Visual acuity gains occurring in a 12-week, fixed-dose period were maintained throughout the 52-week trial of a novel agent (VEGF Trap-Eye, Regeneron Pharmaceuticals) for neovascular age-related macular degeneration. During the 9-month, as-needed dosing phase, the mean number of injections for all patients was two, and gains in visual acuity of up to nine letters were reported.
Scottsdale, AZ-Patients receiving therapy with a novel agent (VEGF Trap-Eye, Regeneron Pharmaceuticals) for neovascular age-related macular degeneration (AMD) had clinically meaningful and lasting improvements in visual acuity (VA) over a 1-year study period and required a mean of only two additional injections following a 12-week fixed dosing period. Biologic measures of neovascular disease also showed durable improvement.
"What was encouraging about this study was that we saw gains from treatment with [the novel agent], which we have come to expect with the strong anti-[vascular endothelial growth factor (VEGF)] agents, and we saw that in the early, fixed dosing phase of the study," said Jeffrey S. Heier, MD, one of the study investigators. One-year results of the phase II CLEAR-IT 2 study were presented at the Retina Society annual meeting here. "Then, as we went to the [as-needed dosing (PRN) stage], it was more encouraging that from the period of 12 to 52 weeks, there were very few injections required, and that was for all the dose groups," said Dr. Heier, a vitreoretinal specialist in Boston.
On top of that, not only were there very few additional injections required, but the visual gains that were achieved in the fixed dosing period were maintained over the course of that time," Dr. Heier added. Up to nine mean letters of best-corrected visual acuity (BCVA) were gained at week 52, and up to –161 µm reductions in central retinal lesion thickness were reported, as measured by optical coherence tomography (OCT).
CLEAR-IT 2 was designed to assess the response at 12 weeks to a range of doses administered monthly and quarterly and the durability of the response with as-needed dosing out to 1 year. The novel anti-VEGF therapy under investigation has a high binding affinity for VEGF-A and placental growth factor.
In this study, 159 subjects were randomly assigned to one of five subgroups in a double-masked, prospective, multicenter trial. Study arms received 0.5 mg every 4 weeks (n = 32); 2 mg every 4 weeks (n = 32); 0.5 mg every 12 weeks (n = 32); 2 mg every 12 weeks (n = 32); or 4 mg every 12 weeks (n = 31). The subjects were on fixed dosing for 12 weeks, receiving either two or four mandatory doses. All patients were re-dosed at 12 weeks, and PRN dosing began at week 16.
Among the 157 patients who were treated, the mean age was 78.2 years (range, 53 to 94 years), the male-to-female ratio was 38:62, and the mean duration of disease at baseline was 3.9 months (range, 0 to 67 months). There were 30 classic and 30 predominantly classic lesions (19.1% each), 37 minimally classic lesions (23.6%), and 60 occult lesions (38.2%). The mean central retinal thickness at baseline was 456 µm (range, 186 to 1,316 µm), the mean foveal thickness was 327 µm (range, 116 to 1,081 µm), and the mean Early Treatment Diabetic Retinopathy Study (ETDRS) assessment of BCVA was 56 letters (range, 27 to 83 letters).
The primary endpoint results from the 12-week, fixed-dosing phase of the trial were reported in the fall of 2007. These results showed significantly improved mean VA and significantly reduced central retinal thickness. The groups dosed at baseline and at week 12 showed improved VA and retinal thickness; the effect was less robust with monthly dosing. Overall, the effect on VA was maintained with a single dose of the novel agent up to 8 weeks, and the drug was generally well tolerated with no drug-related serious adverse events.
After the initial phase of the trial, re-dosing was performed starting at week 16. The criteria included any of the following: an increase in central retinal thickness of ≥100 µm as measured by OCT; a loss of ≥5 ETDRS letters in conjunction with recurrent fluid as indicated by OCT; persistent fluid as indicated by OCT; new-onset classic neovascularization; a new or persistent leak on fluorescein angiography; or new macular hemorrhage.
