126317