Despite a common belief, excessive blood supply is not always beneficial for the tissue. In fact, it could be damaging for the eye, as in the case with corneal neovascularization (CNV).
In a recent issue of the Indian Journal of Ophthalmology, Dr. Sibel Aksoy from the Department of Ophthalmology, Saglik Bilimleri University, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey, reported a successful therapeutic application of aflibercept for the treatment of corneal neovascularization.1 The author presented a clinical case of a seven-year-old patient, who underwent craniotomy surgery for pilocytic astrocytoma and experienced left facial paralysis and significant vision decline, accompanied by redness in the left eye six months after the surgery. He was initially treated with antibiotics and additional topical therapy without significant improvement. Therefore, steroid therapy was applied, albeit without any significant positive effect.
Since therapy with loteprednol was ineffective, aflibercept (Eylea, Bayer, Germany), 2mg/0.05ml, was topically delivered by intravitreal injections. The significant regression of CNV symptoms was achieved three days after starting therapy, and complete recovery was observed within seven days. Neither decreased corneal epithelial regeneration nor adverse systemic effects were detected. Moreover, the yearly follow-up detected no signs of neovascularization.
A common assumption about the pathogenesis of CNV implies that macrophages and other immune cells play a critical part in the tissue damage by promoting hemangiogenesis.2 Therefore, glucocorticoids would often be considered as an effective treatment due to their common immunosuppressive properties. Topical application of steroids is considered to be the first-choice treatment option for CNV, since these anti-inflammatory drugs are expected to inhibit eye inflammation. In line with this, previous studies have reported positive effects of glucocorticoids, such as dexamethasone and triamcinolone acetonide.3 Intriguingly, beneficial outcome of steroid therapy has not been observed in the present clinical case.
Thus, in the present case, steroids had obviously no significant positive effect on the patient’s condition. It is well-known that vascular growth is mediated via activation of growth factors, such as vascular endothelial growth factors (VEGF). CNV is a common pathological feature in ocular disorders, with VEGF being its main trigger. Earlier research has shown that aflibercept inhibits two isoforms of VEGF (VEGF-A and VEGF-B) and placental growth factor, which activates the VEGF receptor (VEGFR) and induces neovascularization. Therefore, instead of focusing on cellular inflammation, Dr. Aksoy aimed to limit vascular growth in the cornea. By suppressing the activation of VEGFR, aflibercept inhibits neovascularization and diminishes vascular permeability. In line with this, the author hypothesized that this drug might enter inflamed cornea and suppress neovascularization. The idea was obviously correct, since complete reduction of CNV was observed. In contrast to glucocorticoids, application of aflibercept has ameliorated the CNV symptoms.
In his report, Dr. Aksoy emphasized the novelty of the study, as aflibercept has so far been used mostly in animal experimental studies. One of the studies has used a rabbit model of CNV to test topical application of aflibercept. Significant reduction of CNV symptoms by both 0.1% and 0.01% topical aflibercept and no side effects have been observed.4 The effects of aflibercept have been comparable to anti-VEGF drug bevacizumab.
According to another study, subconjunctival ziv-aflibercept treatment has shown high treatment benefits in decreasing CNV induced by sulfur mustard exposure in rabbits.5 Noticeably, aflibercept has reduced the symptoms of CNV better than bevacizumab. Another support of aflibercept effects has been provided by a study in rats, where experimentally induced CNV was ameliorated by aflibercept. Moreover, that study found the inhibition of stromal inflammation caused by CD68-expressing macrophages, which are known to contribute to the CNV pathogenesis by releasing inflammatory mediators.6 No adverse symptoms were detected.
To summarize the observed effects, aflibercept combined the anti-inflammatory functions of steroids, such as inhibition of inflammatory corneal hemangiogenesis and anti-angiogenic properties of anti-VEGF antibodies and similar drugs. Furthermore, aflibercept was found to act as an anti-angiogenic and angiosuppressive drug. These combined effects of aflibercept were not accompanied by any side effects common for glucocorticoid therapies.
