Oncology drug safe and effective when injected into eye
At the same time as bevacizumab began to be used in oncology patients, the VEGF inhibitor pegaptanib (Macugen) was approved in the United States for the treatment of wet age-related macular degeneration
(3). Pegaptanib neutralises VEGF165, one of the four isoforms of vascular endothelial growth factor, and it quickly met with competition. Shortly after its approval for colorectal cancer, bevacizumab was administered to patients with wet macular degeneration. A small study showed a clear improvement in visual acuity, reduced retinal thickness and less leakage from neovascular lesions following intravenous administration of bevacizumab (13). American ophthalmologists then began injecting the drug intravitreally (directly into the vitreous of the eye) (14). Norwegian ophthalmology departments were early adopters of this treatment. Intravitreal injections of VEGF inhibitors proved very effective for the treatment of wet age-related macular degeneration and other ocular diseases, with little risk of complications or adverse effects (15, 16). It is also important to note in this context that the development of optical coherence tomography (OCT) has had great clinical, scientific and economic impact within the field of ophthalmology. Optical coherence tomography is a rapid and non-invasive technique that uses light waves to image anatomical structures of the eye with micrometre resolution (17) (Figure 1). The technology is currently used in most subspecialties of ophthalmology, but especially in the diagnosis and follow-up of eye diseases affecting the retina and the choroid. Figures 2 and 3 show OCT images of a macula from the same patient with wet macular degeneration before and after initiation of anti-VEGF treatment.
Figure 1 Optical coherence tomography (OCT) showing a normal macula. In the middle, the fovea centralis, which has the highest photoreceptor density. Cross-sectional images of the retina allow assessment of morphology and measurement of retinal thickness.
Figure 2 OCT of the macula in a patient with wet age-related macular degeneration prior to initiation of anti-VEGF treatment. Retinal thickening and subretinal fluid can be seen. Visual acuity is 0.1.
Figure 3 OCT of the macula in the same patient three years later, following repeated anti-VEGF injections. Conditions are now virtually dry. Visual acuity is 0.63.
Bevacizumab is a full-length monoclonal immunoglobulin G (IgG). Based on studies in which full-length antibodies were injected intravitreally into healthy monkey eyes, it had been assumed that the molecular weight of bevacizumab was too high for it to be able to diffuse through the retina and thus reach retinal blood vessels and neovascularisations originating from the underlying choroid
(18). The manufacturer of bevacizumab therefore developed a modified variant, ranibizumab (Lucentis), for ocular use. The result was an antigen-binding fragment (a so-called Fab fragment) with higher affinity for vascular endothelial growth factor, lower molecular weight, better tissue penetration and shorter systemic half-life (19). Ranibizumab also lacks the Fc fragment of IgG and does not activate the complement system or platelets. Ranibizumab was approved in 2006 by the US pharmaceutical authorities for the treatment of wet age-related macular degeneration (15). The list of indications has subsequently been expanded.
Although bevacizumab has not been formally approved for ocular use, it is nevertheless used in several neovascular ocular diseases. The main motivation for using bevacizumab is financial: One dose of ranibizumab costs almost NOK 8 000, while a dose of bevacizumab costs NOK 2–300. In 2016, the Department of Ophthalmology at Oslo University Hospital performed more than 20 000 injections of VEGF inhibitors. Savings from the use of bevacizumab would thus be substantial. Studies comparing bevacizumab and ranibizumab have also shown that they are equally effective
(20, 21). The initial assumption that intravitreal injection of full-length IgG would not be effective proved to be incorrect. It is likely that in pathological conditions such as age-related macular degeneration, anatomical barriers are defective such that full-length IgG can in fact diffuse through the retina and reach its intended destination. The diffusion studies in monkeys were also performed with antibodies that were subsequently found to bind antigens in the retina, thereby preventing their further diffusion into deeper layers (18).
In addition to pegaptanib and ranibizumab, a third VEGF inhibitor, aflibercept (Eylea), has been approved for ocular use. This is a chimeric fusion protein composed of VEGF receptors 1 and 2 and the Fc portion of human IgG1
(22). Aflibercept binds and blocks VEGF-A, VEGF-B and placental growth factor (PlGF). Compared with ranibizumab and bevacizumab, aflibercept has higher affinity for vascular endothelial growth factor and a longer intravitreal half-life. In practice, three medications are used in intravitreal injections in Norway today: bevacizumab, ranibizumab and aflibercept. Intensive research is being carried out into new and better treatment options, and several exciting drug candidates are undergoing clinical trials. Further knowledge of the mechanisms of vascular eye disease will enable continued drug development and will expand the treatment options available to those patients who, every year, are affected by such conditions.