wAMD Suppl_WebVersion_SinglePages_CMYK

Supplement to
For U.S. Audiences Only
Supplement prepared and sponsored by
EYLEA® (aflibercept) Injection is indicated for the treatment of patients with neovascular (Wet)
Age-related Macular Degeneration (AMD). It is also indicated for the treatment of patients with Macular
Edema following Central Retinal Vein Occlusion (CRVO).
EYLEA is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or
known hypersensitivity to aflibercept or any of the excipients in EYLEA.
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
Distributed with
Neovascular (Wet) AMD and
Anti-VEGF Therapy in Perspective
In diagnosing and managing neovascular (wet) agerelated macular degeneration (AMD), retinal specialists
must routinely address one of the greatest health fears
of older patients – the potential for irreversible vision
loss and blindness. Fear of vision loss outranks fear of
cancer, heart disease, and stroke among adults.1 In less
than a decade, the management of wet AMD has been
transformed by intravitreal therapeutics that simultaneously inhibit aberrant vascularization and pathologic
vascular leakage by blocking multiple isoforms of vascular
endothelial growth factor-A (VEGF-A). Landmark studies
demonstrated that pan-VEGF-A inhibitors could not only
preserve visual acuity in the majority of patients with wet
AMD, but could also produce clinically significant vision
improvements in a substantial proportion of patients.2-5
Because these therapeutic agents are not curative, patient
follow-up is ongoing and indefinite in order to maintain
disease control.4 The challenge is to achieve the vision
outcomes demonstrated by VEGF inhibitors in landmark
clinical trials2-5 while appropriately striking a balance
between the sight-threatening risks of injection-related
complications (e.g., endophthalmitis and retinal detachment) and the sight-threatening risks of undertreating a
progressive disease subject to unpredictable recurrences
of retinal fluid.
A substantial body of evidence has demonstrated that
monthly office visits for monitoring and/or intravitreal
injections have historically been needed in order to
reliably achieve and maintain outcomes.4-8 Monthly visits
for disease monitoring and/or intravitreal injections may
not be a sustainable approach in the real world of clinical
practice, as demonstrated by data from 2006-2008 for
nearly 300,000 Medicare fee-for-service beneficiaries with
newly diagnosed wet AMD. In this dataset in which nearly
95% of patients were treated with a pan-VEGF-A inhibitor,
patients were seen by ophthalmologists an average of
7.1 times in the year following initiation of anti-VEGF
therapy. Anti-VEGF therapy was discontinued within
1 year of initiation in more than half of treated eyes,
although the barriers to care that would account for these
findings could not be determined from the claims data.9
Monthly visits for monitoring/treating wet AMD can
pose potential challenges in the management of wet
AMD for patients and their caregivers. An observational
evaluation was undertaken to understand the time
commitment of just a single visit to monitor/treat wet
AMD in real-world clinical practice. The average visit
time for monitoring/treating wet AMD, based on patient
record data (N=201), was ~90 minutes. In a separate
component of the study, the total average time commitment for an appointment was ~3 hours (pre-appointment
preparation, travel time, and in-office time) for patients
undergoing anti-VEGF therapy; post-injection recovery
time averaged 9 hours. Most patients (72%) were driven
to appointments by someone else, generally the same
person for all appointments. For the one-fourth of caregivers who had to take time from work to accompany
patients, ~3 hours per visit would mean an annual time
commitment for monthly wet AMD care equal to 1 week
(i.e., 36 hours) of time off from work.10
Given the challenges of indefinitely sustaining a regimen
of monthly monitoring injections, an unmet need was
identified to achieve and maintain visual outcomes with
less frequent office visits once therapy is initiated.
Important Safety Information for EYLEA®(aflibercept) Injection
Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal
detachments. Proper aseptic injection technique must always be used when administering EYLEA.
Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment
without delay and should be managed appropriately. Intraocular inflammation has been reported with the
use of EYLEA.
