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`
`

`

` Dalhveny of anti-angiogenic molecu
`
`
`
`| cliseace
`
`
`
` ler
`
`wh,
`ry
`“ a ~) fe Serer
`re oo
`TUNMetaonesWort (FEMME)
`
`
`Owen A. Anderson, James W.B. Bainbridge and David T. Shima
`
`UCL Institute of Ophthalmology, 11-43 Bath Street, Landon EC1V 9EL, United Kingdom
`
`
`
`Angiogenic diseases of the retina are the leading cause of blindness in the developed world. The
`developmentof anti-angiogenic molecular therapies has transformed the prognosis of these conditions,
`especially age-related macular degeneration. With these new treatments comes the new challenge of
`delivering an effective dosage to the retina, over a prolonged period of time andin a safe and cost-
`effective manner. A range of new anti-angiogenics are on the horizon, offering new and varied modesof
`drug delivery. In addition, a range of new sustained-release drug delivery technologies are being
`developed.
`
`Retinopathy of prematurity (ROP), diabetic retinopathy (DR) and
`age-related macular degeneration (AMD)are three different con-
`ditions that broadly affect
`three different age groups.
`In the
`developed world, ROP, DR and AMD are the largest causes of
`blindness in infants, adults of working age andthe elderly, respec-
`tively [1-3]. One feature they all have in common is the patho-
`logical proliferation of new blood vessels (neovascularization). In
`DRand ROP, these blood vessels originate from the retina, bleed
`into the vitreous and, subsequently, cause fibrosis,
`tractional
`retinal detachment and visual loss. In AMD, these blood vesscls
`normally originate from the choroid and invade the overlying
`retina. Subsequent bleeding and exudation can lead to scarring
`and permanent loss of central vision. The neovascularizationinall
`three conditions is driven by an angiogenic cascade, the trigger of
`which is believed to be relative hypoxia and oxidative stress.
`Vascular endothelial growth factor (VEGF-A) is a key component
`of this cascade but is by no means the only mediator of angiogen-
`esis.
`In addition to promoting neovascularization, angiogenic
`factors also promote increased vascular permeability. This can
`lead to sight-threatening oedema in the most sensitive part of
`the retina, the macula. This is a complication seen in both DR and
`AMD, as well as in retinal vein occlusions (RVOs). Molecular
`treatments aimedat halting or reversing angiogenesis (anti-angio-
`genics) can be used to treat both neovascularization and macular
`oedema.
`
`Corresponding author. Anderson, O.A.
`
`(o.anderson@uclac.uk)
`
`2720 www.drugdiscoverytoday.com
`
`Research into the field of ocular angiogenesis has increased
`rapidly, with a variety of treatments coming to clinicaltrial. From
`2001 to 2004, 25 clinical trials involving retinal anti-angiogenic
`molecular therapies were registered on the Clinical'Trials.gov reg-
`istry (http://clinicaltriats.gov). During the following four-year
`period (2005-2008), 273 clinical trials were registered, represent-
`ing a more than tenfold increase (Figure 1).
`The resultant newtherapies targeting the VEGF-A molecule
`have produceda paradigmshift in the management of neovas-
`cular AMD, They have not only improved the prognosis drama-
`tically,
`to a degree not seen before, but also altered patient
`expectations, clinical workloadandthe clinical costing of disease
`management. In addition to patient benefit, the success of the
`first back-of-the-eye pharmacotherapies has also triggered a mas-
`sive increase in capital investment andinterest fromlarger phar-
`maceutical companies. Whereas the turn of the millennium saw
`only a handful of biotechstart-ups - such as the developerof the
`first anti-VEGFfor ocular use, Eyetech ~ today thereat least 30or
`40 small biotechs fuelling drug development for blinding retinal
`disease.
`
`With the designof the new battery of drugs comes the question
`of howto deliver them to the target tissue. Delivering drugs to the
`retina is problematic, often resorting to invasive means such as
`repeated intraocular injections [4]. Newer and potentially safer
`methods are needed. This need has never been greater, owing to
`the rapid rise in new molecular entities becoming available for
`retinal disease.
`This material was copied
`135BASS AMOTAPRotter G 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2010.02.004
`Subject US Coowright Laws.
