Eye (2008) 22, 761–767 & 2008 Nature Publishing Group All rights reserved 0950-222X/08 $30.00 www.nature.com/eye The evolving role of H Dadgostar and N Waheed REVIEW vascular endothelial growth factor inhibitors in the treatment of neovascular age-related macular degeneration Abstract Keywords: VEGF; age related macular degeneration; Intravitreal injection Age-related macular degeneration (AMD) is the leading cause of blindness among the ageing population. The introduction of Introduction molecular inhibitors of vascular endothelial growth factor (VEGF), such as pegaptanib, The introduction of inhibitors of vascular ranibizumab, and bevacizumab, as treatments endothelial growth factor (VEGF)-A to the for exudative AMD has provided new hope for world of ophthalmology has transformed the affected patients and has transformed the management of age-related macular practices of retina specialists. Phase III degeneration (AMD), the leading cause of clinical trials have demonstrated the efficacy blindness among the ageing population in the and safety of monthly ranibizumab for the developing world.1 Retina specialists have preservation as well as improvement of visual largely embraced this new class of medication, acuity in patients with exudative AMD. which has for the first time offered the hope of Ongoing trials are evaluating the effectiveness visual improvement to patients suffering from of different dosing regimens, monitoring AMD. Although a large body of data supports strategies, and combination therapies to the efficacy of intravitreal injections of VEGF Cole Eye Institute, Cleveland determine the optimal niche for this new class inhibitors in AMD, the incorporation of this Clinic Foundation, of drugs in AMD management. Based on new treatment modality into a management Cleveland, OH, USA emerging evidence, most clinicians are now plan remains a challenge for many practitioners adopting a variable VEGF inhibitor dosing because of the current lack of standardized Correspondence: N strategy guided by serial diagnostic re- evidence-based guidelines for treatment and Waheed, Department of evaluation by optical coherence tomography. follow-up. In the present review, we highlight Ophthalmology, Some are also finding benefit through the the findings of the major clinical studies on The Cole Eye Institute, addition of photodynamic therapy and steroids VEGF inhibitors for the treatment of AMD, Cleveland Clinic to the treatment regimen. The results of current discuss emerging management patterns, and Foundation, and upcoming trials systematically addressing briefly examine future directions in the field. Jan-32, 9500 Euclid Avenue, Cleveland, OH 44195, USA these issues are expected to establish new Abnormal angiogenesis is believed to play an Tel: þ 1 216 445 9432; guidelines for the management of AMD. important role in the development and Fax: þ 1 216 445 2226. Indeed, a new paradigm may emerge wherein progression of exudative AMD as well as E-mail: waheedn@ numerous modular therapeutic modalities are proliferative retinopathies and systemic ccf.org administered in customized combinations diseases such as cancer.2 On the cellular level, a based on specific clinical and diagnostic simplified model of angiogenesis involves a Received: 16 October 2007 Accepted in revised form: findings. balance between proangiogenic molecules, such 19 February 2008 Eye (2008) 22, 761–767; doi:10.1038/eye.2008.86; as transforming growth factor (TGF)-a and TGF- Published online: 4 April published online 4 April 2008 b, the angiopoietins, and members of the VEGF 2008 VEGF inhibitors in neovascular AMD H Dadgostar and N Waheed 762 family, and antiangiogenic factors, such as pigment Neovascularization (VISION) study consisted of two epithelium-derived factor, thrombospondin, and prospective, randomized, double-masked, sham- angiostatin.2,3 VEGF-A is a member of a pleiotropic controlled phase III clinical trials demonstrating the multigene family, and multiple splice variants of this efficacy of intravitreal pegaptanib (vs sham injection) for molecule have been described with roles in angiogenesis the treatment of exudative AMD (Table 1).10–12 Subjects as well as vascular permeability and possibly cell with exudative AMD were enrolled without regard to survival.4–6 The biologically active secreted form is a angiographic lesion subtype and were randomized to homodimer that binds the receptor tyrosine kinases one of three doses of pegaptanib or sham injection VEGF receptor (VEGFR)-1 and VEGFR-2 on endothelial every 6 weeks for 48 weeks, with the exception of cells to induce intracellular tyrosine kinase pathways.3,4 subjects with predominantly classic lesions who also In AMD, VEGF-A is believed to be important for the underwent photodynamic therapy (PDT) at the growth and maintenance of choroidal neovascularization discretion of a masked treating ophthalmologist. At 12 (CNV) and has been detected in high levels both within months, 70% of subjects receiving 0.3 mg pegaptanib excised CNV specimens and in the vitreous of patients lost fewer than 15 letters of visual acuity compared to with subretinal