Optometry

Len V. Hua

Download and mail the CE Quiz

Increased vascularity in tumors and its importance in tumor growth was observed more than a century ago. Over the next few decades, a number of theories postulated that tumors may produce signaling factors to stimulate angiogenesis, supporting their rapid proliferation.

However, the first theoretical clinical application of anti-angiogenesis in cancer was not made until 1971, when Judah Folkman hypothesized that tumor growth could be stopped if angiogenesis could be inhibited. Although the concept was intriguing, it did not gain much traction because no angiogenic factor was known then.

‘VEGF’ introduced in 1989

It was not until 1989 that the term vascular endothelial growth factor (VEGF) was introduced as an endothelial-specific mitogen by Napoleone Ferrara of Genentech. In the same year the molecular cloning of VEGF was completed and published by Monsanto Company.

The remarkable characteristics of VEGF recognized early on were its ability to induce endothelial cell proliferation and cause vascular leak and edema. The first study that established the dominance of VEGF in tumor angiogenesis was the demonstration by Genentech that mouse monoclonal antibody designed to block VEGF could strongly inhibit tumor growth in an animal model. This preliminary and seminal finding, however, did not immediately convince others in the pharmaceutical industry to emphasize VEGF as an exciting new drug target for cancer because various other targets with equal potential were being investigated at the time.

Scientists at Genentech continued to develop the next version of the humanized antibody against VEGF and named it bevacizumab (Avastin), which first entered clinical trials in 1997 and achieved U.S. Food and Drug Administration approval in 2004 as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Bevacizumab has since gained additional FDA approvals for other cancer therapies and still remains the standard for angiogenesis-based therapeutics.

While the roles of VEGF in angiogenesis were investigated with respect to tumor growth, its propensity to cause vascular leak and edema was studied by other investigators. Retinal swelling and edema as commonly seen in wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy were the ocular conditions of interest for therapeutic testing. With collaboration from Genentech, bevacizumab was shown to also be effective in reducing ocular neovascularization and edema in animal models in 1994. Bevacizumab, however, was not the first anti-VEGF therapy approved for clinical treatment of wet AMD.

This fundus photo shows advanced AMD in a patient’s left eye. Image: Hua LV

Pegaptanib (Macugen, Pfizer), an RNA aptamer directed against VEGF-165 isoform was shown in clinical trials to slow progressive visual loss in wet AMD. The data on clinical safety and efficacy of pegaptanib was gathered in the ensuing years and led to the FDA approval in 2004 for the treatment of wet AMD.

Although Genentech did not get to the market first for using an anti-VEGF antibody for the treatment of wet AMD, the company knew it had a more effective VEGF blocker. However, the concern was that a full-length antibody, bevacizumab, might not dissolve well enough to reach the retina for optimal efficacy, so a smaller version was designed and named ranibizumab (Lucentis). In addition to being smaller size, ranibizumab had a much higher affinity for multiple VEGFs and, thus, was effective at a lower concentration than bevacizumab.

In comparison to the data from clinical studies of pegaptanib, which merely slowed vision loss, ranibizumab was able to produce vision gain and maintain these gains over time with a monthly intravitreal injection. With subsequent data on clinical safety and efficacy, ranibizumab was approved for the treatment of wet AMD in 2006 and recently also gained approval for the treatment of retinal vein occlusion. Currently, about a quarter of a million patients around the world are treated with ranibizumab annually.

Fittingly and timely, the 2010 Lasker DeBakey Clinical Research Award went to Napoleone Ferrara of Genentech for the discovery of VEGF as a major mediator of angiogenesis and for the development of an effective anti-VEGF therapy for wet AMD.

As one more brief historical perspective, the use of antibody as therapy for ocular complication was first reported in the 1895 by Henri Coppez, a Belgian ophthalmologist who applied anti-diphtheritic serum to treat conjunctival diphtheria in two young children, with astounding success. A century later, therapeutic antibody re-emerges as a remarkable therapy for ocular angiogenesis and edema.

Multiple isoforms of VEGF proteins

Molecular and biochemical studies over the past decade have identified six main spliced VEGF isoforms from eight exons of human VEGF-A gene: 121, 145, 165, 183, 189 and 206 amino acids. VEGF121, the smallest isoform, is free, whereas the larger forms, VEGF189 and VEGF206, are bound to extracellular matrix. The intermediate VEGF165 exists in both free and bound forms. In addition, multiple shorter diffusible forms are made as a result of protein breakdown by extracellular matrix metalloproteinases.