`
`
`
`
`Apotex Exhibit 1051
`Apotex Exhibit 1051
`Page 3 of 13
`Page 3 of 13
`
`

`

`
`Today
`
`
`
`
`80 !
`
`70 |
`
`60 }
`
`| |
`
`{
`50 |
`
`-
`
`40 |
`
`
`
`Nurnberoftrialsregistered
`
`aAeag
`=RN
`2PTEeoeS
`
`Drug Discovery Today * Volume 15,Numbers 7/8 + April 2010
`
`REVIEWS
`
`
`
`-
`
`:
`
`o
`
`—
`
`Number ofclinicaltrials registered each year with Clinica!Trials.gov
`concerning anti-angiogenic molecular therapiesfor retinal disease
`eae
`ne
`ence
`-
`-
`- we
`fe
`-
`®
`
`-
`
`boy
`po
`
`——
`
`se en ne
`
`-
`
`—~
`
`aoe
`
`-
`
`ce eee
`
`|
`
`30 | Se
`
`ae
`
`Qed | ad
`2001
`2002
`2003
`2004
`
`2006
`
`2005
`
`Year
`
`OrugDiscovery
`
`FIGURE 1
`
`Graphdisplaying the numberofclinical trials registered with the ClinicalTrials.gov registry (http://clinicaltrials.gov) each year between 2001 and 2009, Each entry
`concernsthe application of an anti-angiogenic molecular therapy in the treatment of either neovascular AMD, DR, RVO or ROP.
`
`received FDA approval and highlight certain compounds in com-
`monoff-label use or in the very latest stages of development.
`
`Scope
`This paper is divided into two parts. The first part will briefly
`highlight current and potential moleculartherapies for the treat-
`ment of conditions such as AMD, DR, RVO and ROP. Only thera-
`pies currently undergoing development in phase ]-IV human
`clinical trials will be covered. A detailed discussion of individual
`treatments is beyond the scope of the paper. The secondpart will
`be the main focus of the review. Molecular therapies are only
`useful if they can reachthe target tissue; therefore, we will discuss
`current and potential methodsfor the delivery of anti-angiogenic
`molecular therapies in the treatment of retinal disease.
`
`FDA-approved therapies
`Inc.) was the first FDA-
`Pegaptanib (Macugen; Lyetech/Pfizer,
`approved anti-angiogenic treatment for neovascular AMD {6]. It
`is a 28-base PEGylated aptamer, which whenfolded correctly has a
`three-dimensional conformational shape that potently (dissocia-
`tion constant ~50 pM) and specifically binds to the major heparin-
`binding isoforms of VEGE-A, blocking their action [7]. The apta-
`mer’s nucleotides have been modified to make it more resistant to
`degradation by endogenous endonucleases and exonucleases. The
`Current and potential anti-angiogenic molecular
`addition of polyethylene glycol
`(PEG) moieties, or PEGylation,
`increases the molecular weight and increases the half-life in the
`therapies
`vitreous (Macugen Information Sheet, http://www.accessdata.fda.-
`So far, only twoanti-angiogenic drugs havereceived Foodand Drug
`gov/drugsatfda_docs/label/2006/021756s006,s007\bI.pdf). Both of
`Administration (DA) and European Medicines Agency approvalfor
`the treatment of neovascular AMD.Todate, no molecular therapies
`these modificationsincrease the biological half-life of the drug [8].
`Pegaptanib was designed to be delivered by intravitreal injection
`have received FDA approval for the treatment of diabetic macular
`every six weeksfor the treatment of neovascular AMD, althoughits
`oedema (DMO), proliferative diabetic retinopathy (PDR) or ROP.
`Ozurdex (dexamethasone) has received FDA approval forthe treat-
`use for this condition has been largely superseded by ranibizumab
`ment of RVO-associated macular oedema. Althoughit is not for-
`[6]. Pegaptanib is perceived to have a more robust effect in DMO,
`however, andis in phase III clinical testing in Europe.
