`OF OPHTHALMOLOGY®
`Protecting Sight. EmpoweringLives.
`
`(>
`
`:
`|
`
`“
`|
`
`Bevacizumab
`
`
`
` Enroll in the Residentsand Fellowscontest Enroll in the International Ophthalmologistscontest
`Residents and Fellows contestrules | International Ophthalmologists contest rules
`
`Originalarticle
`contributed by:
`
`All contributors:
`
`Peter A.Karth,MD
`
`Brad H. Feldman, M.D., Vinay A. Shah M.D., Vinay A. Shah M.D., Leo A. Kim, MD, PhD, Koushik Tripathy, MD (AIIMS), FRCS
`(Glasgow),Jennifer | Lim MD, Peter A.Karth, MD
`
`Assigned editor:
`
`LeoA.Kim,MD, PhD
`
`Review:
`
`Assigned status Up to Date
`
`by Leo A. Kim, MD, PhD on November2, 2021.
`
`|
`
`Bevacizumab(Avastin; manufactured in the United States by Genentech/Roche)is arecombinant
`humanized monoclonal IgG11 antibodythat binds to and inhibits vascular endothelial growth factor
`(VEGF), reducing the growth of new blood vessels. VEGF is a biochemicalsignal protein that promotes
`angiogenesis throughoutthe bodyandin the eye.
`Contents
`1 Background
`D000068258(https://me
`MeSH (http://enwiki
`1.1. Mechanism of Action (proposed)
`
`4.2 Indicationsand Uses pedia.org/wiki/Medi=shb.nlm.nih.gov/record/u
`cal_Subject_Heading
`i?ui=D000068258)
`1.2.1 OffLabel Use in Ophthalmology
`s)
`1.2.2 Colorectal Cancer
`1.2.3 Lung Cancer
`1.2.4 Brain Cancer
`
`DiseasesDB (http//e
`nwikipedia.org/wiki/
`Diseases_Database)
`
`32964 (http://wwwdisea
`sesdatabase.com/ddb32
` 964.htm)
`
`1.3 Administration and Dosing
`1.4 Preparation
`1.5 Efficacy in Ophthalmic Pathology
`1.6 Adverse Affects and Safety
`1.6.1 General
`1.6.2 Ophthalmic
`1.6.3 Systemic
`1.7. Considerations and Comparison
`2 Additional Resources
`3 References
`
`Background
`VEGFisa memberoftheplatelet-derived growth factor (PDGF) family. The VEGF genefamilyis constituted of VEGF-A, VEGF-B, VEGF-C, VEGF-D and
`placenta growthfactor (PIGF), located on chromosome 6p12.'") The binding of VEGF withits receptors leads to endothelialcell proliferation and new blood
`vessel growth and thusplays a key role in angiogenesis. Physiology of newvessel growth and developmentare an extremely complex and coordinated process
`that requiresa cascade of receptoractivation. In this process, VEGF represents aninitial and critical rate-limiting step in physiological angiogenesis.!2! [3] 4] The
`critical role of VEGF in angiogenesis has been highlightedbythelossof a single VEGF allele resulting in defective vascularization.)
`
`There are nine VEGF-Aisoforms: VEGF491, VEGF145, VEGF14g, VEGF42, VEGF465, VEGF165», VEGF4g3, VEGFigo and VEGF29¢,!4] The most abundantisoform
`found in the eye is VEGF}¢5.!7! 8] VEGF445 is a secreted heparin-binding homodimeric 45-kDaglycoprotein witha significantfraction bound to the cell
`surface.9] VEGF activates endothelial cells by binding VEGFR-1 (Fit-1) and VEGFR-2 (KDR)endothelial cell receptors, whichin turn activatesintracellular
`signal transduction cascades.!*] VEGFR-2 is thoughtto be principally responsible for VEGFsignaling in angiogenesis.!7)
`
`VEGF-Alevels have been found greatly elevated in the vitreous of patients with choroidal neovascularization (CNV) in age-related macular degeneration
`(AMD), 10 among othereye diseases. Choroidal neovascularization may be instigated by several events, such as accumulation of lipid metabolic byproducts,
`oxidative stress, reductionin choriocapillaris blood flow, andalterations in Bruch’s membrane.!19 [11] [12] Hypoxia has been shown to be a majorinducer of
`VEGFgene transcription. As aresponse to metabolic distress, the retinal pigment epithelium (RPE) and the retina produce various factors, particularly VEGF,
`which induce CNV proliferation. VEGF has been shownto be achemo-attractantfor endothelialcell precursors, causing CNV in mouse models.'14) VEGF also
`prevents endothelialcell apoptosis.!14) Additionally, VEGF promotes metalloproteinases production by endothelialcells, causing tissue degradation that
`facilitates invasion by new vessels.!15] [16] VEGFis a powerful agonist of vascular permeability, which causes vascular leakage and macular edema.!17] VEGFis
`thoughtto cause increased vascular permeability by formation of fenestrations in microvascular endothelium.!18118119) Furthermore, VEGF was shownto up-
`regulate leukocyte adhesion to |CAM-1 in mice, thereby promoting vascular permeability and capillary non-perfusion.!2° Onthisbasis, inhibition ofVEGF
`activity is key to treatment of macular edema and prevention of progressive capillary non-perfusion,especially in diabetic retinopathy and retinal vein
`occlusions.
