Long-term efficacy of aflibercept 8 mg in neovascular age-related macular degeneration: 96-week insights from the PULSAR trial

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with the neovascular form (nAMD) accounting for a significant proportion of global vision loss (1). The introduction of anti-vascular endothelial growth factor (anti-VEGF) medications, such as bevacizumab, revolutionized treatment for nAMD. Over the last two decades, agents engineered specifically for retinal vascular disease, such as ranibizumab and aflibercept 2 mg, have established the current standard of care for nAMD.

Despite these advances, a critical limitation of intravitreal therapy is the high treatment burden, which can exacerbate socioeconomic barriers and increase the cumulative risk of endophthalmitis and injection-related complications (2,3). Consequently, there is an unmet clinical need for highly effective medications that provide sustained disease control with extended injection intervals.

Aflibercept 8 mg delivers a 4-fold higher molar dose than the 2 mg concentration, aiming to prolong intraocular VEGF suppression. To evaluate the safety and efficacy of aflibercept 8 mg, the phase 3 PULSAR clinical trial was conducted. Its initial 48-week results established the non-inferiority of aflibercept 8 mg compared to the 2 mg dose in treatment-naïve adults, with the added benefit of treatment intervals extending up to 16 weeks (4). Notably, the initially approved Food and Drug Administration (FDA) label for the 8 mg dose reflects the trial’s induction protocol of three initial monthly doses, followed by all subsequent doses administered at least 8 weeks apart, a regimen that differs from the more flexible dosing schedules of other contemporary anti-VEGF agents (5). In November 2025, the FDA approved 4-week dosing even after loading doses for patients who may not maintain a response with extended dosing intervals (6).

In Ophthalmology, Korobelnik et al. present the 96-week results of the PULSAR trial, demonstrating that aflibercept 8 mg provides durable disease control through 2 years of treatment (7). While the primary endpoint was non-inferior best-corrected visual acuity (BCVA) at 48 weeks, secondary endpoints revealed that the 8 mg dose was superior in reducing macular fluid prevalence. Korobelnik et al. confirmed that these anatomic and functional gains were maintained through week 96. Specifically, the least squares (LS) mean change in BCVA from baseline was +5.5 letters [95% confidence interval (CI), 4.0–7.0] for the 8 mg every-16-week (8q16) group, compared to +6.6 letters (95% CI, 5.2–8.0) for the 2 mg every-8-week (2q8) control. While meeting the prespecified noninferiority margin of 4 letters, the differences numerically favored the more frequently dosed 2 mg arm. Anatomically, the 8q16 group achieved a mean reduction in central retinal thickness (CRT) of −153.4 μm, while the 2q8 group saw a reduction of −135.8 μm.

These results highlight a clinically meaningful reduction in treatment burden. Over 96 weeks, patients in the 8q16 group received an average of 8.2 injections, compared to 12.8 injections in the 2q8 group. Furthermore, 53% of 8q16 patients qualified for subsequent intervals of ≥20 weeks, and 31% reached intervals of ≥24 weeks. These data strongly support the utility of aflibercept 8 mg within a “treat-and-extend” (T&E) framework. Importantly, despite the higher molar concentration and increased volume, the safety profile of the 8 mg dose remained comparable to the 2 mg dose.

