served at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.
13.2 Animal Toxicology and/or Pharmacology
Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see CLINICAL STUDIES (14)].
14 CLINICAL STUDIES
14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and eva luable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.
In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.
Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in TABLE 4 and FIGURE 8 below.
Table 4: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and VIEW2 Studies
VIEW1 VIEW2
EYLEA
2 mg Q8 weeks * EYLEA
2 mg Q4 weeks ranibizumab
0.5 mg Q4 weeks EYLEA
2 mg Q8 weeks * EYLEA
2 mg Q4 weeks ranibizumab
0.5 mg Q4 weeks
Full Analysis Set N=301 N=304 N=304 N=306 N=309 N=291
BCVA = Best Corrected Visual Acuity; CI = Confidence Interval; ETDRS = Early Treatment Diabetic Retinopathy Study; LOCF = Last Observation Carried Forward (baseline values are not carried forward); 95.1% confidence intervals were presented to adjust for safety assessment conducted during the study.
* After treatment initiation with 3 monthly doses † EYLEA group minus the ranibizumab group
Efficacy Outcomes
Proportion of patients who maintained visual acuity (%)
(<15 letters of BCVA loss) 94% 95% 94% 95% 95% 95%
Difference† (%)
(95.1% CI) 0.6
(-3.2, 4.4) 1.3
(-2.4, 5.0) 0.6
(-2.9, 4.0) -0.3
(-4.0, 3.3)
Mean change in BCVA as measured by ETDRS letter score fro |
