[Downloaded free from http://www.ijo.in on Thursday, September 17, 2020, IP: 12.130.14.78]
`November - December 2007
`
`Symposium
`
`437
`
`A comparative debate on the various anti-vascular endothelial growth
`factor drugs: Pegaptanib sodium (Macugen), ranibizumab (Lucentis) and
`bevacizumab (Avastin)
`
`Manish Nagpal, FRCS; Kamal Nagpal, MS; P N Nagpal, MS, FACS
`
`Wet age-related macular degeneration and diabetic retinopathy are pathological consequences of vascular
`endothelial growth factor (VEGF) release as a reaction to de(cid:222) ciency of oxygen and nutrients in the macular
`cells. Conventional treatment modalities have been constrained by limited success. Convincing evidence
`exists that targeting VEGF signaling is a signi(cid:222) cant approach for the therapy of these ocular angiogenesis-
`dependent disorders. We have come a long way since the approval of the (cid:222) rst angiogenesis inhibitors in
`medicine. The clinical use of these drugs has provided enormous tempo to clinical and pharmacological
`research. It has also signi(cid:222) cantly altered patient outcome and expectations. In the following brief, we will
`discuss the development and emergence of these drugs as well as the anticipated future course based on
`evidence.
`
`Key words: Angiogenesis, diabetic retinopathy, vascular endothelial growth factor, wet age-related macular
`degeneration
`
`Indian J Ophthalmol 2007;55:437-9
`
`This PDF is available for free download from
`a site hosted by Medknow Publications
`(www.medknow.com).
`
`Last decade witnessed vast research on angiogenesis, as it
`applies to the physiology and pathology of the human body
`and its relevance to the human eye. This has been a fast-paced,
`critically significant (cid:145)translational research(cid:146)- transforming
`basic science and biotechnology into new dynamic therapeutic
`approaches. Human vascular endothelial growth factor (VEGF)
`is a powerful mediator of vascular permeability as a potent
`endothelial cell mitogen and angiogenic factor. Targeting
`VEGF therefore, allows a double hit strategy: antiangiogenesis
`and antipermeability.1,2 These two pathogenic mechanisms are
`in part responsible for severe vision loss in neovascular age-
`related macular degeneration (AMD) and diabetic macular
`edema (DME), the two leading causes of visual disability in
`the adult population, world-over. Because of the sheer numbers
`involved, anti-VEGF drugs have a potential of enormous socio-
`economic implications. Following is a brief comparative debate
`on the various anti-VGEF drugs commonly in use today, such
`as pegaptanib sodium (Macugen, P(cid:222) zer United States, Eyetech
`Pharmaceuticals Inc.; Pfizer, Inc.), ranibizumab (Lucentis,
`Genentech, Switzerland) and bevacizumab (Avastin, Genentech,
`Switzerland)
`Pegaptanib Sodium3,4
`History: The US Food and Drug Administration (FDA)
`announced the approval of pegaptanib sodium injection in
`December 2004, which at that time was a (cid:147)new therapy to
`slow vision loss in people with the eye disease neovascular
`(wet) AMD(cid:148) It was said that (cid:147)Pegaptanib provides a needed
`addition to the treatment of patients with this disease.(cid:148) It was
`
`Retina Foundation, Ahmedabad, India
`Correspondence to Dr. Manish Nagpal, Retina Foundation, Shahibag,
`Ahmedabad - 4, Gujarat, India. E-mail: drmanishnagpal@yahoo.com
`Manuscript received: 10.02.07; Revision accepted: 15.05.07
`
`the (cid:222) rst approved drug in this category. More than 50,000
`patients with wet AMD were treated with pegaptanib sodium
`in the United States last year. Pegaptanib(cid:146)s approval represented
`a major milestone. It validated VEGF as a major regulator of
`aberrant and excessive blood vessel growth and permeability
`in the eye and is the (cid:222) rst anti-angiogenic therapy indicated for
`the treatment of neovascular AMD. It is the (cid:222) rst aptamer to
`be successfully developed as a therapeutic agent in humans.
`Pegaptanib sodium is an aptamer binding VEGF165, the isoform
`most frequently identi(cid:222) ed with pathological angiogenesis in the
`retina and thus has a selective anti-VEGF action. The strength
`of pegaptanib sodium lies in the following aspects.