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
1
Trap Technology and Aflibercept
Cytokine traps11,12 such as aflibercept are molecules
based on propriety technology developed at Regeneron
Pharmaceuticals. In the case of aflibercept, the trap-like
arms (Fig. 1) are each composed of the second extracellular ligand-binding domain from human VEGF receptor 1
(VEGFR-1) fused to the third extracellular ligand-binding
domain from human VEGF receptor 2 (VEGFR-2)12 –
domains critical for ligand contact and binding.13-15
Aflibercept therefore acts as a soluble decoy receptor,
trapping VEGF-A and placental growth factor (PLGF) to
prevent interactions with native cell-surface receptors.16
The two-arm trap configuration of aflibercept is supported by the constant Fc (Fragment, crystallizable)
region of IgG1.12 In Fc-fusion proteins such as aflibercept,
the Fc region is intended not only to stabilize the protein’s
structure, but also to achieve an acceptable plasma
half-life.17 However, other factors such as the receptor
regions appear to be critical to determining the pharmacokinetics of a Fc-fusion protein.18 In vitro structure studies
with aflibercept demonstrated the contribution of binding
domains to pharmacokinetic activity. Aflibercept displayed
negligible binding to extracellular matrix in vitro.12
The complex formed when aflibercept traps VEGF is
inactive and stable. Studies of the relative serum concentrations of free aflibercept and aflibercept:VEGF complex
following systemic administration in animal models
have provided insight into the dynamics of endogenous
VEGF intraocular blockade as it relates to intraviteal
dosing and duration of VEGF blockade. These studies
demonstrated that after drug administration, the
aflibercept:VEGF complex accumulated rapidly as
aflibercept trapped target ligands and free aflibercept
was converted to bound complex. The level of
aflibercept:VEGF complex plateaued at maximal concentrations when sufficient aflibercept was present to bind
the total pool of endogeneous VEGF being produced by
the tissues. With further increases in dose, free aflibercept
concentrations increased in a dose-dependent manner
since no more VEGF was available for binding with
aflibercept. These observations suggested that the local
VEGF pool would be completely neutralized as long as
free aflibercept levels exceeded aflibercept:VEGF
complex levels.10,19
CLEAR-IT Studies:
Foundation for Intravitreal Aflibercept
Injection Dosing Strategies
Early phase clinical studies of intravitreal aflibercept
injection (IAI), known commercially as EYLEA®
(aflibercept) Injection, in patients with wet AMD identified dosing strategies for evaluation in pivotal Phase 3
studies. Single intravitreal aflibercept doses (0.05 to
4 mg) in the Clinical Evaluation of Anti-angiogenesis in
the Retina Intravitreal Trial 1 (CLEAR-IT 1) in 21 patients
provided initial evidence of the dose-dependent effects
of intravitreal aflibercept injection. Higher single doses
(2 and 4 mg) produced improvements in best-corrected
visual acuity (BCVA) and choroidal neovascular (CNV)
lesion morphology that were sustained for up to 6 weeks
post-injection. With single doses of up to 4 mg intravitreal
aflibercept, there were no reports of ocular, systemic
serious adverse reactions, or laboratory changes.
Intravitreal aflibercept injection was not associated with
intraocular inflammation. In the absence of
Figure 1. Trap structure of aflibercept based on preclinical studies.
Aflibercept incorporates key domains of VEGFR-1 and VEGFR-2 in a homodimeric structure attached to the hinge region
of the Fc domain of IgG1, which provides structural stability and an acceptable half-life in experimental models.12,17
VEGF
dimer
VEGFR1
binding
domain 2
Aflibercept:
VEGFcomplex
VEGFR2
binding
domain 3
Fc region
IgG
Aflibercept
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
2
CLEAR-IT 2: Contributions to Intravitreal Aflibercept Injection Dosing
CLEAR-IT 2 Observation21,22
Implication for Dosing Strategy
■
Greater BCVA improvements at 12 weeks after
3 monthly injections than after a single injection,
a difference that was maintained throughout the
remainder of the 52-week study
■
Therapy initiated with 3 monthly doses
■
Therapeutic effects of 2 mg and 4 mg did not differ
■
2 mg as the maximum dose
■
Clinical effects (improved BCVA; decreased
retinal thickness) following a single injection were
sustained through 8 weeks and began to wane at
12 weeks
■
8-week dose interval
dose-limiting toxicity in this study, a maximum tolerated
intravitreal aflibercept dose was not identified.20
wane at 12 weeks. Visual acuity improvements at
12 weeks were greater in patients who received 3 monthly
injections than in those who received a single injection, a
difference that was maintained throughout the remainder
of the 52-week trial. Ocular adverse events (e.g., conjunctival hemorrhage, transient post-injection increase in
intraocular pressure, refraction disorders, retinal hemorrhage, eye pain, vitreous detachment) were generally
related to the injection procedure; most were mild. The
results of CLEAR-IT 2 were the foundation of dosing
protocols in Phase 3 studies and were incorporated into
subsequent strategies for clinical use in wet AMD.21,22
Based on these findings, a subsequent Phase 2 dose-finding study (CLEAR-IT 2) examined the relative therapeutic
effects of dose (0.5, 2, and 4 mg intravitreal aflibercept
injection) and dosing interval (0.5 mg every 4 or
12 weeks; 2 mg every 4 or 12 weeks; 4 mg every
12 weeks) in order to define dosing strategies for evaluation in Phase 3 trials. In all groups, BCVA improved as
early as 1 week after intravitreal aflibercept administration. Moreover, clinical effects following a single
injection were sustained through 8 weeks and began to
Figure 2. Design of VIEW 1 and 2 studies.23
In patients assigned to intravitreal aflibercept injection 2 mg every 2 months (2Q8),
therapy was initiated with 3 monthly injections. Intravitreal aflibercept injection 0.5 mg
every 4 weeks is not an approved dose.
