Clinical Ophthalmology
`
`Open Access Full Text Article
`
`Dovepress
`
`open access to scientific and medical research
`
`R E v I E w
`
`Comparative effectiveness of aflibercept
`for the treatment of patients with neovascular
`age-related macular degeneration
`
`Michael Thomas1
`Shaymaa S Mousa2
`Shaker A Mousa1
`1Pharmaceutical Research Institute,
`Albany College of Pharmacy and
`Health Sciences, Albany, NY, USA;
`2The Johns Hopkins University,
`Baltimore, MD, USA
`
`Correspondence: Shaker A Mousa
`Pharmaceutical Research Institute,
`Albany College of Pharmacy and Health
`Sciences, 1 Discovery Drive, Rensselaer,
`New York 12144
`Tel +1 518 694 7397
`Fax +1 518 694 7567
`Email shaker.mousa@acphs.edu
`
`Abstract: Wet age-related macular degeneration (AMD) is the most common reason for vision
`loss in the United States. Many treatments, such as laser therapy and photodynamic therapies,
`have been used but their efficacy is limited. Emerging anti-vascular endothelial growth factor
`(VEGF) therapies are now considered the standard of care. Anti-VEGF agents inhibit angiogen-
`esis in the eye by suppressing abnormal blood vessel growth, leading to vision improvement.
`Ranibizumab and bevacizumab are two examples of anti-VEGF drugs that have been approved;
`both showed promise based on the visual acuity scale. Aflibercept, another new therapy known
`to trap VEGF and inhibit multiple growth factors, is promising not only because it can be taken
`bimonthly based on year 1 of the VIEW trials, but it can also be extended, as demonstrated in
`year 2 of the VIEW trials. Based on a cost–effect analysis, aflibercept is comparable to other
`leading therapies. This is a review of relevant clinical trials that have proven the non-inferiority
`and safety of aflibercept compared to the standard of care and its unique role in the current
`management of wet AMD.
`Keywords: aflibercept, VEGF, anti-VEGF, pegatanib, bevacizumab, ranibizumab, VIEW
`trials
`
`Introduction
`Wet age-related macular degeneration (AMD) is the leading cause of vision loss in
`adults over the age of 50 years in industrialized nations.1 Wet AMD has an increased
`incidence in females compared to males and is estimated to affect about 9 million people
`in the United States alone.1,2 As life expectancy increases and the number of senior
`citizens escalates, the number of people affected by wet AMD will continue to grow.
`Treatment options for macular degeneration have drastically improved over the
`past 15 years. In the 1980s, conventional heat laser therapy was used for wet AMD,
`but the repercussions (scarring of the eyes, permanent vision loss) outweighed the
`benefits in the case of subfoveal choroidal neovascular membrane (CNVM).3 In April
`2000, the US Food and Drug Administration (FDA) approved the first treatment for
`wet AMD: photodynamic therapy using verteporfin (Visudyne®; Novartis International
`AG, Basel, Switzerland) injections.3 This treatment was groundbreaking at the time
`because of the substantial decrease of vision loss in patients with subfoveal CNVM
`where heat laser therapy did poorly. In photodynamic therapy, laser treatment acti-
`vates verteporfin in the eye and terminates abnormal blood vessels.4 About one in
`six patients showed improved vision and a slowed progression of disease state with
`this therapy.5,6
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`which permits unrestricted noncommercial use, provided the original work is properly cited.
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`Although photodynamic therapy proved to be effective,
`its use slowly faded because of more effective anti-vascular
`endothelial growth factor (VEGF) therapies. In wet AMD,
`VEGF promotes angiogenesis, the growth of abnormal new
`blood vessels in the eye. Inhibiting VEGF causes a profound
`reduction in vision loss.7 The first anti-VEGF breakthrough
`therapy used for wet AMD was pegatanib (Macugen®;
`OSI Pharmaceuticals, Farmingdale, NY, USA/Pfizer, New
`York, NY, USA) followed by ranibizumab (Lucentis®;
`Genentech Inc, South San Francisco, CA, USA; Novartis
`International AG), which was approved by the FDA in June
`2006.7,8 Ranibizumab is a humanized monoclonal antibody
`fragment that binds to the VEGF.9 Ranibizumab provided
`greater visual acuity benefits than photodynamic therapy.
