Anti-VEGF therapy finds expanding role in ophthalmology

Anti-VEGF therapy, introduced to ophthalmology less than a decade ago, has fast become a mainstay of managing diseases such as age-related macular degeneration and may expand to even more indications.

Ophthalmology has witnessed an explosion in the number of intravitreal injections delivered to patients over the past 10 years, driven in large part by the introduction and rapid incorporation of anti-VEGF therapy. Medical management of retinal diseases has arguably come to dominate clinical practice and, to some experts, has resulted in better delivery of patient care.

The role of vascular endothelial growth factor in the growth of both regular and abnormal blood vessels was identified in the 1980s, and agents that could block the angiogenic cascade first came on the scene for cancer treatments in the early 1990s.

Nearly a decade later, researchers who were looking for an alternate treatment paradigm for the abnormal growth of blood vessels in the eye and the exudation of fluid from otherwise normal blood vessels began to investigate the use of anti-VEGF agents in the treatment of AMD. What resulted was a new treatment paradigm — first came Macugen (pegaptanib sodium, Eyetech/Pfizer) and later the off-label use of Avastin (bevacizumab, Genentech) followed by Lucentis (ranibizumab, Genentech) — that not only slowed vision loss or maintained current visual acuity, but also offered the potential to improve and even restore functional vision.

Philip J. Rosenfeld, MD, PhD, shown giving a patient an intravitreal injection, is a pioneer in the use of bevacizumab for both neovascular AMD and vein occlusions. Image: Bascom Palmer Eye Institute

“For most retinal specialists, Avastin was their first hands-on experience with a treatment that had the potential to improve visual acuity,” Philip J. Rosenfeld, MD, PhD, a pioneer in the use of bevacizumab for both neovascular AMD and vein occlusions and a lead investigator on many of the seminal studies involving anti-VEGF for AMD, said. “It is a very rewarding time to be caring for patients because we have anti-VEGF therapy for a wide spectrum of diseases.”

Expanding indications

The recent results of the BRAVO and CRUISE studies indicated that anti-VEGF therapy is effective at reducing macular edema secondary to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). In those studies, patients experienced rapid vision gain, some within the first 12 to 24 hours after injection. As well, imaging with optical coherence tomography indicated a higher degree of anatomical resolution of edema compared with placebo.

Shortly after the release of data from the two phase 3 clinical trials, the U.S. Food and Drug Administration approved an indication for ranibizumab for both BRVO and CRVO.

Bevacizumab had been used extensively off-label for the treatment of vein occlusions since 2005, and the approval of ranibizumab expanded the treatment options for patients. Before the FDA approval, the only on-label therapies considered viable for BRVO were laser photocoagulation and Ozurdex, a biodegradable dexamethasone-containing implant (Allergan).

The Ozurdex implant is also approved by the FDA for use in CRVO because, in clinical trials, it demonstrated superior vision outcomes compared with observation, the previous gold standard in managing that disease. Ranibizumab, too, proved more efficacious than monitoring of patients with CRVO.

But in the short time since the release of BRAVO and CRUISE data, the availability of anti-VEGF therapy, because of the impact on patient health it can provide, is already leading some to question whether the gold-standard therapy in retinal vein occlusion has changed.

Clinical trials are under way exploring anti-VEGF therapy for macular edema secondary to diabetes, and 2-year data were recently presented at the American Society of Retina Specialists annual meeting. In addition, a prospective clinical trial from the United Kingdom showed the benefit of bevacizumab for diabetic macular edema, and several smaller case reports, case series and investigator-prompted trials have speculated about other indications, such as iris neovascularization and uveitis, for bevacizumab and ranibizumab. There is also the possibility that they may be used prophylactically to stave off corneal neovascularization after corneal transplant.

The rapid expansion of pharmacologic therapy in the management of retinal diseases has, to some, changed the focal point of clinical retinal practice. To others, the question is inconsequential, because the sum of what the introduction of anti-VEGF agents has done amounts to better, more effective treatment options.

