FRESH FROM THE PIPELINE
`Aflibercept
`
`Michael W Stewart, Seden Grippon and Peter Kirkpatrick
`
`In November 2011, aflibercept
`(Eylea; Regeneron Pharmaceuticals),
`a recombinant fusion protein that binds
`to members of the vascular endothelial
`growth factor family, was approved by
`the US Food and Drug Administration
`(FDA) for the treatment of patients
`with neovascular age-related macular
`degeneration.
`
`Age-related macular degeneration (AMD)
`is the leading cause of blindness among the
`• The disorder
`elderly in the developed world1
`is classified into two forms: non-neovascular
`(dry) AMD and neovascular (wet) AMD.
`The neovascular form involves abnormal
`neovascularization under the macula (the
`central part of the retina), which leads to
`leakage of blood or serum that damages the
`macula and causes deterioration in sight.
`Although only -10% of patients with AMD
`have the neovascular form, it accounts for
`-90% of the severe loss ofvision1
`•
`Treatment strategies for neovascular
`AMD have progressed substantially
`in the past decade or so, from thermal
`laser photocoagulation to specific
`pharmacotherapies, in particular those that
`inhibit vascular endothelial growth factor
`(VEGF), which is important in choroidal
`neovascularization (CNV)' . In 2000,
`photodynamic therapy with verteporfin
`(Visudyne; QLT/Novartis), which causes
`selective destruction of CNV lesions,
`became the first FDA-approved treatment for
`neovascular AMD. However, in most patients
`photocoagulation and photodynamic therapy
`only slow the deterioration in vision2
`
`•
`
`Basis of discovery
`VEGF, which acts via two receptor tyrosine
`kinases, VEGFRl and VEGFR2, on the
`surface of endothelial cells, has a key role in
`physiological angiogenesis and pathological
`• Recognition of the importance
`angiogenesis 1
`ofVEGF in cancer and pathological ocular
`neovascularization led to the development
`of various strategies to inhibit VEGF
`signalling 1
`•
`Pegaptanib (Macugen; Eyetech), an
`aptamer that targets the VEGF 165 isoform,
`was approved by the FDA for neovascular
`AMD in 2004. However, its effectiveness
`
`in preventing deterioration of vision is not
`as great as that of ranibizumab (Lucentis;
`Genentech/Roche), a recombinant
`VEGF-specific antibody fragment that
`was approved by the FDA for neovascular
`AMD in 2006 following trials showing that
`it not only maintained visual acuity in more
`than 90% of patients but also improved it
`in around a third of patients2
`• In addition,
`bevacizumab (Avastin; Genentech/Roche),
`a monoclonal VEGF-specific antibody
`that has been developed and approved for
`the treatment of various cancers, has been
`widely used off-label for the treatment
`of neovascular AMD following studies
`indicating its effectiveness, largely owing
`to its lower cost than ranibizumab 1
`•
`Another strategy that has been developed
`to block the activity of cytokines such as
`VEGF is to prevent them from binding to
`their normal receptors by administering
`soluble decoy receptors that are constructed
`by fusing binding domains of the normal
`receptors to an immunoglobulin constant
`• Aflibercept (previously known as
`region3
`VEGF-Trap) was developed by optimizing
`the pharmacokinetic properties of such
`fusion proteins to improve their in vivo
`anticancer activity' . In particular, these
`efforts focused on selecting portions of
`the extracellular domains of VEGFRl and
`VEGFR2 that were anticipated to lead to
`fusion proteins with reduced propensity
`for nonspecific interactions with the
`extracellular matrix, as well as improved
`binding potency3
`
`•
`
`Drug properties
`Aflibercept is a recombinant fusion protein
`that consists of portions of human VEGFRl
`and VEGFR2 extracellular domains fused to
`the Fe portion of human immunoglobulin G 1
`(REFS 3.4]. It binds strongly to VEGF and
`placental growth factor, and thereby inhibits
`the binding and activation of the cognate
`VEGFRs3
`
`·".
`
`Clinical data
`The efficacy and safety of a±libercept
`(administered by intravitreal injection)
`were assessed in two randomized,
`double-masked, active-controlled trials
`in patients with wet AMD4
`• A total of
`
`NEWS & ANALYSIS
`
`2,412 patients were treated and evaluable
`for efficacy in the two trials (known as
`VIEW! and VIEW2)". In each of these
`trials, patients were randomly assigned in
`a 1: 1: 1: 1 ratio to one of the following four
`treatment regimens: a±libercept at a dose of
`2 mg administered every 8 weeks, following
`three initial monthly doses; aflibercept at a
`dose of 2 mg administered every 4 weeks;
`a±libercept at a dose of 0.5 mg administered
`every 4 weeks; and ranibizumab at a dose of
`0.5 mg administered every 4 weeks' . In both
`trials, the primary efficacy end point was
`the proportion of patients who maintained
`vision, defined as losing fewer than 15 letters
`of best corrected visual acuity (BVCA)
`at 52 weeks compared with the baseline•.