`mally consideredto be an anti-angiogenic agent, it does have some
`intrinsic anti-angiogenic activity [5]. The main reasonfor including
`Ranibizumab (Lucentis; Genentech/Novartis/Roche, Inc.) was
`it, however,
`is that it
`is the first FDA-approved biodegradable
`the second FDA-approved anti-angiogenic treatment for neovas-
`cular AMD. Unlike pegaptanib (whichis RNA based), ranibizumab
`sustained-release device for the treatment of angiogenic retinal
`is a humanized Fab fragment of a mouse monoclonal antibody
`disease. Numerous compounds are undergoing phase I-III clinical
`trials (Table 1), and in the meantime, many compoundsare often
`with highaffinity for all isoforms of VEGT-A (unlike pegaptanib,
`whichonly binds VEGF165 and VEGF189).
`used off-label. Here, we briefly discuss compounds that have
`This material was copied
`atthe NLM and marybe
`Subject US Copyright Laws.
`
`www.drugdiscoverytoday.com 273
`
`
`
`
`Apotex Exhibit 1051
`Apotex Exhibit 1051
`Page 4 of 13
`Page 4 of 13
`
`

`

`
`
`Drug Discovery Today* Volume 15, Numbers 7/8 * April 2010
`REVIEWS
`.
`a _
`
`TABLET
`:
`.
`ee
`
`Anti-angiogenic molecular therapies that are currently underclinical development’.
`
`Modeofaction
`Name
`Disease
`Phase
`
`nAMD
`FDA,/
`VEGF inhibitor
`Ranibizumab, pegaptanib
`P ill
`VEGF inhibitor
`Bevacizumab, VEGF trap
`P Ii
`Tyrosine kinase inhibitor
`AL-39324, pazopanib, TG100801, vatalanib
`mTORinhibitor
`Everolimus,sirolimus
`nAChR inhibitor
`Mecamylamine
`RTP801 inhibitor
`PF-4523655
`Corticosteroid
`Fluacinolone, triamcinolone
`NSAID
`Brofenac
`VEGFinhibitor(viral delivery)
`AAV2-sFLTO1
`PEDFinhibitor(viral delivery)
`AdGVPEDF11D
`PDGF inhibitor
`£10030
`a5f1 integrin receptorinhibitor
`JSM6427, volociximab
`Complementinhibitor
`ARC1905, POT-4
`C-raf kinase inhibitor
`iCa-007
`S1P inhibitor
`iSONEP
`TORC1/TORC2 inhibitor
`Palomid 529
`TNFe inhibitor
`Adalimumab, infliximab
`Anti VEGF receptor vaccine
`VEGF R17 & R2
`
`P|
`
`PDR
`
`DMO
`
`RVO
`
`ROP
`
`Pll
`
`Pil
`
`P Atl
`
`Pit
`
`PI
`
`FDA,/
`P ili
`
`PI
`
`PI
`
`VEGF inhibitor
`PKCB inhibitor
`Somatostatin analogue
`Corticosteroid
`MMP inhibitor
`
`VEGF inhibitor
`Corticosteroid
`PKCB inhibitor
`Somatostatin analogue
`VEGF inhibitor
`mTORinhibitor
`nAChR inhibitor
`RTP801 inhibitor
`TNFe inhibitor
`NSAID
`TNFainhibitor
`NSAID
`VEGF inhibitor
`
`Corticosteroid
`VEGF inhibitor
`Corticosteroid
`VEGF inhibitor
`Corticosteroid
`Plasma kallikrein inhibitor
`
`Bevacizumab, ranibizumab
`Ruboxistaurin
`Octreotide
`Triamcinolone
`Doxycycline
`
`Ranibizumab, pegaptanib, bevacizumab
`Fluocinolone, triamcinolone, dexamethasone
`Ruboxistaurin
`Octreotide
`VEGF trap
`Sirolimus
`Mecamylamine
`PF-4523655
`infliximab
`Nepafenac
`Adalimumab
`Brofenac
`MPOQ112
`
`Dexamethasone
`Bavacizumab, ranibizumab, VEGF Trap
`Triamcinolone
`Pegaptanib
`Fluocinolone
`Ecallantide
`
`Pil
`
`VEGF inhibitor
`
`Bevacizumab * Therapies are grouped according to the latest phase of clinical development (FDA approval, phase I-I!i clinical trial) and their mode ofaction. Information is courtesy of the
`ClinicalTrials.gov registry (http://clinicaltrials.gov) and was updated an 1 February 2010.To the best of the authors’ knowledge,all the therapies described are still under development;
`however, developmentofcertain drugs might have been cancelled without public knowledge.
