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 ofthe 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
`elderly in the developed worldl. The disorder
`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 of visionl.
`
`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)2. 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 visionz.
`
`Basis of discovery
`VEGF, which acts via two receptor tyrosine
`kinases, VEGFRI and VEGFR2, on the
`surface of endothelial cells, has a key role in
`physiological angiogenesis and pathological
`angiogenesisl. Recognition of the importance
`of VEGF in cancer and pathological ocular
`neovascularization led to the development
`of various strategies to inhibit VEGF
`signallingl.
`Pegaptanib (Macugen; Eyetech), an
`aptamer that targets the VEGF165 isoform,
`was approved by the FDA for neovascular
`AMD in 2004. However, its effectiveness
`
`in preventing deterioration ofvision 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 patientsz. In addition,
`bevacizumab (Avastin; Genentech/Roche),
`a monoclonal VEGF—specific antibody
`that has been developed and approved for
`the treatment ofvarious 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 ranibizumabl.
`
`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
`region}. Aflibercept (previously known as
`VEGF—Trap) was developed by optimizing
`the pharmacokinetic properties of such
`fusion proteins to improve their in viva
`anticancer activity3. In particular, these
`efforts focused on selecting portions of
`the extracellular domains of VEGFR1 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 potency}.
`
`Drug properties
`Aflibercept is a recombinant fusion protein
`that consists of portions of human VEGFRI
`and VEGFR2 extracellular domains fused to
`
`the Fc portion of human immunoglobulin G1
`[PEPE ‘3 ill. It binds strongly to VEGF and
`placental growth factor, and thereby inhibits
`the binding and activation of the cognate
`VEGFRS“.
`
`Clinical data
`
`The efficacy and safety of aflibercept
`(administered by intravitreal injection)
`were assessed in two randomized,
`double—masked, active—controlled trials
`in patients with wet AMD4. A total of
`
`NEWS 8 ANALYSIS
`
`2,412 patients were treated and evaluable
`for efficacy in the two trials (known as
`VIEWI and VIEW2)‘. In each of these
`trials, patients were randomly assigned in
`a 1212121 ratio to one of the following four
`treatment regimens: aflibercept 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;
`aflibercept 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 baselinei
`Secondary end points included the mean
`change in BVCA as measured by the ETDRS
`(Early Treatment Diabetic Retinopathy
`Study) score from the baseline4.
`After 52 weeks, the efficacy results for
`the two groups that received aflibercept at the
`2 mg dose were clinically equivalent to those
`from the ranibizumab group4. Of the patients
`who received 2 mg aflibercept every 8 weeks
`(after the initial three monthly closes),
`the proportions that maintained visual acuity
`were 94% in VIEWI and 95% in VIEW2
`
`ill. Of the patients who received 2 mg
`IPlEl:
`aflibercept every 4 weeks, the proportions
`
`that maintained visual acuity were 95% in
`VIEWI and 95% in VIEW2 [F
`'
`"2]. Of the
`patients who received ranibizumab, 94%
`maintained visual acuity in VIEWI,
`and 95% maintained visual acuity in
`VIEW2 [PEEP 4;.
`For the secondary end point of mean
`change in BVCA, of the patients who
`received 2 mg aflibercept every 8 weeks
`after three initial monthly doses, the mean
`changes were 7.9 in VIEWI and 8.9 in
`VIEW2 IEfEF. 4}. The mean changes for the
`groups that received 2 mg aflibercept every
`4 weeks were 10.9 in VIEWl and 7.6 in
`
`VIEW2, and for the groups that received
`ranibizumab the mean changes were 8.1
`in VIEWI and 9.4 in VIEW2 I'FEEF.
`f:_l.
`
`Indications
`
`Aflibercept is approved by the FDA for
`the treatment of patients with neovascular
`(wet) AMD4.
`
`> N
`
`ATURE EEK-115116}? | DRUG DISCOVERY
`
`VOHIME. 11 larmt 2012 |169
`
`1:35 2012 l‘fiacnilllan Publishers Ln’i'siie‘j. All rights reserved
`
`Regeneron Exhibit 1022.001
`
`

`

`NEWS 8 ANALYSIS
`
`ANALYSIS | 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 aflibercept 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 ranibizumabs.
`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 weeksi. For patients
`treated according to the labelling guidelines
`(based on the Phase III trial protocols), those
`
`receiving aflibercept require fewer office
`visits and injections than those receiving
`ranibizumab (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 aflibercept 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 aflibercept could be extended
`by an additional 2—4 weeks compared with
`ranibizmnab. 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, aflibercept (~$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 1 | 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 (Lucentis; Genentech/Roche), an antibody
`fragment specific forvascular endothelial growth factor (VEG F), 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 Lucentis (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 6 weeks, and with rapid uptake it has been predicted
`that US sales alone may reach $1 billion in 2016 (Nadeau, P. 5 Bishop, N. Cowen. Company Report on
`Regeneron Pharmaceuticals. 9 February 2012; Meacham, G. et al. 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 patientswith 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 ifsuccessful.
`These strategies include: E10030 (developed by Ophthotech), wh ich is an aptamer that targets
`platelet—derived growth factor B; h|—con1 (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 aflibercept 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 (aflibercept).
`The pivotal AMD trials for ranibizumab
`and aflibercept 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
`of VEGF 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 52224, USA.
`Seden Grippon is at IMS Health, 7 Harewood Avenue,
`London NW1 6J8, UK
`Peter Kirkpatrick is at Nature Reviews Drug Discovery.
`e-mails: Stewart. Michael@mago. edu-
`
`SGriDDon@imsca.com- D.kirkpatrick@nature.com
`{l r:- 1: If!
`I
`'
`
`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, 815e816 (2006].
`3. Holash J. et al. VEGFrTrap: a VEGF blocker with potent
`antitumor effects. Proc. NotlAcool. Sci. USA 99,
`11393413980002].
`4. US Food and Drug Administration. FDA labeling
`information — Eylea. FDA website [online],
`
`http:l/wwwaccessdata.fda.gov/drugsatfda docs/
`label/2011/125387lbl.9df(2011].
`5. Martin, D. F. et al. Ranibizumab and bevacizumab
`for neovascular agerrelated macular degeneration.
`N.Engl.J,Med.364,1897«1908(20111.
`Competing financial interests
`The authors declare competing financial interests: see Web
`version for details.
`
`
`wwwmawretomlreviewsfdrugdisc
`
`210 I APRIL 2012 | VOLUME. 11
`
`2012 Macmillan Publishers Lu'niiefi. All rights reserved
`
`Regeneron Exhibit 1022.002
`
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