However, the broadly comparable functional gains across arms and certain trial design elements warrant careful interpretation. Anatomical endpoints such as CRT reduction and fluid control do not always correlate with patient-oriented outcomes such as visual improvement, quality of life, and treatment burden (8). The anatomical advantages demonstrated with aflibercept 8 mg, while reproducible, have yet to be shown to confer long-term functional benefit beyond what is achievable with the established 2 mg regimen. The current clinical significance of aflibercept 8 mg should therefore be framed primarily around its reduction in treatment burden rather than visual or anatomical superiority. In this regard, the reduction in injection frequency is itself a patient-centred outcome of considerable importance. The burden of frequent intravitreal injections, encompassing clinic visits, patient anxiety, treatment fatigue, and risk of cumulative complications, is well documented, and reduced treatment frequency may meaningfully improve adherence and quality of life in real-world settings (2,9). Additionally, the PULSAR protocol prespecified that only the 8 mg cohorts were eligible for interval extension beyond 52 weeks, preventing a head-to-head comparison of durability against the 2 mg dose. While Korobelnik et al. referenced previous studies (ALTAIR, ARIES, and AZURE) to suggest that aflibercept 2 mg has a ceiling for extension, with roughly 40% of patients unable to extend beyond 12 weeks, these cross-study comparisons are limited by heterogeneous patient populations and protocols (10-12). A direct head-to-head comparison within a clinical trial setting would better quantify the durability advantage of aflibercept 8 mg over the 2 mg dose over 96 weeks, providing the evidence-based data necessary for informed clinical decision-making and patient counseling.

Furthermore, as PULSAR exclusively enrolled treatment-naïve patients, its findings may not fully translate to the recalcitrant, chronically diseased populations seen in daily practice. The available real-world evidence in the pre-treated population derives entirely from retrospective observational studies, and its conclusions must be cautiously interpreted. These studies are subject to selection bias as well as significant heterogeneity in prior treatment history, switching criteria, and loading-phase protocols. The absence of a control arm and randomization in these analyses further limits conclusions that can be drawn about drug performance independent of underlying disease severity. With these caveats in mind, a consistent pattern emerges across multiple independent retrospective cohorts of pre-treated patients. Real-world studies of “switch” patients suggest that achieving 16-week intervals is significantly more challenging in pre-treated eyes. For example, in a retrospective study of 209 eyes switched to aflibercept 8 mg, with an average baseline of 22.6 prior injections, the mean treatment interval significantly increased from 5.8 to 7.4 weeks (13). Notably, 47% of these patients were unable to extend beyond a 7-week interval following the third injection. This cohort’s pre-switch interval was, on average, 2 weeks shorter than the 2 mg control group in PULSAR, highlighting the stark disparity between controlled trial environments and the reality of managing “recalcitrant” disease. While the study found no significant improvements in BCVA or CRT, it did reveal a significant reduction in the prevalence of macular fluid post-switch. Furthermore, most patients in this cohort did not, or could not, adhere to the original FDA-approved induction schedule. Many either maintained their previous intervals or failed to extend to 7 weeks after the third dose, likely because persistent exudation made such an extension clinically untenable.

Several other retrospective cohort studies mirror these findings of modest interval extension and anatomical improvement, but with minimal functional improvement. Lee et al. (654 eyes, 12-month follow-up), demonstrated a significant increase in the proportion of dry maculae from 55% at switch to 76% at 3 months, sustained at 69% at 12 months (P<0.05), with mean treatment intervals extending from 6.0 to 7.8 weeks (P<0.001) (14). However, the study found a slight decline in BCVA, warranting further study into the functional benefits of aflibercept 8 mg in pre-treated eyes. Abu Ishkheidem et al. (181 eyes) observed reductions in intraretinal fluid (34.3% to 19.3%) and subretinal fluid (53.0% to 33.7%, both P<0.001), with a mean interval extension of 1.27 weeks (P=0.0009) (15). Janmohamed et al. (66 treatment-refractory eyes) reported complete macular fluid resolution in 23.9% of eyes with baseline fluid and a median interval increase from 4 to 6 weeks (P<0.001), with 34.8% achieving ≥8-week intervals (16). Taken together, these early real-world data confirm that switching to aflibercept 8 mg yields anatomic improvements and modest treatment interval extension in pretreated nAMD, while visual acuity is largely maintained. However, a substantial proportion of pretreated eyes remain unable to achieve the extended dosing intervals observed in the PULSAR trial, unsurprising given both the far shorter follow-up periods in these real-world studies and the inherent differences between controlled trial environments and routine clinical practice. Nonetheless, the convergence of findings across multiple centres lends credibility to the overall pattern, and suggests that the interval extension benchmarks established in PULSAR are difficult to replicate in the heavily pretreated patients most commonly encountered in practice. To accommodate this reality, the updated FDA guidance permits more flexible dosing for patients who cannot achieve extended intervals but may still derive meaningful benefit from aflibercept 8 mg.

