Anti-VEGF therapy to emerge as the future in treatment of AMD

ByCarmen A. Puliafito, MD, MBA

The advent of verteporfin (Visudyne, Novartis Pharmaceuticals Corp.) and the Treatment of AMD with Photodynamic Therapy Trial (TAP) ushered in the era of retinal pharmacotherapy. The ability to treat choroidal neovascularization with an exogenously applied drug has changed results in patients with subfoveal CNV. Over the past 2 years, AMD therapy has turned toward pharmacologic modulation of the disease, particularly the anti-vascular endothelial growth factor (VEGF) paradigm.^1-3 As is true of all scientific and medical progress, headway can be slow or tumultuous, and the anti-VEGF paradigm is no different. Retina specialists treat patients with AMD in various ways for a number of reasons, as rapid changes and advancements in therapy are reflected in clinical practice.

Rethinking wet AMD treatment

Wet AMD is characterized by chronic upregulation of VEGF, although VEGF is not the cause of AMD. AMD is a diffuse disease that can occur in both the retina (retinal angiomatous proliferation, for example) and in the choroid, indicating that focal treatment is ineffective.

“In anti-VEGF therapy for the treatment of CNV, molecules in the choroid block and prevent VEGF from binding to receptors on blood vessels.”
– Carmen A. Puliafito, MD, MBA

The therapeutic paradigm states the molecular blockade of VEGF is the sine qua non for treating patients with AMD. Much of the structural damage that occurs with wet AMD can be reversed, as the advent of verteporfin and photodynamic therapy has shown. Anti-VEGF therapy improved morphology of the retina and visual acuity.³

Chronic anti-VEGF therapy has become the dominant therapy, replacing laser and PDT. There is evidence that if treatment is stopped, patients may have recrudescence of leakage. In addition, data have shown that most patients lose vision in the first 6 months of developing AMD, reiterating the importance of early detection as a means of saving sight.^4,5

Anti-VEGF developments

In anti-VEGF therapy for the treatment of CNV, molecules in the choroid block and prevent VEGF from binding to receptors on blood vessels. If VEGF binds to these receptors, blood vessels may proliferate or leak. Therapeutic benefits require chronic suppression of the underlying stimulation for leakage and CNV, indicating a need for chronic anti-VEGF therapy.^6-8

Pegaptanib (Macugen, [OSI] Eyetech) was approved in December 2004 by the Food and Drug Administration for treatment of AMD and ranibizumab (Lucentis, Genentech) is in phase 3 trials. In addition, bevacizumab (Avastin, Genentech) was approved in February 2004 for treatment of colon or rectal cancer and is being used off-label for some ophthalmic conditions, including CNV.

Pegaptanib

Administered every 6 weeks through intravitreal injection, pegaptanib is an aptamer that is not immunogenic. It has been proven to selectively block VEGF 165, which is believed by many to be the dominant form of VEGF in CNV.

In the VEGF Inhibition Study in Ocular Neovascularization (VISION), which is the collective results of two identical phase 3 clinical trials, broad enrollment criteria were used, including patients with lesions considered to have a poor prognosis. These criteria included older, larger lesions and lesions with choroidal folds, previous PDT and laser treatment, prominent blood and lipids, and retinal pigment epithelial (RPE) detachments and retinal angiomatous proliferation. Pegaptanib decreased the rate at which patients lost three lines of vision by about 27% at 1 year, extending to about 31% at 2 years.^6-8 Because it is a biological therapy, the treatment effect of pegaptanib extends across all angiographic subtypes, including predominantly classic, minimally classic and occult AMD. Pegaptanib reduces deterioration in vision, as mean visual acuity stabilized toward the end of 1 year in patients treated with pegaptanib, while the visual acuity in the sham group continued to deteriorate (Figure 1).^6-8