Multicenter, active-controlled, double-masked trials
VIEW 1, N=1210; VIEW 2, N=1202
1:1:1:1 randomization
Intravitreal Aflibercept Injection (IAI)
Ranibizumab (RBZ)
0.5 mg every 4 weeks
(RBZ 0.5Q4)
2 mg every 4 weeks
(IAI 2Q4)
2 mg every 8 weeks
(IAI 2Q8)
0.5 mg every 4 weeks
(IAI 0.5Q4)
Endpoints at 52 Weeks
Primary
Proportion (%) patients maintaining
vision, ie, losing <15 letters BCVA vs
baseline
Additional Measures
Mean change from baseline in BCVA
Proportion (%) patients gaining ≥15
letters BCVA from baseline
Anatomic measures of disease activity
Important Safety Information for EYLEA®(aflibercept) Injection
Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including
with EYLEA. Sustained increases in intraocular pressure have also been reported after repeated intravitreal
dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be
monitored and managed appropriately.
3
Figure 3. Primary endpoint at 52 weeks for VIEW 1 and 2 studies separately and integrated.23
Bar chart on left reports proportion of patients who maintained visual acuity. Chart on right depicts
noninferiority analysis for between-group differences in mean visual acuity change at 52 weeks. Last
observation carried forward in the full analysis set. Although intravitreal aflibercept injection 0.5Q4
demonstrated similar efficacy and safety to intravitreal aflibercept injection 2Q4, it is not an approved
dose and is not shown.
Noninferiority Analysis†
Proportion of Patients Who Maintained Visual Acuity
VIEW 1
VIEW 2
Integrated
94% 95% 94%
95% 95% 95%
95% 95% 95%
Statistically
Noninferior
VIEW 1
VIEW 2
% Patients
IAI 2Q8*
IAI 2Q4
RBZ Q4
291 306 309
IAI 2Q4
-0.3
-4.0
Integrated
304 304 302
0.6
-2.9
IAI 2Q8*
4.4
1.3
-2.4
IAI 2Q4
N
0.6
-3.2
IAI 2Q8*
IAI 2Q4
Statistically
Noninferior
Clinically Equivalent
5.0
5.0
3.3
-1.7
0.9
3.5
-1.7
0.9
3.5
595 607 610
IAI 2Q8*
-10
-5
0
RBZ 0.5Q4
5
10
IAI
All intravitreal aflibercept doses noninferior to ranibizumab
*Following 3 initial monthly doses (every 4 weeks)
RBZ, ranibizumab
IAI, intravitreal aflibercept injection
VIEW 1 and VIEW 2 Studies:
Intravitreal Aflibercept Injection
Dosing Strategies in Wet AMD Defined
The efficacy and safety of intravitreal aflibercept injection
in wet AMD has been established in a robust worldwide
program of Phase 3 randomized, double-masked, active
controlled trials, VIEW 1 and VIEW 2 (VEGF Trap-Eye:
Investigation of Efficacy and Safety in Wet Age-Related
Macular Degeneration) studies. These remain the largest
randomized, double-masked controlled studies in wet
AMD, involving ~2400 patients with predominantly
classic, minimally classic, and occult neovascular AMD.23
Because ranibizumab 0.5 mg monthly had been previously
proven to be effective in preventing clinically significant
vision loss in wet AMD at the time of trial design,2,3 sham
control in wet AMD studies would have been unethical.24
Therefore, ranibizumab served as the active control in
the VIEW studies, with the control group ensured of
receiving effective wet AMD standard of care based on
the U.S. Prescribing Information for ranibizumab at the
time of the studies.
