Aflibercept for Exudative AMD
Aflibercept for Exudative AMD
The treatment of exudative AMD continues to evolve. Numerous groups have observed anatomic and sometimes visual improvement after switching to aflibercept in cases with persistent fluid on prior anti-VEGF treatment, reporting similar findings to the current study; as of this writing, no studies have been published.
In the present study, there was significant anatomic improvement after a single aflibercept injection with gains maintained at 6-month follow-up. There are several possible explanations for the observed anatomic benefit after switching to aflibercept, including its pharmacodynamics and the possibility of tachyphylaxis to prior treatment with ranibizumab/bevacizumab. As mentioned, aflibercept binds all isoforms of VEGF-A and VEGF-B, as well as PIGF, with a significantly higher binding affinity for VEGF than either ranibizumab or bevacizumab. Mathematical models predict that a single intravitreal injection of aflibercept 2.0 mg would last between 48 and 83 days (compared with 30 days for ranibizumab) and thus should be efficacious in neutralising VEGF longer and more effectively. Both VEGF-B and PIGF have been implicated in the neovascularisation process of AMD. It is possible that eyes included in this study were not at the peak of their dose-response curve while on prior treatment. However, the HARBOR study failed to find an anatomic or visual difference between 0.5 mg and 2.0 mg of ranibizumab for exudative AMD at 3 years, suggesting that in their overall study population ranibizumab 0.5 mg was sufficient. It is possible that greater VEGF blockage might be helpful for a recalcitrant subset of exudative AMD eyes, as supported by the SAVE trial.
Tachyphylaxis, or a decreasing therapeutic response to a pharmacologic agent following repeated administration over time, is another possible explanation for the observed effect after switching to aflibercept. Eyes with choroidal neovascularisation experiencing an initial morphological response to ranibizumab or bevacizumab therapy but later developing tachyphylaxis despite repeated injections can show an improved response when switched to a different anti-VEGF drug. The anatomic gains in this study were maintained through 6 months on aflibercept. Most likely, both the pharmacodynamics and the possibility of tachyphylaxis are playing roles in aflibercept's observed improvement of previously persistent fluid.
It is unclear if a drier macula achieves better long-term visual acuity. The present study did not find any visual gain (non-best corrected) at 1 or 6 months after switching to aflibercept, and there was a non-significant trend towards worsening visual acuity. In our cohort of patients with persistent fluid despite an average of 20 prior injections of ranibizumab and/or bevacizumab, chronic photoreceptor degeneration might have limited the visual potential after switching to aflibercept. Smaller studies reported significant visual gains after switching to aflibercept,while others have shown no improvement. In VIEW one and two, survival analysis found eyes treated with aflibercept had resolution of macular fluid sooner than eyes treated with ranibizumab, yet there was no clear visual advantage at 1 year. In the combined VIEW trials, 38% of eyes in the ranibizumab arm had persistent fluid at 1 year, compared with 27.6% in the aflibercept 2 mg every 4-week arm, and 32.3% in the aflibercept 2 mg every 8-week arm. It is possible that in a subset of eyes with persistent fluid due to exudative AMD, despite regular ranibizumab and/or bevacizumab treatment, the observed anatomic benefit of aflibercept might make a long-term visual difference.
The strength of the present study is the homogeneity of included eyes with strict inclusion and exclusion criteria, and 6 months of follow-up with a recently approved medication. Limitations of our study include the small cohort, its uncontrolled retrospective design, non-best corrected (but best available) visual acuity, and non-standard treatment protocols. Further, fluorescein angiography was not always performed prior to switching to aflibercept, and the determination of persistent fluid was made on spectral domain, volume scan OCT alone. Future prospective studies could evaluate various protocols switching eyes to aflibercept and evaluate efficacy and costs of individualised treatments for eyes with and without persistent fluid on ranibizumab and/or bevacizumab.
In summary, a significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab and/or bevacizumab treatment respond anatomically to aflibercept 2.0 mg at 1 month, with gains maintained at 6 months. Non-best corrected visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD with persistent fluid on ranibizumab and/or bevacizumab.
