BEYOND IMAGINATION

A decade ago a revolution in the way we treat and therefore conceive retinal disease took place: the introduction of anti-VEGF therapy with the concept of multiple intravitreal injections has completely transformed wet age-related macular degeneration (AMD) treatment, with a major contribution to our understanding of the disease and its ramifications. 
Following years of ablative laser therapy and drug-augmented photodynamic therapy, the opportunity emerged to actually treat the disease’s “main driving force”, i.e angiogenesis.
The wave of interest from the pharmaceutical industry resulted in class “A” data (derived of randomised double blind controlled clinical trials with sophisticated statistical analyses) to guide clinicians in their quest for the most appropriate treatment for their patients. Numerous studies such as MARINA and ANCHOR, followed by CATT, IVAN and many others have produced high-level data and a basis for more advanced research. 
Moreover, it became apparent that not only angiogenesis, but also macular oedema was amenable to anti-VEGF therapy. This opened the gate for other diseases such as diabetic macular oedema (DME) and macular oedema due to retinal vascular occlusion (RVO) as indications for anti-VEGF therapy. 
Additional topics took on a life of their own – for example, research for better anti-VEGF delivery options, and though there are no new extended release anti-VEGF drug delivery technologies approved yet, extensive research has been carried out and the field is growing with new companies/technologies, which eventually will lead to better modes of therapy allowing lower frequency of injections. Another example of expanded research are the studies comparing the efficacy of the various anti-VEGF therapies. 
These studies included thousands of patients, and have expanded our knowledge of the profile of the main anti-VEGF drugs: Avastin, Lucentis and Eylea. It has allowed the medical community to assess the comparative efficacy of those agents which have shown reasonable comparability for wet AMD, while observing the possible superiority of Eylea in DME in patients with worse baseline vision as shown in the DRCRnet Protocol T first-year results.

APPROPRIATE DRUGS
Overall, this helps practitioners choose the most appropriate drugs for their patients, adapted to their own local health systems. The advancement in therapeutic options have moved the field forward so much that wet AMD efficacy assessment has moved from rate of vision loss to rate of vision gained and vision maintenance, one decade following the inception of anti-VEGF therapy in the eye. 
Long-term follow-up of patients treated for wet AMD with anti-VEGF therapy discloses yet additional lines of progressive pathology in the forms of atrophic macular changes that are either part of baseline choroidal neovascularisation (CNV) pathology, or could be a specific response to long-term use of anti-VEGF agents.
The progressive use of anti-VEGF intraocular injections also revived the possible role of corticosteroids for macular oedema, though here new technologies have been developed and approved utilising long-acting delivery modes, such as those seen in the dexamethasone implant Ozurdex and the fluocinolone implant Iluvien. Improving steroid performance via prolonged delivery modes had been a goal of long-standing research for more than two decades. The first long-term delivery steroid product, Retisert, for the treatment of posterior non-infectious uveitis, clearly showed the potential of long-term use of intraocular steroid with three years of drug delivery using an implant. 
However, the adverse event burden of cataract and severe glaucoma leading to intraocular pressure-lowering surgery in approximately 40 per cent of patients did prevent a successful commercial experience. Thus, newer products, first Ozurdex and now Iluvien, with safer steroid concentrations, reveal a more desirable adverse event profile and have been shown to be effective for indications such as DME, RVO and potentially as an adjunct to anti-VEGF therapy. These successful results point to the important role of delivery methodologies for future utilisation of retinal pharmaceuticals. 

DELIVERY TECHNOLOGIES
The future therefore continues to evolve, with new products under research carrying promising mechanisms of action on one hand and better delivery technologies on the other. It seems that the principle of gaining high local drug concentration avoiding systemic adverse events via intraocular injections is capable of opening new horizons unique for retinal drugs, compared with other extraocular target organs. Leading technologies point to combining anti-VEGF with other anti-angiogenic agents, via one or two lead molecules packed together. 
Extensive research on small anti-angiogenic molecules is reaching towards another long-standing goal of eye drops effective for the treatment of retinal diseases, however so far results have been disappointing. Additionally, new molecules are designed to treat other indications such as anti-complement H, 3, and 5 for dry AMD with preliminary results promising. 
New delivery technologies are also being explored such as electroporation, iontophoresis, suprachoroidal injections, implantable refillable reservoirs, and specifically designed materials for extended release of proteins, with the goal of decreasing the burden from patients and doctors  treating retinal disease. 
It is the hope of all of us that the future will bring modes of therapy that are beyond our current imagination, though the first steps are definitely here right now. 

Prof Baruch Kuppermann is the head of the retina section at ISOPT Clinical
Baruch D Kuppermann: bdkupper@uci.edu