Combination Treatments for CNV in AMD

Early reports show promising results with several combinations of therapies.

PETER K. KAISER, MD

Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 50 in the United States and other western countries.^1,2 Most vision loss in AMD results from the development of pathologic choroidal neovascularization (CNV) in the exudative ("wet") form of the disease.³

Until recently, the only therapy shown to be effective in prospective, randomized, controlled trials in reducing the risk of vision loss in people with CNV due to AMD was laser photocoagulation.^4-6 Since 2000, 3 pharmacologic therapies for CNV in AMD have been approved by regulators in the United States: photodynamic therapy (PDT) with intravenous injection of verteporfin (Visudyne, Novartis), intravitreal injection of pegaptanib sodium (Macugen, OSI/Pfizer), and ranibizumab (Lucentis, Genentech). Although not approved by regulators, the use of off-label bevacizumab (Avastin, Genentech) has also gained favor to treat CNV. Other pharmacologic agents are in earlier stages of investigation.

With the availability of these new pharmacologic therapy options, clinicians have begun to explore the possibilities of combining 2 or more agents that address different components of CNV, with the hope of achieving additive or synergistic effects. While no data from prospective, randomized studies of combination therapies for AMD have been published to date, several studies have shown promise in preclinical work and early clinical studies. This article reviews the rationale and the clinical safety and efficacy of combination therapies for CNV in AMD.

A COMPLEX DISEASE

Researchers and clinicians are beginning to understand that exudative AMD is more complex than once thought. More than simply a vascular disease, it includes angiogenic, vascular, and inflammatory components, with interactions among these components. With this complex pathophysiology, researchers postulate that a combination of therapies with different mechanisms of action addressing multiple targets in CNV may have the potential to improve the efficacy of treatments or reduce the number of treatments needed in eyes with CNV due to AMD.

Inflammatory Component

The inflammatory component of CNV can be addressed with corticosteroid therapy — in particular with intravitreal injection of triamcinolone acetonide (IVTA) or dexamethasone. In addition to anti-inflammatory properties, steroids have antiangiogenic, antifibrotic, and antipermeability properties. The direct and indirect angiostatic properties of steroids appear to reduce the permeability of the blood-retina barrier,^7,8 which may reduce the risk of developing CNV. This angiostatic effect, however, is minimal in comparison with the anti-inflammatory effects of steroids, which inhibit the production of prostaglandins and other inflammatory mediators.^9-11

Preclinical models and small clinical trials have shown promising results with IVTA for the inhibition of CNV.^12-20 Improvements in visual acuity (VA) have been seen in clinically treated patients in small-scale trials and case series. However, it should be noted that in the only large-scale, randomized, controlled, double-masked clinical study of IVTA for CNV in AMD, there was no difference in the amount of severe vision loss (30 letters or more) at 12 months between treated and control eyes,^21,22 although there was a reduction in lesion growth in eyes with CNV with a classic component. In that study, IVTA was generally well tolerated, although there was a greater risk of elevated intraocular pressure (IOP) and there was significant progression of cataract in treated eyes. Endophthalmitis has also been reported after intravitreal triamcinolone injection.^23,24

Based on current evidence, the benefits of intravitreal triamcinolone as monotherapy do not appear to outweigh the risks of treatment. However, this treatment modality may deserve investigation in combination with other drugs because of its biological effects.

Vascular Component

The vascular component of CNV is the target of verteporfin photodynamic therapy. Verteporfin, injected intravenously, accumulates in the pathologic choroidal neovascular tissue, and laser is then used to activate the drug, leading to localized occlusion of the new vessels.²⁵ This process, called PDT, also appears to have secondary effects, including upregulation of the expression of vascular endothelial growth factor (VEGF) and inflammatory mediators.²⁶

Verteporfin with PDT has been shown to be effective in reducing the risk of vision loss in patients with classic²⁷ and occult with no classic²⁸ subfoveal CNV in AMD. An extension of 1 of the original 2-year randomized prospective trials that supported the regulatory approval of PDT in the United States found that VA remained stable after 5 years with no new safety concerns.²⁹

Currently, verteporfin with PDT is recommended for treatment in patients with subfoveal lesions composed of predominantly classic CNV, regardless of lesion size, or with small lesions (4 disc areas or less) containing occult with no classic or minimally classic CNV with evidence of recent disease progression.³⁰