Over the 2-year study, pegaptanib-treated patients lost a mean of 9.4 letters of vision, compared with a loss of 17 letters for the sham treatment group.⁹ Treatment with pegaptanib reduced the number of patients who became legally blind, as well, with a 36% treatment benefit at 2 years. Ten percent of pegaptanib-treated patients had an improvement in visual acuity of three or more lines.^6-8 The main serious adverse effect shown with pegaptanib was an increased risk of endophthalmitis due to its intravitreal administration,⁷ and, after a modification to the injection protocol, the rate of endophthalmitis was significantly reduced.¹⁰

Patients may experience a slower treatment response as defined by optical coherence tomography (in terms of the decrease in intraretinal and subretinal fluid and flattening of the RPE detachments) than other anti-VEGF agents seem to produce. This indicates that multiple treatments may be necessary before OCT results are apparent,^6-8 and effects on vision should subsequently be monitored closely.

Recent data indicate that pegaptanib is successful when treatment begins when lesions are designated as early lesions, when photoreceptors are likely to be healthier and respond better to therapy.^6-8 Lesions designated as early included those that were small (less than 2 disc diameters) with relatively good vision, no scarring or atrophy and no previous PDT, and occult lesions with the absence of lipid. This is also an example of how early detection and subsequent treatment can result in enhanced vision outcomes in patients.

Ranibizumab

Ranibizumab is derived from bevacizumab and binds to all isoforms derived from alternative splicing, including VEGF 110, a plasmin-cleaved form of VEGF 165. It has a rapid treatment effect as measured by visual acuity testing and OCT, indicating these measurements can be used to make patient-specific treatment decisions.¹¹ Treatment effect is durable in some eyes and extends across all angiographic subtypes, including predominantly classic, minimally classic and occult AMD.

In the Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis Study (PrONTO), an ongoing study conducted on 40 patients over 2 years, patients were injected with 500 µg of ranibizumab three times a month and underwent OCT imaging at 1, 2, 4, 7 and 14 days post-injection.¹¹ At day 14, visual acuity significantly changed; patients gained a median of six letters and a mean of 5.5 letters.¹⁰ Conversely, central retinal thickness decreased, as measured by OCT.¹³

In the Minimally Classic/Occult Trial of the Anti-VEGF Antibody RhuFab V2 in the Treatment of Neovascular AMD (MARINA), a randomized, multicenter, double-masked, sham injection controlled study evaluating the safety and efficacy of two different doses of ranibizumab (0.3 mg and 0.5 mg) in 716 patients with minimally classic or occult subfoveal wet AMD,³ 62% of the sham group had a loss of fewer than 15 letters. Of the patients treated with ranibizumab, 94% had less than a 15-letter loss at 1 year. Overall, a 17-letter difference was observed between the treated and untreated groups. A 15-letter or greater gain from baseline to 1 year was noted among 24.8% of patients treated with 0.3 mg of ranibizumab, compared with 33.8% of patients treated with 0.5 mg of ranibizumab and 4.6% of the sham treatment group. It should be noted that in the sham group in the MARINA trial, 62% lost less than three lines of vision, indicating patients enrolled in the VISION trial may have had more severe AMD.

Within the sham treatment group, 15.1% of patients had a visual acuity of 20/40 or better at baseline, compared with 10.9% at 1 year. Of the patients treated with 0.3 mg of ranibizumab, 11.3% had a visual acuity of 20/40 or better at baseline, compared with 38.7% at 1 year, and of the patients treated with 0.5 mg, 15% had a 20/40 visual acuity at baseline, compared with 40% at 1 year.³ In a subgroup analysis, ranibizumab proved to be effective across angiographic subtypes (Figure 2).³

