received a mean of 4.6 and 6.9 injections of bevacizumaband ranibizumab over 12 months, respectively. A meta-analysisof anti-VEGF-A treatment regimens for nAMD suggeststhat there is a positive linear correlation with VA gains andnumber of injections over 12 months, although there was aceiling effect, in which over 9 injections annually did notresult in further gains 8.
There are many barriers that posea challenge to patient compliance with frequent anti-VEGF-Ainjection, such as patient anxiety/discomfort, financial burden,time constraints, and lack of transportation 9. Due tothese barriers, there is great interest in development oflong-acting anti-VEGF formulations.Although anti-VEGF-A therapies initially improve vision byreducing leakage from neovascularization during the firstmonths of treatment, they have limited ability to cause regressionof this pathologic submacular neovascularization.Ultimately, the formation of submacular scar limits furthervisual benefit despite treatment; a recent large randomizedcontrolled study showed that submacular scar develops innearly 50% of subjects despite 2 years of anti-VEGF-A treatment10. For those patients with incomplete response toanti-VEGF-A therapy, there is great interest in targeting otherpathways involved in angiogenesis.
3. Existing treatment3.1. Previous nAMD treatmentsPrior to the advent of anti-VEGF-A therapy, nAMD was treatedwith focal laser therapy, intravitreal steroids, photodynamictherapy with verterporfin, and surgical excision of choroidalneovascular membranes. These treatments did not significantlyimprove vision and thus are not used frequently today9. The four currently available anti-VEGF agents are describedbelow and summarized in Table 1.
3.2. PegaptanibIn 2004, pegaptanib sodium (Macugen®, Bausch and Lomb), anaptamer designed to target the 165 isoform of VEGF-A, was thefirst of its class agent approved for the treatment of nAMD.
Registration studies (VISION-1) showed that subjects receivingintravitreal 0.3 mg pegaptanib every 6 weeks for 1 year experiencedapproximately half the vision loss as those subjects whoreceived sham 11. Pegaptanib use has fallen out of favor sincemore effective anti-VEGF-A agents have become available.3.
3. RanibizumabRanibizumab (Lucentis®, Roche/Genentech), a smaller recombinanthumanized monoclonal antibody fragment targetingVEGF-A, was specifically manufactured for use in the eye,and inhibits all known isoforms of VEGF-A. This moleculelacks a fragment crystallizable (Fc) region, which allows forfaster systemic clearance 12. In the MARINA and ANCHORregistration trials involving monthly ranibizumab, nAMD subjectsexperienced a mean improvement in vision acuity of 7.2and 11.3 ETDRS letters respectively at 1 year, compared to amean loss of 10.4 and 9.5 ETDRS letters in the sham andVerteporfin control groups, respectively4,13.
Ranibizumab0.5 mg was approved for the treatment of nAMD in 2006.3.
4. BevacizumabBevacizumab (Avastin®, Roche/Genentech) is a full-length recombinanthumanized monoclonal anti-VEGF that binds all isoforms ofVEGF-A 14. It was originally approved for the treatment of metastaticcolorectal cancer, but was used off-label in 2005 for thetreatment of exudative AMD. It is the least costly anti-VEGF-Aoption 15 and hence the first option considered for manypatients. Off-label bevacizumab 1.25 mg was found to be noninferiorto ranibizumab in the Comparison of AMD TreatmentsTrials (CATT, a National Institutes of Health sponsored study) 13and the analogous IVAN Study performed in the UnitedKingdom 16.3.
5. Aflibercept and ziv-afliberceptAflibercept (Eylea®, Regeneron) is a recombinant fusion proteinthat is composed of human VEGF Receptor-1 and VEGFReceptor-2 fused to the Fc domain of human immunoglobulinG1 domain. It inhibits VEGF-A, VEGF-B, and placental growth