`
`Mechanism of Action (proposed)
`Bevacizumabbinds to soluble VEGFandinhibits the binding of VEGF molecules to its receptors on the surface of endothelial cells. Bevacizumabis a
`nonspecific VEGFinhibitor with two bindingsites per molecule.{512121) Bevacizumab prevents all VEGF-A isoforms from binding to endothelialcell
`receptors.!5121[22] [23] Reduction in activity of VEGF inhibits angiogenesis and vascular permeability.
`
`TheAcademyusescookiestoanalyzeperformanceand provide relevantpersonalizedcontenttousers ofourwebsite.Learnmore Accept
`1/5
`
`U.S. Pat. 9,254,338, Exhibit 2142
`
`Mylan v. Regeneron, IPR2021-00881
`
`Exhibit 2142
`Page 01 of 05
`
`
`
`Bevacizumabuse in ophthalmology is off-label, meaning it is not FDA approved forocular use. In USA more than 20% of the used drugs are off-label. It is most
`commonly used to treat CNV (in AMDand otherdiseases), diabetic macular edema (DME), and macular edema duetoretinalvein occlusions.Interest in
`bevacizumabforocular use began due to the molecularsimilarity it shares with ranibizumab (Lucentis; Genentech), which is FDA approved for AMD, DME, and
`macular edema dueto retinal vein occlusions. The debate overthe use of bevacizumab versusranibizumab will be discussed in the Considerations section.
`
`Off-label use does carry risk for both the practitioner and the patient. Off-label use mayraise the risk of lawsuit should a patient have a negative outcome from
`its use. From the patient's perspective, there may be a theoreticallack of safety data for off-label use as compared to FDA approved drugs. As part of the FDA
`approval process, sponsors submit detailed information about safety and efficacy as shown in large randomized multi-centerclinical trials done for specific
`indications. The approvalprocess involves the FDA carefully examining extensive databasesofstudies in toxicologic evaluations, animal studiesand clinical
`trials!24 Off-label drugs do not receive this structured rigorousevaluation processonanofficial basis by the FDAin particular disease states.!25)
`
`However,the off-label use of medication is extremely prevalentand is a vital part of prescribing practices across medicine. Many patients benefit when they
`receive medications under circumstances not approved by the FDA. Typically, the makers of generic drugs have little financial incentive to attemptthe costly
`process of FDA approvalfor a new indication, despite wide off-label use. In fact, off-label uses are often the standard of care for some health conditions. In
`manyareas of oncology,pediatrics, geriatrics, and obstetrics, patients could not obtain treatment withoutoff-label prescribing. When medicalandscientific
`evidencevalidate off-label uses (both safety andefficacy) and use is accepted by the medical community, physicians may consideruse of these medications in
`the bestinterest of their patients.'25) Both practitioners and patients should weigh the risks and benefits of using medication in an off-label manner and
`patients should always be informed of their treatment options.!2527] Bevacizumabis one of many such drugs witha longhistory ofsafety and efficacy, albeit
`without FDA approvalfor ocular use. Based on its affordability, the world health organization has put bevacizumab and not ranibizumabin WHO modellist of
`essential drugs. http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf
`
`Colorectal Cancer
`Bevacizumabis FDA approved in metastatic colorectal cancer, with intravenous 5-fluorouracil-based chemotherapyas first- or second-line treatment. It also is
`used with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatmentin patients who have progressed on a
`first-line bevacizumab-containing regimen.