Although the safety of ranibizumab appears to be good, a higher rate of cerebrovascular events were reported in patients treated with ranibizumab than those in the sham group.³ In addition, in the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD Trial (ANCHOR), which is a phase 3 trial, a higher rate of myocardial infarctions occurred in patients treated with the higher dose of 0.5 mg of ranibizumab than in the study arms of patients treated with 0.3 mg ranibizumab and patients treated with verteporfin for injection (Visudyne, Novartis Pharmaceutical Corp.) PDT.¹⁴ In terms of visual acuity, data from the 1-year results of the 2-year ANCHOR trial indicate that patients treated with 0.3 mg ranibizumab gained 8.5 letters of visual acuity; those treated with 0.5 mg ranibizumab gained 11 letters; and those treated with verteporfin PDT lost an average of 9.5 letters.¹²

Bevacizumab

In an open-label, single-center, uncontrolled clinical study (SANA: Systemic Bevacizumab [Avastin] Therapy for Neovascular AMD), patients with subfoveal CNV and visual acuity of 20/40 to 20/400 were treated with 5 mg/kg of systemic bevacizumab, followed by additional doses given at 2-week intervals.¹³ Researchers noted improvements in visual acuity, OCT and angiographic outcomes. Increases in visual acuity were evident within 1 week of treatment and, by 12 weeks, the media and mean visual acuity had improved by eight letters (P = .011) and 12 letters (P = .008), respectively. Within 12 weeks of treatment, the median and mean central retinal thickness measurements decreased by 157 µ (P = .008) and 177 µ (P = .001), respectively.¹⁵ In the fellow eye at 12 weeks, median and mean visual acuity increased by 27 letters (P = .018) and 16 letters (P = .012), respectively, and the median and mean central retinal thickness decreased by 59 µ (P = .028) and 92 µ (P = .06), respectively.¹⁵ In all eyes, a marked reduction or absence of leakage from CNV was noted using angiography. The only adverse event identified was a mild elevation of systolic blood pressure, which was controlled with antihypertensive medication and was no longer significant by week 12.¹³

Conclusion

Based on compelling evidence, anti-VEGF therapy may become the mainstay of treating CNV, although the choice of optimal agent(s), dosing intervals and mode of delivery requires further research. Currently, pegaptanib is the only anti-VEGF agent approved by the FDA as both safe and effective for ocular use, but clinical data on ranibizumab and the limited available data on bevacizumab have shown that they may be among other effective therapies, as well.

References

Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983-985.

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306-1309.

Miller JW. Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration. Presented at the annual meeting of the American Society of Retina Specialists; July 18, 2005; Montreal, Quebec, Canada.

TAP Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin. One-year results of 2 randomized clinical trials — TAP report 1. Arch Ophthalmol. 1999;117(10):1329-1345.

Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: Two-year results of 2 randomized clinical trials — TAP report 2. Arch Ophthalmol. 2001;119(2):198-207.

Gragoudas ES. VEGF Inhibition Study in Ocular Neovascularization-1 (VISION-1): Efficacy results from phase II/III Macugen (pegaptanib sodium) clinical trials. Presented at the annual meeting of the Association for Research in Vision and Ophthalmology; April 27, 2004; Fort Lauderdale, Fla.

D’Amico DJ, Bird AC. VEGF Inhibition Study in Ocular Neovascularization-1 (VISION-1): Safety evaluation from the pivotal Macugen (pegaptanib sodium) clinical trials. Abstract 2363, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; April 27, 2004; Fort Lauderdale, Fla.

Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.

D’Amico DJ. Results of the second year of Macugen for the treatment of neovascular AMD (VISION). Presented at the annual meeting of the American Society of Retina Specialists; July 18, 2005; Montreal, Quebec, Canada.

Mieler WF. The VISION Study: Safety of a second year of Macugen treatment for neovascular AMD. Presented at the annual meeting of the American Society of Retina Specialists; July 18, 2005; Montreal, Quebec, Canada.

Fung AE. OCT imaging of neovascular AMD patients treated with ranibizumab (Lucentis): The PrONTO study. Presented at the annual meeting of the American Society of Retina Specialists; July 18, 2005; Montreal, Quebec, Canada.