`Abbreviations: DMO, diabetic macular oedema; FDA’, Food and Drug Administration approved; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; nAChR,nicotinic
`acetylcholine receptor; nAMD, neovascular age-related macular degeneration; NSAID, non-steroidal anti-inflammatory drug; PDGF, platelet-derived growth factor; PDR, proliferative
`diabetic retinopathy; PEDE pigment epithelium-derived factor; PKCB,protein kinase C beta; P I, phase lil; ROP, retinopathy of prematurity; RVO,retinal vein occlusion; S1P, sphingosine-1-
`phosphate; TNFa, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor.
`Ranibizumab was designed to be delivered by intravitreal
`against pegaptanib, better perceived clinical outcomes with
`ranibizumab make blockage of all VEGE-A isoforms the current
`injection every four weeks [9,10], although current practice is
`strategy of choice for AMD. Ranibizumab is also in clinical
`to administer three doses at four-week intervals, then to admin-
`ister according to clinical need [11]. Importanlly, it was the
`testing for PDR, DMO and RVOs. Results seem promising in
`first treatment for neovascular AMD that resulted in a statisti-
`the short term; however,
`in the long term,
`it needs to show
`benefit over and above that of laser therapy. Although laser
`cally significant
`improvement
`in visual acuity in all
`lesion
`subtypes [9,10]. Although no head-to-head trial was performed
`therapy is potentially destructive,
`side-cffects of long-term
`This material was copied
`atthe NLM and may be
`274—wwrw.drugdiscoverytoday.com
`Subject US Copyright Laws
`
`-
`
`
`
`
`Apotex Exhibit 1051
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`Page 5 of 13
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`
`

`

`
`
`Drug Discovery Today * Volume 15, Numbers 7/8 April 2010
`
`REVIEWS
`
`VEGF blockage, particularly in ischaemic diabetic retina, are not
`fully understood.
`
`Off-label therapies
`Bevacizumab (Avastin; Genentech/RKoche, lnc.) is the monoclonal
`antibody from which ranibizumab was derived. Like ranibizumab,
`bevacizumab binds all isoforms of VEGT-A. It wasfirst licensed by
`the FDA for use in metastatic colon cancer.
`The vitreous half-life of bevacizumab is longer than that of
`ranibizumab [12]. Bevacizumab, once alliquoted into unit doses,
`is considerably cheaper than ranibizumab per unit dose. As a
`result,
`it has been extensively used, off label, for the treatment
`of neovascular AMD. A head-to-head trial between bevacizumab
`
`and ranibizumab is currently underway both in the USA (CATT;
`http://clinicaltrials.gov/ct2/show/NCT00593450) and in the UK
`(IVAN;http://www.ivan-trial.co.uk/Default.aspx). These trials will
`provide high-quality efficacy data on bevacizumab.
`Bevacizumab is currently the only anti-angiogenic molecular
`therapy underclinical trial for the treatment of ROP. VEGF is
`important in developmental angiogenesis. Ongoing clinical trials
`will needto assess whether temporary VEGFblockade in premature
`babies has any untoward effects on developmental angiogenesis.
`
`Promising treatments in end stage of development
`VEGITrap is a recombinant protein made up of the domains of
`VEGFreceptors 1 and 2. andthe Fc portion of human IgG[13]. The Fe
`portion increases the intravenous circulating half-life. VEGI‘trap
`has a veryhighaffinity forall isoforms of VEGI-A,as well as other
`VEGTfamily members [14]. This broader range of binding is a key
`difference betweenit andranibizumab. The administration of VEGF
`Trap for the treatment of neovascular AMDinitially concentrated
`primarily onintravitreous delivery. Dose-limiting toxicity was secn
`during a phase I trial of intravenous administration for the same
`condition [15]. The phaseIT study into intravitreal use of VEGF Trap
`for the treatment of neovascular AMD(Clinical Evaluation of Anti-
`angiogenesis in the Retina Study, or CLEAR-IT-2) has recently
`reported final results showing a statistically significant reduction
`inretinal thickness, a statistically significant improvementinvisual
`acuity and an acceptable safety profile following a 2.0 mg dosing
`regime (http://www.viva.vita.bayerhealthcare.com/index.php?id=
`36&tx_ttnews[tt_news]=12724&cHash=81f109c102).
