Pitt Street Health Plan Formulary Monograph TemplateIndividual 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 FormularyAnti-VEGF Anti-VEGFranibizumab (Lucentis®)bevacizumab (Avastin®) – off label

aflibercept (Eylea®)pegaptanib (Macugen®)

TABLE OF CONTENTS:(Click on a link below to view the section.)

Executive SummaryRecommendations Key Questions/Issues:

Issue 1: EfficacyIssue 2: Comparative EffectivenessIssue 3: SafetyIssue 4: Value PropositionIssue 5: Cost-effective Patient Subgroups

Clinical Evidence TablesCost-effectiveness Evidence TablesBackground

Disease BackgroundPharmacotherapyProduct Background

MethodologyAuthorshipReferences

Abbreviations used in this monograph:

Vascular endothelial growth factor (VEGF)Age related macular degeneration (AMD)Quality adjusted-life year (QALY)

1

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 assess real 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?

2

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.

3

ISSUE DETAILS

ISSUE 1: What is the level and quality of evidence for efficacy from 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?

4

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

5

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

6

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.

7

Ref. andEvidence

GradeDrug Regimens N Time Demographics Design* End Points/Results/Comments NNT

VIEW Studies Aflibercept 2 mg every 8 weeks after 3 initial monthly loading doses, (ii) aflibercept 2 mg every 4 weeks, (iii) aflibercept 0.5 mg every 4 weeks, or (iv) ranibizumab 0.5 mg every 4 weeks

2457 pts with neovascular AMD

96 weeks VIEW 1 – North America

VIEW 2 – Worldwide

The mean age was 78 years, 41% of patients were male, and 97% of patients were white. In VIEW 2, the mean age was 73-75 years, 45% of patients were male, and 73% of patients were white. The total mean baseline best-corrected visual acuity score (defined by Early Treatment Diabetic Retinopathy Study [ETDRS] scale) ranged from 54 to 56 letters in VIEW 1 and from 52 to 54 letters in VIEW 2. In both studies, the distribution of occult, minimally classic and predominantly classic lesion types in the study eye was similar across both treatment arms.

Randomized, double-blind Phase III trail

1:1:1:1 randomization

Primary outcome was identified as the percentage of patients who maintained vision at week 52. Maintaining vision was defined as losing less than 15 letters based on the best-corrected visual acuity scaled compared to baseline measurements. The primary endpoint showed noninferiority in all four treatment groups where noninferiority was defined in comparison to the standard of care ranibizumab and concluding that the three aflibercept groups were noninferior. The safety analysis in both VIEW trials found aflibercept to be a well-tolerated drug.

Maintaining BVCA- primary end point- 52 weeks- 1/.961-.944 58 pts

96 weeks 1/.924-.915 111 pts

CLEAR IT Studies

3 monthly injections of aflibercept.

31 pts with exudative AMD and choroidal neovascularization (CNV) in 1 or both eyes.

50 weeks The mean age was 79 years (range 60-88), 13 male and 18 female patients.

Retrospective observational case series

After 3 monthly injections of aflibercept, there was a reduction of either subretinal or intraretinal fluid in 18 or 36 (50.0%) of the treated eyes; the amount of fluid remained stable in 15 eyes (41.7%) and worsened in 3 eyes (8.3%). A significant average decrease was observed for the central macular thickness after 3 injections of 65 micrometers, with no significant change in visual acuity.

Not stated.

9

Ref. andEvidence

GradeDrug Regimens N Time Demographics Design* End Points/Results/Comments NNT

*Abbreviations used in 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 = randomized controlled trial, XO = crossover

Table . Clinical evidence summary

Table . Cost-effectiveness evidence summary (Reviewers may change this table format to better fit the economic study methodology)

10

Ref. andSponsor

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, randomized trials

Aflibercept 2 mg every 8 weeks after 3 initial monthly loading doses, (ii) aflibercept 2 mg every 4 weeks, (iii) aflibercept 0.5 mg every 4 weeks, or (iv) ranibizumab 0.5 mg every 4 weeks

96 Weeks

VIEW 1 – North America

VIEW 2 – Worldwide

The mean age was 78 years, 41% of patients were male, and 97% of patients were white. In VIEW 2, the mean age was 73-75 years, 45% of patients were male, and 73% of patients were white. The total mean baseline best-corrected visual acuity score (defined by Early Treatment Diabetic Retinopathy Study [ETDRS] scale) ranged from 54 to 56 letters in VIEW 1 and from 52 to 54 letters in VIEW 2. In both studies, the distribution of occult, minimally classic and predominantly classic lesion types in the study eye was similar across both treatment arms.

The VIEW studies show that a small percentage of the patients saw that Elyea is effective, but provides no additional benefit to the treatment of wet AMD over existing therapies.

