This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.

Background Despite the success of anti-vascular endothelial growth factors (anti-VEGF), there is currently a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). Purpose To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment designed specifically for intraocular use in humans. Methods In this article, we summarize the pre-clinical and current clinical evidence for brolucizumab, with an outlook to other treatment regimens and additional indications under investigation. Results The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dosing in one intra-vitreal injection compared with other anti-VEGF agents. The Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal Phase III trials HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. Conclusions The pre-clinical and clinical data for brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.

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Purpose: To report the 96-week outcomes from HAWK and HARRIER. Design: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD).Participants: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n ¼ 358), brolucizumab 6 mg (n ¼ 360), aflibercept 2 mg (n ¼ 360; HAWK) or 1:1 to brolucizumab 6 mg (n ¼ 370), aflibercept 2 mg (n ¼ 369; HARRIER).Methods: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w.Main Outcome Measures: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w.Results: Mean change (least squares [LS] mean AE standard error) in BCVA from baseline to 96w in HAWK was 5.6AE0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90AE0.78 letters for brolucizumab 6 mg, and 5.3AE0.78 letters for aflibercept and in HARRIER was 6.1AE0.73 letters for brolucizumab 6 mg and 6.6 AE 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, À174.8 mm vs. À148.7 mm; 95% confidence interval for treatment difference, e46.2 to e5.9 mm; P ¼ 0.0115) and HARRIER (LS mean, e197.7 mm vs. e155.1 mm; 95% confidence interval for treatment difference, e62.0 to e23.3 mm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P ¼ 0.0688) and 24% (P ¼ 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile.Conclusions: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.