`Clinical trials have shown that bevacizumab (Avastin®;
`Genentech Inc; Roche, Basel, Switzerland), another anti-
`VEGF agent, is comparable in efficacy to ranibizumab, but
`it has not been approved for the treatment of wet AMD by the
`FDA as of yet. Bevacizumab showed similar efficacy com-
`pared to ranibizumab in the Comparison of AMD Treatment
`Trials (CATT), in which 60% of patients in both treatment
`groups gained visual improvements after 1 year of therapy.10
`This was an eye opener for physicians because both treat-
`ments are used monthly for the treatment of wet AMD, but
`bevacizumab is a fraction of the cost of ranibizumab, and
`therefore bevacizumab is prescribed for off-label use for
`patients who cannot afford ranibizumab. It is preferred by the
`majority of ophthalmologists as first-line therapy for AMD
`because it was first to market, has an overall lower cost, and
`it has a wider spectrum of reimbursable indications.
`The most recently approved treatment for wet AMD is
`aflibercept (Eylea®),11 co-developed by Sanofi-Aventis (Paris,
`France) and Regeneron Pharmaceuticals (Tarrytown, NY,
`USA) and approved by the FDA in November 2011. It works
`by binding tightly to three isoforms of growth factors (VEGF-
`A, VEGF-B, and placental growth factor).12 This agent has
`high binding affinity and a long half-life, which makes afi-
`bercept lucrative in terms of the possibility of cost savings
`and decreased frequency of use. This review will compare the
`effectiveness of aflibercept versus current therapies based on
`clinical trials for patients with neovascular (wet) AMD.
`
`Methodology
`Using databases such as PubMed, Medline, and
`ClinicalTrials.gov, data were collected to compare the effi-
`cacy of aflibercept versus other therapies in the treatment
`of wet AMD. Data were also collected from online sources
`such as the National Eye Institute,13 Macular Degeneration
`
`Association,2 other drug-dosing information webpages, and
`peer-review journals in order to give a fuller description of the
`pharmaceutical agents and their respective strengths.14,15
`
`Wet AMD pathophysiology
`To fully understand macular degeneration the key compo-
`nents that are affected need to be defined. The macula is
`responsible for fine tuning images within one’s visual field,
`and impairment of this function can lead to ensuing vision
`loss.16 Macular degeneration can be broken down into two
`subsets: dry (nonexudative) AMD and wet (exudative)
`AMD.17 Dry AMD occurs in about 85% of patients diagnosed
`with macular degeneration.12 The less serious of the two, dry
`AMD, is defined by drusen, small yellow deposits located
`near the retina.18 Dry AMD is categorized into stages based
`on the size of the drusen, the degree of vision loss, and retinal
`pigment epithelium hyperpigmentation and atrophy.18
`Wet AMD accounts for only 15% of all macular degen-
`eration, but causes up to 90% of blindness in individuals
`diagnosed with AMD.19 Individuals with wet AMD have
`weak blood vessels underneath the retina and macula, lead-
`ing to the leakage of fluids and blood into the eye and con-
`sequently causing macular damage.2,20 Cytokines and other
`inflammatory markers such as VEGF cause ischemia and
`inflammation, which leads to choroidal neovascularization
`(CNV).2 In CNV, new blood vessels grow into the subretinal
`pigment epithelium (type 1) or subretinal space (type 2) by
`breaking through the Bruch membrane, therefore leading to
`rapid vision loss of central vision and metamorphopsia on
`Amsler grid testing.16
`
`VEGF and its role in wet AMD
`VEGF, which occurs naturally in the body, works by
`stimulating chemical signals to promote the growth of new
`blood vessels in areas of the body that are oxygen deficient.21
`It does so by binding to a tyrosine kinase receptor, causing
`activation by phosphorylation (Figure 1). The VEGF recep-
`tor (VEGFR) consists of seven domains, and almost all
`activation occurs by binding to VEGFR-1 and VEGFR-2
`domains.22 Both VEGFR-1 and VEGFR-2 are located in
`the vascular endothelium, neurosensory retina, and retinal
`pigment epithelium cells.22 Activation of these receptors is
`the focal point of angiogenesis and vascular growth where
`the role of VEGFR-2, but not VEGFR-1, is documented. In
`other disease states, especially in cancer and tumor growth,
`overexpression of VEGF can lead to increased blood vessel
`growth, thus aiding tumor growth by providing an adequate
`oxygen supply.
