New combination approaches for the management of AMD

Ophthalmologists are faced with a challenge in treating patients with age-related macular degeneration: Patients are living longer. The average patient age at diagnosis of AMD is 75. Most patients can expect to live for at least 12 years after being diagnosed. With monthly treatments, the average patient with AMD can receive more than 120 injections per eye in his or her lifetime. In half of those patients, the second eye will be affected within 5 years of onset of the disease in the first eye, so an additional 60 injections may be needed in the other eye. A better treatment strategy than injections each month or every 6 weeks is needed.

Both ocular and systemic safety issues increase with repeated treatments. A longer dosing interval or decreased cumulative drug dosage is preferable. With more than one agent available and approved by the Food and Drug Administration for treatment of choroidal neovascularization in AMD, combination strategies should be considered.

For a patient, the burden associated with treatment with currently available vascular endothelial growth factor (VEGF)-inhibiting drugs can be onerous: 12 injections per year with ranibizumab or nine with pegaptanib. If clinical trial protocols are to be followed, PRN dosing may require less frequent injections, but, with protocols such as that used in the PrONTO (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis) trial, the burden on the patient is not reduced. Intensive patient monitoring is called for, with monthly visits that include optical coherence tomography (OCT) and fluorescein angiography.

Rationale for combination therapy

The rationale for attempting combination therapy for exudative AMD includes the potential for a course of treatment that is lower risk and less demanding for patients and physicians. Combination therapy also raises the possibility of targeting multiple disease pathways, which may lead to a synergistic effect and the potential to improve outcomes over monotherapy. Fewer treatments also by definition bring reduced risk of adverse events. If an ophthalmologist can inject an eye three times per year instead of 12, there is inherently less risk.

Visual acuity outcomes with ranibizumab monotherapy have raised expectations for future treatments. “Improved outcomes” today means not simply a reduction in the visual decline that is the natural history of AMD, but rather improvement in VA and angiographic outcomes and increased duration of benefit.

Pathogenesis of AMD

Several hypotheses have been proposed for the pathogenesis of AMD, but none has been proven. Factors that contribute to the development of AMD include retinal pigment epithelium (RPE) dysfunction, alterations in Bruch’s membrane, oxidative stress, inflammatory processes and ischemia.^1,2The development of CNV is a complex process that involves RPE cells, macrophages and other inflammatory cells and myofibroblasts.^3,4

Current therapies for AMD address the disease through a number of these pathways.

Current available non anti-VEGF therapies

Photodynamic therapy with verteporfin is an angio-occlusive approach to treating CNV. PDT is pro-inflammatory; it upregulates inflammatory mediators, upregulates pigment epithelial derived factor (PEDF) and upregulates VEGF. ^5-8

PDT causes closure of CNV and choroidal vessels and alters the natural history of the disease, reducing the progression of decline in VA, but it has not been shown to result in significant improvement in vision.⁹ The closure of vessels results in tissue hypoxia, and a hypoxia-inducible factor (HIF 1-alpha) then causes the upregulation of VEGF and other factors.¹⁰

PDT’s upregulation of VEGF brings both desired and undesired effects. Undesired effects include recurrent growth of the CNV membrane, increased membrane permeability and leakage from the CNV. Desired effects include preventing hypoxia-induced retinal damage, allowing the recovery of surrounding choroidal vessels and encouraging maturation of CNV that is less permeable and less susceptible to reinitiation of neovascularization. ¹¹

There is a rationale for combination therapies for CNV that combine anti-VEGF therapy with verteporfin PDT. PDT can physically close down the CNV and alter signaling mechanisms in the retinal environment. Then an anti-VEGF therapy can prevent subsequent upregulation of VEGF and inflammatory response to avoid the recurrence of angiogenesis and vessel leakage.

Currently available VEGF inhibitors decrease vessel permeability and are believed to inhibit the initiation of new vessel growth, although apparently they do not destroy mature abnormal vessels.^12,13

Intravitreal injection of corticosteroids, most commonly triamcinolone and dexamethasone, has been used off-label to treat CNV in AMD, both alone and in combination with PDT. Steroids may inhibit inflammatory mediators; they are angiostatic, not angiocidal, and they stabilize the blood- retinal barrier. ^14,15 Other compounds such as anecortave acetate are only available through clinical trials.

