PROPERTY Of THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`
`

`

`The 4 e-journals from Drug Discovery Today
`mol§' ___ ..
`"fooAY
`TECHNOLOGIES DISEASE
`MECHANISMS
`
`DISEASE
`MODELS
`
`Available online-only to Institutional
`subscribers via ScienceDirect.
`For more information go to
`www.drugdiscoverytoday.com
`
`_,,
`·;;, ScienceDirect
`
`' d'ct~M~~
`·
`Check 1f you have full-text access at www.sc1ence 1re
`·
`'
`.
`abstracts and recommend to your information specialist or libra nan
`today. Free abstracts to all articles provided to non-subscribing
`institutes. Full text articles are also available via Pay Per View.
`
`Online Access to Drug Discovery Today
`Full-text online access to Drug Discovery Today is provided free of
`charge as part of an individual's or laboratory's paid print subscription
`copy. Subscribers may claim their access by registering at
`http s:/ I cs.sc i en cedi rect.co m/ activate/ddt/ members.
`Free abstracts to all articles are provided to non-subscribing institutes.
`Full text articles are also available via Pay Per View.
`
`--
`
`The latest developments in drug discovery(cid:173)
`direct to your in box
`Keep up with our Editor's choice of latest papers across the literature in
`drug discovery by signing up fore-alerts to our Editor's Choice newsletter
`at http:/ /www.drugdiscoverytoday.com/echoice.htm.
`
`For more information about Drug Discovery Today and for the
`best guide to the latest innovations in drug discovery, visit
`www.drugdiscoverytoday.com
`
`For a full list of Elsevier products, visit www.elsevier.com
`
`DRUG DISCOVERY
`
`TODAY
`
`www.drugdiscoverytoday.com
`
`Orders, claims, and journal enquiries:
`
`please contact the Regional Sales Office nearest
`you:
`
`SciSearch/Science Citation Index Expanded
`Also covered in the abstract and citation
`database SCOPus•
`Full text available on ScienceDirect"
`
`St.Louis:
`
`Elsevier, Customer Service Department, 11830
`Westline Industrial Drive, St. Louis, MO 63146,
`USA; phone: (877) 8397126 [toll free within
`the USA];(+ 1) (314) 4537076 [outside the
`USA]; fax: ( + 1) (314) 5235153; e-mail:
`JournaiCustomerService-usa@elsevier.com
`
`Amsterdam:
`
`Advertising Enquiries
`
`Commercial Sales Department,
`Elsevier,
`32 Jamestown Road
`London, NW1 7BY, UK.
`Tel: +44 (O) 20 7611 4357
`Fax: +44 (0) 20 7611 4463
`Email: advertising@drugdiscoverytoday.com
`
`Elsevier, Customer Service Department, PO Box
`211,1000 AE Amsterdam, The Netherlands;
`phone:(+31) (20) 4853757;fax: (+31) (20)
`4853432; e-mail: JournalsCustomerServiceEMEA
`@elsevier.com
`
`Global Director of Sales
`
`Kevin Partridge
`Tel:+441865 843717
`Email: k.partridge@elsevier.com
`
`Advertising Sales
`
`USA-Mid-Atlantic/New England
`Victoria Macomber
`Tel:+ 1 (508) 928 1255
`Fax:+ 1 (508) 928 1256
`Email:v.macomber@elsevier.com
`
`USA-Mid West/South East/ Eastern Canada
`Inez Herrero
`Tel:+ 1 (585) 678 4395
`Fax:+l (212)4621915
`Email: i.herrero@elsevier.com
`
`USA-West Coast/Western Canada/Asia
`Lynne Stick rod
`Tel:+1 (415) 9319782
`Fax:+ 1 (415) 520 6940
`Email: l.stickrod@elsevier.com
`
`Advertising Artwork Production
`& Materials
`
`Tracey Miller
`Tel:+44 (0)1865 843808
`Email:adcopy@elsevier.com
`
`Marketing Enquiries
`
`Francesca Webb
`Tel: +44 1865 843244
`Email: F.Webb@elsevier.com
`
`Tokyo:
`
`Elsevier, Customer Service Department,4F
`Higashi-Azabu, 1-Chome Bldg, 1-9-15 Higashi(cid:173)
`Azabu, Minato-ku, Tokyo 106-0044, Japan;
`phone: (+81) (3) 5561 5037;fax: (+81) (3) 5561
`5047; e-maii:JournalsCustomerServiceJapan
`@elsevier.com
`
`Singapore:
`
`Elsevier, Customer Service Department, 3
`Killiney Road, #08-01 Winsland House I,
`Singapore 239519; phone: (+65) 63490222;
`fax: (+65) 6733151 0; e-mail: JournalsCustomer
`ServiceAPAC@elsevier.com
`
`Subscriptions are accepted on a prepaid basis
`only and are entered on a calendar year basis
`for institutions. Issues are sent by standard
`mail to all destinations. Claims for missing
`issues will be met, free of charge, if made
`within three months of the date of dispatch.
