The potential of anti-VEGF in treating glaucoma

Emerging evidence shows promise neovascular glaucoma and post-filtration surgery wound healing.

By Sung Chul Park, MD

About the Author
	Sung Chul Park, MD, is assistant professor of ophthalmology at New York Medical College, and glaucoma specialist and anterior segment surgeon, Peter Crowley Research Scientist, and director, Moise and Chella Safra Advanced Ocular Imaging Laboratory at New York Eye and Ear Infirmary. Disclosure: Dr. Park has no conflict of interest relevant to products mentioned in the article.

In ophthalmology, anti-VEGF agents have been used mainly for the treatment of retinal and choroidal neovascular diseases such as wet AMD, proliferative diabetic retinopathy, retinal vascular occlusions and retinopathy of prematurity. However, investigators and physicians have used anti-VEGF agents as an off-label treatment for neovascular glaucoma (NVG) and for suppressing fibroblastic proliferation and wound healing after glaucoma filtration surgery.

Early reports on the utility of anti-VEGF agents in the treatment of NVG and filtering bleb survival and rescue have been promising. In NVG, IOP can be controlled using medical or surgical treatments, but anti-VEGF agents suppress the angiogenic effect of VEGF for long-term IOP control.

Panretinal photocoagulation is effective to eliminate the source of VEGF, but it does not clear up VEGF molecules that preexist in the aqueous humor and vitreous. Anti-VEGF agents have an immediate effect to neutralize VEGF and suppress or regress neovascularization.

Because of their potential inhibitory effect on postoperative fibroblastic proliferation and wound healing, studies have investigated the utility of anti-VEGF agents in glaucoma filtration surgery to reduce postoperative wound healing. Antifibrotic agents such as mitomycin C (MMC) and 5-FU have improved the success rates of glaucoma filtration surgery, but increased the rates of filtering bleb-related complications, including leakage, blebitis, dysaesthesia, and endophthalmitis. New wound-healing modulators are needed for more predictable and safer filtration surgery.

This article explores the role anti-VEGF therapies may play in arresting or reversing the progression of glaucomatous disease.

ANTI-VEGF: A BRIEF HISTORY

Investigators first discovered vascular endothelial growth factor (VEGF) as a molecule tumor cells secrete to increase vascular permeability.¹ Later, other researchers found VEGF plays a major role in physiological vasculogenesis and angiogenesis in the embryo,² and has a role in the formation of pathologic blood vessels and tumor growth.³

Studies of VEGF in the eye in the 1990s reported that intraocular neovascular membranes of proliferative diabetic retinopathy expressed VEGF, and found intravitreal VEGF levels increased in proliferative diabetic retinopathy as well as other ischemic retinal diseases.^4–6 These discoveries led to the development of VEGF inhibitors commonly used to treat retinal disease today.

The prominent anti-VEGF drugs are:

• Bevacizumab (Avastin, Genentech, South San Francisco, Calif.), a humanized IgG1 monocolonal antibody against all isoforms of VEGF-A.⁷
• Ranibizumab (Lucentis, Genentech), an antigen-binding fragment (Fab) that was affinity-matured to bind all isoforms of VEGF-A.
• Aflibercept (Eylea, Regeneron, Tarrytown, N.Y.), a fusion protein with domains that bind VEGF-A, VEGF-B and placental growth factors 1 and 2, in contrast to the antibody-based VEGF binding strategy of bevacizumab and ranibizumab.

ANTI-VEGF IN NEOVASCULAR GLAUCOMA

The potential of anti-VEGF antibodies in the treatment of NVG derived from a report that intravitreal injections of recombinant human VEGF produced non-inflammatory iris neovascularization in a non-human primate and prolonged exposure led to NVG.⁸ This finding was significant because iris neovascularization and formation of fibrovascular membrane in the iridocorneal angle are key pathologies in NVG. Subsequently, human clinical studies were performed.

Bevacizumab trials

Investigation of the use of anti-VEGF agents in the treatment of NVG started with bevacizumab. Several case studies reported a regression of iris neovascularization and/or reduction of IOP after intravitreal bevacizumab injections.^9–11 One study noted a decrease in iris fluorescein angiography leakage as early as one day after intravitreal injection of bevacizumab.¹²

Another case series reported on six patients who received 1.25 mg/0.05 ml of bevacizumab followed by panretinal photocoagulation, which resulted in complete regression of iris and angle neovascularization.¹³ Two patients in this study had recurrence of iris neovascularization, which resolved after an additional bevacizumab injection.