`Two phase If clinical trials are underway (VIEW-1 in the USA
`and Canada and VILW-2 in liurope, Asia-Pacific, Japan and Latin
`America). These non-inferiority studies aim to compare efficacy of
`VEGFTrap against ranibizimab. Study completion is expected in
`2012 and 2011,
`respectively (http://clinicaltrials.gov/ct2/show/
`NC1T00$09795; http://clinicaltrials.gov/ct2/show/NCT00637377).
`The effect of VEGI Trap on DMOis in phase II clinical testing
`(http://clinicaltrials. gov/ct2/show/NCT00789477), Table
`1
`also
`includes other compoundsin earlier stages of clinical development.
`Delivering these to theretina will be the next challenge, should the
`trials prove to be successful.
`
`retinal pigment epithelial (RPE) interfaces, The retina lies some
`distance from the ocular surface, where topical drugs are adminis-
`tered (Figure 2). Penetration of drugs into the eye is limited by
`structural and functional barriers. Structural barriers, such as
`corneal, conjunctival andscleral tissue, limit drug diffusion. 'unc-
`tional barriers, such as rapid drug clearance by conjunctival ves-
`sels, remove drugs before they can reach the target tissue.
`To designaneffective treatment, one needs to consider not only
`pharmacodynamics (what the drug does to the body) but also
`pharmacokinetics (what the body does to the drug). The chemical
`structure of a drug affects not only its pharmacodynamic proper-
`ties but also its pharmacokinetic properties. Two important char-
`acteristics of the chemical structure are molecular weight (MW)
`andlipophilicity [16,17]. In general, ocular penetration is inver-
`sely proportionalto increasing MW andproportional to increasing
`lipophilicity. Therefore, inherently small lipophilic compounds
`penetrate the eye more easily. Examples of this include the
`aromatic compound pazopanib (GlaxoSmithKline,
`lnc.), which
`is delivered topically in a current
`trial
`for
`the treatment
`of neovascular AMD (http://www.clinicaltrials.gov/ct2/show/
`NCT00612456). Table 2 displays the modeof delivery in humans
`fora range of compounds(underclinical trial) alongside their MW.
`Small molecules tend to be delivered topically or transsclerally
`because they can penctrate the eye more easily. Larger hydrophilic
`molecules, such as the currently licensed VEGI-A inhibitor rani-
`bizumab, tendto be delivered into the eye via aninvasive intravi-
`treal injection because of poor ocular penetration. Because the
`majority of ocular angiogenic diseases are chronic in nature, this
`invasive mode of drug delivery can be repeated many times.
`Repeated treatment incurs financial and manpowercosts, and
`each injection presents a small risk of a blinding complication
`(intraocularinfectionorretinal detachment), In the VISION study
`assessing pegaptanib, the rates per injection of intraocularinfec-
`tion andretinal detachment were 0.16%and 0.08%, respectively
`[6]. In the MARINA study assessing ranibizumab,
`the rate of
`presumed intraocular infection per injection was 0.05%. With
`cachinjection, the cumulative risk increases. Over the two years
`of the MARINAstudy, the cumulative rate increased to 1%[9].
`Therefore,
`issues arise concerning not only how to deliver the
`chosen drug to the target area but also howtodo it safely and cost-
`effectively over a prolonged periodof time.
`
`Intravitreal delivery
`Intravitreal delivery has proved to be the delivery method of
`choice for
`the current approved therapies for AMD. This
`bypasses both the blood-retinal barriers and structural/func-
`tional barriers. In sight-threatening disorders, physicians can
`also be sure that compliance is not an issue because the drug is
`delivered by the physician. There are many techniques under
`investigation that aim to enhance the duration of action follow-
`ing intravitreal drug delivery, leading to a reduced frequencyof
`intervention.