VIEW 1 was conducted in the United States and Canada;
VIEW 2 was conducted in 26 countries worldwide. Equal
numbers of patients were randomized to one of four
treatment arms – ranibizumab dosed 0.5 mg every
4 weeks (0.5Q4) or intravitreal aflibercept injection
dosed 2 mg every 4 weeks (2Q4), 2 mg every 8 weeks
following 3 initial monthly injections (2Q8), or 0.5 mg
every 4 weeks (0.5Q4) (Fig. 2). Fixed-dose regimens were
administered for 52 weeks, the cutoff point for the
primary efficacy analysis. The primary endpoint was proportion of patients who maintained vision, defined as
losing <15 letters as measured by the ETDRS (Early
Treatment Diabetic Retinopathy Study) protocol. Other
efficacy measures included mean change in visual acuity,
proportion of patients who gained ≥15 letters or ≥3 lines
of vision, and the proportion of patients achieving
≥20/40 vision on the Snellen chart. In addition, changes
in anatomic features, measured by time-domain optical
coherence tomography (TD-OCT), compared the pharmacodynamic effects of the different treatment regimens.
Although OCT examinations were performed throughout
the study, they were not used to guide dosing decisions in
the first 52 weeks during fixed-dose administration.23
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
4
Figure 4. A: Mean visual acuity change from baseline over 52 weeks (ETDRS letters). B: Anatomic
effects measured as mean change from baseline in central retinal thickness (TD-OCT) over
52 weeks.10,23
Last observation carried forward in full analysis set. VIEW 1 TD-OCTs: Mandatory at baseline, Weeks
4, 12, 24, 36, 52. VIEW 2 TD-OCTs: Mandatory at all visits. Anatomic measures were not used to guide
dosing decisions in the first 52 weeks of the VIEW 1/VIEW 2 studies.
15
A.
VIEW 1
10.9* IAI 2Q4 (N=304)
BCVA change from baseline, mean ETDRS letters
10
8.1 RBZ Q4 (N=304)
7.9✝ IAI 2Q8 (N=301)
5
0
15
VIEW 2
9.4 RBZ Q4 (N=291)
8.9✝ IAI 2Q8 (N=306)
7.5✝ IAI 2Q4 (N=309)
10
5
0
15
Integrated
9.3✝ IAI 2Q4 (N=613)
8.7 RBZ Q4 (N=595)
8.4✝ IAI 2Q8 (N=610)
10
5
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Central retinal thickness, mean change from baseline, μm
B.
25
52
*P = 0.005
Weeks
✝
P = N5
VIEW 1
-75
-117 IAI 2Q4 (N=304)
-117 RBZ Q4 (N=304)
-129 IAI 2Q8✝ (N=301)
-125
-175
25
VIEW 2
-75
-139 RBZ Q4 (N=291)
-149 IAI 2Q8✝ (N=306)
-157 IAI 2Q4 (N=309)
-125
-175
25
Integrated
-75
-128 RBZ Q4 (N=595)
-137 IAI 2Q4 (N=613)
-139 IAI 2Q8✝ (N=610)
-125
-175
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Weeks
RBZ 0.5Q4
IAI 2Q4
IAI 2Q8✝
✝ Following
3 initial monthly doses (every 4 weeks)
RBZ, ranibizumab
IAI, intravitreal aflibercept injection
Important Safety Information for EYLEA®(aflibercept) Injection
The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.
5
Because the control group was active treatment, the
VIEW 1 and 2 studies were designed as noninferiority
studies to determine whether any of the intravitreal
aflibercept injection dosing regimens were noninferior to
ranibizumab. The statistical analysis used a confidence
interval approach to assess the efficacy difference. In
consultation and agreement with the U.S. FDA, the prespecified parameters for demonstrating noninferiority
were a 95.1% (VIEW 1) or 95% (VIEW 2) confidence
interval of the intravitreal aflibercept-ranibizumab
difference and a 10% margin of difference, i.e., the upper
limit of the confidence interval had to be <10% in order
for intravitreal aflibercept to be proven noninferior to
ranibizumab. Intravitreal aflibercept would be considered clinically equivalent to monthly ranibizumab if the
upper confidence interval limit did not exceed 5% for
the primary endpoint.23
Efficacy Outcomes
Improvement in BCVA was noted as early as week 1 in all
treatment groups, with an overall trend of continued improvement to the week 52 visit (Fig. 4A). Minor differences between groups disappeared when data were
combined across studies, showing that the mean change
in BCVA at week 52 was within 1 letter for all study treatments (8.4 to 9.3 letters). All intravitreal aflibercept
groups, including the 2Q8 group, were similar to
monthly ranibizumab.23
In the combined studies, most patients (79-81%) experienced some degree of visual acuity improvement at 1 year;
31-33% exhibited clinically significant improvement
defined as ≥15-letter gain. A small subset (5-6%) showed
≥30-letter improvement. Compared with an average
baseline Snellen score of 20/80, at least one-third of
patients improved to ≥20/40 BCVA at week 52 (≤5%
had 20/40 vision at baseline). For all of these secondary
endpoints, clinical improvements were similar across
study arms.10
At week 52, primary efficacy outcomes – proportion of
patients in whom best-corrected visual
Table 1. VIEW 1/VIEW 2 Studies: Most Common Adverse Events (≥1%)
acuity was maintained (<15 letter loss on
Over First 52 Weeks
ETDRS chart from baseline to week 52) –
were similar across groups, with vision
Active Control
IAI
maintained in 94-95% of patients (Fig. 3).