Subsequently, larger case series reported the potential value of bevacizumab in the treatment of NVG. A 2008 study¹⁴ reported complete or partial reduction of leakage in iris fluorescein angiography within three weeks after intracameral injection of bevacizumab in 16 of 16 eyes. A case series in Japan¹⁵ retrospectively reviewed 41 cases with secondary iris neovascularization or NVG and found that initial treatment with intravitreal bevacizumab controlled IOP in patients with iris neovascularization alone or early-stage NVG without angle closure.

Intravitreal bevacizumab resulted in a faster decrease in IOP when combined with panretinal photocoagulation.¹⁶ Preoperative intravitreal injection of bevacizumab before Ahmed Glaucoma Valve implantation (AGV, New World Medical, Rancho Cucamunga, Calif.) resulted in a higher surgical success rate than AGV implantation alone (79% vs. 64%), but this difference failed to reach statistical significance.¹⁷

Ranibizumab trials

The use of ranibizumab in the treatment of NVG has been investigated less frequently. One report involved a case of radiation-induced NVG successfully treated with ranibizumab.¹⁸ Iris angiography before ranibizumab treatment showed leakage from iris neovascularization, which improved rapidly after a single intravitreal injection of 0.5 mg/0.05 mL of ranibizumab. IOP decreased from 26 mm Hg to 16 mm Hg two days after injection.

Intravitreal injection of anti-VEGF drugs can clear up VEGF molecules that remain in the aqueous humor and vitreous after panretinal photocoagulation.

A case series of 14 eyes with NVG after proton therapy for uveal melanoma showed promising results using intravitreal ranibizumab either alone or in combination with 180° ciliary body cryotherapy as a last-chance treatment before enucleation.¹⁹ All patients in this series suffered from uncontrolled NVG despite maximal medical treatment. Iris neovascularization resolved in all cases and IOP was normalized in 11 out of 14 patients after the treatment.

A study on intravitreal injection of ranibizumab before Ahmed glaucoma valve implantation showed similar results to bevacizumab; the surgical success rate was better with preoperative ranibizumab (83% vs. 40%), but not statistically significant.²⁰

These results have suggested that anti-VEGF antibodies are useful in preventing glaucoma surgery or improving surgical outcome in patients with NVG.

Aflibercept use in glaucoma

In patients with wet AMD, clinical trials have shown that aflibercept had a similar efficacy to ranibizumab at preventing vision loss, with comparable vision gains and safety, and that aflibercept may offer the effectiveness of ranibizumab with less frequent injections.

Although FDA-approved for the treatment of wet AMD, the use of aflibercept in glaucoma has not been reported in peer-reviewed journals. A clinical trial on the use of intravitreal aflibercept injection for NVG is under way (clinicaltrials.gov identifier NCT01711879).

ANTI-VEGF AGENTS IN FILTRATION SURGERY

The role of anti-VEGF agents in glaucoma filtration surgery should be determined in interaction with conventional anti-fibrotic agents, MMC and 5-FU. Filtering surgery with MMC or 5-FU lowers IOP compared to filtering surgery without such agents, but it is more likely to cause postoperative hypotony or bleb-related complications.

Anti-VEGF agents may not only suppress postoperative wound healing but also reduce hypotony and bleb-related complications by decreasing the dosage of MMC and 5-FU.

Human studies and bevacizumab

Studies have shown VEGF has increased in the aqueous humor of glaucoma patients who had filtration surgery, suggesting that it is involved in the postoperative scarring process.²¹ Bevacizumab was first used in clinical studies in humans to evaluate the effect of anti-VEGF antibodies on wound healing after glaucoma filtration surgery.

Investigators in India in 2008²² performed subconjunctival injection of 1.25 mg of bevacizumab at the end of trabeculectomy in 12 patients, without other anti-fibrotic agents such as MMC or 5-FU. They reported successful IOP reduction in the range of 8 to 14 mm Hg in 11 patients and hypotony in one patient, which resolved spontaneously. Bleb vascularity was increased after three months, but no patient had a thin cystic bleb at six months.

