Durable vision outcomes and extended Tx interval with aflibercept 8 mg in nAMD and DME: Insights for clinical practice
23 Apr 2025
byProf. Michael Stewart, Mayo Clinic, Jacksonville, Florida, US
Anti-vascular endothelial growth factor (anti-VEGF) agents are considered the standard of care (SoC) for neovascular agerelated macular degeneration (nAMD) and diabetic macular oedema (DME). However, the need for frequent intravitreal (IVT) injections leads to a substantial treatment burden. In an interview with MIMS Doctor, Professor Michael Stewart of the Mayo Clinic in Jacksonville, Florida, US, discussed how the highdose formulation of the anti-VEGF agent, aflibercept 8 mg, may address challenges associated with nAMD and DME management based on results of the pivotal PULSAR and PHOTON trials as well as his patients’ early experience.
Tx goals for nAMD and DME
“Achieving sustained disease control is the primary goal in nAMD and DME management,” Stewart said. “This means rapidly and safely controlling the disease by achieving fluid control [ie, dry retina] and maintaining vision gains with extended treatment intervals while administering fewer injections.” [Eye (Lond) 2024;38:3218-3221]
While anti-VEGF agents are SoC for nAMD and DME, lasting vision gains usually require frequent IVT injections, which imposes a substantial treatment burden on patients, their caregivers, and the healthcare system. [Am J Manag Care 2023;29(6 Suppl):S81-S89; Eye (Lond) 2024;38:3218-3221]
Treatment burden of nAMD and DME
“Frequent IVT injections require frequent clinic visits. Since nAMD and DME often affect older individuals, they must often come to the clinics with caregivers,” explained Stewart. [Patient Prefer Adherence 2022;16:587-604; Ophthalmic Res 2024;67:516-527; Eye (Lond) 2024;38:3218-3221] “Frequent clinic visits require time away from work for both patients and their caregivers, further adding to the logistical burden and cost, especially for younger DME patients who are still employed.” [Patient Prefer Adherence 2022;16:587-604; Ophthalmic Res 2024;67:516- 527; Ziemssen F, et al, EURETINA 2023]
“Frequent injections also mean congested clinics, making it difficult to provide the best care for patients with other ophthalmologic problems,” added Stewart. [Loewenstein A, et al, EURETINA 2023; Ziemssen F, et al, EURETINA 2023]
These challenges highlight the need for novel strategies, such as more potent agents or new formulations that require fewer IVT injections and fewer clinic visits, to help reduce the treatment burden of nAMD and DME. [Eye (Lond) 2024;38:3218-3221]
Improving durability with high-dose aflibercept 8 mg
The efficacy and safety of the 2 mg formulation of the multitargeted anti-VEGF agent, aflibercept, are well established in nAMD and DME. [Asia Pac J Ophthalmol (Phila) 2021;10:507-518; Clin Exp Ophthalmol 2018;46:75-86]
“Among the available anti-VEGF agents, aflibercept binds to the widest range of VEGFR-1/2 ligands, which are key drivers of retinal diseases,” stressed Stewart. “Importantly, aflibercept has the highest reported potency and binding affinity to VEGF-A, contributing to the sustained ocular VEGF suppression observed with the standard 2 mg dose.” [Eylea 2 mg Hong Kong Prescribing Information; Eylea 8 mg Hong Kong Prescribing Information; Prog Retin Eye Res 2021;84:100954; Sci Rep 2015;5:17946; Transl Vis Sci Technol 2022;11:36; EMBO Mol Med 2016;8:1265-1288]
“Doubling a drug’s dose theoretically increases its duration of action by one half-life,” Stewart suggested. “However, pharmacokinetic modelling based on data from >2,700 patients indicates that increasing the aflibercept dose from 2 mg to 8 mg actually slowed ocular clearance by 34.4 percent, resulting in a 6- to 8.9-week longer duration of effect vs the 2 mg dose.” [Invest Ophthalmol Vis Sci 2024;65:3154]
These results are consistent with findings of the PULSAR and PHOTON trials, which formed the basis for approval of aflibercept 8 mg in patients with nAMD and DME. [Invest Ophthalmol Vis Sci 2024;65:3154; Lancet 2024;403:1141- 1152; Lancet 2024;403:1153-1163]
Key efficacy and safety results of PULSAR and PHOTON
PULSAR was a 96-week, randomized, phase III noninferiority study in which 1,009 adults with treatment-naive nAMD received either aflibercept 8 mg Q12W (n=335) or Q16W (n=338) or aflibercept 2 mg Q8W (n=336), after three initial monthly injections. [Lancet 2024;403:1141-1152]
PHOTON was a randomized, double-blind, noninferiority, phase II/III trial in previously treated and treatment-naive patients with DME. Patients received either aflibercept 8 mg Q12W (n=328) or Q16W (n=163) or aflibercept 2 mg at Q8W (n=167), following initial monthly dosing. [Lancet 2024;403:1153-1163]