CNV.7,8 This hypothesis ultimately led to 55% of subjects in the sham group (Po0.001). Serious the development of pegaptanib sodium and adverse ocular events related to the injection procedure ranibizumab, the first United States Food and Drug included endophthalmitis (1.3%) and retinal Administration (FDA)-approved biologically targeted detachment (0.6%). treatments for exudative AMD. Ranibizumab (LucentisTM; Genentech, South San Francisco, CA, USA) was developed using the same murine monoclonal antigen-binding site as bevacizumab Pegaptanib and ranibizumab: clinical efficacy trials (AvastinTM; Genentech), a humanized anti-VEGF Pegaptanib sodium (MacugenTM; OSI-Eyetech, New monoclonal antibody that received FDA approval in 2004 York, NY, USA), the first FDA-approved anti-VEGF for the treatment of metastatic colorectal cancer.3,13 therapy for AMD, is a pegylated oligonucleotide aptamer Unlike the full-length bevacizumab, which retains both with high binding specificity for the VEGF165 splice of its antigen-binding sites, ranibizumab has a single isoform.9 The VEGF Inhibition Study in Ocular antigen-binding site because it was derived by affinity Table 1 One-year data from the major randomized, controlled clinical trials of VEGF inhibitors for exudative AMD Study Treatment % Losing % Gaining Control % Losing % Gaining Interval Angiographic o15 letters X15 letters o15 letters X15 letters lesion type (P vs control) (P vs control) Vision Peg 0.3 mg 70 (Po0.001) 6 (P ¼ 0.04) Sham 55 2 6 weeks fixed All (n ¼ 297) (n ¼ 304) Peg 1.0 mg 71 (Po0.001) 7 (P ¼ 0.02) (n ¼ 305) Peg 3.0 mg 65 (P ¼ 0.03) 4 (P ¼ 0.16) (n ¼ 302) Marina Ran 0.3 mg 94.5 (Po0.001) 24.8 (Po0.001) Sham 62.2 5 1 month fixed Minimally classic; (n ¼ 238) (n ¼ 238) occult with no classic Ran 0.5 mg 94.6 (Po0.001) 33.8 (Po0.001) (n ¼ 240) Anchor Ran 0.3 mg 94.3 (Po0.001) 35.7 (Po0.001) PDT 64.3 5.6 1 month fixed Predominantly (n ¼ 140) (n ¼ 143) (Ran); 3 month classic PRN (PDT) Ran 0.5 mg 96.4 (Po0.001) 40.3 (Po0.001) (n ¼ 139) Focus Ran 0.5 mg þ 90 (P ¼ 0.0003) 24 (P ¼ 0.003) Sham þ 68 5 1 month fixed (Ran); Predominantly PDT (n ¼ 105) PDT 3 month PRN (PDT) classic (n ¼ 56) Eye VEGF inhibitors in neovascular AMD H Dadgostar and N Waheed 763 maturation of a humanized Fab fragment of the original the PDT group (P ¼ 0.0003) and 24% of subjects in the monoclonal anti-VEGF antibody. Ranibizumab, like combination group gaining 15 letters or more compared bevacizumab, binds all active isoforms of VEGF-A to 5% in the PDT group. Together, these studies helped and is thus considered a non-selective VEGF-A establish intravitreal ranibizumab not only as a safe and inhibitor.14,15 efficacious treatment for exudative AMD but also as a The safety and efficacy of ranibizumab were evaluated treatment capable of producing visual gain in a in the Minimally Classic/Occult Trial of the Anti-VEGF significant proportion of patients. Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, a 2-year, prospective, randomized, double-masked, sham-controlled trial Bevacizumab (Table 1).16 Subjects enrolled in the study were randomized to receive one of two doses of intravitreal A major challenge in the management of patients who ranibizumab or sham injections every month for a total of require repeated anti-VEGF injections is the cost of 24 injections over 2 years. At 12 months, 95% of subjects ranibizumab.19,20 Bevacizumab, as mentioned above, is a receiving ranibizumab lost fewer than 15 letters of visual full-length humanized anti-VEGF monoclonal antibody acuity compared to 62% of subjects receiving sham with essentially the same specificity as ranibizumab;3 injections (Po0.001). In addition, 25% of subjects however, the cost of an intravitreal dose of bevacizumab, treated with 0.3 mg ranibizumab and 34% of subjects which is marketed in much larger quantities for treated with 0.5 mg ranibizumab gained 15 letters or intravenous administration in cancer patients, is much more of visual acuity compared to 5% of subjects in the lower. control arm (Po0.001). These improvements were In a prospective case series, Chen et al21 report that in maintained at 24 months of follow-up. Serious ocular 102 eyes receiving monthly 1.25 mg bevacizumab adverse events included endophthalmitis (1.0%) and injections until resolution of leakage, mean visual acuity uveitis (1.3%). at 14 weeks of follow-up improved from 20/80 to 20/50 Similar findings were reported in the Anti-VEGF and macular thickness by optical coherence tomography Antibody for the Treatment of Predominantly Classic (OCT) improved from 251 to 210 mm(Po0.05). Similarly, Choroidal Neovascularization in AMD (ANCHOR) trial, Spaide et al22 report that in a retrospective study of 266 another 2-year, prospective, randomized, double- consecutive eyes receiving bevacizumab for neovascular masked, sham-controlled trial comparing ranibizumab AMD, at 3 months of follow-up, the mean visual acuity with PDT.17 Subjects were randomized to one of two improved from 20/184 to 20/109 (Po0.001), with 38.3% doses of intravitreal ranibizumab every month for 2 years of eyes demonstrating improvement in visual acuity.