Currently, there are three anti-VEGF agents available for treating retinal neovascularization. Pegaptanib (Macugen) binds specifically to VEGF165 and spares other isoforms, while bevacizumab (Avastin) and ranibizumab (Lucentis) bind broadly to all VEGF isoforms, thus perhaps yielding greater potency of VEGF inhibitions and better efficacy.

Bevacizumab vs. ranibizumab

In spite of its superior efficacy over pegaptanib in the treatment of wet AMD, the cost of approximately $2,000 per ranibizumab injection was alarming to many patients, insurance carriers and clinicians. At the same time, another anti-VEGF, bevacizumab, also made by Genentech, was available in the market at a much lower cost for treating colorectal cancer.

With the knowledge that anti-VEGF was beneficial to many wet AMD patients and frustration of the high cost of ranibizumab, a group of retinal specialists conducted a pilot study using bevacizumab off-label to treat wet AMD via international collaboration.

The first prospective study using intravitreal bevacizumab off-label for treatment of neovascular AMD was performed in 17 eyes of 17 patients at the American University of Beirut Medical Center, Lebanon. The dose was monthly injection of 2.5 mg in 0.1 mL, twice the dose currently used by most clinicians. The report corroborated the initial hypothesis that bevacizumab could be effective for treating wet AMD at a cheaper price. After 3 months of treatment with bevacizumab, eyes with choroidal neovascularization (CNV) due to AMD showed significant improvement both in retinal anatomy and visual acuity.

This finding ushered in a worldwide clinical adoption of bevacizumab for neovascular AMD. Over the last few years, the off-label use of bevacizumab as an anti-angiogenesis and anti-edema treatment for retinal diseases has become so popular and widespread that it superseded ranibizumab both in applications and publications. This phenomenon could be due to an approximately 40 times lower cost per injection with significant efficacy, despite concerns that have been raised about the clinical safety of off-label use of a large antibody in the eye.

The National Eye Institute (NEI) realized the potential pharmacoeconomic value and safety concern of bevacizumab off-label for not only AMD but potentially for other ocular disorders. As a result, NEI sponsored a head-to-head Comparison of AMD Treatment Trial (CATT) study of bevacizumab vs. ranibizumab in AMD in 2008. The purposes of the trial were to evaluate the relative efficacy and safety of ranibizumab and bevacizumab and to determine whether an as-needed regimen would be adequate as compared with a monthly injection.

In this multicenter, single-masked, randomized prospective trial, 1,208 patients with neovascular AMD were assigned to ranibizumab monthly, bevacizumab monthly or ranibizumab or bevacizumab as needed with monthly vision exam, dilated exam and ocular coherence tomography (OCT). The final goal of comparison was the mean change in visual acuity at 1 year, with a noninferiority deviation of five letters on the eye chart.

In April of 2011, the 1-year findings of CATT were published in the New England Journal of Medicine. The results indicated that monthly injection with bevacizumab was equivalent to monthly injection with ranibizumab, with a gain of approximately eight letters. Moreover, administration as needed yielded a gain of about six letters for both drugs. Ranibizumab as needed was adequate and did not compromise visual acuity as compared to monthly ranibizumab; and the comparison between bevacizumab as needed and monthly bevacizumab was equivalent for 9 months, but monthly bevacizumab was slightly better (2.1 letters) than as needed bevacizumab at the end of the year. However, the significance of this small difference remains to be answered with longer follow-up. It is remarkable to note the outstanding efficacy of the two drugs in the study, because more than 90% of patients did not have a decrease in visual acuity of greater than 15 letters from baseline, and about 30% of patients gained at least 15 letters at the 1-year mark.

The use of bevacizumab in cancer therapy has been associated with arteriothrombic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications and hypertension. The dosage of bevacizumab for cancer therapy however is about 500 times that used in intravitreal injections. In this study, the relative safety of bevacizumab and ranibizumab were similar with respect to rates of death, myocardial infarction and stroke, except bevacizumab was found to slightly increase the risk of at least one serious systemic event. But the overall significance of this difference is unknown and requires a bigger and longer study to elucidate.

Suggested frequency of administration

The initial FDA approval for ranibizumab (Lucentis, Genentech), based on clinical trial data from MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) studies, in 2006 was for neovascular AMD and macular edema following retinal vein occlusion. The dosage was 0.5 mg (0.05 mL) administered by intravitreal injection once a month (about every 28 days). Although monthly injection was recommended for ranibizumab, other possible dosing schedules have been of collective interest to scientists, clinicians and patients. Over the last few years, there have been a few studies conducted to explore variable dosing schedules compared to monthly injection.