Puliafito CA. Ranibizumab for treatment of neovascular ARMD. Presented at Retina 2006, part of Hawaiian Eye 2006; January 16, 2006; Wailea, Maui, Hawaii.

Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic Bevacizumab (Avastin) Therapy for Neovascular Age-Related Macular Degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6):1035-1047.

A summary of treatment methods for choroidal neovascularization

by Linda Christian

Although anti-vascular endothelial growth factor therapy has recently captured attention as treatment for patients with choroidal neovascularization, other treatments have been proven to be effective for treating CNV.

Photodynamic therapy

In PDT, which is used only on patients with predominantly classic AMD, verteporfin for injection (Visudyne, Novartis Pharmaceuticals Corp.), a light-activated dye, is injected into a patient’s arm and activated with a non-thermal laser shined into the eye. Activation of the verteporfin produces a chemical reaction that seals and reduces unhealthy blood vessels.

PDT is effective in occluding or inhibiting CNV and preventing vision loss, according to several studies.^1-7 The Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study (TAP) found a loss of fewer than 15 letters of visual acuity (ETDRS) in 59% of patients treated with PDT vs. 31% of those given placebo (P < .001).^1,2 PDT also led to additional benefits in terms of lesion size, fluorescein leakage, contrast sensitivity and central visual fields.³

In the Verteporfin in Photodynamic Therapy Study (VIP), patients treated with verteporfin were significantly less likely to have moderate or severe vision loss at 2 years.⁴ In a study of 20 patients undergoing PDT, no eyes had deterioration in vision, five eyes had a progression in vision and 15 eyes maintained stable visual acuity.⁵

Data on 948 patients indicate that the relative risk of losing three or more lines of visual acuity at 24 months was 77% vs. control group. The relative risk of losing six or more lines of visual acuity at 24 months was 62% vs. control group.⁶ In a study of patients with poor baseline visual acuity undergoing PDT therapy, the median change in visual acuity over 12 months was + 13 letters.⁷

Focal laser photocoagulation

In laser photocoagulation, used only on patients with CNV, surgery is performed using an argon or diode laser to destroy or seal new blood vessels, preventing leakage. Although it has been proven to protect vision, the procedure is rarely used, and is not used for subfoveal lesions.^8,9 Reasons for this are numerous: CNV had a high rate of recurrence despite photocoagulation, and the procedure can cause scarring (perceived as blind spots by the patient) and leads to a reduction of vision immediately following the procedure.^8,9 In addition, only 10% to 15% of lesions meet the specific requirements that would make them eligible for focal laser photocoagulation.¹⁰

Anecortave acetate

Anecortave acetate (Retaane, Alcon), a steroid analogue, works by preventing extracellular matrix breakdown and the migration and proliferation of endothelial cells. It is an angiostatic cortisone, the first of its type, and is devoid of glucocorticoid activity. Anecortave acetate is administered as a posterior juxtascleral depot using a blunt-tipped cannula. The depot, placed over the macula, releases anecortave acetate for up to 6 months. The drug starts to lose its effect at about 4 months; subsequent changes to dosing regimen and amount are being investigated.

In a previously conducted study, anecortave acetate failed to meet its end point of noninferiority to verteporfin PDT, although there was no statistical difference between treatment outcomes of the two therapies.¹¹ In addition, two potentially controllable factors affected the results and are being addressed. Anecortave acetate was statistically superior to placebo for inhibition of neovascular lesion growth, stabilization of vision, mean change in vision from baseline and prevention of severe vision loss.^12,13

Subsequently, further research is being conducted: The Anecortave Acetate Risk Reduction Trial (AART) is being conducted on 2,500 patients with exudative AMD in the non-study eye and multiple intermediate/large soft and/or confluent drusen, hyperpigmentation and no evidence of exudative AMD or geographic atrophy in the eye to be treated.¹⁴ Participants are randomized to receive posterior juxtascleral administrations of anecortave acetate or a sham procedure every 6 months for 4 years, with a primary efficacy measurement being the development of CNV within 2,500 µ of the foveal center.¹⁴

