Clinical and Pharmacoeconomic analysis was extensivley done on Eylea for its placement on a hypothetical health plans formulary for Macular Degeneration. Information was presented to a panel of pharmacy professionals in managed care and industry

1. 1
Pitt Street Health Plan Formulary Monograph Template
Individual Drug Review
Generic Name: aflibercept for intravitreal injection
Brand Name: Eylea®
Manufacturer: Regeneron Pharmaceuticals, Inc.
Date of Review:
Available Therapeutic Alternatives:
Preferred/Formulary Non-Preferred/Non Formulary
Anti-VEGF Anti-VEGF
ranibizumab (Lucentis®)
bevacizumab (Avastin®) – off label
aflibercept (Eylea®)
pegaptanib (Macugen®)
TABLE OF CONTENTS:
(Click on a link below to view the section.)
Executive Summary
Recommendations
Key Questions/Issues:
Issue 1: Efficacy
Issue 2: Comparative Effectiveness
Issue 3: Safety
Issue 4: Value Proposition
Issue 5: Cost-effective Patient Subgroups
Clinical Evidence Tables
Cost-effectiveness Evidence Tables
Background
Disease Background
Pharmacotherapy
Product Background
Methodology
Authorship
References
Abbreviations used in this monograph:
Vascular endothelial growth factor (VEGF)
Age related macular degeneration (AMD)
Quality adjusted-life year (QALY)

2. 2
REASON FOR REVIEW:
To determine the formulary status for aflibercept for intravitreal injection (EYLEA®
), FDA approved for
treatment of Neovascular (Wet) Age-Related Macular Degeneration (AMD) and Macular Edema
Following Central Retinal Vein Occlusion (CRVO).
EXECUTIVE SUMMARY
Key Questions/Issues and Results of Investigation:
Issue 1: What is the evidence of efficacy from clinical trials?
There is evidence to show that aflibercept is effective in both reducing the macular
thickness, as well as helping to improve vision.1 Both of these were found from the CLEAR
IT 2 trial, a phase 1clinical trial, and the VIEW 1 and 2 trials, both phase 3 clinical trials. The
VIEW 1 trial did find that when compared to Ranibizumab, aflibercept was able to show a
significant improvement in vision. However, in the VIEW 2 trial, the improvement in vision
was not shown to be significantly significant for ranibizumab.2
Issue 2: Is there sufficient evidence to assessreal world comparative effectiveness?
Currently there is real world evidence to assess the effectiveness of aflibercept; however,
more evidence would beneficial to allow for a more complete analysis. Two trials that are
necessary to determine the effectiveness are the VIEW1 and VIEW2 (VEGF Trap-Eye:
Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration) trials. The
trials each lasted 52 weeks and the endpoints, treatment population, and primary outcome
measures were the same.2 The results of the trials revealed the aflibercept groups were
noninferior to ranibizumab.
Issue 3: What is the evidence of safety?
Evidence of safety can also be found from the VIEW1 and VIEW2 trials. It was
concluded that there was no difference between aflibercept and ranibizumab regarding ocular or
systemic adverse effects.2 In the VIEW trials, ranibizumab was dosed monthly and aflibercept
was administered every two months.
Issue 4: What is the value proposition for this product?

3. 3
Currently, Eylea is a product that is demanded by both patients and physicians. Along
with its noninferiority to Ranibizumab, it has been to have the potential to bring cost savings to
patients affected by wet AMD. According to the National Eye Institute, advanced cases of wet
AMD will rise to nearly 3 million cases by the year 2020.3 When analyzing the cost savings
between Ranibizumab and aflibercept, the yearly cost savings is slightly above $3.5 billion and
the quarterly savings is $884 million. This shows there is a large potential for savings without
sacrificing the quality of therapy provided.4
Issue 5: Are there identifiable patient subgroups in which this treatment will be most cost-effective?
There are certain patient subgroups where this treatment would be most cost-effective.
Treatment with aflibercept would be more cost effective than treatment via ranibizumab over the
course of one year. Due to the decreased dosing schedule, there would be a cost saving of
approximately USD 8,600. It is important to note that bevacizumab is able to be used off-label
for treatment of wet Age-Related Macular Degeneration (AMD).2 If a patient is non-responsive
to ranibizumab therapy, aflibercept would be a cost-effective alternative.
RECOMMENDATIONS TO THE COMMITTEE
Therefore,the following P&T action is recommended:
Based on our findings, we recommend bevacizumab as a first line agent for the
treatment of wet age-related macular degeneration (AMD). This is due to both the current
efficacy and cost versus other drugs, bevacizumab and ranibizumab.1 Moreover, we
recommend adding aflibercept to the formulary to be utilized as a second tier agent due to
the effectiveness against resistant macular degeneration.
By first requiring the use of bevacizumab, there is a great cost savings over the course
of a year. Choosing aflibercept as a second tier agent over ranibizumab was due to the
decreased cost per year and its clinically proven noninferiority; this was accomplished by a
decreased number of injections per year.1 In addition, there are some cases where wet
AMD is resistant both bevacizumab and ranibizumab. Thus, it may be necessary to have
another agent in the event the first line agent, bevacizumab, fails to be effective.

