Pilot study of ziv-aflibercept in myopic choroidal neovascularisation patients

The prevalence of pathological myopia in adults is approximately 1–3%, and myopic choroidal neovascularisation (CNV) is one of the most sight-threatening complications, occurring in approximately 5–11% of pathological myopia patients [1, 2]. Several treatment approaches have been proposed due to the poor understanding of its pathological nature [2]. Photodynamic therapy (PDT) is one of the treatment options for myopic CNV that can reduce the risk of visual loss, as supported by several studies [3, 4]. However, patients treated with PDT showed limited improvement in the mean visual acuity that did not remain longer than 2 years [5]. Recently, anti-vascular endothelial growth factor (anti-VEGF) agents such as bevacizumab, ranibizumab, and aflibercept were introduced for the treatment of many retinal diseases, with high safety profiles. The off-label use of bevacizumab and the introduction of ranibizumab and aflibercept as treatment modalities for myopic CNV showed promising results in preventing visual deterioration for a long time with minimal side effects [6, 7]. According to the phase 3 RADIANCE trial [8], ranibizumab has been approved for the treatment of visual impairment due to myopic CNV; in addition, MYRROR, a phase 3 study, confirmed the efficacy and safety of intravitreal aflibercept in the treatment of CNV in pathological myopia patients [9].

Ziv-aflibercept (Zaltrap; Regeneron, New York, USA) is a recombinant fusion protein that is very similar to aflibercept. It was approved by the FDA in August 2012 for the treatment of resistant metastatic colorectal carcinoma. Recently, it was reported that off-label intravitreal ziv-aflibercept is an effective and safe treatment at 4-week intervals, without any ocular toxicity in patients with age-related macular degeneration [10].

The present study evaluated the efficacy and safety of ziv-aflibercept as a primary treatment in patients with myopic CNV younger than and older than 40 years.

This study was performed from March 2019 until September 2019. Twenty eyes with active myopic CNV were collected beginning in March 2019, and the baseline demographic data of all patients, including age, sex, spherical equivalent, number of injections and CNV size, were recorded (Table 1).

Various methods, such as laser photocoagulation, transpupillary thermotherapy (TTT), PDT (photodynamic therapy), submacular surgery, and macular translocation, were attempted to treat myopic CNV before the era of anti-VEGF. Despite all these attempted treatment approaches, the results were unsatisfactory, with no evident clinical improvement. Damage to adjacent photoreceptors and atrophic scar progression hindered clinical improvements and decreased BCVA in laser photocoagulation-treated patients with subfoveal CNV due to age-related macular degeneration [12, 13], with even poorer results in patients with myopic extrafoveal CNV despite the cease of activity [14‐17].

This advocated the shift to PDT with verteporfin, which resulted in more satisfactory results angiographically and clinically in myopic CNV patients. Many studies have supported the use of verteporfin, especially those reported by the Photodynamic Therapy Study Group, which detected an improvement in BCVA in the PDT-treated group in the first 2 years that declined afterward [4, 18]. Another study that included 24 eyes of myopic CNV patients reported that PDT may result in good visual outcomes in patients with extrafoveal CNV lesions when the laser spot is adjusted to spare the fovea [19].

Regarding anti-VEGF treatment for myopic CNV, Baba et al. [20] compared the efficacy of bevacizumab and PDT. Intravitreal bevacizumab showed a greater improvement in BCVA than PDT in eyes with myopic CNV. Additionally, Arias et al. [21] found that the mean visual acuity improved by 8.4 letters following an average of 1.5 intravitreal bevacizumab injections after 6 months of follow-up. Another study conducted by Ikuno et al. [22] reported an improvement in the mean BCVA in a case series of 63 eyes of myopic CNV following one to six bevacizumab injections.

during 12 months of observation. Regarding ranibizumab, the REPAIR study [23, 24] reported an improvement of 13.8 letters following a median of 3 ranibizumab injections based on the PRN regimen after 12 months. The RADIANCE study confirmed the results of the REPAIR study [8], which showed that approximately 40% of ranibizumab-treated patients gained 15 or more letters of visual acuity at the third month compared with only 15% of PDT-treated patients. After 1 year, BCVA improved by 13.8 letters in the first group treated with ranibizumab (based on visual acuity stabilisation in the preceding two follow-up visits) and 14.4 letters in the second group treated with ranibizumab (based on disease activity criteria) compared with 9.3 letters in the group treated with PDT. In addition, some patients in the PDT group switched to ranibizumab from the third month onwards (with a median number of 2.0 injections between months 3 and 12).