(RBZ, N=595)
(N=1824)
Intravitreal aflibercept injection met the
%
%
prespecified statistical parameters for
Conjunctival hemorrhage
28
25
being 1) noninferior to ranibizumab and
2) clinically equivalent to ranibizumab in
Eye pain
9
9
maintaining vision after 52 weeks, with
Cataract
7
7
confidence intervals for mean differences
Vitreous detachment
6
6
falling within ⫾5%. Therefore, intravitreal
Vitreous floaters
7
6
aflibercept injection administered as 2 mg
every 8 weeks (following 3 initial monthly
Intraocular pressure increased
7
5
doses) or as 2 mg every 4 weeks is clinically
Conjunctival hyperemia
8
4
equivalent to ranibizumab 0.5 mg dosed
Corneal erosion
5
4
every 4 weeks in terms of maintaining
23
Retinal pigment epithelium
3
3
vision in patients with wet AMD. These
detachment
outcomes were achieved with substantially
fewer injections in the intravitreal
Injection site pain
3
3
aflibercept injection 2Q8 group; patients
Foreign body sensation in eyes
4
3
assigned to intravitreal aflibercept injection
Lacrimation increased
1
3
2Q8 received an average of 7.5 active injections in VIEW 1 and VIEW 2, respectively
Vision blurred
2
2
vs the 8-injection schedule specified by the
Intraocular inflammation
3
2
protocol. For patients assigned to 0.5Q4
Retinal pigment epithelium tear
1
2
ranibizumab or intravitreal aflibercept
Injection site hemorrhage
2
1
injection 2Q4, 13 injections were scheduled. The mean number of injections was
Eyelid edema
2
1
12.3 for ranibizumab and intravitreal
Corneal edema
1
1
aflibercept injection.25
RZB, ranibizumab
IAI, intravitreal aflibercept injection
Important Safety Information for EYLEA®(aflibercept) Injection
Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections
with EYLEA including endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous
detachment.
6
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
Anatomic Changes
in the other arms.23 Post-hoc analyses examined whether
these minor fluctuations reflected a small subset of
patients in the intravitreal aflibercept injection 2Q8 arm
who were having repeated episodes of larger fluctuations
(e.g., >50 µm) with a negative impact on visual acuity.
The analyses found that ~30% of patients in all treatment
groups had such changes. These large fluctuations generally occurred once or twice during the study, although a
small subset of patients had more frequent episodes.
However, these fluctuations did not correlate with worse
visual outcome at 52 weeks, even for patients who had
several episodes in which central retinal thickness
increased >50 µm, regardless of treatment.25
Anatomic measures were not used to influence treatment
decisions. Changes in central retinal thickness as
measured by optical coherence tomography (OCT) may
generally be regarded as pharmacodynamic indicators of
VEGF inhibition with regard to the reduction of fluid
in/under the retina and retinal pigment epithelium (RPE)
in wet AMD. Intravitreal aflibercept injection and
monthly ranibizumab in both VIEW 1 and VIEW 2 had
similar pharmacodynamic effects on these anatomic
measures. Mean central retinal thickness was reduced by
week 4, with reductions maintained through the end of
year 1 (Fig. 4B). With OCTs being performed at all visits
(monthly) in VIEW 2, minor inter-dose fluctuations in
average central retinal thickness were observed in the
intravitreal aflibercept injection 2Q8 group. The mean
initial increase in retinal thickness was 17 µm between
week 12 and week 16, decreasing steadily to 8 µm at
week 52.23 These minor increases did not appear to have
a negative impact on visual acuity in the overall group
since mean visual acuity gains associated with intravitreal
aflibercept injection 2Q8 were similar to those achieved
Post-hoc analyses also examined the proportion of
patients with a “dry” retina as defined by the masked
reading center criteria of no retinal cysts/edema on
TD-OCT. Across studies, groups were generally similar,
with 62% of patients assigned to ranibizumab monthly
and 72% (2Q4) and 68% (2Q8) receiving intravitreal
aflibercept injection meeting the criteria for a “dry”
retina.23 Similarly, no leakage on fluorescein angiography
was observed in 61%, 71%, and 60%, respectively, when
VIEW 1 and VIEW 2 data
were combined.10 The correTable 2. VIEW 1/ VIEW 2 Studies: Serious Ocular and Nonocular (Systemic)
lation of these anatomic
Adverse Events Over First 52 Weeks*
changes to visual outcomes
is unknown.