“The difference is that we now have effective treatments for conditions that a few years back we would treat with the hope of just slowing the vision loss,” Dr. Rosenfeld said. “We have so many more treatment options for patients that I don’t think it is possible to focus solely on vitreoretinal surgery anymore. Retina specialists need to manage patients with medical retinal diseases as well.”

What anti-VEGF therapy has meant for AMD therapy alone is illustrative. Whereas laser was eventually surpassed by photodynamic therapy as the predominant treatment choice upon its introduction because of better outcomes, PDT is rarely, if ever, used because anti-VEGF therapy better prevents vision loss and has allowed patients to gain vision.

Pan-VEGF blockade

Despite the success of anti-VEGF therapy in treatment of ocular diseases, particularly AMD, there are still significant questions that remain unanswered for practicing clinicians. For example, regarding AMD, the optimal frequency and duration of dosage are still unknown.

In a wider context, there are questions as to what impact exposing patients to continual VEGF blockade may have and whether unintended consequences may occur. While preventing or stopping aberrant vascular formation is beneficial, VEGF may also serve important homeostatic functions. Thus, if administration to the eye were to somehow become systemically available, unforetold cardiac and/or pulmonary complications could ensue. Even local pan-VEGF blockade has been theorized to prevent normal microvascular function after intravitreal injection of anti-VEGF agents.

However, these concerns remain speculative, according to Dr. Rosenfeld.

“This has never been proven in clinical studies, nor am I aware of any literature in humans where local anti-VEGF therapy has been shown to cause damage to the eye, except for the possibility of causing elevated intraocular pressure,” Dr. Rosenfeld said about the potential downside of pan-VEGF blockade.

More definitive answers on this question may arise from the ongoing Comparisons of Age-Related Macular Degeneration Treatments Trials, which is comparing the safety and efficacy of ranibizumab and bevacizumab, as well as investigating various dosing regimens, in the treatment of AMD. Ongoing research on a new anti-VEGF agent, VEGF Trap-Eye (Regeneron), which binds to both VEGF-A and placental growth factor, may also be illustrative, according to Dr. Rosenfeld.

“VEGF Trap has a much higher affinity for VEGF, and if VEGF Trap is shown to be safe, I think all questions about the safety of anti-VEGF therapy will be put to rest,” he said.

IOP elevation

Another concern with intravitreal injection of anti-VEGF agents is the potential to elevate IOP. Changes in pressure in the immediate term are known to occur after intraocular injection, but concerns over more permanent, glaucomatous-like changes after anti-VEGF injection have been raised.

Acute rises in IOP after an intravitreal injection may be expected, according to Malik Y. Kahook, MD, given the architecture of the eye and the inability of the eye wall to expand beyond a given point.

Malik Y. Kahook

“The eye wall itself is not completely elastic, so there is a finite amount of stretching that the sclera and cornea can do. When you are injecting fluid into the eye, you are increasing the volume, and in the process of doing that, you are increasing the pressure,” Dr. Kahook said.

Patients may experience a significant acute spike in pressure after injection, but the long-term consequences are debatable. Ordinarily, the eye naturally accommodates the increase in fluid volume and allows for greater outflow to return to normal pressure. However, in patients with compromised outflow or in patients with optic nerve damage, for example, who are predisposed to damage from even transitory pressure elevation, extra caution may be needed.

In patients with baseline glaucoma who require anti-VEGF injection for a condition such as AMD, pre-treatment with glaucoma medication may be considered. Some surgeons perform a paracentesis to remove aqueous before injection to balance the fluid volume that results after the procedure, Dr. Kahook said. At the least, IOP monitoring can help better gauge the effect of the intraocular injection.

“There is no doubt that intraocular pressure checks after intravitreal injections should be performed routinely by my retina colleagues,” Dr. Kahook said.

Dr. Kahook said that pressure should be checked 20 to 30 minutes after injection and before each injection to note any trend in pressure increase with long-term anti-VEGF therapy.