`
`Lung Cancer
`Bevacizumabis FDA approved for use in non-squamous non-smallcell lung cancer, in conjunction with carboplatin and paclitaxelforfirst line treatment of
`unresectable, locally advanced, recurrent or metastatic disease.
`
`Brain Cancer
`Bevacizumabhas a FDAindicationforglioblastoma, as a single agent for adult patients with progressive disease following prior therapy.
`
`However, the indication of metastatic breast carcinomafor intravenous bevacizumab was removed by the FDA asit did not improvethe survival or the quality
`of life when compared to thepossible life-threatening complications if the intravenous drug.
`
`Administration and Dosing
`In ophthalmology, bevacizumabis typically given by transconjunctival intravitreal injections into the posterior segment, althoughit has been used in the form
`of topical drops or sub-conjunctivalinjection. Intravitreal injections for retinal pathologies are typically administered at4-6 week intervals, althoughthis varies
`widely based ondisease and response. The typical dose is 1.25mgin0.05mlin adults,and halfthat dose in babies. While other doses (2.5mg) have been
`evaluated inlargetrials, nosignificantbenefit has been shown overthe 1.25mg standard dose,!28) although some advocate“super-doses” in certain
`situations:
`
`Preparation
`Bevacizumabisa clear to slightly opalescent, colorless to pale brown,sterile solution for intravenous infusion.Its pH is 6.2. It is supplied in 100 mg and 400 mg
`preservative-free, single-use vials with a volumeof 4 mL or 16 mLof bevacizumab (25 mg/mL) !22)
`
`Bevacizumabis only commercially available inthe 4ml and 16mlintravenousformulation.Intravitreal aliquots are typically compounded from these largevials.
`The American Academy of Ophthalmology risk management guidelines recommend preparing individual syringes. Typically compounding pharmacies provide
`this service.
`
`Several studies have shownnobacterial growth and minimal degradation at three monthsof refrigerated bevazicumab compounded into syringes.{0191132)
`Althoughrare, there have been reported casesof bacterial endophthalmitis associated with contaminated batches of compounded bevacizumabandthis
`continues to be an issue of concern.!341 [34][35]
`
`Anotherissueis counterfeit or spurious batches of Avastin which have been notedto cause cluster endopthImitis.
`
`Efficacy in Ophthalmic Pathology
`Bevacizumabis considered efficacious for treatment of CNV and macular edemaby the ophthalmologic community.As this drug has not been FDA approved
`for ophthalmic indications,classic clinical trials do not uniformly exist, however convincing data has been published for the most commonly treated
`pathologies.
`
`Age-related Macular Degeneration (neovascular with CNV) - The shaminjection/untreated arm of the Minimally Classic/Occult Trial of the Anti-VEGF
`Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA)!*4trial showed vision loss of 14.9 letters from baseline
`over 24 months, whichis often quoted as the natural history of neovascular AMD. While the Comparison of Age-related Macular Degeneration Treatments
`Trials (CATT)!97] did not have an untreated arm,it was perhaps the most well-structured clinicaltrial involving bevacizumab and showeda7.8 letter gain from
`baseline with monthly adminisration. The Inhibit VEGF in the Age-Related Choroidal Neovascularizationtrial (IVAN)!°8) echoed this positive result.
`
`Diabetic Macular Edema (DME) - The Pan-AmericanCollaborative Retina Study Group (PACORES)!99)trial compared monthly intravitreal bevacizumab with
`macular focal-grid laser photocoagulation (standard of care at that time) and showed an anverageof 11.86 letters gained with bevacizumaband 3.66letters
`gained with focalgrid laser over 24-months.
`
`Macual Edema due to Retinal Vein Occlusion - The untreated macular edema arm (Group M)of the Central Vein Occlusion Study (CVOS)!“4l trial lost
`approximately 5 letters from baseline. The PACOREStrialfor central vein occlusion,44) which did not have a untreated arm buthadsimilarinclusioncriteria,
`showed 19letters of improvementfrom baseline over 12 months with monntly/as-needed intravitreal bevacizumab.
`
`Various other papers have been published showingtheefficacy of intravitreal bevacizumabin control of myopic CNV, proliferative diseases, and various other
`eye diseases.
