Introduction and Highlights
The management of neovascular age-related macular degeneration (nAMD) has been revolutionized by anti-vascular endothelial growth factor (VEGF) therapies. However, polypoidal choroidal vasculopathy (PCV), a distinct clinical entity often considered a subtype of nAMD, presents unique therapeutic challenges, particularly in Asian populations where its prevalence is significantly higher. The PULSAR randomized clinical trial recently evaluated the efficacy of a high-dose (8 mg) formulation of aflibercept compared to the standard 2 mg dose. This post hoc analysis specifically scrutinizes the outcomes for the subgroup of patients diagnosed with PCV.
Key Highlights
Visual Acuity Maintenance: Aflibercept 8 mg demonstrated best-corrected visual acuity (BCVA) gains that were noninferior to the 2 mg dose at week 48.
Extended Durability: Approximately 87% of participants receiving the 8 mg dose were able to maintain dosing intervals of 12 weeks or longer, significantly reducing the treatment burden compared to the standard 8-week cycle.
Anatomic Efficacy: Regression of polypoidal lesions was comparable across all treatment arms, supporting the use of 8 mg aflibercept as an effective monotherapy for PCV.
Background: The Challenge of Polypoidal Choroidal Vasculopathy
Polypoidal choroidal vasculopathy is characterized by a branching vascular network (BVN) and terminal aneurysmal dilatations, or polyps, within the choroidal circulation. Clinically, PCV often manifests with recurrent serosanguineous pigment epithelial detachments (PEDs) and subretinal hemorrhages. While standard anti-VEGF therapy is effective in reducing exudation, achieving complete regression of the polypoidal lesions—often considered a marker of disease stability—can be difficult with standard-dose monotherapy.
The Study of the Effects of High-Dose Aflibercept Injected Into the Eye of Patients With an Age-Related Disorder That Causes Loss of Vision Due to Growth of Abnormal Blood Vessels at the Back of the Eye (PULSAR) was designed to address the need for longer-acting therapies that do not compromise on visual or anatomic outcomes. By increasing the molar concentration of the drug, clinicians aim to extend the duration of VEGF suppression within the vitreous and retina.
Study Design and Methodology
This study was a post hoc subgroup analysis of the PULSAR trial, a phase 3, double-masked, multicenter randomized controlled trial. The analysis focused on 139 adults with nAMD who had indocyanine green angiography (ICGA)-confirmed PCV. ICGA remains the gold standard for diagnosing PCV, as it allows for the visualization of the characteristic branching vascular networks and polyps that may be obscured on standard fluorescein angiography.
Intervention Groups
Participants were randomized into three distinct treatment arms:
1. Aflibercept 8 mg every 12 weeks (q12).
2. Aflibercept 8 mg every 16 weeks (q16).
3. Aflibercept 2 mg every 8 weeks (q8).
All groups received three initial monthly loading doses. Starting from week 16, dosing intervals for the 8 mg groups were adjusted based on predefined disease activity criteria. The primary measure for this analysis was the least-squares (LS) mean change in BCVA from baseline to week 48.
Key Findings: Visual and Anatomic Outcomes
The results of the analysis provide strong evidence for the efficacy of high-dose aflibercept in the PCV population. At week 48, the LS mean BCVA change from baseline was +9.5 letters for the 8 mg q12 group, +8.4 letters for the 8 mg q16 group, and +9.1 letters for the 2 mg q8 group. The estimated differences compared to the 2 mg dose were minimal (0.40 letters for q12 and -0.7 letters for q16), with confidence intervals confirming noninferiority.
Durability and Injection Frequency
One of the most significant findings was the reduction in treatment frequency. Participants in the 8 mg q16 group received a mean of 5.1 injections over 48 weeks, compared to 7.0 injections in the 2 mg q8 group. Crucially, 87% of those assigned to the 8 mg arms successfully maintained an injection interval of at least 12 weeks. This suggests that the higher dose effectively extends the therapeutic window, which is a major factor in improving patient compliance and reducing the logistical burden on healthcare systems.
Anatomic Regression
Anatomic outcomes were equally encouraging. Polypoidal lesions were absent at week 48 in 37% of the 8 mg q12 group, 47% of the 8 mg q16 group, and 38% of the 2 mg q8 group. These rates of polyp closure suggest that aflibercept 8 mg monotherapy is as potent as the standard dose in addressing the underlying vascular abnormalities of PCV, despite the longer intervals between treatments.
Expert Commentary and Clinical Implications
The findings from the PULSAR post hoc analysis are particularly relevant for retina specialists treating PCV. The ability to achieve nearly 10 letters of visual gain while extending treatment to 16 weeks represents a significant step forward in personalized medicine. The pharmacokinetic profile of the 8 mg dose—providing a higher peak concentration and a longer duration above the inhibitory threshold—appears to be well-suited for the high-exudative nature of PCV.
Mechanistic Insights
In PCV, the choroidal hyperpermeability and the presence of polyps often require robust VEGF inhibition. The increased molar load of aflibercept 8 mg may provide more consistent suppression of VEGF-A and placental growth factor (PlGF) over time. This sustained suppression is likely responsible for the high percentage of patients maintaining extended intervals without a loss of visual acuity or a return of fluid.
Limitations
As this was a post hoc analysis, the study was not originally powered specifically for the PCV subgroup. Additionally, while ICGA was used for diagnosis, the study primarily focused on BCVA and fluid resolution rather than a primary endpoint of total polyp regression. Future prospective studies focusing exclusively on PCV populations may further clarify the optimal dosing strategies for this patient group.
Conclusion
The post hoc analysis of the PULSAR trial confirms that aflibercept 8 mg is a highly effective monotherapy for patients with polypoidal choroidal vasculopathy. It offers visual and anatomic outcomes comparable to the standard 2 mg dose while significantly extending the interval between injections. For clinicians, this represents a valuable tool in the effort to reduce the treatment burden of nAMD and its variants, potentially leading to better long-term real-world outcomes through improved adherence.
Funding and Registration
The PULSAR trial was funded by Bayer and Regeneron Pharmaceuticals. The trial is registered at ClinicalTrials.gov with the identifier NCT04423718.
References
1. Lee WK, Wong TY, Chen SJ, et al. Aflibercept 8 mg in Polypoidal Choroidal Vasculopathy: Post Hoc Analysis of the PULSAR Randomized Clinical Trial. JAMA Ophthalmol. 2025 Dec 18. doi: 10.1001/jamaophthalmol.2025.5098.
2. Lanzetta P, et al. Intravitreal aflibercept 8 mg in patients with neovascular age-related macular degeneration: 48-week results from the PULSAR phase 3 trial. The Lancet. 2024.
3. Cheung CMG, et al. Polypoidal choroidal vasculopathy: consensus on diagnosis and treatment. South Asia-Pacific PCV Roundtable Study Group. Ophthalmology. 2018.