Emerging methods of treatment

Emerging methods of treatment for CNV include other VEGF treatments, such as VEGF Trap (Regeneron Pharmaceuticals, Inc.) and small interference RNA (siRNA).

siRNA is showing promise as a treatment for wet AMD by “turning off the gene” and subsequently blocking the VEGF-inducing protein from being formed. In a phase 1 clinical trial, Cand5 (Acuity Pharmaceuticals) was found to be safe and well tolerated,¹⁵ and a phase 2 trial is underway. Sirna-027 (Sirna Therapeutics) showed a stabilization of visual acuity in all 23 patients participating in a phase 1 study as well.¹⁶ In addition, 23% experienced an improvement of visual acuity of three lines or more within 8 weeks of injection.¹⁶ A phase 2 trial is being conducted, as further research on siRNA is necessary to determine its efficacy.

VEGF Trap has shown promise as a treatment for AMD by “trapping” VEGF, preventing it from stimulating the VEGF receptor. In preclinical experiments, VEGF Trap prevented the development of clinically significant CNV and showed regression of established, active CNV.^17,18 Further research is needed, however, and is being conducted.

References

Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of 2 randomized clinical trials — TAP report No. 1. Arch Ophthalmol. 1999;117:1329-1345.

Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: Two-year results of 2 randomized clinical trials — TAP report 2. Arch Ophthalmol. 2001;119:198-207.

Schmidt-Erfurth UM, Elsner H, Terai N, Benecke A, Dahmen G, Michels SM. Effects of verteporfin therapy on central visual field function. Ophthalmology. 2004;111:931-939.

Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization — verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131:541-560.

Jin C, Ge J, Shou S, et al. Photodynamic therapy for age-related macular degeneration [article in Chinese]. Yan Ke Xue Bao. 2004;20(3):158-162.

Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2005; October 19; 4:CD002030.

Potter MJ, Szabo SM. One-year outcomes after photodynamic therapy in patients with age-related macular degeneration with poor baseline visual acuity. Graefes Arch Clin Exp Ophthalmol. 2005; December 8: 1-3 [Epub ahead of print].

Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol. 1994;112:500-509.

Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. 1991;109:1109-1114.

Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol. 1994;112(4):480-488.

Regillo CD. New and investigational therapies for age-related macular degeneration, 2004. Presented at the annual meeting of the American Academy of Ophthalmology; October 23-26; New Orleans, La.

Schmidt-Erfurth U, Michels S, Michels R, Aue A. Anecortave acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Eur J Ophthalmol. 2005;15(4):482-485.

D’Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: Twelve-month clinical outcomes. Ophthalmology. 2003;110(12):2372-2383; discussion 2384-2385.

Russell SR, Slakter JS, Ho AC, et al. Anecortave acetate treatment of “dry” AMD to reduce risk of progression to “wet” AMD — The Anecortave Acetate Risk Reduction Trial (AART). Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 3134.

Thompson J. Presented at the annual meeting of the American Academy of Ophthalmology; October 23-26, 2004; New Orleans, La.

Kaiser PK. VEGF Trap for AMD. Presented at Retina 2006, held in conjunction with Hawaiian Eye 2006; January 17, 2006; Wailea, Maui, Hawaii.

Wiegand SJ, Zimmer E, Nork TM, et al. VEGF Trap both prevents experimental choroidal neovascularization and causes regression of established lesions in non-human primates. Poster 1411/B180, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 2, 2005; Fort Lauderdale, Fla.

Wen R, Zhao L, Liu Y, et al. VEGF Trap induces significant regression of existing choroidal neovascularization (CNV). Poster 5307/B510, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 5, 2005; Fort Lauderdale, Fla.