High-dose aflibercept 8 mg as therapy for polypoidal choroidal vasculopathy

The results of a post-hoc analysis¹ of the PULSAR randomized clinical trial (NCT04423718) in participants with polypoidal choroidal vasculopathy (PCV) showed that aflibercept HD 8 mg and aflibercept 2 mg (Eylea, Regeneron Pharmaceuticals) achieved similar visual and anatomic outcomes and supported aflibercept 8 mg as an alternative monotherapy for PCV, according to the study authors led by first author Won Ki Lee, MD, PhD. He is from the Nune Eye Hospital, Seoul, Republic of Korea.

The authors explained the background for the study. “The criterion standard in PCV diagnosis is indocyanine green angiography (ICGA)-based imaging, which is an invasive and costly procedure that is not routinely performed in all countries.^2-5

Photodynamic therapy (PDT) and anti–vascular endothelial growth factor (anti-VEGF) therapies have been considered for PCV.⁶ “PDT was initially considered the mainstay of PCV treatment, although hampered by limited availability^6-8; however, clinical trial data have since supported anti-VEGF monotherapy with aflibercept, 2 mg. Anti-VEGF agents can effectively reduce exudation from polypoidal lesions and abnormal neovascular networks,⁶ although the need for frequent injections can result in poor treatment adherence.^6,9 It remains paramount to develop durable monotherapies that can be administered over prolonged dosing intervals while achieving robust clinical outcomes,” they emphasized.

When the two aflibercept doses were compared in the phase 3 PULSAR trial,¹⁰ treatment with aflibercept, 8 mg, every 12 or 16 weeks provided noninferior best-corrected visual acuity (BCVA) gains (4-letter noninferiority margin) at week 48 compared with every-8-week aflibercept, 2 mg.

The investigators conducted the post hoc subgroup analysis under discussion to compare the safety and efficacy of aflibercept, 8 mg, with aflibercept, 2 mg, through week 48 in participants with PCV that had been confirmed on indocyanine green angiography (ICGA) images. The subgroup analysis included 12 institutions from across Europe and Asia.

Post hoc methodology and results

The patients were randomized 1:1:1 to aflibercept, 8 mg, every 12 weeks or 16 weeks, or aflibercept, 2 mg, every 8 weeks, after they received three initial monthly doses. From the week 16 time point, the dosing intervals in patients receiving 8 mg every 12 weeks and every 16 weeks were shortened if predefined disease activity criteria were met at prespecified visits, according to the investigators.

A total of 139 patients were included in this analysis, all of whom had ICGA-confirmed PCV.

“In the treatment arms receiving aflibercept, 8 mg, every 12 and 16 weeks and aflibercept, 2 mg, every 8 weeks, the mean BCVA change from baseline at week 48 was +9.5, +8.4, and +9.1 letters, respectively (estimated difference, 0.40; 95% confidence interval [CI], −4.4 to 5.2 letters for 8 mg every 12 weeks vs 2 mg every 8 weeks; −0.7; 95% CI, −4.6 to 3.2 letters for 8 mg every 16 weeks vs 2 mg every 8 weeks), and polypoidal lesions were absent in 37%, 47%, and 38% of participants, respectively, who completed week 48,” Dr. Lee and colleagues reported.

They commented on their findings, “There remains an unmet need for PCV treatments that obviate the requirement for ICGA assessments and rescue PDT, while achieving standard of care efficacy with a regimen that reduces treatment burden and is practical for real-world implementation. Findings from the PULSAR trial showed that aflibercept, 8 mg, monotherapy can be administered with extended dosing intervals of every 12 to 16 weeks after 3 initial monthly doses in participants with nAMD, and this PULSAR trial post hoc subgroup analysis in participants with PCV demonstrated similar visual and anatomic improvements with aflibercept, 8 mg vs 2 mg, as administered in this trial, supporting its use as an alternative monotherapy for PCV.”

References

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2. Chaikitmongkol V, Cheung CMG, Koizumi H, Govindahar V, Chhablani J, Lai TYY. Latest developments in polypoidal choroidal vasculopathy: epidemiology, etiology, diagnosis, and treatment. Asia Pac J Ophthalmol (Phila). 2020;9:260-8. doi:10.1097/01.APO.0000656992.00746.48

3. Cheung CMG, Lai TYY, Teo K, et al. Polypoidal choroidal vasculopathy: consensus nomenclature and non–indocyanine green angiograph diagnostic criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup. Ophthalmology. 2021;128:443-52. doi:10.1016/j.ophtha.2020.08.006

4. Zhao J, Chandrasekaran PR, Cheong KX, Wong M, Teo K. New concepts for the diagnosis of polypoidal choroidal vasculopathy. Diagnostics (Basel). 2023;13:1680. doi:10.3390/diagnostics13101680

5. Fukuyama H, BouGhanem G, Moir J, Skondra D, Gomi F, Fawzi AA. Clinical variations of polypoidal choroidal vasculopathy: a cohort study from Japan and the USA. Sci Rep. 2023;13:4800. doi:10.1038/s41598-023-31649-x

6. Sen P, Manayath G, Shroff D, Salloju V, Dhar P. Polypoidal choroidal vasculopathy: an update on diagnosis and treatment. Clin Ophthalmol. 2023;17:53-70. doi:10.2147/OPTH.S385827

7. Cheung CMG, Lai TYY, Ruamviboonsuk P, et al. Polypoidal choroidal vasculopathy: definition, pathogenesis, diagnosis, and management. Ophthalmology. 2018;125:708-24. doi:10.1016/j.ophtha.2017.11.019

8. Sirks MJ, Subhi Y, Rosenberg N, et al. Perspectives and update on the global shortage of verteporfin (Visudyne). Ophthalmol Ther. 2024;13:1821-1831. doi:10.1007/s40123-024-00952-9

9. Ghanchi F, Bourne R, Downes SM, et al. An update on long-acting therapies in chronic sight-threatening eye diseases of the posterior segment: AMD, DMO, RVO, uveitis and glaucoma. Eye (Lond). 2022;36:1154-67. doi:10.1038/s41433-021-01766-w

10. Lanzetta P, Korobelnik JF, Heier JS, et al; PULSAR Investigators. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet. 2024;403:1141-1152. doi:10.1016/S0140-6736(24)00063-1