CANDELA Study Suggests Therapeutic Potential of Aflibercept 8 mg in nAMD

Charles C. Wykoff, MD, PhD

Credit: Retina Consultants of Texas

The use of aflibercept 8 mg trended toward better anatomic and visual outcomes, with similar safety, compared to aflibercept 2 mg, in patients with neovascular age-related macular degeneration (nAMD), according to new research.

Results from the phase 2 CANDELA randomized clinical trial showed more eyes treated with aflibercept 8 mg had no fluid in the central subfield at 16 weeks compared with aflibercept 2 mg; however, a statically significant difference was not achieved at the 2-sided 5% significance level.

“Within the CANDELA trial, consistent improvements in anatomic and visual outcomes were achieved with aflibercept, 8 mg, that trended toward a numeric benefit vs. aflibercept, 2 mg,” wrote the investigative team, led by Charles C. Wykoff, MD, PhD, of the Retina Consultants of Texas. “Treatment with aflibercept, 8 mg, was well tolerated with a similar safety profile to aflibercept, 2 mg, through week 44.”

An increase in the molar dose of an anti-vascular endothelial growth factor (VEGF) agent could presumably provide additional anatomic benefits, but these effects have been variable across trial findings. Results from the SAVE trial showed ranibizumab 2 mg may lead to functional and anatomical benefit for patients with recalcitrant nAMD, compared with ranibizumab 0.5 mg, but improvements were not observed among treatment-naive patients with nAMD in the HARBOR trial.^2,3

Multiple trials, including the phase 3 VIEW 1 and 2 trials and the phase 2 CLEAR-IT 2 trial, have shown higher dose aflibercept led to improved clinical outcomes among patients. However, without definitively establishing where a higher molar dose of aflibercept could lead to improved visual and anatomic outcomes with extended dosing intervals, there is a need for further evaluation in clinical trials.

The CANDELA trial assessed the safety and efficacy of aflibercept 8 mg, a 4-fold higher molar dose of aflibercept 2 mg, in individuals with treatment-naive nAMD. The single-masked, open-label, 44-week clinical trial was conducted across 45 sites in the United States between November 2019 - November 2021. It recruited eligible participants ≥50 years old with treatment-naive, active subfoveal choroidal neovascularization (CNV) secondary to nAMD and a best-corrected visual acuity score (BCVA) of 78 to 24 (equivalent 20/32 to 20/320).

For the purpose of analysis, 106 eyes were randomized in a 1:1 ratio to receive 3 monthly doses of aflibercept 8 mg (n = 53), or aflibercept 2 mg (n = 53) followed by doses at weeks 20 and 32. Co-primary outcomes for the trial were the proportion of eyes with the absence of intraretinal and subretinal fluid in the central subfield at week 16, as well as safety, assessed by the incidence of treatment-emergent adverse events (TEAEs) through week 4 and week 44.

Upon analysis, at week 16, the proportion of eyes without fluid in the central subfield was 50.9% (n = 27) in the aflibercept 8 mg group and 34.0% (n = 18) in the aflibercept 2 mg group (treatment difference, 17.0 percentage points [95% CI, –1.6 to 35.5]; P = .08).

Additionally, at week 44, more eyes in the aflibercept 8 mg group (39.6%) compared with aflibercept 2 mg (28.3%) achieved a fluid-free central subfield (treatment difference, 11.3 percentage points [95% CI, –6.6 to 29.2]; nominal P = .22).

Further results showed the mean change from baseline in central retinal thickness at week 44 was –159.4 µm for aflibercept 8 mg versus –137.2 µm for aflibercept 2 mg (least-squares mean difference, –9.5 [95% CI, –51.4 to 32.4]; nominal P = .65). By week 44, participants receiving aflibercept 8 mg achieved a +7.9-letter improvement in BCVA compared with +5.1 letters in the aflibercept 2 mg group (least-squares mean difference, +2.8 [95% CI, –1.4 to +7.0]; nominal P = .20).

Investigators observed no new safety signals for aflibercept 8 mg at week 4 for the primary safety endpoint and through the 44-week study period, with a similar safety profile to aflibercept 2 mg. These results were supported by recent 48-week primary endpoint data from the ongoing phase 3 PULAR trial in nAMD showing non-inferior visual gains and a greater proportion of participants achieving dryness in the central subfield with aflibercept 8 mg treatment.

“Further evaluation in the pivotal 96-week PULSAR (in nAMD) and PHOTON (in diabetic macular edema) trials may support the long-term therapeutic potential of aflibercept, 8 mg, for improving outcomes and decreasing treatment burden for patients with exudative retinal diseases,” investigators wrote.

References

1. 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 03, 2023. doi:10.1001/jamaophthalmol.2023.2421
2. Brown DM, Chen E, Mariani A, Major JC Jr; SAVE Study Group. Super-dose anti-VEGF (SAVE) trial: 2.0 mg intravitreal ranibizumab for recalcitrant neovascular macular degeneration-primary end point. Ophthalmology. 2013;120(2):349-354.
3. Busbee BG, Ho AC, Brown DM, et al; HARBOR Study Group. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120(5):1046-1056.