Angiogenic Component

The most recent pharmacologic development in the treatment of CNV in AMD has been the introduction of drugs that address the angiogenic component of the disease. Two antiangiogenic compounds, pegaptanib and ranibizumab, have been approved by US regulators for treatment of CNV in AMD, and a third, bevacizumab, is used off-label. The rationale for these therapies is the interruption of the angiogenic cascade that leads to the formation of neovasculature. By inhibiting VEGF and other factors involved in angiogenesis, these drugs reduce the growth of existing CNV and may also lead to regression of new vessels if targeted early enough in the process of vessel formation.³¹

Pegaptanib monotherapy was shown in 2 prospective, randomized, controlled, double-masked clinical trials to reduce the risk of vision loss from CNV in patients with AMD.³² At 1-year follow-up, 70% of subjects receiving 0.3 mg pegaptanib via intravitreal injection lost less than 3 lines (15 letters) of VA from baseline vs 55% of those receiving sham injection. VA was maintained in patients in the trial who continued on pegaptanib therapy for a second year.³³

Ranibizumab was investigated in 2 prospective, randomized, controlled, double-masked trials.^34,35 In the MARINA study,³⁴ 2 doses of ranibizumab (0.3 mg and 0.5 mg) were compared with sham injection. In the ANCHOR study,³⁵ the same 2 doses were compared with verteporfin therapy. In the MARINA trial, in patients with minimally classic or occult with no classic CNV, at 1 year almost 95% of subjects in the 2 treatment arms lost less than 15 letters of VA from baseline vs 62% of those receiving sham injection, and these results were sustained through year 2. In the ANCHOR trial, in patients with predominantly classic CNV, approximately 95% of patients in the 2 ranibizumab treatment arms lost less than 15 letters of VA from baseline, vs 64% of those receiving verteporfin with PDT.

Another drug, anecortave acetate (Retaane, Alcon), has been approved for treatment of exudative AMD in Australia. It is an angiostatic steroid that has been shown to inhibit neovascularization in laboratory work^36-39 and has been evaluated in several clinical studies.^40-43

Other antiangiogenic agents are in earlier stages of evaluation for treatment of CNV in AMD. Bevacizumab (Avastin, Genentech) is an oncology drug that has been used off-label by ophthalmologists for treatment of exudative AMD. It is approved for treatment of colorectal cancer and is formulated for systemic use, not for ophthalmic use.⁴⁴ Its safety and efficacy in the treatment of patients with CNV in AMD has not been evaluated in a prospective, randomized, controlled clinical trial. Nonetheless, promising reports of its use intravitreally in small-series and open-label studies in patients with CNV^45,46 have generated considerable interest in the ophthalmic community.

RATIONALE FOR COMBINATION THERAPY

The use of combination therapy is based on the concept that drugs with different mechanisms of action may have additive or synergistic effects and may therefore improve efficacy and may reduce the number of treatments needed to combat a disease. Combination therapy has been widely used in other medical specialties, including oncology and cardiology and in the treatment of human immunodeficiency infection.

In the treatment of CNV, combinations of therapies can be used to simultaneously address more than one of the 3 components of CNV — inflammatory, vascular, and angiogenic.

For example, a rapid inflammatory response has been seen following verteporfin with PDT, and inflammatory cells have been noted in CNV specimens excised after PDT.^47-49 Adding an anti-inflammatory treatment such as a steroid to PDT might therefore reduce edema following the treatment and reduce visual disturbances, improving visual results.

Similarly, the closure of pathologic new vessels with verteporfin plus PDT leads to localized tissue hypoxia, which results in upregulation of VEGF and other factors.⁵⁰ Therefore, treatment with an antiangiogenic agent at the time of PDT might target not only VEGF production due to the pathogenesis of CNV, but also block the increase in VEGF expression due to PDT.

To evaluate these potential synergies or additive effects, a number of combination therapies for CNV in AMD have been investigated in the laboratory and the clinic.

IVTA PLUS PDT

Several small-scale or pilot studies have shown promising results with a combination of IVTA and verteporfin with PDT in patients with CNV in AMD.

Spaide and colleagues^51,52 reported their results with this combination in 13 patients who had previously undergone verteporfin with PDT and 13 treatment-naïve patients. In the treatment-naïve patients, a mean improvement of 2.5 lines of VA (13 letters) was seen at 1 year after combination therapy. In patients previously treated with PDT, an improvement of 0.44 lines (2 letters) was seen at 1 year. Improvement in vision was associated with decreased leakage on fluorescein angiography. The frequency of retreatment in the first year in this study was reduced by more than half in comparison with the frequency reported in the clinical trials that supported regulatory approval of PDT.^27,28 However, because of the different entry criteria and sample sizes in these studies, they cannot be directly compared. Increases in IOP in 39% of patients were controlled with topical medication.