`Please send notices of change of address at
`least eight weeks in advance, including both
`old and new addresses.
`
`Abstracting & Indexing
`
`Biochemistry and Biophysics Citation Index
`BIOSIS/Biological Abstracts
`CAB Abstracts International
`Chemical Abstracts
`Current Contents (Life Science)
`EMBASE/Excerpta Medica
`Index Medicus
`International Pharmaceutical Abstracts
`Life Sciences Collection
`Medline/MEDLARS Online
`Science Citation Index
`
`Copyright Statement
`© 2010 Elsevier Ltd. All rights reserved.
`This journal and the Individual contributions contained
`in it are protected under copyright by Elsevier Ltd, and
`the following terms and conditions apply to their use:
`
`Photocopying
`Single photocopies of single articles may be made for
`personal use as allowed by national copyright laws.
`Permission of the publisher and payment of a fee is
`required for all other photocopying, including multiple
`or systematic copying, copying for advertising or
`promotional purposes, resale, and a!! forms of
`document delivery. Special rates are available for
`educational institutions that wish to make
`photocopies for non-profit educational classroom use.
`For more information on how to seek permissions
`visit www.elsevier.com/permissions or call: (+44) 1865
`843830 (UK)/(+ 1) 215 239 3804 (USA).
`
`Derivative Works
`Subscribers may reproduce tables of contents or
`prepare lists of articles including abstracts for internal
`circulation within their institutions. Permission of the
`publisher is required for resale or distribution outside
`the Institution.
`Permission of the publisher is required for all other
`derivative works, including compilations and
`translations.
`
`Electronic Storage or Usage
`Permission of the publisher is required to store or use
`electronically any material contained in this journal,
`including any article or part of an article. Except as
`outlined above, no part of this publication may be
`reproduced, stored In a retrieval system or transmitted
`in any form or by any means, electronic, mechanical,
`photocopying, recording or otherwise, without prior
`written permission of the publisher.
`
`Address permissions requests to: Elsevier Rights &
`Permissions Department, at the mail, fax and e-mail
`addresses noted above.
`
`Notice
`No responsibility is assumed by the Publisher for any
`injury and/or damage to persons or property as a
`matter of products liability, negligence or otherwise,
`or from any use or operation of any methods, products,
`instructions or ideas contained in the material herein.
`Because of rapid advances in the medical sciences,
`in particular, independent verification of diagnoses
`and drug dosages should be made.
`Although all advertising material is expected to
`conform to ethical (medical) standards, inclusion
`in this publication does not constitute a guarantee
`or endorsement of the quality or value of such
`product or of the claims made of it by its
`manufacturer.
`
`d
`,
`,
`USA mailing notice
`Drug Discovery Today (ISSN 1359-6446) IS publlshe
`24 times a year by Elsevier Science (P.O. Box 211, 1 OOO
`AE Amsterdam, The Netherlands). Periodical postage
`rate paid at Rahway, NJ and additional mailing offices.