Another study²³ compared the effect of bevacizumab and MMC on postoperative wound healing and demonstrated that both groups exhibited successful IOP reduction after surgery, but that bevacizumab had a less prominent effect. A European study published this year²⁴ reported that perioperative administration of intracameral bevacizumab resulted in a significantly higher success rate of trabeculectomy and reduced the need for needling.

Ranibizumab and trabeculectomy

A pilot study²⁵ randomized 10 patients with primary open-angle glaucoma to trabeculectomy with either intraoperative intravitreal ranibizumab injection and topical MMC application or MMC alone. The investigators found statistically significant differences in peripheral bleb area, vascularity and non-bleb-related vascularity between the two groups, with the intravitreal ranibizumab and topical MMC group exhibiting more diffuse blebs with a lower degree of vascularity. Both groups had similar IOP values before surgery and at six months after surgery.

Anti-VEGF in needle revision

In addition to reports of anti-VEGF antibodies as adjuncts in glaucoma filtration surgery, their use in needle revision of filtering blebs has also been reported. A couple of reports demonstrated the utility of bevacizumab in bleb needling procedures after failed trabeculectomy.^26,27 A comparative study²⁸ found that bleb needling with bevacizumab was less effective in lowering IOP than needling with 5-FU, with success rates of 25% vs. 80%.

Another trial²⁹ reported a reduction in IOP and bleb vascularity after bleb needle revision with ranibizumab. A study also reported on the potential beneficial effect of topical bevacizumab (5 mg/mL, 5 times a day for approximately 20 days) after trabeculectomy.³⁰

In vitro and animal studies

Laboratory studies have informed us about many roles VEGF has in the development of NVG. For example, in addition to the recruitment of blood vessels, VEGF also plays a pivotal role in normal embryonic development and would healing.³¹ Keloid fibroblasts have demonstrated in vitro over-expression of TGF-beta and VEGF, and both in vitro and in vivo studies confirmed keloid fibroblasts had higher angiogenic activity than normal fibroblasts.³² Further, dexamethasone induces keloid regression that suppresses endogenous VEGF expression and fibroblast proliferation.³³

Tenon fibroblasts mediate the wound-healing process and scar formation after glaucoma filtration surgery;³⁴ angiogenesis inhibitors have been shown to inhibit the proliferation and migration of tenon fibroblasts in vitro.³⁵ One study of rabbit eyes showed VEGF was up-regulated in the aqueous humor after trabeculectomy and stimulated tenon fibroblast proliferation.²¹ An in vitro trial³⁶ demonstrated that addition of VEGF induced tenon fibroblast proliferation, and found the subsequent addition of bevacizumab in a dose-dependent manner subsequently inhibited this activity.

Two animal studies demonstrated that subconjunctival injections of bevacizumab improved the outcomes of glaucoma filtration surgery as defined by bleb survival.^37,38

An in vitro study³⁹ found that at concentrations commonly used in clinical practice, ranibizumab induced a greater dose-dependent reduction in the number of human tenon fibroblasts than bevacizumab. So one can hypothesize that ranibizumab may have a better inhibitory effect against the subconjunctival encapsulation and scar tissue formation after glaucoma filtration surgery.

COST FACTORS CONSIDERABLE

Current studies on the utility of bevacizumab in intraocular diseases are more abundant than ranibizumab, even though the latter is FDA-approved for intraocular diseases such as neovascular AMD and macular edema while physicians have used bevacizumab off-label.

One of the greatest factors is cost. A single dose of ranibizumab is approximately 40 times more expensive than bevacizumab. The price of aflibercept is similar to ranibizumab. Difference in cost has enormous economic implications and clinicians should take this into consideration when treating patients.

CONCLUSION

Further long-term studies are required on the appropriate dosage, route of delivery, and the timing, number and frequency of injections in different stages of NVG. Likewise, further investigations are needed to determine detailed protocols for the use of anti-VEGF agents in glaucoma filtration surgery in different types of glaucoma, especially focusing on cases with a higher risk of surgical failure.

Studies comparing different anti-VEGF agents in glaucomatous conditions are also warranted. Additionally, side effects of repetitive injections, including trabecular meshwork toxicity, should be investigated in the future. OM

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