Active Control
IAI
(RBZ, N=595)
(N=1824)
Tolerability and Safety
%
%
Any serious ocular adverse event
3.4
2.1
Visual acuity reduced
0.5
0.5
Retinal hemorrhage
0.5
0.3
Endophthalmitis
0.5
0.2
Cataract
0.2
0.2
Retinal pigment epithelium tear
0.2
0.2
Intraocular pressure increased
0.2
0.1
Retinal detachment
0.2
0.1
Macular hole
0
0.1
Posterior capsular opacification
0.3
0
Any serious non-ocular adverse event
14
14
3.5
2
Cardiac
3
3
Neoplasms
2
2.5
Vascular disorders
1
1
Injury/poisoning/procedural complications
1
2
Musculoskeletal/connective tissue
1
0.5
Gastrointestinal
1
1.5
Respiratory/thoracic/mediastinal
1
1
General/administration site
1
1
0.5
2
Infections/infestations
Nervous system
*Occurring in ≥2 patients in either group
RZB, ranibizumab
IAI, intravitreal aflibercept injection
in Wet AMD
Across the VIEW 1 and
VIEW 2 studies, 1824 patients
were exposed to intravitreal
aflibercept injection (all
doses combined) during the
first 52 weeks; 595 were
exposed to active control
ranibizumab.23 Analysis of
ocular and nonocular adverse
events across intravitreal
aflibercept injection dosage
groups did not reveal a
dose/exposure effect on tolerability or safety. The most
common adverse events
reported in ≥5% patients
receiving intravitreal
aflibercept injection were
conjunctival hemorrhage, eye
pain, cataract, vitreous
detachment, vitreous floaters,
and increased intraocular
pressure (Table 1). The occurrence rates were similar for
intravitreal aflibercept injection and active control.
Hypersensitivity has been
reported in <1% of patients
7
treated with intravitreal aflibercept injection. The overall
incidence of serious ocular adverse events (Table 2) was
similar between intravitreal aflibercept injection (2.1%)
and active control (3.4%) groups. Serious adverse events
reported in <1% of patients treated with intravitreal
aflibercept injection were retinal detachment, retinal tear,
and endophthalmitis.
With intravitreal aflibercept injection, adverse events
potentially related to systemic VEGF inhibition were
uncommon and equally distributed among treatment
groups (Table 2). Because VEGF-A helps regulate vascular
tone, increased blood pressure is believed to be one of
the most sensitive biomarkers of endogenous VEGF-A
inhibition systemically.26 In the VIEW 1 and VIEW 2
studies, mean systolic blood pressure decreased from
baseline over 52 weeks in all treatment arms; mean
diastolic pressures also decreased slightly. Although
mean blood pressure did not increase in the VIEW 1 and
VIEW 2 studies, hypertension was reported as an adverse
event along with reports of hypertension as serious
adverse events; incidences were similar across intravitreal
aflibercept injection and ranibizumab groups.
Using the Antiplatelet Trialists’ Collaboration (APTC)
criteria for classification of arterial thromboembolic
events (ATEs) defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of
unknown cause),27 the incidence of ATEs with intravitreal
aflibercept injection in clinical trials was 1.8% during the
first year and 1.5% with active control.
