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. 2023 Sep 1;141(9):834-842.
doi: 10.1001/jamaophthalmol.2023.2421.

Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial

Charles C Wykoff  1 , David M Brown  1 , Kimberly Reed  2 , Alyson J Berliner  2 , Adam T Gerstenblith  3 , Aurora Breazna  2 , Prema Abraham  4 , Jordana G Fein  5 , Karen W Chu  2 , W Lloyd Clark  6 , Sergio Leal  7 , Thomas Schmelter  8 , Boaz Hirshberg  2 , George D Yancopoulos  2 , Robert Vitti  2 ; CANDELA Study Investigators
Collaborators, Affiliations

Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial

Charles C Wykoff et al. JAMA Ophthalmol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wykoff reports serving as a consultant for Acucela, Adverum, Aerpio, Alcon, Alimera Sciences, Allergan, Alnylam, Apellis, Arctic Vision, Bausch + Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong Biotechnologies, Clearside Biomedical, Corcept Therapeutics, Dutch Ophthalmic Research Center, EyePoint, Genentech, Gyroscope, IVERIC Bio, Kodiak Sciences, Merck, NGM Biopharmaceuticals, Notal Vision, Novartis, OccuRx, ONL Therapeutics, Opthea, Oxurion, Palatin, Polyphotonix, Recens Medical, Regeneron Pharmaceuticals, RegenXBio, Roche, Santen, Takeda, Thea Open Innovation, and Verana Health; personal fees from 4DMT, AbbVie, Aerie, AGTC, Alimera, Allgenesis, Annexon, Arrowhead, Boehringer Ingelheim, Cholgene, Clearside, Curacle, Foresite, Frontera, IACTA, Janssen, Kato, Kiora, Kodiak, Kriya, Nanoscope, Ocular Therapeutix, Ocuterra, OliX, Oxular, PerceiveBio, Perfuse, Ray, Regeneron, Resonance, SciNeuro, Stealth, Surrozen, TissueGen, and Valo; grants for research support from 4DMTAdverum, Aerie Pharmaceuticals, AffaMed, Aldeyra, Allergan, Alexion, Alimera, Alkahest, Allgenesis, Apellis, Amgen, Annexin, Annexon, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong Biotechnologies, Clearside Biomedical, Curacle, EyePoint, Gemini Therapeutics, Genentech, GlaxoSmithKline, Graybug Vision, Gyroscope, IONIS Pharmaceutical, IVERIC Bio, Kodiak Sciences, LMRI, Mylan, Neurotech Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Nanoscope, Ocular Therapeutix, Ocuphire, OcuTerra, Ophthotech, Opthea, Outlook Therapeutics, Oxurion, Oxular, Oyster Point, PerceiveBio, Recens Medical, Regeneron Pharmaceuticals, RegenXBio, Roche, Samsung Bioepis, Santen, Senju, Taiwan Liposome Company, SamChunDang Pharm, Sandoz, UNITY, Verily, and Xbrane BioPharma; speaker fees from Regeneron Pharmaceuticals; and other support from ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, and Vitranu outside the submitted work. Dr Brown reports grants and personal fees from Regeneron/Bayer during the conduct of the study; grants and personal fees from Genentech/Roche, Kodiak Sciences, and Clearside Pharma outside the submitted work; serves as a consultant for Regeneron Pharmaceuticals, Genentech/Roche, Novartis, Heidelberg, Allergan, Chengdu Kanghong Biotechnology, Santen, OHR, Clearside Biomedical, Adverum, RegenXBio, Samsung, Bayer, Optos, Kodiak, Senju, and Biotime; and research support from Regeneron Pharmaceuticals, Genentech/Roche, Novartis, Heidelberg, Allergan, Chengdu Kanghong Biotechnology, Santen, OHR, Clearside Biomedical, Adverum, RegenXBio, and Samsung. Dr Reed reports stock/stock options from Regeneron Pharmaceuticals during the conduct of the study. Dr Berliner reports an international patent application publication no. WO2022/245739 pending; and holds stock/stock options in Regeneron Pharmaceuticals. Dr Gerstenblith reports personal consultant fees from Regeneron and Allergan outside the submitted work. Dr Breazna holds stock/stock options in Regeneron Pharmaceuticals. Dr Abraham reports grants from Regeneron, Roche-Genentech, Alexion, Amgen, RegenXBio, Kodiak Sciences, Opthea, Apellis, Iveric Bio, Oculls SA, Ocuphire, Stealth, SanChunDang Pharm, Sandoz, Gemini Therapeutics, and NGM Bio. Dr Fein reports personal fees from Regeneron, Genentech, Bausch and Lomb, and Apellis outside the submitted work and serves as a consultant for Regeneron, Bausch and Lomb, Genentech/Roche, and Apellis; and serves as a speaker for Regeneron, Genentech/Roche, and Apellis Pharmaceuticals. Ms Chu holds stock/stock options in Regeneron Pharmaceuticals. Dr Clark reports grants and personal fees from Regeneron Pharmaceuticals and grants from Bayer during the conduct of the study; grants and personal fees from Genentech/Roche outside the submitted work; serves as a consultant for Genentech and Regeneron; research support from Genentech; serves as a lecturer for Bayer, Genentech, and Regeneron; and receives travel support from Bayer, Genentech, and Regeneron. Dr Leal is a stockholder in Bayer Consumer Care AG. Dr Schmelter is a stockholder in Bayer AG. Dr Hirschberg holds stock/stock options in Regeneron. Dr Yancopoulos hold stock/stock options in Regeneron Pharmaceuticals and has a patent to EYLEA. Dr Vitti holds stock/stock options in Regeneron Pharmaceuticals and has a patent to International patent application publication no. WO2022/245739 pending. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Key Anatomic Outcomes in the Full Analysis Set
For last observation carried forward, missing observations were imputed by the last nonmissing postbaseline observation. For participants receiving additional treatment at week 16, measurements after week 16 were imputed using last observation carried forward prior to additional treatment. Least squares mean difference was determined based on an analysis of covariance model with treatment as the main effect and baseline measurement as covariates. CRT indicates central retinal thickness. aNo fluid in the central subfield was defined as absence of intraretinal and subretinal fluid in the central subfield on spectral-domain optical coherence tomography. bScheduled dose visit. cTreatment difference was 17.0% (95% CI, –1.6% to 35.5%; P = .08) at week 16 (primary efficacy end point). dTreatment difference was 11.3% (95% CI, –6.6% to 29.2%; nominal P = .22) at week 44. eLeast squares mean difference at week 44 was –9.5 (95% CI, –51.4 to 32.4) letters vs 2-mg aflibercept (nominal P = .65).
Figure 2.
Figure 2.. Key Visual Outcomes in the Full Analysis Set
For last observation carried forward, missing observations were imputed by the last nonmissing postbaseline observation. For participants receiving additional treatment at week 16, measurements after week 16 were imputed using the last observation carried forward prior to additional treatment. Least squares mean difference was determined based on an analysis of covariance model with treatment as the main effect and baseline measurement as covariates. BCVA indicates best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study. aLeast squares mean difference at week 44 was 2.8 (95% CI, –1.4 to 7.0) letters (nominal P = .20) vs 2-mg aflibercept. bScheduled dose visit. cTwo participants in the aflibercept, 2 mg, group did not have postbaseline values.
Figure 3.
Figure 3.. Mean Change From Baseline in Predose Intraocular Pressure (IOP) and Blood Pressure (BP) in the Safety Analysis Set
aScheduled dose visit.
See this image and copyright information in PMC

Comment in

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