The targets of these treatments for CNV include exudation and fibrosis. The compounds that address permeability include steroids, bevacizumab, ranibizumab and pegaptanib.¹⁶ Off-label steroids are the only compounds at present that also address fibrosis in AMD.¹⁷ This is important because the two principal reasons for loss of vision in AMD are RPE atrophy and fibrosis, and current agents approved for treatment of CNV in AMD do not address fibrosis.

Past and ongoing combination studies

A number of combination studies for treatment of AMD have been undertaken.

In the RhuFab V2 Ocular Treatment Combining the Use of Verteporfin to Evaluate Safety (FOCUS) study, ranibizumab plus PDT was more efficacious than PDT alone for treating neovascular AMD.¹⁸ Positive interim results have been reported for the PROTECT study,¹⁹ which is examining same-day PDT plus ranibizumab. In the VEGF Inhibition Study In Ocular Neovascularization (VISION) trial, a 2-year evaluation of pegaptanib, PDT was allowed at the physician’s discretion in all study arms for predominantly classic lesions (Figure 1).²⁰

Ongoing combination studies include the Verteporfin Intravitreal Triamcinolone Acetonide (VERITAS) study, in which PDT is combined with triamcinolone 1-mg or 4-mg injections or with pegaptanib. The Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD (LEVEL) trial is investigating an induction-maintenance strategy, in which patients are treated with a nonselective VEGF inhibitor and maintained on pegaptanib, which is selective for inhibition of the isoform VEGF. ¹⁶⁵

Also ongoing are the U.S. DENALI and the European MONT BLANC trials, both of which are comparing a combination of ranibizumab plus PDT to monthly ranibizumab.

Pegaptanib + PDT for 54 Weeks Results in Seven Line Gain

Figure 1. An eye treated with PDT and pegaptanib improved by seven lines of VA, from 20/320 at baseline to 20/63 after 1 year of treatment.

Source: Hughes MS

Recent additional studies

Results of other combination studies are emerging. Our center recently published results in a series of 20 treatment-naïve eyes treated with bevacizumab induction followed by pegaptanib maintenance.²¹

When this study was begun in 2005, case reports by Rosenfeld and colleagues²² described the off-label use of intravitreal bevacizumab, an oncology drug, for the treatment of CNV in AMD. We were concerned about the long-term use of nonselective VEGF-blocking agents, so we elected to induce patients with a single-shot 1.25-mg intravitreal injection of bevacizumab followed by maintenance with 0.3-mg pegaptanib. The first injection of pegaptanib was given 3 weeks after bevacizumab induction and then every 6 weeks, with re-evaluation of the patient at 18 weeks. Patients received a “booster” of bevacizumab when the greatest linear dimension of the leakage area on fluorescein angiography increased by more than 15%. Patients were followed for 1 year.

In this series, the mean Snellen VA results (Figure 2) follow a curve similar to the results in the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody RhuFab V2 in the Treatment of Neovascular AMD) trial, showing improvement in vision persisting to the end of the follow-up.²³ Mean Snellen VA improved from 20/200 at baseline to slightly better than 20/80 at 54 weeks. Four patients required a booster shot of bevacizumab at week 18. At 24, 36 and 54 weeks, no one, including the four patients who received the injection at 18 weeks, required an additional bevacizumab injection.

VA at 12 months improved three lines or more from baseline in 45% of patients, and 55% had smaller gains or maintained stable VA. No patient lost lines of VA. Mean gain of VA was 2.4 lines, and 95% of patients gained at least one line.