In both trials, the primary endpoint of noninferior visual gains with aflibercept 8 mg vs 2 mg at week 48 were met, with visual acuity (VA) improvements maintained through 96 weeks. Central retinal thickness (CRT) changes were similar in all treatment groups through 96 weeks. [Lancet 2024;403:1141-1152; Lanzetta P, et al, EURETINA 2023; Lancet 2024;403:1153-1163; Do DV, et al, ASRS 2023]
These vision gains were achieved and maintained over 96 weeks with approximately eight injections in the aflibercept 8 mg Q16W arms of both studies vs up to 14 injections in the aflibercept 2 mg arm. Overall, of patients initially randomized to receive aflibercept 8 mg Q16W, 53 and 46 percent achieved a last assigned treatment interval of ≥Q20W in the PULSAR and PHOTON studies, respectively. (Figure 1) [Lanzetta P, et al, EURETINA 2023; Do DV, et al, ASRS 2023]
“For patients with DME, the 3-year results of PHOTON continued to demonstrate durable vision gains and anatomic improvements with extended dosing intervals,” shared Stewart. In this optional extension study, approximately 88 percent and 48 percent of patients had a last assigned dosing interval of ≥Q12W and ≥Q20W, respectively, at the end of 3 years of treatment. [Do DV, et al, AAO 2024]
Aflibercept 8 mg also had a comparable safety profile to the 2 mg dose. Ocular adverse events (AEs) in the study eyes, including intraocular inflammation (IOI), were similar across all treatment groups in a pooled analysis of CANDELA, PULSAR, and PHOTON (n=1,773). [Invest Ophthalmol Vis Sci 2023;64:3724]
Clinical experience with aflibercept 8 mg
“Although aflibercept 8 mg has been available for <2 years in the US, my nAMD and DME patients’ results align with PULSAR and PHOTON,” noted Stewart. “[In PULSAR,] aflibercept 8 mg offers superior drying effects [at week 16] and early VA improvements, allowing many to start a treat-and-extend [T&E] regimen immediately.”
Patient eligibility
“All patients with nAMD and DME can start or switch to aflibercept 8 mg,” suggested Stewart. “Its rapid and durable effects are especially notable in treatment-naive nAMD patients. In these patients, I immediately prescribe the 8 mg formulation to achieve early disease control and minimize treatment burden, aligning with the PULSAR patient population.” [Lancet 2024;403:1141-1152]
“I have also used aflibercept 8 mg in patients with nAMD with prior use of anti-VEGFs, including those with difficult-to-treat disease,” added Stewart. (Case 1)
“DME usually requires more intensive treatment due to the multifactorial nature of its pathophysiology, which may partly explain why the process of retinal drying may take longer vs nAMD,” he noted. [Cells 2022;11:3362] “However, we still observe superior drying effects of aflibercept 8 mg vs 2 mg, allowing extended treatment intervals for many patients, including challenging cases.” (Case 2) [Lancet 2024;403:1153-1163; Khurana RN, et al, Macula Society 2024]
T&E practices with aflibercept 8 mg
“We are seeing a gradual shift from using aflibercept 2 mg to 8 mg in our clinical practice because of the solid clinical evidence and our positive early experiences with this high-dose formulation,” shared Stewart.
“In patients eligible for a T&E regimen after completing the 3 loading doses,I increase the dosing intervals by 2- to 4-week increments,” said Stewart. “Because of its consistent, superior and durable drying effects in both nAMD and DME, we are now more confident in extending treatment intervals in most patients without requiring follow-ups between injections, as long as their vision gains are maintained, and their anatomic findings remain stable.”
“At each clinic visit for patients with nAMD or DME, I always perform VA assessment, pupil dilation, and an optical coherence tomography scan,” he noted. “During the dilated eye examination, I look out for any new haemorrhages or signs of disease worsening to decide on the appropriate treatment interval.”
“We do not routinely check intraocular pressure [IOP] after IVT injection,” added Stewart. “Performing counting fingers immediately after injecting aflibercept 8 mg should suffice to screen for vision abnormalities.”
Summary
“Aflibercept 8 mg improves functional and anatomic outcomes with extended treatment intervals in nAMD and DME while maintaining a similar safety profile to the 2 mg formulation,” reiterated Stewart. “With the robust results from PULSAR and PHOTON as well as our patients’ early positive experiences, aflibercept 8 mg is one of my preferred agents, allowing longer treatment intervals and fewer injections while sustaining vision outcomes, potentially reducing treatment burden and improving patients’ quality of life.