`
`Issues regarding delivery of anti-angiogenic molecular
`therapies
`The eye is a structurally unique organ. Asa result, drug delivery can
`be problematic. The retina receives a rich blood supply but is
`protected by a bload-retinal barrier at the endothelial cell and
`Thi
`atthe ALMand may be
`Subject US Copyright Laws
`
`Intravitreal injection
`MWandlipophilicity influence the penetration of drugs into the
`eye. These characteristics of a drug also influence its half-life in the
`vitreous [18,19]. Small drugs escape tromthe vitreous more easily
`than large ones. This has led to small molecules, such as the
`
`www.drugdiscoverytoday.com 275
`
`
`
`
`Apotex Exhibit 1051
`Apotex Exhibit 1051
`Page 6 of 13
`Page6 of 13
`
`

`

`ARC1905
`£10030
`Pegaptanib
`PF-4523655
`iCo-007
`
`Complement inhibitor
`PDGF inhibitor
`VEGF inhibitor
`RTP8O1 inhibitor
`C-raf kinase inhibitor
`
`Oligonucleotide
`
`Cortisol based
`Corticosteroid (synthetic)
`
`Macrolide
`
`Macrocyclic bisindolylmaleimide
`Pyrrolidine derivative
`
`Dexamethasone
`Fluocinolone
`Triamcinolone
`Other synthetic organic compounds
`Amidated bicyclo hydrocarbon
`Mecamylamine
`Aromatic compound
`AL-39324
`Bromfenac
`Doxycycline
`Nepafenac
`Palomid 529
`Pazopanib
`TG100801
`Vatalanib
`Everolimus
`Sirolimus
`Ruboxistaurin
`JSM6427
`
`Corticosteroid
`Corticosteroid
`Corticosteroid
`
`nAChR inhibitor
`AL-39324
`NSAID
`MMPinhibitor
`NSAID
`TORC1/TORC2 Inhibitor
`Tyrosine kinase inhibitor
`Tyrosine kinase inhibitor
`Tyrosine kinase inhibitor
`mTOR inhibitor
`mTOR inhibitor
`PKCB inhibitor
`581 integrin receptor inhibitor
`
`NA
`NA
`~50
`~13.3
`NA
`
`0.39
`0.45
`0.43
`
`0.17
`0.38
`0.33
`0.44
`0.25
`0.41
`0.47
`~0.57
`0.35
`0.96
`0.91
`0.47
`NA
`
`e
`°
`°e
`9
`e
`
`e
`
`°
`oe
`
`°
`e
`°
`
`°
`
`eo
`
`e
`e
`e
`°
`e
`
`e
`
`e
`
`e
`e
`
`e
`e
`e
`
`e “Therapies are grouped accordingto their chemical structure becausethisis the feature mostlikely to influence their modeof delivery into the eye. A brief description of their mode of
`
`REVIEWS
`Drug Discovery Today Volume15, Numbers 7/8 + April 2010
`
`CrnnCRRI
` HEEB
`ition
`
`TABLE 2
`/
`
`Modeof delivery of anti-angiogenic molecular therapies in humanclinical trials.
`
`Structure
`Name
`Modeof action
`MW (kDa)
`Top
`TS
`ITV Inj
`ITV Imp
`Sys
`
`Amino acid based
`Adenoviral vector
`AdGVPEDF.11D
`PEDFinhibitor
`NA
`°
`Adeno-associated viral vector
`AAV2-sFLTO1
`VEGF inhibitor
`NA
`e
`Cyclic peptide
`POT-4
`Complementinhibitor
`1.74
`e
`DARPin protein
`MPO112
`VEGF inhibitor
`NA
`°
`Fab fragment
`Ranibizumab
`VEGF inhibitor
`48
`e
`Monoclonal antibody
`Adalimumab
`TNFe inhibitor
`144
`e
`Bevacizumab
`VEGFinhibitor
`149
`°
`Infliximab
`TNFa inhibitor
`144
`°
`iSONEP
`S1P inhibitor
`NA
`e
`Volociximab
`«581 integrin receptor inhibitor
`146
`°
`VEGFR1 and R2
`Anti VEGFR vaccine
`NA
`°
`Ecallantide
`Plasma kallikrein inhibitor
`7.05
`Octreotide
`Somatostatin analogue
`1.02
`VEGF Trap
`VEGFinhibitor
`115
`
`@
`
`e
`
`e
`
`e
`°
`
`e
`
`
`
`Peptide
`
`Octapeptide
`Recombinant protein
`Nucleic acid based
`PEGylated aptamer
`
`action is given. Molecular weight is presented alongside modeofdrug delivery. Informationis courtesy of the ClinicalTrials.gov registry (http://clinicaltrials.gov) and was updated on the 1
`February 2010. To the best of the authors’ knowledge,all the therapies described arestill under development; however, developmentofcertain drugs may have been cancelled, without
`public knowledge.
