A turning point in nAMD treatment with high-dose aflibercept formulation

Increasing experience among ophthalmologists and patients attests to the durable efficacy and safety of the 8 mg formulation of the anti–vascular endothelial growth factor (anti-VEGF), aflibercept, in the treatment of neovascular age-related macular degeneration (nAMD). At an industrysponsored meeting, Dr Kenneth Fan of the Retina Consultants of Texas in Houston, Texas, US, reaffirmed the benefits of high-dose aflibercept in nAMD, highlighting how the positive experiences of his patients align with results of the pivotal PULSAR trial.

Overcoming treatment burden in nAMD
“nAMD often requires frequent intravitreal [IVT] injections of currently available standard-of-care anti-VEGF agents to achieve adequate disease control,” said Fan. “This results in a high treatment burden for patients, caregivers, doctors, and the healthcare system.” [Ophthalmologica 2020;243:1-8; Am J Manag Care 2023;29:S81-S89; Eye (Lond) 2024;38:3218-3221]

“The multi-targeted anti-VEGF agent, aflibercept 2 mg, has been widely used for over a decade due to its improved pharmacodynamic properties vs other agents, demonstrated efficacy in improving and maintaining vision in nAMD patients, and well-established safety profile,” he continued. [Prog Retin Eye Res 2021;84:100954; Transl Vis Sci Technol 2022;11:36; EMBO Mol Med 2016;8:1265-1288; Asia Pac J Ophthalmol (Phila) 2021;10:507- 518; Eylea 2 mg Hong Kong Prescribing Information] “However, treatment burden persists for many patients who continue to require frequent IVT anti-VEGF injections, leading to challenges with adherence and achieving optimal outcomes.” Nearly 40 percent of patients are nonadherent with their anti-VEGF treatment timeframes. [Loewenstein A, et al, EURETINA 2023; Ophthalmologica 2020;243:1-8; EURETINA Clinical Trends Survey, 2022]

To address this treatment burden, a high-dose formulation of aflibercept at 8 mg was developed to help achieve rapid and resilient fluid control, lasting vision gains, extended treatment intervals, and fewer injections. [Eye (Lond) 2024;38:3218-3221]

PULSAR: Sustained disease control with aflibercept 8 mg
The approval of aflibercept 8 mg for nAMD is based on PULSAR, a 96-week, randomized, double-blind, phase III noninferiority study involving 1,009 adult patients with treatment-naive nAMD who received either aflibercept 8 mg at Q12W (n=335) or Q16W (n=338), or aflibercept 2 mg at Q8W (n=336), after three initial monthly injections. [Lancet 2024;403:1141-1152]

The study revealed superior drying effects with aflibercept 8 mg. At week 16, significantly more patients in the pooled 8 mg groups had no retinal fluid in the centre subfield vs the 2 mg group (63 vs 52 percent; p=0.0002). [Lancet 2024;403:1141-1152]

“PULSAR’s post hoc analysis also suggests that early fluid resolution during the initial treatment phase may be a valid biomarker for the likelihood of maintaining extended treatment intervals with aflibercept 8 mg,” said Fan. “About 80 percent of patients in the aflibercept 8 mg Q16W arm who were fluid-free at week 4 maintained a Q16W interval through week 48.” [Zarranz- Ventura J, et al, EURETINA 2023]

At week 96, 78 percent of patients on aflibercept 8 mg Q16W achieved a last assigned treatment interval of ≥Q16W, while 53 percent achieved ≥Q20W (Q20W, 22 percent; Q24W, 31 percent). [Lanzetta P, et al, EURETINA 2023] Exploratory analysis also demonstrated that fewer patients treated with aflibercept 8 mg vs 2 mg required treatment intervals <Q8W (10.5 vs 22.4 percent). [Sivaprasad S, et al, ARVO 2024]

In terms of visual outcomes, week 96 results showed that aflibercept 8 mg Q12W and Q16W dosing regimens provided sustained and noninferior best corrected visual acuity (BCVA) gains vs aflibercept 2 mg Q8W (least squares mean BCVA changes from baseline, +5.6 and +5.5 vs +6.6 letters). [Lanzetta P, et al, EURETINA 2023]

Safety profiles were comparable between aflibercept 8 mg and 2 mg, with no new safety signals identified. The rate of intraocular inflammation was low (<2 percent) and similar across all treatment groups through 60 weeks. [Lanzetta P, et al, EURETINA 2023]

“These results indicate that aflibercept 8 mg improves treatment outcomes and provides rapid and sustained disease control in patients with nAMD, potentially reducing the treatment burden with fewer IVT injections and less frequent disease monitoring and clinic visits,” said Fan.