There have also been reports in the literature of more chronic IOP elevation after patients receive single or multiple injections of anti-VEGF agents, and several mechanisms have been proposed.

One theory postulates that variations in the preparation and delivery of individual doses may cause IOP elevations. For example, bevacizumab is not available in single-dose formulations, and because its distribution in that fashion is regulated, physicians must purchase doses from compounding pharmacies. However, Dr. Kahook noted, there is no uniform standard for how doses are prepared. It is not that one compounding pharmacy prepares individual bevacizumab doses better than another, but different preparations may alter the final product delivered in the office.

“Compounding pharmacies use different brands of syringes. They have different protocols for drawing up the medication, storing the medication and then delivering the medication to offices around the country,” Dr. Kahook said. “All of these things can lead to silicone leaching from the syringe wall into the formulation as well as protein aggregation.”

Where that may have relevance is in the potential for silicone to deposit into the vitreous and migrate to the trabecular meshwork. These contaminants can be too large to travel any further, thereby causing a blockage that prevents aqueous outflow. What potentially results, Dr. Kahook said, may be an ocular hypertensive state that mimics glaucoma and is recalcitrant to regular medical management.

Even though there is suggestion that at least some cases of IOP elevation after anti-VEGF injection are due to the dose preparation, Dr. Kahook said that the theory is in the early stages of proof and so remains controversial and speculative.

“There may be other causes linked to pharmacogenomics or a subclinical inflammatory response in some patients,” he added.

Another potential mechanism that has been proposed is that cumulative volumetric increases result in permanent or semi-permanent IOP changes.

Use in glaucoma

Part of the concern over IOP elevation after anti-VEGF injection is due to the increasing popularity of using these agents in various ophthalmic indications.

However, whereas multiple intravitreal injections of anti-VEGF agents may well be a cause of IOP elevation, anti-VEGFs have also proven invaluable in the reduction of IOP, especially due to glaucoma subtypes involving neovascularization.

Historically, Dr. Kahook said, neovascular glaucoma was treated with a combination of medication to lower IOP and laser panretinal photocoagulation to abate angiogenesis. But “oftentimes, these patients would have to go to surgery emergently to place a glaucoma drainage device because existing therapies did not decrease IOP fast enough,” he said.

The main benefit of anti-VEGF therapy is that it offers relief within the first 24 to 48 hours after injection. The rapid onset of relief, Dr. Kahook said, allows the physician to assess whether more permanent surgical options are necessary.

Anti-VEGF therapy may find its way into other areas of glaucoma management as well. Dr. Kahook is involved in research exploring the use of ranibizumab at the time of trabeculectomy surgery to modulate the wound healing process.

What he has found in early experimental studies is that the addition of an injection of anti-VEGF to the use of mitomycin C results in a healthier-looking bleb postoperatively. Although there was equal pressure-lowering efficacy in patients treated with MMC alone and patients treated with MMC and ranibizumab, the latter group of patients had blebs that appeared to be less elevated and more diffuse with less vascularity.

“We have added a third arm recently of Lucentis standalone vs. mitomycin vs. mitomycin with Lucentis. So, we are going to get a clearer picture of what Lucentis alone can do to the bleb post-trabeculectomy,” Dr. Kahook said.

Use in ROP cases

Another way in which the use of anti-VEGF agents promises to proliferate is if they can be used in new patient populations. For instance, there is ongoing research to investigate whether anti-VEGF therapy may be beneficial in certain forms of retinopathy of prematurity.

W. Lloyd Clark

“ROP is a vasoproliferative disease in the same way that other adult retinal diseases are, like diabetic retinopathy, and it has been well-described that VEGF levels in the vitreous are very high in ROP. So, conceivably, if you can block safely the VEGF in the eye of a baby with ROP, then presumably we will be able to regress the neovascular process,” W. Lloyd Clark, MD, said.