Discussion
The treatment of exudative AMD continues to evolve. Numerous groups have observed anatomic and sometimes visual improvement after switching to aflibercept in cases with persistent fluid on prior anti-VEGF treatment, reporting similar findings to the current study; as of this writing, no studies have been published.
In the present study, there was significant anatomic improvement after a single aflibercept injection with gains maintained at 6-month follow-up. There are several possible explanations for the observed anatomic benefit after switching to aflibercept, including its pharmacodynamics and the possibility of tachyphylaxis to prior treatment with ranibizumab/bevacizumab. As mentioned, aflibercept binds all isoforms of VEGF-A and VEGF-B, as well as PIGF, with a significantly higher binding affinity for VEGF than either ranibizumab or bevacizumab. Mathematical models predict that a single intravitreal injection of aflibercept 2.0 mg would last between 48 and 83 days (compared with 30 days for ranibizumab) and thus should be efficacious in neutralising VEGF longer and more effectively. Both VEGF-B and PIGF have been implicated in the neovascularisation process of AMD. It is possible that eyes included in this study were not at the peak of their dose-response curve while on prior treatment. However, the HARBOR study failed to find an anatomic or visual difference between 0.5 mg and 2.0 mg of ranibizumab for exudative AMD at 3 years, suggesting that in their overall study population ranibizumab 0.5 mg was sufficient. It is possible that greater VEGF blockage might be helpful for a recalcitrant subset of exudative AMD eyes, as supported by the SAVE trial.
Tachyphylaxis, or a decreasing therapeutic response to a pharmacologic agent following repeated administration over time, is another possible explanation for the observed effect after switching to aflibercept. Eyes with choroidal neovascularisation experiencing an initial morphological response to ranibizumab or bevacizumab therapy but later developing tachyphylaxis despite repeated injections can show an improved response when switched to a different anti-VEGF drug. The anatomic gains in this study were maintained through 6 months on aflibercept. Most likely, both the pharmacodynamics and the possibility of tachyphylaxis are playing roles in aflibercept's observed improvement of previously persistent fluid.
It is unclear if a drier macula achieves better long-term visual acuity. The present study did not find any visual gain (non-best corrected) at 1 or 6 months after switching to aflibercept, and there was a non-significant trend towards worsening visual acuity. In our cohort of patients with persistent fluid despite an average of 20 prior injections of ranibizumab and/or bevacizumab, chronic photoreceptor degeneration might have limited the visual potential after switching to aflibercept. Smaller studies reported significant visual gains after switching to aflibercept,while others have shown no improvement. In VIEW one and two, survival analysis found eyes treated with aflibercept had resolution of macular fluid sooner than eyes treated with ranibizumab, yet there was no clear visual advantage at 1 year. In the combined VIEW trials, 38% of eyes in the ranibizumab arm had persistent fluid at 1 year, compared with 27.6% in the aflibercept 2 mg every 4-week arm, and 32.3% in the aflibercept 2 mg every 8-week arm. It is possible that in a subset of eyes with persistent fluid due to exudative AMD, despite regular ranibizumab and/or bevacizumab treatment, the observed anatomic benefit of aflibercept might make a long-term visual difference.
The strength of the present study is the homogeneity of included eyes with strict inclusion and exclusion criteria, and 6 months of follow-up with a recently approved medication. Limitations of our study include the small cohort, its uncontrolled retrospective design, non-best corrected (but best available) visual acuity, and non-standard treatment protocols. Further, fluorescein angiography was not always performed prior to switching to aflibercept, and the determination of persistent fluid was made on spectral domain, volume scan OCT alone. Future prospective studies could evaluate various protocols switching eyes to aflibercept and evaluate efficacy and costs of individualised treatments for eyes with and without persistent fluid on ranibizumab and/or bevacizumab.
In summary, a significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab and/or bevacizumab treatment respond anatomically to aflibercept 2.0 mg at 1 month, with gains maintained at 6 months. Non-best corrected visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD with persistent fluid on ranibizumab and/or bevacizumab.
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