`Abbreviations:ITVInj, intravitreal injection; ITV imp,intravitreal implant; MMP, matrix metalloproteinase; MTOR, mammalian target of rapamycin; MW, molecular weight; nAChR,nicotinic
`acetylcholine receptor; NSAID, non steroidal anti-inflammatory drug; PDGF, platelet derived growth factor; PEDF, pigment epithelium-derived factor; PKCB, protein kinase C beta; $1P,
`sphingosine-1-phosphate, Sys, systemic; Top, topical; TS, transscleral; TNFa, tumour necrosis factor alpha; VEGF, vascular endothelial growthfactor; VEGFR, VEGF receptor.
`
`aptamerpegaptanib, being PEGylated, to increase their MW, Other
`VEGE-A inhibitors have the intrinsic advantage of having a che-
`mical structure with a high MW (bevacizumab, ranibizumab and
`VEGFTrap). VEGFTrap has an intravitreal half-life in the rabbit eye
`of 4.79 days, compared with 2.88 days for ranibizumab and 4.32
`days for bevacizumab (Regeneron Pharmaceuticals, Tarrytown,
`NewYork, USA, unpublished) [12]. This is longer than expected
`considering its MWlies between that of ranibizumab and bevaci-
`zumab(Table 2). There is another characteristic of VEGF Trap that
`Despite modifications andvariations in the chemical structure
`might influenceits clinical ability to maintain VEGF-A blockade
`after intravitreal injection: the dissociation constant (Kd). VEGF
`promoting an increased intravitreal half-life, it will still be short
`when compared with the duration of disease. Therefore, other
`trap has a dissociation constant for all VEGF-A isoforms of <1 pM
`(compared with 0.15 nMand 1.1.nM for ranibizumab and beva-
`intravitreal delivery techniques, which deliver the chosen drug for
`a longer period of time, have been developed.
`cizumab, respectively) [15,20,21]. Therefore, it shows an approxi-
`This material was copied
`atthe NLM and maybe
`276=wwv.drugdiscoverytoday.com
`Subject US Copyright Laws
`
`mately 1S0-fold and 1100-fold higher affinity for VEGF-A than
`ranibizumab and bevacizumab, respectively. Mathematical mod-
`eling, taking into account thedissociation constants of VEGI' Trap
`and ranibizumab, shows that 79 days after VEGF Trap injection,
`the intravitreal VEGE-binding activity should be comparable to
`ranibizumab at 30 days [22]. Theoretically, VEGF Trap might be
`given less frequently while maintaining efficacy. Whether this
`theory equates into practice is dependent on the outcome of
`clinical trials.
`
`
`
`
`Apotex Exhibit 1051
`Apotex Exhibit 1051
`Page 7 of 13
`Page 7 of 13
`
`

`

`Drug Discovery Today * Volume 15, Numbers 7/8» April 2010
`
`REVIEWS
`
`Intravitreal
`
`Topical
`
`.
`Optic nerve
`
`NN,
`
`Subretinal
`
`’ yi
`
`e
`
`&
`=,
`
`
`
`
`
`
`
`Transscleral
`
`SCREEN
`aesfy
`
`|
`
`
`
`
`
`
`
`
`
`Vitreous
`
`Macula
`
`Retinaot
`
`Sclera
`
`QO=Ss
`
`Systemic
`DrugDiscoveryToday
`
`FIGURE 2
`
`Diagram showing the structure of the eye, alongside a variety of different methods of delivering anti-angiogenic molecular therapies to the retina.
`
`Modics, Inc.). ‘This is a non-ferrous metallic implant shaped like a
`corkscrew. The corkscrewregionis coated with a durable polymer
`matrix especially suited to the delivery of hydrophobic molecules.
`‘The implanttraverses the sclera, with the corkscrew regionlying in
`the vitreous cavity. This novel design makesit relatively easy to
`insert and remove. PhaseII trials assessing a triamcinolone-loaded
`Ivation’™ implantare u