Rechtman and colleagues⁵³ reported retrospectively on 14 patients who received a single dose of IVTA within 6 weeks of verteporfin therapy. With a median 18-month follow-up, 57% of patients maintained stable VA or improved by 30 letters or more.

Similar supportive findings have been reported by investigators in small studies or pilot trials using the combination of IVTA and verteporfin in eyes with subfoveal, minimally classic, subfoveal, juxtafoveal, and extrafoveal CNV lesions, as well as presumed ocular histoplasmosis syndrome. These results have not been published but have been reported at numerous professional meetings.^54-62

Some reports have raised concerns that this combination therapy may increase the risk of elevated IOP and cataract development. For example, in the 14-patient series reported by Rechtman and colleagues,⁵³ 29% of eyes experienced mild IOP elevation and 50% of phakic eyes experienced cataract progression. It is advisable to monitor IOP regularly during treatment with intravitreal steroids.

PDT PLUS ANTI-VEGF THERAPY

Investigators have evaluated the combination of PDT and antiangiogenic therapies for CNV in AMD in a number of small clinical trials.

In a dose-ranging study in 21 patients with subfoveal CNV,⁶³ 10 patients received pegaptanib alone and 11 received pegaptanib plus verteporfin with PDT. Pegaptanib was given every 28 days, with verteporfin administered 5 to 10 days previous in patients receiving both treatments. After 3 months, improvement in VA of 3 lines or more was seen in 60% of patients receiving the combination vs 25% of those receiving pegaptanib alone.

In the 2 VISION trials (in the United States and Europe),³² patients with predominantly classic CNV were allowed to undergo verteporfin with PDT at the discretion of the investigator. In the US study, in eyes with predominantly classic CNV (therefore eligible for PDT), there was a statistically significant difference at 1 year in the proportion of responders (those losing less than 15 letters of VA from baseline) between those receiving pegaptanib (73%) and placebo (51%). In the European study, in which PDT was less frequently employed (40% of patients vs 62% in the U.S. study), the difference was not statistically significant. However, it is impossible to determine whether this difference in the use of PDT explains the difference in visual outcomes.

For both the VISION study and the dose-ranging study referenced above, the small sample sizes and other confounding factors make it inadvisable to draw conclusions about the relative efficacy of pegaptanib monotherapy vs the combination treatment. A larger, double-masked study comparing these 2 modalities in 360 patients with predominantly classic CNV was designed to shed more light on the safety and efficacy of the combination, but this study has been terminated.

The combination of verteporfin with PDT and ranibizumab was evaluated in the multicenter, randomized FOCUS study,⁶⁴ in which 162 patients were randomized 2:1 to undergo verteporfin plus PDT quarterly as needed and either ranibizumab or sham injection monthly for 23 months. At 1-year follow-up, 90% of eyes receiving the combination had lost less than 15 letters of VA from baseline, compared with 68% of those receiving verteporfin alone. Those receiving the combination gained a mean of 5 letters vs a loss of 8 letters with verteporfin alone. In addition, patients receiving the combination required significantly fewer additional PDT treatments than those who received verteporfin alone.

A lyophilized version of ranibizumab was used in the FOCUS study,⁶⁴ unlike the ANCHOR and MARINA clinical trials, in which a liquid formulation (now used in commercially available ranibizumab) was used.^34,35 It is thought that the lyophilized preparation was the cause of an increased incidence of uveitis seen in the FOCUS study but not in the subsequent ANCHOR and MARINA studies.

While the FOCUS study showed that the combination of verteporfin PDT plus ranibizumab was more effective than verteporfin alone, it is not clear that the combination is more effective than ranibizumab alone. In the FOCUS study, in the group receiving the combination treatment, 90% of eyes lost less than 3 lines of VA. In the ANCHOR study, 96% of eyes receiving ranibizumab lost less than 3 lines. These results appear to be similar, although it must be noted that the 2 studies had different baseline characteristics and patient populations.

Even if no additional efficacy is demonstrated for the combination therapy over ranibizumab alone, the combination may still hold benefits for patients. Long-term data on the effects of continued administration of ranibizumab and the consequences of its discontinuation are lacking. One group has reported that, in 7 patients whose monthly ranibizumab therapy was discontinued after 2 years, 3 patients developed recurrent CNV after a mean interval of 6.2 months.⁶⁵ This suggests that there may be a rationale for using verteporfin in combination with ranibizumab to reduce the number of injections needed and the potential consequences of repeated injections.