Dr. Clark is an investigator for the BEAT-ROP (Bevacizumab eliminates the angiogenic threat of retinopathy of prematurity) study, which is seeking to determine the safety and efficacy of bevacizumab in zone 1 or posterior 2 (stage 3) ROP compared with laser therapy.

If successful, anti-VEGF therapy could replace laser photocoagulation, which is known to damage peripheral vision in some infants as well as cause the development of significant myopia. Early studies suggest a biological response to anti-VEGF therapy in patients with ROP, but recommendations for use are still long away, Dr. Clark said.

“There are numerous safety concerns, and it is one of the most difficult aspects of considering anti-VEGF therapy,” he said.

VEGF is an important growth factor in normal vascular development in infants; might blockade of VEGF activity be detrimental and tip the risk-benefit ratio in ROP therapy? Additionally, infants with ROP typically have significant comorbidities, and the interaction of anti-VEGF therapy with other health problems is unknown. It is also not known at what rate injections should be given or what kind of injection-related complications, such as infection or retinal detachment, may occur.

“In general, because the drugs are cleared rapidly, I think the chances of long-term complications from the drug are relatively low,” Dr. Clark said.

BEAT-ROP is an ongoing trial that has enrolled 150 eyes randomized in a 1:1 fashion, bevacizumab to laser. The primary outcome is the effectiveness of therapy in active, historically difficult-to-manage cases of ROP. The trial also plans to seek answers on a number of safety and secondary outcomes, and it may well define whether the use of anti-VEGF therapy expands even further.

“In my opinion, the standard of care [in ROP] is still laser, but clearly our early anecdotal experience and our experience in the clinical trials show that anti-VEGF therapy is a very exciting alternative,” Dr. Clark said. – by Bryan Bechtel and Courtney Preston

Is there any role for prophylactic antibiotics in conjunction with intravitreal anti-VEGF injections?

References:

• Eliott D. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Presented at: American Society of Retina Specialists annual meeting; Aug. 31, 2010; Vancouver, British Columbia.
• Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents [published online ahead of print Aug. 11, 2010]. Br J Ophthalmol. doi:10.1136/bjo.2010.180729.
• Horsley MB, Mandava N, Maycotte MA, Kahook MY. Retinal nerve fiber layer thickness in patients receiving chronic anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2010;150(4):558-561.
• Kahook MY. Bleb morphology and vascularity after trabeculectomy with intravitreal ranibizumab: a pilot study. Am J Ophthalmol. 2010;150(3):399-403.
• Kahook MY, Liu L, Ruzycki P, et al. High-molecular-weight aggregates in repackaged bevacizumab. Retina. 2010;30(6):887-892.
• Mintz-Hittner HA, Best LM. Antivascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatr. 2009;21(2):182-187.

• W. Lloyd Clark, MD, can be reached at Palmetto Retina Center, 2750 Laurel St., Suite 101 Columbia, SC 29204; 803-931-0077; fax: 803-931-0076; e-mail: LClark@palmettoretina.com. Dr. Clark has received grant support from Genentech, Regeneron, Allergan and Pfizer. He is a consultant to Genentech and Regeneron.
• Malik Y. Kahook, MD, can be reached at Department of Ophthalmology, University of Colorado School of Medicine, Rocky Mountain Lions Eye Institute, 1675 Aurora Court, P.O. Box 6510, Mailstop F-731, Aurora, CO 80045; 720-848-2500; fax: 720-848-5014; e-mail: malik.kahook@ucdenver.edu. Dr. Kahook has received research support from the state of Colorado, Genentech, Allergan, Alcon, Merck and Actelion. He is a consultant to the FDA, Alcon, Allergan, Merck and Genentech and a founding member of Shape Ophthalmics LLC.
• Philip J. Rosenfeld, MD, PhD, can be reached at Bascom Palmer Eye Institute, 900 NW 17th St., Miami, FL 33136; 305-326-6148; fax: 305-326-6417; e-mail: prosenfeld@med.miami.edu. Dr. Rosenfeld has received research support from Genentech in the past but has no current financial relationship with Genentech.