Inhibiting Platelet Derived Growth Factor: The Next Step in the Treatment of Exudative Age-Related Macular Degeneration

Abstract

®® ® , Regeneron, Tarrytown, NY, USA) into eyes with subfoveal or juxtafoveal Choroidal Neovascular Membranes (CNVM) result in visual improvements which average +6.9 letters to +11.3 letters [1-4]. Furthermore, vision is stabilized in most eyes, with severe loss of vision (>15 letters) occurring in only 5% of patients. Since physicians around the world rapidly adopted this therapeutic strategy, rates of blindness in industrialized nations have already fallen significantly [5]. The unqualified success of anti-VEGF therapy juxtaposes sharply with the deficiencies associated with previously available treatments (thermal laser photocoagulation, photodynamic therapy, transpupillary thermotherapy, and macular translocation surgery) [6-9]. These therapies were indicated for only a small percentage of affected patients, were followed by frequent neovascular recurrences, were plagued by unacceptable complication rates, and rarely improved the visual acuity. Much of what we know about both the benefits and limitations of anti-VEGF therapy is derived from pre-clinical studies with bevacizumab and aflibercept. These drugs impressively suppress the growth of orthotopic tumors in various animal models, and phase 1 and 2 trials in humans with advanced solid tumors demonstrated that the drugs were reasonably well tolerated. Unfortunately, monotherapy produced limited improvements in progression-free and overall survival for most patients [10]. The only human tumor currently treated with anti-VEGF monotherapy is glioblastoma, whereas for all other tumors, anti-VEGF agents are combined with multi-drug chemotherapeutic regimens. Though newly developed anti-VEGF drugs possess stronger VEGF binding affinities than their predecessors (bevacizumab < ranibizumab < aflibercept) [11], they have not resulted in greater visual improvements for patients with exudative AMD. Thus it appears that anti-VEGF monotherapy for AMD may have hit a therapeutic “ceiling”. Based on these observations, some investigators have suggested that further improvements in the treatment of AMD will require combination therapy (similar to the experience with tumors). Different treatment modalities (photodynamic therapy, radiation therapy) have already been combined with anti-VEGF pharmacotherapy, but these offer no additional advantage in efficacy (maximum number of letters gained) and little advantage in durability (duration of treatment effect) [12-14]. Intravitreal corticosteroids decrease VEGF synthesis, and stabilize cell membranes and tight junctions, but provide little additional benefit when used with anti-VEGF drugs, or used as triple therapy (combined with both anti-VEGF drugs and photodynamic therapy).