`(cid:149)
`Because of the structural speci(cid:222) city (by only targeting the
`165 isoform of VEGF), pegaptanib sodium might help in
`preventing major systemic vascular accidents. Ranibizumab
`and bevacizumab on the other hand target all the isoforms
`of VEGF. The patient population suffering from AMD
`is likely to have co-morbid systemic vascular conditions
`such as ischemic heart and cerebro-vascular disorders,
`hypertension, diabetes and lipid disorders. Although
`systemic absorption of ranibizumab and bevacizumab,
`if given intravitreally appears to be minimal, long-term
`studies are essential to completely shelve this issue.
`Pegaptanib sodium may in future be available through
`other systemic routes of administration, because it spares
`all other VEGF isomers.
`Ranibizumab and Bevacizumab
`History: The US FDA approved of ranibizumab for the
`treatment of macular degeneration on June 30, 2006 aft er a
`priority review (six-month). In the FDA release, it was said
`that (cid:145)Ranibizumab is the (cid:222) rst treatment which, when dosed
`monthly, can maintain the vision of more than 90 percent of
`patients with wet AMD(cid:146).
`
`(cid:149)
`
`Novartis Exhibit 2018.001
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`[Downloaded free from http://www.ijo.in on Thursday, September 17, 2020, IP: 12.130.14.78]
`438
`Indian Journal of Ophthalmology
`
`Vol. 55 No. 6
`
`(cid:149)
`
`This PDF is available for free download from
`a site hosted by Medknow Publications
`(www.medknow.com).
`
`Bevacizumab was approved by the US FDA in 2004 for
`the treatment of colorectal cancer. Limited visual results
`of pegaptanib sodium and unavailability of ranibizumab
`prompted Rosenfeld and coworkers at the Bascom Palmer
`Eye Institute to try systemic and subsequently intravitreal
`bevacizumab as an off-label indication in wet AMD with
`exceptional results.
`Basic science: Ranibizumab is derived from a full-length
`(cid:147)affi nity matured(cid:148) antibody whereas bevacizumab is only
`the Fab (antigen binding domain) of bevacizumab. The
`company claims that the binding constant for ranibizumab
`is (cid:222) ve to 10 times more potent to all VEGF isoforms than
`is bevacizumab.5 Its low molecular weight as compared to
`bevacizumab (approximately one-third) aids penetration of
`the full-thickness retina, which was questioned in an animal
`model for bevacizumab.6 However, in a recent study on albino
`rabbits, it was shown that full-thickness retinal penetration of
`bevacizumab was present at 24h and was essentially absent at
`four weeks based on confocal immunohistochemistry. It was
`nontoxic to the retina based on electrophysiologic studies.7
`Further, bevacizumab has two binding sites per molecule
`and the edematous state of the diseased retina, as in eyes
`with choroidal neovascular membrane (CNVM) might further
`enhance penetration. However, as the retinal edema decreases
`during treatment, perhaps, the penetration advantage of
`ranibizumab may be useful. Given its larger molecular weight,
`bevacizumab likely has a longer half-life in the vitreous and
`therefore may require less frequent re-injections.
`Major clinical results: Ranibizumab has been shown to have
`remarkable results following extensive, stringent clinical trials.
`MARINA8 and ANCHOR9 are both Phase III, multi-center,
`randomized, double-masked trials which showed visual
`improvements in patients with wet AMD. In a significant
`proportion of patients, unlike pegaptanib, not only is there a
`prevention of visual loss but also an improvement in visual
`acuity. The FDA approval imparts huge advantages pertaining
`risk evaluation, safety, insurance coverage and relative immunity
`from patient litigation. All clinical trials10-12 with bevacizumab
`have been uncontrolled and, therefore anecdotal and short-term.
`Initially, bevacizumab was used to treat patients not doing well
`on other therapies such as pegaptanib sodium or photodynamic
`therapy (PDT), visually or on optical coherence tomography
`(OCT) scans, with monthly re-injections. No signi(cid:222) cant ocular
`or systemic side-effects were observed. Bevacizumab has
`potentially bett er visual results than either pegaptanib sodium
`or photodynamic therapy. Very few problems and side-eff ects
`have been found in its anecdotal experience. It is freely available
`and could be used immediately for several indications including
`diabetic retinopathy, CNVM associated with high myopia and
`other causes of macular leakage. The off -label use of bevacizumab
`is responsible for its cost being miniscule compared to those
`developed directly for intraocular use. Single dose of pegaptanib
`sodium costs $1,000 and ranibizumab is priced at $2,000 per
`injection. The cumulative cost of monthly or six-weekly injections
`for several months to years becomes forebiding.