`
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`Aflibercept for wet AMD treatment
`
`Vascular endothelial growth factor (VEGF) receptor binding and intracellular signaling
`
`VEGF
`
`VEGF
`
`VEGFR-2
`
`Vascular endothelial cell
`plasma membrane
`
`Vascular
`permeability
`
`Akt/PKB
`
`PI3K
`
`P
`
`P
`
`P
`
`P
`
`Endothelial cell
`survival
`
`p38MAPK
`
`Endothelial cell
`migration
`
`Raf
`
`MEK
`
`Erk
`
`Endothelial cell
`proliferation
`
`Figure 1 vEGF binds to the vEGFR-2 receptor, activating angiogenic response by phosphorylating domains within the receptor and below the endothelial membrane.
`Note: Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved. From: Rini BI, Small EJ. Biology and clinical development of vascular
`endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23(5):1028–1043.50
`Abbreviations: vEGF, vascular endothelial growth factor; vEGFR, vEGF receptor.
`
`Wet AMD is illustrated by the development of CNV. In
`CNV the innermost layer, the Bruch’s membrane, becomes
`inflamed and causes thickening of the vascular endothe-
`lium.23,24 Irregular growth of blood vessels under the macula
`supports this thickening and causes rapid central vision loss.
`Even in advanced stages of wet AMD partial vision is still
`retained, and severe loss of peripheral vision is uncommon.25
`The thickening and addition of new blood vessels leads to
`inflammation of the macula and eventual scarring of the retina
`and macula.26 The vessels are undeveloped and cause a leakage
`of fluids into the eye, leading to inflammation.
`CNV has a strong link to the increased expression of the
`VEGF gene.27 VEGF is often considered the main growth
`factor leading to the increased angiogenesis within the
`eye. VEGF maintains this vessel growth, along with other
`cytokines such as tumor necrosis factor-alpha and a host of
`interleukins.8 In wet AMD, inflammatory events that cause
`damage to the eye happen at a much faster rate than in dry
`AMD. Additionally, oxidative stress, complement factor H
`gene, and lifestyle factors such as diet and smoking might
`play a role in the etiology of AMD.28,29
`
`Current management of wet AMD
`Wet AMD treatment options continue to expand, with
`new and more effective agents. Photodynamic therapy is
`
`no longer recommended as a monotherapy regimen, but
` success has been shown in combination with pharmacologi-
`cal treatment.30 Currently, the standard of care for wet AMD
`is either a monthly dose of bevacizumab or ranibizumab.31
`Ranibizumab shows promising results in patients with wet
`AMD, improving vision in over one-third of the patients
`tested.32 It has relatively few side effects, such as eye irritation
`and redness, most of which are due to the injection itself.33
`Bevacizumab has shown non-inferior results when compared
`to ranibizumab in the CATTs.10 Many physicians tend to use
`this medication off-label due to its cost effectiveness versus
`ranibizumab.
`
`Aflibercept
`Aflibercept, unlike other VEGF inhibitors, is a recombinant
`protein in which VEGFR-1 (second binding domain) and
`VEGFR-2 (third binding domain) are attached to the Fc
` portion of human immunoglobulin G.34 Aflibercept differs
`from ranibizumab and bevacizumab in the mode of action
`by targeting VEGF via acting as a dummy receptor for
`VEGF, thus effectively inhibiting the angiogenic response.35
`This targeted response traps VEGF by binding to it even
`more tightly than its native receptor, triggering no angiogenic
`action from the VEGF and leaving it inactive.12 Without the
`cascade of angiogenic responses, fewer leaky vessels grow
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`into the macula. Aflibercept slows the progression of wet
`AMD, allowing patients to retain central vision for much
`longer.