`
`Adverse Affects and Safety
`General
`Bevacizumabhas3 black box warnings; gastrointestinal perforation, surgery and wound healing complications, and severe or fatal hemorrhage, hemoptysis,
`gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding. It is unknown whetherintravitreal bevacizumab is associated with the same black box safety
`issues howeverthese types of complications are not included in the known complicationsfollowing intravitreal used of bevacizumab.The risk of these severe
`adverse effects are thought to be very lowastheintravitreal dose is 300-500 times less than the intravenous dose andis administered less frequently.5121)
`However, we do know that systemic/serum levels ofVEGF are reduced withintravitreal administration (IVAN), but the significance ofthis is not yet clear.
`Furthermore, somestudies suggest a fellow eye effect.42)
`
`The Academy uses cookies to analyze performance and provide relevant personalized content tousers of our website.
`
`Accept
`
`2/5
`
`Exhibit 2142
`
`Page 02 of 05
`
`Exhibit 2142
`Page 02 of 05
`
`
`
`Bevacizumabhas been used in the eye withoutsignificantintraoculartoxicity.!49) Transient elevationof intraocular pressure (IOP)after intravitrealinjection is
`commonandtypically normalizes rapidly withoutintervention.!“4)
`However, some believe this may cause long term increases in IOP, leading to glaucoma.!45) It
`is generally thought that these potential manageable complications are outweighedbythe benefit ofthese injections.
`
`Acuteintraocular inflammation(or ‘sterile endophthalmitis’) is a more serious ocular adverse event, but rarely occurs. At 24-months, the CATTtrial reported
`only twocases of ‘pseudo-endophthalmitis; one case in the bevacizumab group and onecase inthe ranibizumab group.
`
`Bacterial endophthalmitis is rare but is the most serious and vision threatening complication of intravitreal bevacizumaband is associated with the procedure
`rather than the medication.44] At 24-months,the CATT trial reported 11 total cases of bacterial endophthalmitis, yielding an infection rate of0.9%, with 7
`cases inthe bevacizumab groupsand 4 cases in the ranibizumab groups (nostatistical difference). However muchlarger retrospective reviews show the rate of
`infection to be between 0.022% and 0.16%.!47] One suchlarge review,looked at over 26,000 injections of both bevacizumabandranibizumab and showed an
`over allinfection rate of 0.02%. Interestingly, both the bevacizumaband ranibizumab groups had 2 cases ofendophthalmitisfor a 0.02% infection rate for each
`group.
`
`Meta-analysis of clinical trials show serious ocular adverse effects to be less than 1.2% for bevacizumab.!48)
`
`Systemic
`The occurrence of serious systemic adverse effects are rare with intravitreal bevacizumab. The exact systemicrisk attributable to intravitreal bevacizumabis
`unknown. Firstly, due to the fact that large scale randomized placebo-controlled studies have not been conducted on this drug,it is not possible to obtain pure
`safety data to answerthis question. Secondly, even the best studies that collected safety data on bevacizumab did so in non-uniform ways and published the
`data in non-comparable generalities and vary widely. For instance, the IVAN trial showed serious adverse effects (SAE) to be 12.5% in the bevacizumab group
`while the CATT trial showed SAE rate of 40%. The Bevacizumabor Laser Therapy (BOLT)!4%)trial, which compared bevacizumabversus macularlaser, showed
`approximately 5% SAEin the bevacizumab group and 10% in thelaser group. Furthermore, in the |VAN study, the data trended toward bevacizumabbeing the
`safer therapy, while the CATT trial trended toward the opposite.
`
`Interestingly in the IVAN study, there wasa clear trend toward fewer systemic SAEs with continuous monthly treatmentversus as-needed treatment, although
`the significance of this is unknown.
`
`Considerations and Comparison
`Thereis a large debate over the use of bevacizumabversusranibizumabfor ocular pathology. Somekey areas of comparisonarelisted here.
`
`Ranibizumabis a Fab of an antibody and is about one-third the size of bevacizumab, whichisa full length antibody (48 vs 149 kilodaltons). Theoretically, a
`smaller molecule size mayallow betterretinal penetration after intravitreal injection. Studies in rabbits and monkeys demonstrated that smaller antibody
`moieties such as Fabs have better tissue penetration thanfull-length antibodies.) However,in the CATT andIVANtrials, no difference in treatmenteffect
`was shown betweenthese two drugs in AMD.Recently, the SCORE2 study showed "nodifference" in the meanvisual acuity between bevacizumab and
`aflibercept (non-inferiority trial at 6 months (primary outcomepoint).