4. 4
ISSUE DETAILS
ISSUE 1: What is the level and quality of evidence for efficacyfrom clinical trials?
The CLEAR IT 2 study showed a reduction in macular thickness of 66% as well as
significant improvement in vision. In the View 1 study those receiving aflibercept had an
improvement of 10.9 letters compared to an improvement of 8.1 letters in those receiving
Ranibuzumab. Also the VIEW 1 showed a reduction in macular thickness that ranged from 218
to 230 micrometers. Although these results are not statistically very different, the results do show
significant increases in visual acuity.5 According to 91.7% of patients achieved stabilized or
reduced intraretinal fluid and an average macular thickness reduction of 65 micrometers, after
just 3 monthly injections.1 Each of these studies show that aflibercept is able to reduce macular
thickness and increase vision acuity in AMD patients.5
ISSUE 2: Is there sufficient evidence to assess real world comparative effectiveness?
Currently there is evidence to assess the real world comparative effectiveness of
aflibercept; however, more evidence would enable a more confident conclusion to be reached.
Unlike both bevacizumab and ranibizumab, aflibercept is able target VEGF by presenting
itself as a receptor for VEGF. Aflibercept is then able to bind to VEGF more tightly than the
native VEGF receptor is. Furthermore, aflibercept is a able to target both VEGF-B and PIGF,
specific subclasses of VEGF, while bevacizumab and ranibizumab are unable to target them
effectively. The ability to target more angiogenic factors makes it possible that aflibercept
may be more effective in treating wet AMD.
When aflibercept was compared to ranibizumab it was found that aflibercept was
considered to be noninferior to ranibizumab. Both the VIEW1 and VIEW2 trials took place
over a 52 week period and each had almost identical results for the primary endpoint.
The one place where real world evidence is lacking is a comparison between aflibercept and
bevacizumab. Although bevacizumab is not FDA indicated for the treatment of wet AMD, it
has been successfully utilized to help patients with the disease. A real world clinical trial of
both bevacizumab and aflibercept would enable a more comprehensive comparison of both
medications.
ISSUE 3: What is the level and quality of evidence for safety?

5. 5
There is ample evidence to be able to assess the quality and level of safety for
aflibercept. Some of the most important information regarding the safety comes from two
phase III trials, VIEW1 and VIEW2. In each trial, the overall safety and efficacy of
aflibercept was monitored. In regards to safety, it was determined that aflibercept was able to
produce similar results as ranibizumab.2
It was able to be determined that over the course of 52 weeks, that both systemic and
ocular side effects were comparable in safety between the treatment and control group.6
Some particular adverse events such as myocardial infarction and stroke produced a slightly
lower incidence than ranibizumab for each disease in each VIEW trial.7 Due to the decreased
number of injections per year, there is a benefit for aflibercept. It is possible to have an
adverse local event in the event there is a problem with the injection.
Based on the each VIEW trial being double-blinded, randomized and there was monthly data
obtained, the level of this trial would be classified as a Level II-3 based on the U.S.
Preventive Services Task Force.
ISSUE 4: What is the value proposition for this product?
Summary of Product Value
Eylea accounted for $1.4 billion in sales in 2013. It is a product patients and doctors are
demanding on a large scale. Eylea saves, as shown below, a substantial amount of money on a
micro and macro type basis. The product has shown non-inferiority to Ranibizumab while
providing the patient with less shots/doctor’s visits, all while being the cheaper alternative to
Ranibizumab.
Manufacturer-Submitted Modeling
Budget Impact Analysis: Approximately 15 million people in the United States have AMD, and
more than 1.7 million Americans have the advanced form of the disease.
About 200,000 new cases of wet AMD are diagnosed each year in North America. Due to
the aging baby boomer population, the National Eye Institute estimates that the prevalence of
advanced AMD will grow to nearly 3 million by 2020.3
Eylea saves $8,000 for a full year’s treatment compared to Ranibizumab per person. That is
a $2,000 dollar saving per person per Fiscal quarter. With 1.7 million people having wet AMD.
In August, BioTrend Research Group surveyed U.S ophthalmologists and found in terms of their