Gaurav Shah, MD, has shared results of a study he will present at the upcoming meeting of the American Society of Retinal Surgeons, in which verteporfin PDT was combined with nonselective VEGF blockade with bevacizumab. ²⁴ Twenty-four treatment-naïve eyes with subfoveal and juxtafoveal CNV lesions received bevacizumab followed by PDT, with a 1-week to 2-week interval between injection and PDT. Re-treatment was based on subretinal fluid on OCT or leakage on fluorescein angiography. In 24 eyes followed for 7 months, 20 eyes (83%) maintained stable VA and 16 (67%) had improvement in VA. VA improved by three lines or more in nine eyes (38%), and five (22%) achieved 20/40 or better VA. Fifteen eyes (63%) required only the initial treatment of combination therapy, and eight eyes (33%) required one re-treatment by the 7-month follow-up interval.

We have submitted for publication our experience with another combination approach: reduced-fluence verteporfin PDT plus nonselective VEGF blockade with ranibizumab.²⁵ This is a prospective analysis of 20 treatment-naïve patients over the past 6 months. Four-month follow-up data are reported. A variety of lesion types were included, both occult and classic. Mean baseline VA was 20/200, and mean baseline retina thickness on OCT was 378 µm. Average age was 80.2 years, with a range from 68 to 92 years. Thirteen patients were women. Exudative AMD was unilateral in 13 patients and bilateral in seven patients. The average greatest linear dimension of lesions in the study was 2,250 µm, with a range from 525 µm to 5,400 µm.

In reduced-fluence PDT, a time of 60 seconds or less is used rather than the normal treatment of 80 seconds. Ranibizumab was injected intravitreally within 1 to 2 days after PDT. Ranibizumab was injected every 4 weeks when fluid was seen on OCT. At 12 weeks, evaluation included fluorescein angiography and OCT, and patients were treated again with reduced-fluence PDT and ranibizumab when leakage was seen on fluorescein angiography. Twenty patients have been followed for 4 months.

Patients with CNV secondary to AMD were included. Excluded were patients with previous PDT in the study eye or any intraocular surgery. Patients with incomplete follow-up were excluded from our analysis.

At 4 months, seven (35%) eyes gained three lines or more of VA; mean gain of VA was 2.2 lines. No eyes lost lines of vision. Overall, 16 eyes (80%) required only one treatment over the 4 months; four eyes (20%) required one re-treatment (Figure 3).

This is early follow-up, and evaluations at 6 and 12 months are needed, but initial results are promising for a reduced burden of treatment using this strategy.

Mean Visual Acuity (Snellen): 12 Months

Figure 2. Hughes and colleagues’ trial showed that bevacizumab induction followed by pegaptanib maintenance improved visual acuity.

Source: Hughes MS

VA End points (Snellen): 4 months

Figure 3. Reduced-fluence PDT and ranibizumab improved visual acuity in patients with CNV secondary to AMD.

Source: Hughes MS

Other combination approaches

Other combination treatments have been attempted, but in some clinical trials enrollment has been slow. One such trial was a randomized, double-masked trial comparing combined selective VEGF inhibition with pegaptanib plus verteporfin PDT or sham PDT. Enrollment was scheduled for 360 patients, but only 168 have been enrolled, and the study is no longer being funded. Early results in a small number of patients in phase 1b of that trial suggest that PDT plus pegaptanib may confer additional benefit. Sixty percent of those treated with the combination gained three lines of VA or more vs. 25% of those who received pegaptanib alone (n=10 in the pegaptanib+PDT group and n=8 in the pegaptanib control group).

A number of centers have investigated a triple therapy combining PDT, intravitreal dexamethasone 400 µm or 800 µm and anti-VEGF treatment with ranibizumab, bevacizumab or pegaptanib. Our triple regimen has included standard or reduced-duration PDT, dexamethasone and pegaptanib or ranibizumab.

Conclusions

CNV secondary to AMD is a dynamic, multifactorial process involving vascular, nonvascular and inflammatory components. A pharmacologic hypothesis for treatments addresses the biochemical and physical (ie, scarring) aspects of neovascular AMD. Ongoing clinical trials are investigating the safety and efficacy of a number of combination therapies. As with hypertension and diabetes, it is likely that the best therapy for CNV in AMD will not be a single monotherapy or a “cookbook” approach for all patients, but a customized combination of therapies.

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