`
`per molecule, while ranibizumab only
`Ranibizumabhasa higher affinity to binding VEGF than does bevacizumab, however bevacizumab has twobinding sites
`has one. It has been shownthatatclinical doses, bevacizumaband ranibizumabare equally potentat binding VEGF,211221123151)[52)
`
`Theincidenceof serious systemic adverse effects are rare with bothintravitreal bevacizumaband ranibizumab.!“4) The large head-to-head clinicaltrials show
`no statistical difference in serious artheriorthrombotic eventsorall-cause-death between bevacizumab and ranibizumab!®II53) [n the 24-month CATT and
`IVANreports, there was a trend toward ranibizumabhaving less systemic adverse effects, althoughnotstatistically significant. However, in 24-month CATT
`trial, the category of “One or moreserious adverse events” showed a statistically significant outcome of ranibizumab having less such events (31.7% versus
`39.9%), representing the only statistically significant difference in safety outcome in these trials. A 'serious systemic event' was defined as death from any
`cause, arteriothrombotic event, nonfatal myocardial infarction, nonfatal stroke, death from vascular causes, venous thrombotic event, transient ischemic
`attack and hypertension.[51154] [55]
`
`Bevacizumabhas a longer systemic half-life than ranibizumab (20hvs. 4h). This means that bevacizumab maypersist longer in the eye than ranibizumab.
`However, the CATT and IVANtrials showed nodifference in treatment effect between these two drugs in AMD. However, dueto the longerhalf-life,
`bevacizumabalso persists longer systemically in the serum,4! [57] which may be an explanation for the increased systemic adverse effects seen inthe CATT
`trial inthe bevacizumab groups,if indeed this wasa realeffect.
`
`An other explanationfor possible differences in systemic adverse effects may be rates of systemic absorption. Animal and humanstudies have shown that
`systemic absorption does occur,56158] The IVANtrial, which examined VEGFlevels in serum showed areduction from 173 to 151 pg/ml(15% reduction) inthe
`ranibizumab group and a reduction from 203 to 83 pg/ml (60% reduction) in the bevacizumabgroup. This might be explained by the longer half-life of
`bevacizumab.
`
`Large well-structured clinicaltrials, such as CATT and IVAN, indicate that both medications are equally effective in the treatment of CNV in AMD.
`Furthermore, both drugs are effective in DME and vein occlusions and both are commonlyusedbyclinicians although head to headtrials have not yet been
`published.Thereis little debate that both drugs are effective within the ophthalmic community. The debatestill remains unsettled as to the true difference in
`systemic adverse effects between the two drugs, with the focus being 1) the addedrisk from the necessity to compound bevacizumaband 2)the inherent
`systemic risk of each compound.
`
`Bevacizumabwasavailable and used intravenously for cancer treatment before the approvalof ranibizumab.Off-label use of the intravenous formulation of
`bevacizumab was compoundedfortheintravitreal route in the treatmentof ocular disorders around mid-2005.'59I [6] Ranibizumabwas not approved until
`June 2006.
`
`Complicating matters in this debateis the fact that ranibizumabis more than 50 times more expensive than bevacizumab.The cost for one dose of intravitreal
`bevacizumabas reimbursed by Medicareis $64.62, while one dose of ranibizumabis reimbursed $1,986.29,(61)
`
`Thecost difference is a potential reason why the manufacturerof both the drugs, Roche are against theintraocular use of the cheaper drug Avastin. The
`financial benefit of the company may have prevented the companyto apply for an FDA approvalfor intraocular use ofAvastin which has been shown to be
`equally effective, safe and affordable than the much costlier alternative Lucentis.
`
`Additionally, thereis a significant net revenuedifferential between the two drugs due to the 6% mark-up allowed for in-office medication administration.
`
`Overall, it is still unclear if either ranibizumab or bevacizumab offers a treatmentor safety advantageto the patient.
`
`Additional Resources
`© Turbert D,Janigian RH. Avastin (https://www.aao.org/eye-health/drugs/avastin-list). American Academy of Ophthalmology. EyeSmart® Eye health.
`https://www.aao.org/eye-health/drugs/avastin-list. Accessed March 07, 2019.
`© Turbert D, Vemulakonda GA. Anti-VEGF Treatments (htt ps://www.aao.org/eye-health/drugs/anti-vegf-treatments-list). American Academy of
`Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/drugs/anti-vegf-treatments-list. Accessed March 07, 2019.
`
`References
`1. Pasqualetti G, Danesi R, Del Tacca M,Bocci G. Vascular endothelial
`
`2. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J.
