A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis Rishi P Singh, Sunil Srivastava, Justis P Ehlers, Rumneek Bedi, Andrew P Schachat, Peter K Kaiser Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA Correspondence to Dr Rishi P Singh, Department of Ophthalmology, Cole Eye center, Cole Eye Institute, 9500 Euclid Avenue, i32, Cleveland, OH 44195; drrishisingh@gmail.com Received 16 December 2013 Revised 7 March 2014 Accepted 12 March 2014 To cite: Singh RP, Srivastava S, Ehlers JP, et al. Br J Ophthalmol 2014;98: i22–i27. ABSTRACT Aim To evaluate efficacy and safety of intravitreal aflibercept injection (IAI) in subjects who were previously treated with ranibizumab and/or bevacizumab for active exudative age-related macular degeneration (AMD). Methods Patients (n=26) were enrolled in a 12-month prospective, interventional, single arm, investigator- initiated study with planned 6-month interim analysis. Patients with active exudative AMD, previously treated with ranibizumab and/or bevacizumab, were treated with 2 mg IAI every month for the first 3 months, followed by a fixed dosing schedule of 2 mg IAI every 2 months. The primary study endpoint was the mean absolute change from baseline central subfield thickness (CST) at month 12 as measured by SDOCT. Secondary outcomes included mean change from baseline best-corrected visual acuity (BCVA) score, percentage of subjects who gained or lost greater than or equal to 15 letters of vision, percentage of subjects who are 20/40 or better, percentage of subjects who are 20/200 or worse, and the incidence of adverse events (AE) and serious AEs. Results Planned 6-month interim analysis demonstrated a mean decrease in CST of 38.6 mm (p<0.001) and a mean increase in ETDRS BCVA of +5.9 letters ( p<0.001). Fifteen percent of subjects experienced a greater than 15-letter improvement in visual acuity, 84.6% of patients gained visual acuity, and no patient lost 3 lines of vision from baseline. Forty- two percent of subjects were 20/40 or better, and 11.5% of subjects were 20/200 or worse at month 6. No serious ocular or systemic AEs were encountered. Conclusions IAI-treated eyes demonstrated improved short-term functional and anatomic endpoints in subjects with active exudative AMD switching from previous anti- VEGF treatment when given in a fixed dosing scheme for 6 months. Trial registration number NCT01617148. INTRODUCTION Age-related macular degeneration (AMD) is a leading cause of adult blindness in the developed world. 1 Severe visual loss from AMD is caused by subfoveal geographic atrophy and choroidal neo- vascularisation, which is the hallmark of exudative AMD. Vascular endothelial growth factor (VEGF) is a growth factor that has been implicated as a major pathogenic factor in exudative AMD as it sti- mulates angiogenesis and increases vascular perme- ability. 2 Inhibitors of VEGF have provided significant therapeutic benefit to subjects suffering from this disorder. 3–5 Aflibercept is a recombinant fusion protein con- sisting of key human VEGF receptor extracellular domains from receptors 1 and 2 (VEGFR1 and VEGFR2) fused to the Fc domain of human IgG1. 6 It is a dimeric glycoprotein with a molecular weight of 97 kDa that is ∼15% glycosylated, giving a total molecular weight of 115 kDa. Aflibercept has several theoretical advantages over other VEGF blockers: (1) it has a much higher binding affinity for VEGF (∼0.5 pM dissociation constant for VEGF 165 and VEGF 121 ) than either bevacizumab or ranibizumab 7 ; (2) it binds related growth factors, such as placental growth factors 1 and 2 (PLGF1 and PLGF2) and VEGF-B, which may be advanta- geous in certain disease situations, including retinal neovascularisation 8 and (3) the vitreous half-life of aflibercept (18 days) is longer than ranibizumab (9 days), but slightly shorter than bevacizumab (21 days). 9 The pivotal, phase 3, VIEW studies that led to Food and Drug Administration approval required that enrolled subjects be naive of previous AMD treatments. Subjects were randomised to various intravitreal aflibercept injection (IAI) doses and dosing regimens, and compared to monthly ranibi- zumab treatment in a non-inferiority statistical design. Results revealed that subjects exhibited similar visual outcomes when comparing IAI 2 mg, dosed every 2 months after a 3-monthly loading dose, to monthly ranibizumab 0.5 mg at the primary outcome of 52 weeks. 10 11 Thus, using IAI in this fashion reduced the number of injections without compromising visual outcomes compared to the gold standard of monthly ranibizumab. 10 However, the majority of retina specialists do not treat using a fixed dosing pattern as used in the VIEW studies. Subjects are generally treated with as-needed dosing ( pro ne rata, PRN) or on a treat-and-extend (TAE) paradigm. Studies, such as the Comparison of Age Related Macular Degeneration Treatment Trials (CATT) indicate that these treatment regimens are similar but not Open Access Scan to access more free content i22 Singh RP, et al. Br J Ophthalmol 2014;98:i22–i27. doi:10.1136/bjophthalmol-2013-304798 Original article on September 22, 2021 by guest. 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