Benefits, Risks Surround Switching Anti-VEGF Therapy

For treating AMD, the 3 anti-VEGF agents report similar efficacy and safety results in trials but different molecular structure and biochemical properties.

Irmela Mantel, MD

An international review aimed at determining the benefits and risks of switching between anti-vascular endothelial growth factor (anti-VEGF) agents for treatment of age-related macular degeneration (AMD) found that, despite a lack of evidence that one anti-VEGF agent is superior to another for AMD treatment, there may be a subset of patients with “particular genetic (partial refractoriness) or pharmacodynamic (drug tolerance) characteristic for whom a drug switch might be beneficial."

Lead author Irmela Mantel, MD, with the Jules Gonin Eye Hospital and Department of Ophthalmology at the University of Lausanne, Switzerland, and colleagues gathered insights on "switching" between the 3 major anti-VEGF agents: aflibercept, ranibizumab, and bevacizumab. The researchers gauged 89 published papers and personal clinical observations in order to determine whether switching anti-VEGF agents is clinically warranted.

The researchers state found the 3 anti-VEGF agents, despite similar efficacy and safety results in trials, differ in "molecular structure and biochemical properties." And those properties affect the binding affinity" of each anti-VEGF agent to specific receptors, as well as the half-life of agents.

Mantel reported that, generally switching is performed following an unsatisfactory treatment response from use of another anti-VEGF agent, and often the switch is based on "structural criteria on OCT [Optical coherence tomography] rather than functional outcomes relevant for refractoriness" such as retinal fluid levels, visual acuity (VA), and treatment history.

An overview of switching outcomes in studies by researchers showed that there was some evidence that patients switching to ranibizumab/bevacizumab therapies from aflibercept resulted in a reduction of retinal thickness determined by OCT scans (reductions ranged from 23 µ to 112 µ), and lower injection rates after switching to aflibercept. However, there was little agreement among studies reporting changes in VA for AMD patients.

Mantel and colleagues argued that the current published data on switching results in few secure conclusions about the clinical benefits of changing anti-VEGF regimens.

"On examination of the published anti-VEGF switching data, most observers reach one of two conclusions: either that anatomical improvement with or without improvements in VA are observed upon switching or that the relatively minor changes observed after switch are not clearly attributable to switchin," Mantel wrote.

He and colleagues also reported that the majority of already-published data entails studies with outcomes for patients switching from ranibizumab and/or bevacizumab to aflibercept, and that many of the research papers on switching between anti-VEGF agents are difficult to compare due to dissimilarities and asymmetries in the methodologies of published reports, the lack of a control arm, and various design and selection biases.

Those studies reporting a structural and/or functional benefit to switching anti-VEGF agents argued that the addition of an additional VEGF agent, with different pharmacodynamics and pharmacokinetics may assist some AMD patients, particularly those with genetic variations in the VEGF-A gene which has been theorized to be resistant to specific anti-VEGF agents.

Researchers suggested that switching anti-VEGF agents has clinical value, but argued that results of switching in a larger patient population may be "masked" within the patient population as a whole, and that that as yet identified subpopulation may be more likely to benefit from switching to an alternative anti-VEGF agent.

Studies reporting a lack of statistical evidence that switching anti-VEGF agents for treatment of AMD, Mantel states, often argue for the equivalency of the anti-VEGF agents based on the agents' equivalent outcomes in efficacy and safety trials, that changes to patient responsiveness and treatment frequency are to be expected over time" but are not necessarily the result of switching medications, and that those changes (for better or worse) over time can be credited to length of treatment or other confounding factors.

Though there is no clear evidence for a generalized superiority of 1 drug over the other, Mantel and her colleagues believed more research may be needed to determine if there is indeed a subset of patients with particular genetic characteristics for whom a switch would be beneficial.

The study, "Switching between ranibizumab and aflibercept for the treatment of neovascular age-related macular degeneration (nAMD)" was published online in the Survey of Ophthalmology last month.

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