The PIER (Phase 3b, Multicenter, Randomized, Double Masked, Sham Injection Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects With Subfoveal CNV With or Without Classic CNV Secondary to AMD) study was the first to evaluate the 12-month efficacy of dosing ranibizumab (0.3 mg and 0.5 mg) every 3 months after the initial three consecutive monthly injections (six doses per year) vs. the recommended 12 doses per year. The findings published in 2008 confirmed that both 0.3-mg and 0.5-mg ranibizumab injections yielded significant visual acuity improvement compared with sham treatment, but quarterly ranibizumab dosing groups had minimal average gain in visual acuity of less than two letters compared to those of monthly dosing regimens of greater than seven letters in earlier MARINA and ANCHOR studies. Thus, the study concluded that a quarterly dosing regimen was less effective than monthly dosing.

PrONTO (Prospective OCT Imaging of Patients With Neovascular AMD Treated With Intraocular Ranibizumab) is another study that investigated a variable dosing schedule. In this case it attempted to evaluate an as-needed dosing based on monthly OCT imaging for central retinal thickness (CRT) and quarterly fluorescein angiography (FA) assessment. Patients with neovascular AMD received three consecutive monthly intravitreal injections of ranibizumab (0.5 mg). Afterward, retreatment with ranibizumab was administered only if OCT CRT increased more than 100 µm, VA loss was greater than five letters or any qualitative increase in the amount of fluid was detected. In 2008, at the end of 2 years and an average of 10 injections, 37 patients completed the study with mean VA improvement of 11.1 letters and OCT CRT decrease by 212 µm. Even though the study population was relatively small, PrONTO showed that with regular monitoring by OCT and FA assessments, an as-needed dosing regimen was effective and economical.

The EXCITE (Efficacy and Safety of Monthly vs. Quarterly Ranibizumab Treatment in Neovascular AMD) study made a direct comparison between monthly and quarterly dosing regimens and was an extension of the PIER study. In the EXCITE study, patients had better VA improvement of about four letters in the 0.3-mg quarterly group compared to 1.6 letters achieved in the PIER study, but the final analysis still indicated that VA gain was higher in the monthly regimen than the quarterly regimen at month 12. Thus, the efficacy results from the EXCITE study further supported the earlier findings of the PIER study that quarterly ranibizumab treatment was not as efficacious as monthly treatment. Interestingly, it is between months 3 and 4 that there was a prominent dissociation between monthly and quarterly regimens suggesting a possible optimal dosing frequency somewhere between 1 and 3 months.

PIER, EXCITE and PrONTO are important studies in establishing dosage and frequency of administration for ranibizumab. The results from these studies have encouraged many retinal specialists to give three consecutive monthly injections of 0.3 mg of ranibizumab followed by as-needed administration based on OCT or FA findings. While there was no study to establish dosing for bevacizumab prior to the CATT study, most clinicians have used dosing regimens similar to that for ranibizumab. Fortuitously, the findings from the latest CATT trial indicating that less-than-monthly dosing of 1.25 mg of bevacizumab was as effective as a monthly injection provided solid support to the way many clinicians have been using it off-label for the past few years. At the moment, individualized and as-needed dosing after the initial three consecutive monthly injections for both drugs is used by most retinal experts.

Issues in optometric comanagement

When it comes to comanagement of neovascular AMD, optometrists as primary eye care providers play an essential role in educating patients about the disease and necessary treatment, in providing surgeons with medical and ocular history of the patient prior to treatment and continuing patient care after each treatment. Thus, it is important that optometrists keep up with the latest findings from clinical trials on efficacy and safety of intravitreal anti-VEGF injections.

No one likes to have a needle stuck in the eye, not even once, but with the current treatment paradigm, patients will have to put up with the uneasy feelings almost once a month for at least a few years. So, it is critical to emphasize that “it sounds worse than it actually is” and, if possible, refer the patient to other patients who have been through the process a few times as support.

Current tailored dosing frequency (modified from PrONTO protocol).

In addition to educating and calming the patient about intravitreal injection, information about potential adverse effects from the treatment should be discussed and made available. Based on multiple clinical studies with hundreds of patients and thousands of injections, common ocular adverse effects for ranibizumab injections included conjunctival hemorrhage, eye pain and transient increase in intraocular pressure; therefore, it is important to check IOP after every injection. Because it is an invasive procedure, endophthalmitis, uveitis, retinal detachment, vitreous hemorrhage and cataract have rarely (less than 1% incidence) been associated with intravitreal injection.