`VEGF is categorized into VEGF-A, VEGF-B, VEGF-C,
`VEGF-D, VEGF-E, and placenta growth factor (PIGF).14,35
`Aflibercept, a fusion protein with binding domains from
`native VEGF receptors, binds with high affinity to VEGF-A,
`VEGF-B, PIGF1, and PIGF2.14 Preclinical studies demon-
`strated that aflibercept suppressed CNV in several animal
`models.34 The result of Phase III trials in humans showed
`effective short-term suppression of CNV in patients with
`exudative AMD and suggested longer durability of aflibercept
`compared with ranibizumab and bevacizumab.36,37 A pivotal
`Phase III VEGF trial in patients with wet AMD showed that
`aflibercept was noninferior to ranibizumab in preventing
`vision loss with comparable vision gains, safety, and perhaps
`at lower cost than ranibizumab.35
`
`Pharmacokinetics
`Aflibercept has the highest affinity for VEGF165 (Kd 0.49 Pm)
`compared to ranibizumab (Kd 46 Pm) and bevacizumab
`(Kd 58 Pm).19,37 Moreover, aflibercept is the only approved
`therapy for exudative AMD that inhibits VEGF-B and PIGF,
`giving it further claim to be a promising solution for wet
`AMD. Using aflibercept can potentially inhibit more angio-
`genic factors, possibly treating wet AMD more effectively
`than current therapies.
`The most captivating aspect of aflibercept is its extended
`half-life. According to reviews of aflibercept by Stewart8 and
`Stewart et al,35 the estimated serum half-life of intravitreal
`aflibercept is approximately 18 days versus ranibizumab
`and bevacizumab, which have half-lives of approximately
`4.75 days and 8.25 days, respectively. Stewart et al estimated
`intravitreal half-life for aflibercept to be 7.1 days.35 The reason
`for aflibercept’s unusually long half-life is due to its relatively
`large molecular weight of 115 Kd, which allows it to circulate
`within the eye for a longer time.22 Owing to its prolonged
`half-life, bimonthly dosing is possible and has altered current
`regimens of monthly dosing for exudative AMD. Dosing in
`such a way can provide immediate benefits to patients who
`have a difficult time with intravitreal dosage administration.
`Also with the extended dosing intervals, patients are less
`likely to face side effects from the dosage regimen and are
`less likely to have medication administration errors.
`
`Clinical evidence
`Aflibercept gained FDA approval after two randomized,
`double-blind Phase III trials were conducted: VIEW 1 and
`
`VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy and
`Safety in Wet Age-Related Macular Degeneration).36,37
`These studies were done to measure the safety and efficacy
`of aflibercept compared to the current standard of care for
`wet AMD, ranibizumab. It is important to note that the
`VIEW studies were run concurrently in different parts of
`the world and both studies had the same endpoints, treat-
`ment group population, and primary outcome measures. The
`only difference was that VIEW 1 was conducted in North
`America, whereas VIEW 2 was conducted internationally.