`Secondary end points included the mean
`change in BVCA as measured by the ETD RS
`(Early Treatment Diabetic Retinopathy
`Study) score from the baseline".
`After 52 weeks, the efficacy results for
`the two groups that received a±libercept at the
`2 mg dose were clinically equivalent to those
`from the ranibizumab group". Of the patients
`who received 2 mg aflibercept every 8 weeks
`(after the initial three monthly doses),
`the proportions that maintained visual acuity
`were 94% in VIEW! and 95% in VIEW2
`[REF 4]. Of the patients who received 2 mg
`atlibercept every 4 weeks, the proportions
`that maintained visual acuity were 95% in
`VIEW! and 95% in VIEW2 [REF. 4] . Of the
`patients who received ranibizumab, 94%
`maintained visual acuity in VIEW!,
`and 95% maintained visual acuity in
`VIEW2 [REF 4).
`For the secondary end point of mean
`change in BVCA, of the patients who
`received 2 mg aflibercept every 8 weeks
`a±ter three initial monthly doses, the mean
`changes were 7.9 in VIEW! and 8.9 in
`VIEW2 [REF 4). The mean changes for the
`groups that received 2 mg a±libercept every
`4 weeks were 10.9 in VIEW! and 7.6 in
`VIEW2, and for the groups that received
`ranibizumab the mean changes were 8.1
`in VIEW! and 9.4 in VIEW2 [REF 4].
`
`Indications
`Aflibercept is approved by the FDA for
`the treatment of patients with neovascular
`(wet) AMD".
`
`~
`
`NATURE REVIEWS I DRUG DISCOVERY
`
`VOLUM E 11 I APRIL 20 12 I 269
`
`© 2012 Macmilla n Publishers Limited . All rights reserved
`
`Regeneron Exhibit 1022.001
`
`

`

`NEWS & ANALYSIS
`
`ANALYSIS I AGE-RELATED MACULAR DEGENERATION
`
`.. Analysing issues in the treatment of AMD is
`Michael W Stewart, M.D., Chair, Department
`of Ophthalmology, Mayo Clinic, Mayo School
`of Medicine, Jacksonville, Florida, USA.
`
`The recent approval of atlibercept provides
`ophthalmologists and patients with a third
`excellent anti-VEGF therapy for AMD.
`Whereas bevacizumab was developed for
`the treatment of advanced solid tumours
`and has been used off-label for AMD and
`other ophthalmic disorders, ranibizumab
`was developed exclusively for ophthalmic
`conditions. The pivotal Phase III trials for
`ranibizumab2 established monthly injections
`as the standard against which other drugs and
`dosing regimens have since been compared.
`Despite this, many physicians have preferred
`low-cost bevacizumab (-US$50 per dose)
`over the higher-cost ranibizumab (-$1,950
`per dose) for the initial treatment of AMD,
`although only recently has bevacizumab
`(administered monthly) been shown to
`produce improvements in vision that are
`comparable to ranibizumab5
`The year 1 results of the Phase III VIEW
`trials for aflibercept demonstrated for the
`first time that injections of an anti-VEGF
`drug every 8 weeks (aflibercept; 2 mg)
`improve vision comparably to ranibizumab
`administered every 4 weeks<. For patients
`treated according to the labelling guidelines
`(based on the Phase III trial protocols), those
`
`•
`
`receiving a±libercept require fewer office
`visits and injections than those receiving
`ranibizwnab (7 versus 12) during the first year.
`To reduce the burden of clinic visits
`and intravitreal injections, however, most
`physicians use 'treat and observe' or 'treat
`and extend' strategies. Although the VIEW
`trials did not strictly evaluate either of these
`strategies, in the second year a 'treat and
`observe' strategy with a 3-month cap (that
`required injection) was used. During year 2,
`the developer Regeneron has reported that
`both ranibizumab and a±libercept performed
`well, as patients receiving either drug lost
`an average of only 0.8 letters of visual acuity.
`Compared with ranibizumab, aflibercept
`showed slightly better durability for each group
`studied, suggesting that the duration between
`injections for a±libercept could be extended
`by an additional 2-4 weeks compared with
`ranibizwnab. However, doubling the injection
`intervals, as suggested by the year 1 result,
`is probably not achievable for most patients.
`For patients treated according to the
`VIEW protocols, a±libercept ( -$1,850 per
`dose) reduces costs and patient visits by
`42% compared with ranibizumab. For those
`on 'treat and observe' or 'treat and extend'
`regimens, the savings will be considerably
`lower. As physicians gain experience with
`aflibercept, it is possible that many could
`switch from ranibizumab for cases when a
`high-affinity anti-VEGF drug is indicated.
`
`Box 11 Market for age-related macular degeneration
`
`Analysing the market for therapies for wet age-related macular degeneration (AMD) is Seden
`Grippon, IMS Health, London, UK.