6. 6
total number of wet AMD patients, now they treat 26 % with Eylea, a significant increase from a
year ago where the figure was 21%.4 That is a yearly cost savings $3,536,000,000 on a
nationwide level and a quarterly cost savings of $884,000,000. With the prevalence of wet and
almost doubling by 2020 these savings on a macro level will almost double compared to using
Ranibizumab.
Cost-Utility Analysis: Regeneron has priced Eylea lower than Ranibizumab: just $100 lower on
a per-injection basis, but about $8,000 less for a full year's treatment, if the company's less-
frequent injection schedule holds true. Eylea will run $1,850 per dose, Bloomberg reports,
compared with $2,000 for Ranibizumab, and $16,000 for a full year, compared with $24,000 for
the Roche drug.8
It was indicated an incremental quality adjusted life year (QALY) gain with aflibercept of
0.0107 but a lower cost and thus that aflibercept would be the dominant medicine (lower cost,
more effective).9
ISSUE 5: Are there identifiable patient subgroups in which this treatment will be most
cost-effective?
There are identifiable patient subgroups in which this treatment would be most cost-
effective. When treating wet AMD, the most common forms of therapy include bevacizumab,
ranibizumab, and aflibercept. When considering what therapy to utilize it is important to take
both the cost and effectiveness into consideration. Of all three treatment options, it has been
shown that bevacizumab has the lowest cost, at an estimated USD600 per year. This would
take into account bevacizumab being administered 1 time per month over the course of a
year.2
Patient populations that would benefit from treatment with aflibercept would include
patients who are nonresponsive to bevacizumab therapy or patients who experience an
adverse reaction to bevacizumab therapy. In this case, the choice of therapy would be either
aflibercept or ranibizumab. One distinct difference between the two forms of therapy
involves the frequency of injections. Ranibizumab would need to be administered 12 times
per year, while on the other hand aflibercept would require 8 doses over the course of one
year. Not including costs of injection and physician visits, this would result in an average
savings of approximately USD 8,600.2

7. 7
According to the manufacture of aflibercept, a one-way sensitivity analysis was able to
determine with 100% probability that there would be a cost savings by using aflibercept
compared to ranibizumab. In regards to the incremental cost-effectiveness ratio (ICER), it was
found that £20,000 per quality-adjusted life year (QALY). This would be equivalent to
approximately USD 33,000 per QALY gained.10
Regarding clinical practice, it should be noted that aflibercept does not significantly
differ from current therapies due to the fact that it requires one to visit a doctor’s office for the
medication to be administrated. One benefit over current therapy is that aflibercept requires less
office visits, which could result in greater compliance of therapy.2 Consequently, in patients
where bevacizumab therapy was not found to be appropriate, there is a cost-effective savings by
utilizing aflibercept therapy.

