High-Dose Aflibercept Improves Therapeutic Benefit, May Reduce Treatment Burden

Aflibercept injections delivered at a high dose appear to have greater therapeutic benefits than standard dosing, laying the groundwork for a potential reduction in treatment burden.

High-dose aflibercept appear to have a greater therapeutic benefit than standard dosing, according to the review of a clinical trial published in JAMA Ophthalmology. Researchers suggest this finding sets the stage for investigations into whether an extended dosing interval with the higher dose injection could reduce treatment burden for patients with exudative retinal diseases.

Prior reports indicate that intravitreal aflibercept, 2 mg or 4 mg, can treat neovascular age-related macular degeneration (nAMD), enhancing anatomic gains compared with 0.5-mg injections. The 44-week, phase II CANDELA trial (ClinicalTrials.gov Identifier: NCT04126317), launched in 2019, demonstrates that aflibercept 8 mg can reliably improve structural and functional outcomes compared with 2 mg, although this finding is not statistically significant. The high-dose aflibercept appears to have no new safety concerns or changes to intraocular pressures (IOP), according to the research.

The 45-site trial enrolled 106 eyes with treatment-naïve nAMD-related subfoveal choroidal neovascularization. Participants were randomly assigned 1:1 to receive 3 monthly doses of 8 mg (n=53) or 2 mg (n=53) aflibercept, followed by additional injections at 20 and 32 weeks. In the 8 mg (70 µl) arm, 50.9% of eyes exhibited no central subfield fluid at 16 weeks — the efficacy end point — compared with 34% that were treated with 2 mg (50 µl) doses (P =.08).

Researchers used analysis of covariance to find 44-week exploratory end points: 39.6% having 8 mg therapy achieved fluid-free status vs 28.3% in the 2-mg cohort (nominal P =.22).

Fewer participants in the aflibercept, 8 mg, group lost 5 or more letters, 10 or more letters, or 15 or more letters compared with the aflibercept, 2 mg, group at week 44.

Participants who received the high-dose aflibercept achieved +7.9 (1.5) letters gained by week 44, more than the +5.1 (1.5) letters in the 2 mg arm (nominal P =.20). The researchers report that other investigations note similar improvements for participants of phase 3 trials of currently approved anti-vascular endothelial growth factor (VEGF) agents with dosing regimens of every 4 weeks and every 8 weeks.

Also, at 44 weeks, those undergoing high-dose aflibercept therapy attained mean (SE) central retinal thickness change of -159.4 (16.4) µm compared with -137.2 (22.8) µm for eyes in the 2 mg group; a least squares mean difference of -9.5 (95% CI, -51.4 to 32.4, nominal P =.65).

“Fewer participants in the aflibercept, 8 mg, group lost 5 or more letters, 10 or more letters, or 15 or more letters compared with the aflibercept, 2 mg, group at week 44,” the investigators explain. “Conversely, more participants in the aflibercept, 8 mg, group gained 10 or more or 15 or more letters compared with the aflibercept, 2 mg, group.”

Previous trials have also shown potentially enhanced durability in favor of ranibizumab, 2 mg vs 0.5 mg, as well as a similar trend with brolucizumab, 6 mg compared with 3 mg. Conversely, “improved visual or anatomic outcomes were not observed” in an analysis comparing ranibizumab 2 mg and 0.5 mg for treatment-naïve nAMD eyes.

The proof-of-concept nature of the investigation may be a study limitation. Also, for head-to-head comparison, patients receiving aflibercept, 2 mg, underwent different intervals than labeled.

Disclosure: Multiple study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Wykoff CC, Brown DM, Reed K, et al. Effect of high-dose intravitreal aflibercept, 8 mg, in patients with neovascular age-related macular degeneration: The phase 2 CANDELA randomized clinical trial. JAMA Ophthalmol. Published online August 3, 2023. doi:10.1001/jamaophthalmol.2023.2421