Treatment outcomes of ziv‐aflibercept for treatment‐naïve polypoidal choroidal vasculopathy

Ziv-aflibercept (Zaltrap; Regeneron, New York, USA), a chemotherapeutic agent initially FDA-approved for metastatic colorectal cancer, has also shown promising results in the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (Ashraf et al. 2016) and branch retinal vein occlusion (Chan et al. 2017). In a recent study, ziv-aflibercept achieved visual and structural outcomes comparable to that demonstrated by aflibercept in the VIEW1 and two trials of nAMD (Heier et al. 2012; Mansour et al. 2016). Antivascular endothelial growth factor (anti-VEGF) agents remain a cornerstone of treatment for fluid recurrences in polypoidal choroidal vasculopathy (PCV), a variant of nAMD (Oishi et al. 2013). In an earlier safety evaluation of a single injection of ziv-aflibercept in nAMD and PCV patients conducted by our group, no ocular or electrophysiologic adverse effects were noted (Chhablani et al. 2017). However, the intermediate-term efficacy and safety outcomes of ziv-aflibercept remain unknown. We conducted a prospective 9-month multicentre pilot study including 23 treatment-naïve PCV patients (24 eyes). All eyes were treated with intravitreal 1.25 mg/0.05 ml of ziv-aflibercept at baseline and Pro-re-nata (PRN) ziv-aflibercept over 9 months. Indocyanine green angiography (ICGA) was performed at baseline to confirm the diagnosis of PCV. A comprehensive clinical examination including Snellen visual acuity (VA) assessment, dilated fundus examination, and spectral domain optical coherence tomography (SD-OCT) was performed at baseline, and at each monthly visit. Retreatment with ziv-aflibercept was based on the presence of macular oedema on SD-OCT, increase in central macular thickness (CMT) >100 μm, VA deterioration by Snellen equivalent of 0.1 logMAR or new haemorrhage on fundus examination. The primary outcomes were reduction in CMT and improvement in VA. Secondary outcomes included average number of injections administered, and incidence of ocular and systemic side-effects. The 23 patients (17 men and 6 women) had a mean age of 62.6 ± 6.8 years. At baseline, the mean logMAR VA was 0.55 ± 0.43 (20/70 Snellen equivalent), and mean CMT was 380.2 ± 105.3 μm (Table 1). At the 9-month visit, logMAR VA improved by 0.16 ± 0.18 to 0.39 ± 0.37 (20/50 Snellen equivalent; p < 0.001). Central macular thickness (CMT) decreased by 106.5 ± 115.4 μm to 273.7 ± 107.8 μm (p < 0.001). Over 9 months, each eye received an average of 3.0 ± 1.2 injections. No ocular and systemic side-effects were observed. These results are promising, and compare favourably with that of prior anti-VEGF monotherapy studies in PCV. Yamamoto et al. (2015) conducted a prospective fixed-dosing evaluation with monthly injections of aflibercept for the first 3 months and bimonthly for the remaining 9 months in PCV. At 12 months, logMAR VA improved by approximately 0.14 and CMT improved by 111 μm. The ranibizumab arm in the LAPTOP clinical trial involved fixed monthly dosing of ranibizumab for 3 months, followed by PRN injections. At 12 months, similar results for VA gain of 0.11 logMAR, and CMT reduction of 107 μm, were achieved (Oishi et al. 2013). The average number of injections was 4.5 over 12 months, which was slightly higher than that in our cohort, possibly due to the three initial mandatory loading injections and the slightly longer follow-up time. To date, no ocular or systemic safety concerns with the use of ziv-aflibercept have been raised. In an earlier study conducted by our group, electroretinography (ERG) demonstrated no evidence of retinal toxicity following a single injection of ziv-aflibercept (Chhablani et al. 2017). de Oliveira Dias et al. (2016) also did not detect ERG alterations in a cohort of nAMD patients treated with PRN ziv-aflibercept for 6 months. Although ERG testing was not performed in the current study, our results are consistent with all prior reports showing no safety issues with ziv-aflibercept. Our data provide encouraging evidence of the intermediate-term efficacy and safety of ziv-aflibercept in the treatment of PCV. The low cost of ziv-aflibercept relative to that of aflibercept confers a clear benefit in the provision of cost-effective treatment, particularly in low-income countries. Larger prospective studies confirming the longer-term efficacy of ziv-aflibercept are warranted, particularly for its ability to achieve polyp regression and reduce fluid recurrences.

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