`
`The Academy uses cookies to analyze performance and provide relevant personalized content tousers of our website.
`
`Accept
`
`3/5
`
`Exhibit 2142
`
`Page 03 of 05
`
`Exhibit 2142
`Page 03 of 05
`
`
`
`28. WuL, Arevalo JF, Maia M, Berrocal MH, SanchezJ, EvansTetal.
`3.Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9(6):653-
`60.
`Comparing outcomes in patients with subfoveal choroidal
`4. Jain RK. Molecular regulation ofvessel maturation. Nat Med.
`neovascularization secondary to age-related macular degeneration
`2003;9(6):685-93.
`treated with twodifferent doses of primary intravitreal bevacizumab:
`5. Ferrara N. Vascular endothelial growthfactor: basic science andclinical
`results of the Pan-American Collaborative Retina Study Group
`(PACORES)at the 12-monthfollow-up. Jpn J Ophthalmol.
`progress. Endocr Rev. 2004;25(4):581-611.
`2009;53(2):125-30.
`6. Bhisitkul RB. Vascular endothelial growth factorbiology:clinical
`implications for ocular treatments. Br J Ophthalmol. 2006;90(12):1542-7.
`29. Wykoff CC, Brown DM, Chen E, Major JC, Croft DE, MarianiA et al. SAVE
`7.SokerS, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1is
`(Super-dose anti-VEGF) trial: 2.0 mg ranibizumabfor recalcitrant
`expressed by endothelial and tumorcells as anisoform-specific receptor
`neovascular age-related macular degeneration: 1-year results.
`for vascular endothelial growth factor. Cell. 1998;92(6):735-45.
`Ophthalmic surgery, lasers & imaging retina. 2013;44(2):121-6.
`30. Chen YH, WuPC,Shiea J, Lo LH, Wu YC, Kuo HK. Evaluationof the
`8. Keyt BA, Berleau LT, Nguyen HV, Chen H, Heinsohn H, VandlenR et al. The
`carboxyl-terminal domain (111-165) of vascular endothelial growth factor
`sterility, stability, and efficacy of bevacizumabstored in multiple-dose
`vials for 6 months. J Ocul Pharmacol Ther. 2009;25(1):65-9.
`is critical for its mitogenic potency. J Biol Chem. 1996;271(13):7788-95.
`9.Ng EWM,Adamis AP.Targeting angiogenesis, the underlying disorderin
`31. Bakri SJ, Snyder MR, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-
`neovascular age-related macular degeneration. Can J Ophthalmol.
`monthstability of bevacizumab(Avastin) binding to vascular endothelial
`2005;40(3):352-68.
`growthfactorafter withdrawalinto a syringe and refrigeration or
`10. Gass JD, Pathogenesis of disciform detachmentof the neuroepithelium.
`freezing. Retina. 2006;26(5):519-22.
`Am J Ophthalmol. 1967;63(3):Suppl:1-139.
`32. Ornek K, KarahanZC,Ergin A, Tekeli A, Tekeli O. Bevacizumabsterility in
`11.Green WR, Enger C. Age-related macular degeneration histopathologic
`multiple doses from a single-use vial. Ann Pharmacother.
`2008;42(10):1425-8.
`studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology.
`1993;100(10):1519-35.
`33. Hoevenaars NED, Gans D, MissottenT, van Rooij J, Lesaffre E, van Meurs
`12.Green WR. Histopathology of age-related macular degeneration. Mol Vis.
`JC. Suspected bacterial endophthalmitis following intravitreal anti-VEGF
`1999;5:27.
`injection: case series andliterature review. Ophthalmologica.
`2012;228(3):143-7.
`13. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, |waguro H et al. VEGF
`contributes to postnatal neovascularization by mobilizing bone marrow-
`34. Goldberg RA, Flynn HW,Isom RF, Miller D, Gonzalez S. An outbreak of
`derived endothelial progenitorcells. EMBO J.1999;18(14):3964-72.
`streptococcus endophthalmitis after intravitreal injection of
`14. Alon T, Hemol,Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial
`bevacizumab. Am J Ophthalmol. 2012;153(2):204-8.e1.
`growthfactoracts asa survival factor for newly formedretinal vessels
`35. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreakof fungal
`and has implications for retinopathy of prematurity. Nat Med.
`endophthalmitis after intravitreal injection of compounded combined
`1995;1(10):1024-8.