`
`POSTMASTER: send address changes to Drug
`Discovery Today, 11830 Westline Industrial Drive,
`St.louis, MO 63146, USA
`
`AIRFREIGHT AND MAILING in the USA by
`Mercury International Ltd, 365, Blair Road, Avenel,
`NJ 07001, USA
`
`ua;
`
`u
`
`.:: • .
`
`9.
`
`"'
`
`This material was co-pied
`at th,e N LM and may b-e
`ri ht Laws
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`

`

`r~---···---·~·--;;:- -.,- ·. ··--.,------o··-··cc····~--· ---"~- ---· ··~· .. -···-··-·
`fil;ifJ f:M·"
`I:
`
`~{IE~Y~fJ>J ®1: [)[n_flifi=t§)fii_@LKEJiJ@ji~)[~: cn-_n@Js~r~~tiJ~xf'
`G[n~(~JJCil[~h0 G®T ut:;(iflcn-_~n csJEr;;c~~
`
`Owen A. Anderson, James W.B. Bainbridge and David T. Shima
`
`UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, United Kingdom
`
`Angiogenic diseases of the retina are the leading cause of blindness in the developed world. The
`development of 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 and in a safe and cost(cid:173)
`effective manner. A range of new anti-angiogenics are on the horizon, offering new and varied modes of
`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(cid:173)
`ditions that broadly affect three different age groups. In the
`developed world, ROI', DR and AMD are the largest causes of
`blindness in infants, adults of working age and the elderly, respec(cid:173)
`tively [1~3]. One feature they all have in common is the patho(cid:173)
`logical proliferation of new blood vessels (neovascularization). In
`DR and 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 vessels
`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 neovascularization in all
`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(cid:173)
`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 aimed at halting or reversing angiogenesis (anti-angio(cid:173)
`genics) can be used to treat both neovascularization and macular
`oedema.
`
`Corresponding author. Anderson, O.A. (o.anderson@ucl.ac.uk)
`
`272 www.drugdiscoverytoday.com
`
`Research into the field of ocular angiogenesis has increased
`rapidly, with a variety of treatments coming to clinical trial. From
`2001 to 2004, 25 clinical trials involving retinal anti-angiogenic
`molecular therapies were registered on the ClinicalTrials.gov reg(cid:173)
`istry (http:/ /clinicaltrials.gov). During the following four-year
`period (2005~2008), 273 clinical trials were registered, represent(cid:173)
`ing a more than tenfold increase (Figure 1).
`The resultant new therapies targeting the VEGF-A molecule
`have produced a paradigm shift in the management of neovas(cid:173)
`cular AMD. They have not only improved the prognosis drama(cid:173)
`tically, to a degree not seen before, but also altered patient
`expectations, clinical workload and the 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(cid:173)
`sive increase in capital investment and interest from larger phar(cid:173)
`maceutical companies. Whereas the turn of the millennium saw
`only a handful of biotech start-ups~ such as the developer of the
`fmt anti-VEGF for ocular use, Eyetech ~today there at least 30 or
`40 small biotechs fuelling drug development for blinding retinal
`disease.
`With the design of the new battery of drugs comes the question
`of how to 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 co-
`ied
`13~64'ift5N:!tf?~aJ1;~~fBfliflfnatter ''J 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2010.02.004
`~ui:J.ject USCopcyright Laws
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`

`

`Drug Discovery Today • Volume 15, Numbers 7/8 • April 2010
`
`REVIEWS
`
`Number of clinical trials registered each year with ClinicaiTrials.gov
`concerning anti-angiogenic molecular therapies for retinal disease
`
`80
`
`70 !
`
`60
`
`(f)
`
`""0
`~
`Q) u; 50
`"6>
`~
`(ij 40
`E
`0
`(D
`.0
`E
`:::l z
`
`30 :
`!
