Volume 16, Issue 4, Pages 791-799 (April 2008) Ranibizumab for Macular Edema Due to Retinal Vein Occlusions: Implication of VEGF as a Critical Stimulator  Peter A Campochiaro, Gulnar Hafiz, Syed Mahmood Shah, Quan Dong Nguyen, Howard Ying, Diana V Do, Edward Quinlan, Ingrid Zimmer-Galler, Julia A Haller, Sharon D Solomon, Jennifer U Sung, Yasmin Hadi, Kashif A Janjua, Nida Jawed, David F Choy, Joseph R Arron  Molecular Therapy  Volume 16, Issue 4, Pages 791-799 (April 2008) DOI: 10.1038/mt.2008.10 Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 1 Cross sections through the fovea obtained by optical coherence tomography in patients with central retinal vein occlusion. The horizontal cross sections at baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), and month 3 (M3, primary endpoint) are shown for five randomly selected patients of the 10 patients treated with (a) 0.3 mg or (b) 0.5 mg of ranibizumab. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 2 Excess foveal thickness at each visit from baseline (BL) to month 6 (M6) in patients with central retinal vein occlusion. The bars represent excess foveal thickness (central 1 mm retinal thickness—212 μm), which is a measure of the amount of macular edema, at BL just prior to injection of ranibizumab, and at day 7 (D7) and months 1 (M1), 2 (M2), 3 (M3), 4 (M4), and 6 (M6) for patients that received three injections of (a) 0.3 mg or (b) 0.5 mg of ranibizumab. The arrows show when injections were done (R, ranibizumab; B, bevacizumab; T, triamcinolone). Fairly rapid improvement in excess foveal thickness occurred in essentially all patients in the 0.5-mg dose group and most patients in the 0.3-mg group, but a few patients in the latter group showed small and/or delayed responses. Most patients showed recurrent edema 1–3 months after the last injection. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 3 Cross sections through the fovea obtained by optical coherence tomography in patients with branch retinal vein occlusion. The horizontal cross sections at baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), and month 3 (M3, primary endpoint) are shown for five randomly selected patients of the ten patients treated with (a) 0.3 mg or (b) 0.5 mg of ranibizumab. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 4 Excess foveal thickness at each visit from baseline (BL) to month 6 (M6) in patients with branch retinal vein occlusion. The bars represent excess foveal thickness (central 1 mm retinal thickness—212 μm), which is a measure of the amount of macular edema, at BL just prior to injection of ranibizumab, and at day 7 (D7) and months 1 (M1), 2 (M2), 3 (M3), 4 (M4), and 6 (M6) for patients who received three injections of (a) 0.3 mg or (b) 0.5 mg of ranibizumab. The arrows show when injections of ranibizumab were done. The response was uniformly good in all patients of both groups. Several patients in each group showed recurrent edema 1–3 months after the last injection. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 5 Median excess foveal thickness and median change from baseline in visual acuity (VA) for patients in each of the four treatment groups. The bars show the median excess foveal thickness at baseline, day 7 (D7), and months 1 (M1), 2 (M2), 3 (M3), 4 (M4), and 6 (M6) for patients with central retinal vein occlusion (CRVO) who received three injections of (a) 0.3 or (b) 0.5 mg of ranibizumab or patients with branch retinal vein occlusion (BRVO) who received (c) 0.3 or (d) 0.5 mg of ranibizumab. The scale, in microns, for excess foveal thickness is shown along the left side of each graph. The median number of letters for VA that has improved from baseline is shown by the points connected by lines and the scale is located along the right side of each graph. The arrows show when injections of ranibizumab were done. Substantial improvements in edema and VA occurred in each group. After injections were stopped, recurrent edema was more substantial in the CRVO patients, particularly those treated with 0.3 mg of ranibizumab. FTH, foveal thickness. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 6 Impact of patient age and duration of disease on visual outcome. (a) Visual outcome (expressed as change in visual acuity between baseline and month 3 in number of letters read at 4 m by standardized protocol) was plotted versus patient age for central retinal vein occlusion (CRVO) patients. (b) Visual outcome (expressed as change in visual acuity between baseline and month 3 in number of letters read at 4 m by standardized protocol) was plotted versus duration of disease for CRVO. (c) Visual outcome (expressed as change in visual acuity between baseline and month 3 in number of letters read at 4 m by standardized protocol) was plotted versus patient age for branch retinal vein occlusion (BRVO) patients. (d) Visual outcome (expressed as change in visual acuity between baseline and month 3 in number of letters read at 4 m by standardized protocol) was plotted versus duration of disease for BRVO patients. There was no inverse correlation for either indicating that neither age nor duration of disease had a negative impact on visual outcome. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions

Figure 7 Negative correlation between baseline aqueous vascular endothelial growth factor (VEGF) levels and change in visual acuity (VA) between baseline and month 3. The aqueous humor levels of VEGF at baseline are plotted against the change in VA between baseline and month 3 for all patients for whom measurements could be made [n = 18 for central retinal vein occlusion (CRVO); n = 17 for branch retinal vein occlusion (BRVO)]. Two CRVO patients and one BRVO patient experienced a net loss of VA at 3 months and were included in the analysis, but are not depicted in the graph, as negative values cannot be plotted on a logarithmic scale. Spearman rank order correlation analysis was conducted and a significant correlation was observed for CRVO alone (P = 0.038) and for CRVO and BRVO considered together (P = 0.038); although BRVO alone did not reach statistical significance (P = 0.278). CRVO patients are depicted as closed squares, BRVO patients are depicted as open squares. Molecular Therapy 2008 16, 791-799DOI: (10.1038/mt.2008.10) Copyright © 2008 The American Society of Gene Therapy Terms and Conditions