The PROTECT study,⁶⁶ which evaluated the safety of same-day administration of liquid ranibizumab and verteporfin with PDT in patients with predominantly classic or occult CNV in AMD, found no additional safety concerns. In contrast to the FOCUS study, in which lyophilized ranibizumab was used, no inflammatory reaction was seen in this trial using the commercial formulation.

The combination of bevacizumab and verteporfin PDT has also been investigated in several small trials for the treatment of CNV in AMD.

Combined bevacizumab and verteporfin was compared to the individual agents as monotherapies in a randomized pilot study.⁶⁷ In 165 treatment-naïve eyes with minimally classic or occult CNV in AMD, subjects received either 1 verteporfin treatment, 1 intravitreal injection of bevacizumab, or bevacizumab within 1 hour of PDT. Significant improvement in VA was seen at 1 month in the bevacizumab and combination treatment groups, but not in the PDT-alone group. The VA improvement was maintained at 3 months only in the combination group.

In a nonrandomized, prospective study, 11 patients underwent combined verteporfin with PDT and bevacizumab injection.⁶⁸ Improvement in VA from baseline was 1.5 at 12 weeks and 1 line at 24 weeks. One additional treatment session was required in 7 eyes by week 24. No progression of neovascular lesions was seen, and no safety concerns were identified in the study period. Other noncomparative series have shown similarly promising results with the combination of intravitreal bevacizumab and verteporfin PDT for treatment of CNV in AMD.^69,70

No large-scale, prospective, randomized, controlled clinical trials of any antiangiogenic agent in combination with verteporfin PDT have published results to date. Several ongoing studies are investigating combinations of verteporfin and antiangiogenic agents. These include the VERITAS study,⁷¹ in which patients receive 1 of 3 treatment regimens on a prn treatment basis: verteporfin plus triamcinolone (1 mg or 4 mg) or verteporfin plus pegaptanib. The DENALI and Mont Blanc trials are 2 large-scale studies that are currently enrolling patients that will compare ranibizumab monotherapy to same-day administration of ranibizumab and either standard or reduced fluence verteporfin.⁷²

Michels and colleagues⁷³ recently demonstrated that verteporfin with PDT with a reduced fluence produced an effect on CNV similar to the standard light dose, but with less choroidal hypoperfusion. Because the hypoperfusion caused by PDT is probably associated with upregulation of VEGF, it may be that this reduced-fluence PDT will result in better outcomes when used in combination with VEGF-blocking treatments. A number of trials currently assessing combination therapies incorporating PDT are using a reduced-fluence light dose.

TRIPLE THERAPY

It is possible that triple therapy addressing each of the three components of CNV — inflammatory, vascular, and angiogenic — may offer advantages over current monotherapy options.

Augustin and colleagues⁷⁵ have reported their experience with a series of 104 patients treated with triple therapy of reduced-fluence verteporfin plus PDT followed by intravitreal injection of dexamethasone and bevacizumab. All patients received 1 cycle of triple treatment, 5 received a second cycle because of persisting CNV activity, and 18 received an additional injection of bevacizumab. With a mean follow-up of 40 weeks, VA improved by a mean of 1.8 lines from baseline. In most patients, 1 cycle of triple treatment resulted in significant and sustained improvement in VA.

The RADICAL study, currently recruiting participants, will evaluate the triple combination of verteporfin with PDT, ranibizumab, and dexamethasone.⁷⁶ That trial's expected completion date is 2010.

CONCLUSION

Investigators have published promising preliminary results from clinical studies of a number of combination therapies for treatment of CNV in AMD. Combining the anti-inflammatory effects of steroids with the vesseloccluding effects of verteporfin PDT and/or the antiangiogenic effects of VEGF inhibitors may offer advantages over current monotherapeutic modalities for CNV in AMD. Among the possible additive or synergistic effects of these combinations are reduction in the number of treatments needed, improvement in VA outcomes, reduction in the growth of CNV lesions, and reduction in visual disturbances that accompany some of these treatments as monotherapies. Large-scale, prospective, randomized clinical trials to assess the safety and efficacy of these combinations, in addition to their cost-effectiveness and the resulting quality of life of patients, are needed to guide clinical decision-making for treatment of CNV in AMD in the future. RP

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