`
`20
`
`10
`
`0
`
`- .J
`
`2001
`
`2002
`
`I
`J
`2003
`
`2004
`
`2005
`
`Year
`
`2006
`
`2007
`
`2008
`
`2009
`
`Drug Discovery Today
`
`FIGURE 1
`Graph displaying the number of clinical trials registered with the ClinicaiTrials.gov registry (http://clinicaltrials.gov) each year between 2001 and 2009. Each entry
`concerns the 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(cid:173)
`mon off-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 molecular therapies for the treat(cid:173)
`ment of conditions such as AMD, DR, RVO and ROP. Only thera(cid:173)
`pies currently undergoing development in phase I-IV human
`clinical trials will be covered. A detailed discussion of individual
`treatments is beyond the scope of the paper. The second part will
`be the main focus of the review. Molecular therapies are only
`useful if they can reach the target tissue; therefore, we will discuss
`current and potential methods for the delivery of anti-angiogenic
`molecular therapies in the treatment of retinal disease.
`
`FDA-approved therapies
`l'egaptanib (Macugen; Eyetech/i'fizer, Inc.) was the fmt FDA(cid:173)
`approved anti-angiogenic treatment for neovascular AMD [6]. It
`is a 28-base PEGylated aptamer, which when folded correctly has a
`three-dimensional conformational shape that potently (dissocia(cid:173)
`tion constant ~so pM) and specifically binds to the major heparin(cid:173)
`binding isofonns of VEGF-A, blocking their action 17]. The apta(cid:173)
`mer's nucleotides have been modified to make it more resistant to
`degradation by endogenous endonucleases and exonucleascs. The
`Current and potential anti-angiogenic molecular
`addition of polyethylene glycol (PEG) moieties, or l'EGylation,
`increases the molecular weight and increases the half-life in the
`therapies
`vitreous (Macugen Information Sheet, http:/ /www.accessdata.fda.(cid:173)
`So far, only two anti-angiogenic drugs have received Food and Drug
`gov/clrugsatfda_docs/label/2006/0217S6s006,s007lbl.pdf). !3oth of
`Administration (FDA) and European Medicines Agency approval for
`these modifications increase the biological half-life of the drug IS].
`the treatment of neovascular AMD. To date, no molecular therapies
`Pegaptanib was designed to be delivered by intravitreal injection
`have received FDA approval for the treatment of diabetic macular
`every six weeks for the treatment of neovascular AMD, although its
`oedema (DMO), proliferative diabetic retinopathy (I'DR) or ROP.
`use for this condition has been largely superseded by ranibizumab
`Ozurdex (dexamethasone) has received FDA approval for the treat(cid:173)
`[6]. Pegaptanib is perceived to have a more robust effect in DMO,
`ment of !NO-associated macular oedema. Although it is not for(cid:173)
`however, and is in phase III clinical testing in Europe.
`mally considered to be an anti-angiogenic agent, it does have some
`Ranibizumab (Lucentis; Genentech/Novartis/Roche, Inc.) was
`intrinsic anti-angiogenic activity IS 1. The main reason for including
`the second FDA-approved anti-angiogenic treatment for neovas(cid:173)
`it, however, is that it is the fmt FDA-approved biodegradable
`cular AMD. Unlike pegaptanib (which is 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
`with high affmity for all isoforms of VEGF-A (unlike pegaptanib,
`trials (Table 1), and in the meantime, many compounds are often
`which only binds VEGF16S and VEGF189).
`used off-label. Here, we briefly discuss compounds that have
`This material was copcied
`at the N LM and may b,e
`~ubject USCopcyright Laws
`
`www.drugdiscoverytoday.com 273
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 4
`
`

`

`HEVIEIJJS
`
`Drug Discovery Today • Volume 15, Numbers 7/8 • April 2010
`
`_TA_Bl_E_1 _______________________________________ _
`Anti-angiogenic molecular therapies that are currently under clinical developmenta.