Nonocular adverse effects including nasopharyngitis and hypertension were more common with ranibizumab, whereas incidence of arteriothrombotic events (myocardial infarctions or cerebral vascular events) were relatively low. In the CATT study, endophthalmitis developed in less than 0.1% of treated patients. Uveitis, retinal detachment, vein occlusion, retinal tear and vitreous hemorrhage each occurred in less than 1% of patients.

The proportions of patients with arteriothrombotic events, such as myocardial infarction and transient ischemic attack, were similar with ranibizumab and bevacizumab at about 2.5%, which is within the expected incidence in the general population of patients with AMD. Therefore, ranibizumab may not significantly increase the risks for arteriothrombotic events, but it is difficult to prove either way. In response of this concern, Genentech issued a letter of warning that patients with a history of stroke may have a higher risk of subsequent stroke. On a positive note, many patients can appreciate the improvement of vision in a relative short time, because the two drugs are effective and can substantially reduce the total retinal thickness as early as a month after the initial injection.

Indications beyond wet AMD

Angiogenesis was one of the properties discovered in the initial investigation of the role of VEGF; the other was its association to vascular leakage and edema, which is a common sequelae to other retinal disorders. Thus, it was anticipated at an early stage of anti-VEGF development that the molecule could be useful in relieving retinal edema for various conditions in addition to neovascular AMD. After receiving FDA approval in 2006 for treating wet AMD, the focus was broadened to study ranibizumab for treating retinal vein occlusion.

BRAVO (a Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion) demonstrated that monthly intravitreal injections of 0.3 mg or 0.5 mg of ranibizumab provided rapid, effective treatment for macular edema after branch retinal vein occlusion (BRVO). At 6 months, the percentage of patients who gained at least 15 letters in best corrected visual acuity was about 60% in the ranibizumab groups and 30% in the sham group. The median percent reduction in excess foveal thickness was about 97% and 28%, respectively.

CRUISE (a Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion) also confirmed that monthly intravitreal injections of 0.3 mg or 0.5 mg of ranibizumab provided rapid improvement in 6-month visual acuity and macular edema after central retinal vein occlusion (CRVO). At 6 months, the benefits found in CRVO patients were even better than what was found for BRVO. The percentage of patients who gained 15 letters in BCVA at month 6 was 47% in the ranibizumab group and 17% in the sham group. The median percent reduction in excess foveal thickness was 96% and 23.9%, respectively. These dramatic beneficial results led to FDA approval of ranibizumab for treatment of retinal edema secondary to retinal vein occlusion in 2010. Prior to these studies, retinal vein occlusions had been managed largely with a “wait-and-see” approach for the initial few to several months without an effective treatment guideline.

With evidence that anti-VEGFs are beneficial for treating edema commonly found in wet AMD and retinal vein occlusion, diabetic macular edema (DME), a retinal condition with the same theme, is the next natural target. Several studies (READ-2, RESTORE trials) conducted by the Diabetic Retinal Clinical Research Network (http://drcrnet.jaeb.org) reported that ranibizumab alone or in combination with photocoagulation yielded significantly more letters of visual acuity gain compared to less than one letter gained by laser treatment alone. In addition, central serous chorioretinopathy is another condition of retinal edema that had been relieved with anti-VEGF in a number of studies.

The clinical applications of anti-VEGF (ranibizumab or bevacizumab) for ocular disorders continue to expand as more positive results are found for other vascular ocular disorders. The arena is now moving more anteriorly from posterior retina to anterior segment. An increasing number of studies in recent years have shown the beneficial effects of anti-VEGF, from neovascular glaucoma to corneal neovascularization. The general theme seems to be as long as abnormal angiogenesis and edema are part of the pathophysiology of a disease, anti-VEGF would probably be efficacious in some way, regardless of disease manifestation.

Future directions – anti-VEGF, laser

The results from various randomized clinical trials to date have provided concrete evidence on the superb efficacy of ranibizumab and bevacizumab for the treatment of neovascular AMD. Nonetheless, approximately one in five patients may not get the full benefit or be nonresponders. Therefore, retinal specialists have continued to explore combining the new anti-VEGF with older therapy such as corticosteroids and verteporfin photodynamic therapy (PDT).