Clinical experience with aflibercept 8 mg
Patient eligibility
“In nAMD, we offer aflibercept 8 mg to as many patients as possible due to its proven efficacy and safety, to help reduce the overall treatment burden,” said Fan.

“In general, we anticipate the best response from treatment-naive patients [Case 1], similar to the patient profile in PULSAR,” he continued. “In patients with newly diagnosed nAMD, it is crucial to control the disease to improve and preserve functional and anatomic outcomes.” [Lancet 2024;403:1141-1152]

“We have also been using aflibercept 8 mg in previously treated patients, including those with difficult-to-extend disease [Case 2] and those with persistent retinal fluid,” he noted. “Sustained disease control with aflibercept 8 mg is achievable in these patients. While we may not be able to extend the treatment of all patients to ≥Q16W, we are still able to extend most of them beyond Q8W, which is still better than a monthly dosing regimen.”

Administration and safety concerns
“Aflibercept 8 mg may feel more viscous than the 2 mg formulation during administration, especially if using a 32 G or 33 G needle instead of the prescribed 30 G x ¹/₂ inch injection needle,” shared Fan. “However, the administration procedure is generally the same, with no additional precautions needed.” [Eylea 2 mg Hong Kong Prescribing Information; Eylea 8 mg Hong Kong Prescribing Information]

“Since 2023, we’ve performed over 5,000 injections with aflibercept 8 mg in patients with retinal diseases. Overall, our patients’ experiences have been positive and consistent with results of PULSAR,” said Fan. “While increased intraocular pressure [IOP] may be a concern, I have not observed marked IOP increases that required intervention in my patients, consistent with PULSAR’s results.” [Lancet 2024;403:1141-1152]

Systemic adverse events (AEs) have been reported following IVT anti-VEGF injections. However, rates of systemic AEs were generally low in PULSAR, with no increase in AE frequency with aflibercept 8 mg vs 2 mg. Nevertheless, caution should be exercised in patients with a history of stroke, transient ischaemic attack, or myocardial infarction within the last 6 months, as there are limited data on safety in these patient groups. [Lancet 2024;403:1141-1152; Eylea 8 mg Hong Kong Prescribing Information]

Comparison with other anti-VEGF agents
 “Based on PULSAR and our clinical experience, aflibercept 8 mg may soon replace the 2 mg formulation as the standard of care in nAMD management,” opined Fan. “Meanwhile, evidence regarding targeting angiopoietin-2 [Ang-2] in addition to VEGF is not yet solid for nAMD, as large-scale head-to-head trials are still lacking.”

 “We do have some preliminary evidence comparing the Ang-2/VEGF-A inhibitor, faricimab vs aflibercept 8 mg in patients with diabetic macular oedema [DME], but this if from an indirect comparison and not a head-to-head trial,” he added. [Wells JA, et al, MS 2025] “In my opinion, in many patients with uncontrolled DME, disease may remain persistent if insufficient anti-VEGF treatment is provided to achieve sustained disease control.”

 “Importantly, aflibercept also targets the placental growth factor, which may be more critical in the pathogenesis of retinal diseases such as DME than Ang-2,” he added. [Curr Eye Res 2023;48:297-311]

Summary
Aflibercept 8 mg represents a new paradigm in nAMD treatment, offering the potential for extended dosing intervals without compromising efficacy. Through sustained disease control, it provides lasting vision gains, rapid and resilient fluid control, and extended treatment intervals, with a safety profile comparable to that of aflibercept 2 mg.