`Phase
`Mode of action
`Disease
`
`Name
`
`nAMD
`
`FDAJ
`pIll
`p II
`
`PI
`
`pIll
`
`p II
`
`pIll
`
`p II
`
`PI
`
`FDAJ
`pIll
`
`P II
`
`PI
`
`VEGF inhibitor
`VEGF inhibitor
`Tyrosine kinase inhibitor
`mTOR inhibitor
`nAChR inhibitor
`RTP801 inhibitor
`Corticosteroid
`NSAID
`VEGF inhibitor (viral delivery)
`PEDF inhibitor (viral delivery)
`PDGF inhibitor
`aS~ 1 integrin receptor inhibitor
`Complement inhibitor
`C-raf kinase inhibitor
`51 P inhibitor
`TORCl /TORC2 inhibitor
`TNFt~ inhibitor
`Anti VEGF receptor vaccine
`
`VEGF inhibitor
`PKC~ inhibitor
`Somatostatin analogue
`Corticosteroid
`MMP inhibitor
`
`VEGF inhibitor
`Corticosteroid
`PKC~ inhibitor
`Somatostatin analogue
`VEGF inhibitor
`mTOR inhibitor
`nAChR inhibitor
`RTP801 inhibitor
`TNFa inhibitor
`NSAID
`TNFa inhibitor
`NSAID
`VEGF inhibitor
`
`Corticosteroid
`VEGF inhibitor
`Corticosteroid
`VEGF inhibitor
`Corticosteroid
`Plasma kallikrein inhibitor
`
`Ranibizumab, pegaptanib
`Bevacizumab, VEGF trap
`AL-39324, pazopanib, TGl 00801, vatalanib
`Everolimus, sirolimus
`Mecamylamine
`PF-4523655
`Fluocinolone, triamcinolone
`Brofenac
`AAV2-sFLT01
`AdGVPEDF.ll D
`E10030
`JSM6427, volociximab
`ARC1905, POT-4
`iCo-007
`iSONEP
`Palomid 529
`Adalimumab, infliximab
`VEGF Rl & R2
`
`Bevacizumab, ranibizumab
`Ruboxistaurin
`Octreotide
`Triamcinolone
`Doxycycline
`
`Ranibizumab, pegaptanib, bevacizumab
`Fluocinolone, triamcinolone, dexamethasone
`Ruboxistaurin
`Octreotide
`VEGF trap
`Sirolimus
`Mecamylamine
`PF-4523655
`lnfliximab
`Nepafenac
`Adalimumab
`Brofenac
`MP0112
`
`Dexamethasone
`Bevacizumab, ranibizumab, VEGF Trap
`Triamcinolone
`Pegaptanib
`Fluocinolone
`Ecallantide
`
`PDR
`
`DMO
`
`RVO
`
`ROP
`
`VEGF inhibitor
`
`P II
`Bevacizumab
`''Therapies are grouped according to the latest phase of clinical development (FDA approval, phase 1-111 clinical trial) and their mode of action. Information is courtesy of the
`ClinicaiTrials.gov registry (http://clinicaltrials.gov) and was updated on 1 February 2010. To the best of the authors' knowledge, all the therapies described are still under development;
`however, development of certain drugs might have been cancelled without public knowledge.
`Abbreviations: DMO, diabetic macular oedema; FDA.J, 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-infiammatory drug; PDGF, platelet-derived growth factor; PDR. proliferative
`diabetic retinopathy; PEDF, pigment epithelium-derived factor; PKCf:l, protein kinase C beta; PIll, phase Ill; ROP, retinopathy of prematurity; RVO, retinal vein occlusion; S 1 P, sphingosine-1-
`phosphate; TNFtY, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor.
