August 5, 2015
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Eylea

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Eylea




CLINICAL PHARMACOLOGY

Mechanism Of Action

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Pharmacodynamics

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions [see Clinical Studies].

Macular Edema Following Retinal Vein Occlusion (RVO)

Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions [see Clinical Studies].

Diabetic Macular Edema (DME)

Reductions in mean retinal thickness were observed in VIVID and VISTA at weeks 52 and 100 compared to baseline. Anatomic data were not used to influence EYLEA treatment decisions [see Clinical Studies].

Pharmacokinetics

EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of EYLEA, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).

Absorption/Distribution

Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF.

The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.

Metabolism/Elimination

Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.

Specific Populations

Renal Impairment

Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients.

Other

No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).

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].

Clinical Studies

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 evaluable 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

Full Analysis Set VIEW1 VIEW2
EYLEA 2 mg Q8 weeks a
N=301
EYLEA 2 mg Q4 weeks
N=304
ranibizu- mab 0.5 mg Q4 weeks
N=304
EYLEA 2 mg Q8 weeks a
N=306
EYLEA 2 mg Q4 weeks
N=309
ranibizu- mab 0.5 mg Q4 weeks
N=291
Efficacy Outcomes
Proportion of patients who maintained visual acuity (%) ( < 15 letters of BCVA loss) 94% 95% 94% 95% 95% 95%
  Differenceb
(%) (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 from Baseline 7.9 10.9 8.1 8.9 7.6 9.4
  Differenceb in LS mean
(95.1% CI)
0.3
(-2.0, 2.5)
3.2
(0.9, 5.4)
  -0.9
(-3.1, 1.3)
-2.0
(-4.1, 0.2)
 
Number of patients who gained at least 15 letters of vision from Baseline (%) 92
(31%)
114
(38%)
94
(31%)
96
(31%)
91
(29%)
99
(34%)
  Differenceb
(%) (95.1% CI)
-0.4
(-7.7, 7.0)
6.6
(-1.0, 14.1)
  -2.6
(-10.2, 4.9)
-4.6
(-12.1, 2.9)
 
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.
aAfter treatment initiation with 3 monthly doses
bEYLEA group minus the ranibizumab group

Figure 8: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and VIEW2 Studies

Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and VIEW2 Studies - Illustration

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with EYLEA) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.

Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 9 below.

Table 5: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in COPERNICUS and GALILEO Studies

  COPERNICUS GALILEO
Control
N=73
EYLEA 2 mg Q4 weeks
N=114
Control
N=68
EYLEA 2 mg Q4 weeks
N=103
Efficacy Outcomes
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 12% 56% 22% 60%
  Weighted Difference a,b (%) (95.1% CI)   44.8%c
(32.9, 56.6)
  38.3%c
(24.4, 52.1)
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) -4.0
(18.0)
17.3
(12.8)
3.3
(14.1)
18.0
(12.2)
  Difference in LS mean a,d
(95.1% CI)
  21.7c
(17.3, 26.1)
  14.7c
(10.7, 18.7)
aDifference is EYLEA 2 mg Q4 weeks minus Control
bDifference and CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for baseline factors; 95.1% confidence intervals were presented to adjust for the multiple assessments conducted during the study.
cp < 0.01 compared with Control
dLS mean and CI based on an ANCOVA model

Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in COPERNICUS and GALILEO Studies

Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 - Illustration

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.

Macular Edema Following Branch Retinal Vein Occlusion (BRVO)

The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Patient ages ranged from 42 to 94 years with a mean of 65 years.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.

Detailed results from the analysis of the VIBRANT study are shown in Table 6 and Figure 10 below.

Table 6: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in VIBRANT Study

  VIBRANT
Control
N=90
EYLEA 2 mg Q4 weeks
N=91
Efficacy Outcomes
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 26.7% 52.7%
  Weighted Difference a,b (%)
(95% CI)
  26.6%c
(13.0, 40.1)
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 6.9
(12.9)
17.0
(11.9)
  Difference in LS mean a,d
(95% CI)
  10.5c
(7.1, 14.0)
aDifference is EYLEA 2 mg Q4 weeks minus Control
bDifference and CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category ( > 20/200 and ≤ 20/200)
cp < 0.01 compared with Control
dLS mean and CI based on an ANCOVA model

Figure 10: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study

Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 - Illustration

Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.

Diabetic Macular Edema (DME)

The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Patient ages ranged from 23 to 87 years with a mean of 63 years.

Of those, 576 were randomized to EYLEA groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 5 initial monthly injections (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the EYLEA groups could receive laser and patients in the laser group could receive EYLEA.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both EYLEA 2Q8 and EYLEA 2Q4 groups was statistically superior to the control group. This statistically superior improvement in BCVA was maintained at week 100 in both studies.

