Perspective
Safety Implications of Vascular Endothelial Growth Factor Blockade for Subjects Receiving Intravitreal Anti–Vascular Endothelial Growth Factor Therapies

https://doi.org/10.1016/j.ajo.2009.06.014Get rights and content

Purpose

To evaluate potential safety risks associated with nonspecific inhibition of vascular endothelial growth factor (VEGF).

Design

A perspective, reviewing the current literature.

Methods

Herein, we discuss the systemic safety of VEGF-targeted therapies, address safety issues for VEGF-targeted therapies in neovascular age-related macular degeneration, and propose the consideration of methods for identifying low rate systemic safety signals from patients treated with these agents.

Results

Several prospective, randomized clinical trials have demonstrated that intravitreal anti-VEGF therapies generally are well tolerated. However, within these trials, there is some circumstantial evidence that links systemic VEGF inhibition to systemic adverse events, particularly systemic thromboembolic events. Because all of the intravitreal anti-VEGF agents have been associated with detectable levels in the systemic circulation, there is a scientific rationale for the occurrence of potential systemic adverse events. However, if safety issues are present, they occur at very low rates and may go undetected in controlled clinical trials of premarketed drugs.

Conclusions

We propose that highly sensitive methodologies be put into place for identifying low rate safety signals, including postmarketing clinical trials, chart reviews, electronic medical records, and various national and international registries and databases, to evaluate the systemic safety of antiangiogenic agents in ocular diseases such as neovascular age-related macular degeneration.

Section snippets

Route of Administration of Anti–Vascular Endothelial Growth Factor Agents and Systemic Safety

The route of administration must be considered to understand potential systemic effects of anti-VEGF agents used to treat neovascular AMD. Interestingly, intraocular drugs also have been found in the systemic circulation, despite the presence of the blood-ocular barrier (ie, blood-retinal barrier), which shields the retina from circulating blood.5 Ocular drugs that are injected into the eye may enter the systemic circulation after absorption through uveal vessels (iris or ciliary body) or by

Systemic Safety of Systemically Administered Anti–Vascular Endothelial Growth Factor Agents

Systemic AEs with VEGF isoform inhibition must be considered because of the ubiquitous distribution of the molecule and because VEGF isoform levels can change in response to disease conditions. It is possible that patients with lower systemic levels of VEGF-A have lower thresholds of tolerance to anti-VEGF agents and are at higher risk for systemic AEs that result directly from VEGF inhibition. To gain an understanding of potential systemic AEs that may emerge with intravitreal administration

Pegaptanib Sodium

Pegaptanib sodium is a 28-base ribonucleic aptamer that binds with high affinity to VEGF165 and larger isoforms. In the phase 3 VEGF Inhibition Study in Ocular Neovascularization (VISION) clinical trial, intravitreal pegaptanib sodium was well tolerated. Serious ocular AEs associated with pegaptanib sodium in the first year of the VISION were endophthalmitis, traumatic cataract, and retinal detachment, which were attributed to the injection preparation or procedure rather than to the drug

Mechanisms for Identifying Low Rate Systemic Safety Signals

It is useful to interpret trial-generated safety profiles to help predict AE risk for real-life patients. Notably, however, safety profiles of marketed drugs used in the real-life setting may differ from those anticipated based on clinical trial data because extremely rare AEs may be undetected during clinical trials.

Even large-scale clinical trials, including the MARINA (n = 716), ANCHOR (n = 423), SAILOR (n = 4,300), and the ongoing CATT (n = 1,200) and VIEW 1 (n = 1,200) and VIEW 2 (n =

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