`against pegaptanib, better perceived clinical outcomes with
`Ranibizumab was designed to be delivered by intravitreal
`injection every four weeks [9, IOJ, although current practice is
`ranibizumab make blockage of all VEGF-A isoforms the current
`strategy of choice for AMD. Ranibizumab is also in clinical
`to administer three doses at four-week intervals, then to admin(cid:173)
`ister according to clinical need [llj. Importantly, it was the
`testing for !'DR, DMO and RVOs. Results seem promising in
`first treatment for neovascular AMD that resulted in a statisti(cid:173)
`the short term; however, in the long term, it needs to show
`cally significant improvement in visual acuity in all lesion
`benefit over and above that of laser therapy. Although laser
`subtypes [9, 10[. Although no head-to-head trial was performed
`therapy is potentially destructive, side-effects of long-term
`This material was copied
`at the NLM and may be
`~ubject US Copyright Laws
`
`274 www.drugdiscoverytoday.com
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`

`

`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
`llevacizumab (Avastin; Genentech/Roche, Inc.) is the monoclonal
`antibody from which ranibizumab was derived. Like ranibizurnab,
`bevacizumab binds all isoforms of VEGF-A. It was first licensed by
`the FDA for usc in metastatic colon cancer.
`The vitreous half-life of bcvacizumab is longer than that of
`ranibizumab [12]. llevacizumab, 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 /\MD. i\ head-to-head trial between bevacizumab
`and ranibizumab is currently underway both in the USA (CA1T;
`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 under clinical trial for the treatment of ROI'. VEGF is
`important in developmental angiogenesis. Ongoing clinical trials
`will need to assess whether temporary VEGF blockade in premature
`babies has any untoward effects on developmental angiogenesis.
`
`Promising treatments in end stage of development
`VEGF Trap is a recombinant protein made up of the domains of
`VEGFreceptors I and2and the Fe portion of human IgG [13]. The Fe
`portion increases the intravenous circulating half-life. VEGF Trap
`has a very high affmity for all isoforms of VEGF-A, as well as other
`VEGF family members ]14]. This broader range of binding is a key
`difference between it and ranibizumab. The administration ofVEGF
`Trap for the treatment of ncovascular AMD initially concentrated
`primarily on intravitreous delivery. Dose-limiting toxicity was seen
`during a phase I trial of intravenous administration for the same
`condition ]15 ]. The phase II study into intravitrcal use ofVEGF Trap
`for the treatment of neovascular AMD (Clinical Evaluation of Anti(cid:173)
`angiogenesis in the Retina Study, or CLEAR-IT-2) has recently
`reported fmal results showing a statistically significant reduction
`in retinal thickness, a statistically significant improvement in visual
`acuity and an acceptable safety profile following a 2.0 rng dosing
`regime (http://www. viva. vita.!Jaycrhcalthcare.corn/index. php'?id=
`36&tx_ttnews[tt_news]=12724&cHash=81f109cl02).
`Two phase III clinical trials arc underway (VIEW-I in the USA
`and Canada and VIEW-2 in Europe, Asia-l'acifJc, Japan and Latin
`America). These non-inferiority studies aim to compare efficacy of
`VEGF Trap against ranibizimab. Study completion is expected in
`2012 and 2011, respectively (http://clinicaltrials.gov/ct2/show/
`NCT00509795; http:/ /clinicaltrials.gov/ct2/show /NCT006373 77).
`The effect of VEGF Trap on DMO is in phase II clinical testing
`(http://clinicaltrials.gov/ct2/show/NCT00789477). Table 1 also
`includes other compounds in earlier stages of clinical development.
`Delivering these to the retina 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 arc adminis(cid:173)
`tered (Figure 2). Penetration of drugs into the eye is limited by
`structural and functional barriers. Structural barriers, such as
`corneal, conjunctival and scleral tissue, limit drug diffusion. Func(cid:173)
`tional barriers, such as rapid drug clearance by conjunctival ves(cid:173)
`sels, remove drugs before they can reach the target tissue.
