Ocular microparticle formulations for 6-month delivery of anti-VEGF.

Dr. Judah Folkman’s groundbreaking research in the fields of angiogenesis and vascular biology has been translated into successful medicines in the eye to treat disorders, such as wet age-related macular degeneration (AMD) and diabetic retinopathy. Although preceded by the ill-fated aptamer, pegaptanib (Macugen), the development of ranibizumab (Lucentis), the first protein-based vascular endothelial growth factor (VEGF) inhibitor for wet AMD, was the most significant and revolutionary [1]. These VEGF inhibitors are administered by intravitreal (IVT) injection, locally into the eye. While Lucentis is highly effective, it is also highly expensive. Efforts have been focused on using cheaper alternatives, led by the off-label use of bevacizumab (Avastin), a full antibodyVEGF inhibitor developed for cancer, aswell as onfinding drugs and drug formulations that would extend the efficacy to several months. The more potent and longer acting aflibercept (VEGF Trapeye, Eylea), another biologic, with an extended label of bi-monthly administration is now becoming the leading VEGF inhibitor for wet AMD treatment by IVT injection [2]. The challenge to extend the efficacy of a VEGF inhibitor to several months or longer has become a ‘holy grail’ in the controlled release field. The paper by Dr. Ian R. Catchpole and his team in this issue has addressed some of the many challenges of delivering an active anti-VEGF biologic in a controlled release system over 6 months in the eye of a non-human primate (NHP) [3]. The work demonstrates that it is possible to loadmicroparticles with sufficient amounts of a potent anti-VEGF molecule and inject IVT to sustain release over 6 months in the NHP at sufficient levels to protect against laser choroidal neovascularisation (CNV), the pre-clinical model of wet AMD. The approach was modelled to predict clinical efficacy in man. Despite this considerable success, the work highlights further challenges to overcome before long-acting microparticle formulations could be used in man. It is still difficult to find an ideal delivery system that could provide high drug loading capacity, a stable environment for protein, minimal initial burst release followed by a steady state release over 6months, and a degradation kinetics thatmatches the release rate. The limited intravitreal volume cannot afford additional doses without timely degradation of the previous delivery system. Ocular inflammation in response to injection of particulates is something expected. One unexpected observation in the study, however, was particle migration from the vitreous to the anterior chamber of the eye in the primate. This finding appears to be related to the ocular biology of primate and man, and was not seen in the many rabbit studies performed by the authors andmany other scientists. The paper highlights the risks that could be directly applicable to other particle based delivery systems for IVT administration. It shows the need for the use of a NHPmodel as a validation of such systems.