Several theories may explain the attenuated response in chronic cohorts, though it is important to note that these remain hypotheses informed by the broader literature rather than conclusions directly supported by the PULSAR trial or the retrospective studies cited above. First, the disease phenotype in chronically treated cohorts often represents a more aggressive or ‘recalcitrant’ baseline compared to treatment-naïve participants (17). In these eyes, the higher molar concentration of aflibercept 8 mg may provide additional “drying” power, yet remain insufficient to fully overcome the high VEGF production rate required for significant interval extension. Second, chronic exposure to anti-VEGF therapy can lead to secondary resistance through multiple mechanisms. Long-term treatment may trigger tachyphylaxis, a rapid decrease in drug response potentially caused by the upregulation of alternative pro-angiogenic pathways, such as VEGF-C, VEGF-D, or Angiopoietin-2, which are not neutralized by aflibercept (18). Additionally, chronic sub-retinal inflammation and the development of sub-retinal fibrosis can create a physical barrier to fluid resorption and stabilize the neovascular complex, making it less sensitive to even high-dose VEGF inhibition (19). In such cases, while aflibercept 8 mg can maximize VEGF-A suppression, the underlying structural changes and redundant signalling pathways in ‘pre-treated’ eyes may prevent the dramatic durability seen in the treatment-naïve PULSAR population. Taken together, these considerations suggest that, in pre-treated eyes, underlying structural changes and redundant signalling pathways may limit the dramatic durability seen in the treatment-naïve PULSAR population. However, these explanations remain speculative, and dedicated mechanistic studies in chronic or refractory nAMD cohorts are needed to substantiate them.

Despite the inherent difficulties of cross-study comparisons, the 96-week outcomes of PULSAR align broadly with the 2-year results of the TENAYA and LUCERNE trials, which evaluated the bispecific antibody faricimab (20). Both therapeutic regimens demonstrated non-inferior visual acuity gains compared to the traditional aflibercept 2q8, with LS mean BCVA increases of +5.5 to +5.6 letters in PULSAR and +3.7 to +5.0 letters in the faricimab trials. Crucially, both agents demonstrate increased durability. While 74.1–81.2% of faricimab patients achieved ≥12-week dosing by year two, 87% of the aflibercept 8q12 group maintained that interval through week 96. These collective data signal a paradigm shift toward extended-durability therapies that reduce treatment burden without compromising ocular safety. While real-world data for both aflibercept 8 mg and faricimab suggest a more modest extension than their respective clinical trials, both agents show significant promise in decreasing the treatment burden for nAMD patients (21).

The 96-week PULSAR data establish aflibercept 8 mg as a potent tool for extending the “durability ceiling” in treatment-naïve nAMD. However, its real-world utility was initially complicated by rigid, FDA-mandated dosing. This created a clinical paradox for recalcitrant “switch” patients who often demonstrate persistent exudation before the 7-week mark, yet the regulatory framework offered little formal flexibility for maintenance dosing between 4 and 7 weeks, potentially leading to issues with insurance coverage and reimbursement. As of November 2025, the more flexible 4-week dosing is welcome. Due to the trial design, we do not know if a longer monthly loading phase past 3 doses may allow for even further extension. Ultimately, to fully realize the potential of this higher molar dose, the field must transition from this “one-size-fits-all” protocol toward a clinician-driven approach. Further research is warranted to optimize dosing strategies for pre-treated patients and to determine if aflibercept 8 mg can be safely and effectively administered on a monthly basis if necessary to achieve adequate disease control.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0025/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0025/coif). D.A.M. received consulting fees from Apellis, Bausch & Lomb, ANI and EyePoint, and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Apellis, Bausch & Lomb and ANI. The other author has no conflicts of interest to declare.

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