9. 9
Ref. and
Evidence
Grade
Drug Regimens N Time Demographics Design* End Points/Results/Comments NNT
VIEW Studies Aflibercept 2 mgevery8
weeks after 3 initial
monthly loadingdoses, (ii)
aflibercept 2 mgevery4
weeks, (iii) aflibercept 0.5
mgevery 4 weeks, or (iv)
ranibizumab0.5 mgevery
4 weeks
2457
pts
with
neovas
cular
AMD
96 weeks VIEW 1 – NorthAmerica
VIEW 2 – Worldwide
The meanage was 78
years, 41% of patients
were male, and97% of
patients were white. In
VIEW 2, the meanage
was 73-75 years, 45% of
patients were male, and
73% of patients were
white. Thetotal mean
baseline best-corrected
visual acuity score
(definedby Early
Treatment Diabetic
RetinopathyStudy
[ETDRS] scale) ranged
from 54 to56letters in
VIEW 1 andfrom 52 to 54
letters in VIEW 2. Inboth
studies, the distributionof
occult, minimallyclassic
andpredominantlyclassic
lesion types in thestudy
eye was similar across
both treatment arms.
Randomized, double-blindPhase III
trail
1:1:1:1 randomization
Primaryoutcome was identifiedas the percentage ofpatients
who maintainedvisionat week 52. Maintainingvisionwas
definedas losingless than 15letters basedon the best-
correctedvisual acuity scaledcomparedto baseline
measurements. The primaryendpoint showednoninferiority
in all four treatment groups where noninferioritywas defined
in comparison to thestandardof careranibizumaband
concludingthat the three aflibercept groups were noninferior.
The safety analysis in bothVIEW trials foundaflibercept to
be a well-tolerateddrug.
Maintaining
BVCA-
primary end
point-52
weeks- 1/.961-
.944 58 pts
96 weeks
1/.924-.915111
pts

10. 10
CLEAR IT
Studies
3 monthly injections of
aflibercept.
31 pts
with
exudati
ve
AMD
and
choroi
dal
neovas
culariz
ation
(CNV)
in 1 or
both
eyes.
50 weeks The meanage was 79
years (range 60-88),13
male and18 female
patients.
Retrospective observational case
series
After 3 monthly injections ofaflibercept,therewas a
reduction of either subretinal orintraretinal fluidin 18 or36
(50.0%) ofthe treatedeyes; the amount offluidremained
stable in 15 eyes (41.7%)andworsenedin 3 eyes (8.3%). A
significant average decrease was observedfor the central
macular thickness after 3 injections of 65micrometers, with
no significant change in visual acuity.
Not stated.
*Abbreviations usedin this table: AC =active control, CCS= case-control study,DB = double blind, PC = placebo control,PCS= prospective cohort study, PG= parallel group, MA= meta-analysis MC = multicenter,
RCS = retrospective cohort study, RCT = randomizedcontrolledtrial, XO = crossover

11. 11
Table . Clinical evidence summary
Table . Cost-effectiveness evidence summary (Reviewers may change this table format to better fit the economic study methodology)
Ref. and
Sponsor
Study Design and
Treatments Compared
Time Horizon and
Demographics
Model Inputs and Data
Sources
Results:
Base Case, Sensitivity Analysis and Limitations
Regeneron
Pharmaceuticals
Double-masked,
multicenter,parallel-group,
active controlled,
randomizedtrials
Aflibercept 2 mgevery8
weeks after 3 initial
monthly loadingdoses, (ii)
aflibercept 2 mgevery4
weeks, (iii) aflibercept 0.5
mgevery 4 weeks, or (iv)
ranibizumab0.5 mgevery4
weeks
96 Weeks
VIEW 1 – NorthAmerica
VIEW 2 – Worldwide
The meanage was 78
years, 41% of patients
were male, and97% of
patients were white. In
VIEW 2, the meanage
was 73-75 years, 45% of
patients were male, and
73% of patients were
white. Thetotal mean
baseline best-corrected
visual acuity score
(definedby Early
Treatment Diabetic
RetinopathyStudy
[ETDRS] scale) ranged
from 54 to56letters in
VIEW 1 andfrom 52 to 54
letters in VIEW 2. Inboth
studies, the distributionof
occult, minimallyclassic
andpredominantlyclassic
lesion types in thestudy
eye was similar across
both treatment arms.
The VIEW studies showthat a
small percentage of the
patients sawthat Elyea is
effective, but provides no
additional benefit tothe
treatment of wet AMD over
existingtherapies.
Aflibercept 2 mgevery8 weeks after 3 initial monthly loadingdoses, followedby 2 mgevery other
monthresultedin noninferiority in bothefficacyandsafetywhen comparedtoranibizumab0.5mg
administeredevery4 weeks

12. 12
Ref. and
Sponsor
Study Design and
Treatments Compared
Time Horizon and
Demographics
Model Inputs and Data
Sources
Results:
Base Case, Sensitivity Analysis and Limitations
Abbreviations used in this table: LYS = life-years saved, QALY = quality-adjusted life-year, QOL= quality of life.