`
`The global market for wet AMD therapies is currently worth -US$4 billion annually, according to data
`from IMS Health. This market is dominated by ranibizumab (Lucent is; Genentech/Roche), an antibody
`fragment specific for vascular endothelial growth factor (VEGF), which accounts for-98% of sales.
`Aflibercept (Eylea, Regeneron Pharmaceuticals), a fusion protein that also targets VEGF, was
`launched into this market in the United States in November 2011, following its approval by the
`US Food and Drug Administration. In Europe, aflibercept is at the preregistration phase. Its less
`frequent dosing compared with Lucent is (see main text) appears to be perceived by physicians as
`a moderate advantage, and analysts predict that its uptake will be robust, potentially taking more
`than half of Lucentis's market share in the next 3 years; in February 2012, the number of patients
`on Eylea had grown by 50% over the previous 6weeks, and with rapid uptake it has been predicted
`that US sales alone may reach $1 billion in 2016 (Nadeau, P. & Bishop, N. Cowen. Company Report on
`Regeneron Pharmaceuticals. 9 February 2012; Meacham, G. eta!. JP Morgan Report on Regeneron
`Pharmaceuticals. 13 February 2012). Aflibercept is also in development for other ophthalmic
`indications, including diabetic macular oedema, central retinal vein occlusion, myopic choroidal
`neovascularization and branch retinal vein occlusion. Finally, as only-30% of patients with wet AMD
`experience a significant improvement in vision with anti-VEGF therapy, alternative strategies that
`are currently being investigated in Phase II trials have a high chance of physician uptake if successful.
`These strategies include: E10030 (developed byOphthotech), which is an aptamer that targets
`platelet-derived growth factor B; hl-conl (developed by Iconic Therapeutics), which is a fusion protein
`that targets tissue factor; and mesenchymal precursor cells (developed by Mesoblast).
`
`Despite the savings resulting from less
`frequent a±libercept therapy, however,
`monthly bevacizumab remains the less
`expensive alternative. When choosing an
`anti-VEGF drug, physicians and patients
`will need to consider the trade-offs between
`lower costs (bevacizumab) versus less
`frequent visits and injections (a±libercept).
`The pivotal AMD trials for ranibizumab
`and a±libercept all showed that regularly
`administered anti-VEGF injections improve
`visual acuity by 8-11 letters over the study
`period, leading many physicians to believe that
`anti-VEGF monotherapy has hit an efficacy
`'ceiling'. Future anti-VEGF agents, such as the
`designed ankyrin repeat protein (DARPin)
`MP0112 (which has completed Phase I/II
`trials), will need to be differentiated from
`current drugs based on improved durability.
`Improving the efficacy of AMD treatment
`by reducing the size of the neovascular
`complex, thereby improving the anatomy and
`function of the photoreceptors, retinal pigment
`epithelium and choriocapillaris, will probably
`require combination drug therapy. Several
`drugs that inhibit the actions of molecules that
`are crucial to the growth of the neovascular
`complex -
`including integrins, complement
`component 5 and platelet-derived growth
`factor - are in various stages of development.
`Effective combination therapy, however,
`is still several years away. Given the crucial role
`ofVEGF in wet AMD and the demonstrated
`efficacy of the currently available drugs,
`anti-VEGF therapy will remain an important
`component of AMD therapy for many years.
`
`Michael W Stewart is at the Department of
`Ophthalmology, Mayo Clinic, Mayo School of Medicine,
`Jacksonville, Florida 32224, US4.
`Seden Grippon is at IMS Health, 7 Harewood Avenue,
`London NW/ 6JB, UK.
`Peter Kirkpatrick is at Nature Reviews Drug Discovery.
`
`e-mails: Stewart.Michael@mauo.edu·
`SGrippon@imsca.com· p.kirkpatrick@nature.com
`
`doi: I0.1038/nrd3700
`
`1. Stewart, M. W. The expanding role of vascular
`endothelial growth factor inhibitors in ophthalmology.
`Mayo Clin. Proc. 87, 77-88 (2012).
`2. Narayanan , R. et al. Ranibizumab. Nature Rev. Drug
`Discov 5, 815-816 (2006).
`3. Holash J. et al. VEGF-Trap: a VEGF blocker with potent
`antitumor effects. Proc. Natl Acad. Sci. USA 99,
`11393-11398 (2002).
`4. US Food and Drug Administration. FDA labeling
`information - Eylea. FDA website lonline].
`http://www.accessdata.fda.gov/drugsatfda docs/
`label/2011/1253871bl.pdf (201 1 ).
`5. Martin, D. F. et al. Ranibizumab and bevacizumab
`for neovascular age-related macular degeneration.
`N. Engl. J. Med. 364, 1897-1908 (2011).
`
`Competing financial interests
`The authors declare competing financial interests: see Web
`version for details.
`
`270 I APRI L 20 12 1 VO LUME 11
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`www.natu re .com/rev iews/d rugdisc
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`© 2012 Macmilla n Publishers Limited . All rights reserved
`
`Regeneron Exhibit 1022.002
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