`Both trials had a set outcome goal at 52 weeks of treatment
`and the 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 scale compared to baseline
`measurements.36 There were four treatment groups into which
`patients were randomly placed (Table 1).36,37
`The results in all four treatment groups yielded similar
`conclusions. 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 noninfe-
`rior.36,37 The most pertinent data for the use of aflibercept
`show the success of aflibercept dosed every 8 weeks. In
`year 2 of the VIEW trials, when dosing was switched to
`as-needed, aflibercept again proved noninferior to ranibi-
`zumab.37 The safety analysis in both VIEW trials found
`aflibercept to be a well-tolerated drug.38 When compared
`to ranibizumab, the safety profile was of approximately
`equivalent measures.36,39 In conclusion, aflibercept dosed
`intravitreally each month or every 2 months after three
`initial monthly doses resulted in comparable efficacy and
`safety to monthly ranibizumab. Side effects, either ocular or
`systemic, were similar across treatment groups, with no dif-
`ferences between aflibercept administered every 2 months
`and monthly ranibizumab.38
`These studies provided a foundation for using aflibercept
`therapy in wet AMD. Potential advantages of aflibercept
`
`Table 1 Treatment groups in the vIEw 1 and vIEw 2 clinical trials
`Drug
`Dosage
`Dosing frequency (n)
`(intravitreal
`(mg)
`(every n weeks for
`injection)
`52 weeks, then as needed)
`0.5
`Ranibizumab
`4
`0.5
`Aflibercept
`4
`2
`Aflibercept
`4
`2
`Aflibercept
`8
`Abbreviation: VIEW, VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet
`Age-Related Macular Degeneration.
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`Aflibercept for wet AMD treatment
`
`might include extended dosing periods that might lead to
`fewer hospital and physician visits and less financial cost to
`the patient due to less frequent dosing.
`
`Cost–effect analysis
`The recommended dose for aflibercept is 2 mg every 4
`weeks for 3 months, followed by 2 mg every 8 weeks.40
`More frequent dosing was not found to be advantageous
`to patients.41 Ranibizumab is currently dosed at 0.5 mg
`monthly as per guidelines.9 Although there are only three
`FDA-approved therapies for wet AMD, it should also be
`noted that bevacizumab is the most-used therapy for wet
`AMD because of its relatively low cost and comparable
`efficacy to ranibizumab. Bevacizumab is most often dosed
`at 1.25–2.5 mg per monthly treatment for macular degen-
`eration.42 All three therapies are considered to have equal
`efficacy across the board based on studies and clinical data
`that have been evaluated.31
`For one treatment of ranibizumab, the cost of medication
`totals USD1950 per vial/dose.43 If a patient is on ranibizumab
`for 1 year, the cost of therapy is USD23,400 (12 doses).44 For
`aflibercept, due to the less intensive dosing regimen, clear
`savings can be seen. A single dose/treatment of aflibercept
`costs approximately USD1850 and the yearly cost averages
`USD14,800 (eight doses). Bevacizumab is the cheapest,
`costing roughly USD50 per dose/treatment. A yearly treat-
`ment of one bevacizumab dose per month would cost about
`USD600.45,46 Not included in these cost analyses is the cost
`of treatment (physician visits, optical coherence tomography
`costs, and injection costs), which varies from center to center
`and is not readily available.
`
`Other indications for aflibercept
`Experiments to use intravitreal aflibercept for the treatment
`of diabetic macular edema have shown promising results
`in clinical trials.47–49 The results of a Phase II clinical trial
`showed that anti-VEGF therapies improved vision compared
`to the standard of care for diabetic macular edema, which is
`photocoagulation therapy.
`
`Conclusion
`It is obvious that aflibercept has a role in macular degeneration
`therapy, but its use is currently limited. The major limiting
`factor is the cost of the therapy and administration. With
`bevacizumab already being the most-used anti-VEGF drug for
`macular degeneration, even though it is being used off-label,
`its use is not anticipated to subside. The CATT research group
`found the monthly use of either bevacizumab or ranibizumab
`
`results in the same visual acuity outcome.10 Such comparisons
`have raised questions about which drug to choose. Physicians
`tend to prescribe bevacizumab due to its extremely low cost
`compared to aflibercept and ranibizumab.
`Aflibercept is an intriguing choice for patients who have
`a difficult time with the intravitreal injections. After the ini-
`tial three loading doses, bimonthly dosing can be beneficial
`for noncompliant patients. Compared to current treatments,
`aflibercept has shown equal efficacy and safety. Its unique
`pharmacokinetics and binding to multiple receptors may
`allow it to expand its role in other disease states as well.
`
`Disclosure
`The authors report no conflicts of interest in this work.
`
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