The Role of Intravitreal Aflibercept
Injection in Wet AMD Management
The progressive and often rapid visual acuity loss associated with wet AMD highlights the need for early
diagnosis and effective treatment. Clinical studies have
demonstrated that therapeutic proteins broadly targeting
ligands of VEGFR-1 and VEGFR-2 can stabilize and even
reverse vision loss in wet AMD, 2,3 making pan-VEGF-A
inhibition a current standard of care in wet AMD. To
reliably achieve and maintain these outcomes, patients
(and caregivers) have historically had to follow a regimen
of monthly office visits.6-8 Numerous studies have
explored alternative treatment/monitoring regimens in
order to reduce the frequency of monitoring visits and
injections, thus suggesting a need for additional therapies.
Aflibercept is a fusion protein containing all human
amino acid sequences that serves as a decoy receptor to
trap the VEGFR-1 and VEGFR-2 ligands VEGF-A and
PLGF and inhibit receptor signaling.12 Formulated as an
iso-osmotic solution compatible with the intraoacular
environment, intravitreal aflibercept injection is a
purified and formulated preparation of aflibercept,
specifically for intravitreal injection.16 Intravitreal
aflibercept injection is produced in recombinant Chinese
hamster ovary (CHO) cells.
For the primary measure of proportion of patients losing
<15 EDTRS letters of best-corrected visual acuity from
baseline, intravitreal aflibercept injection therapy allows
the injection interval to be extended in wet AMD to
8 weeks following 3 initial monthly injections, as
demonstrated by the VIEW 1 and VIEW 2 studies. In
these studies, intravitreal aflibercept injection administered as 2 mg every 2 months (8 weeks) following
3 monthly (4 weeks) injections was statistically noninferior and clinically equivalent to ranibizumab monthly.23
The most common adverse events (≥5%) seen in the
VIEW studies in patients treated with intravitreal
aflibercept injection were conjunctival hemorrhage, eye
pain, cataract, vitreous detachment, vitreous floaters,
and increased intraocular pressure.
Important Safety Information for EYLEA®(aflibercept) Injection
There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF inhibitors,
including EYLEA, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including
deaths of unknown cause). The incidence of ATEs in the VIEW 1 and VIEW 2 wet AMD studies in patients
treated with EYLEA was 1.8% during the first year. The incidence of ATEs in the COPERNICUS and GALILEO
CRVO studies was 0% in patients treated with EYLEA compared with 1.4% in patients receiving sham control
during the first six months.
8
Please see Important Prescribing and Safety Information on back cover and the accompanying full
Prescribing Information
References
1. American Foundation for the Blind. American Foundation for
the Blind Survey: Americans fear impact of vision loss more
than cancer,HIV/AIDS, heart disease and stroke. 2007.
http://www.prnewswire.com/news-releases/american-foundation-for-the-blind-launches-web-site-to-help-people-with-visionloss-maintain-independence-57786412.html Accessed July 15,
2013
2. Brown DM, Kaiser PK, Michels M et al. Ranibizumab versus
verteporfin for neovascular age-related macular degeneration.
New Engl J Med 2006;355:1432-44
3. Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. New Engl J Med
2006;355:1419-31
4. Martin DF, Maguire MG, Fine SL et al. Ranibizumab and
bevacizumab for treatment of neovascular age-related macular
degeneration: Two-year results. Ophthalmology 2012;2012:26
5. CATT Research Group, Martin DF, Maguire MG et al.
Ranibizumab and bevacizumab for neovascular age-related macular degeneration. New Engl J Med 2011;364:1897-908
6. Regillo CD, Brown DM, Abraham P et al. Randomized, doublemasked, sham-controlled trial of ranibizumab for neovascular
age-related macular degeneration: PIER study year 1. Am J
Ophthalmol 2008;145:239-48
7. Boyer DS, Heier JS, Brown DM et al. A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular agerelated macular degeneration. Ophthalmology 2009;116:1731-9
8. Schmidt-Erfurth U, Eldem B, Guymer R et al. Efficacy and safety
of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: The EXCITE study.