`To design an effective 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(cid:173)
`ties but also its pharmacokinetic properties. Two important char(cid:173)
`acteristics of the chemical structure are molecular weight (MW)
`and lipophilicity ]16,17]. In general, ocular penetration is inver(cid:173)
`sely proportional to increasing MW and proportional to increasing
`lipophilicity. Therefore, inherently small lipophilic compounds
`penetrate the eye more easily. Examples of this include the
`aromatic compound pazopanib (GlaxoSmithKline, Inc.), 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 mode of delivery in humans
`for a range of compounds (under clinical trial) alongside their MW.
`Small molecules tend to be delivered topically or transsclerally
`because they can penetrate the eye more easily. Larger hydrophilic
`molecules, such as the currently licensee! VEGF-A inhibitor rani(cid:173)
`bizumab, tend to be delivered into the eye via an invasive intravi(cid:173)
`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 fmancial and manpower costs, and
`each injection presents a small risk of a blinding complication
`(intraocular infection or retinal detachment). In the VISION study
`assessing pegaptanib, the rates per injection of intraocular infec(cid:173)
`tion and retinal detachment were 0.16(XJ and 0.08%, respectively
`[6]. In the MARINA study assessing ranibizumab, the rate of
`presumed intraocular infection per injection was 0.05%. With
`each injection, the cumulative risk increases. Over the two years
`of the MARINA study, 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 how to do it safely and cost(cid:173)
`effectively over a prolonged period of time.
`
`lntravitreal delivery
`Intravitrcal 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(cid:173)
`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(cid:173)
`ing intravitreal drug delivery, leading to a reduced frequency of
`intervention.
`
`Issues regarding delivery of anti-angiogenic molecular
`therapies
`The eye is a structurally unique organ. As a result, drug delivery can
`be problematic. The retina receives a rich blood supply but is
`protected by a blood-retinal barrier at the endothelial cell and
`
`Iutruvitreal iujection
`MW and lipophilicity 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 from the vitreous more easily
`than large ones. This has led to small molecules, such as the
`
`at the N LM and may b,e
`~ubject US Copyright Laws
`
`www.drugdiscoverytoday.com 275
`
`Mylan Exhibit 1073
`Mylan v. Regeneron, IPR2021-00880
`Page 6
`
`

`

`REVIEWS
`
`Drug Discovery Today • Volume 15, Numbers 7/8 • April 2010
`
`TABLE 2
`---------------------------------------------------------------
`Mode of delivery of anti-angiogenic molecular therapies in human clinical trialsa.
`Structure
`
`Name
`
`Mode of action
`
`MW (kDa)
`
`Top
`
`TS
`
`lTV lnj
`
`lTV Imp
`
`Sys
`
`Amino acid based
`Adenoviral vector
`Adena-associated viral vector
`Cyclic peptide
`DARPin protein
`Fab fragment
`Monoclonal antibody
`
`Peptide
`
`Octapeptide
`Recombinant protein
`
`Nucleic acid based
`PEGylated aptamer
`
`Oligonucleotide
`
`Cortisol based
`Corticosteroid (synthetic)
`
`AdGVPEDF.11 D
`AAV2-sFLT01
`POT-4
`MP0112
`Ranibizumab
`Adalimumab
`Bevacizumab
`lnfliximab
`iSONEP
`Volociximab
`VEGFR1 and R2
`Ecallantide
`Octreotide
`VEGF Trap
`
`PEDF inhibitor
`VEGF inhibitor
`Complement inhibitor
`VEGF inhibitor
`VEGF inhibitor
`TNFa inhibitor
`VEGF inhibitor
`TNFa inhibitor
`S 1 P inhibitor
`a5f31 integrin receptor inhibitor
`Anti VEGFR vaccine
`Plasma kallikrein inhibitor
`Somatostatin analogue