`bevacizumabandtriamcinolone. JAMAophthalmology. 2013;131(7):864-
`9.
`15. Lamoreaux WJ,Fitzgerald ME, Reiner A, Hasty KA, Charles ST. Vascular
`endothelial growth factor increases release of gelatinase A and decreases
`36. Rosenfeld PJ, Brown DM, HeierJS, Boyer DS, Kaiser PK, Chung CY et al.
`release of tissue inhibitor of metalloproteinases by microvascular
`Ranibizumabfor neovascular age-related macular degeneration. N EnglJ
`Med. 2006;355(14):1419-31.
`endothelialcells in vitro. Microvasc Res. 1998;55(1):29-42.
`16. Hiratsuka S, Nakamura K, lwai S, Murakami M, Itoh T, Kijima H etal.
`37. Martin D, Maguire M,Fine S, Ying G, Jaffe G, Grunwald J et al. Comparison
`MMP¢9induction byvascular endothelial growth factor receptor-1 is
`of Age-related Macular Degeneration TreatmentsTrials (CATT) Research
`Group, 3rd. Ranibizumab and bevacizumabfor treatment of neovascular
`involved in lung-specific metastasis. Cancer Cell. 2002;2(4):289-300.
`17.Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF.
`age-related macular degeneration: two-year results. Ophthalmology Jul.
`2012;119(7):1388-98.
`Tumorcells secrete a vascular permeability factor that promotes
`accumulationofascites fluid. Science. 198 3;219(4587):983-5.
`38. Chakravarthy U, Harding SP, Rogers CA, Downes SM,Lotery AJ, Culliford
`18. Roberts WG,Palade GE. Increased microvascular permeability and
`LAet al. Alternative treatments to inhibit VEGF in age-related choroidal
`endothelial fenestration induced by vascular endothelial growthfactor.J
`neovascularisation: 2-yearfindings ofthe IVAN randomised controlled
`Cell Sci. 1995;108 ( Pt 6):2369-79.
`trial. Lancet. 2013;382(9900):1258-67.
`19. Roberts WG,Palade GE. Neovasculature induced by vascular endothelial
`39. Arevalo JF, Lasave AF, Wu L, Diaz-Llopis M, Gallego-Pinazo R,
`Alezzandrini AA et al. Intravitreal bevacizumabplusgrid laser
`growthfactoris fenestrated. Cancer Res. 1997;57(4):765-72.
`20. MiyamotoK, KhosrofS, Bursell SE, MoromizatoY, Aiello LP, Ogura Y etal.
`photocoagulation or intravitreal bevacizumabor grid laser
`Vascular endothelial growth factor (VEGF)-induced retinal vascular
`photocoagulation for diffuse diabetic macular edema:results of the Pan-
`permeability is mediated byintercellular adhesion molecule-1 (ICAM-1).
`american Collaborative Retina Study Group at 24 months.Retina.
`Am J Pathol. 2000;156(5):1733-9.
`2013;33(2):403-13.
`21.FerraraN,Hillan KJ, Gerber HP, Novotny W. Discovery and development
`40. Group M, PubMed P. Evaluationofgrid pattern photocoagulation for
`macular edema in central vein occlusion. The Central Vein Occlusion
`of bevacizumab, an anti-VEGFantibody for treating cancer. Nat Rev Drug
`Discov. 2004;3(5):391-400.
`Study report Ophthalmology Oct 9097788. 1995;102(10):1425-33.
`41. Wu L,Arevalo JF, Berrocal MH, Maia M, Roca JA, Morales-Cant6nVet al.
`22. Avastin (bevacizumab)[packageinsert]. San Francisco, CA: Genentech
`Inc.; 2006..
`Comparison of two doses of intravitreal bevacizumabas primary
`treatment for macular edema secondary to centralretinal vein occlusion:
`23.Chen Y, WiesmannC,FuhG,Li B, Christinger HW, McKayPetal. Selection
`and analysis of an optimized anti-VEGFantibody:crystal structure of an
`results ofthe pan American collaborative retina study group at 24
`months. Retina. 2010;30(7):1002-11.
`affinity-matured Fab in complex with antigen. J MolBiol.
`1999;293(4):865-81.
`42. Matsuyama K, Ogata N, Matsuoka M, Wada M,Nishimura T, Takahashi K.
