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Clinical Trial
. 2023 Dec 1;141(12):1152-1160.
doi: 10.1001/jamaophthalmol.2023.5248.

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial

Rishi P Singh  1 , Mark R Barakat  2   3 , Michael S Ip  4 , Charles C Wykoff  5 , David A Eichenbaum  6   7 , Sunir Joshi  8 , David Warrow  9 , Veeral S Sheth  10 , Jana Stefanickova  11 , Yong Soo Kim  12 , Fanyin He  13 , Ga Eun Cho  14 , Yuhua Wang  12 , Andrés Emanuelli  15   16
Affiliations
Clinical Trial

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial

Rishi P Singh et al. JAMA Ophthalmol. .

Abstract

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME).

Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME.

Design, participants, and setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021.

Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks.

Main outcomes and measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52.

Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 μm; aflibercept, -196.5 μm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion.

Conclusions and relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified.

Trial registration: ClinicalTrials.gov Identifier: NCT03917472.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Singh reported personal fees from Genentech, Regeneron, Alcon, Apellis, Gyroscope, Novartis, and Iveric Bio during the conduct of the study. Dr Barakat reported grants, personal fees, and nonfinancial support from Novartis during the conduct of the study; grants and personal fees from Adverum Biotech, CalciMedica, Clearside Biomedical, EyePoint Pharma, Genentech, Kodiak Sciences, Ocular Therapeutix, Opthea, and RegenXBio; grants from Annexon Biosciences, Gemini Therapeutics, Gyroscope Therapeutics, Oculis, Oxular, Oxurion, ReNeuron, Ribomic, Stealth Biotherapeutics, and Unity Biotechnology; personal fees from AbbVie, Alcon, Alimera, Allergan, Apellis, Arctic Vision, Bausch and Lomb, Biogen, Coherus Biosciences, Iveric Bio, Outlook Therapeutics, Palatin Technologies, Regeneron, and Roche; nonfinancial support from Regeneron; and nonfinancial support from RevOpsis Therapeutics, Oxurion, and NeuBase outside the submitted work. Dr Ip reported personal fees from Alimera, Allergan, Amgen, Apellis, Biogen, Clearside Biomedical, Genentech, Iveric Bio, Lineage Cell Therapeutics, ONL Therapeutics, Novartis, Regeneron, RegenXBio, and 4DMT outside the submitted work. Dr Wykoff reported grants from 4DMT, Adverum, Aerie, AffaMed, Alexion, Alimera, Alkahest, Allergan, Aldeyra, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Graybug, Gyroscope, Ionis, iRENIX, Iveric Bio, Kodiak Sciences, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Ophthotech, Opthea, Outlook Therapeutics, Oxurion, Oxular, Oyster Point, PerceiveBio, RecensMedical, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, Senju, Taiwain Liposome, Unity Biotechnology, Verily, and Xbrane; personal fees from 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, Arrowhead, Bausch and Lomb, Bayer, Bionic Vision Technologies, Boehringer Ingelheim, Cholgene, Clearside, Curacle, EyePoint, Foresite, Frontera, Genentech, Gyroscope, IACTA, Iveric Bio, Janssen, Kato, Kiora, Kodiak Sciences, Kriya, Merck, Nanoscope, NGM, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, Ocuterra, OliX, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, Roche, SciNeuro, Stealth, Surrozen, Suzhou Raymon, Takeda, THEA, TissueGen, Valo, and Verana; and nonfinancial support from ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, and Vitranu outside the submitted work. Dr Eichenbaum reported grants from Novartis during the conduct of the study; grants and personal fees from Allergan, Bayer, EyePoint, Genentech, Gyroscope, Iveric Bio, Kodiak Sciences, Novartis, Ocular Therapeutix, Opthea, Recens Medical, Regeneron, and RegenXBio; grants from 4DMT, Alexion, Alkahest, Allegenesis, Annexon, AsclepiX, Chengdu, Gemini, Ionis, Mylan, NGM, and Unity Biotechnology; personal fees from Alimera, Apellis, Bausch & Lomb, Coherus, Crinetics, DORC, KKR, Outlook, ReVive, and US Retina; and nonfinancial support from Boston Image Reading Center, Hemera Biopharmaceuticals, Network Eye, ReVive, and US Retina outside the submitted work. Dr Sheth reported grants from Novartis during the conduct of the study; grants and personal fees from Genentech, Alimera, Apellis, Iveric Bio, EyePoint, and Regeneron; and grants from Allergan, Opthea, Oxurion, Regenxbio, Santen, SamChungDang, Gyroscope, Chengdu, NGM Bio, 4DMT, Ashvattha, Olix, Janssen, and OcuTerra outside the submitted work. Dr Štefanickova reported nonfinancial support from Roche, personal fees and nonfinancial support from AbbVie, and grants, personal fees, and nonfinancial support from Bayer outside the submitted work. Dr Emanuelli reported grants from Novartis during the conduct of the study as well as grants from Regeneron Pharmaceuticals, Roche/Genentech, Kodiak Sciences, Adverum Biotechnologies, RegenxBio, and Nanoscope Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Participant Disposition
Following the intent-to-treat principle, participants from the full analysis set were analyzed according to the treatment assigned at randomization.
Figure 2.
Figure 2.. Change in Best-Corrected Visual Acuity (BCVA) From Baseline at Week 52 in the Full Analysis Set
Noninferiority of the primary end point was analyzed using an analysis of variance model using the last observation carried forward method, with baseline BCVA categories (≤34 vs >34 Early Treatment Diabetic Retinopathy Study [ETDRS] letter score [approximate Snellen equivalent, 20/200]), age categories (younger than 65 years vs 65 years and older), and treatment as fixed effect factors. A 2-sided 95% CI for the least squares mean difference (brolucizumab − aflibercept) is presented. Noninferiority was considered established if the lower limit of the corresponding 95% CI was greater than the noninferiority margin of −4 letter score. 1-sided P value for noninferiority is presented. Error bars indicate 95% CIs.
Figure 3.
Figure 3.. Anatomical Improvements in the Brolucizumab and Aflibercept Treatment Groups
A, Mean difference in central subfield thickness (CST). Noninferiority of the secondary end point was analyzed using an analysis of variance model using the last observation carried forward method, with baseline best-corrected visual acuity categories (≤34 vs >34 Early Treatment Diabetic Retinopathy Study letter score [approximate Snellen equivalent, 20/200]), age categories (younger than 65 years vs 65 years and older), and treatment as fixed effect factors. B, Proportion of participants with a fluid-free macula through week 52. Superiority of the secondary end point was analyzed using logistic regression using the last observation carried forward method, adjusting for baseline fluid status (simultaneous absence vs present), age categories (younger than 65 years vs 65 years and older), and treatment as fixed effect factors. 95% CIs for the treatment difference were estimated using the bootstrap method. C, Time to first absence of subretinal fluid (SRF) and intraretinal fluid (IRF). The secondary end point was analyzed using the last observation carried forward method.
See this image and copyright information in PMC

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