13. 13
BACKGROUND INFORMATION
DISEASE BACKGROUND
Neovascular age related macualer degeneration is a leading cuase of vision loss in older
populations. Age related macular degeneration accounts for more than 54% of all vision loss in
the white population in the United States.11 The disease is much more common among white
individuals in the population and other people with European decent.11 An estimated 8 million
Americans are affected with early age-related macular degeneration, of whom over 1 million will
develop advanced age-related macular degeneration within the next 5 years.11 Macular
degeneration occurs in 0.2% of the population in those 54-64 and increasing to 13% in those
older than 85 years.11 Neovascualar age-related macular degeneration is the most common cause
of severe central visual loss.11
There are several risk factors associated with the disease. The largest risk factor for age
related macular degeneration with patients over the age of 85 people the biggest group at risk.11
An individual being of the white ethnicity is a risk factor.11 There have been some genetic
factors that have been linked to age related macular degeneration. In addition females have a
greater. A controllable risk factor is cigarette smoking.11
DISEASE BURDEN
The burden on the patient for neovascular age related macular degeneration consists of
decreased eyesight, lifestyle changes, and a financial burden. Patients can lose their vision very
gradually vision loss over months to years or can lose vision within days as a result of subretinal
hemorrhage.11 The patient would also have to make lifestyle changes to decrease the progression
of the disease. For one, the patient would need brighter light to see things and would also need
magnification to read smaller print. There are several lifestyle changes the patient would have to
make. For example, the patient would need to lose weight if they are currently obese, relieve
hypertension if it’s a problem, decrease dietary intake of vegetable fat, and increase consumption
of antioxidants and zinc.12 The quality of life for mild AMD was an average of 17%, a decrease
of an average of 32% decrease among patients with moderate AMD, and a decrease of an
average of 53% among patients with severe AMD. Finally the financial undertaking for the
patient to treat their AMD is quiet substantial.12 The disease also puts burdens on family and
caregivers to make sure the patient stays safe.

14. 14
PATHOPHYSIOLOGY
Neovascular age-related macular degeneration is characterized by the hemorrhagic
detachment of either the retinal pigment epithelium or sensory retina, the presence of subretinal
fibrous tissue, or minimal subretinal fibrosis.11 Neovascularization can develop under the retina,
which can leak fluid or bleed. Onset of vision loss is acute.11 Age related macular degeneration
is characterized by degenerative changes involving the outer portion of the retina, retinal pigment
epithelium, and the Bruch’s membrane.13 A major aspect of the pathophysiology are basal
deposits in the eye.13 The deposits that form can result in the formation of drusen which is are
tiny yellow or white accumulations of extracellular material that build up between Bruch's
membrane and the retinal pigment epithelium of the eye.13 The retinal pigment epithelium cells
can undergo hypotrophy, hypertrophy, hypopigmentation, hyperpigmentation, atrophy,
migration, and the loss of outer retinal cells.13 The outer retinal cells see a 77% reduction in
disease affected eyes compared to non-diseased eyes. Since retinal epithelial cells are
undergoing hypertrophy and hypotrophy, inhibiting vascular endothelial growth factors would be
beneficial to the patient.13
Treatment Alternatives
There are multiple options when treating Neovascular (Wet) Age-Related Macular
Degeneration (AMD). Monotherapy of Anti-VEGF Agents is the gold standard of treatment for
AMD.14 Ranibuzumab (Lucentis) is an Anti-VEGF agent that is a preferred treatment according
to the formulary. The treatment algorithm for Ranibuzumab is the injection of 0.5 mg monthly.
Then based upon the individual patient, after 4 treatments the dosing may be reduced to 0.5 mg
every 3 months. Bevacizumab (Avastin) is a preferred treatment which is used off label. The
treatment algorithm for Bevacizumab is 1.25 mg (0.5mL) monthly for 3 months. Then based
upon the individual patient it is given monthly as needed. A non-preferred medication in the
same category as Eylea is Pegaptanib (Macugen). 0.3 mg of Pegaptanib is injected every 6
weeks to the patient.15
Advanced neovascular AMD has a variety of treatment therapies including Anti-VEGF
injections, photodynamic therapy, as well as laser surgery. Anti-VEGF injections block the
growth of abnormal blood vessels. Photodynamic therapy involves the treatment with the use of
lasers to areas of the retina. Verteporfin is injected intravenously into the patient’s arm.
Verteporfin travels to the newly growing blood vessels. The eye doctor then shines a laser into
the patient’s eye which activates the drug in the newly formed blood vessel. This treatment will