Another case series conducted on ranibizumab in 16 patients with myopic CNV by Lai et al. [25] reported an improvement in the mean BCVA of 3 lines after 1 year in 75% of eyes, with recurrence demonstrated by angiography in only two eyes after 3 months that required retreatment between the 3rd and 9th months. A significant reduction in the mean central foveal thickness by OCT was also reported.

Another study by Chen et al. [26] compared the efficacy of ranibizumab and PDT in myopic CNV patients and revealed that in Asian patients, ranibizumab achieved superior efficacy compared to verteporfin photodynamic therapy at the third month, with continuation of its therapeutic effect at month 12. Furthermore, a recent 5-year, prospective, multicenter study that was conducted on ranibizumab in myopic CNV in 488 clinical sites in 42 countries revealed tremendous VA gains in treatment-naive patients and VA maintenance in patients previously treated with ranibizumab [27].

With respect to aflibercept in myopic CNV, the MYRROR study reported a mean change of + 13.5 letters in BCVA in aflibercept-treated patients after a median of two injections within 12 weeks that was maintained throughout 48 weeks compared with + 3.9 letters in sham-treated patients. No further injections were needed throughout the study. Visual gain correlated significantly with a reduction in central retinal thickness [9]. Other studies confirmed the efficacy of aflibercept in myopic CNV patients. For example, Brue and co-authors showed an improvement in BCVA from 0.69 LogMAR to 0.15 LogMAR after 18 months [28]. Moreover, Pece and Milani reported an improvement of 10.6 letters after 1 year of follow-up [29].

The present study evaluated the efficacy and safety of ziv-aflibercept in myopic CNV patients and reported that fewer injections were needed in patients younger than 40 years. In addition, CNV was smaller in the younger age group, with a more notable improvement in BCVA. These results are similar to those of Yoshida et al. [30], who also showed more notable clinical improvements with a smaller CNV in patients younger than 40 years. To explain the less notable improvement in older patients, several factors, such as decreased integrity and function of the retinal pigment epithelium in myopic patients, may be involved, as these might reduce the inhibition of angiogenesis, leading to the formation of a larger and more active CNV, as well as a delay in the regression of CNV in older patients. Moreover, myopic CNV in older patients shows a clinicopathological correlation with both AMD and high myopia and tends to correlate with chorioretinal atrophic changes that markedly affect visual acuity [20]. Another study evaluated the influence of ethnicity and age on the response to ranibizumab injection in myopic CNV and revealed that East Asians showed better BCVA gains than Caucasians. Variable numbers of injections were given to the different subgroups, indicating the need for individualized treatment [31].

Additionally, the improvement in BCVA and the reduction in CMT after injection were achieved in both groups, with statistical significance that reflects the efficacy of the new drug in myopic CNV patients with a high safety profile and low cost. This finding was quite similar to those from recent studies performed on ziv-aflibercept on a larger number of patients [32, 33] that discussed the application of ziv-aflibercept in different retinal diseases and detected a reasonable safety profile for the drug comparable with those of other anti-VEGF agents. Moreover, Braimah et al. [11] studied the efficacy of ziv-aflibercept on retinal diseases other than AMD, such as high myopia, macular telangiectasia, central serous chorioretinopathy, choroidal osteoma, choroiditis, Best’s disease and idiopathic macular degeneration, and reported a marked reduction in CMT and a moderate improvement in BCVA.

In contrast, a study performed by Chhablani et al. on patients with age-related macular degeneration suggested immediate IOP elevation after injection in four eyes that needed anterior chamber paracentesis [34]. Anterior chamber paracentesis was not performed in the present study, as IOP did not change significantly after the injection of ziv-aflibercept either immediately or an extended period of time. This demonstrates the safety of ziv-aflibercept on IOP.

The costs per dose of intravitreal bevacizumab and ziv-aflibercept are low [35, 36]; however, those of aflibercept and ranibizumab are 20 to 30 times higher [37]. Thus, this drug can be of great benefit in low-income countries with deficient insurance coverage.

The main limitations of this study are the small number of patients, the short duration of follow-up (6 months) and the lack of a control group; thus, a larger number of patients and a longer follow-up period are needed to confirm our results.

Ziv aflibercept is a cheap and effective anti-VEGF agent in patients with active myopic CNV, with a high safety profile. The authors recommend the use of this new anti-VEGF agent in retinal diseases such as myopic CNV. However, a larger number of patients and a longer follow-up period are needed in further studies to confirm these results.