Results from the analysis of the VIVID and VISTA studies are shown in Table 7 and Figure 11 below.

Table 7: Efficacy Outcomes at Weeks 52 and 100 (Full Analysis Set with LOCF) in VIVID and VISTA Studies

Full Analysis Set VIVID VISTA
EYLEA 2 mg Q8 weeksa
N=135
EYLEA 2 mg Q4 weeks
N=136
Control
N=132
EYLEA 2 mg Q8 weeks a
N=151
EYLEA 2 mg Q4 weeks
N=154
Control
N=154
Efficacy Outcomes at Week 52
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 10.7
(9.3)
10.5
(9.6)
1.2
(10.6)
10.7
(8.2)
12.5
(9.5)
0.2
(12.5)
  Differenceb, c in LS mean
(97.5% CI)
9.1d
(6.3, 11.8)
9.3d
(6.5, 12.0)
  10.5d
(7.7, 13.2)
12.2d
(9.4, 15.0)
 
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 33.3% 32.4% 9.1% 31.1% 41.6% 7.8%
Adjusted Differencec, e (%)
(97.5% CI)
24.2%d
(13.5, 34.9)
23.3%d
(12.6, 33.9)
  23.3%d
(13.5, 33.1)
34.2%d
(24.1, 44.4)
 
Efficacy Outcomes at Week 100
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 9.4
(10.5)
11.4
(11.2)
0.7
(11.8)
11.1
(10.7)
11.5
(13.8)
0.9
(13.9)
  Differenceb, c in LS mean
(97.5% CI)
8.2d
(5.2, 11.3)
10.7d
(7.6, 13.8)
  10.1d
(7.0, 13.3)
10.6d
(7.1, 14.2)
 
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 31.1% 38.2% 12.1% 33.1% 38.3% 13.0%
  Adjusted Differencec,e (%)
(97.5% CI)
19.0%d
(8.0, 29.9)
26.1%d
(14.8, 37.5)
  20.1%d
(9.6, 30.6)
25.8%d
(15.1, 36.6)
 
aAfter treatment initiation with 5 monthly injections
bLS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, protocol specified stratification factors were included in the model.
cDifference is EYLEA group minus Control group
dp < 0.01 compared with Control
eDifference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors.

Figure 11: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 in VIVID and VISTA Studies

Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 - Illustration

Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor na´ve prior to study participation.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.

Diabetic Retinopathy (DR) In Patients With DME

In the VIVID and VISTA studies, an efficacy outcome was the change in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (ETDRS-DRSS). The ETDRS-DRSS score was assessed at baseline and approximately every 6 months thereafter for the duration of the studies [see Clinical Studies].

All enrolled patients had DR and DME at baseline. The majority of patients enrolled in these studies (77%) had moderate-to-severe nonproliferative diabetic retinopathy (NPDR) based on the ETDRS-DRSS. At week 100, the proportion of patients improving by at least 2 steps on the ETDRS-DRSS was significantly greater in both EYLEA treatment groups (2Q4 and 2Q8) when compared to the control group.

Results from the analysis of ETDRS-DRSS at week 100 in the VIVID and VISTA studies are shown in Table 8 below.

Table 8: Proportion of Patients who Achieved a ≥ 2-Step Improvement from Baseline in the ETDRS-DRSS Score at Week 100 (LOCFa) in VIVID and VISTA Studies

Evaluable Patientsc VIVID VISTA
EYLEA 2 mg Q8 weeks b
N=101
EYLEA 2 mg Q4 weeks
N=97
Control
N=99
EYLEA 2 mg Q8 weeks b EYLEA 2 mg Q4 weeks
N=153
Control
N=150
Number of patients with a ≥ 2-step improvement on ETDRS-DRSS from Baseline (%) 32
(32%)
27
(28%)
7
(7%)
56
(38%)
58
(38%)
24
(16%)
Differenced,e (%)
(97.5% CI)
24%f
(12, 36)
21%f
(9, 33)
  22%f
(11, 33)
22%f
(11, 33)
 
aNon-gradable post-baseline ETDRS-DRSS values were treated as missing and were imputed using the last gradable ETDRS-DRSS values (including baseline values if all post-baseline values were missing or non-gradable)
bAfter treatment initiation with 5 monthly injections
cThe number of evaluable patients included all patients who had valid ETDRS-DRSS data at baseline
dDifference with confidence interval (CI) was calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors
eDifference is EYLEA minus Control group
fp < 0.01 compared with Control

Results of the evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity) on the proportion of patients who achieved a ≥ 2-step improvement on the ETDRS-DRSS from baseline to week 100 were, in general, consistent with those in the overall population.

Last reviewed on RxList: 4/8/2015
This monograph has been modified to include the generic and brand name in many instances.

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