Clinical Evaluation of Pazopanib Eye Drops versus Ranibizumab Intravitreal Injections in Subjects with Neovascular Age-Related Macular Degeneration Karl G. Csaky, MD, 1 Pravin U. Dugel, MD, 2 Amy J. Pierce, 3 Michael A. Fries, PhD, 3 Deborah S. Kelly, MD, 3 Ronald P. Danis, MD, 4 John I. Wurzelmann, MD, MPH, 3 Chun-Fang Xu, PhD, 3 Mohammad Hossain, PhD, 3 Trupti Trivedi, PhD 3 Purpose: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Design: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose- ranging study of eye drops. Participants: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by antievascular endothelial growth factor intravitreal injections. Methods: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n ¼ 73); pazopanib 5 mg/ml instilled 3 (n ¼ 72) or 4 times daily (n ¼ 74); pazopanib 10 mg/ml instilled 2 (n ¼ 73), 3 (n ¼ 73), or 4 times daily (n ¼ 72); or ranibizumab injection administered once every 4 weeks (n ¼ 73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. Main Outcome Measures: The main outcome measures were best-corrected visual acuity (BCVA) and in- jection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concen- trations were determined at weeks 4 and 24. Results: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3e1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by 50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. Conclusions: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone. Ophthalmology 2015;122:579-588 ª 2015 by the American Academy of Ophthalmology. Supplementary material is available at www.aaojournal.org. Angiogenesis is a key factor in the progression of age- related macular degeneration (AMD). 1 In the late stage of AMD, choroidal neovascularization (CNV) may cause leakage of blood or serum and macular scarring leading to vision loss. 2,3 Angiogenesis pathways are, therefore, important targets for pharmacologic therapies of neo- vascular AMD. The vascular endothelial growth factor (VEGF) pathway is a clinically validated target in the treatment of neovascular AMD. Ranibizumab (a humanized monoclonal VEGF antibody fragment), bevacizumab (a recombinant mono- clonal VEGF antibody), and aflibercept (a fusion protein) bind with high affinity to and neutralize all biologically active isoforms of VEGF. 4,5 Therapy with these agents is common and highly effective for the treatment of neo- vascular AMD. 6,7 At the time that this clinical study was initiated, ranibi- zumab was the only licensed agent for the treatment of AMD, with a labeled treatment regimen of once-monthly injections. Although highly effective and representing a 579 Ó 2015 by the American Academy of Ophthalmology Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2014.09.036 ISSN 0161-6420/14