`24. Kesselheim AS, Avorn J. Pharmaceutical promotion to physicians and First
`Effects of intravitreally injected bevacizumab onvascular endothelial
`Amendmentrights. N Engl J Med. 2008;358(16):1727-32.
`growth factorin fellow eyes. J Ocul Pharmacol Ther. 2011;27(4):379-83.
`43. Wu L, Martinez-Castellanos MA, Quiroz-MercadoH, Arevalo JF, Berrocal
`25. Dresser R, FraderJ. Off-label prescribing: a call for heightened
`professional and governmentoversight. J Law Med Ethics.
`MH,Farah ME etal. Twelve-monthsafety of intravitreal injections of
`2009;37(3):476-86, 396.
`bevacizumab(Avastin): results of the Pan-American Collaborative Retina
`26. Jansen RM.Theoff-label use of medication: the latest on the Avastin -
`Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol.
`Lucentis debacle. Med Law. 2013;32(1):65-77.
`2008;246(1):81-7.
`44.Sharei V, Hohn F, Kohler T, Hattenbach LO, Mirshahi A. Course of
`27.ZiemssenF, Grisanti S, Bartz-Schmidt KU,Spitzer MS. Off-label use of
`bevacizumabfor the treatment ofage-related macular degeneration:
`intraocular pressure after intravitreal injection of 0.05 mL ranibizumab
`(Lucentis). Eur J Ophthalmol. 2010;20(1):174-9.
`whatis the evidence? Drugs Aging. 2009;26(4):295-320.
`
`The Academy uses cookies to analyze performance and provide relevant personalized content tousers of our website.
`
`Accept
`
`4/5
`
`Exhibit 2142
`
`Page 04 of 05
`
`Exhibit 2142
`Page 04 of 05
`
`
`
`45. TsengJJ, Vance SK, Della Torre KE, MendoncaLS, Cooney MJ, Klancnik
`JMet al. Sustained increased intraocular pressurerelatedto intravitreal
`antivascular endothelial growth factor therapy for neovascular age-
`related macular degeneration. J Glaucoma. 2012;21(4):241-7.
`46. JohnsonD, Sharma S. Ocular and systemic safety of bevacizumab and
`ranibizumabin patients with neovascular age-related macular
`degeneration. Curr Opin Ophthalmol. 2013;24(3):205-12.
`47.Fintak DR, Shah GK, Blinder KJ, Regillo CD, Pollack J, Heier JS et al.
`Incidence of endophthalmitis related to intravitrealinjection of
`bevacizumaband ranibizumab.Retina. 2008;28(10):1395-9.
`48. SchmuckerC,Ehiken C, Agostini HT, Antes G, Ruecker G, Lelgemann M et
`al. Asafety review and meta-analyses of bevacizumaband ranibizumab:
`off-label versus goldstandard. PloS one. 2012;7(8):e42701.
`49. Michaelides M, Kaines A, Hamilton RD,Fraser-Bell S, Rajendram R, Quhill
`F et al. A prospective randomized trialof intravitreal bevacizumaborlaser
`therapy in the managementof diabetic macular edema (BOLTstudy) 12-
`monthdata: report 2. Ophthalmology. 2010;117(6):1078-86.e2.
`50. FerraraN, DamicoL, Shams N, Lowman H, Kim R. Development of
`ranibizumab, an anti-vascular endothelial growth factor antigen binding
`fragment, as therapy for neovascular age-related macular degeneration.
`Retina. 2006;26(8):859-70.
`51. SharmaS, Johnson D, AbouammohM,HollandsS, Brissette A. Rate of
`serious adverse effects in a series of bevacizumab and ranibizumab
`injections. Can J Ophthalmol. 2012;47(3):275-9.
`52. Lucentis (ranibizumab)[packageinsert]. San Francisco, CA: Genentech
`Inc.; 2006..
`53. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE,
`Fine SLet al. Ranibizumab and bevacizumabfor neovascular age-related
`macular degeneration. N Engl J Med. 2011;364(20):1897-908.
`62. Frank RN. Growthfactors in age-related macular degeneration: pathogenic and therapeutic implications. Ophthalmic Res. 1997;29(5):341-53.
`63. Scott 1U, VanVeldhuisen PC, Ip MSetal. Effect of bevacizumab vs.aflibercept on visual acuity amongpatients with macular edemadueto centralretinal
`vein occlusion.: The SCORE2 randomized clinical trial. JAMA 2017;317(20):2072-2087.
`
`54. Curtis LH, Hammill BG, Schulman KA, C