At 52 weeks, 134 of the patients (84.3%) had completed the study, and 23 (14.5%) had withdrawn for various reasons. The mean number of injections over the PRN phase was 2.01 for all study arms, whereas eyes that received 2 mg of the novel agent dosed monthly had the lowest mean number of additional treatments, 1.55. The means for the other treatment groups were: 1.7 (4 mg q12), 1.84 (0.5 mg q12), 2.48 (2 mg q12), and 2.52 (0.5 mg q4).
"By following those patients and treating them when we needed to, we were able to maintain the gains and did it without requiring monthly dosing," Dr. Heier said. The findings, however, underline the importance of regular follow-up examinations in helping patients maintain gains from anti-VEGF therapies, he added.
In other re-treatment outcomes, the mean number of days to the first injection over the PRN phase was 129 for all groups combined, and the median was 110. Eyes that had received the novel-agent dose of 0.5 mg q4 had the lowest mean number of days to re-injection, 102, whereas eyes receiving 2 mg q4 had the highest mean number of days, 160. Those two arms also had the shortest and longest median intervals to re-treatment in the PRN phase of the trial, 85 and 150, respectively.
The two subgroups showing the strongest mean change in VA in the PRN dosing phase were those receiving monthly injections of 2 or 0.5 mg of the novel agent; the gains were 9 lines (p < 0.0001) and 5.4 lines (p = 0.085), respectively. Gains for the other groups were 5.2 lines in the 2 mg q12 arm (p = 0.0412); 4.2 lines in the 4 mg q12 arm (p = 0.0154); and 2.6 lines in the 0.5 mg q12 group (p = 0.344).
At 52 weeks, 29% of patients in both the 2 mg q4 and 2 mg q12 arms showed a ≥ 15 letter gain, as did 22% of patients receiving a dose of 0.5 mg q12, 19% of those receiving a 0.5 mg q4 dose, and 10% of those receiving 4 mg q12.
Dr. Heier said the results reveal some interesting differences between the monthly and quarterly dosing arms. Patients receiving monthly treatment had four doses before the PRN phase, whereas those receiving quarterly treatment had two doses, and all had approximately the same number of injections during the PRN phase.
"Yet the quarterly patients never had their visual gains catch up to those of the monthly patients," Dr. Heier said. He explained that the quarterly patients typically lost some VA between treatments in the initial phase of the study, and this loss could have influenced their outcomes during the PRN phase.
This finding may suggest that there is a benefit to a loading dose, he added, although the CLEAR-IT 2 study was too small to prove this hypothesis.
Fluorescein angiography results showed a statistically significant mean change in total lesion size only in eyes receiving the 2 mg q4 dose (p = 0.04); the mean change was a decrease of 1.75 µm. A decrease of 1 µm was observed in eyes dosed with 4 mg q12, and a decrease of 0.85 µm was seen in the 0.5 mg q12 group.
The mean change in total active chroidal neovascularization size was statistically significant for four of the five treatment groups. The greatest amount of change occurred in the 2 mg q4 group, a decrease of 3.41 µm (p < 0.001). Decreases also were seen in the 4 mg q12 arm (2.59 µm), 2 mg q12 arm (2.29 µm), and 0.5 mg q4 group (1.42 µm) (all, p < 0.05). The decrease of 1.35 µm seen in the 0.5 mg q12 arm was not significant.
Few adverse events
Safety results showed few serious adverse events. One case of culture-negative endophthalmitis/uveitis was seen, but it was deemed unrelated to the study drug. Likewise, none of the systemic serious adverse events were thought to have been caused by the novel agent these included two deaths, one from pre-existing pulmonary hypertension, one from pancreatic carcinoma, and one case of hemorrhagic stroke in a subject with a history of prior stroke.
The subjects in this study are still being followed; meanwhile, two phase III trials of the novel agent in wet AMD are underway, sponsored by Regeneron and Bayer HealthCare. The agent dosed 0.5 mg every 4 weeks, 2 mg every 4 weeks, or 2 mg every 8 weeks, following three monthly doses, is being compared with ranibizumab (Lucentis, Genentech) administered 0.5 mg every 4 weeks. The VIEW1 study is enrolling patients in the United States and Canada, and the VIEW2 study is enrolling patients in Europe, the Asia-Pacific region, Japan, and Latin America.