Aflibercept 2 mg every 8 weeks after 3 initial monthly loading doses, followed by 2 mg every other month resulted in noninferiority in both efficacy and safety when compared to ranibizumab 0.5mg administered every 4 weeks

11

Ref. andSponsor

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.

12

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.

13

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 AlternativesThere 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 14

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

15

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

16

Bioavailability: 1Time to Peak: 1 to 3 daysMultiple dosing: Once every 4 months for 12, then once every 8 weeksClearance: 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

17

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 NRandomized controlled trials (RCT) 3Meta-analyses 1Indirect Comparison studies 2

18

Prospective observational studies 1Retrospective observational studies 2Economic or QALY modeling studies 1Case Series 0RCT abstracts, not peer-reviewed 1Other 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

1. Bakall B, Folk JC, Boldt HC, Sohn EH, Stone EM, Russell SR, Mahajan VB. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol. 2013 Jul;156(1):15-22.el. Available at http://www.ncbi.nlm.nih.gov/pubmed/23706500. Accessed January 15, 2014.

2. Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Opthalmol. 2013;7:495-501. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595183/#!po=32.6087. Accessed January 15, 2014.

3. Age-Related Macular Degeneration (AMD) Fact Sheet. Roche. Available at: http://www.gene.com/patients/disease-education/amd-fact-sheet. Accessed January 18, 2014.

4. Geschek, Peter. Regeneron’s Blockbuster Eylea and Emerging Competition. Seeking Alpha. N.p, 13 Aug 2013. Available at: http://seekingalpha.com/article/1657682-regenerons-blockbuster-eylea-and-the-emerging-competition. Accessed January 18, 2014.

5. Stewart, MW. Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol. 2012;6:1175-1186. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422153/?report=classic. Accessed January 23, 2014.

6. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23084240/. Accessed January 17, 2014.

7. Semeraro F, Morescalchi F, Duse S, Parmeggiani F, Gambicorti E, Costagliola C. Aflibercept in wet AMD: specific role and optimal use. Drug Des Devel Ther. 2013 Aug 5;7:11-22. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749085/. Accessed January 17, 2014.

19

8. Scottish Medicine Consortium. Professor Angela Timoney. Available at: http://www.scottishmedicines.org.uk/files/advice/aflibercept_Eylea_FINAL_March_2013_Amended_030413_for_website.pdf. Accessed January 18, 2014.

9. Staton, Tracy. Eylea may beat Lucentis on price, but what of Avastin? Available at: http://www.fiercepharmac.com/story/eyela-may-beat-lucentis-price-what-avastin/2011-11-21. Accessed January 18, 2014.

10. National Institute for Health Care Excellence. Aflibercept solution for injection for treating wet age-related macular degeneration. July 2013. Available at: http://www.nice.org.uk/nicemedia/live/14227/64572/64572.pdf. Accessed January 20, 2014.

11. Coleman, HR. Age-related Macular Degeneration. The Lancet. November 2008. Available at: http://www.sciencedirect.com/science/article/pii/S0140673608617596. Accessed January 21, 2014.

12. Brown GC, Brown MM, Stein J. The Burden of Age-Related Macular Degeneration: A Value-Based Medicine Analysis. Transactions of the American Ophthalmological Society. December 2005. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1447589/. Accessed January 21, 2014.

13. Jager RD, Mieler WF, Miller JW. Age-related Macular Degeneration. The New England Journal of Medicine. N.p, 12 June 2008. Available at: http://www.nejm.org/doi/full/10.1056/NEJMra0801537. Accessed January 21, 2014.

14. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011 May;151(5):887-895.el. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21310390. Accessed January 23, 2014.

15. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.; January 23, 2014.

16. National Eye Institute. Facts About Age-Related Macular Degeneration. Available at: http://www.nei.nih.gov/health/maculardegen/armd_facts.asp#b. Accessed January 23, 2014.

17. Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW. Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. Available at: http://www.ncbi.nlm.nih.gov.authenticate.library.duq.edu/pubmed/22813448. Accessed January 23, 2014.

18. Centers for Medicare & Medicaid Services. Medicare Part B Drug Average Sales Price: Manufacturer reporting of Average Sales Price (ASP) data. April 16, 2013. Available at: http://www.cms.gov/McrPartBDrugAvgSalesPrice/01a17_2012ASPFiles.asp. Accessed January 27, 2014.

19. U.S. Food and Drug Administration. FDA approves Eylea for eye disorders in older people. November 18, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280601.htm. Accessed January 27, 2014.

20. Eylea (package insert). Regeneron Pharmaceuticals, Inc., Tarryntown, NY; November 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf. Accessed January 27, 2014.

20

21