15. 15
not cause harm to normal blood vessels. Verteporfin will close the newly formed blood vessel.
This treatment is less common than Anti-VEGF injections, but can be used as combination
therapy.16 Studies have shown that photodynamic therapy has decreased efficacy with increased
age. Patients over the age of 75 are less likely to benefit from therapy.15 This is important due to
the fact that Age-Related Macular Degeneration most commonly occurs in patients over the age
of sixty. Photodynamic therapy is less efficient in comparison to Anti-VEGF agents unless used
in combination.
Laser surgery is the least common strategy among the different treatments. A laser is
pointed into the abnormal blood vessels in the eye and destroys them. This is most commonly
used when blood vessel growth is centralized in one area of the eye away from the macula. This
can harm healthy tissue and can result in a blind spot where the laser was focused. Immediately
after surgery, vision may be worse than it was prior to surgery, but the vision lost in the future
years will be decreased.
Preferred Existing Therapy
Monotherapy of Anti-VEGF Agents is the gold standard of treatment for AMD.14
Ranibizumab trials with monthly injections are the standard for comparison in most trials.
Researchers have been aiming at increasing the dosing interval. Many of the adverse effects in
regards to patients receiving Age-Related Macular Degeneration treatment are due to the
procedure just as much, if not more than the drug itself. With each injection, there is an
increased risk of error as well as infection which may occur.
The price of Bevacizumab is greatly lower than Ranibizumab. Physicians often prefer
Bevacizumab even though it is used off label for AMD due to cost-savings and the belief that its
efficacy is comparable with that of Ranibizumab. The results of The Complications of Age-
Related Macular Degeneration Treatment Trials (CATT) support this position.5 This trial
showed that monthly Bevacizumab injections had similar vision gains as monthly Ranibizumab
injections. Aflibercept decreases the frequency of injections. Physician preferring Bevacizumab
will now have the option of less frequent treatment with Aflibercept.17
Bevacizumab is the preferred Anti-VEGF treatment agent by nearly sixty percent of physicians
due to its similar efficacy and much lower price than Ranibizumab.5
Other Therapeutic Alternatives

16. 16
Related Macular Degeneration most commonly occurs in patients over the age of sixty.
There have been links found by researchers between Age-Related Macular Degeneration and
multiple lifestyle choices. Researchers have found that smoking abstinence, regular exercise,
healthy blood pressure levels, healthy cholesterol levels, and a diet rich in fish and vegetables
decrease the risk of AMD and also slows the progression.16
Researchers at the National Eye Institute found that nutritional supplements could have
protective properties against AMD in the Age-Related Eye Disease Study (AREDS and
AREDS2 Studies). These supplements were shown to slow the progression of the disease in
patients with intermediate AMD or late AMD in one eye. The first AREDS Trial showed that a
combination of Vitamin C, Vitamin E, beta-carotene, zinc, and copper can reduce the risk of
AMD by twenty-five percent. AREDS2 Trial found that replacing beta-carotene with a five to
one ration of lutein and zeaxanthin may reduce the risk of late AMD. Beta-carotene has also
been linked with an increase in lung cancer prevalence in current and former smokers and thus
should be avoided in patients who are smokers or have a history of smoking.16
There are many supplements available with different ingredients than what was tested in
the AREDS trial. The effective doses tested in the AREDS and AREDS2 study are 500 mg of
Vitamin C, 400 IU of vitamin E, 80 mg of zinc as zinc oxide (25 mg in the AREDS2 Study), 2
mg of copper as cupric oxide, and 15 mg of beta-carotene (or 10 mg lutein and 2mg zeaxanthin).
These supplements should be considered if a patient is at risk for acquiring AMD even if the
patient is taking a multivitamin regularly.16
PRODUCT BACKGROUND
PHARMACOLOGY
Aflibercept works by inhibiting vascular endothelial growth factor (VEGF) by binding to
VEGF with a higher affinity than its native receptor. This trapping prevents VEGF from being
able to carry out its angiogenic effects, effectively rendering VEGF ineffective. Aflibercept is
unique because of its higher affinity for VEGF-A, VEGF-B, and PIGF1; none of the other
current therapies are able to target VEGF-B or PIGF.2
PHARMACOKINETICS
Route of
Administration:
Intravitreal