`
`(cid:149)
`
`(cid:149)
`
`(cid:149)
`
`to near stabilization with pegaptanib sodium.
`The popularity of the (cid:145)off -label(cid:146) bevacizumab use has placed
`this genre of treatment in a unique situation. It was neither
`developed and formulated, nor studied and approved
`for intraocular use. Yet, it has been widely adopted.
`Although, off -label use of drugs is not illegal (intravitreal
`triamcinolone, tissue plasminogen activators, intracameral
`vancomycin or lignocaine are off -label treatments), it does
`raise ethical issues and safety concerns.
`The paradox, that the same company (Genentech) developed
`both bevacizumab and ranibizumab might obstruct FDA
`approval for bevacizumab for this use.
`All the published reports of bevacizumab are uncontrolled,
`non-randomized and have short follow-ups. Many studies
`used Snellen charts, which are not as precise or reproducible
`as the ETDRS charts.
`Although it seems unlikely that systemic toxicity, such as
`thromboembolic events and gastrointestinal problems, will
`develop this risk must be studied with both bevacizumab
`and ranibizumab.
`The real issue: Ranibizumab versus bevacizumab:
`In the absence of controlled studies comparing bevacizumab
`to ranibizumab, no de(cid:222) nite assumptions can be made; however,
`the two drugs appear very similar in their visual results pro(cid:222) le.
`When looking at the various studies, stability or improvement of
`visual function has been encountered in about 90 to 95% of eyes
`treated with either drug. Even the percentage of eyes showing
`a particular number of lines of improvement, when treated by
`either of the drugs appears similar. Recently a head to head
`trial has been funded by the NIH (USA) to directly compare
`ranibizumab and bevacizumab, results of which might take us
`closer to resolving the issue.
`Currently, most retinal surgeons are happy injecting
`bevacizumab because of its cost-eff ectiveness, which remains
`a crucial parameter. As far as the approval status is concerned,
`we don(cid:146)t think that patients are too concerned. Having been
`approved, ranibizumab is establishing a role in those for
`whom cost is not a big issue and those under insurance cover.
`Recently, Genentech the founder company for ranibizumab and
`bevacizumab has given a warning about a potential stroke risk
`with 0.5 mg ranibizumab injections in predisposed patients
`- having preexisting history of myocardial infarction or stroke
`and thus pegaptanib sodium is being recommended for this
`category of patients because of its speci(cid:222) city in targeting the
`pathologic VEGF molecule. Complete counseling and discussion
`about bene(cid:222) ts and risks with the patients is mandatory.
`We are in a very interesting era of anti-VEGF therapy and
`whether or not we (cid:222) nd an answer to which one of them is
`the overall best in effi cacy and safety, our patients are (cid:222) nally
`bene(cid:222) ting from a treatment for a condition which previously was
`crippling for them. The future holds even bett er news for them as
`many such molecules will see its way with bett er effi cacy.
`References
`Ferrara N. Vascular endothelial growth factor basic science and
`1.
`clinical progress. Endocr Rev 2004;25:581-611.
`Ferrara N. VEGF and the quest for tumour angiogenesis factors.
`Nat Rev Cancer 2002;2:795-803.
`
`The dilemma
`Pegaptanib sodium is probably out of the main race for
`(cid:149)
`AMD treatment since both bevacizumab and ranibizumab
`have raised the bar of patients(cid:146) expectations by actually
`consistently showing visual improvement, as compared
`
`2.
`
`Novartis Exhibit 2018.002
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`[Downloaded free from http://www.ijo.in on Thursday, September 17, 2020, IP: 12.130.14.78]
`
` Nagpal et al.: Comparative debate on the various anti-VEGF drugs
`November - December 2007
`
`439
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`
`Source of Support: Nil, Confl ict of Interest: None declared.
`
`This PDF is available for free download from
`a site hosted by Medknow Publications
`(www.medknow.com).
`
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