Ophthalmology 2011;118:831-9
9. Curtis LH, Hammill BG, Qualls LG et al. Treatment patterns for
neovascular age-related macular degeneration: Analysis of 284
380 Medicare beneficiaries. Am J Ophthalmol 2012;153:1116-24 e1
10. Data on file. Regeneron Pharmaceuticals, Inc.
11. Economides AN, Carpenter LR, Rudge JS et al. Cytokine traps:
Multi-component, high-affinity blockers of cytokine action. Nat
Med 2003;9:47-52
12. Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: A VEGF
blocker with potent antitumor effects. Proc Natl Acad Sci U S A
2002;99:11393-8
13. Davis-Smyth T, Chen H, Park J et al. The second immunoglobulinlike domain of the VEGF tyrosine kinase receptor FLT-1 determines ligand binding and may initiate a signal transduction
cascade. EMBO J 1996;15:4919-27
14. Lu D, Kussie P, Pytowski B et al. Identification of the residues in
the extracellular region of KDR important for interaction with
vascular endothelial growth factor and neutralizing anti-KDR
antibodies. J Biol Chem 2000;275:14321-30
15. Wiesmann C, Fuh G, Christinger HW et al. Crystal structure at
1.7 a resolution of VEGF in complex with domain 2 of the FLT-1
receptor. Cell 1997;91:695-704
16. Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related
ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171-85
17. Czajkowsky DM, Hu J, Shao Z et al. Fc-fusion proteins: New
developments and future perspectives. EMBO Mol Med
2012;4:1015-28
18. Suzuki T, Ishii-Watabe A, Tada M et al. Importance of neonatal
FcR in regulating the serum half-life of therapeutic proteins
containing the Fc domain of human IgG1: A comparative study
of the affinity of monoclonal antibodies and Fc-fusion proteins
to human neonatal FcR. J Immunology 2010;184:1968-76
19. Rudge JS, Holash J, Hylton D et al. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker
for predicting efficacious angiogenic blockade. Proc Natl Acad
Sci U S A 2007;104:18363-70
20. Nguyen QD, Shah SM, Browning DJ et al. A phase I study of
intravitreal vascular endothelial growth factor trap-eye in
patients with neovascular age-related macular degeneration.
Ophthalmology 2009;116:2141-8 e1
21. Brown DM, Heier JS, Ciulla T et al. Primary endpoint results of
a phase II study of vascular endothelial growth factor trap-eye
in wet age-related macular degeneration. Ophthalmology
2011;118:1089-97
22. Heier JS, Boyer D, Nguyen QD et al. The 1-year results of
CLEAR-IT 2, a Phase 2 study of vascular endothelial growth
factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology 2011;118:1098-106
23. Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept
(VEGF Trap-Eye) in wet age-related macular degeneration.
Ophthalmology 2012;119:2537-48
24. Food & Drug Administration. Guidance for industry: Non-inferiority clinical trials. March 2010.
25. Regeneron Pharmaceuticals Inc. FDA Briefing Document.
Accessed at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOp
hthalmicDrugsAdvisoryCommittee/UCM259143.pdf
26. Jain RK, Duda DG, Willett CG et al. Biomarkers of response
and resistance to antiangiogenic therapy. Nat Rev Clin Oncol
2009;6:327-38
27. Antiplatelet Trialists' Collaboration. Collaborative overview of
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Collaboration. BMJ 1994;308:81-106.
9
IMPORTANT PRESCRIBING INFORMATION FOR EYLEA® (aflibercept) INJECTION
EYLEA® (aflibercept) Injection is indicated for the treatment of patients with neovascular (Wet)
Age-related Macular Degeneration (AMD). The recommended dose for EYLEA is 2 mg administered by
intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once
every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
(monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared
to every 8 weeks.
EYLEA is indicated for the treatment of patients with Macular Edema following Central Retinal Vein
Occlusion (CRVO). The recommended dose for EYLEA is 2 mg administered by intravitreal injection
every 4 weeks (monthly).
IMPORTANT SAFETY INFORMATION FOR EYLEA® (aflibercept) INJECTION
EYLEA® (aflibercept) Injection is contraindicated in patients with ocular or periocular infections, active
intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients of EYLEA.
Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and
retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA.
Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment
without delay and should be managed appropriately. Intraocular inflammation has been reported with
the use of EYLEA.
Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection,
including with EYLEA. Sustained increases in intraocular pressure have also been reported after
repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic
nerve head should be monitored and managed appropriately.
There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF
inhibitors, including EYLEA, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death
(including deaths of unknown cause). The incidence of ATEs in the VIEW 1 and VIEW 2 wet AMD
studies in patients treated with EYLEA was 1.8% during the first year. The incidence of ATEs in the
COPERNICUS and GALILEO CRVO studies was 0% in patients treated with EYLEA compared with
1.4% in patients receiving sham control during the first six months.
The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival
hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.
Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal
injections with EYLEA including endophthalmitis, traumatic cataract, increased intraocular pressure,
and vitreous detachment.
Please see accompanying full Prescribing Information.
©2013, Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road, Tarrytown, NY 10591
All rights reserved
10/2013
LEA-0321