Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration
Authors: Wykoff Charles C. , Brown David M. , Reed Kimberly , Berliner Alyson J. , Gerstenblith Adam T. , Breazna Aurora , Abraham Prema , Fein Jordana G. , Chu Karen W. , Clark W. Lloyd , Leal Sergio , Schmelter Thomas , Hirshberg Boaz , Yancopoulos George D. , Vitti Robert ,   CANDELA Study Investigators, Alam Suhail , Gonzalez Ramos Astrid , Alfaro Daniel Virgil , Adrean Sean , Payne John , Brooks Harold , Chittum Mark , Callanan David , Paylor Ralph , Chan Clement , Allen John , Chaudhry Nauman , Chang Margaret , Chen Sanford , Bridges William , Dooner James , Solley Wayne , Emanuelli Andres , Teed Ronald , Friedman Scott , Moinfar Nader , Ghorayeb Ghassan , Lee Shelly , Berinstein Daniel , Goff Mitchell , Reiser Harvey , Guerami Amir , Ashmore Emily , Hagedorn Curtis , Martinez Jose , Hahn Paul , Colina-Biscotto Juner , Hershberger Vrinda , Joondeph Brian , Kruger Erik , Bryan J. Shepard , Lee Michael , Chiu Mark , Roybal C. Nathaniel , Wyant Frank , Luu James , Byun Matthew , Palmer James , Wieland Mark , Pearlman Joel , Berger Evan , Pitcher John , Rathod Rajiv , Punjabi Omar , Feiner Leonard , Ramkumar Hema , Lin Steven , Reddy Rahul , Dreyer Richard , Steinle Nathan , Sheth Veeral , Faber David , Stone Cameron , Engstrom Robert , Wirthlin Robert , El-Gasim Mahmood , Parnes Robert 
Published: August 2023

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