One of the earlier studies to demonstrate the effectiveness of combination therapy was the FOCUS (Ranibizumab Combined With Verteporfin Photodynamic Therapy in Neovascular Age-related Macular Degeneration) study. The study showed that, on average, ranibizumab with PDT had less progression and greater reduction of retinal edema and required fewer PDT retreatments than PDT alone. Furthermore, the VIA (Verteporfin and Bevacizumab) study demonstrated that a combination of PDT with bevacizumab significantly reduced the number of bevacizumab treatments required over 6 months. In another combination-therapy study, intravitreal bevacizumab combined with triamcinolone was administered to patients with neovascular AMD that were resistant to bevacizumab alone. The results suggested that patients who were nonresponders to bevacizumab monotherapy may experience mild improvement in vision with combined intravitreal injection.

Therefore, the field of combination therapy for ocular angiogenesis and edema is ongoing and evolving as more studies are being carried out. At the same time, other anti-angiogenic agents are slowly progressing through the drug pipelines, including VEGF-Trap-Eye (Regeneron/Bayer) with more sustained release.

Focus shifts to dry AMD

As the saying goes “Dry is the new wet.” Now that a lot of success has been made in the management of wet AMD, more attention is being paid to finding effective therapy to stop or reverse dry AMD, which accounts for the majority of AMD. In addition to AREDS2 (Age-Related Dry Eye Disease Study 2) in finding a combination of vitamins and antioxidants that can slow the progression of dry AMD, there are various clinical trials on its potential treatments.

For example, complement inhibition with eculizumab for the treatment of nonexudative AMD is a phase 2 study being conducted by the University of Miami. Kaplan Medical Center is conducting a phase 3 trial with Copaxone (glatiramer acetate, Teva), a drug for patients with relapsing-remitting multiple sclerosis. GlaxoSmithKline is working on a tyrosine kinase inhibitor, pazopanib, that may be formulated as a topical anti-VEGF drop for maintenance therapy.

In addition, other modes of therapy are also being investigated such as localized radiation therapy (EpiRad, NeoVista), rheopheresis (Apheresis Research Institute) and photobiomodulation (NCT00940407). As defined by the corresponding companies who ventured in these novel arenas: “Epimacular beta radiation therapy is approved for the treatment of wet AMD in the European Union. Rheopheresis is therapeutic apheresis using the methodology of double filtration plasmapheresis to treat microcirculatory disorders. Photobiomodulation is the application of nonthermal, nonlaser light of specific wavelengths and energy directly on the eye to improve retinal function and delay AMD progression.”

Ultimately, gene therapy may offer a way to deliver anti-VEGF protein or other therapeutic agents directly to the site of ocular disorders.

In summary, there has been a great leap forward over the past decade in understanding the mechanism of angiogenesis and management of ocular disorders resulting from abnormal angiogenesis. Ranibizumab and bevacizumab are the blockbuster drugs for patients with wet AMD, while the scientific community is working hard to come up with similar agents for the more common dry form of AMD. Older therapy such as PDT or photocoagulation and corticosteroids continues to play an important role as a sole or an adjunct therapy in combination with the new anti-VEGF molecules for abnormal ocular angiogenesis as in wet AMD, diabetic retinopathy and BRVO. For optometrists, our roles as primary eye care providers will not change drastically. As new intravitreal drugs come into market, the most important thing we can do is to keep up with developments in eye care, provide excellent care and educate our patients.

References:

• Brown DM, Kaiser PK, Michels M, et al, ANCHOR Study Group. N Engl J Med. 2006;355:1432-1444.
• Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010;16:1107-1111.
• Lalwani GA, Rosenfeld PJ, Fung AE, et al. Am J Ophthalmol. 2009; 145:43-58.
• Magdelaine-Beuzelin, Pinault C, Paintaud G, et al. Therapeutic antibodies in ophthalmology: old is new again. mAbs. 2010;2(2):176-180.
• Martin DF, Maguire MG, Ying G, et al. CATT Research Group. N Engl J Med. 2011;364:1897-1908.
• Regillo CD, Brown DM, Abraham P, et al., PIER Study Group. PIER Study year 1. Am J Ophthalmol. 2008;145:239-248.
• Regillo CD, Brown DM, Abraham P, et al., PIER Study Group. PIER Study year 2. Am J Ophthalmol. 2010;150:315-324.
• Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331-335.
• Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
• Schmidt-Erfurth U, Eldem B, Guymer R, et al. The EXCITE Study Group. Ophthalmology. 2011;118(5):831-839.
• Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95-113.

For more information:

• Len V. Hua, PhD, OD, FAAO, is an assistant professor at Pacific University College of Optometry. He can be reached at 2043 College Way, Forest Grove, OR 97116; (503) 352-3059; fax: (503) 352-2929; lenvhua@pacificu.edu.
• Disclosure: Dr. Hua has no relevant financial disclosures.