18 When patients leave the tightly controlled clinical trial environment, their eyesight, on average, falls to pretreatment levels. In practice, anti-VEGF therapies are not delivering the level of benefit that their pivotal clinical trials suggested. In the pivotal Lucentis trials MARINA and ANCHOR, patients were able to gain and maintain vision gains with monthly dosing over two years. After exiting the clinical trials, patients were followed in the HORIZON study with as needed dosing (Pro Re Nata or PRN) for three more years. Gradual vision decline can be seen immediately after exiting the trials, returning to pre- treatment baseline vision before the end of the third year of follow-up in HORIZON. Figure: Mean change in visual acuity (VA) letter score in MARINA and ANCHOR (years one and two) and in HORIZON (years three to five). VA gradually decreased immediately after the patients exited monthly dosing in a clinical trial setting. A study funded by the National Eye Institute followed patients who left the tightly controlled clinical trial environment into clinical practice and showed that these patients, on average, lost all the gains in visual acuity that they obtained while enrolled in the trial. 10 5 0 –5 –10 –15 –20 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months since initial study –16.1 –0.1 2.0 4.1 9.0 –11.8 –11.8 –9.6 Initial study Lucentis randomized Initial study control randomized Initial study HORIZON Change from initial study baseline (letters) 80 75 70 65 60 55 50 Visual Acuity, Letters Overall Lucentis Avastin N=319 N=316 N=318 N=319 N=328 N=326 N=325 N=328 Baseline Year 1 Year 2 Year 5 20/25 20/32 20/40 20/50 20/63 20/80 20/100 Snellen Equivalent 80 75 70 65 60 55 50 Visual Acuity, Letters Overall Monthly N=164 N=160 N=162 N=164 Switched N=157 N=156 N=155 N=157 PRN N=326 N=326 N=326 N=326 N=647 N=642 N=643 N=647 Baseline Year 1 Year 2 Year 5 20/25 20/32 20/40 20/50 20/63 20/80 20/100 Snellen Equivalent Overall Lucentis Avastin PRN Overall Lucentis Avastin 71, 70) (71, 70, 69) (58, 59, 60) (61, 63, 62, 62) (71, 71, 70, 71)(72, 68, 69, 70) (62, 62, 62) (61, 59, 58, 59) N=647 N=642 N=643 N=647