17. 17
Bioavailability: 1
Time to Peak: 1 to 3 days
Multiple dosing: Once every 4 months for 12, then once every 8 weeks
Clearance: 5 to 6 days
ADVERSE EFFECT PROFILE
The serious adverse effects of aflibercept include Endophthalmitis and Retinal
Detachments (due to administration technique and aseptic technique), increased intraocular
pressure (side effect of VEGF inhibitors), and thromboembolic effects (side effect of VEGF
inhibitors). The common adverse effects include eye pain, conjunctival hemorrhage, increased
intraocular pressure, corneal erosion, vitreous floaters, conjunctival hyperemia, foreign body
sensitation in eyes, vitreous detachment, increased lacrimation, injection site pain, blurry vision,
intraocular inflammation, cataract, eyelid edema, corneal edema, retinal tear, hypersensitivity,
and endophthalmitis.20
The common adverse effects of aflibercept did not significantly vary from the control
(placebo) drug, with the exception of eye pain (13% in aflibercept vs 5% placebo).20 These
adverse effects would therefore be primarily due to the administration technique required to use
the drug and not due to the effects of the drug itself.
Aflibercept is a therapeutic protein and alike all therapeutic proteins there is the potential
for immune response; the production of antibodies that would cause rejection of the agent.
Although the potential for the reaction is there, in both the AMD and CRVO studies there were
no differences in efficacy or safety between patients with or without immunogenecity.20
DRUG INTERACTIONS
There are no known drug interactions.
CONTRACTING AND SITE OF CARE
The National Medicare Physician Fee allowable is $116 for treatment in an outpatient
physician’s office. When the injection is performed in a facility, the reimbursement is $104 due
to site-of-service differential. These do not include the cost of the supply of the stock of Eylea.
The 2 mg vial was assigned the price of $1,961.00 by Medicare.18 The recommended site of
service is an outpatient physician’s office. The patient would remain in the office for a short

18. 18
time after the injection to ensure that the patient’s eye and vision are monitored. Eylea can also
be administered in a hospital outpatient department. According to the Medicare, Eylea is
categorized within the ambulatory payment classification which pays $217 for treatment in a
hospital outpatient department.19
METHODOLOGY OF THIS REVIEW
DATABASES SEARCHED:
Pubmed, Ovid, Google Scholar
SECONDARY SOURCES:
Lexicomp, Drugdex
SEARCH STRATEGY:
In order to be able to successfully research all of the elements necessary to formulate a
recommendation, multiple search strategies were employed. First and foremost, in order to gain
a greater understanding of the medication, aflibercept, databases such as Lexicomp and
Micromedex were searched. By starting with these databases, it enabled us to have a greater
understanding of aflibercept. While the information provided was not sufficient, it gave an idea
of how to direct our future searches.
After getting a foundation, searches were performed in both Pubmed and Ovid. These
databases enabled us to perform more specific searches to target the information vital to making
a recommendation.
INCLUSION CRITERIA:
For the CLEAR IT studies, patients had to be greater than 60 years old and have a diagnosis of
exudative AMD,including presence of dursen, as well as pigment epithelial changes in combination with
choroidal neovascularization, confirmed by fluorescein angiogram and optical coherence tomography.1
Only eyes that had been previously injected with either 1.25 mg bevacizumab or 0.5 mg ranibizumab and
had an initial response, followed by a recurrent increase or persistent subretinal fluid or retinal edema on
OCT.1
Search Results:
Study Type N
Randomized controlled trials (RCT) 3
Meta-analyses 1
Indirect Comparison studies 2

19. 19
Prospective observational studies 1
Retrospective observational studies 2
Economic or QALY modeling studies 1
Case Series 0
RCT abstracts,not peer-reviewed 1
Other abstracts,posters, etc.,not peer-reviewed 6
Articles Excluded from Evidence Synthesis:
Reason for Exclusion N
AUTHORSHIP
Timothy Porter, Kemper May, Scott Borton, Nicolas McCloskey, Gregory
Caspero, Beth Traverse Brian Donahoe
REFERENCES
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