To obtain an expert’s opinion on Dr. Aksoy’s report, Dr. Harvey Uy, the medical director at Peregrine Eye and Laser Institute in Makati, Philippines, commented on the study. “This is a very useful case report, which presents topical aflibercept as an effective, non-interventional method for mitigating the effects of persistent corneal neovascularization from exposure keratopathy,” said Dr. Uy. “Despite prior non-response to topical steroids, the patient still improved with a short course of angiorecessive anti-VEGF drops.”
Dr. Uy also agreed that local anti-angiogenic treatment may be highly beneficial for patients with CNV. “It should be mentioned that addressing other factors such as lubrication may also be vital for treatment success. This well-written article adds support to the use of topical anti-VEGF drops (aflibercept, bevacizumab, ranibizumab) for non-inflammatory, ocular surface neovascularization.”
In line with this statement, aflibercept has been shown to be highly effective for the treatment of diabetic macular edema, including vision improvement in patients with severe initial visual acuity.7
In addition, Dr. Uy complemented his statement by referring to an earlier study published by his group, where similar regression of CNV by topical bevacizumab drops was observed when bevacizumab treatment was combined with topical steroids.8 Dr. Uy proposed to compare the safety effectiveness of different commercially available ocular anti-VEGF drugs in patients with CNV. Current anti-VEGF therapies include specific neutralizing anti-VEGF antibodies, such as bevacizumab, tocilizumab and ranibizumab, an RNA aptamer pegaptanib and tyrosine kinase inhibitor regorafenib.9
In conclusion, recent studies suggest that in some forms of CNV, the neovascularization mechanism predominates and should be the main therapeutic target; while in other forms with pronounced inflammatory pathogenesis, corticosteroids might be combined with anti-angiogenic drugs. The present report demonstrated that treatment with aflibercept might be an effective and safe therapeutic approach for CNV. Due to its efficiency and absence of side effects, aflibercept likely has high chances to occupy a strong position within the competitive therapeutic CNV landscape.
Future clinical trials are needed to estimate whether aflibercept would be superior over other inhibitors of vasculogenesis and identify its minimal effective dose.
Editor’s Note: Dr. Harvey Uy was not part of the studies mentioned, but he was generous enough to contribute his expert opinion to this article.
References
1Aksoy S. Treatment of corneal neovascularization with topical aflibercept in a case of exposure keratopathy following cerebellar astrocytoma surgery. Indian J Ophthalmol. 2019;67(1):145-147.
2Abdelfattah NS, Amgad M, Zayed, AA. Host immune cellular reactions in corneal neovascularization. Int J Ophthalmol. 2016;18;9(4):625-633.
3Liu X, Wang S, Wang X, Liang J, Zhang Y. Recent drug therapies for corneal neovascularization. Chem Biol Drug Des. 2017;90(5):653-664.
4Park, YR, Chung, SK. Inhibitory effect of topical aflibercept on corneal neovascularization in rabbits. Cornea. 2015;34(10):1303-1307.
5Gore A, Horwitz V, Cohen M, et al. Successful single treatment with ziv-aflibercept for existing corneal neovascularization following ocular chemical insult in the rabbit model. Exp Eye Res. 2018;171:183-191.
6Sella R, Gal-Or O, Livny E, et al. Efficacy of topical aflibercept versus topical bevacizumab for the prevention of corneal neovascularization in a rat model. Exp Eye Res. 2016;146:224-232.
7Al-Debasi T, Al-Bekairy A, Al-Katheri A, Al Harbi S, Mansour M. Topical versus subconjunctival anti-vascular endothelial growth factor therapy (Bevacizumab, Ranibizumab and Aflibercept) for treatment of corneal neovascularization. Saudi J Ophthalmol. 2017;31(2):99-105.
8Uy HS, Chan PS, Ang RE. Topical bevacizumab and ocular surface neovascularization in patients with stevens-johnson syndrome. Cornea. 2008;27(1):70-73.
9Voiculescu OB, Voinea LM, Alexandrescu C. Corneal neovascularization and biological therapy. JMed Life. 2015;8(4):444-448.