`VEGF inhibitor
`
`ARC1905
`E10030
`Pegaptanib
`PF-4523655
`iCo-007
`
`Complement inhibitor
`PDGF inhibitor
`VEGF inhibitor
`RTP801 inhibitor
`C-raf kinase inhibitor
`
`Dexamethasone
`Fluocinolone
`Triamcinolone
`
`Corticosteroid
`Corticosteroid
`Corticosteroid
`
`Other synthetic organic compounds
`Mecamylamine
`Amidated bicyclo hydrocarbon
`AL-39324
`Aromatic compound
`Bromfenac
`Doxycycline
`Nepafenac
`Palomid 529
`Pazopanib
`TG100801
`Vatalanib
`Everolimus
`Sirolimus
`Ruboxistaurin
`JSM6427
`
`Macrocyclic bisindolylmaleimide
`Pyrrolidine derivative
`
`Macrolide
`
`nAChR inhibitor
`AL-39324
`NSAID
`MMP inhibitor
`NSAID
`TORC1/TORC2 Inhibitor
`Tyrosine kinase inhibitor
`Tyrosine kinase inhibitor
`Tyrosine kinase inhibitor
`mTOR inhibitor
`mTOR inhibitor
`PKCf3 inhibitor
`a5f31 integrin receptor inhibitor
`
`NA
`NA
`1.74
`NA
`48
`144
`149
`144
`NA
`146
`NA
`7.05
`1.02
`115
`
`NA
`NA
`~so
`
`~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
`
`0
`0
`
`0
`0
`
`•
`• •
`
`0
`0
`0
`
`•
`•
`
`0
`
`0
`0
`0
`0
`0
`
`• •
`
`• •
`
`0
`
`0
`
`•
`•
`
`•
`•
`•
`•
`•
`
`• •
`•
`
`•
`
`•
`•
`•
`
`•
`•
`
`•
`•
`•
`
`''Therapies are grouped according to their chemical structure because this is the feature most likely to influence their mode of delivery into the eye. A brief description of their mode of
`action is given. Molecular weight is presented alongside mode of drug delivery. information is courtesy of the ClinicaiTrials.gov registry (http://clinicaltrials.gov) and was updated on the 1
`February 2010. To the best of the authors' knowledge, all the therapies described are still under development; however, development of certain drugs may have been cancelled, without
`public knowledge.
`Abbreviations: lTV lnj, intravitreal injection; lTV 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; PKC[3, protein kinase C beta; 51 P,
`sphingosine-1-phosphate, Sys, systemic; Top, topical; TS, transscleral; TN Fe~ tumour necrosis factor alpha; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
`
`aptamer pegaptanib, being PEGylated, to increase their MW. Other
`mately 150-folcl and 1100-fold higher affmity for VEGF-A than
`ranibizumab and bevacizumab, respectively. Mathematical mod(cid:173)
`VEGF-A inhibitors have the intrinsic advantage of having a che(cid:173)
`eling, taking into account the dissociation constants of VEGF Trap
`mical structure with a high MW (bevacizumab, ranibizumab and
`VEGF Trap). VEGF Trap has an intravitreal half-life in the rabbit eye
`and ranibizumab, shows that 79 days after VEGF Trap injection,
`the intravitreal VEGF-binding activity should be comparable to
`of 4.79 days, compared with 2.88 days for ranibizumab and 4.32
`days for bevacizumab (Regeneron Pharmaceuticals, Tarrytown,
`ranibizumab at 30 days [22]. Theoretically, VEGF Trap might be
`New York, USA, unpublished) [12]. This is longer than expected
`given less frequently while maintaining efficacy. Whether this
`theory equates into practice is dependent on the outcome of
`considering its MW lies between that of ranibizumab and bevaci(cid:173)
`clinical trials.
`zumab (Table 2). There is another characteristic of VEGF Trap that
`Despite modifications and variations in the chemical structure
`might influence its clinical ability to maintain VEGF-A blockade
`promoting an increased intravitreal half-life, it will still be short
`after intravitreal injection: the dissociation constant (Kd). VEGF
`when compared with the duration of disease. Therefore, other
`trap has a dissociation constant for all VEGF-A isoforms of< 1 pM
`intravitreal delivery techniques, which delive