KINGFISHER: Brolucizumab Demonstrates Noninferiority to Aflibercept in DME Treatment


The phase 3 trial results show brolucizumab had superior anatomic improvements compared to aflibercept, with no clinically meaningful differences in visual outcomes.

Andrés Emanuelli, MD | Image Credit: Emanuelli Research & Development

Andrés Emanuelli, MD

Credit: Emanuelli Research & Development

New 52-week data from the phase 3 KINGFISHER randomized clinical trial showed no clinically meaningful differences in visual acuity outcomes between every 4-week treatment with brolucizumab 6 mg versus aflibercept 2 mg among patients with diabetic macular edema (DME).1

Results from KINGFISHER, involving more than 500 patients with DME, showed superior anatomical improvements up to week 52 in the brolucizumab arm compared with the aflibercept arm. Those in the brolucizumab arm achieved normal central subfield thickness (CST) of <280μm as early as week 4, with resolution of retinal fluid and time to the absence of retinal fluid each notably faster in the brolucizumab arm.

“In the KINGFISHER study, greater reductions in CST from baseline were achieved with brolucizumab compared with aflibercept while maintaining visual acuity, similar to the HAWK and HARRIER clinical trials in neovascular age-related macular degeneration (nAMD), and the KESTREL and KITE trials in DME,” wrote the investigative team, led by Andrés Emanuelli, MD of the department of ophthalmology at the University of Puerto Rico School of Medicine.

The introduction of anti-VEGF agents has been shown to improve visual outcomes, particularly compared to the previous standard of care, but many patients still require frequent dosing to improve and maintain functional and anatomical outcomes. Thus, the need remains for better treatment options to improve response rates and reduce the treatment burden faced by patients with retinal diseases.

KINGFISHER was a head-to-head comparison of the efficacy and safety of intravitreal brolucizumab, 6 mg, compared with intravitreal aflibercept, 2 mg, administered every 4 weeks in both treatment-naive and previously treated participants with visual impairment due to DME. However, the every-4-week dosing regimen is not approved for brolucizumab, due to a high reported frequency of intraocular inflammation (IOI), retinal vasculitis, and retinal vascular occlusion, as reported in the MERLIN study among patients with nAMD.2

Data in KINGFISHER were collected from September 2019 to March 2020, with data analysis occurring from April 2020 to February 2021.1 Patients were randomized 2:1 to brolucizumab 8 mg or aflibercept 2 mg every 4 weeks and stratified by baseline best-corrected visual acuity (BCVA) (≤34 vs. >34 Early Treatment Diabetic Retinopathy Study [ETDRS] letter score).

Among 765 screened participants, 517 patients were randomized in a 2:1 ratio to the brolucizumab arm (n = 346) or aflibercept arm (n = 171) between September 2019 and March 2020. In this population, 299 patients (57.8%) were male, and the mean age was 60.7 years.

Upon analysis, the study met its primary endpoint, showing the noninferiority of brolucizumab to aflibercept for the change from baseline in BCVA at week 52. There was an estimated 12.2-letter improvement in the brolucizumab arm and 11.0-letter score improvement in the aflibercept arm (difference, 1.1 letter score; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P <.001).

Brolucizumab was also superior to aflibercept for the proportion of eyes without IRF and SRF at week 52 (difference, 20.0%; 95% CI, 12.5 - 28.6; P <.001). Cox proportional hazard ratios of 2.3 (95% CI, 1.7 to 3.2), 1.4 (95% CI, 1.0 to 1.9), and 2.3 (95% CI, 1.7 to 3.2) for time to the first absence of IRF, SRF, and SRF and IRF, respectively, showed a faster time to the first fluid-free macula with brolucizumab.

Regarding mean CST change, brolucizumab was superior to aflibercept in mean CST change at week 52 (difference, –41.4 µm; 95% CI, –58.9 to –23.8; P <.001). A higher proportion of participants in the brolucizumab arm (66.2%) compared with the aflibercept arm (41.5%) had CST <280µm at week 52.

The brolucizumab arm also showed a higher proportion of patients with ≥2-step improvement in DRSS scores at each assessment, including at week 52 (43.0% vs. 38.1%). Estimated treatment differences at week 52 helped confirm the noninferiority of brolucizumab to aflibercept (difference, 6.0%; 95% CI, –3.9 to 16.1; P = .002).

Safety data revealed comparable ocular and non-ocular adverse events reported between treatment arms and consistent findings with the established safety profile. The incidence of IOI was 4.0% in the brolucizumab arm and 2.9% in the aflibercept arm, while the incidence of retinal vasculitis was 0.9% and 0.6%, respectively. The incidence of retinal vascular occlusion was 0.3% and 0.6%, respectively, while 1 participant in the brolucizumab arm had retinal artery occlusion.

Due to the lack of new safety concerns, Emanuelli and colleagues indicated underlying diabetes did not worsen the impact on the brolucizumab-related incidence of IOI among the eyes with DME. In fact, the team noted the reported rates of IOI in KINGFISHER were lower than those in previous studies of brolucizumab in nAMD (HAWK and HARRIER) and DME (KESTREL and KITE studies).

“The reason for the decrease in IOI rate in the data set reported, in contrast to the increase seen with dosing every 4 weeks in participants with AMD in the MERLIN study, is uncertain,” investigators noted.


  1. Singh RP, Barakat MR, Ip MS, et al. Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial. JAMA Ophthalmol. Published online November 16, 2023. doi:10.1001/jamaophthalmol.2023.5248
  2. Khanani AM, Brown DM, Jaffe GJ, et al. MERLIN: Phase 3a, Multicenter, Randomized, Double-Masked Trial of Brolucizumab in Participants with Neovascular Age-Related Macular Degeneration and Persistent Retinal Fluid. Ophthalmology. 2022;129(9):974-985. doi:10.1016/j.ophtha.2022.04.028
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